Brachytherapy with Intratumoral Injections of Radiometal-Labeled Polymers That Thermoresponsively Self-Aggregate in Tumor Tissues.

PubMed

Sano, Kohei; Kanada, Yuko; Kanazaki, Kengo; Ding, Ning; Ono, Masahiro; Saji, Hideo

2017-09-01

Brachytherapy is a type of radiotherapy wherein titanium capsules containing therapeutic radioisotopes are implanted within tumor tissues, enabling high-dose radioirradiation to tumor tissues around the seeds. Although marked therapeutic effects have been demonstrated, brachytherapy needs a complicated implantation technique under general anesthesia and the seeds could migrate to other organs. The aim of this study was to establish a novel brachytherapy using biocompatible, injectable thermoresponsive polymers (polyoxazoline [POZ]) labeled with 90 Y, which can self-aggregate above a specific transition temperature (Tt), resulting in long-term intratumoral retention of radioactivity and therapeutic effect. Therefore, we evaluated the tumor retention of radiolabeled POZ derivatives and their therapeutic effects. Methods: Using oxazoline derivatives with ethyl (Et), isopropyl (Isp), and propyl (Pr) side chains, we synthesized EtPOZ, IspPOZ, Isp-PrPOZ (heteropolymer), and PrPOZ and measured their characteristic Tts. The intratumoral retention of 111 In-labeled POZ was evaluated until 7 d after injection in nude mice bearing PC-3 human prostate cancer. The intratumoral localization of 111 In-labeled POZ derivatives was investigated by an autoradiographic study. Furthermore, a therapeutic study using 90 Y-labeled Isp-PrPOZ was performed, and tumor growth and survival rate were evaluated. Results: The Tts of EtPOZ, IspPOZ, Isp-PrPOZ, and PrPOZ (∼20 kDa) were greater than 70°C, 34°C, 25°C, and 19°C, respectively. In the intratumoral injection study, Isp-PrPOZ and PrPOZ (2,000 μM) with Tts lower than tumor temperature (33.5°C under anesthesia) showed a significantly higher retention of radioactivity at 1 d after injection (73.6% and 73.9%, respectively) than EtPOZ (5.6%) and IspPOZ (15.8%). Even at low injected dose (100 μM), Isp-PrPOZ exhibited high retention (68.3% at 1 d). The high level of radioactivity of Isp-PrPOZ was retained in the tumor 7 d after injection (69.5%). The autoradiographic study demonstrated that the radioactivity of 111 In-labeled Isp-PrPOZ and PrPOZ was localized in a small area. In the therapeutic study using 90 Y-labeled Isp-PrPOZ, significant suppression of tumor growth and prolonged survival rate were achieved in an injection dose-dependent manner compared with that observed for the vehicle-injected group and nonradioactive Isp-PrPOZ-injected group. Conclusion: The injectable 90 Y-labeled Isp-PrPOZ was retained for a prolonged period within tumor tissues via self-aggregation and exhibited marked therapeutic effect, suggesting its usefulness for brachytherapy. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Intratumoral IL-12 and TNF-alpha-loaded microspheres lead to regression of breast cancer and systemic antitumor immunity.

PubMed

Sabel, Michael S; Skitzki, Joseph; Stoolman, Lloyd; Egilmez, Nejat K; Mathiowitz, Edith; Bailey, Nicola; Chang, Wen-Jian; Chang, Alfred E

2004-02-01

Local, sustained delivery of cytokines at a tumor can enhance induction of antitumor immunity and may be a feasible neoadjuvant immunotherapy for breast cancer. We evaluated the ability of intratumoral poly-lactic-acid-encapsulated microspheres (PLAM) containing interleukin 12 (IL-12), tumor necrosis factor alpha (TNF-alpha), and granulocyte-macrophage colony stimulating factor (GM-CSF) in a murine model of breast cancer to generate a specific antitumor response. BALB/c mice with established MT-901 tumors underwent resection or treatment with a single intratumoral injection of PLAM containing IL-12, TNF-alpha, or GM-CSF, alone or in combination. Two weeks later, lymph nodes and spleens were harvested, activated with anti-CD3 monoclonal antibodies (mAb) and rhIL-2, and assessed for antitumor reactivity by an interferon gamma (IFNgamma) release assay. Tumor-infiltrating lymphocyte (TIL) analysis was performed on days 2 and 5 after treatment by mechanically processing the tumors to create a single cell suspension, followed by three-color fluorescence-activated cell sorter (FACS) analysis. Intratumoral injection of cytokine-loaded PLAM significantly suppressed tumor growth, with the combination of IL-12 and TNF-alpha leading to increased infiltration by polymorphonuclear cells and CD8+ T-cells in comparison with controls. The induction of tumor-specific reactive T-cells in the nodes and spleens, as measured by IFN-gamma production, was highest with IL-12 and TNF-alpha. This treatment resulted in resistance to tumor rechallenge. A single intratumoral injection of IL-12 and TNF-alpha-loaded PLAM into a breast tumor leads to infiltration by polymorphonuclear cells and CD8+ T-cells with subsequent tumor regression. In addition, this local therapy induces specific antitumor T-cells in the lymph nodes and spleens, resulting in memory immune response.

Phase I Trial of Intratumoral Administration of NIS-Expressing Strain of Measles Virus in Unresectable or Recurrent Malignant Peripheral Nerve Sheath Tumor

DTIC Science & Technology

2017-10-01

Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Study approved by Mayo IRB on April 18 , 2016, and by USAMRMC/ORP/HRPO on May 6, 2016. All...Sheath Tumor(MPNST), MV-NIS, Oncolytic Virus, Measles Virus 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18 . NUMBER OF PPAGES 19a. NAME...virus incorporation and persistence in MPNST after injection Subtask 2: Assess viremia and viral shedding 1. Received Mayo IRB approval on 04/ 18 /2016

Heterogeneous intratumoral distribution of gadolinium nanoparticles within U87 human glioblastoma xenografts unveiled by micro-PIXE imaging.

PubMed

Carmona, Asuncion; Roudeau, Stéphane; L'Homel, Baptiste; Pouzoulet, Frédéric; Bonnet-Boissinot, Sarah; Prezado, Yolanda; Ortega, Richard

2017-04-15

Metallic nanoparticles have great potential in cancer radiotherapy as theranostic drugs since, they serve simultaneously as contrast agents for medical imaging and as radio-therapy sensitizers. As with other anticancer drugs, intratumoral diffusion is one of the main limiting factors for therapeutic efficiency. To date, a few reports have investigated the intratumoral distribution of metallic nanoparticles. The aim of this study was to determine the quantitative distribution of gadolinium (Gd) nanoparticles after direct intratumoral injection within U87 human glioblastoma tumors grafted in mice, using micro-PIXE (Particle Induced X-ray Emission) imaging. AGuIX (Activation and Guiding of Irradiation by X-ray) 3 nm particles composed of a polysiloxane network surrounded by gadolinium chelates were used. PIXE results indicate that the direct injection of Gd nanoparticles in tumors results in their heterogeneous diffusion, probably related to variations in tumor density. All tumor regions contain Gd, but with markedly different concentrations, with a more than 250-fold difference. Also Gd can diffuse to the healthy adjacent tissue. This study highlights the usefulness of mapping the distribution of metallic nanoparticles at the intratumoral level, and proposes PIXE as an imaging modality to probe the quantitative distribution of metallic nanoparticles in tumors from experimental animal models with micrometer resolution. Copyright © 2017 Elsevier Inc. All rights reserved.

Intratumoral Epidermal Growth Factor Receptor Antisense DNA Therapy in Head and Neck Cancer: First Human Application and Potential Antitumor Mechanisms

PubMed Central

Lai, Stephen Y.; Koppikar, Priya; Thomas, Sufi M.; Childs, Erin E.; Egloff, Ann Marie; Seethala, Raja R.; Branstetter, Barton F.; Gooding, William E.; Muthukrishnan, Ashok; Mountz, James M.; Lui, Vivian W.Y.; Shin, Dong M.; Agarwala, Sanjiv S.; Johnson, Rita; Couture, Larry A.; Myers, Eugene N.; Johnson, Jonas T.; Mills, Gordon; Argiris, Athanassios; Grandis, Jennifer R.

2009-01-01

Purpose Squamous cell carcinoma of the head and neck (SCCHN) is characterized by upregulation of the epidermal growth factor receptor (EGFR). We developed a novel strategy to target EGFR by using a therapeutic gene that consisted of an EGFR antisense (AS) gene sequence under U6 promoter control. A phase I clinical trial was conducted to evaluate the safety and biologic effects of EGFR AS. Patients and Methods Patients with advanced SCCHN who were refractory to standard therapies and who had at least one assessable and accessible lesion were enrolled. The EGFR AS dose was escalated in successive cohorts (six dose levels; 60 to 1,920 μg/injection). Patients received four weekly intratumoral EGFR AS injections. Tumor biopsies were performed before and after completion of therapy. Treatment response was assessed by tumor volume measurements (positron emission tomography/computed tomography), and levels of target proteins were assessed by immunohistochemistry. Results Seventeen assessable patients were treated. No grades 3 to 4 or dose-limiting toxicities were noted, and a maximum-tolerated dose was not reached. Five patients (29%) achieved a clinical response, which included two complete responses (CRs) and three partial responses (PRs); two additional patients had stable disease (SD) as the best response. Patients with disease control (CR + PR + SD) had tumors with higher EGFR and lower STAT3 expression at baseline compared with patients who had progressive disease (P = .0312 and P = .095, respectively). Conclusion Intratumoral EGFR AS was safe and resulted in antitumor activity in patients with advanced SCCHN. Baseline levels of high EGFR and low STAT3 may be associated with antitumor effects. PMID:19204206

Treatment of isolated mediastinal and hilar recurrence of lung cancer with bronchoscopic endobronchial ultrasound guided intratumoral injection of chemotherapy with cisplatin.

PubMed

Mehta, Hiren J; Begnaud, Abbie; Penley, Andrea M; Wynne, John; Malhotra, Paras; Fernandez-Bussy, Sebastian; Cope, Jessica M; Shuster, Jonathan J; Jantz, Michael A

2015-12-01

A common pattern of recurrence in lung cancer after receiving full dose external beam radiation therapy (EBRT) to targeted sites is isolated mediastinal and hilar recurrence (IMHR). Treatment options for these patients are limited to palliative radiation, chemotherapy, and/or best supportive care. We describe our experience with treating IMHR with bronchoscopic endobronchial ultrasound (EBUS) guided intratumoral injection of cisplatin (ITC). Patients treated between Jan 2009-September 2014 with ITC for IMHR were included. Patient demographics, tumor histology, size, concurrent therapy, location, number of sites treated, treatment sessions, and encounters were abstracted. Responses were analyzed on follow-up scans 8-12 weeks after the last treatment session using RECIST 1.1 criteria. Locoregional recurrence, progression-free survival (PFS), and overall survival were measured. 50 sites were treated in 36 patients (19 males, 17 females) with mean age 61.9±8.5 years. Eight sites treated on subsequent encounters were excluded and one patient had an unevaluable response, leaving 35 patients and 41 sites for final analysis. 24/35 (69%) had complete or partial response (responders), whereas 11/35 (31%) had stable or progressive disease (non-responders). There were no significant differences in response based on histology, size, and concurrent therapy. Median survival for the group was 8 months (95% CI of 6-11 mo). Responders had significantly higher survival and PFS than non-responders. Two patients treated with concurrent EBRT, developed broncho-mediastinal fistula. EBUS guided intratumoral cisplatin for IMHR appears to be safe and effective, and may represent a new treatment paradigm for this patient population. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Dependency of the effect of a vascular disrupting agent on sensitivity to tirapazamine and gamma-ray irradiation upon the timing of its administration and tumor size, with reference to the effect on intratumor quiescent cells.

PubMed

Masunaga, Shin-ichiro; Nagasawa, Hideko; Nagata, Kenji; Suzuki, Minoru; Uto, Yoshihiro; Hori, Hitoshi; Kinashi, Yuko; Ono, Koji

2007-01-01

The effect of vascular disrupting agent ZD6126 with time on the sensitivity to the hypoxic cytotoxin tirapazamine (TPZ) and gamma-rays was examined in large and small solid tumors. Mice bearing SCC VII tumors 1 or 1.5 cm in diameter received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all proliferating (P) cells, followed by injection with or without ZD6126. In the absence of ZD6126, or 1 or 24 h following ZD6126 injection, the response to TPZ or gamma-ray irradiation in quiescent (Q) cells was assessed in terms of induced micronucleus (MN) frequency using immunofluorescence staining for BrdU. The MN frequency in the total cell population was determined from the tumors not pretreated with BrdU. Another group of tumor-bearing mice received a series of test doses of gamma-rays while alive or after tumor clamping to obtain hypoxic fractions (HFs) in the tumors. One hour after ZD6126 injection, both small and large tumors showed lower and higher sensitivity, and 24 h after, higher and lower sensitivity, to gamma-rays and TPZ, respectively, than the tumors not treated with ZD6126. Further, they showed larger and smaller HFs 1 and 24 h after ZD6126 injection, respectively. Without ZD6126 and 1 h after injection, small tumors were more sensitive to gamma-rays and less sensitive to TPZ than large tumors, probably due to the smaller HFs than large tumors. In contrast, 24 h after the injection, these differences in sensitivity and the HF between small and large tumors were reversed. The changes in sensitivity and the size of the HF were more marked in the total cell population than in Q cells. Following ZD6126 treatment, in terms of tumor control, especially large tumors and total tumor cell population, administering TPZ 1 h later and gamma-ray irradiation 24 h later were effective. Intratumor physiologic factors such as the size of the HF, depending on the time after ZD6126 injection, have to be taken into account when combining another treatment with ZD6126.

Color Doppler Ultrasound and Gamma Imaging of Intratumorally Injected 500 nm Iron-Silica Nanoshells

PubMed Central

Liberman, Alexander; Wu, Zhe; Barback, Christopher V.; Viveros, Robert; Blair, Sarah L.; Ellies, Lesley G.; Vera, David R.; Mattrey, Robert F.; Kummel, Andrew C.; Trogler, William C.

2013-01-01

Perfluoropentane gas filled iron-silica nanoshells have been developed as stationary ultrasound contrast agents for marking tumors to guide surgical resection. It is critical to establish their long term imaging efficacy, as well as biodistribution. This work shows that 500 nm Fe-SiO2 nanoshells can be imaged by color Doppler ultrasound over the course of 10 days in Py8119 tumor bearing mice. The 500 nm non-biodegradable SiO2 and biodegradable Fe-SiO2 nanoshells were functionalized with diethylenetriamine pentaacetic acid (DTPA) ligand and radiolabeled with 111In3+ for biodistribution studies in nu/nu mice. The majority of radioactivity was detected in the liver and kidneys following intravenous (IV) administration of nanoshells to healthy animals. By contrast, after nanoshells were injected intratumorally, most of the radioactivity remained at the injection site; however, some nanoshells escaped into circulation and were distributed similarly as those given intravenously. For intratumoral delivery of nanoshells and IV delivery to healthy animals, little difference was seen between the biodistribution of SiO2 and biodegradable Fe-SiO2 nanoshells. However, when nanoshells were administered IV to tumor bearing mice, a significant increase was observed in liver accumulation of SiO2 nanoshells relative to biodegradable Fe-SiO2 nanoshells. Both SiO2 and Fe-SiO2 nanoshells accumulate passively in proportion to tumor mass, during intravenous delivery of nanoshells. This is the first report of the biodistribution following intratumoral injection of any biodegradable silica particle, as well as the first report demonstrating the utility of DTPA-111In labeling for studying silica nanoparticle biodistributions. PMID:23802554

The prognostic advantage of preoperative intratumoral injection of OK-432 for gastric cancer patients

PubMed Central

Gochi, A; Orita, K; Fuchimoto, S; Tanaka, N; Ogawa, N

2001-01-01

To investigate, by a multi-institutional randomized trial, the prognostic significance of the augmentation of tumour-infiltrating lymphocytes (TILs) by preoperative intratumoral injection of OK-432 (OK-432 it), a bacterial biological response modifier, in patients with gastric cancer. The 10-year survival and disease-free survival were examined and analysis of the factors showing survival benefit was performed. 370 patients who had undergone curative resection of gastric cancer were enrolled in this study and followed up for 10 years postoperatively. Patients were randomized into either an OK-432 it group or a control group. Ten Klinishe Einheit (KE) of OK-432 was endoscopically injected at 1 to 2 weeks before the operation in the OK-432 it group. Both groups received the same adjuvant chemoimmunotherapy consisting of a bolus injection of mitomycin C (0.4 mg kg−1i.v.) and administration of tegafur and OK-432 from postoperative day 14 up to 1 year later. Tegafur (600 mg day−1) was given orally and OK-432 (5 KE/2 weeks) was injected intradermally for a maintenance therapy. The TILs grades in resected tumour specimens and presence of metastasis and metastatic pattern in dissected lymph nodes were examined. Multivariate analysis was performed to determine the efficacy of OK-432 it on prognostic factors. All patients were followed up for 10 years. The overall 5- and 10-year survival rates and disease-free survival rates of the OK-432 it group were not significantly higher than those of the control group. However, OK-432 it significantly increased the 5- and 10-year survival rates of patients with stage IIIA + IIIB, moderate lymph node metastasis (pN2), and positive TILs. OK-432 it was most effective at prolonging the survival of patients who had both positive TILs and lymph node metastasis. The OK-432 it group with positive TILs showed a significant decrease in metastatic lymph node frequency and in the number of lymph node micro- metastatic foci when compared to the control group. This study showed that only one time preoperative OK-432 it, particularly when it triggers TILs, is effective for reduction of regional lymph node metastasis. OK-432 it probably acts partly by eliminating micro-metastatic foci in lymph nodes. Preoperative intratumoral injection of OK-432 is technically very easy and has no serious adverse effects, so it is a promising form of neoadjuvant immunotherapy for advanced gastric cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11207036

Cycles of Transient High-Dose Cyclophosphamide Administration and Oncolytic Adenovirus Vector Intratumoral Injection for Long Term Tumor Suppression in Syrian Hamsters

PubMed Central

Dhar, Debanjan; Toth, Karoly; Wold, William S.M.

2014-01-01

Immune responses against oncolytic adenovirus (Ad) vectors are thought to limit vector anti-tumor efficacy. In Syrian hamsters, which are immunocompetent and whose tumors and normal tissues are permissive for replication of Ad5-based oncolytic Ad vectors, treating with high-dose cyclophosphamide to suppress the immune system and exert chemotherapeutic effects enhances Ad vector anti-tumor efficacy. However, long term cyclophosphamide treatment and immunosuppression can lead to anemia and vector spread to normal tissues. Here we employed three cycles of transient high-dose cyclophosphamide administration plus intratumoral injection of the oncolytic Ad vector VRX-007 followed by withdrawal from cyclophosphamide. Each cycle lasted 4-6 weeks. This protocol allowed the hamsters to remain healthy so the study could be continued for ~100 days. The tumors were very well suppressed throughout the study. With immunocompetent hamsters, the vector retarded tumor growth initially, but after 3-4 weeks the tumors resumed rapid growth and further injections of vector were ineffective. Preimmunization of the hamsters with Ad5 prevented vector spillover from the tumor to the liver yet still allowed for effective long term anti-tumor efficacy. Our results suggest that a clinical protocol might be developed with cycles of transient chemotherapy plus intratumoral vector injection to achieve significant anti-tumor efficacy while minimizing the side effects of cytostatic treatment. PMID:24722357

Cycles of transient high-dose cyclophosphamide administration and intratumoral oncolytic adenovirus vector injection for long-term tumor suppression in Syrian hamsters.

PubMed

Dhar, D; Toth, K; Wold, W S M

2014-04-01

Immune responses against oncolytic adenovirus (Ad) vectors are thought to limit vector anti-tumor efficacy. With Syrian hamsters, which are immunocompetent and whose tumors and normal tissues are permissive for replication of Ad5-based oncolytic Ad vectors, treating with high-dose cyclophosphamide (CP) to suppress the immune system and exert chemotherapeutic effects enhances Ad vector anti-tumor efficacy. However, long-term CP treatment and immunosuppression can lead to anemia and vector spread to normal tissues. Here, we employed three cycles of transient high-dose CP administration plus intratumoral injection of the oncolytic Ad vector VRX-007 followed by withdrawal of CP. Each cycle lasted 4-6 weeks. This protocol allowed the hamsters to remain healthy so the study could be continued for ~100 days. The tumors were very well suppressed throughout the study. With immunocompetent hamsters, the vector retarded tumor growth initially, but after 3-4 weeks the tumors resumed rapid growth and further injections of vector were ineffective. Preimmunization of the hamsters with Ad5 prevented vector spillover from the tumor to the liver yet still allowed for effective long-term anti-tumor efficacy. Our results suggest that a clinical protocol might be developed with cycles of transient chemotherapy plus intratumoral vector injection to achieve significant anti-tumor efficacy while minimizing the side effects of cytostatic treatment.

Intratumoral Injection of 188Re labeled Cationic Polyethylenimine Conjugates: A Preliminary Report

PubMed Central

Kim, Eun-Mi; Heo, Young-Jun; Moon, Hyung-Bae; Bom, Hee-Seung; Kim, Chang-Guhn

2004-01-01

188Re(Rhenium) is easily obtained from an in-house 188W/188Re generator that is similar to the current 99Mo/99mTc generator, making it very convenient for clinical use. This characteristic makes this radionuclide a promising candidate as a therapeutic agent. Polyethylenimine (PEI) is a cationic polymer and has been used as a gene delivery vector. Positively charged materials interact with cellular blood components, vascular endothelium, and plasma proteins. In this study, the authors investigated whether intratumoral injection of 188Re labeled transferrin (Tf)-PEI conjugates exert the effect of radionuclide therapy against the tumor cells. When the diameters of the Ramos lymphoma (human Burkitt's lymphoma) xenografted tumors reached approximately 1 cm, 3 kinds of 188Re bound compounds (HYNIC-PEI-Tf, HYNIC-PEI, 188Re perrhenate) were injected directly into the tumors. There were increases in the retention of 188Re inside the tumor when PEI was incorporated with 188Re compared to the use of free 188Re. The 188Re HYNIC-Tf-PEI showed the most retention inside the tumor (retention rate=approximately 97%). H&E stain of isolated tumor tissues showed that 188Re labeled HYNIC-PEI-Tf caused extensive tumor necrosis. These results support 188Re HYNIC-PEI-Tf as being a useful radiopharmaceutical agent to treat tumors when delievered by intratumoral injection. PMID:15483337

Stereotactic Injection of DTI-015 into Recurrent Malignant Gliomas: Phase I/II Trial

PubMed Central

Hassenbusch, Samuel J; Nardone, Emilio M; Levin, Victor A; Leeds, Norman; Pietronigro, Dennis

2003-01-01

Abstract DTI-015 (BCNU in 100% ethanol) utilizes solvent facilitated perfusion for the intratumoral treatment of gliomas. The ethanol solvent vehicle facilitates a rapid and thorough saturation of the tumor with the dissolved anticancer agent BCNU. We conducted a phase I/II dose escalation study of DTI-015 in 40 heavily pretreated patients with inoperable recurrent malignant glioma. The study goals were to establish a maximally tolerated dose (MTD) for DTI-015 and assess its safety and activity. Patients received stereotactic intratumoral injection of DTI-015 under magnetic resonance imaging guidance. Dose escalation was performed in two phases. First, DTI-015 volume was escalated at a set BCNU concentration of 12.5 mg/ml; second, BCNU mg dose was escalated by increasing BCNU concentration to 30, 45, 60, and 75 mg/ml. A MTD of 5 ml and 240 mg was established. Twenty-five of 28 DTI-015 treatments (89%) using ≤MTD were administered safely without producing high-grade drug-related adverse events. Median survival for GBM patients administered DTI-015 at ≤MTD was 55 weeks. Magnetic resonance imaging demonstrated stable disease in 72% of evaluable patients with a median of 10.5 weeks. The results suggest that DTI-015 administered at ≤MTD is well tolerated and active in patients with inoperable recurrent GBM. PMID:12659665

Palladium nanoparticle-decorated 2-D graphene oxide for effective photodynamic and photothermal therapy of prostate solid tumors.

PubMed

Thapa, Raj Kumar; Soe, Zar Chi; Ou, Wenquan; Poudel, Kishwor; Jeong, Jee-Heon; Jin, Sung Giu; Ku, Sae Kwang; Choi, Han-Gon; Lee, You Mie; Yong, Chul Soon; Kim, Jong Oh

2018-05-23

Intratumoral injection of nanoparticles is a viable alternative for treating solid tumors. In this study, we used intratumorally-injected palladium nanoparticle (Pd NP)-decorated graphene oxide (GO) (GO-Pd NPs) for the treatment of solid prostate tumors. GO was synthesized using the modified Hummer's method and GO-Pd NPs were prepared using the one pot synthesis method. Studies on physicochemical characterization and in vitro/in vivo anticancer properties were performed using GO-Pd NPs. Successful preparation of GO-Pd NPs was confirmed by transmission electron microscopy, Fourier transform infrared spectroscopy, energy dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy. Compared to GO or Pd NPs alone, GO-Pd NPs showed higher cytotoxic effects in prostate cancer 3 (PC3) cells. Irradiation of treated cells with near infrared (NIR) laser considerably enhanced apoptosis induced by synergistic photothermal effect and reactive oxygen species (ROS) generation. Intratumorally-injected GO-Pd NPs showed promising in vivo localized distribution, photothermal ablation, and anti-tumor effects in the PC3 xenograft mouse model. Furthermore, the minimal organ toxicity of GO-Pd NPs was an added advantage. Hence, GO-Pd NPs could be a potential formulation for localized treatment of prostate solid tumors. Copyright © 2018. Published by Elsevier B.V.

Interstitial laser photochemotherapy with new anthrapyrazole drugs for the treatment of xenograft tumors.

PubMed

Paiva, M B; Saxton, R E; Letts, G A; Chung, P S; Soudant, J; Vanderwerf, Q; Castro, D J

1995-10-01

Photodynamic therapy (PDT) with lasers and new dyes has gained popularity in recent years as a minimally invasive technique with high tumoricidal effects in vitro and in some cancer patients. However, because new laser dyes are not FDA approved at present, the clinical evaluation of PDT may be years away. During the past 6 years we have used laser alone for photothermal ablation in both preclinical studies and in a large number of patients with an observed 60% tumor response rate. The 40% treatment failure led us to explore the possibility of combined therapy with lasers and standard chemotherapeutic drugs. We have recently tested a promising preclinical alternative using implantation of a bare 600-microns KTP 532 laser fiberoptic in multiple tumor sites 30 min after intratumor injection of the anthrapyrazole DUP-941. As a control, this drug was injected in 3 sites of P3 human squamous cell tumor transplants in nude mice, which led to tumor stasis without regression. Similar 400-600 mm3 tumors exposed to laser illumination alone (0.8 W for 5 sec) at multiple sites resulted in tumor regrowth after 10 weeks in 80% of the animals. However, combining interstitial laser illumination with intratumor DUP-941 injections led to complete tumor regression in 85% of the mice. We propose that intratumor drug injection followed by interstitial laser fiberoptic treatment represents a potentially useful new method for tumor ablation in advanced cancer patients.

[Cytosine deaminase and thymidine kinase double suicide gene system driven by carcinoembryonic antigen promoter for the treatment of colorectal carcinoma xenograft in nude mice].

PubMed

Huang, Zheng-jie; Feng, Qing-zhao; You, Jun; Xu, Lin; Luo, Wei-yuan; Yi, Wen-cheng; Zeng, Yue-yue; Luo, Qi

2013-07-23

To explore the therapeutic efficacy of double suicide gene system driven by carcinoembryonic antigen (CEA) promoter (Cp-CDglyTK) on colorectal carcinoma xenograft in nude mice. The plasmid pcDNA3.1(-)Cp-CDglyTK was transfected into the CEA-positive SW480 and CEA-negative HeLa cells respectively. The expression of suicide gene was detected by RT-PCR. And the transfected cells were treated with 5-fluorocytosine (5-FC) and ganciclovir (GCV) at different concentrations and the cell-killing and bystander effects assayed by methyl thiazolyl tetrazolium (MTT). By a transplantation of cultivated cells, SW480 or HeLa cell lines were injected subcutaneously into right axillary of nude mice to establish 96 SW480 and 72 HeLa tumor animal models. Nude mice were completely randomized with statistical software according to tumor volume. For prodrug therapy, 48 SW480-bearing mice were divided equally into 4 groups of I-IV. At the same time, 48 HeLa-bearing mice were divided equally into 4 groups of V-VIII. Groups I & V received an intratumoral injection of PBS, groups II & VIGCV and 5-FC intratumorally, groups III & VII PBS intraperitoneally and groups IV & VIII GCV and 5-FC intraperitoneally. Forty-eight SW480-bearing mice were divided equally into 4 groups of IX∼XII and 24 Hela-bearing ones into groups of & in therapy experiment by suicide gene plus prodrug. Six groups received an intratumoral injection of liposome Lipofectamine and plasmid CP-CDglyTK and then an intraperitoneal injection of drug. The groups of IX and received an injection of PBS, group X GCV, group XI 5-FC and groups XII & GCV and 5-FC. The observation parameters included tumor bulk, tumor weight, survival time and treatment effect in each group. SW480 cells transfected by plasmid pcDNA3.1(-)Cp- CDglyTK expressed CDglyTK gene. The inhibition rates of GCV and 5-FC were significantly higher than those of HeLa cells (59.87% ± 0.21% vs 9.90% ± 0.09%, P < 0.01). And higher inhibition rates and stronger bystander effect existed in double versus single produg (all P < 0.05). Tumor size, final tumor weight and survival time of nude mice in groups ofII, IV, VI & VIII had no significant difference with groups ofI, III, V & VII (all P < 0.05). Final tumor size and weight of group XII was significantly smaller than those of groups of IX, X and XI ((150.0 ± 3.2) vs (522.5 ± 1.9) and (256.8 ± 10.4) and (260.7 ± 2.2) mm(3), (54.1 ± 10.4) vs (682.0 ± 12.0) and (251.8 ± 15.1) and (271.6 ± 17.7) mg, all P < 0.05). Meanwhile, the tumor inhibition rate and survival time of group XII(92.1% and (25.7 ± 0.8)d) were significant higher and longer than group X (63.1% and (21.8 ± 0.5) d) and group XI (60.2% and (18.0 ± 0.9) d) (all P < 0.05). However, no significant difference existed in tumor size, final tumor weight and survival time between groups and (all P > 0.05). The inhibition rate of group was merely 0.9%. CDglyTK double suicide gene system driven by CEA promoter may inhibit CEA positive colorectal cancer xenograft in prodrug-treated nude mice.

Effects of curcumin-loaded PLGA nanoparticles on the RG2 rat glioma model.

PubMed

Orunoğlu, Merdan; Kaffashi, Abbas; Pehlivan, Sibel Bozdağ; Şahin, Selma; Söylemezoğlu, Figen; Oğuz, Kader Karli; Mut, Melike

2017-09-01

Curcumin, the active ingredient of turmeric, has a remarkable antitumor activity against various cancers, including glioblastoma. However, it has poor absorption and low bioavailability; thus, to cross the blood-brain barrier and reach tumor tissue, it needs to be transferred to tumor site by special drug delivery systems, such as nanoparticles. We aimed to evaluate the antitumor activity of curcumin on glioblastoma tissue in the rat glioma-2 (RG2) tumor model when it is loaded on poly(lactic-co-glycolic acid)-1,2-distearoyl-glycerol-3-phospho-ethanolamine-N-[methoxy (polyethylene glycol)-2000] ammonium salt (PLGA-DSPE-PEG) hybrid nanoparticles. Glioblastoma was induced in 42 adult female Wistar rats (250-300g) by RG2 tumor model. The curcumin-loaded nanoparticles were injected by intravenous (n=6) or intratumoral route (n=6). There were five control groups, each containing six rats. First control group was not applied any treatment. The remaining four control groups were given empty nanoparticles or curcumin alone by intravenous or intratumoral route, respectively. The change in tumor volume was assessed by magnetic resonance imaging and histopathology before and 5days after drug injections. Tumor size decreased significantly after 5days of intratumoral injection of curcumin-loaded nanoparticle (from 66.6±44.6 to 34.9±21.7mm 3 , p=0.028), whereas it significantly increased in nontreated control group (from 33.9±21.3 to 123.7±41.1mm 3 , p=0.036) and did not significantly change in other groups (p>0.05 for all). In this in vivo experimental model, intratumoral administration of curcumin-loaded PLGA-DSPE-PEG hybrid nanoparticles was effective against glioblastoma. Curcumine-loaded nanoparticles may have potential application in chemotherapy of glioblastoma. Copyright © 2017 Elsevier B.V. All rights reserved.

Doxorubicin-induced co-assembling nanomedicines with temperature-sensitive acidic polymer and their in-situ-forming hydrogels for intratumoral administration.

PubMed

Wan, Jiangshan; Geng, Shinan; Zhao, Hao; Peng, Xiaole; Zhou, Qing; Li, Han; He, Ming; Zhao, Yanbing; Yang, Xiangliang; Xu, Huibi

2016-08-10

Doxorubicin (DOX)-induced co-assembling nanomedicines (D-PNAx) with temperature-sensitive PNAx triblock polymers have been developed for regional chemotherapy against liver cancer via intratumoral administration in the present work. Owing to the formation of insoluble DOX carboxylate, D-PNAx nanomedicines showed high drug-loading and entrapment efficacy via a simple mixing of doxorubicin hydrochloride and PNAx polymers. The sustained releasing profile of D-PNA100 nanomedicines indicated that only 9.4% of DOX was released within 1day, and 60% was released during 10days. Based on DOX-induced co-assembling behavior and their temperature sensitive in-situ-forming hydrogels, D-PNA100 nanomedicines showed excellent antitumor activity against H22 tumor using intratumoral administration. In contrast to that by free DOX solution (1.13±0.04 times at 9days) and blank PNA100 (2.11±0.34 times), the tumor volume treated by D-PNA100 had been falling to only 0.77±0.13 times of original tumor volume throughout the experimental period. In vivo biodistribution of DOX indicated that D-PNA100 nanomedicines exhibited much stronger DOX retention in tumor tissues than free DOX solution via intratumoral injection. D-PNA100 nanomedicines were hopeful to be developed as new temperature sensitive in-situ-forming hydrogels via i.t. injection for regional chemotherapy. Copyright © 2016. Published by Elsevier B.V.

Pharmacokinetic properties of new antitumor radiopharmaceutical on the basis of diamond nanoporous composites labeled with rhenium-188

NASA Astrophysics Data System (ADS)

Petriev, V. M.; Tishchenko, V. K.; Kuril'chik, A. A.; Skvortsov, V. G.

2017-01-01

Today the development of address therapeutic radionuclide delivery systems directly to tumor tissue is of current interest. It can be achieved by the design of drug containers of specific sizes and shapes from carbon-based composite materials. It will be allowed to enhance the efficacy of anticancer therapy and avoid serious side effects. In this work we studied the pharmacokinetic properties of nanodiamond nanoporous composite labeled with rhenium-188 in rats with hepatocholangioma PC-1 after intratumoral injection. It was established that substantial part of injected radioactivity remained in tumor tissue. Within three hours after 188Re-nanoporous composites injection activity in tumor constituted 79.1-91.3% of injected dose (ID). Then activity level declined to 45.9% ID at 120 hours. No more than 1.34% ID entered the bloodstream. In soft organs and tissues, except thyroid gland, the content of compound didn’t exceed 0.3% ID/g. The highest activity in thyroid gland was 6.95% ID/g. In conclusion, received results suggest 188Re-nanoporous composites can be promising radionuclide delivery systems for cancer treatment.

Synergistic anti-tumor activity through combinational intratumoral injection of an in-situ injectable drug depot.

PubMed

Kim, Da Yeon; Kwon, Doo Yeon; Kwon, Jin Seon; Park, Ji Hoon; Park, Seung Hun; Oh, Hyun Ju; Kim, Jae Ho; Min, Byoung Hyun; Park, Kinam; Kim, Moon Suk

2016-04-01

Here, we describe combinational chemotherapy via intratumoral injection of doxorubicin (Dox) and 5-fluorouracil (Fu) to enhance the efficacy and reduce the toxicity of systemically administered Fu and Dox in cancer patients. As the key concept in this work, mixture formulations of Dox-loaded microcapsules (Dox-M) and Fu-loaded Pluronic(®) hydrogels (Fu-HP) or Fu-loaded diblock copolymer hydrogels (Fu-HC) have been employed as drug depots. The in vitro and in vivo drug depot was designed as a formulation of Dox-M dispersed inside an outer shell of Fu-HP or Fu-HC after injection. The Dox-M/Fu-HP and Dox-M/Fu-HC formulations are free flowing at room temperature, indicating injectability, and formed a structural gelatinous depot in vitro and in vivo at body temperature. The Fu-HP, Fu-HC, Dox-M/Fu-HP, Dox-M/Fu-HC, and Dox-M formulations were easily injected into tumor centers in mice using a needle. Dox-M/Fu-HC produced more significant inhibitory effects against tumor growth than that by Dox-M/Fu-HP, while Fu-HP, Fu-HC and Dox-M had the weakest inhibitory effects of the tested treatments. The in vivo study of Dox and Fu biodistribution showed that high Dox and Fu concentrations were maintained in the target tumor only, while distribution to normal tissues was not observed, indicating that Dox and Fu concentrations below their toxic plasma concentrations should not cause significant systemic toxicity. The Dox-M/Fu-HP and Dox-M/Fu-HC drug depots described in this work showed excellent performance as chemotherapeutic delivery systems. The results reported here indicate that intratumoral injection using combination chemotherapy with Dox-M/Fu-HP or Dox-M/Fu-HC could be of translational research by enhancing the synergistic inhibitory effects of Dox and Fu on tumor growth, while reducing their systemic toxicity in cancer patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Myeloma Xenograft Destruction by a Nonviral Vector Delivering Oncolytic Infectious Nucleic Acid

PubMed Central

Hadac, Elizabeth M; Kelly, Elizabeth J; Russell, Stephen J

2011-01-01

The feasibility of using a nonviral vector formulation to initiate an oncolytic viral infection has not been previously demonstrated. We therefore sought to determine whether infectious nucleic acid (INA) could be used in place of virus particles to initiate an oncolytic picornavirus infection in vivo. Infectious RNA encoding coxsackievirus A21 (CVA21) was transcribed from plasmid DNA using T7 polymerase. Within 48 hours of injecting this RNA into KAS6/1 myeloma xenografts, high titers of infectious CVA21 virions were detected in the bloodstream. Tumors regressed rapidly thereafter and mice developed signs of myositis. At euthanasia, CVA21 was recovered from regressing tumors and from skeletal muscles. Treatment outcomes were comparable following intratumoral injection of naked RNA or fully infectious CVA21 virus. Dose–response studies showed that an effective oncolytic infection could be established by intratumoral injection of 1 µg of infectious RNA. The oncolytic infection could also be initiated by intravenous injection of infectious RNA. Our study demonstrates that INA is a highly promising alternative drug formulation for oncolytic virotherapy. PMID:21505425

The Effect of p53 Status of Tumor Cells on Radiosensitivity of Irradiated Tumors With Carbon-Ion Beams Compared With γ-Rays or Reactor Neutron Beams.

PubMed

Masunaga, Shin-Ichiro; Uzawa, Akiko; Hirayama, Ryoichi; Matsumoto, Yoshitaka; Sakurai, Yoshinori; Tanaka, Hiroki; Tano, Keizo; Sanada, Yu; Suzuki, Minoru; Maruhashi, Akira; Ono, Koji

2015-08-01

The aim of the study was to clarify the effect of p53 status of tumor cells on radiosensitivity of solid tumors following accelerated carbon-ion beam irradiation compared with γ-rays or reactor neutron beams, referring to the response of intratumor quiescent (Q) cells. Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector (SAS/neo) were injected subcutaneously into hind legs of nude mice. Tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells. They received γ-rays or accelerated carbon-ion beams at a high or reduced dose-rate. Other tumor-bearing mice received reactor thermal or epithermal neutrons at a reduced dose-rate. Immediately or 9 hours after the high dose-rate irradiation (HDRI), or immediately after the reduced dose-rate irradiation (RDRI), the tumor cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labeling (Q cells) was determined using immunofluorescence staining for BrdU. The difference in radiosensitivity between the total (P + Q) and Q cells after γ-ray irradiation was markedly reduced with reactor neutron beams or carbon-ion beams, especially with a higher linear energy transfer (LET) value. Following γ-ray irradiation, SAS/neo tumor cells, especially intratumor Q cells, showed a marked reduction in sensitivity due to the recovery from radiation-induced damage, compared with the total or Q cells within SAS/mp53 tumors that showed little repair capacity. In both total and Q cells within both SAS/neo and SAS/mp53 tumors, carbon-ion beam irradiation, especially with a higher LET, showed little recovery capacity through leaving an interval between HDRI and the assay or decreasing the dose-rate. The recovery from radiation-induced damage after γ-ray irradiation was a p53-dependent event, but little recovery was found after carbon-ion beam irradiation. With RDRI, the radiosensitivity to reactor thermal and epithermal neutron beams was slightly higher than that to carbon-ion beams. For tumor control, including intratumor Q-cell control, accelerated carbon-ion beams, especially with a higher LET, and reactor thermal and epithermal neutron beams were very useful for suppressing the recovery from radiation-induced damage irrespective of p53 status of tumor cells.

The Effect of p53 Status of Tumor Cells on Radiosensitivity of Irradiated Tumors With Carbon-Ion Beams Compared With γ-Rays or Reactor Neutron Beams

PubMed Central

Masunaga, Shin-ichiro; Uzawa, Akiko; Hirayama, Ryoichi; Matsumoto, Yoshitaka; Sakurai, Yoshinori; Tanaka, Hiroki; Tano, Keizo; Sanada, Yu; Suzuki, Minoru; Maruhashi, Akira; Ono, Koji

2015-01-01

Background The aim of the study was to clarify the effect of p53 status of tumor cells on radiosensitivity of solid tumors following accelerated carbon-ion beam irradiation compared with γ-rays or reactor neutron beams, referring to the response of intratumor quiescent (Q) cells. Methods Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector (SAS/neo) were injected subcutaneously into hind legs of nude mice. Tumor-bearing mice received 5-bromo-2’-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells. They received γ-rays or accelerated carbon-ion beams at a high or reduced dose-rate. Other tumor-bearing mice received reactor thermal or epithermal neutrons at a reduced dose-rate. Immediately or 9 hours after the high dose-rate irradiation (HDRI), or immediately after the reduced dose-rate irradiation (RDRI), the tumor cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labeling (Q cells) was determined using immunofluorescence staining for BrdU. Results The difference in radiosensitivity between the total (P + Q) and Q cells after γ-ray irradiation was markedly reduced with reactor neutron beams or carbon-ion beams, especially with a higher linear energy transfer (LET) value. Following γ-ray irradiation, SAS/neo tumor cells, especially intratumor Q cells, showed a marked reduction in sensitivity due to the recovery from radiation-induced damage, compared with the total or Q cells within SAS/mp53 tumors that showed little repair capacity. In both total and Q cells within both SAS/neo and SAS/mp53 tumors, carbon-ion beam irradiation, especially with a higher LET, showed little recovery capacity through leaving an interval between HDRI and the assay or decreasing the dose-rate. The recovery from radiation-induced damage after γ-ray irradiation was a p53-dependent event, but little recovery was found after carbon-ion beam irradiation. With RDRI, the radiosensitivity to reactor thermal and epithermal neutron beams was slightly higher than that to carbon-ion beams. Conclusion For tumor control, including intratumor Q-cell control, accelerated carbon-ion beams, especially with a higher LET, and reactor thermal and epithermal neutron beams were very useful for suppressing the recovery from radiation-induced damage irrespective of p53 status of tumor cells. PMID:28983338

Technique, pharmacokinetics, toxicity, and efficacy of intratumoral etanidazole and radiotherapy for treatment of spontaneous feline oral squamous cell carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Evans, S.M.; LaCreta, F.; Helfand, S.

1991-04-01

The histologic appearance, locoregional recurrence, and rate/site of metastases of spontaneous feline oral squamous cell carcinoma are similar to head and neck cancer in humans. A feasibility study of intratumoral Etanidazole, a hypoxic cell sensitizer, and radiation therapy were instituted in this model. Eleven cats with feline squamous cell carcinoma were treated with intratumoral Etanidazole and radiation therapy. Total Etanidazole doses were 1.5-24.0 gms/m2 (0.5-6.9 gms). The tumor partial response rate was 100% (11/11); the median volume regression was 70%. All cats have died as a result of tumor recurrence or tumor-related complications. Median survival was 116 days. Ten catsmore » have been autopsied. Non-necrotic and necrotic tumor cells were identified at the treatment site in all cats. Pharmacokinetic studies were performed in six cats. Following intravenous infusion, the plasma elimination of the Etanidazole was biexponential. The systemic availability following intratumoral administration was 61.2 +/- 21.1%. Peak plasma Etanidazole levels were observed 14 minutes following intratumoral injection, after which elimination was biexponential. Thirty minutes following intratumoral Etanidazole administration, tumor Etanidazole levels were 62.8% of plasma levels. Feline squamous cell carcinoma appears to be a useful model of human head and neck cancer. Cats tolerate substantial doses of intratumoral and intravenous Etanidazole. Etanidazole and radiation therapy cause rapid regression, but not cure, of feline squamous cell carcinoma. There is a similarity between the intravenous kinetics of Etanidazole in humans and cats. Further studies in this model are planned.« less

Near-infrared mediated tumor destruction by photothermal effect of PANI-Np in vivo

NASA Astrophysics Data System (ADS)

Ibarra, L. E.; Yslas, E. I.; Molina, M. A.; Rivarola, C. R.; Romanini, S.; Barbero, C. A.; Rivarola, V. A.; Bertuzzi, M. L.

2013-06-01

Photothermal therapy is a therapy in which photon energy is converted into heat to kill cancer. The purpose of this study is to evaluate the in vivo efficacy of photothermal therapy, toxicity and hepatic and renal function of polyaniline nanoparticles (PANI-Np) in a tumor-bearing mice model. The in vivo efficacy of nanoparticles, following NIR light exposure, was assessed by examining tumor growth over time compared to the untreated control. Signs of drug toxicity and the histopathology and morphology of tumor and tissues, after intratumoral injection treatment, were examined or monitored. Excellent photothermal therapy efficacy is achieved upon intratumoral injection of PANI-Np followed by near-infrared light exposure. These results suggest that PANI-Np could be considered as an effective photothermal agent and pave the way to future cancer therapeutics.

Intra-tumor distribution of PEGylated liposome upon repeated injection: No possession by prior dose.

PubMed

Nakamura, Hiroyuki; Abu Lila, Amr S; Nishio, Miho; Tanaka, Masao; Ando, Hidenori; Kiwada, Hiroshi; Ishida, Tatsuhiro

2015-12-28

Liposomes have proven to be a viable means for the delivery of chemotherapeutic agents to solid tumors. However, significant variability has been detected in their intra-tumor accumulation and distribution, resulting in compromised therapeutic outcomes. We recently examined the intra-tumor accumulation and distribution of weekly sequentially administered oxaliplatin (l-OHP)-containing PEGylated liposomes. In that study, the first and second doses of l-OHP-containing PEGylated liposomes were distributed diversely and broadly within tumor tissues, resulting in a potent anti-tumor efficacy. However, little is known about the mechanism underlying such a diverse and broad liposome distribution. Therefore, in the present study, we investigated the influence of dosage interval on the intra-tumor accumulation and distribution of "empty" PEGylated liposomes. Intra-tumor distribution of sequentially administered "empty" PEGylated liposomes was altered in a dosing interval-dependent manner. In addition, the intra-tumor distribution pattern was closely related to the chronological alteration of tumor blood flow as well as vascular permeability in the growing tumor tissue. These results suggest that the sequential administrations of PEGylated liposomes in well-spaced intervals might allow the distribution to different areas and enhance the total bulk accumulation within tumor tissue, resulting in better therapeutic efficacy of the encapsulated payload. This study may provide useful information for a better design of therapeutic regimens involving multiple administrations of nanocarrier drug delivery systems. Copyright © 2015 Elsevier B.V. All rights reserved.

Direct intratumoral infusion of liposome encapsulated rhenium radionuclides for cancer therapy: Effects of nonuniform intratumoral dose distribution

PubMed Central

Hrycushko, Brian A.; Li, Shihong; Goins, Beth; Otto, Randal A.; Bao, Ande

2011-01-01

Purpose: Focused radiation therapy by direct intratumoral infusion of lipid nanoparticle (liposome)-carried beta-emitting radionuclides has shown promising results in animal model studies; however, little is known about the impact the intratumoral liposomal radionuclide distribution may have on tumor control. The primary objective of this work was to investigate the effects the intratumoral absorbed dose distributions from this cancer therapy modality have on tumor control and treatment planning by combining dosimetric and radiobiological modeling with in vivo imaging data. Methods:99mTc-encapsulated liposomes were intratumorally infused with a single injection location to human head and neck squamous cell carcinoma xenografts in nude rats. High resolution in vivo planar imaging was performed at various time points for quantifying intratumoral retention following infusion. The intratumoral liposomal radioactivity distribution was obtained from 1 mm resolution pinhole collimator SPECT imaging coregistered with CT imaging of excised tumors at 20 h postinfusion. Coregistered images were used for intratumoral dosimetric and radiobiological modeling at a voxel level following extrapolation to the therapeutic analogs, 186Re∕188Re liposomes. Effective uniform dose (EUD) and tumor control probability (TCP) were used to assess therapy effectiveness and possible methods of improving upon tumor control with this radiation therapy modality. Results: Dosimetric analysis showed that average tumor absorbed doses of 8.6 Gy∕MBq (318.2 Gy∕mCi) and 5.7 Gy∕MBq (209.1 Gy∕mCi) could be delivered with this protocol of radiation delivery for 186Re∕188Re liposomes, respectively, and 37–92 MBq (1–2.5 mCi)∕g tumor administered activity; however, large intratumoral absorbed dose heterogeneity, as seen in dose-volume histograms, resulted in insignificant values of EUD and TCP for achieving tumor control. It is indicated that the use of liposomes encapsulating radionuclides with higher energy beta emissions, dose escalation through increased specific activity, and increasing the number of direct tumor infusion sites improve tumor control. For larger tumors, the use of multiple infusion locations was modeled to be much more efficient, in terms of activity usage, at improving EUD and TCP to achieve a tumoricidal effect. Conclusions: Direct intratumoral infusion of beta-emitting radionuclide encapsulated liposomes shows promise for cancer therapy by achieving large focally delivered tumor doses. However, the results of this work also indicate that average tumor dose may underestimate tumoricidal effect due to substantial heterogeneity in intratumoral liposomal radionuclide distributions. The resulting intratumoral distribution of liposomes following infusion should be taken into account in treatment planning and evaluation in a clinical setting for an optimal cancer therapy. PMID:21520844

Direct intratumoral infusion of liposome encapsulated rhenium radionuclides for cancer therapy: Effects of nonuniform intratumoral dose distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hrycushko, Brian A.; Li Shihong; Goins, Beth

2011-03-15

Purpose: Focused radiation therapy by direct intratumoral infusion of lipid nanoparticle (liposome)-carried beta-emitting radionuclides has shown promising results in animal model studies; however, little is known about the impact the intratumoral liposomal radionuclide distribution may have on tumor control. The primary objective of this work was to investigate the effects the intratumoral absorbed dose distributions from this cancer therapy modality have on tumor control and treatment planning by combining dosimetric and radiobiological modeling with in vivo imaging data. Methods: {sup 99m}Tc-encapsulated liposomes were intratumorally infused with a single injection location to human head and neck squamous cell carcinoma xenografts inmore » nude rats. High resolution in vivo planar imaging was performed at various time points for quantifying intratumoral retention following infusion. The intratumoral liposomal radioactivity distribution was obtained from 1 mm resolution pinhole collimator SPECT imaging coregistered with CT imaging of excised tumors at 20 h postinfusion. Coregistered images were used for intratumoral dosimetric and radiobiological modeling at a voxel level following extrapolation to the therapeutic analogs, {sup 186}Re/{sup 188}Re liposomes. Effective uniform dose (EUD) and tumor control probability (TCP) were used to assess therapy effectiveness and possible methods of improving upon tumor control with this radiation therapy modality. Results: Dosimetric analysis showed that average tumor absorbed doses of 8.6 Gy/MBq (318.2 Gy/mCi) and 5.7 Gy/MBq (209.1 Gy/mCi) could be delivered with this protocol of radiation delivery for {sup 186}Re/{sup 188}Re liposomes, respectively, and 37-92 MBq (1-2.5 mCi)/g tumor administered activity; however, large intratumoral absorbed dose heterogeneity, as seen in dose-volume histograms, resulted in insignificant values of EUD and TCP for achieving tumor control. It is indicated that the use of liposomes encapsulating radionuclides with higher energy beta emissions, dose escalation through increased specific activity, and increasing the number of direct tumor infusion sites improve tumor control. For larger tumors, the use of multiple infusion locations was modeled to be much more efficient, in terms of activity usage, at improving EUD and TCP to achieve a tumoricidal effect. Conclusions: Direct intratumoral infusion of beta-emitting radionuclide encapsulated liposomes shows promise for cancer therapy by achieving large focally delivered tumor doses. However, the results of this work also indicate that average tumor dose may underestimate tumoricidal effect due to substantial heterogeneity in intratumoral liposomal radionuclide distributions. The resulting intratumoral distribution of liposomes following infusion should be taken into account in treatment planning and evaluation in a clinical setting for an optimal cancer therapy.« less

Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma

PubMed Central

Doty, Rosalinda A; Liu, Jia; McFadden, Grant; Roy, Edward J; MacNeill, Amy L

2013-01-01

Two recombinant myxoma viruses (MYXV expressing a fluorescent protein [MYXV-Tred] and MYXV-Tred encoding murine interleukin-15 [MYXV-IL15]) were evaluated for therapeutic effects in an aggressive B16F10 melanoma model in immunocompetent mice. It was hypothesized that continuous expression of IL-15 within a tumor would recruit cytotoxic effector cells to induce an antitumor immune response and improve treatment efficacy. Weekly intratumoral injections were given to evaluate the effect of treatment on the median survival time of C57BL/6 mice bearing established B16F10 melanomas. Mice that received MYXV-Tred or MYXV-IL15 lived significantly longer than mice given treatment controls. Unexpectedly, the median survival time of MYXV-IL15-treated mice was similar to that of MYXV-treated mice. At 1, 2, and 4 days postinoculation, viral plaque assays detected replicating MYXV-Tred and MYXV-IL15 within treated tumors. At these time points in MYXV-IL15-treated tumors, IL-15 concentration, lymphocyte grades, and cluster of differentiation-3+ cell counts were significantly increased when compared to other treatment groups. However, viral titers, recombinant protein expression, and lymphocyte numbers within the tumors diminished rapidly at 7 days postinoculation. These data indicate that treatment with recombinant MYXV should be repeated at least every 4 days to maintain recombinant protein expression within a murine tumor. Additionally, neutrophilic inflammation was significantly increased in MYXV-Tred- and MYXV-IL15-treated tumors at early time points. It is speculated that neutrophilic inflammation induced by intratumoral replication of recombinant MXYV contributes to the antitumoral effect of MYXV treatment in this melanoma model. These findings support the inclusion of neutrophil chemotaxins in recombinant poxvirus oncolytic virotherapy. PMID:25866742

Effective Treatment of Transmissible Venereal Tumors in Dogs with Vincristine and IL2.

PubMed

DEN Otter, Willem; Hack, Margot; Jacobs, John J L; Tan, Jurgen F V; Rozendaal, Lawrence; VAN Moorselaar, R Jeroen A

2015-06-01

To improve treatment of inoperable transmissible venereal tumors (TVTs) in dogs. Recently, we showed that TVT is sensitive to intratumoral treatment with interleukin-2 (IL2). In addition it is known that TVT is sensitive to intravenous treatment with vincristine. In the present study we tried to establish the therapeutic effect of intratumoral treatment with vincristine and IL2. We treated 12 dogs with TVT with 1-4 intratumoral treatments with vincristine and IL-2. Per treatment we used vincristine (0.5-0.7 mg/m(2)) and IL2 (2×10(6) units). The injections were given at weekly intervals. Early therapeutic effects were: three complete regressions, four partial regressions, three stable disease, and two progressive disease. Late therapeutic effects were established 45-60 months after the first presentation; there were five complete regressions, no partial regressions, nor stable or progressive diseases. Interestingly, all five dogs with late therapeutic effects were in good health. No tumor recurrence was noted. Intratumoral treatment of TVT with vincristine and IL2 appears to have impressive therapeutic effects. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Antitumor activity of photodynamic therapy performed with nanospheres containing zinc-phthalocyanine

PubMed Central

2013-01-01

Background The increasing incidence of cancer and the search for more effective therapies with minimal collateral effects have prompted studies to find alternative new treatments. Among these, photodynamic therapy (PDT) has been proposed as a very promising new modality in cancer treatment with the lowest rates of side effects, revealing itself to be particularly successful when the photosensitizer is associated with nanoscaled carriers. This study aimed to design and develop a new formulation based on albumin nanospheres containing zinc-phthalocyanine tetrasulfonate (ZnPcS4-AN) for use in the PDT protocol and to investigate its antitumor activity in Swiss albino mice using the Ehrlich solid tumor as an experimental model for breast cancer. Methods Ehrlich tumor’s volume, histopathology and morphometry were used to assess the efficacy of intratumoral injection of ZnPcS4-AN in containing tumor aggressiveness and promoting its regression, while the toxicity of possible treatments was assessed by animal weight, morphological analysis of the liver and kidneys, hemogram, and serum levels of total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase, creatinine and urea. In order to evaluate the efficacy of PDT, groups of animals treated with intratumoral injection of doxorubicin (Dox) were also investigated. Results Intratumoral injection of ZnPcS4-AN was found to be efficient in mediating PDT to refrain tumor aggressiveness and to induce its regression. Although tumor volume reduction was not significant, PDT induced a remarkable increase in the necrosis area seen in the tumor’s central region, as in other experimental groups, including tumor and Dox treated groups, but also in the tumor’s peripheral region. Further, PDT showed minimal adverse effects. Indeed, the use of ZnPcS4-AN in mediating PDT revealed anti-neoplastic activity similar to that obtained while using intratumoral Dox therapy. Conclusions PDT mediated by the new formulation ZnPcS4-AN enhanced the inhibition of tumor growth while producing practically no adverse effects and thus emerges as a very promising nanotechnology-based strategy for solid cancer treatment. PMID:24341795

Intratumoral CpG-B promotes anti-tumoral neutrophil, cDC, and T cell cooperation without reprograming tolerogenic pDC.

PubMed

Humbert, Marion; Guery, Leslie; Brighouse, Dale; Lemeille, Sylvain; Hugues, Stephanie

2018-03-27

Cancer immunotherapies utilize distinct mechanisms to harness the power of the immune system to eradicate cancer cells. Therapeutic vaccines, aimed at inducing active immune responses against an existing cancer, are highly dependent on the immunological microenvironment, where many immune cell types display high levels of plasticity and, depending on the context, promote very different immunological outcomes. Among them, plasmacytoid dendritic cells (pDC), known to be highly immunogenic upon inflammation, are maintained in a tolerogenic state by the tumor microenvironment. Here we report that intratumoral (i.t.) injection of established solid tumors with CpG oligonucleotides-B (CpG-B) inhibits tumor growth. Interestingly, control of tumor growth was independent of tumor-associated (TA) pDC, which remained refractory to CpG-B stimulation and whose depletion did not alter the efficacy of the treatment. Instead, tumor growth inhibition subsequent to i.t. CpG-B injection depended on the recruitment of neutrophils into the milieu, resulting in the activation of conventional dendritic cells (cDC), subsequent increased anti-tumor T cell priming in draining lymph nodes, and enhanced effector T cell infiltration in the tumor microenvironment. These results reinforce the concept that intratumoral delivery of TLR9 agonists alters the tumor microenvironment by improving the anti-tumor activity of both innate and adaptive immune cells. Copyright ©2018, American Association for Cancer Research.

A Phase I/II Study of Intratumoral Injection of SD-101

ClinicalTrials.gov

2017-09-04

Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma

Devascularization of Head and Neck Paragangliomas by Direct Percutaneous Embolization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ozyer, Umut, E-mail: umut_ozyer@yahoo.com; Harman, Ali; Yildirim, Erkan

2010-10-15

Preoperative transarterial embolization of head and neck paragangliomas using particulate agents has proven beneficial for decreasing intraoperative blood loss. However, the procedure is often incomplete owing to extensive vascular structure and arteriovenous shunts. We report our experience with embolization of these lesions by means of direct puncture and intratumoral injection of n-butyl cyanoacrylate (NBCA) or Onyx. Ten patients aged 32-82 years who were referred for preoperative embolization of seven carotid body tumors and three jugular paragangliomas were retrospectively analyzed. Intratumoral injections were primarily performed in four cases with multiple small-caliber arterial feeders and adjunctive to transarterial embolization in six casesmore » with incomplete devascularization. Punctures were performed under ultrasound and injections were performed under roadmap fluoroscopic guidance. Detailed angiographies were performed before and after embolization procedures. Control angiograms showed complete or near-complete devascularization in all tumors. Three tumors with multiple small-caliber arterial feeders were treated with primary NBCA injections. One tumor necessitated transarterial embolization after primary injection of Onyx. Six tumors showed regional vascularization from the vasa vasorum or small-caliber branches of the external carotid artery following the transarterial approach. These regions were embolized with NBCA injections. No technical or clinical complications related to embolization procedures occurred. All except one of the tumors were surgically removed following embolization. In conclusion, preoperative devascularization with percutaneous direct injection of NBCA or Onyx is feasible, safe, and effective in head and neck paragangliomas with multiple small-caliber arterial feeders and in cases of incomplete devascularization following transarterial embolization.« less

Tumor regression induced by intratumor therapy with a disabled infectious single cycle (DISC) herpes simplex virus (HSV) vector, DISC/HSV/murine granulocyte-macrophage colony-stimulating factor, correlates with antigen-specific adaptive immunity.

PubMed

Ali, Selman A; Lynam, June; McLean, Cornelia S; Entwisle, Claire; Loudon, Peter; Rojas, José M; McArdle, Stephanie E B; Li, Geng; Mian, Shahid; Rees, Robert C

2002-04-01

Direct intratumor injection of a disabled infectious single cycle HSV-2 virus encoding the murine GM-CSF gene (DISC/mGM-CSF) into established murine colon carcinoma CT26 tumors induced a significant delay in tumor growth and complete tumor regression in up to 70% of animals. Pre-existing immunity to HSV did not reduce the therapeutic efficacy of DISC/mGM-CSF, and, when administered in combination with syngeneic dendritic cells, further decreased tumor growth and increased the incidence of complete tumor regression. Direct intratumor injection of DISC/mGM-CSF also inhibited the growth of CT26 tumor cells implanted on the contralateral flank or seeded into the lungs following i.v. injection of tumor cells (experimental lung metastasis). Proliferation of splenocytes in response to Con A was impaired in progressor and tumor-bearer, but not regressor, mice. A potent tumor-specific CTL response was generated from splenocytes of all mice with regressing, but not progressing tumors following in vitro peptide stimulation; this response was specific for the gp70 AH-1 peptide SPSYVYHQF and correlated with IFN-gamma, but not IL-4 cytokine production. Depletion of CD8(+) T cells from regressor splenocytes before in vitro stimulation with the relevant peptide abolished their cytolytic activity, while depletion of CD4(+) T cells only partially inhibited CTL generation. Tumor regression induced by DISC/mGM-CSF virus immunotherapy provides a unique model for evaluating the immune mechanism(s) involved in tumor rejection, upon which tumor immunotherapy regimes may be based.

The biodistribution and pharmacokinetic evaluation of choline-bound gold nanoparticles in a human prostate tumor xenograft model.

PubMed

Razzak, Rene; Zhou, Joe; Yang, XiaoHong; Pervez, Nadim; Bédard, Eric Lr; Moore, Ronald B; Shaw, Andrew; Amanie, John; Roa, Wilson H

2013-06-01

Gold nanoparticles (GNPs) have attracted significant attention in the treatment of cancer due to their potential as novel radiation enhancers, particularly when functionalized with various targeting ligands. The aim of this study was to assess the biodistribution and pharmacokinetic characteristics of a novel choline-bound GNP (choline-GNP) stabilized with polyethelenimine (PEI). Choline bound to 27 nm diameter GNPs was characterized using transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). Toxicity of choline-GNPs was examined on DU-145 prostate cancer cells using an MTT assay. Using balb/c mice bearing flank DU-145 prostate tumors, choline-GNPs bio-distribution was measured using inductively coupled mass spectroscopy (ICP-MS). Blood, heart, lung, liver, spleen, brain, kidney and tumor gold content were examined at multiple time points over a 24-hour period after tail vein injection. An MTT assay using DU-145 prostate cancer cells yielded a 95% cell viability 72 hours after choline-GNP administration. The tumor GNP area under the concentration-time curve during the first 4 hours (AUC0-4) was 2.2 µg/ml h, representing 13% of the circulating blood GNP concentration over the same time period. The maximum intra-tumor GNP concentration observed was 1.4% of the injected dose per gram of tumor tissue (%ID/g) one hour post injection. GNPs functionalized with choline demonstrates a viable future nanoparticle platform with increased intra-tumor uptake as compared to unconjugated GNPs. Decreased intra-hepatic accumulation appears to be the reason for the improved systemic bioavailability. The next logical translational investigation will incorporate external beam radiation with the observed maximum intra-tumor uptake.

A Phase I trial using local regional treatment, nonlethal irradiation, intratumoral and systemic polyinosinic-polycytidylic acid polylysine carboxymethylcellulose to treat liver cancer: in search of the abscopal effect

PubMed Central

de la Torre, Andrew N; Contractor, Sohail; Castaneda, Ismael; Cathcart, Charles S; Razdan, Dolly; Klyde, David; Kisza, Piotr; Gonzales, Sharon F; Salazar, Andres M

2017-01-01

Purpose To determine the safety of an approach to immunologically enhance local treatment of hepatocellular cancer (HCC) by combining nonlethal radiation, local regional therapy with intratumoral injection, and systemic administration of a potent Toll-like receptor (TLR) immune adjuvant. Methods Patients with HCC not eligible for liver transplant or surgery were subject to: 1) 3 fractions of 2-Gy focal nonlethal radiation to increase tumor antigen expression, 2) intra-/peri-tumoral (IT) injection of the TLR3 agonist, polyinosinic-polycytidylic acid polylysine carboxymethylcellulose (poly-ICLC), to induce an immunologic “danger” response in the tumor microenvironment with local regional therapy, and 3) systemic boosting of immunity with intramuscular poly-ICLC. Primary end points were safety and tolerability; secondary end points were progression-free survival (PFS) and overall survival (OS) at 6 months, 1 year, and 2 years. Results Eighteen patients with HCC not eligible for surgery or liver transplant were treated. Aside from 1 embolization-related severe adverse event, all events were ≤grade II. PFS was 66% at 6 months, 39% at 12 months, and 28% at 24 months. Overall 1-year survival was 69%, and 2-year survival 38%. In patients <60 years old, 2-year survival was 62.5% vs. 11.1% in patients aged >60 years (P<0.05). Several patients had prolonged PFS and OS. Conclusion Intra-tumoral injection of the TLR3 agonist poly-ICLC in patients with HCC is safe and tolerable when combined with local nonlethal radiation and local regional treatment. Further work is in progress to evaluate if this approach improves survival compared to local regional treatment alone and characterize changes in anticancer immunity. PMID:28848723

Restoration of Patency to Central Airways Occluded by Malignant Endobronchial Tumors Using Intratumoral Injection of Cisplatin.

PubMed

Mehta, Hiren J; Begnaud, Abbie; Penley, Andrea M; Wynne, John; Malhotra, Paras; Fernandez-Bussy, Sebastian; Cope, Jessica; Shuster, Jonathan J; Jantz, Michael A

2015-09-01

Malignant airway obstruction is commonly found in patients with lung cancer and is associated with significant morbidity and mortality. Relieving malignant obstruction may improve symptoms, quality of life, and life expectancy. The objective of this study was to analyze our experience with bronchoscopic endobronchial intratumoral injection of cisplatin for malignant airway obstruction. We conducted a retrospective analysis of patients with malignant airway obstruction treated with bronchoscopic intratumoral injection of cisplatin. Patient characteristics, histology, degree of airway obstruction, procedural methods, treatment cycles, performance status, and therapeutic outcomes were evaluated. Tumor response was analyzed based on bronchoscopic measurements performed on completion the of final treatment session. Adverse events and overall survival were abstracted. Between January 2009 and September 2014, 22 patients (10 men, 12 women; mean age ± SD, 64.4 ± 9.5 yr) were treated with one to four injections of 40 mg of cisplatin mixed in 40 ml of 0.9% NaCl. Treatments were completed 1 week apart. The primary etiologies of airway obstruction included squamous cell carcinoma (n = 11), adenocarcinoma (n = 6), small cell carcinoma (n = 2), large cell undifferentiated carcinoma (n = 1), and metastatic endobronchial cancer (n = 2). Twenty-one of 22 patients were evaluable for response. The majority of patients (15/21, 71.4%) responded to therapy, defined as greater than 50% relative reduction in obstruction from baseline. Treatment response was obtained regardless of tumor histology, concurrent systemic therapy, number of treatment cycles administered, performance status, or use of additional ablative interventions. Responders had significantly improved overall survival as compared with nonresponders, although the difference was small. Severe treatment-related side effects or complications were not observed. Subject to the limitations of a single-center retrospective study and a subjective primary outcome measure, we have demonstrated the feasibility of improving the patency of central airways that are largely or completely occluded by endobronchial malignant tumor using intraluminal injection of cisplatin. Additional longer-term, larger-scale safety and comparative effectiveness studies of this palliative treatment modality are warranted.

Cryo-Assisted Resection En Bloc, and Cryoablation In Situ, of Primary Breast Cancer Coupled With Intraoperative Ultrasound-Guided Tracer Injection: A Preliminary Clinical Study.

PubMed

Korpan, Nikolai N; Xu, Kecheng; Schwarzinger, Philipp; Watanabe, Masashi; Breitenecker, Gerhard; Patrick, Le Pivert

2018-01-01

The aim of the study was to perform cryosurgery on a primary breast tumor, coupled with simultaneous peritumoral and intratumoral tracer injection of a blue dye, to evaluate lymphatic mapping. We explored the ability of our strategy to prevent tumor cells, but not that of injected tracers, to migrate to the lymphovascular drainage during conventional resection of frozen breast malignancies. Seventeen patients aged 51 (14) years (mean [standard deviation]), presenting primary breast cancer with stage I to IV, were randomly selected and treated in The Rudolfinerhaus Private Clinic in Vienna, Austria, and included in this preliminary clinical study. Under intraoperative ultrasound, 14 patients underwent curative cryo-assisted tumor resection en bloc, coupled with peritumoral tracer injection, which consisted of complete tumor freezing and concomitant peritumor injection with a blue dye, before resection and sentinel lymph node dissection (group A). Group B consists of 3 patients previously refused any standard therapy and had palliative tumor cryoablation in situ combined with intratumoral tracer injection. The intraoperative ultrasound facilitated needle positioning and dye injection timing. In group A, the frozen site extruded the dye that was distributed through the unfrozen tumor, the breast tissue, and the resection cavity for 12 patients. One to 4 lymph nodes were stained for 10 of 14 patients. The resection margin was evaluable. Our intraoperative ultrasound-guided performance revealed the injection and migration of a blue dye during the frozen resection en bloc and cryoablation in situ of primary breast tumors. Sentinel lymph node mapping, pathological determination of the tumor, and resection margins were achievable. The study paves the way for intraoperative cryo-assisted therapeutic strategies for breast cancer.

Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer.

PubMed

Lindström, Linda S; Yau, Christina; Czene, Kamila; Thompson, Carlie K; Hoadley, Katherine A; Van't Veer, Laura J; Balassanian, Ron; Bishop, John W; Carpenter, Philip M; Chen, Yunn-Yi; Datnow, Brian; Hasteh, Farnaz; Krings, Gregor; Lin, Fritz; Zhang, Yanhong; Nordenskjöld, Bo; Stål, Olle; Benz, Christopher C; Fornander, Tommy; Borowsky, Alexander D; Esserman, Laura J

2018-01-19

Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99). Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors. © The Author(s) 2018. Published by Oxford University Press.

Lymphoscintigraphy and SPECT/CT in multicentric and multifocal breast cancer: does each tumour have a separate drainage pattern? Results of a Dutch multicentre study (MULTISENT).

PubMed

Brouwer, O R; Vermeeren, L; van der Ploeg, I M C; Valdés Olmos, R A; Loo, C E; Pereira-Bouda, L M; Smit, F; Neijenhuis, P; Vrouenraets, B C; Sivro-Prndelj, F; Jap-a-Joe, S M; Borgstein, P J; Rutgers, E J Th; Oldenburg, H S A

2012-07-01

To investigate whether lymphoscintigraphy and SPECT/CT after intralesional injection of radiopharmaceutical into each tumour separately in patients with multiple malignancies in one breast yields additional sentinel nodes compared to intralesional injection of the largest tumour only. Patients were included prospectively at four centres in The Netherlands. Lymphatic flow was studied using planar lymphoscintigraphy and SPECT/CT until 4 h after administration of (99m)Tc-nanocolloid in the largest tumour. Subsequently, the smaller tumour(s) was injected intratumorally followed by the same imaging sequence. Sentinel nodes were intraoperatively localized using a gamma ray detection probe and vital blue dye. Included in the study were 50 patients. Additional lymphatic drainage was depicted after the second and/or third injection in 32 patients (64%). Comparison of planar images and SPECT/CT images after consecutive injections enabled visualization of the number and location of additional sentinel nodes (32 axillary, 11 internal mammary chain, 2 intramammary, and 1 interpectoral. A sentinel node contained metastases in 17 patients (34%). In five patients with a tumour-positive node in the axilla that was visualized after the first injection, an additional involved axillary node was found after the second injection. In two patients, isolated tumour cells were found in sentinel nodes that were only visualized after the second injection, whilst the sentinel nodes identified after the first injection were tumour-negative. Lymphoscintigraphy and SPECT/CT after consecutive intratumoral injections of tracer enable lymphatic mapping of each tumour separately in patients with multiple malignancies within one breast. The high incidence of additional sentinel nodes draining from tumours other than the largest one suggests that separate tumour-related tracer injections may be a more accurate approach to mapping and sampling of sentinel nodes in patients with multicentric or multifocal breast cancer.

The inflammation markers in serum of tumor-bearing rats after plasmonic photothermal therapy

NASA Astrophysics Data System (ADS)

Bucharskaya, Alla B.; Maslyakova, Galina N.; Terentyuk, Georgy S.; Afanasyeva, Galina A.; Navolokin, Nikita A.; Zakharova, Natalia B.; Khlebtsov, Boris N.; Khlebtsov, Nikolai G.; Bashkatov, Alexey N.; Genina, Elina A.; Tuchin, Valery V.

2018-02-01

We report on plasmonic photothermal therapy of rats with inoculated cholangiocarcinoma through the intratumoral injection of PEG-coated gold nanorods followed by CW laser light irradiation. The length and diameter of gold nanorods were 41+/-8 nm and 10+/-2 nm, respectively; the particle mass-volume concentration was 400 μg/mL, which corresponds to the optical density of 20 at the wavelength 808 nm. The tumor-bearing rats were randomly divided into three groups: (1) without any treatment (control); (2) with only laser irradiation of tumor; (3) with intratumoral administration of gold nanorods and laser irradiation of tumors. An hour before laser irradiation, the animals were injected intratumorally with gold nanorod solutions in the amount of 30% of the tumor volume. The infrared 808-nm laser with power density of 2.3 W/cm2 was used for plasmonic photothermal therapy (PTT). The withdraw of animals from the experiment was performed 24 h after laser exposure. The content of lipid peroxidation products and molecular markers of inflammation (TNF-α, IGF-1, VEGF-C) was determined by ELISA test in serum of rats. The standard histological techniques with hematoxylin and eosin staining were used for morphological examination of tumor tissues. It was revealed that the significant necrotic changes were noted in tumor tissue after plasmonic photothermal therapy, which were accompanied by formation of inflammatory reaction with release of proinflammatory cytokines and lipid peroxidation products into the bloodstream

Theranostic nanoparticles carrying doxorubicin attenuate targeting ligand specific antibody responses following systemic delivery.

PubMed

Yang, Emmy; Qian, Weiping; Cao, Zehong; Wang, Liya; Bozeman, Erica N; Ward, Christina; Yang, Bin; Selvaraj, Periasamy; Lipowska, Malgorzata; Wang, Y Andrew; Mao, Hui; Yang, Lily

2015-01-01

Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles. In this study, we found that repeated administrations of magnetic iron oxide nanoparticles (IONPs) conjugated with mouse or human derived targeting ligands induced high levels of ligand specific antibody responses in normal and tumor bearing mice while injections of unconjugated mouse ligands were weakly immunogenic and induced a very low level of antibody response in mice. Mice that received intravenous injections of targeted and polyethylene glycol (PEG)-coated IONPs further increased the ligand specific antibody production due to differential uptake of PEG-coated nanoparticles by macrophages and dendritic cells. However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin. Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles. Results of this study support the potential of further development of targeted theranostic nanoparticles for the treatment of human cancers.

Tumor relapse prevented by combining adoptive T cell therapy with Salmonella typhimurium

PubMed Central

Binder, David C.; Arina, Ainhoa; Wen, Frank; Tu, Tony; Zhao, Ming; Hoffman, Robert M.; Wainwright, Derek A.; Schreiber, Hans

2016-01-01

ABSTRACT We recently reported that therapeutic vaccination with live tumor antigen-producing Salmonella typhimurium rescues dysfunctional endogenous T cell responses and eradicates long-established tumors refractory to αCTLA-4 and αPD-L1 checkpoint inhibitor blockade. Here, we show that live intravenously injected or heat-killed (HK) intratumorally injected Salmonella typhimurium, even when not producing tumor antigen, synergize with adoptive T cell therapy to eradicate tumors. These data demonstrate that the combination of adoptive T cell transfer with the injection of live or dead Salmonella typhimurium is a promising approach for cancer treatment. PMID:27471609

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cao Wei, E-mail: cawe-001@163.com; Li Jing, E-mail: lijing02@fmmu.edu.cn; Wu Zhiqun, E-mail: zhiqunwu@fmmu.edu.cn

Purpose. This study evaluates the influence of transcatheter arterial infusion with heated saline on hepatic arterial and portal venous blood flows to tumor and normal hepatic tissues in a rabbit VX2 tumor model. Methods. All animal experiments were approved by the institutional animal care and use committee. Twenty rabbits with VX2 liver tumors were divided into the following two groups: (a) the treated group (n = 10), which received a 60 mL transarterial injection of 60 Degree-Sign C saline via the hepatic artery; (b) the control group (n = 10), which received a 60 mL injection of 37 Degree-Sign Cmore » saline via the hepatic artery. Using ultrasonography, the blood flows in both the portal vein and hepatic artery were measured, and the changes in the hemodynamic indices were recorded before and immediately after the injection. The changes in the tumor and normal liver tissues of the two groups were histopathologically examined by hematoxylin and eosin staining after the injection. Results. After the transcatheter arterial heated infusion, there was a decrease in the hepatic arterial blood flow to the tumor tissue, a significant decrease in the hepatic artery mean velocity (P < 0.05), and a significant increase in the resistance index (P < 0.05). On hematoxylin and eosin staining, there were no obvious signs of tissue destruction in the normal liver tissue or the tumor tissue after heated perfusion, and coagulated blood plasma was observed in the cavities of intratumoral blood vessels in the treated group. Conclusions. The changes in tumor blood flow in the rabbit VX2 tumor model were presumably caused by microthrombi in the tumor vessels, and the portal vein likely mediated the heat loss in normal liver tissue during the transarterial heated infusion.« less

Direct Endoscopic Intratumoral Injection of Onyx for the Preoperative Embolization of a Recurrent Juvenile Nasal Angiofibroma

PubMed Central

Hira, A.; Chao, K.

2011-01-01

Summary Percutaneous injection of embolization material within head and neck tumors is being described as an alternative or adjunct to transarterial embolization. Access in these reports is by computed tomography (CT) guidance, which is cumbersome given the need to transport the patient from the CT scanner to angiography suite. We describe a case of direct percutaneous onyx embolization of juvenile nasal angiofibroma following endoscopic access in the angiography suite including self-sustained onyx combustion during surgical electrocautery. PMID:22192553

Radiation Dosimetry of Intratumoral Injection of Radionuclides into Human Breast Cancer

DTIC Science & Technology

2005-07-01

0.1200 0.0240 Bone Surfaces 0.0120 0.0060 0.1700 0.0340 Skin 0.0170 0.0085 0.1600 0.0320 Spleen 0.0130 0.0065 0.1100 0.0220...Vries J. Lymphatic mapping with intralesional tracer administration in breast carcinoma patients. Cancer. 88(11):2546-52, 2000. 10. Bergqvist L... cavitary injection of eight radionuclides in five shell models. J Nucl Med, 43(5):90P, 2002, Suppl. 20. Colombetti LG, Goodwin DA, Togami E. Ga-68

Enhanced Peptide Radiotherapy of Prostate Cancer Using Targeted Adenoviral Vectors

DTIC Science & Technology

2004-06-01

regard to binding of 64Cu - octreotide. In vitro experiments were performed with DU-145 and PC-3 human prostate cancer cells. Expression levels of SSTR2...were determined using a 64Cu -octreotide saturation binding assay on cell membrane preparations. In vivo experiments were conducted in scid mice bearing...subcutaneous DU-l45 or PC-3 cells. AdSSTR2 was injected intratumorally followed 48 h later by an i.v. injection of 64Cu -octreotide. The mice were

Intra-tumoral gene delivery of feIL-2, feIFN-gamma and feGM-CSF using magnetofection as a neoadjuvant treatment option for feline fibrosarcomas: a phase-I study.

PubMed

Jahnke, A; Hirschberger, J; Fischer, C; Brill, T; Köstlin, R; Plank, C; Küchenhoff, H; Krieger, S; Kamenica, K; Schillinger, U

2007-12-01

Despite aggressive pre- or postoperative treatment, feline fibrosarcomas have a high relapse rate. In this study, a new treatment option based on immune stimulation by intra-tumoral delivery of three feline cytokine genes was performed. The objective of this phase-I dose-escalation study was to determine a safe dose for further evaluation in a subsequent phase-II trial. Twenty-five client-owned cats with clinical diagnosis of fibrosarcoma - primary tumours as well as recurrences - entered the study. Four increasing doses of plasmids coding for feIL-2, feIFN-gamma or feGM-CSF, respectively, were previously defined. In groups I, II, III and IV these doses were 15, 50, 150 and 450 microg per plasmid and a corresponding amount of magnetic nanoparticles. Two preoperative intra-tumoral injections of the magnetic DNA solution were followed by magnetofection. A group of four control cats received only surgical treatment. Side effects were registered and graded according to the VCOG-CTCAE scale and correlated to treatment. Statistical analyses included one-way anova, post hoc and Kruskal-Wallis tests. ELISA tests detecting plasma feIFN-gamma and plasma feGM-CSF were performed. One cat out of group IV (450 microg per plasmid) showed adverse events probably related to gene delivery. As these side effects were self-limiting and occurred only in one of eight cats in group IV, this dose was determined to be well tolerable. Altogether six cats developed local recurrences during a 1-year observation period. Four of these cats had been treated with dose IV. Regarding these observations, a subsequent phase-II trial including a representative amount of cats should be tested for the efficacy of dose IV as well as dose III.

Localized thermo-cisplatin therapy: a pilot study in spontaneous canine and feline tumours.

PubMed

Théon, A P; Madewell, B R; Moore, A S; Stephens, C; Krag, D N

1991-01-01

Local hyperthermia combined with intralesional cisplatin chemotherapy is a logical and potentially effective therapeutic approach for localized cancers. A trial using outbred animals with spontaneously occurring tumours was initiated to evaluate the toxicity and efficacy of this approach. Treatment consisted of injection of a colloidal suspension of cisplatin into the tumour prior to hyperthermia once a week for 4 weeks. Immediately after intratumoral injection of a mixture of cisplatin and collagen, thermotherapy was given. The goal temperature was 42 +/- 1 degrees C for 30 min. Ten animals (nine dogs and one cat) with soft tissue neoplasms were treated with one to four hyperthermia and cisplatin sessions for a total of 30 treatment sessions. Complete responses occurred in 4/10 cases (one carcinoma, two sarcomas, one melanoma). One dog with haemangiopericytoma had partial response. The lack of systemic toxicity and the minimal local normal tissue reactions indicate that the treatments were well tolerated. These data provide preliminary evidence that a combination of local hyperthermia and intratumoral cisplatin chemotherapy is a safe and effective method for the treatment of selected localized neoplasms.

Sentinel node biopsy and concomitant probe-guided tumor excision of nonpalpable breast cancer.

PubMed

van Rijk, Maartje C; Tanis, Pieter J; Nieweg, Omgo E; Loo, Claudette E; Olmos, Renato A Valdés; Oldenburg, Hester S A; Rutgers, Emiel J Th; Hoefnagel, Cornelis A; Kroon, Bin B R

2007-02-01

Preliminary data have shown encouraging results of a single intratumoral radiopharmaceutical injection that enables both sentinel node biopsy and probe-guided excision of the primary tumor in patients with nonpalpable breast cancer. The aim of the study was to evaluate this approach in a large group of patients. Lymphoscintigraphy was performed in 368 patients with nonpalpable breast cancer after intratumoral injection of (99m)Tc-nanocolloid (.2 mL, 123 MBq, 3.3 mCi) guided by ultrasound or stereotaxis. The sentinel node was pursued with the aid of vital blue dye (1.0 mL, intratumoral) and a gamma ray detection probe. In case of breast-conserving surgery, the probe was used to guide the excision. At least one sentinel node could be identified intraoperatively in 357 patients (97%), of whom 69 had involved nodes (19%). Age over 60 years was associated with less frequent nonaxillary lymphatic drainage and absence of internal mammary chain dissemination. Tumor-free margins were obtained in 262 (89%) of the 293 patients who underwent segmental excision. Re-excision of the primary tumor bed was performed in six patients (2%). During a median follow-up of 22 months, one breast recurrence and one axillary recurrence were observed. Lymphatic mapping and probe-guided tumor excision of nonpalpable breast cancer by intralesional administration of a single dose of (99m)Tc-nanocolloid and blue dye resulted in 97% identification of the sentinel node and in tumor-free margins in 89% of the patients who underwent breast-conserving surgery. Longer follow-up is needed to substantiate the accuracy and safety of this technique.

Tumor cell apoptosis induces tumor-specific immunity in a CC chemokine receptor 1- and 5-dependent manner in mice.

PubMed

Iida, Noriho; Nakamoto, Yasunari; Baba, Tomohisa; Kakinoki, Kaheita; Li, Ying-Yi; Wu, Yu; Matsushima, Kouji; Kaneko, Shuichi; Mukaida, Naofumi

2008-10-01

The first step in the generation of tumor immunity is the migration of dendritic cells (DCs) to the apoptotic tumor, which is presumed to be mediated by various chemokines. To clarify the roles of chemokines, we induced apoptosis using suicide gene therapy and investigated the immune responses following tumor apoptosis. We injected mice with a murine hepatoma cell line, BNL 1ME A.7R.1 (BNL), transfected with HSV-thymidine kinase (tk) gene and then treated the animals with ganciclovir (GCV). GCV treatment induced massive tumor cell apoptosis accompanied with intratumoral DC infiltration. Tumor-infiltrating DCs expressed chemokine receptors CCR1 and CCR5, and T cells and macrophages expressed CCL3, a ligand for CCR1 and CCR5. Moreover, tumor apoptosis increased the numbers of DCs migrating into the draining lymph nodes and eventually generated a specific cytotoxic cell population against BNL cells. Although GCV completely eradicated HSV-tk-transfected BNL cells in CCR1-, CCR5-, or CCL3-deficient mice, intratumoral and intranodal DC infiltration and the subsequent cytotoxicity generation were attenuated in these mice. When parental cells were injected again after complete eradication of primary tumors by GCV treatment, the wild-type mice completely rejected the rechallenged cells, but the deficient mice exhibited impairment in rejection. Thus, we provide definitive evidence indicating that CCR1 and CCR5 and their ligand CCL3 play a crucial role in the regulation of intratumoral DC accumulation and the subsequent establishment of tumor immunity following induction of tumor apoptosis by suicide genes.

Treatment of breast cancers by magnetic thermoablation: in vivo experiments in mice

NASA Astrophysics Data System (ADS)

Hilger, I.; Andra, W.; Hergt, R.; Hiergeist, R.; Kaiser, W. A.

2001-09-01

The objective of the present study was to investigate the feasibility of a minimal-invasive method for the elimination of tumors in the breast by local heating. Heating is generated by an intratumoral iron oxide (magnetite) loading of the tumor and exposure of the breast to an alternating magnetic field. The methodology consisted in the implantation of human adenocarcinomas (MX-1 cells) into 10 immunodeficient mice. After application of coated iron oxide particles (average total particle diameter: 10 nm) the intratumoral particle deposition was controlled by radiography. Iron contents in selected organs were determined using atomic absorption spectrometry at 50 min p.i.. During exposure of mice (4 min) to an AC magnetic field (frequency: 400 kHz, amplitude: 6.5 kA/m) intratumoral and rectal temperatures were measured. 6.7±2.3%; 2.8± 0.9% and 2.4 ± 0.1% of injected iron dose per g dried tissue was found in the spleen, liver and blood, respectively at 50 min p.i.. No injected iron was found in the lung. Temperatures of 87 ± 7°C and 71 ± 8°C (distal and proximal tumor periphery, respectively) were measured at the end of magnetic field exposure. From the data we deduce that the method enables the generation of localized heat spots that damage tumor cells within several minutes and that the prototype particles are adequately retained at the tumor site. The introduction of the technique in future interventional radiological procedures is promising. Tables 1, Figs 4, Refs 14.

Radiation Dosimetry from Intratumoral Injection of Radionuclides in Human Breast Cancer

DTIC Science & Technology

2004-07-01

0.1700 0.0340 Skin 0.0170 0.0085 0.1600 0.0320 Spleen 0.0130 0.0065 0.1100 0.0220 Testes 0.0011 0.0006 0.0053 0.0011 Thymus 0.0530 0.0265 0.5800 0.1160...Lymphatic mapping with intralesional tracer administration in breast carcinoma patients. Cancer. 88(11):2546-52, 2000. 10. Bergqvist L, Strand SE, Persson B...dosimetry in intra- cavitary injection of eight radionuclides in five shell models. J Nucl Med, 43(5):90P, 2002, Suppl. 20. Colombetti LG, Goodwin DA

Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol

PubMed Central

2012-01-01

Background The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany. Methods ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months. Discussion This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application of an oncolytic virus. Due to its study design the trial will not only generate data on the local effect of H-1PV but it will also investigate the penetration of H-1PV into the tumor after systemic delivery and obtain safety data from systemic delivery possibly supporting clinical trials with H-1PV in other, non-CNS malignancies. Trial registration ClinicalTrials.gov Identifier: NCT01301430 PMID:22436661

Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment

PubMed Central

Takagi, K; Ishida, T; Miki, Y; Hirakawa, H; Kakugawa, Y; Amano, G; Ebata, A; Mori, N; Nakamura, Y; Watanabe, M; Amari, M; Ohuchi, N; Sasano, H; Suzuki, T

2013-01-01

Background: Estrogens have important roles in ductal carcinoma in situ (DCIS) of the breast. However, the significance of presurgical aromatase inhibitor treatment remains unclear. Therefore, we examined intratumoral concentration of estrogens and changes of clinicopathological factors in DCIS after letrozole treatment. Methods: Ten cases of postmenopausal oestrogen receptor (ER)-positive DCIS were examined. They received oral letrozole before the surgery, and the tumour size was evaluated by ultrasonography. Surgical specimens and corresponding biopsy samples were used for immunohistochemistry. Snap-frozen specimens were also available in a subset of cases, and used for hormone assays and microarray analysis. Results: Intratumoral oestrogen levels were significantly lower in DCIS treated with letrozole compared with that in those without the therapy. A great majority of oestrogen-induced genes showed low expression levels in DCIS treated with letrozole by microarray analysis. Moreover, letrozole treatment reduced the greatest dimension of DCIS, and significantly decreased Ki-67 and progesterone receptor immunoreactivity in DCIS tissues. Conclusion: These results suggest that estrogens are mainly produced by aromatase in DCIS tissues, and aromatase inhibitors potently inhibit oestrogen actions in postmenopausal ER-positive DCIS through rapid deprivation of intratumoral estrogens. PMID:23756858

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.

PubMed

Demaria, Olivier; De Gassart, Aude; Coso, Sanja; Gestermann, Nicolas; Di Domizio, Jeremy; Flatz, Lukas; Gaide, Olivier; Michielin, Olivier; Hwu, Patrick; Petrova, Tatiana V; Martinon, Fabio; Modlin, Robert L; Speiser, Daniel E; Gilliet, Michel

2015-12-15

Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.

Combination Treatment of Stereotactic Body Radiation Therapy and Immature Dendritic Cell Vaccination for Augmentation of Local and Systemic Effects.

PubMed

Choi, Chul Won; Jeong, Min Ho; Park, You-Soo; Son, Cheol-Hun; Lee, Hong-Rae; Koh, Eun-Kyoung

2018-06-06

The purpose of this study was to investigate the efficacy of stereotactic body radiation therapy (SBRT) as a tumor-associated antigen (TAA) presentation method for dendritic cell (DC) sensitization and evaluate its effect in combination with immunotherapy using an intratumoral injection of immature DCs (iDCs). CT-26 colon carcinoma cell was used as a cancer cell line. Annexin V staining and phagocytosis assays were performed to determine the appropriate radiation dose and incubation time to generate TAAs. BALB/c mice were used for in vivo experiments. Cancer cells were injected into the right legs and left flanks to generate primary and metastatic tumors, respectively. The mice were subjected to radiation therapy (RT) alone, intradermal injection of electroporated DCs alone, or RT in combination with iDC intratumoral injection (RT/iDC). Tumor growth measurement and survival rate analysis were performed. Enzyme-linked immunospot and cytotoxicity assays were performed to observe the effect of different treatments on the immune system. Annexin V staining and phagocytosis assays showed that 15 Gy radiation dose and 48 hours of incubation was appropriate for subsequent experiments. Maximum DC sensitization and T-cell stimulation was observed with RT as compared to other TAA preparation methods. In vivo assays revealed statistically significant delay in the growth of both primary and metastatic tumors in the RT/iDC group. The overall survival rate was the highest in the RT/iDC group. The combination of SBRT and iDC vaccination may enhance treatment effects. Clinical trials and further studies are warranted in the future.

Synergistic inhibition of malignant melanoma proliferation by melphalan combined with ultrasound and microbubbles.

PubMed

Matsuo, Miki; Yamaguchi, Kazuki; Feril, Loreto B; Endo, Hitomi; Ogawa, Koichi; Tachibana, Katsuro; Nakayama, Juichiro

2011-09-01

The cavitational effects of ultrasound (US) exposure induce transient pores on the cell membrane (sonoporation). Sonoporation have been applied in the field of cancer therapy by promoting delivery of extracellular molecules such as drugs and genes into cytoplasm. In addition, it is known that using US together with microbubbles (MB) elevates permeability of these agents. In this study, by applying the US-MB strategy for melanoma chemotherapy, we evaluated the antitumor effect of melphalan combined with US-MB on a melanoma cell line (C32) in vitro and in vivo. The in vitro cytotoxic effect of the melphalan with US-MB was greater than that of melphalan alone or melphalan in combination with US. In vivo experiments using xenografts, intratumoral injection of melphalan and MB with US exposure led to a greater degree of tumor regression than did the intratumoral injection of the melphalan alone or melphalan in combination with US. These results suggest that US-MB promotes the antitumor effect of melphalan by increasing delivery of molecules into cells and that this strategy may become an effective method of adjuvant therapy against malignant melanoma. Copyright © 2011 Elsevier B.V. All rights reserved.

Ultrasound-guided direct delivery of 3-bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer.

PubMed

Ota, Shinichi; Geschwind, Jean-Francois H; Buijs, Manon; Wijlemans, Joost W; Kwak, Byung Kook; Ganapathy-Kanniappan, Shanmugasundaram

2013-06-01

Studies in animal models of cancer have demonstrated that targeting tumor metabolism can be an effective anticancer strategy. Previously, we showed that inhibition of glucose metabolism by the pyruvate analog, 3-bromopyruvate (3-BrPA), induces anticancer effects both in vitro and in vivo. We have also documented that intratumoral delivery of 3-BrPA affects tumor growth in a subcutaneous tumor model of human liver cancer. However, the efficacy of such an approach in a clinically relevant orthotopic tumor model has not been reported. Here, we investigated the feasibility of ultrasound (US) image-guided delivery of 3-BrPA in an orthotopic mouse model of human pancreatic cancer and evaluated its therapeutic efficacy. In vitro, treatment of Panc-1 cells with 3-BrPA resulted in a dose-dependent decrease in cell viability. The loss of viability correlated with a dose-dependent decrease in the intracellular ATP level and lactate production confirming that disruption of energy metabolism underlies these 3-BrPA-mediated effects. In vivo, US-guided delivery of 3-BrPA was feasible and effective as demonstrated by a marked decrease in tumor size on imaging. Further, the antitumor effect was confirmed by (1) a decrease in the proliferative potential by Ki-67 immunohistochemical staining and (2) the induction of apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphospate nick end labeling staining. We therefore demonstrate the technical feasibility of US-guided intratumoral injection of 3-BrPA in a mouse model of human pancreatic cancer as well as its therapeutic efficacy. Our data suggest that this new therapeutic approach consisting of a direct intratumoral injection of antiglycolytic agents may represent an exciting opportunity to treat patients with pancreas cancer.

Complete regression of human malignant mesothelioma xenografts following local injection of midkine promoter-driven oncolytic adenovirus

PubMed Central

Kubo, Shuji; Kawasaki, Yoshiko; Yamaoka, Norie; Tagawa, Masatoshi; Kasahara, Noriyuki; Terada, Nobuyuki; Okamura, Haruki

2010-01-01

Background Malignant mesothelioma is a highly aggressive tumor with poor prognosis. Conventional therapies for mesothelioma are generally non-curative, and new treatment paradigms are urgently needed. We hypothesized that the tumor-specific midkine (Mdk) promoter could confer transcriptional targeting to oncolytic adenoviruses for effective treatment of malignant mesothelioma. Methods We analyzed Mdk expression by quantitative RT-PCR in six human mesothelioma cell lines, and tested Mdk promoter activity by luciferase reporter assay. Based on these data, we constructed a replication-selective oncolytic adenovirus, designated AdMdk-E1-iresTK, which contains an Mdk promoter-driven adenoviral E1 gene and HSV-thymidine kinase (TK) suicide gene, and CMV promoter-driven green fluorescent protein (GFP) marker gene. Selectivity of viral replication and cytolysis were characterized in normal vs. mesothelioma cells in vitro, and intratumoral spread and antitumor efficacy were investigated in vivo. Results Mdk promoter activity was restricted in normal cells, but highly activated in mesothelioma cell lines. AdMdk-E1-iresTK was seen to efficiently replicate, produce viral progeny, and spread in multiple mesothelioma cell lines. Lytic spread of AdMdk-E1-iresTK mediated efficient killing of these mesothelioma cells, and its in vitro cytocidal effect was significantly enhanced by treatment with the prodrug, ganciclovir. Intratumoral injection of AdMdk-E1-iresTK caused complete regression of MESO4 and MSTO human mesothelioma xenografts in athymic mice. In vivo fluorescence imaging demonstrated intratumoral spread of AdMdk-E1-iresTK-derived signals, which vanished after tumor eradication. Conclusions These data indicate that transcriptional targeting of viral replication by the Mdk promoter represents a promising general strategy for oncolytic virotherapy of cancers with upregulated Mdk expression, including malignant mesothelioma. PMID:20635326

Targeted Drug and Gene Delivery Systems for Lung Cancer Therapy

PubMed Central

Sundaram, Sneha; Trivedi, Ruchit; Durairaj, Chandrasekar; Ramesh, Rajagopal; Ambati, Balamurali K.; Kompella, Uday B.

2009-01-01

Purpose To evaluate the efficacy of a novel docetaxel derivative of deslorelin, a luteinizing hormone releasing hormone (LHRH) agonist, and its combination in-vivo with RGD peptide conjugated nanoparticles encapsulating an anti-angiogenic, anti-VEGF intraceptor (Flt23k) (RGD-Flt23k-NP) in H1299 lung cancer cells and/or xenografts in athymic nude BALB/c mice. Experimental Design The in-vitro and in-vivo efficacy of the deslorelin-docetaxel conjugate (D-D) was evaluated in H1299 cells and xenografts in athymic nude mice. Co-administration of D-D and RGD-Flt23k-NP was tested in-vivo in mice. Tumor inhibition, apoptosis and VEGF inhibition were estimated in each of the treatment groups. Results The conjugate enhanced in-vitro docetaxel efficacy by 13-fold in H1299 cells compared to docetaxel at 24h, and this effect was inhibited following reduction of LHRH-receptor expression by an antisense oligonucleotide. Combination of the conjugate with the RGD-Flt23k-NP in-vivo resulted in an 82- and 15-fold tumor growth inhibition on day 39 following repeated weekly intravenous injections and a single intratumoral injection, respectively. These effects were significantly greater than individual targeted therapies or docetaxel alone. Similarly, apoptotic indices for the combination therapy were 14 and 10% in the intravenous and intratumoral groups, respectively, and higher than the individual therapies. Combination therapy groups exhibited greater VEGF inhibition in both the intravenous and intratumoral groups. Conclusions Docetaxel efficacy was enhanced by LHRH-receptor targeted deslorelin conjugate and further improved by combination with targeted anti-angiogenic nanoparticle gene therapy. Combination of novel targeted therapeutic approaches described here provides an attractive alternative to the current treatment options for lung cancer therapy. PMID:19920099

Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients.

PubMed

Tong, Alex W; Nemunaitis, John; Su, Dan; Zhang, Yuan; Cunningham, Casey; Senzer, Neil; Netto, George; Rich, Dawn; Mhashilkar, Abner; Parker, Karen; Coffee, Keith; Ramesh, Rajagopal; Ekmekcioglu, Suhendan; Grimm, Elizabeth A; van Wart Hood, Jill; Merritt, James; Chada, Sunil

2005-01-01

The mda-7 gene (approved gene symbol IL24) is a novel tumor suppressor gene with tumor-apoptotic and immune-activating properties. We completed a Phase I dose-escalation clinical trial, in which a nonreplicating adenoviral construct expressing the mda-7 transgene (INGN 241; Ad-mda7) was administered intratumorally to 22 patients with advanced cancer. Excised tumors were evaluated for vector-specific DNA and RNA, transgenic MDA-7 expression, and biological effects. Successful gene transfer as assessed by DNA- and RT-PCR was demonstrated in 100% of patients evaluated. DNA analyses demonstrated a dose-dependent penetration of INGN 241 (up to 4 x 10(8) copies/mug DNA at the 2 x 10(12) vp dose). A parallel distribution of vector DNA, vector RNA, MDA-7 protein expression, and apoptosis induction was observed in all tumors, with signals decreasing with distance away from the injection site. Additional evidence for bioactivity of INGN 241 was illustrated via regulation of the MDA-7 target genes beta-catenin, iNOS, and CD31. Transient increases (up to 20-fold) of serum IL-6, IL-10, and TNF-alpha were observed. Significantly higher elevations of IL-6 and TNF-alpha were observed in patients who responded clinically to INGN 241. Patients also showed marked increases of CD3+CD8+ T cells posttreatment, suggesting that INGN 241 increased systemic TH1 cytokine production and mobilized CD8+ T cells. Intratumoral delivery of INGN 241 induced apoptosis in a large volume of tumor and elicited tumor-regulatory and immune-activating events that are consistent with the preclinical features of MDA-7/IL-24.

Noninvasive visualization of tumoral fibrin deposition using a peptidic fibrin-binding single photon emission computed tomography tracer.

PubMed

Starmans, Lucas W E; van Mourik, Tiemen; Rossin, Raffaella; Verel, Iris; Nicolay, Klaas; Grüll, Holger

2015-06-01

Fibrin deposition plays an important role in the formation of mature tumor stroma and provides a facilitating scaffold for tumor angiogenesis. This study investigates the potential of the (111)In-labeled fibrin-binding peptide EPep for SPECT imaging of intratumoral fibrin deposition. (111)In-EPep and negative control (111)In-NCEPep were synthesized and characterized in vitro. In vivo SPECT images and ex vivo biodistribution profiles and autoradiographs were obtained in a fibrin-rich BT-20 breast cancer mouse model. Furthermore, biodistribution profiles were obtained in the fibrin-poor MDA-MD-231 model. In vitro, (111)In-EPep displayed significantly more binding than (111)In-NCEPep toward human and mouse derived fibrin. SPECT/CT images displayed a marked SPECT signal in the tumor area for BT-20 tumor bearing mice injected with EPep but not for mice injected with NCEPep. Biodistribution profiles of BT-20 tumor bearing mice 3 h post-tracer injection showed significantly higher tumor uptake for EPep with respect to NCEPep (0.39 ± 0.14 and 0.11 ± 0.03% ID g(-1), respectively), whereas uptake in other organs was similar for EPep and NCEPep. Autoradiography of BT-20 tumor sections displayed a high signal for EPep which colocalized with intratumoral fibrin deposits. Histological evaluation of MDA-MB-231 tumor sections displayed no significant tumor stroma and only minute fibrin deposits. Biodistribution profiles in MDA-MB-231 tumor bearing mice 3 h post-injection showed EPep tumor uptake (0.14 ± 0.04% ID g(-1)) which was significantly lower with respect to EPep BT-20 tumor uptake, indicating fibrin-specificity of EPep tumoral uptake. In conclusion, this work demonstrates the potential of EPep SPECT imaging for visualization of tumoral fibrin deposition.

Intratumoral immunocytokine treatment results in enhanced antitumor effects.

PubMed

Johnson, Erik E; Lum, Hillary D; Rakhmilevich, Alexander L; Schmidt, Brian E; Furlong, Meghan; Buhtoiarov, Ilia N; Hank, Jacquelyn A; Raubitschek, Andrew; Colcher, David; Reisfeld, Ralph A; Gillies, Stephen D; Sondel, Paul M

2008-12-01

Immunocytokines (IC), consisting of tumor-specific monoclonal antibodies fused to the immunostimulatory cytokine interleukin 2 (IL2), exert significant antitumor effects in several murine tumor models. We investigated whether intratumoral (IT) administration of IC provided enhanced antitumor effects against subcutaneous tumors. Three unique ICs (huKS-IL2, hu14.18-IL2, and GcT84.66-IL2) were administered systemically or IT to evaluate their antitumor effects against tumors expressing the appropriate IC-targeted tumor antigens. The effect of IT injection of the primary tumor on a distant tumor was also evaluated. Here, we show that IT injection of IC resulted in enhanced antitumor effects against B16-KSA melanoma, NXS2 neuroblastoma, and human M21 melanoma xenografts when compared to intravenous (IV) IC injection. Resolution of both primary and distant subcutaneous tumors and a tumor-specific memory response were demonstrated following IT treatment in immunocompetent mice bearing NXS2 tumors. The IT effect of huKS-IL2 IC was antigen-specific, enhanced compared to IL2 alone, and dose-dependent. Hu14.18-IL2 also showed greater IT effects than IL2 alone. The antitumor effect of IT IC did not always require T cells since IT IC induced antitumor effects against tumors in both SCID and nude mice. Localization studies using radiolabeled (111)In-GcT84.66-IL2 IC confirmed that IT injection resulted in a higher concentration of IC at the tumor site than IV administration. In conclusion, we suggest that IT IC is more effective than IV administration against palpable tumors. Further testing is required to determine how to potentially incorporate IT administration of IC into an antitumor regimen that optimizes local and systemic anticancer therapy.

Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines.

PubMed

Moon, Edmund K; Wang, Liang-Chuan S; Bekdache, Kheng; Lynn, Rachel C; Lo, Albert; Thorne, Stephen H; Albelda, Steven M

2018-01-01

T cell trafficking into tumors depends on a "match" between chemokine receptors on effector cells (e.g., CXCR3 and CCR5) and tumor-secreted chemokines. There is often a chemokine/chemokine receptor "mismatch", with tumors producing minute amounts of chemokines, resulting in inefficient targeting of effectors to tumors. We aimed to alter tumors to produce higher levels of CXCL11, a CXCR3 ligand, to attract more effector cells following immunotherapy. Mice bearing established subcutaneous tumors were studied. In our first approach, we used modified chimeric antigen receptor (CAR)-transduced human T cells to deliver CXCL11 (CAR/CXCL11) into tumors. In our second approach, we intravenously (iv) administered a modified oncolytic vaccinia virus (VV) engineered to produce CXCL11 (VV.CXCL11). The effect of these treatments on T cell trafficking into the tumors and anti-tumor efficacy after subsequent CAR T cell injections or anti-tumor vaccines was determined. CAR/CXCL11 and VV.CXCL11 significantly increased CXCL11 protein levels within tumors. For CAR/CXCL11, injection of a subsequent dose of CAR T cells did not result in increased intra-tumoral trafficking, and appeared to decrease the function of the injected CAR T cells. In contrast, VV.CXCL11 increased the number of total and antigen-specific T cells within tumors after CAR T cell injection or vaccination and significantly enhanced anti-tumor efficacy. Both approaches were successful in increasing CXCL11 levels within the tumors; however, only the vaccinia approach was successful in recruiting T cells and augmenting anti-tumor efficacy. VV.CXCL11 should be considered as a potential approach to augment adoptive T cell transfer or vaccine immunotherapy.

Photodynamic Therapy (PDT) using intratumoral injection of the 5- aminolevulinic acid (5-ALA) for the treatment of eye cancer in cattle

NASA Astrophysics Data System (ADS)

Hage, Raduan; Mancilha, Geraldo; Zângaro, Renato A.; Munin, Egberto; Plapler, Hélio

2007-02-01

A six-year old Holstein cow with an eye cancer (ocular squamous cell carcinoma) involving the third eyelid and conjunctiva was submitted to photodynamic therapy using intratumoral 20% aminolevulinic acid (5-ALA - Aldrich Chemical Company, Milwaukee, USA) and a light emitting diode (LED - VET LED - MMOptics (R)) with wavelength between 600 and 700 nm, 2 cm diameter circular light beam, power of 150 mW, light dose of 50 J/cm2 as a source of irradiation. Fifteen days after the experimental procedure we observed about 50% tumor reduction and complete remission after 3 months. Relapse was not observed up to 12 months after the treatment. Although the study only includes one animal not allowing definite conclusions, it indicates that PDT represents a safe and technically feasible approach in the treatment of eye cancer in cattle.

Increased tumor localization and reduced immune response to adenoviral vector formulated with the liposome DDAB/DOPE.

PubMed

Steel, Jason C; Cavanagh, Heather M A; Burton, Mark A; Abu-Asab, Mones S; Tsokos, Maria; Morris, John C; Kalle, Wouter H J

2007-04-01

We aimed to increase the efficiency of adenoviral vectors by limiting adenoviral spread from the target site and reducing unwanted host immune responses to the vector. We complexed adenoviral vectors with DDAB-DOPE liposomes to form adenovirus-liposomal (AL) complexes. AL complexes were delivered by intratumoral injection in an immunocompetent subcutaneous rat tumor model and the immunogenicity of the AL complexes and the expression efficiency in the tumor and other organs was examined. Animals treated with the AL complexes had significantly lower levels of beta-galactosidase expression in systemic tissues compared to animals treated with the naked adenovirus (NA) (P<0.05). The tumor to non-tumor ratio of beta-galactosidase marker expression was significantly higher for the AL complex treated animals. NA induced significantly higher titers of adenoviral-specific antibodies compared to the AL complexes (P<0.05). The AL complexes provided protection (immunoshielding) to the adenovirus from neutralizing antibody. Forty-seven percent more beta-galactosidase expression was detected following intratumoral injection with AL complexes compared to the NA in animals pre-immunized with adenovirus. Complexing of adenovirus with liposomes provides a simple method to enhance tumor localization of the vector, decrease the immunogenicity of adenovirus, and provide protection of the virus from pre-existing neutralizing antibodies.

Magnesium silicide nanoparticles as a deoxygenation agent for cancer starvation therapy

NASA Astrophysics Data System (ADS)

Zhang, Chen; Ni, Dalong; Liu, Yanyan; Yao, Heliang; Bu, Wenbo; Shi, Jianlin

2017-05-01

A material that rapidly absorbs molecular oxygen (known as an oxygen scavenger or deoxygenation agent (DOA)) has various industrial applications, such as in food preservation, anticorrosion of metal and coal deoxidation. Given that oxygen is vital to cancer growth, to starve tumours through the consumption of intratumoral oxygen is a potentially useful strategy in fighting cancer. Here we show that an injectable polymer-modified magnesium silicide (Mg2Si) nanoparticle can act as a DOA by scavenging oxygen in tumours and form by-products that block tumour capillaries from being reoxygenated. The nanoparticles are prepared by a self-propagating high-temperature synthesis strategy. In the acidic tumour microenvironment, the Mg2Si releases silane, which efficiently reacts with both tissue-dissolved and haemoglobin-bound oxygen to form silicon oxide (SiO2) aggregates. This in situ formation of SiO2 blocks the tumour blood capillaries and prevents tumours from receiving new supplies of oxygen and nutrients.

Magnesium silicide nanoparticles as a deoxygenation agent for cancer starvation therapy.

PubMed

Zhang, Chen; Ni, Dalong; Liu, Yanyan; Yao, Heliang; Bu, Wenbo; Shi, Jianlin

2017-05-01

A material that rapidly absorbs molecular oxygen (known as an oxygen scavenger or deoxygenation agent (DOA)) has various industrial applications, such as in food preservation, anticorrosion of metal and coal deoxidation. Given that oxygen is vital to cancer growth, to starve tumours through the consumption of intratumoral oxygen is a potentially useful strategy in fighting cancer. Here we show that an injectable polymer-modified magnesium silicide (Mg 2 Si) nanoparticle can act as a DOA by scavenging oxygen in tumours and form by-products that block tumour capillaries from being reoxygenated. The nanoparticles are prepared by a self-propagating high-temperature synthesis strategy. In the acidic tumour microenvironment, the Mg 2 Si releases silane, which efficiently reacts with both tissue-dissolved and haemoglobin-bound oxygen to form silicon oxide (SiO 2 ) aggregates. This in situ formation of SiO 2 blocks the tumour blood capillaries and prevents tumours from receiving new supplies of oxygen and nutrients.

Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death -1 (PD-1) allows their intratumoral delivery and an improved tumor-growth inhibition.

PubMed

Kleinpeter, Patricia; Fend, Laetitia; Thioudellet, Christine; Geist, Michel; Sfrontato, Nathalie; Koerper, Véronique; Fahrner, Catherine; Schmitt, Doris; Gantzer, Murielle; Remy-Ziller, Christelle; Brandely, Renée; Villeval, Dominique; Rittner, Karola; Silvestre, Nathalie; Erbs, Philippe; Zitvogel, Laurence; Quéméneur, Eric; Préville, Xavier; Marchand, Jean-Baptiste

2016-01-01

We report here the successful vectorization of a hamster monoclonal IgG (namely J43) recognizing the murine Programmed cell death-1 (mPD-1) in Western Reserve (WR) oncolytic vaccinia virus. Three forms of mPD-1 binders have been inserted into the virus: whole antibody (mAb), Fragment antigen-binding (Fab) or single-chain variable fragment (scFv). MAb, Fab and scFv were produced and assembled with the expected patterns in supernatants of cells infected by the recombinant viruses. The three purified mPD-1 binders were able to block the binding of mPD-1 ligand to mPD-1 in vitro . Moreover, mAb was detected in tumor and in serum of C57BL/6 mice when the recombinant WR-mAb was injected intratumorally (IT) in B16F10 and MCA 205 tumors. The concentration of circulating mAb detected after IT injection was up to 1,900-fold higher than the level obtained after a subcutaneous (SC) injection (i.e., without tumor) confirming the virus tropism for tumoral cells and/or microenvironment. Moreover, the overall tumoral accumulation of the mAb was higher and lasted longer after IT injection of WR-mAb1, than after IT administration of 10 µg of J43. The IT injection of viruses induced a massive infiltration of immune cells including activated lymphocytes (CD8 + and CD4 + ). Interestingly, in the MCA 205 tumor model, WR-mAb1 and WR-scFv induced a therapeutic control of tumor growth similar to unarmed WR combined to systemically administered J43 and superior to that obtained with an unarmed WR. These results pave the way for next generation of oncolytic vaccinia armed with immunomodulatory therapeutic proteins such as mAbs.

Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death -1 (PD-1) allows their intratumoral delivery and an improved tumor-growth inhibition

PubMed Central

Kleinpeter, Patricia; Fend, Laetitia; Thioudellet, Christine; Geist, Michel; Sfrontato, Nathalie; Koerper, Véronique; Fahrner, Catherine; Schmitt, Doris; Gantzer, Murielle; Remy-Ziller, Christelle; Brandely, Renée; Villeval, Dominique; Rittner, Karola; Silvestre, Nathalie; Erbs, Philippe; Zitvogel, Laurence; Quéméneur, Eric; Préville, Xavier; Marchand, Jean-Baptiste

2016-01-01

ABSTRACT We report here the successful vectorization of a hamster monoclonal IgG (namely J43) recognizing the murine Programmed cell death-1 (mPD-1) in Western Reserve (WR) oncolytic vaccinia virus. Three forms of mPD-1 binders have been inserted into the virus: whole antibody (mAb), Fragment antigen-binding (Fab) or single-chain variable fragment (scFv). MAb, Fab and scFv were produced and assembled with the expected patterns in supernatants of cells infected by the recombinant viruses. The three purified mPD-1 binders were able to block the binding of mPD-1 ligand to mPD-1 in vitro. Moreover, mAb was detected in tumor and in serum of C57BL/6 mice when the recombinant WR-mAb was injected intratumorally (IT) in B16F10 and MCA 205 tumors. The concentration of circulating mAb detected after IT injection was up to 1,900-fold higher than the level obtained after a subcutaneous (SC) injection (i.e., without tumor) confirming the virus tropism for tumoral cells and/or microenvironment. Moreover, the overall tumoral accumulation of the mAb was higher and lasted longer after IT injection of WR-mAb1, than after IT administration of 10 µg of J43. The IT injection of viruses induced a massive infiltration of immune cells including activated lymphocytes (CD8+ and CD4+). Interestingly, in the MCA 205 tumor model, WR-mAb1 and WR-scFv induced a therapeutic control of tumor growth similar to unarmed WR combined to systemically administered J43 and superior to that obtained with an unarmed WR. These results pave the way for next generation of oncolytic vaccinia armed with immunomodulatory therapeutic proteins such as mAbs. PMID:27853644

The efficacy of combination therapy with oncolytic herpes simplex virus HF10 and dacarbazine in a mouse melanoma model.

PubMed

Tanaka, Rui; Goshima, Fumi; Esaki, Shinichi; Sato, Yoshitaka; Murata, Takayuki; Nishiyama, Yukihiro; Watanabe, Daisuke; Kimura, Hiroshi

2017-01-01

Advanced melanoma has long been treated with chemotherapy using cytotoxic agents like dacarbazine (DTIC), but overall survival rates with these drugs have been generally low. Recently, immunoregulatory monoclonal antibodies and molecularly targeted therapy with a BRAF inhibitor and/or a MEK inhibitor, have been used to treat malignant melanoma and have improved the survival rate of patients with advanced melanoma. However, high prices of these drugs are problematic. In this study, we evaluated the oncolytic efficacy of HF10, an attenuated, replication-competent HSV, with DTIC in immunocompetent mice model of malignant melanoma. For in vitro studies, cytotoxicity assays were conducted in clone M3 mouse melanoma cells. For the in vivo studies, subcutaneous melanoma models were prepared in DBA/2 mice with clone M3 cells, and then HF10 was intratumorally inoculated with/without intraperitoneal DTIC injection. The efficacy of the therapies was evaluated by survival, growth of subcutaneous tumor, and histopathological and immunological analyses. Both HF10 infection and DTIC treatment showed cytotoxic effects in melanoma cells, but combination treatment with HF10 and DTIC showed a rapid and strong cytotoxic effect compared with monotherapy. In the subcutaneous melanoma model, intratumoral HF10 inoculation significantly inhibited tumor growth. HF10 also inhibited the growth of non-inoculated contralateral tumors when it was injected into the ipsilateral tumors of mice. In histologic and immunohistochemical analysis, tumor lysis and inflammatory cell infiltration were observed after intratumoral HF10 inoculation. When mice were treated with HF10 and DTIC, the combination therapy induced a robust systemic anti-tumor immune response and prolonged survival. IFN-γ secretion from splenocytes of the HF10-DTIC combination therapy group showed more IFN-γ secretion than did the other groups. These data showed the efficacy of HF10 and DTIC combination therapy in a mouse melanoma model.

The efficacy of combination therapy with oncolytic herpes simplex virus HF10 and dacarbazine in a mouse melanoma model

PubMed Central

Tanaka, Rui; Goshima, Fumi; Esaki, Shinichi; Sato, Yoshitaka; Murata, Takayuki; Nishiyama, Yukihiro; Watanabe, Daisuke; Kimura, Hiroshi

2017-01-01

Advanced melanoma has long been treated with chemotherapy using cytotoxic agents like dacarbazine (DTIC), but overall survival rates with these drugs have been generally low. Recently, immunoregulatory monoclonal antibodies and molecularly targeted therapy with a BRAF inhibitor and/or a MEK inhibitor, have been used to treat malignant melanoma and have improved the survival rate of patients with advanced melanoma. However, high prices of these drugs are problematic. In this study, we evaluated the oncolytic efficacy of HF10, an attenuated, replication-competent HSV, with DTIC in immunocompetent mice model of malignant melanoma. For in vitro studies, cytotoxicity assays were conducted in clone M3 mouse melanoma cells. For the in vivo studies, subcutaneous melanoma models were prepared in DBA/2 mice with clone M3 cells, and then HF10 was intratumorally inoculated with/without intraperitoneal DTIC injection. The efficacy of the therapies was evaluated by survival, growth of subcutaneous tumor, and histopathological and immunological analyses. Both HF10 infection and DTIC treatment showed cytotoxic effects in melanoma cells, but combination treatment with HF10 and DTIC showed a rapid and strong cytotoxic effect compared with monotherapy. In the subcutaneous melanoma model, intratumoral HF10 inoculation significantly inhibited tumor growth. HF10 also inhibited the growth of non-inoculated contralateral tumors when it was injected into the ipsilateral tumors of mice. In histologic and immunohistochemical analysis, tumor lysis and inflammatory cell infiltration were observed after intratumoral HF10 inoculation. When mice were treated with HF10 and DTIC, the combination therapy induced a robust systemic anti-tumor immune response and prolonged survival. IFN-γ secretion from splenocytes of the HF10-DTIC combination therapy group showed more IFN-γ secretion than did the other groups. These data showed the efficacy of HF10 and DTIC combination therapy in a mouse melanoma model. PMID:28861325

The Assessment of Estrogen Receptor Status and Its Intratumoral Heterogeneity in Patients With Breast Cancer by Using 18F-Fluoroestradiol PET/CT.

PubMed

Yang, Zhongyi; Sun, Yifei; Xu, Xiaoping; Zhang, Yongping; Zhang, Jianping; Xue, Jing; Wang, Mingwei; Yuan, Huiyu; Hu, Silong; Shi, Wei; Zhu, Beiling; Zhang, Yingjian

2017-06-01

The aim of this study was to investigate the clinical value of F-fluoroestradiol (F-FES) PET/CT in the assessment of the estrogen receptor (ER) and its intratumoral heterogeneity in breast cancer patients. Forty-six female patients (50 lesions) with histologically confirmed invasive breast cancer who underwent both F-FES and F-FDG PET/CT in our center were retrospectively included. All the patients enrolled were scheduled to undergo biopsy. The F-FES and FDG uptakes were compared with pathological features (tumor size, ER, progesterone receptor, human epidermal growth factor receptor 2, and Ki67%). The optimal threshold to discriminate ER-positive and ER-negative lesions was determined by receiver operating characteristic curve analysis. Furthermore, we observed the intratumoral heterogeneity by a heterogeneity index (SUVmax/SUVmean) and compared the results with the Chang-Gung Image Texture Analysis. There was good agreement between F-FES uptake and ER, progesterone receptor, and human epidermal growth factor receptor 2 expression (P < 0.001), and the use of SUVmean instead of SUVmax can provide a slightly better correlation. The optimal threshold for F-FES PET/CT to discriminate between ER-positive and ER-negative lesions, as determined by receiver operating characteristic curve analysis, was an SUVmax of 1.82 (sensitivity = 88.2% and specificity = 87.5%) and SUVmean of 1.21 (sensitivity = 85.3% and specificity = 93.7). Our simplified heterogeneity index-FES can easily observe ER heterogeneity. In addition, our results suggested that recurrent/metastatic patients and lesions located other than breast might have greater heterogeneity. F-FES PET/CT is a feasible, noninvasive method for assessing ER expression in breast cancer patients. Because intratumoral heterogeneity exists, F-FES PET/CT might better reflect the ER expression, especially in metastatic patients after treatment, thus assisting in making individualized treatment decisions.

Optimising intratumoral treatment of head and neck squamous cell carcinoma models with the diterpene ester Tigilanol tiglate.

PubMed

Barnett, Catherine M E; Broit, Natasa; Yap, Pei-Yi; Cullen, Jason K; Parsons, Peter G; Panizza, Benedict J; Boyle, Glen M

2018-04-18

The five-year survival rate for patients with head and neck squamous cell carcinoma (HNSCC) has remained at ~50% for the past 30 years despite advances in treatment. Tigilanol tiglate (TT, also known as EBC-46) is a novel diterpene ester that induces cell death in HNSCC in vitro and in mouse models, and has recently completed Phase I human clinical trials. The aim of this study was to optimise efficacy of TT treatment by altering different administration parameters. The tongue SCC cell line (SCC-15) was identified as the line with the lowest efficacy to treatment. Subcutaneous xenografts of SCC-15 cells were grown in BALB/c Foxn1 nu and NOD/SCID mice and treated with intratumoral injection of 30 μg TT or a vehicle only control (40% propylene glycol (PG)). Greater efficacy of TT treatment was found in the BALB/c Foxn1 nu mice compared to NOD/SCID mice. Immunohistochemical analysis indicated a potential role of the host's innate immune system in this difference, specifically neutrophil infiltration. Neither fractionated doses of TT nor the use of a different excipiant led to significantly increased efficacy. This study confirmed that TT in 40% PG given intratumorally as a single bolus dose was the most efficacious treatment for a tongue SCC mouse model.

Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells.

PubMed

Dai, Peihong; Wang, Weiyi; Yang, Ning; Serna-Tamayo, Cristian; Ricca, Jacob M; Zamarin, Dmitriy; Shuman, Stewart; Merghoub, Taha; Wolchok, Jedd D; Deng, Liang

2017-05-19

Advanced cancers remain a therapeutic challenge despite recent progress in targeted therapy and immunotherapy. Novel approaches are needed to alter the tumor immunosuppressive microenvironment and to facilitate the recognition of tumor antigens that leads to antitumor immunity. Poxviruses, such as modified vaccinia virus Ankara (MVA), have potential as immunotherapeutic agents. We show that infection of conventional dendritic cells (DCs) with heat- or ultraviolet-inactivated MVA leads to higher levels of interferon induction than MVA alone through the cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase)-STING cytosolic DNA-sensing pathway. Intratumoral injection of inactivated MVA (iMVA) was effective and generated adaptive antitumor immunity in murine melanoma and colon cancer models. iMVA-induced antitumor therapy was less effective in STING- or Batf3-deficient mice than in wild-type mice, indicating that both cytosolic DNA sensing and Batf3-dependent CD103 + /CD8α + DCs are essential for iMVA immunotherapy. The combination of intratumoral delivery of iMVA and systemic delivery of immune checkpoint blockade generated synergistic antitumor effects in bilateral tumor implantation models as well as in a unilateral large established tumor model. Our results suggest that inactivated vaccinia virus could be used as an immunotherapeutic agent for human cancers. Copyright © 2017, American Association for the Advancement of Science.

Effective immunotherapy of rat glioblastoma with prolonged intratumoral delivery of exogenous heat shock protein Hsp70.

PubMed

Shevtsov, Maxim A; Pozdnyakov, Alexander V; Mikhrina, Anastasia L; Yakovleva, Ludmila Y; Nikolaev, Boris P; Dobrodumov, Anatolii V; Komarova, Elena Y; Meshalkina, Darya A; Ischenko, Alexander M; Pitkin, Emil; Guzhova, Irina V; Margulis, Boris A

2014-11-01

Chaperone Hsp70 can activate adaptive immunity suggesting its possible application as an antitumor vaccine. To assess the therapeutic capacity of Hsp70 we administered purified chaperone into a C6 glioblastoma brain tumor and explored the viability and tumor size as well as interferon gamma (IFNγ) production and cytotoxicity of lymphocytes in the treated animals. Targeted intratumoral injection of Hsp70 resulted in its distribution within the area of glioblastoma, and caused significant inhibition of tumor progression as confirmed by magnetic resonance imaging. The delay in tumor growth corresponded to the prolonged survival of tumor-bearing animals of up to 31 days versus 20 days in control. Continuous administration of Hsp70 with an osmotic pump increased survival even further (39 days). Therapeutic efficacy was associated with infiltration to glioblastoma of NK cells (Ly-6c+) and T lymphocytes (CD3+, CD4+ and CD8+) as well as with an increase in the activity of NK cells (granzyme B production) and CD8+ T lymphocytes as shown by IFNγ ELISPOT assay. Furthermore, we found that Hsp70 treatment caused concomitantly, with a tenfold elevated IFNγ production, an increase in anti-C6 tumor cytotoxicity of lymphocytes. In conclusion, continuous intratumoral delivery of Hsp70 demonstrates high therapeutic potential and therefore could be applied in the treatment of glioblastoma. © 2014 UICC.

Intratumoral delivery of low doses of anti-CD40 mAb combined with monophosphoryl lipid A induces local and systemic antitumor effects in immunocompetent and T cell-deficient mice

PubMed Central

Van De Voort, Tyler J.; Felder, Mildred A. R.; Yang, Richard K.; Sondel, Paul M.; Rakhmilevich, Alexander L.

2012-01-01

In this study, an agonistic anti-CD40 monoclonal antibody was combined with monophosphoryl lipid A (MPL), a nontoxic derivative of LPS and agonist of toll-like receptor 4, to assess the immunomodulatory and antitumor synergy between the two agents in mice. Anti-CD40 was capable of priming macrophages to subsequent ex vivo activation by MPL in immunocompetent and T cell-depleted mice. Intraperitoneal injections of anti-CD40+MPL induced additive to synergistic suppression of poorly immunogenic B16-F10 melanoma growing subcutaneously in syngeneic mice. When anti-CD40+MPL were injected directly into the subcutaneous tumor, the combination treatment was more effective, even with a 25-fold reduction in dose. Low-dose intratumoral treatment also slowed the growth of a secondary tumor growing simultaneously at a distant, untreated site. Antitumor effects were also induced in immunodeficient SCID mice and in T cell-depleted C57BL/6 mice. Taken together, our results show that the antitumor effects of anti-CD40 are enhanced by subsequent treatment with MPL, even in T cell-deficient hosts. These preclinical data suggest that an anti-CD40+MPL combined regimen is appropriate for clinical testing in human patients, including cancer patients that may be immunosuppressed from prior chemotherapy. PMID:23211623

Adenovirus-mediated gene transfer of pathogen-associated molecular patterns for cancer immunotherapy.

PubMed

Tosch, C; Geist, M; Ledoux, C; Ziller-Remi, C; Paul, S; Erbs, P; Corvaia, N; Von Hoegen, P; Balloul, J-M; Haegel, H

2009-04-01

The delivery of stimulatory signals to dendritic cells (DCs) in the tumor microenvironment could be an effective means to break tumor-induced tolerance. The work presented here evaluates the immunostimulatory properties of pathogen-associated molecular patterns (PAMPs), microbial molecules which bind Toll-like receptors and deliver activating signals to immune cells, when expressed in tumor cells using adenoviral (Ad) vectors. In vitro, transduction of A549 tumor cells with Ad vectors expressing either flagellin from Listeria monocytogenes or P40 protein from Klebsiella pneumoniae induced the maturation of human monocyte-derived DCs in co-cultures. In mixed lymphocyte reactions (MLRs), Ad-flagellin and Ad-P40 transduction of tumor cells stimulated lymphocyte proliferation and the secretion of IFN-gamma. In vivo, these vectors were used either as stand-alone immunoadjuvants injected intratumorally or as vaccine adjuvants combined with a tumor antigen-expressing vector. When Ad-PAMPs were administered intratumorally to mice bearing subcutaneous syngeneic B16F0-CAR (cocksackie-adenovirus receptor) melanomas, tumor progression was transiently inhibited by Ad-P40. In a therapeutic vaccine setting, the combination of Ad-MUC1 and Ad-PAMP vectors injected subcutaneously delayed the growth of implanted RenCa-MUC1 tumors and improved tumor rejection when compared with vaccination with Ad-MUC1 alone. These results suggest that Ad-PAMPs could be effective immunoadjuvants for cancer immunotherapy.

Oncolytic Sendai Virus Therapy of Canine Mast Cell Tumors (A Pilot Study).

PubMed

Ilyinskaya, Galina V; Mukhina, Elena V; Soboleva, Alesya V; Matveeva, Olga V; Chumakov, Peter M

2018-01-01

Background: Canine mastocytomas (mast cell tumors) represent a common malignancy among many dog breeds. A typical treatment strategy for canine mastocytomas includes surgery, chemo- and radio-therapy, although in many cases the therapy fails and the disease progression resumes. New treatment approaches are needed. Aims: The goal of this pilot study was to examine safety and efficacy of oncolytic Sendai virus therapy administered to canine patients with cutaneous or subcutaneous mastocytomas. Materials and Methods: Six canine patients, with variable grades and stages of the disease, received virus therapy, either as a monotherapy, or in combination with surgery. The therapy included two or more virus applications administered weekly or biweekly. Each application of Sendai virus (10 7 -10 8.6 EID50) consisted of multiple individual 0.01-0.1 ml injections delivered intratumorally, intradermally around a tumor, and under a tumor bed. Results: The treatment was well tolerated, with minor transitory side effects. Of the six dogs, two did not receive surgery or any other treatment besides the virus injections. The other four animals underwent radical or debulking surgeries, and in three of them the subsequent administration of Sendai virus completely cleared locally recurrent or/and remaining tumor masses. Five dogs demonstrated a complete response to the treatment, the animals remained disease free during the time of observation (2-3 years). One dog responded only partially to the virotherapy; its after-surgical recurrent tumor and some, but not all, metastases were cleared. This dog had the most advanced stage of the disease with multiple enlarged lymph nodes and cutaneous metastases. Conclusion: The results of the pilot study suggest that Sendai virus injections could be safe and efficient for the treatment of dogs affected by mastocytomas.They also suggest the need of further studies for finding optimal schemes and schedules for this kind of therapy.

Adenovirus-mediated p53 gene delivery potentiates the radiation-induced growth inhibition of experimental brain tumors.

PubMed

Badie, B; Kramar, M H; Lau, R; Boothman, D A; Economou, J S; Black, K L

1998-05-01

Patients with malignant gliomas continue to have very poor prognosis even after surgical resection, radiation and chemotherapy. Because these tumors often have alterations in the p53 tumor suppressor gene, which plays a key role in the cellular response to DNA damaging agents, we investigated the role of p53 gene therapy in conjunction with ionizing radiation in a rat brain tumor model. Exposure of cultured rat 9L gliosarcoma cells, which contain a mutant p53 gene, to a recombinant adenovirus-vector bearing the wild-type p53 gene (Adp53), induced apoptosis within 24 hours. Although ionizing radiation had no additional effect on apoptosis within this time frame, it caused G1 arrest in non-apoptotic cells after Adp53 therapy. In contrast, wild-type 9L cells demonstrated little G1 arrest after X-irradiation. When animals bearing brain tumors were irradiated after intratumoral Adp53 injections, more than 85% reduction in tumor size was noted. Moreover, the group of rats receiving both radiation and Adp53 therapy had a significant increase in survival as compared to animals receiving either therapy alone. These results support the use of p53 gene therapy as an adjunct to radiation in treatment of malignant brain tumors.

Combination of SLC administration and Tregs depletion is an attractive strategy for targeting hepatocellular carcinoma

PubMed Central

2013-01-01

Background Secondary lymphoid tissue chemokine (SLC) is a key CC chemokine for chemotaxis of immune cells and has been an attractive candidate for anti-tumor treatments. However, among the immune cells recruited by SLC to tumors, the CD25+ Foxp3+ regulatory T cells (Tregs) compromise the anti-tumor effects. In this study, we proposed the combination therapy of intratumoral co-administration of SLC and anti-CD25 monoclonal antibodies (mAbs). We hypothesized that the intratumoral injections of SLC and depletion of Tregs would have stronger inhibition effects on the progression of hepatocellular carcinoma (HCC) in mice. Methods C57BL/6 mice were inoculated subcutaneously with the murine HCC cell line, and mice with visible tumors were treated intratumorally with SLC, SLC plus anti-CD25 mAbs or the control antibodies. The percentages of Tregs, effector CD8+ T cells and CD4+ T cells were checked in the tumors, lymph nodes, spleen and liver at regular intervals. The levels of intratumoral IL-12, IFN-γ, IL-10 and TGF-β1 were evaluated. The final anti-tumor effects were measured by the tumor volume and weight as well as the intratumoral activity of MMP2 and MMP9. Bone-marrow-derived dendritic cells were used to explore the mechanisms of maturation induced by SLC in vitro. Results Our experiments showed the combination therapy significantly decreased the frequency of Tregs, and increased CD8+ T cells and CD4+ T cells at tumor sites. These alterations were accompanied by an increased level of IL-12 and IFN-γ, and decreased level of IL-10 and TGF-β1. Unexpectedly, we observed a significantly decreased percentage of Tregs, and increased CD8+ T cells and CD4+ T cells in the lymph nodes, spleen and liver after the combination therapy. The growth and invasiveness of HCC was also maximally inhibited in the combination therapy compared with the SLC alone. Furthermore, we confirmed SLC induced the maturation of DCs via NF-κB p65 and this maturation would benefit the combination therapy. Conclusions Our data demonstrated that intratumoral co-administration of SLC and anti-CD25 mAbs was an effective treatment for HCC, which was correlated with the altered tumor microenvironment and systemically optimized percentages of Tregs, CD8+ T cells and CD4+ T cells in peripheral immune organs. PMID:24304581

Expression of connective tissue growth factor and interleukin-11 in intratumoral tissue is associated with poor survival after curative resection of hepatocellular carcinoma.

PubMed

Xiang, Zuo-Lin; Zeng, Zhao-Chong; Fan, Jia; Tang, Zhao-You; Zeng, Hai-Ying

2012-05-01

In the present study, we evaluated the prognostic value of intratumoral and peritumoral expression of connective tissue growth factor (CTGF), transforming growth factor-beta 1 (TGF-β1), and interleukin-11 (IL-11) in patients with hepatocellular carcinoma (HCC) after curative resection. Expression of CTGF, TGF-β1, and IL-11 was assessed by immunohistochemical staining of tissue microarrays containing paired tumor and peritumoral liver tissue from 290 patients who had undergone hepatectomy for histologically proven HCC. The prognostic value of these and other clinicopathologic factors were evaluated. The median follow-up time was 54.3 months (range, 4.3-118.3 months). High intratumoral CTGF expression was associated with vascular invasion (P = 0.015), intratumoral IL-11 expression correlated with higher tumor node metastasis (TNM) stage (P = 0.009), and peritumoral CTGF overexpression correlated with lack of tumor encapsulation (P = 0.031). Correlation analysis of these proteins revealed that intratumoral CTGF and IL-11 correlated with high intratumoral TGF-β1 expression (r = 0.325, P < 0.001; and r = 0.273, P < 0.001, respectively). TNM stage (P < 0.001), high intratumoral CTGF levels (P = 0.010), and intratumoral IL-11 expression (P = 0.015) were independent prognostic factors for progression-free survival (PFS). Vascular invasion (P = 0.032), TNM stage (P < 0.001), high intratumoral CTGF levels (P = 0.036), and intratumoral IL-11 expression (P = 0.013) were independent prognostic factors for overall survival (OS). High intratumoral CTGF and intratumoral IL-11 expression were associated with PFS and OS after hepatectomy, and the combination of intratumoral CTGF with IL-11 may be predictive of survival.

Effects of arginine-glycine-aspartic acid peptide-conjugated quantum dots-induced photodynamic therapy on pancreatic carcinoma in vivo.

PubMed

Li, Ming-Ming; Cao, Jia; Yang, Jia-Chun; Shen, Yu-Jie; Cai, Xiao-Lei; Chen, Yuan-Wen; Qu, Chun-Ying; Zhang, Yi; Shen, Feng; Xu, Lei-Ming

2017-01-01

Quantum dots (QDs) conjugated with integrin antagonist arginine-glycine-aspartic acid (RGD) peptides (QDs-RGD) are novel nanomaterials with a unique optical property: a high molar extinction coefficient. Previously, we have shown that QDs-RGD demonstrate a photodynamic therapy (PDT) effect as new photosensitizers for the pancreatic cancer cell line SW1990 in vitro. Here, we investigate the application of QDs-RGD in mice bearing pancreatic tumors using PDT. To ensure that more photosensitizers accumulated in tumors, QDs-RGD were injected intratumorally. After selection of an adequate dosage for injection from analyses of biodistribution images captured by an IVIS system, PDT was initiated. Three groups were created according to different PDT procedures. In group 1, mice were injected with QDs-RGD intratumorally, and an optical fiber connected to a laser light was inserted directly into the tumor. Irradiation was sustained for 20 min with a laser light (630 nm) at 100 mW/cm 2 . In group 2, the laser optical fiber was placed around, and not inserted into, tumors. In group 3, PDT was conducted as in group 1 but without injection of QDs-RGD. After 28 days of observation, tumors on the back of mice in group 1 grew slowly (V/V 0 =3.24±0.70) compared with the control groups, whose tumors grew quickly, and the mean V/V 0 reached 6.08±0.50 (group 2) and 7.25±0.82 (group 3). Histology of tumor tissues showed more necrotic tissues, more inflammatory cells, and less vascular tissue in the PDT group than those in the control groups. These results suggest that QDs-RGD-mediated PDT, with illumination using an optical fiber inserted directly into the tumor, can inhibit the growth of SW1990 tumors with high efficiency in nude mice.

Multidetector Computed Tomography Features in Differentiating Exophytic Renal Angiomyolipoma from Retroperitoneal Liposarcoma

PubMed Central

Wang, Qiushi; Juan, Yu-Hsiang; Li, Yong; Xie, Jia-Jun; Liu, Hui; Huang, Hongfei; Liu, Zaiyi; Zheng, Junhui; Saboo, Ujwala S.; Saboo, Sachin S.; Liang, Changhong

2015-01-01

Abstract This study aims to evaluate the multidetector computed tomography (CT) imaging features in differentiating exophytic renal angiomyolipoma (AML) from retroperitoneal liposarcoma. We retrospectively enrolled 42 patients with confirmed exophytic renal AML (31 patients) or retroperitoneal liposarcoma (11 patients) during 8 years period to assess: renal parenchymal defect at site of tumor contact, supply from branches of renal artery, tumoral vessel extending through the renal parenchyma, dilated intratumoral vessels, hemorrhage, non–fat-containing intratumoral nodules with postcontrast enhancement, calcification, renal sinus enlargement, anterior displacement of kidneys, and other associated AML. Renal parenchymal defect, renal arterial blood supply, tumoral vessel through the renal parenchyma, dilated intratumoral vessels, intratumoral/perirenal hemorrhage, renal sinus enlargement, and associated AML were seen only or mainly in exophytic renal AML (all P value < 0.05); however, non–fat-attenuating enhancing intratumoral nodules, intratumoral calcification, and anterior displacement of the kidney were more common in liposarcoma (all P value < 0.05). AMLs reveal renal parenchymal defect at the site of tumor contact, supply from renal artery, tumoral vessel extending through the renal parenchyma, dilated intratumoral vessels, intratumoral and/or perirenal hemorrhage, renal sinus enlargement, and associated AML. Non–fat-attenuating enhancing intratumoral nodules, intratumoral calcifications, and anterior displacement of kidney were more commonly seen in liposarcoma. PMID:26376398

Radiation Dosimetry of Intratumoral Injection of Radionuclides into Human Breast Cancer

DTIC Science & Technology

2007-07-01

2 sites will be selected for a single inoculation each. The site will be shaved, the skin will be prepared in sterile fashion using betadine...0.0200 Ovaries 0.0150 0.0030 Pancreas 0.1400 0.0280 Red Marrow 0.1200 0.0240 Bone Surfaces 0.1700 0.0340 Skin 0.1600 0.0320 Spleen 0.1100 0.0220...mapping with intralesional tracer administration in breast carcinoma patients. Cancer. 88(11):2546-52, 2000. 10. Bergqvist L, Strand SE, Persson B, et

Radiation Dosimetry of Intratumoral Injection of Radionuclides into Human Breast Cancer. Revision

DTIC Science & Technology

2007-07-01

2 sites will be selected for a single inoculation each. The site will be shaved, the skin will be prepared in sterile fashion using betadine...0.0200 Ovaries 0.0150 0.0030 Pancreas 0.1400 0.0280 Red Marrow 0.1200 0.0240 Bone Surfaces 0.1700 0.0340 Skin 0.1600 0.0320 Spleen 0.1100 0.0220...mapping with intralesional tracer administration in breast carcinoma patients. Cancer. 88(11):2546-52, 2000. 10. Bergqvist L, Strand SE, Persson B, et

Imaging the Vascular and Metabolic Impact on Claudin-7, a Tight Junction Protein, in Transgenic Human Breast Cancer Models

DTIC Science & Technology

2004-06-01

intratumoral administration of CPE (10 ug) to xenograft tumors of T47D breast cancer cells in immunodeficient mice resulted in a significant reduction (p...prolongs the life of the mice by two fold. Slow release fonrmulations using polymer wafers, polymer beads and nanoparticles is ongoing to provide a... intramuscular injection of 1.5 mg/kg depo- 30 minutes. CLDN 3 and 4 protein was visualized using estradiol (Florida Infusion Co., Palm Harbor, FL

Pembrolizumab With Intratumoral Injection of Clostridium Novyi-NT

ClinicalTrials.gov

2018-06-22

Malignant Neoplasm of Breast; Malignant Neoplasms of Digestive Organs; Malignant Neoplasms of Eye Brain and Other Parts of Central Nervous System; Malignant Neoplasms of Female Genital Organs; Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites; Malignant Neoplasms of Independent (Primary) Multiple Sites; Malignant Neoplasms of Lip Oral Cavity and Pharynx; Malignant Neoplasms of Male Genital Organs; Malignant Neoplasms of Mesothelial and Soft Tissue; Malignant Neoplasms of Respiratory and Intrathoracic Organs; Malignant Neoplasms of Thyroid and Other Endocrine Glands; Malignant Neoplasms of Urinary Tract

A cytokine-delivering polymer is effective in reducing tumor burden in a head and neck squamous cell carcinoma murine model.

PubMed

Lin, Yuan; Luo, Jie; Zhu, Weichao Eric; Srivastava, Minu; Schaue, Dorthe; Elashoff, David A; Dubinett, Steven M; Sharma, Sherven; Wu, Benjamin; St John, Maie A

2014-09-01

This study aimed to evaluate the therapeutic efficacy of a novel polymer platform delivering cisplatin and cytokines in the treatment of head and neck squamous cell carcinoma (HNSCC). In vivo study. Academic research laboratory. Mice were randomized to receive implantation of (1) no polymer, (2) plain polymer, (3) plain polymer with local cisplatin injection, or (4) cisplatin polymer. The 2 groups of mice implanted with cisplatin polymer or no polymer were further randomized to receive (1) 4 Grays external beam radiation for 4 days or (2) no radiation. For cytokine studies, mice were grouped into (1) no polymer, (2) plain polymer, (3) plain polymer with intratumoral injection of recombinant CCL21 twice a week, (4) polymer containing parental dendritic cells, or (5) polymer containing dendritic cells secreting CCL21 (DC-CCL21). The cisplatin-secreting polymer effectively reduced tumors in the mice by more than 16-fold (P < .01). We also observed a statistically significant lower tumor weight among mice treated with cisplatin polymer and concomitant radiation compared to control groups. The DC-CCL21 polymer reduced SCCVII/SF tumors in the C3H/HeJ mice by more than 41% (P < .01). Herein, we demonstrate the efficacy of a novel polymer platform in delivering cisplatin and cytokines. We also demonstrate that we can effectively grow dendritic cells in the polymer that can actively secrete CCL21 for a minimum of 5 days. This polymer may represent a new therapeutic modality for patients with HNSCC. Once this polymer platform is optimized, we will plan to pursue prospective trials in patients with HNSCC. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.

A B-cell lymphoma vaccine using a depot formulation of interleukin-2 induces potent antitumor immunity despite increased numbers of intratumoral regulatory T cells.

PubMed

Grille, Sofía; Brugnini, Andreína; Nese, Martha; Corley, Esteban; Falkenberg, Frank W; Lens, Daniela; Chabalgoity, José A

2010-04-01

Therapeutic vaccination holds great potential as complementary treatment for non-Hodgkin's lymphoma. Here, we report that a therapeutic whole cell vaccine formulated with IL-2 adsorbed onto aluminum hydroxide as cytokine-depot formulation elicits potent antitumor immunity and induces delayed tumor growth, control of tumor dissemination and longer survival in mice challenged with A20-lymphoma. Therapeutic vaccination induced higher numbers of tumor's infiltrating lymphocytes (CD4(+) and CD8(+) T cells and NK cells), and the production of IFN-gamma and IL-4 by intratumoral CD4(+) T cells. Further, strong tumor antigen-specific cellular responses were detected at systemic level. Both the A20-derived antigenic material and the IL-2 depot formulation were required for induction of an effective immune response that impacted on cancer progression. All mice receiving any form of IL-2, either as part of the vaccine or alone as control, showed higher numbers of CD4(+)CD25(+/high)Foxp3(+) regulatory T cells (Treg) in the tumor, which might have a role in tumor progression in these animals. Nevertheless, for those animals that received the cytokine as part of the vaccine formulation, the overall effect was improved immune response and less disseminated disease, suggesting that therapeutic vaccination overcomes the potential detrimental effect of intratumoral Treg cells. Overall, the results presented here show that a simple vaccine formulation, that can be easily prepared under GMP conditions, is a promising strategy to be used in B-cell lymphoma and may have enough merit to be tested in clinical trials.

Interventional Therapy of Head and Neck Cancer with Lipid Nanoparticle-Carried Rhenium-186 Radionuclide

PubMed Central

French, J. Tyler; Goins, Beth; Saenz, Marcela; Li, Shihong; Garcia-Rojas, Xavier; Phillips, William T.; Otto, Randal A.; Bao, Ande

2010-01-01

Purpose Minimally invasive interventional cancer therapy of drug-carrying lipid nanoparticles (liposomes) via convection enhanced delivery generally applied by the use of an infusion pump can increase intratumoral drug concentration and retention while facilitating broad distribution throughout solid tumors. We investigated the utility of liposome-carrying β-emitting radionuclides to treat head and neck cancer in nude rats by direct intratumoral infusion. Methods Four groups of nude rats were subcutaneously inoculated with human tongue cancer cells. After tumors reached an average size of 1.6 cm3, the treatment group received an intratumoral infusion of liposomal rhenium-186 (186Re) (185 MBq (5 mCi)/cm3 tumor). Three control groups were intratumorally infused with either, 1) unlabeled liposomes, 2) unencapsulated 186Re-perrhenate, or 3) unencapsulated intermediate 186Re-compound (186Re-BMEDA). In vivo distribution of 186Re-activity was measured by planar gamma camera imaging. Tumor therapy and toxicity were assessed by measurements of tumor size, body weight, and hematology. Results Average tumor volume of the 186Re-liposome group on post-treatment day-14 decreased to 87.7±20.1%, while tumor volumes increased to 395.0% - 514.4% on average in other three groups (P<0.001 vs 186Re-liposome group). 186Re-liposomes provided much higher intratumoral retention of 186Re-activity, resulting in an average tumor radiation absorbed dose of 526.3±93.3 Gy, whereas 186Re-perrhenate and 186Re-BMEDA groups had only 3.3±1.2 and 13.4±9.2 Gy tumor doses respectively. No systemic toxicity was observed. Conclusion Liposomal 186Re effectively treated the head and neck cancer with minimal side effects after convection enhanced interventional delivery. These results suggest the potential of liposomal 186Re for clinical application in interventional therapy of cancer. PMID:20478719

The effect of leukocyte interleukin injection (Multikine) treatment on the peritumoral and intratumoral subpopulation of mononuclear cells and on tumor epithelia: a possible new approach to augmenting sensitivity to radiation therapy and chemotherapy in oral cancer--a multicenter phase I/II clinical Trial.

PubMed

Tímár, József; Forster-Horváth, C; Lukits, J; Döme, B; Ladányi, A; Remenár, E; Kásler, M; Bencsik, M; Répássy, G; Szabó, G; Velich, N; Suba, Z; Elõ, J; Balatoni, Z; Bajtai, A; Chretien, P; Talor, Eyal

2003-12-01

The main objective of this study was to investigate the effect of the administration of a novel immunoadjuvant, leukocyte interleukin injection, as part of an immuno-augmenting treatment regimen on the peritumoral and intratumoral subpopulations of the tumor infiltrating mononuclear cells and on the epithelial and stromal components, when administered to patients with advanced primary oral squamous cell carcinoma classified as T2-3N0-2M0, as compared with disease-matched control patients (not treated with leukocyte interleukin injection). Multicenter Phase I/II clinical trial. Fifty-four patients from four clinical centers were included in the dose-escalating study (27 in each group [leukocyte interleukin injection-treated and control groups]). Cumulative leukocyte inter-leukin injection doses were 2400, 4800, and 8000 IU (as interleukin-2 equivalent). Paraffin-embedded tumor samples obtained at surgical resection of the residual tumor (between days 21 and 28 after treatment initiation) were used. Histological analysis, necrosis evaluation, and American Joint Committee on Cancer grading were performed from H&E-stained sections. Immunohistochemical analysis was performed on three different tumor regions (surface, zone 1; center, zone 2; and tumor-stroma interface, zone 3). Trichrome staining was used to evaluate connective tissue, and morphometric measurements were made using ImagePro analysis software. Cell cycling was determined by the use of Ki-67 marker. Leukocyte interleukin injection treatment induced a shift from stromal infiltrating T cells toward intraepithelial T cells and posted a significant (P <.05) increase in intraepithelial CD3-positive T cells independent of the leukocyte interleukin injection dose, whereas the increase in CD25 (interleukin-2 receptor alpha [IL-2Ralpha])-positive lymphoid cells was significant only at the lowest leukocyte interleukin injection dose (P <.05). Furthermore, both low- and medium-dose leukocyte interleukin injection treatment induced a significant (P <.05) increase in the number of cycling tumor cells, as compared with control values. The results could be highly beneficial for patients with oral squamous cell carcinoma. First, leukocyte interleukin injection treatment induces T-cell migration into cancer nests and, second, noncycling cancer cells may enter cell cycling on administration of leukocyte interleukin injection. This latter effect may modulate the susceptibility of cancer cells to radiation therapy and chemotherapy. The findings may indicate a need to re-evaluate the way in which follow-up treatment (with radiation therapy and chemotherapy) of patients with head and neck cancer is currently approached.

DNA nanotechnology-based composite-type gold nanoparticle-immunostimulatory DNA hydrogel for tumor photothermal immunotherapy.

PubMed

Yata, Tomoya; Takahashi, Yuki; Tan, Mengmeng; Nakatsuji, Hirotaka; Ohtsuki, Shozo; Murakami, Tatsuya; Imahori, Hiroshi; Umeki, Yuka; Shiomi, Tomoki; Takakura, Yoshinobu; Nishikawa, Makiya

2017-11-01

Success of tumor photothermal immunotherapy requires a system that induces heat stress in cancer cells and enhances strong anti-tumor immune responses. Here, we designed a composite-type immunostimulatory DNA hydrogel consisting of a hexapod-like structured DNA (hexapodna) with CpG sequences and gold nanoparticles. Mixing of the properly designed hexapodna and oligodeoxynucleotide-modified gold nanoparticles resulted in the formation of composite-type gold nanoparticle-DNA hydrogels. Laser irradiation of the hydrogel resulted in the release of hexapodna, which efficiently stimulated immune cells to release proinflammatory cytokines. Then, EG7-OVA tumor-bearing mice received an intratumoral injection of a gold nanoparticle-DNA hydrogel, followed by laser irradiation at 780 nm. This treatment increased the local temperature and the mRNA expression of heat shock protein 70 in the tumor tissue, increased tumor-associated antigen-specific IgG levels in the serum, and induced tumor-associated antigen-specific interferon-γ production from splenocytes. Moreover, the treatment significantly retarded the tumor growth and extended the survival of the tumor-bearing mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neoadjuvant gene delivery of feline granulocyte-macrophage colony-stimulating factor using magnetofection for the treatment of feline fibrosarcomas: a phase I trial.

PubMed

Hüttinger, Cornelia; Hirschberger, Johannes; Jahnke, Anika; Köstlin, Roberto; Brill, Thomas; Plank, Christian; Küchenhoff, Helmut; Krieger, Stefan; Schillinger, Ulrike

2008-06-01

Despite aggressive pre- or postoperative treatment, feline fibrosarcomas have high recurrence rates. Immunostimulatory gene therapy is a promising approach in veterinary oncology. This phase I dose-escalation study was performed to determine toxicity and feasibility of gene therapy with feline granulocyte-macrophage colony-stimulating factor (feGM-CSF) in cats with fibrosarcomas. Twenty cats were treated with plasmid coding for feGM-CSF attached to magnetic nanoparticles in doses of 50, 250, 750 and 1250 microg. Two preoperative intratumoral injections followed by magnetofection were given. Four control cats received only surgical treatment. Adverse events were recorded and correlated according to the veterinary co-operative oncology group toxicity scale. An enzyme-linked immunosorbent assay was performed to detect plasma feGM-CSF concentrations. No significant treatment related toxicity was observed. Preliminary recurrence results were encouraging as, on day 360, ten of 20 treated cats were recurrence-free. In conclusion, 1250 microg of feGM-CSF plasmid DNA applied by magnetofection is safe and feasible for phase II testing.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shukla, R.; Chanda, N.; Zambre, A.

Systemic delivery of therapeutic agents to solid tumors is hindered by vascular and interstitial barriers. We hypothesized that prostate tumor specific epigallocatechingallate( EGCg) functionalized radioactive gold nanoparticles, when delivered intratumorally (IT), will circumvent transport barriers, resulting in targeted delivery of therapeutic payloads. The results described herein provide unequivocal validation of our hypothesis. We report the development of inherently therapeutic gold nanoparticles derived from Au-198 isotope; the range of 198Au β-particle ( ~ 11 mm in tissue or ~1100 cell diameters) is sufficiently long to provide cross-fire effects of radiation dose delivered to cells within the prostate gland and short enoughmore » to minimize radiation dose to critical tissues near the periphery of the capsule. The formulation of biocompatible 198AuNPs utilizes the redox chemistry of prostate tumor specific phytochemical EGCg as it converts gold salt into gold nanoparticles and also selectively binds with excellent affinity to Laminin67R receptors which are over expressed in prostate tumor cells. Pharmacokinetic studies in PC-3 xenograft SCID mice showed ~72% retention of 198AuNP-EGCg in tumors 24 h after intratumoral administration. Therapeutic studies showed 80% reduction of tumor volumes after 28 days demonstrating significant inhibition of tumor growth compared to controls. This innovative “green nanotechnological“approach serves as a basis for designing target specific antineoplastic agents. This novel intratumorally injectable 198AuNP-EGCg nanotherapeutic agent may provide significant advances in oncology for use as an effective treatment for prostate and other solid tumors.« less

Novel multifunctional theranostic liposome drug delivery system: construction, characterization, and multimodality MR, near-infrared fluorescent, and nuclear imaging.

PubMed

Li, Shihong; Goins, Beth; Zhang, Lujun; Bao, Ande

2012-06-20

Liposomes are effective lipid nanoparticle drug delivery systems, which can also be functionalized with noninvasive multimodality imaging agents with each modality providing distinct information and having synergistic advantages in diagnosis, monitoring of disease treatment, and evaluation of liposomal drug pharmacokinetics. We designed and constructed a multifunctional theranostic liposomal drug delivery system, which integrated multimodality magnetic resonance (MR), near-infrared (NIR) fluorescent and nuclear imaging of liposomal drug delivery, and therapy monitoring and prediction. The premanufactured liposomes were composed of DSPC/cholesterol/Gd-DOTA-DSPE/DOTA-DSPE with the molar ratio of 39:35:25:1 and having ammonium sulfate/pH gradient. A lipidized NIR fluorescent tracer, IRDye-DSPE, was effectively postinserted into the premanufactured liposomes. Doxorubicin could be effectively postloaded into the multifunctional liposomes. The multifunctional doxorubicin-liposomes could also be stably radiolabeled with (99m)Tc or (64)Cu for single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging, respectively. MR images displayed the high-resolution micro-intratumoral distribution of the liposomes in squamous cell carcinoma of head and neck (SCCHN) tumor xenografts in nude rats after intratumoral injection. NIR fluorescent, SPECT, and PET images also clearly showed either the high intratumoral retention or distribution of the multifunctional liposomes. This multifunctional drug carrying liposome system is promising for disease theranostics allowing noninvasive multimodality NIR fluorescent, MR, SPECT, and PET imaging of their in vivo behavior and capitalizing on the inherent advantages of each modality.

Efficacy, pharmacokinetics, and biodistribution of thermosensitive chitosan/β-glycerophosphate hydrogel loaded with docetaxel.

PubMed

Li, Cuiyun; Ren, Shuangxia; Dai, Yu; Tian, Fengjie; Wang, Xin; Zhou, Sufeng; Deng, Shuhua; Liu, Qi; Zhao, Jie; Chen, Xijing

2014-04-01

Docetaxel (DTX) is a widely used anticancer drug for various solid tumors. However, its poor solubility in water and lack of specification are two limitations for clinical use. The aim of the study was to develop a thermosensitive chitosan/β-glycerophosphate (C/GP) hydrogel loaded with DTX for intratumoral delivery. The in vitro release profiles, in vivo antitumor efficacy, pharmacokinetics, and biodistribution of DTX-loaded C/GP hydrogel (DTX-C/GP) were evaluated. The results of in vitro release study demonstrated that DTX-C/GP had the property of controlled delivery for a reasonable time span of 3 weeks and the release period was substantially affected by initial DTX strength. The antitumor efficacy of DTX-C/GP was observed at 20 mg/kg in H22 tumor-bearing mice. It was found that the tumor volume was definitely minimized by intratumoral injection of DTX-C/GP. Compared with saline group, the tumor inhibition rate of blank gel, intravenous DTX solution, intratumoral DTX solution, and DTX-C/GP was 2.3%, 29.8%, 41.9%, and 58.1%, respectively. Further, the in vivo pharmacokinetic characteristics of DTX-C/GP correlated well with the in vitro release. DTX-C/GP significantly prolonged the DTX retention and maintained a high DTX concentration in tumor. The amount of DTX distributed to the normal tissues was minimized so that the toxicity was effectively reduced. In conclusion, DTX-C/GP demonstrated controlled release and significant efficacy and exhibited potential for further clinical development.

Photoacoustic spectroscopic imaging of intra-tumor heterogeneity and molecular identification

NASA Astrophysics Data System (ADS)

Stantz, Keith M.; Liu, Bo; Cao, Minsong; Reinecke, Dan; Miller, Kathy; Kruger, Robert

2006-02-01

Purpose. To evaluate photoacoustic spectroscopy as a potential imaging modality capable of measuring intra-tumor heterogeneity and spectral features associated with hemoglobin and the molecular probe indocyanine green (ICG). Material and Methods. Immune deficient mice were injected with wildtype and VEGF enhanced MCF-7 breast cancer cells or SKOV3x ovarian cancer cells, which were allowed to grow to a size of 6-12 mm in diameter. Two mice were imaged alive and after euthanasia for (oxy/deoxy)-hemoglobin content. A 0.4 mL volume of 1 μg/mL concentration of ICG was injected into the tail veins of two mice prior to imaging using the photoacoustic computed tomography (PCT) spectrometer (Optosonics, Inc., Indianapolis, IN 46202) scanner. Mouse images were acquired for wavelengths spanning 700-920 nm, after which the major organs were excised, and similarly imaged. A histological study was performed by sectioning the organ and optically imaging the fluorescence distribution. Results. Calibration of PCT-spectroscopy with different samples of oxygenated blood reproduced a hemoglobin dissociation curve consistent with empirical formula with an average error of 5.6%. In vivo PCT determination of SaO II levels within the tumor vascular was measurably tracked, and spatially correlated to the periphery of the tumor. Statistical and systematic errors associated with hypoxia were estimated to be 10 and 13%, respectively. Measured ICG concentrations determined by contrast-differential PCT images in excised organs (tumor, liver) were approximately 0.8 μg/mL, consistent with fluorescent histological results. Also, the difference in the ratio of ICG concentration in the gall bladder-to-vasculature between the mice was consistent with excretion times between the two mice. Conclusion. PCT spectroscopic imaging has shown to be a noninvasive modality capable of imaging intra-tumor heterogeneity of (oxy/deoxy)-hemoglobin and ICG in vivo, with an estimated error in SaO II at 17% and in ICG at 0.8 μg/mL in excised tissue. Ongoing development of spectroscopic analysis techniques, probe development, and calibration techniques are being developed to improve sensitivity to both exogenous molecular probes and (oxy/deoxy)-hemoglobin fraction.

Gadolinium-loaded chitosan nanoparticles for neutron-capture therapy: Influence of micrometric properties of the nanoparticles on tumor-killing effect.

PubMed

Ichikawa, Hideki; Uneme, Takeshi; Andoh, Tooru; Arita, Yuya; Fujimoto, Takuya; Suzuki, Minoru; Sakurai, Yoshinori; Shinto, Hiroyuki; Fukasawa, Tomonori; Fujii, Fumihiko; Fukumori, Yoshinobu

2014-06-01

As a nanoparticulate device for controlled delivery of Gd in NCT, the authors have developed gadolinium-loaded chitosan nanoparticles (Gd-nanoCPs). In the present study, influence of micrometric properties such as particle size, particle-surface charge and Gd content of Gd-nanoCPs on tumor-killing effect by Gd-NCT was investigated with Gd-nanoCPs. Two types of Gd-nanoCPs with different mean particle size, zeta potential and Gd-content (Gd-nanoCP-400; 391nm, 28mV, 9wt% and Gd-nanoCP-200; 214nm, 19mV, 24wt%) could be prepared by using chitosans with different molecular weights. Gd-nanoCPs incorporating 1.2mg of natural Gd were injected intratumorally once or twice to mice subcutaneously-bearing B16F10 melanoma. Eight hours after the last administration, thermal neutron was irradiated to tumor region of the mice. Remarkable tumor-growth was observed in both hot and cold control groups. In contrast, Gd-NCT groups showed significant tumor-growth suppression effect, though their efficacy was found to depend on the micrometric properties of Gd-nanoCPs. In particular, the Gd-nanoCP-200 exhibited stronger tumor-killing effect than the Gd-nanoCP-400 at the same Gd dose and it was still similar to Gd-nanoCP-400 in tumor-growth suppressing effect even at the half of Gd dose of Gd-nanoCP-400. This significance in tumor-killing effect would be ascribed from a higher Gd retention in the tumor tissue and an improved distribution of Gd with intratumorally administered Gd-nanoCP-200. Indeed, the Gd concentration in tumor tissue at the time corresponding to the onset of thermal neutron irradiation was determined to be significantly higher in Gd-nanoCP-200, compared with Gd-nanoCP-400. These results demonstrated that appropriate modification of Gd-nanoCPs in micrometric properties would be an effective way to improve the retention of Gd in the tumor tissue after intratumoral injection, leading to the enhanced tumor-killing effect in Gd-NCT. Copyright © 2013 Elsevier Ltd. All rights reserved.

Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles

NASA Astrophysics Data System (ADS)

Colby, Aaron H.; Liu, Rong; Schulz, Morgan D.; Padera, Robert F.; Colson, Yolonda L.; Grinstaff, Mark W.

2016-01-01

Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal chemotherapy (e.g., gemcitabine, cisplatin, pemetrexed, and paclitaxel) with limited results. Here, we show that a “two-step” nanoparticle (NP) delivery system may address this limitation. This two-step approach involves the separate administration of NP and drug where, first, the NP localizes to tumor. Second, subsequent administration of drug then rapidly concentrates into the NP already stationed within the target tissue. This two-step method results in a greater than 5-fold increase in intratumoral drug concentrations compared to conventional “drug-alone” administration. These results suggest that this unique two-step delivery may provide a novel method for increasing drug concentrations in target tissues.

Improved Hyperthermia Treatment of Tumors Under Consideration of Magnetic Nanoparticle Distribution Using Micro-CT Imaging.

PubMed

Dähring, H; Grandke, J; Teichgräber, U; Hilger, I

2015-12-01

Heterogeneous magnetic nanoparticle (MNP) distributions within tumors can cause regions of temperature under dosage and reduce the therapeutic efficiency. Here, micro-computed tomography (CT) imaging was used as a tool to determine the MNP distribution in vivo. The therapeutic success was evaluated based on tumor volume and temperature distribution. Tumor-bearing mice were intratumorally injected with iron oxide particles. MNP distribution was assessed by micro-CT with a low radiation dose protocol. MNPs were clearly visible, and the exact distribution to nontumor structures was detected by micro-CT. Knowledge of the intratumoral MNP distribution allowed the generation of higher temperatures within the tumor and led to higher temperature values after exposure to an alternating magnetic field (AMF). Consequently, the tumor size after 28 days was reduced to 14 and 73 % of the initial tumor volume for the MNP/AMF/CT and MNP/AMF groups, respectively. The MNP distribution pattern mainly governed the generated temperature spots in the tumor. Knowing the MNP distribution enabled individualized hyperthermia treatment and improved the overall therapeutic efficiency.

Synthesis of Poly[APMA]-DOTA-64Cu conjugates for interventional radionuclide therapy of prostate cancer: assessment of intratumoral retention by micro-positron emission tomography.

PubMed

Yuan, Jianchao; You, Yezi; Lu, Xin; Muzik, Otto; Oupicky, David; Peng, Fangyu

2007-01-01

To develop new radiopharmaceuticals for interventional radionuclide therapy of locally recurrent prostate cancer, poly[N-(3-aminopropyl)methacrylamide] [poly(APMA)] polymers were synthesized by free radical precipitation polymerization in acetone-dimethylsulfoxide using N,N'-azobis(isobutyronitrile) as the initiator. The polymers were characterized with nuclear magnetic resonance, size exclusion chromatography, and dynamic light scattering (M(n) = 2.40 x 10(4), M(w)/M(n) = 1.87). Subsequently, poly[APMA] was coupled with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as an activator, followed by conjugation with (64)Cu radionuclide. Prolonged retention of poly[APMA]-DOTA-(64)Cu conjugates within the tumor tissues was demonstrated by micro-positron emission tomography at 24 hours following intra-tumoral injection of the conjugates to human prostate xenografts in mice. The data suggest that the poly[APMA]-DOTA-(64)Cu conjugates might be useful for interventional radionuclide therapy of locally recurrent prostate cancer in humans.

Liposomes loaded with hydrophilic magnetite nanoparticles: Preparation and application as contrast agents for magnetic resonance imaging.

PubMed

German, S V; Navolokin, N A; Kuznetsova, N R; Zuev, V V; Inozemtseva, O A; Anis'kov, A A; Volkova, E K; Bucharskaya, A B; Maslyakova, G N; Fakhrullin, R F; Terentyuk, G S; Vodovozova, E L; Gorin, D A

2015-11-01

Magnetic fluid-loaded liposomes (MFLs) were fabricated using magnetite nanoparticles (MNPs) and natural phospholipids via the thin film hydration method followed by extrusion. The size distribution and composition of MFLs were studied using dynamic light scattering and spectrophotometry. The effective ranges of magnetite concentration in MNPs hydrosol and MFLs for contrasting at both T2 and T1 relaxation were determined. On T2 weighted images, the MFLs effectively increased the contrast if compared with MNPs hydrosol, while on T1 weighted images, MNPs hydrosol contrasting was more efficient than that of MFLs. In vivo magnetic resonance imaging (MRI) contrasting properties of MFLs and their effects on tumor and normal tissues morphology, were investigated in rats with transplanted renal cell carcinoma upon intratumoral administration of MFLs. No significant morphological changes in rat internal organs upon intratumoral injection of MFLs were detected, suggesting that the liposomes are relatively safe and can be used as the potential contrasting agents for MRI. Copyright © 2015 Elsevier B.V. All rights reserved.

Radiobiologic significance of response of intratumor quiescent cells in vivo to accelerated carbon ion beams compared with gamma-rays and reactor neutron beams.

PubMed

Masunaga, Shin-Ichiro; Ando, Koichi; Uzawa, Akiko; Hirayama, Ryoichi; Furusawa, Yoshiya; Koike, Sachiko; Sakurai, Yoshinori; Nagata, Kenji; Suzuki, Minoru; Kashino, Genro; Kinashi, Yuko; Tanaka, Hiroki; Maruhashi, Akira; Ono, Koji

2008-01-01

To clarify the radiosensitivity of intratumor quiescent cells in vivo to accelerated carbon ion beams and reactor neutron beams. Squamous cell carcinoma VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine to label all intratumor proliferating cells. Next, they received accelerated carbon ion or gamma-ray high-dose-rate (HDR) or reduced-dose-rate (RDR) irradiation. Other tumor-bearing mice received reactor thermal or epithermal neutrons with RDR irradiation. Immediately after HDR and RDR irradiation or 12 h after HDR irradiation, the response of quiescent cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for 5-bromo-2'-deoxyuridine. The response of the total (proliferating plus quiescent) tumor cells was determined from the 5-bromo-2'-deoxyuridine nontreated tumors. The difference in radiosensitivity between the total and quiescent cell populations after gamma-ray irradiation was markedly reduced with reactor neutron beams or accelerated carbon ion beams, especially with a greater linear energy transfer (LET) value. Clearer repair in quiescent cells than in total cells through delayed assay or a decrease in the dose rate with gamma-ray irradiation was efficiently inhibited with carbon ion beams, especially with a greater LET. With RDR irradiation, the radiosensitivity to accelerated carbon ion beams with a greater LET was almost similar to that to reactor thermal and epithermal neutron beams. In terms of tumor cell-killing effect as a whole, including quiescent cells, accelerated carbon ion beams, especially with greater LET values, are very useful for suppressing the dependency on the heterogeneity within solid tumors, as well as depositing the radiation dose precisely.

Application of organic IR788-loaded semi-interpenetrating network dyes for photoacoustic imaging

NASA Astrophysics Data System (ADS)

Phuc Nguyen, Van; Kim, Hyejin; Kang, Mingyeong; Kwak, Minseok; Kang, Hyun Wook

2017-07-01

In this study, we present the feasibility of a biocompatible Lumogen® IR788-loaded polymeric nanoparticle (NP) as a novel photoabsorbing agent for photoacoustic (PA) imaging. The NP was fabricated through a semi-interpenetrating network (sIPN) within the core of F127 resulting in IR788-sIPN formation. To evaluate the PA sensitivity of the material, tubing phantoms were injected with various concentrations of IR788-sIPN, and H1975 lung-tumor-bearing mice were intratumorally injected with IR788-sIPN. Compared with the background, the PA contrast was enhanced up to 80 and 40% in the phantom and in vivo experiments, respectively. IR788-sIPN can be a feasible IR-absorbing material for early cancer detection.

Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors

PubMed Central

Diop-Frimpong, Benjamin; Chauhan, Vikash P.; Krane, Stephen; Boucher, Yves; Jain, Rakesh K.

2011-01-01

The dense collagen network in tumors significantly reduces the penetration and efficacy of nanotherapeutics. We tested whether losartan—a clinically approved angiotensin II receptor antagonist with noted antifibrotic activity—can enhance the penetration and efficacy of nanomedicine. We found that losartan inhibited collagen I production by carcinoma-associated fibroblasts isolated from breast cancer biopsies. Additionally, it led to a dose-dependent reduction in stromal collagen in desmoplastic models of human breast, pancreatic, and skin tumors in mice. Furthermore, losartan improved the distribution and therapeutic efficacy of intratumorally injected oncolytic herpes simplex viruses. Finally, it also enhanced the efficacy of i.v. injected pegylated liposomal doxorubicin (Doxil). Thus, losartan has the potential to enhance the efficacy of nanotherapeutics in patients with desmoplastic tumors. PMID:21282607

Multisite tumor sampling enhances the detection of intratumor heterogeneity at all different temporal stages of tumor evolution.

PubMed

Erramuzpe, Asier; Cortés, Jesús M; López, José I

2018-02-01

Intratumor heterogeneity (ITH) is an inherent process of tumor development that has received much attention in previous years, as it has become a major obstacle for the success of targeted therapies. ITH is also temporally unpredictable across tumor evolution, which makes its precise characterization even more problematic since detection success depends on the precise temporal snapshot at which ITH is analyzed. New and more efficient strategies for tumor sampling are needed to overcome these difficulties which currently rely entirely on the pathologist's interpretation. Recently, we showed that a new strategy, the multisite tumor sampling, works better than the routine sampling protocol for the ITH detection when the tumor time evolution was not taken into consideration. Here, we extend this work and compare the ITH detections of multisite tumor sampling and routine sampling protocols across tumor time evolution, and in particular, we provide in silico analyses of both strategies at early and late temporal stages for four different models of tumor evolution (linear, branched, neutral, and punctuated). Our results indicate that multisite tumor sampling outperforms routine protocols in detecting ITH at all different temporal stages of tumor evolution. We conclude that multisite tumor sampling is more advantageous than routine protocols in detecting intratumor heterogeneity.

PubMed

Fridman, Wolf Hervé

2016-11-01

HISTORY OF IMMUNOTHERAPY. PARADIGM CHANGE?: Born at the dawn of the 20th century with W.B. Coley's intratumoral injections of bacteria, cancer immunotherapy was built on the corpus of the immune surveillance theory in 1957, modified by R.D. Schreiber in 2004. Scientific knowledge and technological advances have allowed it to become efficacious and to expand in the 21st century as the 4th and most important pillar of cancer treatment. © 2016 Société Française du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.

A Novel Multifunctional Theranostic Liposome Drug Delivery System: Construction, Characterization, and Multimodality MR, Near-infrared Fluorescent and Nuclear Imaging

PubMed Central

Li, Shihong; Goins, Beth; Zhang, Lujun; Bao, Ande

2012-01-01

Liposomes are effective lipid nanoparticle drug delivery systems, which can also be functionalized with non-invasive multimodality imaging agents with each modality providing distinct information and having synergistic advantages in diagnosis, monitoring of disease treatment, and evaluation of liposomal drug pharmacokinetics. We designed and constructed a multifunctional theranostic liposomal drug delivery system, which integrated multimodality magnetic resonance (MR), near-infrared (NIR) fluorescent and nuclear imaging of liposomal drug delivery, and therapy monitoring and prediction. The pre-manufactured liposomes were composed of DSPC/cholesterol/Gd-DOTADSPE/DOTA-DSPE with the molar ratio of 39:35:25:1 and having ammonium sulfate/pH gradient. A lipidized NIR fluorescent tracer, IRDye-DSPE, was effectively post-inserted into the pre-manufactured liposomes. Doxorubicin could be effectively post-loaded into the multifunctional liposomes. The multifunctional doxorubicin-liposomes could also be stably radiolabeled with 99mTc or 64Cu for single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging, respectively. MR images displayed the high resolution micro-intratumoral distribution of the liposomes in squamous cell carcinoma of head and neck (SCCHN) tumor xenografts in nude rats after intratumoral injection. NIR fluorescent, SPECT and PET images also clearly showed either the high intratumoral retention or distribution of the multifunctional liposomes. This multifunctional drug carrying liposome system is promising for disease theranostics allowing non-invasive multimodality NIR fluorescent, MR, SPECT and PET imaging of their in vivo behavior and capitalizing on the inherent advantages of each modality. PMID:22577859

Non-invasive assessment of intratumoral vascularity using arterial spin labeling: A comparison to susceptibility-weighted imaging for the differentiation of primary cerebral lymphoma and glioblastoma.

PubMed

Furtner, J; Schöpf, V; Preusser, M; Asenbaum, U; Woitek, R; Wöhrer, A; Hainfellner, J A; Wolfsberger, S; Prayer, D

2014-05-01

Using conventional MRI methods, the differentiation of primary cerebral lymphomas (PCNSL) and other primary brain tumors, such as glioblastomas, is difficult due to overlapping imaging characteristics. This study was designed to discriminate tumor entities using normalized vascular intratumoral signal intensity values (nVITS) obtained from pulsed arterial spin labeling (PASL), combined with intratumoral susceptibility signals (ITSS) from susceptibility-weighted imaging (SWI). Thirty consecutive patients with glioblastoma (n=22) and PCNSL (n=8), histologically classified according to the WHO brain tumor classification, were included. MRIs were acquired on a 3T scanner, and included PASL and SWI sequences. nVITS was defined by the signal intensity ratio between the tumor and the contralateral normal brain tissue, as obtained by PASL images. ITSS was determined as intratumoral low signal intensity structures detected on SWI sequences and were divided into four different grades. Potential differences in the nVITS and ITSS between glioblastomas and PCNSLs were revealed using statistical testing. To determine sensitivity, specificity, and diagnostic accuracy, as well as an optimum cut-off value for the differentiation of PCNSL and glioblastoma, a receiver operating characteristic analysis was used. We found that nVITS (p=0.011) and ITSS (p=0.001) values were significantly higher in glioblastoma than in PCNSL. The optimal cut-off value for nVITS was 1.41 and 1.5 for ITSS, with a sensitivity, specificity, and accuracy of more than 95%. These findings indicate that nVITS values have a comparable diagnostic accuracy to ITSS values in differentiating glioblastoma and PCNSL, offering a completely non-invasive and fast assessment of tumoral vascularity in a clinical setting. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

NO-donating aspirin inhibits angiogenesis by suppressing VEGF expression in HT-29 human colon cancer mouse xenografts

PubMed Central

Ouyang, Nengtai; Williams, Jennie L.; Rigas, Basil

2008-01-01

The inhibitory effect of NO-donating aspirin (NO-ASA) on colon cancer has been demonstrated in vivo and in vitro but its mechanism is still obscure. We investigated the effect of NO-ASA on angiogenesis. Four groups of athymic mice (N = 12) bearing subcutaneous xenotransplants of HT-29 human colon cancer cells were injected intratumorally twice a week for 3 weeks with vehicle or m-NO-ASA or p-NO-ASA; the fourth group received no injections. The necrotic area of tumors, expressed as percentage of total area, was similar in the non-injected and vehicle-injected groups (51.8 ± 2.8 versus 52.2 ± 4.1, P > 0.05; mean ± SEM for these and subsequent values). Compared with the vehicle group, the necrotic area of tumors was higher in the m-NO-ASA-treated (61.0 ± 2.7, P < 0.02) and p-NO-ASA (65.8 ± 2.4, P < 0.001)-treated groups. NO-ASA decreased microvessel density: vehicle = 11.7 ± 0.8; m-NO-ASA = 7.8 ± 0.6 (P = 0.0003 versus vehicle) and p-NO-ASA 6.2 ± 0.7 (P = 0.0001 versus vehicle). The expression of vascular endothelial growth factor (VEGF) was significantly reduced in response to NO-ASA, with the p- isomer being more potent than the m-. NO-ASA altered the spatial distribution of VGEF expression, with 16.7% of the vehicle-treated xenografts displaying diminished VEGF in the inner region of the area between necrosis and the outer perimeter of the tumor, compared with those treated with m- (58.3%) or p-NO-ASA (75%, P < 0.01 for both versus control). Our findings indicate that NO-ASA suppresses the expression of VEGF, which leads to suppressed angiogenesis. The antiangiogenic activity of NO-ASA may be part of its antineoplastic effect. PMID:18544566

[Application of 1% lauromacrogol in the treatment of facial refractory hemangioma and vascular malformations].

PubMed

Wang, Yin; Zhu, Fei; Ning, Jin-long; Li, Xiao-jing; Liu, Ye

2012-11-01

To investigate the clinical effect of 1% lauromacrogol for the treatment of facial refractory hemangioma and vascular malformation. From Sept 2009 to Nov 2011, 55 patients (20 male, 35 female, 1 month to 30 years) with different types of facial hemangiorwa and vascular malformation about 1.0 cm x (0. 5-5.0) cm x 10.0 cm in size, underwent 1% lauromacrogol intratumor injection therapy. Generally, the injection dose, concentration, frequency were determined by the age of the patients, the volume and depth of the lesion. The dose was limited to 10 mg every time. The injection interval is 14 weeks. After followed up for 3-16 months, 41 cases were cured, 9 cases were greatly improved, and 5 were partially improved. Skin necrosis happened in only 2 cases. Lauromacrogol is safe, simple and effective as a sderosing agent for the treatment of facial refractory hemangioma and vascular malformation. It provides a new and alternative way for the treatment of facial refractory hemangioma and vascular malformation.

Selective uptake of multi-walled carbon nanotubes by tumor macrophages in a murine glioma model.

PubMed

VanHandel, Michelle; Alizadeh, Darya; Zhang, Leying; Kateb, Babak; Bronikowski, Michael; Manohara, Harish; Badie, Behnam

2009-03-31

Carbon nantotubes (CNTs) are emerging as a new family of nanovectors for drug and gene delivery into biological systems. To evaluate potential application of this technology for brain tumor therapy, we studied uptake and toxicity of multi-walled CNTs (MWCNTs) in the GL261 murine intracranial glioma model. Within 24 h of a single intratumoral injection of labeled MWCNTs (5 microg), nearly 10-20% of total cells demonstrated CNT internalization. Most CNT uptake, however, occurred by tumor-associated macrophages (MP), which accounted for most (75%) MWCNT-positive cells. Within 24 h of injection, nearly 30% of tumor MP became MWCNT-positive. Despite a transient increase in inflammatory cell infiltration into both normal and tumor-bearing brains following MWCNT injection, no significant toxicity was noted in mice, and minor changes in tumor cytokine expression were observed. This study suggests that MWCNTs could potentially be used as a novel and non-toxic vehicle for targeting MP in brain tumors.

Effective immuno-targeting of the IDH1 mutation R132H in a murine model of intracranial glioma.

PubMed

Pellegatta, Serena; Valletta, Lorella; Corbetta, Cristina; Patanè, Monica; Zucca, Ileana; Riccardi Sirtori, Federico; Bruzzone, Maria Grazia; Fogliatto, Gianpaolo; Isacchi, Antonella; Pollo, Bianca; Finocchiaro, Gaetano

2015-01-21

The R132H mutation of cytosolic isocitrate dehydrogenase (IDH1) is present in the majority of low grade gliomas.Immunotherapy in these tumors has an interesting, still unexploited, therapeutic potential, as they are less immunosuppressive than glioblastomas. Using site-directed mutagenesis we introduced the R132H mutation into the murine glioma cell line GL261,creating mIDH1-GL261. Presence of the mutation was confirmed by immunoblotting and production of the oncometabolite 2-hydroxyglutarate (2HG), demonstrated by mass spectrometry (LC-MS/MS) performed on cell supernatant. In vitro mIDH1-GL261 had different morphology but similar growth rate than parental GL261 (p-GL261). After intracranial injection, MRI suggested that the initial growth rate was slower in mIDH1-GL261 than p-GL261 gliomas but overall survival was similar. mIDH1-GL261 gliomas showed evidence of R132H expression and of intratumoral 2HG production (evaluated by MRS and LC-MS/MS). Immunizations were performed nine days after intracranial implantation of mIDH1- or p-GL261 cells by three subcutaneous injections of five different peptides encompassing the IDH1 mutation site, all emulsified with Montanide ISA-51, in association with GM-CSF. Control mice were injected with four ovalbumin peptides or vehicle. Mice with mIDH1-GL261 but not p-GL261 gliomas treated with mIDH1 peptides survived longer than controls; 25% of them were cured. Immunized mice showed higher amounts of peripheral CD8+ T cells, higher production of IFN-γ, and evidence of anti-mIDH1 antibodies.Immunizations led to intratumoral up-regulation of IFN-γ, granzyme-b and perforin-1 and down-regulation of TGF-β2 and IL-10. These results support the translational potential of immunotherapeutic targeting of gliomas carrying IDH1 mutations.

The assesment of effectiveness of plasmonic resonance photothermal therapy in tumor-bearing rats after multiple intravenous administration of gold nanorods

NASA Astrophysics Data System (ADS)

Bucharskaya, Alla B.; Maslyakova, Galina N.; Navolokin, Nikita A.; Terentyuk, Georgy S.; Khlebtsov, Boris N.; Khlebtsov, Nikolai G.; Bashkatov, Alexey N.; Genina, Elina A.; Tuchin, V. V.

2017-03-01

To assess the effectiveness of plasmonic photothermal therapy (PPT) multiple intravenous strategy of gold nanorods (GNRs) administration was used before laser exposure. The model of alveolar liver cancer PC-1 was used in male outbred albino rats, which were intravenously administrated by single and multiple injections of GNRs and then were treated by PPT. The gold dosage was 400 μg (single injection group), 800 μg (double injection group), 1200 μg (triple injection group), and absorption maximum of gold nanorods suspension was at the wavelength of 808 nm. 24 hours after last injection the tumors were irradiated by the 808-nm diode laser during 15 min at power density 2.3 W/cm2. Temperature control of the tumor heating was provided by IR imager. 24 hours after the PPT the half of animals from each group was withdrawn from the experiments and the sampling tumor tissue for morphological study was performed. In survived animals the growth of tumors was evaluated during 21 days after the PPT. The antitumor effects of PPT after triple intravenous injection were comparable with those obtained at direct intratumoral administration of similar total dose of GNRs. The effectiveness of PPT depended on gold accumulation in tumor, probably, due to sufficient vascularization of tumor tissue.

Intratumoral Delivery of Doxorubicin on Folate-Conjugated Graphene Oxide by In-Situ Forming Thermo-Sensitive Hydrogel for Breast Cancer Therapy

PubMed Central

Fong, Yi Teng; Chen, Chih-Hao

2017-01-01

By taking advantage of the pH-sensitive drug release property of graphene oxide (GO) after intracellular uptake, we prepared folic acid (FA)-conjugated GO (GOFA) for targeted delivery of the chemotherapeutic drug doxorubicin (DOX). GOFA-DOX was further encapsulated in an injectable in-situ forming thermo-sensitive hyaluronic acid-chitosan-g-poly(N-isopropylacrylamide) (HACPN) hydrogel for intratumoral delivery of DOX. As the degradation time of HACPN could be extended up to 3 weeks, intratumoral delivery of GOFA-DOX/HACPN could provide controlled and targeted delivery of DOX through slow degradation HACPN and subsequent cellular uptake of released GOFA-DOX by tumor cells through interactions of GOFA with folate receptors on the tumor cell’s surface. GOFA nano-carrier and HACPN hydrogel were first characterized for the physico-chemical properties. The drug loading experiments indicated the best preparation condition of GOFA-DOX was by reacting 0.1 mg GOFA with 2 mg DOX. GOFA-DOX showed pH-responsive drug release with ~5 times more DOX released at pH 5.5 than at pH 7.4 while only limited DOX was released from GOFA-DOX/HACPN at pH 7.4. Intracellular uptake of GOFA by endocytosis and release of DOX from GOFA-DOX in vitro could be confirmed from transmission electron microscopic and confocal laser scanning microscopic analysis with MCF-7 breast cancer cells. The targeting effect of FA was revealed when intracellular uptake of GOFA was blocked by excess FA. This resulted in enhanced in vitro cytotoxicity as revealed from the lower half maximal inhibitory concentration (IC50) value of GOFA-DOX (7.3 μg/mL) compared with that of DOX (32.5 μg/mL) and GO-DOX (10 μg/mL). The flow cytometry analysis indicated higher apoptosis rates for cells treated with GOFA-DOX (30%) compared with DOX (8%) and GO-DOX (11%). Animal studies were carried out with subcutaneously implanted MCF-7 cells in BALB/c nude mice and subject to intratumoral administration of drugs. The relative tumor volumes of control (saline) and GOFA-DOX/HACPN groups at day 21 were 2.17 and 1.79 times that at day 0 with no significant difference. In comparison, the relative tumor volumes of treatment groups at the same time were significantly different at 1.02, 0.67 and 0.48 times for DOX, GOFA-DOX and GOFA-DOX/HACPN groups, respectively. The anti-tumor efficacy was also supported by images from an in vivo imaging system (IVIS) using MCF-7 cells transfected with luciferase (MCF-7/Luc). Furthermore, tissue biopsy examination and blood analysis indicated that intratumoral delivery of DOX using GOFA-DOX/HACPN did not elicit acute toxicity. Taken together, GOFA-DOX/HACPN could be deemed as a safe and efficient intratumoral drug delivery system for breast cancer therapy. PMID:29135959

Human fibulin-3 protein variant expresses anti-cancer effects in the malignant glioma extracellular compartment in intracranial xenograft models

PubMed Central

Li, Yanyan; Hu, Yuan; Liu, Chuanjin; Wang, Qingyue; Han, Xiaoxiao; Han, Yong; Xie, Xue-Shun; Chen, Xiong-Hui; Li, Xiang; Siegel, Eric R.; Afrasiabi, Kambiz; Linskey, Mark E.; Zhou, You-Xin; Zhou, Yi-Hong

2017-01-01

Background Decades of cytotoxic and more recently immunotherapy treatments for malignant glioma have had limited success due to dynamic intra-tumoral heterogeneity. The dynamic interplay of cancer cell subpopulations has been found to be under the control of proteins in the cancer microenvironment. EGF-containing fibulin-like extracellular matrix protein (EFEMP1) (also fibulin-3) has the multiple functions of suppressing cancer growth and angiogenesis, while promoting cancer cell invasion. EFEMP1-derived tumor suppressor protein (ETSP) retains EFEMP1’s anti-growth and anti-angiogenic functions while actually inhibiting cancer cell invasion. Methods In this study, we examined the therapeutic effect on glioblastoma multiforme (GBM) of an in vitro synthesized protein, ZR30, which is based on the sequence of ETSP, excluding the signaling peptide. Results ZR30 showed the same effects as ETSP in blocking EGFR/NOTCH/AKT signaling pathways, when applied to cultures of multiple GBM cell lines and primary cultures. ZR30’s inhibition of MMP2 activation was shown not only for GBM cells, but also for other types of cancer cells having overexpression of MMP2. A significant improvement in survival of mice with orthotopic human GBM xenografts was observed after a single, intra-tumoral injection of ZR30. Using a model mimicking the intra-tumoral heterogeneity of GBM with cell subpopulations carrying different invasive and proliferative phenotypes, we demonstrated an equal and simultaneous tumor suppressive effect of ZR30 on both tumor cell subpopulations, with suppression of FOXM1 and activation of SEMA3B expressions in the xenografts. Conclusion Overall, the data support a complementary pleiotrophic therapeutic effect of ZR30 acting in the extracellular compartment of GBM. PMID:29290950

Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Kwang-Hun; Liapi, Eleni A.; Cornell, Curt

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20more » ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.« less

Doxorubicin-loaded QuadraSphere microspheres: plasma pharmacokinetics and intratumoral drug concentration in an animal model of liver cancer.

PubMed

Lee, Kwang-Hun; Liapi, Eleni A; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A; Ventura, Veronica Prieto; Geschwind, Jean-Francois H

2010-06-01

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

TCR repertoires of intratumoral T-cell subsets.

PubMed

Linnemann, Carsten; Mezzadra, Riccardo; Schumacher, Ton N M

2014-01-01

The infiltration of human tumors by T cells is a common phenomenon, and over the past decades, it has become increasingly clear that the nature of such intratumoral T-cell populations can predict disease course. Furthermore, intratumoral T cells have been utilized therapeutically in clinical studies of adoptive T-cell therapy. In this review, we describe how novel methods that are either based on T-cell receptor (TCR) sequencing or on cancer exome analysis allow the analysis of the tumor reactivity and antigen-specificity of the intratumoral TCR repertoire with unprecedented detail. Furthermore, we discuss studies that have started to utilize these techniques to probe the link between cancer exomes and the intratumoral TCR pool. Based on the observation that both the cancer epitope repertoire and intratumoral TCR repertoire appear highly individual, we outline strategies, such as 'autologous TCR gene therapy', that exploit the tumor-resident TCR repertoire for the development of personalized immunotherapy. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Oxaliplatin loaded PLAGA microspheres: design of specific release profiles.

PubMed

Lagarce, F; Cruaud, O; Deuschel, C; Bayssas, M; Griffon-Etienne, G; Benoit, J

2002-08-21

Oxaliplatin loaded PLAGA microspheres have been prepared by solvent extraction process. Parameters affecting the release kinetics in vitro have been studied in order to design specific release profiles suitable for direct intra-tumoral injection. By varying the nature and the relative proportions of different polymers we managed to prepare microspheres with good encapsulation efficiency (75-90%) and four different release profiles: zero order kinetics (type II) and the classical sigmoïd release profile with three different sizes of plateau and burst. These results, if correlated with in vivo activity, are promising to enhance effectiveness of local tumor treatment.

Intratumor Heterogeneity of ALK-Rearrangements and Homogeneity of EGFR-Mutations in Mixed Lung Adenocarcinoma

PubMed Central

Marino, Federica Zito; Liguori, Giuseppina; Aquino, Gabriella; La Mantia, Elvira; Bosari, Silvano; Ferrero, Stefano; Rosso, Lorenzo; Gaudioso, Gabriella; De Rosa, Nicla; Scrima, Marianna; Martucci, Nicola; La Rocca, Antonello; Normanno, Nicola; Morabito, Alessandro; Rocco, Gaetano; Botti, Gerardo; Franco, Renato

2015-01-01

Background Non Small Cell Lung Cancer is a highly heterogeneous tumor. Histologic intratumor heterogeneity could be ‘major’, characterized by a single tumor showing two different histologic types, and ‘minor’, due to at least 2 different growth patterns in the same tumor. Therefore, a morphological heterogeneity could reflect an intratumor molecular heterogeneity. To date, few data are reported in literature about molecular features of the mixed adenocarcinoma. The aim of our study was to assess EGFR-mutations and ALK-rearrangements in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas and adenosquamous carcinomas. Methods 590 Non Small Cell Lung Carcinomas tumor samples were revised in order to select mixed adenocarcinomas with available tumor components. Finally, only 105 mixed adenocarcinomas and 17 adenosquamous carcinomas were included in the study for further analyses. Two TMAs were built selecting the different intratumor histotypes. ALK-rearrangements were detected through FISH and IHC, and EGFR-mutations were detected through IHC and confirmed by RT-PCR. Results 10/122 cases were ALK-rearranged and 7 from those 10 showing an intratumor heterogeneity of the rearrangements. 12/122 cases were EGFR-mutated, uniformly expressing the EGFR-mutated protein in all histologic components. Conclusion Our data suggests that EGFR-mutations is generally homogeneously expressed. On the contrary, ALK-rearrangement showed an intratumor heterogeneity in both mixed adenocarcinomas and adenosquamous carcinomas. The intratumor heterogeneity of ALK-rearrangements could lead to a possible impact on the therapeutic responses and the disease outcomes. PMID:26422230

Silver nanoparticles: a novel radiation sensitizer for glioma?

NASA Astrophysics Data System (ADS)

Liu, Peidang; Huang, Zhihai; Chen, Zhongwen; Xu, Ruizhi; Wu, Hao; Zang, Fengchao; Wang, Cailian; Gu, Ning

2013-11-01

Malignant gliomas are the most common primary intracranial tumors with a dismal prognosis. Previous investigations by our group demonstrated the radiosensitizing effect of silver nanoparticles (AgNPs) on glioma cells in vitro. The goal of the present study was to evaluate the efficacy of intratumoral administration of AgNPs in combination with a single dose of ionizing radiation at clinically relevant MV energies for the treatment of C6 glioma-bearing rats. AgNPs (10 or 20 μg/10 μl) were stereotactically administered on day 8 after tumor implantation. One day after AgNP injection, rats bearing glioma received 10 Gy radiation. The mean survival times were 100.5 and 98 days, the corresponding percent increase in life spans was 513.2% and 497.7%, and the cure rates were 41.7 and 38.5% at 200 days for the 10 and 20 μg AgNPs and radiation combination groups, respectively. In contrast, the mean survival times for irradiated controls, 10 and 20 μg AgNPs alone, and untreated controls were 24.5, 16.1, 19.4, and 16.4 days, respectively. Furthermore, a cooperative antiproliferative and proapoptotic effect was obtained when gliomas were treated with AgNPs followed by radiotherapy. Our results showed the therapeutic efficacy of AgNPs in combination with radiotherapy without apparent systemic toxicity, suggesting the clinical potential of AgNPs in improving the outcome of malignant glioma radiotherapy.Malignant gliomas are the most common primary intracranial tumors with a dismal prognosis. Previous investigations by our group demonstrated the radiosensitizing effect of silver nanoparticles (AgNPs) on glioma cells in vitro. The goal of the present study was to evaluate the efficacy of intratumoral administration of AgNPs in combination with a single dose of ionizing radiation at clinically relevant MV energies for the treatment of C6 glioma-bearing rats. AgNPs (10 or 20 μg/10 μl) were stereotactically administered on day 8 after tumor implantation. One day after AgNP injection, rats bearing glioma received 10 Gy radiation. The mean survival times were 100.5 and 98 days, the corresponding percent increase in life spans was 513.2% and 497.7%, and the cure rates were 41.7 and 38.5% at 200 days for the 10 and 20 μg AgNPs and radiation combination groups, respectively. In contrast, the mean survival times for irradiated controls, 10 and 20 μg AgNPs alone, and untreated controls were 24.5, 16.1, 19.4, and 16.4 days, respectively. Furthermore, a cooperative antiproliferative and proapoptotic effect was obtained when gliomas were treated with AgNPs followed by radiotherapy. Our results showed the therapeutic efficacy of AgNPs in combination with radiotherapy without apparent systemic toxicity, suggesting the clinical potential of AgNPs in improving the outcome of malignant glioma radiotherapy. Electronic supplementary information (ESI) available. See DOI: 10.1039/c3nr01351k

Taxane-Grafted Metal-Oxide Nanoparticles as a New Theranostic Tool against Cancer: The Promising Example of Docetaxel-Functionalized Titanate Nanotubes on Prostate Tumors.

PubMed

Loiseau, Alexis; Boudon, Julien; Mirjolet, Céline; Créhange, Gilles; Millot, Nadine

2017-08-01

The combination of anticancer drugs and metal oxide nanoparticles is of great interest in cancer nanomedicine. Here, the development of a new nanohybrid, titanate nanotube-docetaxel (TiONts-DTX) is reported, the two parts of which are conjugated by covalent linkages. Unlike most nanoparticles currently being developed for biomedical purposes, TiONts present a needle-shaped morphology. The surface of TiONts is linked with 3-aminopropyl triethoxysilane and with a hetero-bifunctional polymer (polyethylene glycol) to create well-dispersed and biocompatible nanovectors. The prefunctionalized surface of this scaffold has valuable attachments to graft therapeutic agents (DTX in our case) as well as chelating agents (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to monitor the nanohybrids. To evaluate drug efficacy, in vitro tests have demonstrated that the association between TiONts and DTX shows cytotoxic activity against a hormone-refractory prostate cancer cell line (22Rv1) whereas TiONts without DTX do not. Finally, the first in vivo tests with intratumoral injections show that more than 70% of TiONts nanovectors are retained within the tumor for at least 7 d. Moreover, tumor growth in mice receiving TiONts-DTX is significantly slower than that in mice receiving free DTX. This nanohybrid can thus become a promising new tool in biomedicine to fight against prostate cancer. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Peptide micelle-mediated delivery of tissue-specific suicide gene and combined therapy with avastin in a glioblastoma model.

PubMed

Oh, Binna; Han, Jaesik; Choi, Eunji; Tan, Xiaonan; Lee, Minhyung

2015-04-01

Bevacizumab (Avastin) is an angiogenesis inhibitor used as a treatment for various cancers. In this study, the combination therapy of Avastin and glioblastoma-specific thymidine kinase gene [pEpo-NI2-SV-herpes simplex virus thymidine kinase(HSVtk)] was evaluated in a glioblastoma animal model. The R7L10 peptide was used as a gene carrier of pEpo-NI2-SV-HSVtk. Gel retardation assays confirmed that R7L10 formed stable complexes with pEpo-NI2-SV-HSVtk. R7L10 protected DNA from nuclease digestion. R7L10 had lower transfection efficiency than polyethylenimine (PEI; 25 kDa). However, the in vitro and in vivo toxicity assays showed that R7L10 had lower cytotoxicity than PEI, suggesting that R7L10 is safer than PEI. For the combination therapy, Avastin was injected intravenously and the pEpo-NI2-SV-HSVtk/R7L10 complexes were injected intratumorally in the glioblastoma animal model. Tumor growth was most effectively inhibited by the combination therapy of Avastin and the gene. The immunostaining results confirmed that the HSVtk genes were expressed in the groups with the pEpo-NI2-SV-HSVtk/R7L10 complex. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed a higher level of apoptotic cells in the combination group than the pEpo-NI2-SV-HSVtk/R7L10 complex or Avastin group. In conclusion, the combination of Avastin and the glioblastoma-specific HSVtk gene has a higher antitumor effect than single therapy of Avastin or HSVtk after intratumoral administration in glioblastoma animal model. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Intracerebral CpG Immunotherapy with Carbon Nanotubes Abrogates Growth of Subcutaneous Melanomas in Mice

PubMed Central

Fan, Haitao; Zhang, Ian; Chen, Xuebo; Zhang, Leying; Wang, Huaqing; Fonseca, Anna Da; Manuel, Edwin R.; Diamond, Don J.; Raubitschek, Andrew; Badie, Behnam

2012-01-01

Purpose Recently, we showed that intratumoral delivery of low-dose, immunostimulatory CpG oligodeoxynucleotides conjugated with carbon nanotubes (CNT-CpG) was more effective than free CpG and not only eradicated intracranial (i.c.) gliomas, but also induced antitumor immunity that protected mice from subsequent i.c. or systemic tumor rechallenge. Here, we examined if the same “intracerebral immunotherapy” strategy could be applied to the treatment of metastatic brain tumors. Experimental Design Mice with both i.c. and subcutaneous (s.c.) melanomas were injected intratumorally with CNT-CpG into either location. Antitumor responses were assessed by flow cytometry, bioluminescent imaging, and animal survival. Results When given s.c., CNT-CpG response was mostly local, and it only modestly inhibited the growth of i.c. melanomas. However, i.c. CNT-CpG abrogated the growth of not only brain, but also s.c. tumors. Furthermore, compared to s.c. injections, i.c. CNT-CpG elicited a stronger inflammatory response that resulted in more potent antitumor cytotoxicity and improved in vivo trafficking of effector cells into both i.c. and s.c. tumors. To investigate factors that accounted for these observations, CNT-CpG biodistribution and cellular inflammatory responses were examined in both tumor locations. Intracranial melanomas retained the CNT-CpG particles longer and were infiltrated by TLR-9-positive microglia. In contrast, myeloid-derived suppressive cells were more abundant in s.c. tumors. Although depletion of these cells prior to s.c. CNT-CpG therapy enhanced its cytotoxic responses, antitumor responses to brain melanomas were unchanged. Conclusions These findings suggest that intracerebral CNT-CpG immunotherapy is more effective than systemic therapy in generating antitumor responses that target both brain and systemic melanomas. PMID:22904105

Intracerebral CpG immunotherapy with carbon nanotubes abrogates growth of subcutaneous melanomas in mice.

PubMed

Fan, Haitao; Zhang, Ian; Chen, Xuebo; Zhang, Leying; Wang, Huaqing; Da Fonseca, Anna; Manuel, Edwin R; Diamond, Don J; Raubitschek, Andrew; Badie, Behnam

2012-10-15

Recently, we showed that intratumoral delivery of low-dose, immunostimulatory CpG oligodeoxynucleotides conjugated with carbon nanotubes (CNT-CpG) was more effective than free CpG and not only eradicated intracranial (i.c.) gliomas but also induced antitumor immunity that protected mice from subsequent i.c. or systemic tumor rechallenge. Here, we examined whether the same "intracerebral immunotherapy" strategy could be applied to the treatment of metastatic brain tumors. Mice with both i.c. and s.c. melanomas were injected intratumorally with CNT-CpG into either location. Antitumor responses were assessed by flow cytometry, bioluminescent imaging, and animal survival. When given s.c., CNT-CpG response was mostly local, and it only modestly inhibited the growth of i.c. melanomas. However, i.c. CNT-CpG abrogated the growth of not only brain but also s.c. tumors. Furthermore, compared with s.c. injections, i.c. CNT-CpG elicited a stronger inflammatory response that resulted in more potent antitumor cytotoxicity and improved in vivo trafficking of effector cells into both i.c. and s.c. tumors. To investigate factors that accounted for these observations, CNT-CpG biodistribution and cellular inflammatory responses were examined in both tumor locations. Intracranial melanomas retained the CNT-CpG particles longer and were infiltrated by Toll-like receptor (TLR-9)-positive microglia. In contrast, myeloid-derived suppressive cells were more abundant in s.c. tumors. Although depletion of these cells before s.c. CNT-CpG therapy enhanced its cytotoxic responses, antitumor responses to brain melanomas were unchanged. These findings suggest that intracerebral CNT-CpG immunotherapy is more effective than systemic therapy in generating antitumor responses that target both brain and systemic melanomas. ©2012 AACR

Successful adenovirus-mediated wild-type p53 gene transfer in patients with bladder cancer by intravesical vector instillation.

PubMed

Kuball, Jürgen; Wen, Shu Fen; Leissner, Joachim; Atkins, Derek; Meinhardt, Patricia; Quijano, Erlinda; Engler, Heidrun; Hutchins, Beth; Maneval, Daniel C; Grace, Michael J; Fritz, Mary Ann; Störkel, Stefan; Thüroff, Joachim W; Huber, Christoph; Schuler, Martin

2002-02-15

To study safety, feasibility, and biologic activity of adenovirus-mediated p53 gene transfer in patients with bladder cancer. Twelve patients with histologically confirmed bladder cancer scheduled for cystectomy were treated on day 1 with a single intratumoral injection of SCH 58500 (rAd/p53) at cystoscopy at one dose level (7.5 x 10(11) particles) or a single intravesical instillation of SCH 58500 with a transduction-enhancing agent (Big CHAP) at three dose levels (7.5 x 10(11) to 7.5 x 10(13) particles). Cystectomies were performed in 11 patients on day 3, and transgene expression, vector distribution, and biologic markers of transgene activity were assessed by molecular and immunohistochemical methods in tumors and normal bladder samples. Specific transgene expression was detected in tissues from seven of eight assessable patients treated with intravesical instillation of SCH 58500 but in none of three assessable patients treated with intratumoral injection of SCH 58500. Induction of RNA and protein expression of the p53 target gene p21/WAF1 was demonstrated in samples from patients treated with SCH 58500 instillation at higher dose levels. Distribution studies after intravesical instillation of SCH 58500 revealed both high transduction efficacy and vector penetration throughout the whole urothelium and into submucosal tumor cells. No dose-limiting toxicity was observed, and side effects were local and of transient nature. Intravesical instillation of SCH 58500 combined with a transduction-enhancing agent is safe, feasible, and biologically active in patients with bladder cancer. Studies to evaluate the clinical efficacy of this treatment in patients with localized high-risk bladder cancer are warranted.

Benefit of a combined treatment of cryotherapy and chemotherapy on tumour growth and late cryo-induced angiogenesis in a non-small-cell lung cancer model.

PubMed

Forest, Valérie; Peoc'h, Michel; Campos, Lydia; Guyotat, Denis; Vergnon, Jean-Michel

2006-10-01

In the treatment of lung cancers, a local cryotherapy can be proposed as a palliative option for bronchial clearance. But this therapy can also be used as an adjuvant treatment, for instance in association with chemotherapy. We have already demonstrated differential biological effects of these therapies and the benefit to combine them. The aim of this study was to determine if this benefit observed at a molecular level was correlated with tumour growth. As vascular changes occur after cryotherapy, intratumoral angiogenesis was also studied. Cells from the A549 cell line were inoculated into SCID mice. Tumours were treated by cryotherapy (nitrous oxide cryoprobe), chemotherapy (injection of Vinorelbine) or both. Tumour growth was studied in each group and the T/C ratios were compared. Tumours treated by cryochemotherapy presented a significantly reduced volume and the lower T/C ratio, confirming the benefit of a combined treatment. Angiogenesis was assessed at variable time points after cryotherapy by immunohistochemical staining of VEGF and western blot analysis. A late cryo-induced angiogenesis was observed 8-15 days after treatment (expression of VEGF increased from 13% in untreated tumours to 77 and 70%, respectively). To determine if this hypervascularization could enhance the efficiency of chemotherapy, the drug was injected 15 days after cryotherapy and the induction of cell death was investigated (morphological study, immunohistochemical staining of cleaved caspase-3, TUNEL). Necrosis was increased but not apoptosis, suggesting that though a crucial parameter, intratumoral microvessel density is not the only factor to consider to reach an optimal efficiency of a combined treatment.

From the Cover: A polymer library approach to suicide gene therapy for cancer

NASA Astrophysics Data System (ADS)

Anderson, Daniel G.; Peng, Weidan; Akinc, Akin; Hossain, Naushad; Kohn, Anat; Padera, Robert; Langer, Robert; Sawicki, Janet A.

2004-11-01

Optimal gene therapy for cancer must (i) deliver DNA to tumor cells with high efficiency, (ii) induce minimal toxicity, and (iii) avoid gene expression in healthy tissues. To this end, we generated a library of >500 degradable, poly(-amino esters) for potential use as nonviral DNA vectors. Using high-throughput methods, we screened this library in vitro for transfection efficiency and cytotoxicity. We tested the best performing polymer, C32, in mice for toxicity and DNA delivery after intratumor and i.m. injection. C32 delivered DNA intratumorally 4-fold better than one of the best commercially available reagents, jetPEI (polyethyleneimine), and 26-fold better than naked DNA. Conversely, the highest transfection levels after i.m. administration were achieved with naked DNA, followed by polyethyleneimine; transfection was rarely observed with C32. Additionally, polyethyleneimine induced significant local toxicity after i.m. injection, whereas C32 demonstrated no toxicity. Finally, we used C32 to deliver a DNA construct encoding the A chain of diphtheria toxin (DT-A) to xenografts derived from LNCaP human prostate cancer cells. This construct regulates toxin expression both at the transcriptional level by the use of a chimeric-modified enhancer/promoter sequence of the human prostate-specific antigen gene and by DNA recombination mediated by Flp recombinase. C32 delivery of the A chain of diphtheria toxin DNA to LNCaP xenografts suppressed tumor growth and even caused 40% of tumors to regress in size. Because C32 transfects tumors locally at high levels, transfects healthy muscle poorly, and displays no toxicity, it may provide a vehicle for the local treatment of cancer. prostate | cationic polymers

Arterial spin-labeling assessment of normalized vascular intratumoral signal intensity as a predictor of histologic grade of astrocytic neoplasms.

PubMed

Furtner, J; Schöpf, V; Schewzow, K; Kasprian, G; Weber, M; Woitek, R; Asenbaum, U; Preusser, M; Marosi, C; Hainfellner, J A; Widhalm, G; Wolfsberger, S; Prayer, D

2014-03-01

Pulsed arterial spin-labeling is a noninvasive MR imaging perfusion method performed with the use of water in the arterial blood as an endogenous contrast agent. The purpose of this study was to determine the inversion time with the largest difference in normalized intratumoral signal intensity between high-grade and low-grade astrocytomas. Thirty-three patients with gliomas, histologically classified as low-grade (n = 7) or high-grade astrocytomas (n = 26) according to the World Health Organization brain tumor classification, were included. A 3T MR scanner was used to perform pulsed arterial spin-labeling measurements at 8 different inversion times (370 ms, 614 ms, 864 ms, 1114 ms, 1364 ms, 1614 ms, 1864 ms, and 2114 ms). Normalized intratumoral signal intensity was calculated, which was defined by the signal intensity ratio of the tumor and the contralateral normal brain tissue for all fixed inversion times. A 3-way mixed ANOVA was used to reveal potential differences in the normalized vascular intratumoral signal intensity between high-grade and low-grade astrocytomas. The difference in normalized vascular intratumoral signal intensity between high-grade and low-grade astrocytomas obtained the most statistically significant results at 370 ms (P = .003, other P values ranged from .012-.955). The inversion time by which to differentiate high-grade and low-grade astrocytomas by use of normalized vascular intratumoral signal intensity was 370 ms in our study. The normalized vascular intratumoral signal intensity values at this inversion time mainly reflect the labeled intra-arterial blood bolus and therefore could be referred to as normalized vascular intratumoral signal intensity. Our data indicate that the use of normalized vascular intratumoral signal intensity values allows differentiation between low-grade and high-grade astrocytomas and thus may serve as a new, noninvasive marker for astrocytoma grading.

Evaluation of hypoxia in a feline model of head and neck cancer using 64Cu-ATSM positron emission tomography/computed tomography

PubMed Central

2013-01-01

Background Human and feline head and neck squamous cell carcinoma (HNSCC) share histology, certain molecular features, as well as locally aggressive and highly recurrent clinical behavior. In human HNSCC, the presence of significant hypoxia within these tumors is considered an important factor in the development of a more aggressive phenotype and poor response to therapy. We hypothesized that feline head and neck tumors, particularly HNSCC, would exhibit hypoxia and that 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) positron emission tomography/computed tomography (PET/CT) would permit detection of intratumoral hypoxia. Methods 12 cats with measureable head and neck tumors were given 64Cu-ATSM and iodinated contrast for PET/CT scan. The presence or absence of hypoxia was also assessed using an intratumoral fluorescent life-time probe to quantitate pO2 and pimonidazole immunohistochemical staining in biopsy specimens. In two cats, intratumoral O2 and 64Cu-ATSM uptake was measured before and after treatment with anti-angiogenic agents to determine the effect of these agents on hypoxia. Results Eleven of twelve feline tumors demonstrated significant 64Cu-ATSM uptake, regardless of malignant or benign etiology. The presence (and absence) of hypoxia was confirmed using the fluorescent O2 detection probe in nine tumors, and using pimonidazole staining in three tumors. Squamous cell carcinomas (HNSCC) demonstrated the highest degree of hypoxia, with Tmax/M ratios ranging from 4.3 to 21.8. Additional non-neoplastic tissues exhibited 64Cu-ATSM uptake suggestive of hypoxia including reactive draining lymph nodes, non-malignant thyroid pathology, a tooth root abscess, and otitis media. In two cats with HNSCC that received anti-vascular agents, the pattern of 64Cu-ATSM uptake was altered after treatment, demonstrating the potential of the feline model to study the modulation of tumor oxygenation. Conclusion Feline HNSCC serves as a clinically relevant model for the investigation of intratumoral hypoxia including its measurement, modulation and targeting. PMID:23631652

Collagen analysis by second-harmonic generation microscopy predicts outcome of luminal breast cancer.

PubMed

Natal, Rodrigo A; Vassallo, José; Paiva, Geisilene R; Pelegati, Vitor B; Barbosa, Guilherme O; Mendonça, Guilherme R; Bondarik, Caroline; Derchain, Sophie F; Carvalho, Hernandes F; Lima, Carmen S; Cesar, Carlos L; Sarian, Luís Otávio

2018-04-01

Second-harmonic generation microscopy represents an important tool to evaluate extracellular matrix collagen structure, which undergoes changes during cancer progression. Thus, it is potentially relevant to assess breast cancer development. We propose the use of second-harmonic generation images of tumor stroma selected on hematoxylin and eosin-stained slides to evaluate the prognostic value of collagen fibers analyses in peri and intratumoral areas in patients diagnosed with invasive ductal breast carcinoma. Quantitative analyses of collagen parameters were performed using ImageJ software. These parameters presented significantly higher values in peri than in intratumoral areas. Higher intratumoral collagen uniformity was associated with high pathological stages and with the presence of axillary lymph node metastasis. In patients with immunohistochemistry-based luminal subtype, higher intratumoral collagen uniformity and quantity were independently associated with poorer relapse-free and overall survival, respectively. A multivariate response recursive partitioning model determined 12.857 and 11.894 as the best cut-offs for intratumoral collagen quantity and uniformity, respectively. These values have shown high sensitivity and specificity to differentiate distinct outcomes. Values of intratumoral collagen quantity and uniformity exceeding the cut-offs were strongly associated with poorer relapse-free and overall survival. Our findings support a promising prognostic value of quantitative evaluation of intratumoral collagen by second-harmonic generation imaging mainly in the luminal subtype breast cancer.

Expression of LAG-3 defines exhaustion of intratumoral PD-1+ T cells and correlates with poor outcome in follicular lymphoma

PubMed Central

Yang, Zhi-Zhang; Kim, Hyo Jin; Villasboas, Jose C.; Chen, Ya-Ping; Price-Troska, Tammy; Jalali, Shahrzad; Wilson, Mara; Novak, Anne J.; Ansell, Stephen M.

2017-01-01

Exhausted T-cells in follicular lymphoma (FL) typically express PD-1, but expression of PD-1 is not limited to exhausted cells. Although expected to be functionally suppressed, we found that the population of intratumoral PD-1+ T cells were predominantly responsible for production of cytokines and granules. This surprising finding prompted us to explore the involvement of LAG-3 to specifically identify functionally exhausted T cells. We found that LAG-3 was expressed on a subset of intratumoral T cells from FL and LAG-3+ T cells almost exclusively came from PD-1+ population. CyTOF analysis revealed that intratumoral LAG-3+ T cells were phenotypically heterogeneous as LAG-3 was expressed on a variety of T cell subsets. In contrast to PD-1+LAG-3- cells, intratumoral PD-1+LAG-3+ T cells exhibited reduced capacity to produce cytokines and granules. LAG-3 expression could be substantially upregulated on CD4+ or CD8+ T cells by IL-12, a cytokine that has been shown to induce T-cell exhaustion and be increased in the serum of lymphoma patients. Furthermore, we found that blockade of both PD-1 and LAG-3 signaling enhanced the function of intratumoral CD8+ T cells resulting in increased IFN-γ and IL-2 production. Clinically, LAG-3 expression on intratumoral T cells correlated with a poor outcome in FL patients. Taken together, we find that LAG-3 expression is necessary to identify the population of intratumoral PD-1+ T cells that are functionally exhausted and, in contrast, find that PD-1+LAG-3- T cells are simply activated cells that are immunologically functional. These findings may have important implications for immune checkpoint therapy in FL. PMID:28977875

Phenotypic Intratumoral Heterogeneity of Endometrial Carcinomas.

PubMed

Silva, Cátia; Pires-Luís, Ana S; Rocha, Eduardo; Bartosch, Carla; Lopes, José M

2018-03-01

Intratumoral heterogeneity has been shown to play an important role in diagnostic accuracy, development of treatment resistance, and prognosis of cancer patients. Recent studies have proposed quantitative measurement of phenotypic intratumoral heterogeneity, but no study is yet available in endometrial carcinomas. In our study we evaluated the phenotypic intratumoral heterogeneity of a consecutive series of 10 endometrial carcinomas using measures of dispersion and diversity. Morphometric architectural (%tumor cells, %solid tumor, %differentiated tumor, and %lumens) and nuclear [volume-weighted mean nuclear volume ((Equation is included in full-text article.))] parameters, as well as estrogen receptor, progesterone receptor, p53, vimentin, and beta-catenin immunoexpression (H-score) were digitally analyzed in 20 microscopic fields per carcinoma. Quantitative measures of intratumoral heterogeneity included coefficient of variation (CV) and relative quadratic entropy (rQE). In each endometrial carcinoma there was slight variation of architecture from field to field, resulting in globally low levels of heterogeneity measures (mean CV %tumor cells: 0.10, %solid tumor: 0.73, %differentiated tumor: 0.19, %lumens: 0.61 and mean rQE %tumor cells: 18.5, %solid tumor: 20.3, %differentiated tumor: 25.6, %lumens: 21.8). Nuclear intratumoral heterogeneity was also globally low (mean (Equation is included in full-text article.)CV: 0.23 and rQE: 27.3), but significantly higher than the heterogeneity of architectural parameters within most carcinomas. In general, there was low to moderate variability of immunoexpression markers within each carcinoma, but estrogen receptor (mean CV: 0.56 and rQE: 46.2) and progesterone receptor (mean CV: 0.60 and rQE: 39.3) displayed the highest values of heterogeneity measures. Intratumoral heterogeneity of immunoexpression was significantly higher than that observed for morphometric parameters. In conclusion, our study indicates that endometrial carcinomas present a variable but predominantly low degree of phenotypic intratumoral heterogeneity.

Expression of a model gene in prostate cancer cells lentivirally transduced in vitro and in vivo.

PubMed

Bastide, C; Maroc, N; Bladou, F; Hassoun, J; Maitland, N; Mannoni, P; Bagnis, C

2003-01-01

In a preclinical model for prostate cancer gene therapy, we have tested lentiviral vectors as a practical possibility for the transfer and long-term expression of the EGFP gene both in vitro and in vivo. The human prostate cancer cell lines DU145 and PC3 were transduced using experimental conditions which permitted analysis of the expression from a single proviral vector per cell. The transduced cells stably expressed the EGFP transgene for 4 months. After injection of the transduced cell populations into Nod-SCID mice a decrease in EGFP was only observed in a minority of cases, while the majority of tumors maintained transgene expression at in vitro levels. In vivo injection of viral vector preparations directly into pre-established subcutaneous or orthotopic tumor masses, obtained by implantation of untransduced PC3 and DU145 cells led to a high transduction efficiency. While the efficiency of direct intratumoral transduction was proportional to the dose of virus injected, the results indicated some technical limitations inherent in these approaches to prostate cancer gene therapy.

Endobronchial ultrasound-guided transbronchial needle injection for local control of recurrent non-small cell lung cancer.

PubMed

Khan, Farrah; Anker, Christopher J; Garrison, Garth; Kinsey, C Matthew

2015-01-01

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an established technique for the diagnosis of thoracic malignancies. Non-ultrasound-guided transbronchial needle injection has been used previously to deliver chemotherapeutic agents. To use endobronchial ultrasound-guided transbronchial needle injection (EBUS-TBNI) to achieve local control of recurrent early-stage lung cancer. A 63-year-old man presented with recurrent early stage non-small cell lung carcinoma after chemotherapy and external beam radiation. We used EBUS-TBNI to deliver cisplatin into the tumor located outside the airway. This procedure was performed on three separate occasions without complication. EBUS-TBNI resulted in resolution of fluorodeoxyglucose avidity, measured by positron emission tomography-computed tomography, in the region at 4 weeks. However, at 5 months, there was evidence of distal recurrence. This is the first description of EBUS-TBNI to treat local recurrence of lung cancer and one of the first reports of the use of EBUS for intratumoral therapy. Additional research is warranted to determine the clinical usefulness and safety of this therapeutic approach.

The intratumoral distribution of radiolabeled 177Lu-BR96 monoclonal antibodies changes in relation to tumor histology over time in a syngeneic rat colon carcinoma model.

PubMed

Örbom, Anders; Eriksson, Sophie E; Elgström, Erika; Ohlsson, Tomas; Nilsson, Rune; Tennvall, Jan; Strand, Sven-Erik

2013-08-01

The therapeutic effect of radioimmunotherapy depends on the distribution of the absorbed dose in relation to viable cancer cells within the tumor, which in turn is a function of the activity distribution. The aim of this study was to investigate the distribution of (177)Lu-DOTA-BR96 monoclonal antibodies targeting the Lewis Y antigen over 7 d using a syngeneic rat model of colon carcinoma. Thirty-eight tumor-bearing rats were intravenously given 25 or 50 MBq of (177)Lu-DOTA-BR96 per kilogram of body weight and were sacrificed 2, 8, 24, 48, 72, 96, 120, or 168 h after injection, with activity measured in blood and tumor samples. Adjacent cryosections of each tumor were analyzed in 3 ways: imaging using a silicon-strip detector for digital autoradiography, staining for histologic characterization, or staining to determine the distribution of the antigen, vasculature, and proliferating cells using immunohistochemistry. Absorbed-dose rate distribution images at the moment of sacrifice were calculated using the activity distribution and a point-dose kernel. The correlations between antigen expression and both activity uptake and absorbed-dose rate were calculated for several regions of interest in each tumor. Nine additional animals with tumors were given unlabeled antibody to evaluate possible immunologic effects. At 2-8 h after injection, activity was found in the tumor margins; at 24 h, in viable antigen-expressing areas within the tumor; and at 48 h and later, increasingly in antigen-negative areas of granulation tissue. The correlation between antigen expression and both the mean activity and the absorbed-dose rate in regions of interest changed from positive to negative after 24 h after injection. Antigen-negative areas also increased over time in animals injected with unlabeled BR96, compared with untreated tumors. The results indicate that viable Lewis Y-expressing tumor cells are most efficiently treated during the initial uptake period. The activity then seems to remain in these initial uptake regions after the elimination of tumor cells and formation of granulation tissue. Further studies using these techniques could aid in determining the effects of the intratumoral activity distribution on overall therapeutic efficacy.

Strategies for improving the intratumoral distribution of liposomal drugs in cancer therapy

PubMed Central

Goins, Beth; Phillips, William T.; Bao, Ande

2016-01-01

Introduction A major limitation of current liposomal cancer therapies is the inability of liposome therapeutics to penetrate throughout the entire tumor mass. This inhomogeneous distribution of liposome therapeutics within the tumor has been linked to treatment failure and drug resistance. Both liposome particle transport properties and tumor microenvironment characteristics contribute to this challenge in cancer therapy. This limitation is relevant to both intravenously and intratumorally administered liposome therapeutics. Areas covered Strategies to improve the intratumoral distribution of liposome therapeutics are described. Combination therapies of intravenous liposome therapeutics with pharmacologic agents modulating abnormal tumor vasculature, interstitial fluid pressure, extracellular matrix components, and tumor associated macrophages are discussed. Combination therapies using external stimuli (hyperthermia, radiofrequency ablation, magnetic field, radiation, and ultrasound) with intravenous liposome therapeutics are discussed. Intratumoral convection-enhanced delivery (CED) of liposomal therapeutics is reviewed. Expert opinion Optimization of the combination therapies and drug delivery protocols are necessary. Further research should be conducted in appropriate cancer types with consideration of physiochemical features of liposomes and their timing sequence. More investigation of the role of tumor associated macrophages in intratumoral distribution is warranted. Intratumoral infusion of liposomes using CED is a promising approach to improve their distribution within the tumor mass. PMID:26981891

Mathematical modeling analysis of intratumoral disposition of anticancer agents and drug delivery systems.

PubMed

Popilski, Hen; Stepensky, David

2015-05-01

Solid tumors are characterized by complex morphology. Numerous factors relating to the composition of the cells and tumor stroma, vascularization and drainage of fluids affect the local microenvironment within a specific location inside the tumor. As a result, the intratumoral drug/drug delivery system (DDS) disposition following systemic or local administration is non-homogeneous and its complexity reflects the differences in the local microenvironment. Mathematical models can be used to analyze the intratumoral drug/DDS disposition and pharmacological effects and to assist in choice of optimal anticancer treatment strategies. The mathematical models that have been applied by different research groups to describe the intratumoral disposition of anticancer drugs/DDSs are summarized in this article. The properties of these models and of their suitability for prediction of the drug/DDS intratumoral disposition and pharmacological effects are reviewed. Currently available mathematical models appear to neglect some of the major factors that govern the drug/DDS intratumoral disposition, and apparently possess limited prediction capabilities. More sophisticated and detailed mathematical models and their extensive validation are needed for reliable prediction of different treatment scenarios and for optimization of drug treatment in the individual cancer patients.

Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma.

PubMed

Parker, Nicole R; Hudson, Amanda L; Khong, Peter; Parkinson, Jonathon F; Dwight, Trisha; Ikin, Rowan J; Zhu, Ying; Cheng, Zhangkai Jason; Vafaee, Fatemeh; Chen, Jason; Wheeler, Helen R; Howell, Viive M

2016-03-04

Heterogeneity is a hallmark of glioblastoma with intratumoral heterogeneity contributing to variability in responses and resistance to standard treatments. Promoter methylation status of the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) is the most important clinical biomarker in glioblastoma, predicting for therapeutic response. However, it does not always correlate with response. This may be due to intratumoral heterogeneity, with a single biopsy unlikely to represent the entire lesion. Aberrations in other DNA repair mechanisms may also contribute. This study investigated intratumoral heterogeneity in multiple glioblastoma tumors with a particular focus on the DNA repair pathways. Transcriptional intratumoral heterogeneity was identified in 40% of cases with variability in MGMT methylation status found in 14% of cases. As well as identifying intratumoral heterogeneity at the transcriptional and epigenetic levels, targeted next generation sequencing identified between 1 and 37 unique sequence variants per specimen. In-silico tools were then able to identify deleterious variants in both the base excision repair and the mismatch repair pathways that may contribute to therapeutic response. As these pathways have roles in temozolomide response, these findings may confound patient management and highlight the importance of assessing multiple tumor biopsies.

Microbubble-assisted p53, RB, and p130 gene transfer in combination with radiation therapy in prostate cancer.

PubMed

Nande, Rounak; Greco, Adelaide; Gossman, Michael S; Lopez, Jeffrey P; Claudio, Luigi; Salvatore, Marco; Brunetti, Arturo; Denvir, James; Howard, Candace M; Claudio, Pier Paolo

2013-06-01

Combining radiation therapy and direct intratumoral (IT) injection of adenoviral vectors has been explored as a means to enhance the therapeutic potential of gene transfer. A major challenge for gene transfer is systemic delivery of nucleic acids directly into an affected tissue. Ultrasound (US) contrast agents (microbubbles) are viable candidates to enhance targeted delivery of systemically administered genes. Here we show that p53, pRB, and p130 gene transfer mediated by US cavitation of microbubbles at the tumor site resulted in targeted gene transduction and increased reduction in tumor growth compared to DU-145 prostate cancer cell xenografts treated intratumorally with adenovirus (Ad) or radiation alone. Microbubble-assisted/US-mediated Ad.p53 and Ad.RB treated tumors showed significant reduction in tumor volume compared to Ad.p130 treated tumors (p<0.05). Additionally, US mediated microbubble delivery of p53 and RB combined with external beam radiation resulted in the most profound tumor reduction in DU-145 xenografted nude mice (p<0.05) compared to radiation alone. These findings highlight the potential therapeutic applications of this novel image-guided gene transfer technology in combination with external beam radiation for prostate cancer patients with therapy resistant disease.

Biodistribution and Safety Assessment of Bladder Cancer Specific Recombinant Oncolytic Adenovirus in Subcutaneous Xenografts Tumor Model in Nude Mice

PubMed Central

Wang, Fang; Wang, Zhiping; Tian, Hongwei; Qi, Meijiao; Zhai, Zhenxing; Li, Shuwen; Li, Renju; Zhang, Hongjuan; Wang, Wenyun; Fu, Shenjun; Lu, Jianzhong; Rodriguez, Ronald; Guo, Yinglu; Zhou, Liqun

2012-01-01

Background The previous works about safety evaluation for constructed bladder tissue specific adenovirus are poorly documented. Thus, we investigated the biodistribution and body toxicity of bladder specific oncolytic adenovirus Ad-PSCAE-UPII-E1A (APU-E1A) and Ad-PSCAE-UPII-E1A-AR (APU-E1A-AR), providing meaningful information prior to embarking on human clinical trials. Materials and Method Conditionally replicate recombinant adenovirus (CRADs) APU-E1A, APU-EIA-AR were constructed with bladder tissue specific Uroplakin II (UP II) promoter to induce the expression of Ad5E1A gene and E1A-AR fusing gene, and PSCAE was inserted at upstream of promoter to enhance the function of promoter. Based on the cytopathic and anti-tumor effect of bladder cancer, these CRADs were intratumorally injected into subcutaneous xenografts tumor in nude mice. We then determined the toxicity through general health and behavioral assessment, hepatic and hematological toxicity evaluation, macroscopic and microscopic postmortem analyses. The spread of the transgene E1A of adenovirus was detected with RT-PCR and Western blot. Virus replication and distribution were examined with APU-LUC administration and Luciferase Assay. Results General assessment and body weight of the animals did not reveal any alteration in general behavior. The hematological alterations of groups which were injected with 5×108 pfu or higher dose (5×109 pfu) of APU-E1A and APU-E1A-AR showed no difference in comparison with PBS group, and only slight increased transaminases in contrast to PBS group at 5×109 pfu of APU-E1A and APU-E1A-AR were observed. E1A transgene did not disseminate to organs outside of xenograft tumor. Virus replication was not detected in other organs beside tumor according to Luciferase Assay. Conclusions Our study showed that recombinant adenovirus APU-E1A-AR and APU-E1A appear safe with 5×107 pfu and 5×108 pfu intratumorally injection in mice, without any discernable effects on general health and behavior. PMID:22384806

Biodistribution and safety assessment of bladder cancer specific recombinant oncolytic adenovirus in subcutaneous xenografts tumor model in nude mice.

PubMed

Wang, Fang; Wang, Zhiping; Tian, Hongwei; Qi, Meijiao; Zhai, Zhenxing; Li, Shuwen; Li, Renju; Zhang, Hongjuan; Wang, Wenyun; Fu, Shenjun; Lu, Jianzhong; Rodriguez, Ronald; Guo, Yinglu; Zhou, Liqun

2012-04-01

The previous works about safety evaluation for constructed bladder tissue specific adenovirus are poorly documented. Thus, we investigated the biodistribution and body toxicity of bladder specific oncolytic adenovirus Ad-PSCAE-UPII-E1A (APU-E1A) and Ad-PSCAE-UPII-E1A-AR (APU-E1A-AR), providing meaningful information prior to embarking on human clinical trials. Conditionally replicate recombinant adenovirus (CRADs) APU-E1A, APU-EIA-AR were constructed with bladder tissue specific UroplakinII(UPII) promoter to induce the expression of Ad5E1A gene and E1A-AR fusing gene, and PSCAE was inserted at upstream of promoter to enhance the function of promoter. Based on the cytopathic and anti-tumor effect of bladder cancer, these CRADs were intratumorally injected into subcutaneous xenografts tumor in nude mice. We then determined the toxicity through general health and behavioral assessment, hepatic and hematological toxicity evaluation, macroscopic and microscopic postmortem analyses. The spread of the transgene E1A of adenovirus was detected with RT-PCR and Western blot. Virus replication and distribution were examined with APU-LUC administration and Luciferase Assay. General assessment and body weight of the animals did not reveal any alteration in general behavior. The hematological alterations of groups which were injected with 5x10(8) pfu or higher dose (5x10(9) pfu) of APU-E1A and APU-E1A-AR showed no difference in comparison with PBS group, and only slight increased transaminases in contrast to PBS group at 5x10(9) pfu of APU-E1A and APU-E1A-AR were observed. E1A transgene did not disseminate to organs outside of xenograft tumor. Virus replication was not detected in other organs beside tumor according to Luciferase Assay. Our study showed that recombinant adenovirus APU-E1A-AR and APU-E1A appear safe with 5x10(7) pfu and 5x10(8) pfu intratumorally injection in mice, without any discernable effects on general health and behavior.

Experimental and theoretical investigation of intratumoral nanoparticle distribution to enhance magnetic nanoparticle hyperthermia

NASA Astrophysics Data System (ADS)

Attaluri, Anilchandra

Magnetic nanoparticles have gained prominence in recent years for use in clinical applications such as imaging, drug delivery, and hyperthermia. Magnetic nanoparticle hyperthermia is a minimally invasive and effective approach for confined heating in tumors with little collateral damage. One of the major problems in the field of magnetic nanoparticle hyperthermia is irregular heat distribution in tumors which caused repeatable heat distribution quite impossible. This causes under dosage in tumor area and overheating in normal tissue. In this study, we develop a unified approach to understand magnetic nanoparticle distribution and temperature elevations in gel and tumors. A microCT imaging system is first used to visualize and quantify nanoparticle distribution in both tumors and tissue equivalent phantom gels. The microCT based nanoparticle concentration is related to specific absorption rate (SAR) of the nanoparticles and is confirmed by heat distribution experiments in tissue equivalent phantom gels. An optimal infusion protocol is identified to generate controllable and repeatable nanoparticle distribution in tumors. In vivo animal experiments are performed to measure intratumoral temperature elevations in PC3 xenograft tumors implanted in mice during magnetic nanoparticle hyperthermia. The effect of nanofluid injection parameters on the resulted temperature distribution is studied. It shows that the tumor temperatures can be elevated above 50°C using very small amounts of ferrofluid with a relatively low magnetic field. Slower ferrofluid infusion rates result in smaller nanoparticle distribution volumes in the tumors, however, it gives the much required controllability and repeatability when compared to the higher infusion rates. More nanoparticles occupy a smaller volume in the vicinity of the injection site with slower infusion rates, causing higher temperature elevations in the tumors. Based on the microCT imaging analyses of nanoparticles in tumors, a mass transport model is developed to simulate nanoparticle convection and diffusion in tumors, heat-induced tumor structural changes, as well as nanoparticle re-distribution during nanoparticle hyperthermia procedures. The modeled thermal damage induced nanoparticle redistribution predicts a 20% increase in the radius of the spherical tissue region containing nanoparticles. The developed model has demonstrated the feasibility of enhancing nanoparticle dispersion from injection sites using targeted thermal damage.

Three-dimensional power doppler ultrasound is useful to monitor the response to treatment in a patient with primary papillary serous carcinoma of the peritoneum.

PubMed

Su, Jen-Min; Huang, Yu-Fang; Chen, Helen H W; Cheng, Ya-Min; Chou, Cheng-Yang

2006-05-01

To date, this is the first report to monitor changes of intratumor vascularization and the response to radiation and Cyberknife therapy in a patient with recurrent primary papillary serous carcinoma of the peritoneum by three dimensional (3D) power Doppler ultrasonography (PDUS). Transvaginal 3D PDUS detected a recurrent presacral tumor with abundant intratumor vascularity. Serial examinations of the tumor volume and serum CA-125 level were studied before, during, and 6 mo after therapy. Meanwhile, the intratumor blood flow was measured and expressed as vascularity indices. All of the tumor volume, intratumor vascularity indices and serum CA-125 level decreased progressively following therapy. A remaining lesion with nearly absent intratumor power Doppler signals suggested a scarring lesion posttreatment. Indeed, CT-guided tissue biopsy confirmed fibrotic change. 3D PDUS is useful to monitor the response to treatments and to differentiate residual tumors from lesions of scarring change posttreatment. It provides more accurate posttreatment information than pelvic computed tomography.

Comparison of circulating and intratumoral regulatory T cells in patients with renal cell carcinoma.

PubMed

Asma, Gati; Amal, Gorrab; Raja, Marrakchi; Amine, Derouiche; Mohammed, Chebil; Amel, Ben Ammar Elgaaied

2015-05-01

The clear evidence that tumor-infiltrating lymphocytes (TIL) exists in the tumor microenvironment raises the question why renal cell carcinoma (RCC) progresses. Numerous studies support the implication of CD4(+)CD25(high) regulatory T (Treg) cells in RCC development. We aimed in this study to characterize the phenotype and function of circulating and intratumoral Treg cells of RCC patient in order to evaluate their implication in the inhibition of the local antitumor immune response. Our results demonstrate that the proportion of Treg in TIL was, in average, similar to that found in circulating CD4(+) T cells of patients or healthy donors. However, intratumoral Treg exhibit a marked different phenotype when compared with the autologous circulating Treg. A higher CD25 mean level, HLA-DR, Fas, and GITR, and a lower CD45RA expression were observed in intratumoral Treg, suggesting therefore that these cells are effector in the tumor microenvironment. Additionally, intratumoral Treg showed a higher inhibitory function on autologous CD4(+)CD25(-) T cells when compared with circulating Treg that may be explained by an overexpression of FoxP3 transcription factor. These findings suggest that intratumoral Treg could be major actors in the impairment of local antitumor immune response for RCC patients.

Mass Spectrometry Imaging for the Investigation of Intratumor Heterogeneity.

PubMed

Balluff, B; Hanselmann, M; Heeren, R M A

2017-01-01

One of the big clinical challenges in the treatment of cancer is the different behavior of cancer patients under guideline therapy. An important determinant for this phenomenon has been identified as inter- and intratumor heterogeneity. While intertumor heterogeneity refers to the differences in cancer characteristics between patients, intratumor heterogeneity refers to the clonal and nongenetic molecular diversity within a patient. The deciphering of intratumor heterogeneity is recognized as key to the development of novel therapeutics or treatment regimens. The investigation of intratumor heterogeneity is challenging since it requires an untargeted molecular analysis technique that accounts for the spatial and temporal dynamics of the tumor. So far, next-generation sequencing has contributed most to the understanding of clonal evolution within a cancer patient. However, it falls short in accounting for the spatial dimension. Mass spectrometry imaging (MSI) is a powerful tool for the untargeted but spatially resolved molecular analysis of biological tissues such as solid tumors. As it provides multidimensional datasets by the parallel acquisition of hundreds of mass channels, multivariate data analysis methods can be applied for the automated annotation of tissues. Moreover, it integrates the histology of the sample, which enables studying the molecular information in a histopathological context. This chapter will illustrate how MSI in combination with statistical methods and histology has been used for the description and discovery of intratumor heterogeneity in different cancers. This will give evidence that MSI constitutes a unique tool for the investigation of intratumor heterogeneity, and could hence become a key technology in cancer research. © 2017 Elsevier Inc. All rights reserved.

A new PET scanner with semiconductor detectors enables better identification of intratumoral inhomogeneity.

PubMed

Shiga, Tohru; Morimoto, Yuichi; Kubo, Naoki; Katoh, Norio; Katoh, Chietsugu; Takeuchi, Wataru; Usui, Reiko; Hirata, Kenji; Kojima, Shinichi; Umegaki, Kikuo; Shirato, Hiroki; Tamaki, Nagara

2009-01-01

An autoradiography method revealed intratumoral inhomogeneity in various solid tumors. It is becoming increasingly important to estimate intratumoral inhomogeneity. However, with low spatial resolution and high scatter noise, it is difficult to detect intratumoral inhomogeneity in clinical settings. We developed a new PET system with CdTe semiconductor detectors to provide images with high spatial resolution and low scatter noise. Both phantom images and patients' images were analyzed to evaluate intratumoral inhomogeneity. This study was performed with a cold spot phantom that had 6-mm-diameter cold sphenoid defects, a dual-cylinder phantom with an adjusted concentration of 1:2, and an "H"-shaped hot phantom. These were surrounded with water. Phantom images and (18)F-FDG PET images of patients with nasopharyngeal cancer were compared with conventional bismuth germanate PET images. Profile curves for the phantoms were measured as peak-to-valley ratios to define contrast. Intratumoral inhomogeneity and tumor edge sharpness were evaluated on the images of the patients. The contrast obtained with the semiconductor PET scanner (1.53) was 28% higher than that obtained with the conventional scanner (1.20) for the 6-mm-diameter cold sphenoid phantom. The contrast obtained with the semiconductor PET scanner (1.43) was 27% higher than that obtained with the conventional scanner (1.13) for the dual-cylinder phantom. Similarly, the 2-mm cold region between 1-mm hot rods was identified only by the new PET scanner and not by the conventional scanner. The new PET scanner identified intratumoral inhomogeneity in more detail than the conventional scanner in 6 of 10 patients. The tumor edge was sharper on the images obtained with the new PET scanner than on those obtained with the conventional scanner. These phantom and clinical studies suggested that this new PET scanner has the potential for better identification of intratumoral inhomogeneity, probably because of its high spatial resolution and low scatter noise.

Ultrasound image-guided therapy enhances antitumor effect of cisplatin.

PubMed

Sasaki, Noboru; Kudo, Nobuki; Nakamura, Kensuke; Lim, Sue Yee; Murakami, Masahiro; Kumara, W R Bandula; Tamura, Yu; Ohta, Hiroshi; Yamasaki, Masahiro; Takiguchi, Mitsuyoshi

2014-01-01

The aim of this study was to clarify whether ultrasound image-guided cisplatin delivery with an intratumor microbubble injection enhances the antitumor effect in a xenograft mouse model. Canine thyroid adenocarcinoma cells were used for all experiments. Before in vivo experiments, the cisplatin and microbubble concentration and ultrasound exposure time were optimized in vitro. For in vivo experiments, cells were implanted into the back of nude mice. Observed by a diagnostic ultrasound machine, a mixture of cisplatin and ultrasound contrast agent, Sonazoid, microbubbles was injected directly into tumors. The amount of injected cisplatin and microbubbles was 1 μg/tumor and 1.2 × 10(7) microbubbles/tumor, respectively, with a total injected volume of 20 μl. Using the same diagnostic machine, tumors were exposed to ultrasound for 15 s. The treatment was repeated four times. The combination of cisplatin, microbubbles, and ultrasound significantly delayed tumor growth as compared with no treatment (after 18 days, 157 ± 55 vs. 398 ± 49 mm(3), P = 0.049). Neither cisplatin alone nor the combination of cisplatin and ultrasound delayed tumor growth. The treatment did not decrease the body weight of mice. Ultrasound image-guided anticancer drug delivery may enhance the antitumor effects of drugs without obvious side effects.

Convection enhanced delivery of boronated EGF as a molecular targeting agent for neutron capture therapy of brain tumors

PubMed Central

Yang, Weilian; Wu, Gong; Huo, Tianyao; Tjarks, Werner; Ciesielski, Michael; Fenstermaker, Robert A.; Ross, Brain D.; Wikstrand, Carol J.; Riley, Kent J.; Binns, Peter J.

2010-01-01

In the present study, we have evaluated a boronated dendrimer-epidermal growth factor (BD-EGF) bioconjugate as a molecular targeting agent for boron neutron capture therapy (BNCT) of the human EGFR gene-transfected F98 rat glioma, designated F98EGFR. EGF was chemically linked to a heavily boronated polyamidoamine dendrimer (BD) by means of the heterobifunctional reagent, mMBS. Biodistribution studies were carried out at 6 h and 24 h following intratumoral (i.t.) injection or intracerebral (i.c.) convection enhanced delivery (CED) of 125I-labeled or unlabeled BD-EGF (40 μg 10B/10 μg EGF) to F98 glioma bearing rats. At 24 h. there was 43% more radioactivity in EGFR(+) tumors following CED compared to i.t. injection, and a doubling of the tumor boron concentration (22.3 μg/g vs. 11.7 μg/g). CED of BD-EGF resulted in a 7.2× increase in the volume of distribution within the infused cerebral hemisphere and a 1.9× increase in tumor uptake of BD-EGF compared with i.t. injection. Based on these favorable bio-distribution data, BNCT was carried out at the Massachusetts Institute of Technology nuclear reactor 14 days following i.c. tumor implantation and 24 h. after CED of BD-EGF. These animals had a MST of 54.1 ± 4.7 days compared to 43.0 ± 2.8 days following i.t. injection. Rats that received BD-EGF by CED in combination with i.v. boronophenylalanine (BPA), which has been used in both experimental and clinical studies, had a MST of 86.0 ± 28.1 days compared to 39.8 ± 1.6 days for i.v. BPA alone (P < 0.01), 30.9 ± 1.4 days for irradiated controls and 25.1 ± 1.0 days for untreated controls (overall P < 0.0001). These data have demonstrated that the efficacy of BNCT was significantly increased (P < 0.006), following i.c CED of BD-EGF compared to i.t injection, and that the survival data were equivalent to those previously reported by us using the boronated anti-human-EGF mAb, C225 (cetuximab). PMID:19588228

Multimodality Imaging of Gene Transfer with a Receptor-Based Reporter Gene

PubMed Central

Chen, Ron; Parry, Jesse J.; Akers, Walter J.; Berezin, Mikhail Y.; El Naqa, Issam M.; Achilefu, Samuel; Edwards, W. Barry; Rogers, Buck E.

2010-01-01

Gene therapy trials have traditionally used tumor and tissue biopsies for assessing the efficacy of gene transfer. Non-invasive imaging techniques offer a distinct advantage over tissue biopsies in that the magnitude and duration of gene transfer can be monitored repeatedly. Human somatostatin receptor subtype 2 (SSTR2) has been used for the nuclear imaging of gene transfer. To extend this concept, we have developed a somatostatin receptor–enhanced green fluorescent protein fusion construct (SSTR2-EGFP) for nuclear and fluorescent multimodality imaging. Methods An adenovirus containing SSTR2-EGFP (AdSSTR2-EGFP) was constructed and evaluated in vitro and in vivo. SCC-9 human squamous cell carcinoma cells were infected with AdEGFP, AdSSTR2, or AdSSTR2-EGFP for in vitro evaluation by saturation binding, internalization, and fluorescence spectroscopy assays. In vivo biodistribution and nano-SPECT imaging studies were conducted with mice bearing SCC-9 tumor xenografts directly injected with AdSSTR2-EGFP or AdSSTR2 to determine the tumor localization of 111In-diethylenetriaminepentaacetic acid (DTPA)-Tyr3-octreotate. Fluorescence imaging was conducted in vivo with mice receiving intratumoral injections of AdSSTR2, AdSSTR2-EGFP, or AdEGFP as well as ex vivo with tissues extracted from mice. Results The similarity between AdSSTR2-EGFP and wild-type AdSSTR2 was demonstrated in vitro by the saturation binding and internalization assays, and the fluorescence emission spectra of cells infected with AdSSTR2-EGFP was almost identical to the spectra of cells infected with wild-type AdEGFP. Biodistribution studies demonstrated that the tumor uptake of 111In-DTPA-Tyr3-octreotate was not significantly different (P > 0.05) when tumors (n = 5) were injected with AdSSTR2 or AdSSTR2-EGFP but was significantly greater than the uptake in control tumors. Fluorescence was observed in tumors injected with AdSSTR2-EGFP and AdEGFP in vivo and ex vivo but not in tumors injected with AdSSTR2. Although fluorescence was observed, there were discrepancies between in vivo imaging and ex vivo imaging as well as between nuclear imaging and fluorescent imaging. Conclusion These studies showed that the SSTR2-EGFP fusion construct can be used for in vivo nuclear and optical imaging of gene transfer. PMID:20720053

SU-E-QI-21: Iodinated Contrast Agent Time Course In Human Brain Metastasis: A Study For Stereotactic Synchrotron Radiotherapy Clinical Trials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Obeid, L; Esteve, F; Adam, J

2014-06-15

Purpose: Synchrotron stereotactic radiotherapy (SSRT) is an innovative treatment combining the selective accumulation of heavy elements in tumors with stereotactic irradiations using monochromatic medium energy x-rays from a synchrotron source. Phase I/II clinical trials on brain metastasis are underway using venous infusion of iodinated contrast agents. The radiation dose enhancement depends on the amount of iodine in the tumor and its time course. In the present study, the reproducibility of iodine concentrations between the CT planning scan day (Day 0) and the treatment day (Day 10) was assessed in order to predict dose errors. Methods: For each of days 0more » and 10, three patients received a biphasic intravenous injection of iodinated contrast agent (40 ml, 4 ml/s, followed by 160 ml, 0.5 ml/s) in order to ensure stable intra-tumoral amounts of iodine during the treatment. Two volumetric CT scans (before and after iodine injection) and a multi-slice dynamic CT of the brain were performed using conventional radiotherapy CT (Day 0) or quantitative synchrotron radiation CT (Day 10). A 3D rigid registration was processed between images. The absolute and relative differences of absolute iodine concentrations and their corresponding dose errors were evaluated in the GTV and PTV used for treatment planning. Results: The differences in iodine concentrations remained within the standard deviation limits. The 3D absolute differences followed a normal distribution centered at zero mg/ml with a variance (∼1 mg/ml) which is related to the image noise. Conclusion: The results suggest that dose errors depend only on the image noise. This study shows that stable amounts of iodine are achievable in brain metastasis for SSRT treatment in a 10 days interval.« less

Evaluating dynamic contrast-enhanced and photoacoustic CT to assess intra-tumor heterogeneity in xenograft mouse models

NASA Astrophysics Data System (ADS)

Stantz, Keith M.; Liu, Bo; Cao, Minsong; Reinecke, Dan; Dzemidzic, Mario; Liang, Yun; Kruger, Robert

2006-03-01

Purpose: To evaluate photoacoustic CT spectroscopy (PCT-S) and dynamic contrast-enhanced CT (DCE-CT) ability to measure parameters - oxygen saturation and vascular physiology - associated with the intra-tumor oxygenation status. Material and Methods: Breast (VEGF165 enhance MCF-7) and ovarian (SKOV3x) cancer cells were implanted into the fat pads and flanks of immune deficient mice and allowed to grow to a diameter of 8-15 mm. CT was used to determine physiological parameters by acquiring a sequence of scans over a 10 minute period after an i.v. injection of a radio-opaque contrast agent (Isovue). These time-dependent contrast-enhanced curves were fit to a two-compartmental model determining tumor perfusion, fractional plasma volume, permeability-surface area produce, and fractional interstitial volume on a voxel-by-voxel basis. After which, the tumors were imaged using photoacoustic CT (Optosonics, Inc., Indianapolis, IN 46202). The near infrared spectra (700-910 nm) within the vasculature was fit to linear combination of measured oxy- and deoxy-hemoglobin blood samples to obtain oxygen saturation levels (SaO II). Results: The PCT-S scanner was first calibrated using different samples of oxygenated blood, from which a statistical error ranging from 2.5-6.5% was measured and a plot of the hemoglobin dissociation curve was consistent with empirical formula. In vivo determination of tumor vasculature SaO II levels were measurably tracked, and spatially correlated to the periphery of the tumor. Tumor depend variations in SaO II - 0.32 (ovarian) and 0.60 (breast) - and in vascular physiology - perfusion, 1.03 and 0.063 mL/min/mL, and fractional plasma volume, 0.20 and 0.07 - were observed. Conclusion: Combined, PCT-S and CED-CT has the potential to measure intra-tumor levels of tumor oxygen saturation and vascular physiology, key parameters associated with hypoxia.

Intratumor heterogeneity of DCE-MRI reveals Ki-67 proliferation status in breast cancer

NASA Astrophysics Data System (ADS)

Cheng, Hu; Fan, Ming; Zhang, Peng; Liu, Bin; Shao, Guoliang; Li, Lihua

2018-03-01

Breast cancer is a highly heterogeneous disease both biologically and clinically, and certain pathologic parameters, i.e., Ki67 expression, are useful in predicting the prognosis of patients. The aim of the study is to identify intratumor heterogeneity of breast cancer for predicting Ki-67 proliferation status in estrogen receptor (ER)-positive breast cancer patients. A dataset of 77 patients was collected who underwent dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) examination. Of these patients, 51 were high-Ki-67 expression and 26 were low-Ki-67 expression. We partitioned the breast tumor into subregions using two methods based on the values of time to peak (TTP) and peak enhancement rate (PER). Within each tumor subregion, image features were extracted including statistical and morphological features from DCE-MRI. The classification models were applied on each region separately to assess whether the classifiers based on features extracted from various subregions features could have different performance for prediction. An area under a receiver operating characteristic curve (AUC) was computed using leave-one-out cross-validation (LOOCV) method. The classifier using features related with moderate time to peak achieved best performance with AUC of 0.826 than that based on the other regions. While using multi-classifier fusion method, the AUC value was significantly (P=0.03) increased to 0.858+/-0.032 compare to classifier with AUC of 0.778 using features from the entire tumor. The results demonstrated that features reflect heterogeneity in intratumoral subregions can improve the classifier performance to predict the Ki-67 proliferation status than the classifier using features from entire tumor alone.

Surgical and survival outcomes of lung cancer patients with intratumoral lung abscesses.

PubMed

Yamanashi, Keiji; Okumura, Norihito; Takahashi, Ayuko; Nakashima, Takashi; Matsuoka, Tomoaki

2017-05-26

Intratumoral lung abscess is a secondary lung abscess that is considered to be fatal. Therefore, surgical procedures, although high-risk, have sometimes been performed for intratumoral lung abscesses. However, no studies have examined the surgical outcomes of non-small cell lung cancer patients with intratumoral lung abscesses. The aim of this study was to investigate the surgical and survival outcomes of non-small cell lung cancer patients with intratumoral lung abscesses. Eleven consecutive non-small cell lung cancer patients with intratumoral lung abscesses, who had undergone pulmonary resection at our institution between January 2007 and December 2015, were retrospectively analysed. The post-operative prognoses were investigated and prognostic factors were evaluated. Ten of 11 patients were male and one patient was female. The median age was 64 (range, 52-80) years. Histopathologically, 4 patients had Stage IIA, 2 patients had Stage IIB, 2 patients had Stage IIIA, and 3 patients had Stage IV tumors. The median operative time was 346 min and the median amount of bleeding was 1327 mL. The post-operative morbidity and mortality rates were 63.6% and 0.0%, respectively. Recurrence of respiratory infections, including lung abscesses, was not observed in all patients. The median post-operative observation period was 16.1 (range, 1.3-114.5) months. The 5-year overall survival rate was 43.3%. No pre-operative, intra-operative, or post-operative prognostic factors were identified in the univariate analyses. Surgical procedures for advanced-stage non-small cell lung cancer patients with intratumoral lung abscesses, although high-risk, led to satisfactory post-operative mortality rates and acceptable prognoses.

Phase I Trial of Intratumoral Administration of NIS Expressing Strain of Measles Virus in Unresectable or Recurrent Malignant Peripheral Nerve Sheath Tumor

DTIC Science & Technology

2016-10-01

Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Study approved by Mayo IRB on April 18 , 2016, and by USAMRMC/ORP/HRPO on May 6...MV-NIS, Oncolytic Virus, Measles Virus 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18 . NUMBER OF PPAGES 19a. NAME OF...1. Received Mayo IRB approval on 04/ 18 /2016 2. The US Army Medical Research and Materiel Command (USAMRMC), Office of Research Protections (ORP

The antiviral agent cidofovir [(S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine] has pronounced activity against nasopharyngeal carcinoma grown in nude mice.

PubMed

Neyts, J; Sadler, R; De Clercq, E; Raab-Traub, N; Pagano, J S

1998-02-01

The effect of the antiviral agent (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine (cidofovir) on the EBV-associated tumor nasopharyngeal carcinoma (NPC) was evaluated in NPC xenografts in athymic mice. Intratumoral injection arrested tumor growth within 1 week, and by 4 weeks, tumors regressed to 8-75% (39 +/- 33%) of the original size, whereas control tumors injected with PBS grew to 282 +/- 25% of the original size. Ganciclovir slowed but did not arrest or cause regression of tumor growth. A striking antitumor effect was also produced by systemic administration; at 4 weeks, tumors were 79 +/- 49% of the original size, compared with 635 +/- 91% for the controls. Widespread apoptosis was detected after treatment for 2-6 days in C15 as well as two other NPC xenografts, C17 and C18; the latter NPCs have mutations in the p53 gene. These data indicate that cidofovir induces rapid cell death through apoptosis in EBV-transformed epithelial cells.

In vivo covalent cross-linking of photon-converted rare-earth nanostructures for tumour localization and theranostics

NASA Astrophysics Data System (ADS)

Ai, Xiangzhao; Ho, Chris Jun Hui; Aw, Junxin; Attia, Amalina Binte Ebrahim; Mu, Jing; Wang, Yu; Wang, Xiaoyong; Wang, Yong; Liu, Xiaogang; Chen, Huabing; Gao, Mingyuan; Chen, Xiaoyuan; Yeow, Edwin K. L.; Liu, Gang; Olivo, Malini; Xing, Bengang

2016-01-01

The development of precision nanomedicines to direct nanostructure-based reagents into tumour-targeted areas remains a critical challenge in clinics. Chemical reaction-mediated localization in response to tumour environmental perturbations offers promising opportunities for rational design of effective nano-theranostics. Here, we present a unique microenvironment-sensitive strategy for localization of peptide-premodified upconversion nanocrystals (UCNs) within tumour areas. Upon tumour-specific cathepsin protease reactions, the cleavage of peptides induces covalent cross-linking between the exposed cysteine and 2-cyanobenzothiazole on neighbouring particles, thus triggering the accumulation of UCNs into tumour site. Such enzyme-triggered cross-linking of UCNs leads to enhanced upconversion emission upon 808 nm laser irradiation, and in turn amplifies the singlet oxygen generation from the photosensitizers attached on UCNs. Importantly, this design enables remarkable tumour inhibition through either intratumoral UCNs injection or intravenous injection of nanoparticles modified with the targeting ligand. Our strategy may provide a multimodality solution for effective molecular sensing and site-specific tumour treatment.

[Basic Studies on Locoregional Injection of a Newly Designed Chitin Sol].

PubMed

Chiba, Takehiro; Sugitachi, Akio; Kume, Kouhei; Segawa, Takenori; Nishinari, Yutaka; Ishida, Kaoru; Noda, Hironobu; Nishizuka, Satoshi; Kimura, Yusuke; Koeda, Keisuke; Sasaki, Akira

2015-11-01

Systemic chemotherapy in advanced cancer cases often provokes serious adverse events. We aimed to examine the fundamental properties and efficacy of a novel chitin sol, an anti-cancer agent with minor side effects designed to avoid the adverse effects of chemotherapy and enhance the QOL and ADL of patients. DAC-70 was used to create the novel agent termed DAC-70 sol. The anti-proliferative activity was assayed by the WST method using different types of cell lines. The anti-cancer efficacy of the novel agent was examined using cancer-bearing mice. DAC-70 sol was easily injectable through a 21-G needle. The sol suppressed proliferation of the cells in vitro. Intra-tumor injection of DAC-70 sol inhibited the rapid growth of solid tumors in the mice. CDDP-loaded DAC-70 sol, CDDP/DAC-70 sol, successfully controlled malignant ascites in the mice (p<0.05). Neither recurrence nor severe complications were encountered in these animals. These basic data strongly suggest that locoregional administration of our newly designed DAC-70 sol and CDDP/DAC-70 sol is clinically useful as novel cancer chemotherapy for advanced cases. This warrants further clinical studies in cancer chemotherapy.

The inhibitory effect of disulfiram encapsulated PLGA NPs on tumor growth: Different administration routes.

PubMed

Fasehee, Hamidreza; Zarrinrad, Ghazaleh; Tavangar, Seyed Mohammad; Ghaffari, Seyed Hamidollah; Faghihi, Shahab

2016-06-01

The strong anticancer activity of disulfiram is hindered by its rapid degradation in blood system. A novel folate-receptor-targeted poly (lactide-co-glycolide) (PLGA)-polyethylene glycol (PEG) nanoparticle (NP) is developed for encapsulation and delivery of disulfiram into breast cancer tumor using passive (EPR effect) and active (folate receptor) targeting. The anticancer activity of disulfiram and its effect on caspase-3 activity and cell cycle are studied. The administration of encapsulated PLGA NPs using intra-peritoneal, intravenous and intra-tumor routes is investigated using animal model. Disulfiram shows strong cytotoxicity against MCF7 cell line. The activity of caspase-3 inhibited with disulfiram via dose dependent manner while the drug causes cell cycle arrest in G0/G1 and S phase time-dependently. The encapsulated disulfiram shows higher activity in apoptosis induction as compared to free drug. In nontoxic dose of encapsulated disulfiram, the highest and lowest efficacy of NPs in tumor growth inhibition is observed for intravenous injection and intraperitoneal injection. It is suggested that administration of disulfiram by targeted PLGA nanoparticles using intravenous injection would present an alternative therapeutic approach for solid tumor treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Intraepithelial Attack Rather than Intratumorally Infiltration of CD8+T Lymphocytes is a Favorable Prognostic Indicator in Pancreatic Ductal Adenocarcinoma.

PubMed

Zhang, J; Wang, Y F; Wu, B; Zhong, Z X; Wang, K X; Yang, L Q; Wang, Y Q; Li, Y Q; Gao, J; Li, Z S

2017-01-01

Tumor-infiltrating lymphocytes (TILs) are one of the major participants in the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC). However, the mechanism of interaction between TILs and tumors is complex and remains unclear. To evaluate the state of immunoreactions in PDAC tissues, and explore the prognostic value of these markers in a large sample, to provide a new theoretical basis for PDAC immunotherapy. Immunohistochemical staining of CD4+ and CD8+T cells was performed in a tissue microarray (TMA) of 143 cases of PDAC. Two major variables for the spatial distributions of CD4+T and CD8+T cells in PDAC tissues, intraepithelial attack and intratumoral infiltration, were used to evaluate the state of immunoreactions, and the interrelationships with the clinicopathological variables were analyzed. Our data showed that both the intraepithelial CD4+T and CD8+T attack were less frequent than the intratumoral infiltration. CD8+T intraepithelial attack and intratumoral infiltration were more intense than CD4+T. CD8+T intraepithelial attack was an independent favorable prognostic factor for overall survival, correlating negatively with vascular invasion and positively with CD4+T and CD8+T high intratumoral infiltration. CD8+T high intratumoral infiltration without CD8+T intraepithelial attack was a poor prognostic factor. CD8+T high intratumoral infiltration was accompanied by T stage progression. Conclusively, in PDAC progression, imbalances of T cells occurred in CD4+ and CD8+ immunoreactions. The CD8+T intraepithelial attack was an independent favorable prognostic indicator, however the intraepithelial attack of CD4+T and the both intratumoral infiltration of CD8+T and CD4+T played an ambiguous role. Our data suggested that it is a potential approach to increasing the number of intraepithelial attacking CD8+T cells for tumor immunotherapy, and exploring a new mechanism for immunosuppression in a tumor microenvironment with high T cell infiltration without attack. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

T Cells Redirected to a Minor Histocompatibility Antigen Instruct Intratumoral TNFα Expression and Empower Adoptive Cell Therapy for Solid Tumors.

PubMed

Manzo, Teresa; Sturmheit, Tabea; Basso, Veronica; Petrozziello, Elisabetta; Hess Michelini, Rodrigo; Riba, Michela; Freschi, Massimo; Elia, Angela R; Grioni, Matteo; Curnis, Flavio; Protti, Maria Pia; Schumacher, Ton N; Debets, Reno; Swartz, Melody A; Corti, Angelo; Bellone, Matteo; Mondino, Anna

2017-02-01

Donor-derived allogeneic T cells evoke potent graft versus tumor (GVT) effects likely due to the simultaneous recognition of tumor-specific and host-restricted minor histocompatibility (H) antigens. Here we investigated whether such effects could be reproduced in autologous settings by TCR gene-engineered lymphocytes. We report that T cells redirected either to a broadly expressed Y-encoded minor H antigen or to a tumor-associated antigen, although poorly effective if individually transferred, when simultaneously administered enabled acute autochthonous tumor debulking and resulted in durable clinical remission. Y-redirected T cells proved hyporesponsive in peripheral lymphoid organs, whereas they retained effector function at the tumor site, where in synergy with tumor-redirected lymphocytes, they instructed TNFα expression, endothelial cell activation, and intratumoral T-cell infiltration. While neutralizing TNFα hindered GVT effects by the combined T-cell infusion, a single injection of picogram amounts of NGR-TNF, a tumor vessel-targeted TNFα derivative currently in phase III clinical trials, substituted for Y-redirected cells and enabled tumor debulking by tumor-redirected lymphocytes. Together, our results provide new mechanistic insights into allogeneic GVT, validate the importance of targeting the tumor and its associated stroma, and prove the potency of a novel combined approach suitable for immediate clinical implementation. Cancer Res; 77(3); 658-71. ©2016 AACR. ©2016 American Association for Cancer Research.

Pinhole Micro-SPECT/CT for Noninvasive Monitoring and Quantitation of Oncolytic Virus Dispersion and Percent Infection in Solid Tumors

PubMed Central

Penheiter, Alan R.; Griesmann, Guy E.; Federspiel, Mark J.; Dingli, David; Russell, Stephen J.; Carlson, Stephanie K.

2011-01-01

The purpose of our study was to validate the ability of pinhole micro-single-photon emission computed tomography/computed tomography (SPECT/CT) to 1) accurately resolve the intratumoral dispersion pattern and 2) quantify the infection percentage in solid tumors of an oncolytic measles virus encoding the human sodium iodide symporter (MV-NIS). NIS RNA level and dispersion pattern were determined in control and MV-NIS infected BxPC-3 pancreatic tumor cells and mouse xenografts using quantitative, real-time, reverse transcriptase, polymerase chain reaction, autoradiography, and immunohistochemistry (IHC). Mice with BxPC-3 xenografts were imaged with 123I or 99TcO4 micro-SPECT/CT. Tumor dimensions and radionuclide localization were determined with imaging software. Linear regression and correlation analyses were performed to determine the relationship between tumor infection percentage and radionuclide uptake (% injected dose per gram) above background and a highly significant correlation was observed (r2 = 0.947). A detection threshold of 1.5-fold above the control tumor uptake (background) yielded a sensitivity of 2.7% MV-NIS infected tumor cells. We reliably resolved multiple distinct intratumoral zones of infection from noninfected regions. Pinhole micro-SPECT/CT imaging using the NIS reporter demonstrated precise localization and quantitation of oncolytic MV-NIS infection and can replace more time-consuming and expensive analyses (eg, autoradiography and IHC) that require animal sacrifice. PMID:21753796

Resveratrol Targets AKT and p53 in Glioblastoma and Glioblastoma Stem-like Cells to Suppress Growth and Infiltration

PubMed Central

Clark, Paul A.; Bhattacharya, Saswati; Elmayan, Ardem; Darjatmoko, Soesiawati R.; Thuro, Bradley A.; Yan, Michael B.; van Ginkel, Paul R.; Polans, Arthur S.; Kuo, John S.

2016-01-01

Object Glioblastoma multiforme (GBM) is an aggressive brain cancer with median survival of less than two years with current treatment. GBM exhibits extensive intra-tumor and inter-patient heterogeneity, suggesting that successful therapies should exert broad anti-cancer activities. Therefore, the natural non-toxic pleiotropic agent, resveratrol, was studied for anti-tumorigenic effects against GBM. Methods Resveratrol’s effects on cell proliferation, sphere-forming ability, and invasion were tested using multiple patient-derived GBM stem-like cell (GSC) lines and established U87 glioma cells, and changes in oncogenic AKT and tumor suppressive p53 were analyzed. Resveratrol was also tested in vivo against U87 glioma flank xenografts using multiple delivery methods, including direct tumor injection. Finally, resveratrol was delivered directly to brain tissue to determine toxicity and achievable drug concentrations in the brain parenchyma. Results Resveratrol significantly inhibited proliferation in U87 glioma and multiple patient-derived GSC lines, demonstrating similar inhibitory concentrations across these phenotypically heterogeneous lines. Resveratrol also inhibited the sphere-forming ability of GSCs, suggesting anti-stem cell effects. Additionally, resveratrol blocked U87 glioma and GSC invasion in an in vitro Matrigel transwell assay at doses similar to those mediating anti-proliferative effects. In U87 glioma cells and GSCs, resveratrol reduced AKT phosphorylation and induced p53 expression and activation that led to transcription of downstream p53 target genes. Resveratrol administration via oral gavage or ad libitum in the water supply significantly suppressed GBM xenograft growth; intra-tumor or peri-tumor resveratrol injection further suppressed growth and approximating tumor regression. Intracranial resveratrol injection resulted in 100-fold higher local drug concentration compared to intravenous delivery, and with no apparent toxicity. Conclusions Resveratrol potently inhibited GBM and GBM stem-like cell growth and infiltration, acting partially via AKT deactivation and p53 induction, and suppressed glioblastoma growth in vivo. The ability of resveratrol to modulate AKT and p53, as well as reportedly many other anti-tumorigenic pathways, is attractive for therapy against a genetically heterogeneous tumor such as GBM. Although resveratrol exhibits low bioavailability when administered orally or intravenously, novel delivery methods such as direct injection (i.e. convection enhanced delivery) could potentially be used to achieve and maintain therapeutic doses in brain. Resveratrol’s non-toxic nature and broad anti-GBM effects make it a compelling candidate to supplement current GBM therapies. PMID:27419830

Chromic-P32 phosphate treatment of implanted pancreatic carcinoma: mechanism involved.

PubMed

Liu, Lu; Feng, Guo-Sheng; Gao, Hong; Tong, Guan-Sheng; Wang, Yu; Gao, Wen; Huang, Ying; Li, Cheng

2005-04-14

To study the effects of chromic-P32 phosphate (32P colloids) interstitial administration in Pc-3 implanted pancreatic carcinoma, and investigate its anticancer mechanism. Ninety-eight tumor bearing nude mice were killed at different time points after the injection of 32P colloids to the tumor core with observed radioactivity. The light microscopy, transmission electron microscopy (TEM) and immuno-histochemistry and flow cytometry were used to study the rates of tumor cell necrosis, proliferating cell nuclear antigen index, the micro vessel density (MVD). The changes of the biological response to the lymphatic transported 32P colloids in the inguinal lymph node (ILN) were dynamically observed, and the percentage of tumor cell apoptosis, and Apo2.7, caspase-3, Bcl-2, Bax-related gene expression were observed too. The half-life of effective medication is 13 d after injection of 32P colloids to the tumor stroma, in 1-6 groups, the tumor cell necrosis rates were 20%, 45%, 65%, 70%, 95% and 4%, respectively (F = 4.14-105.36, P<0.01). MVD were 38.5+/-4.0, 28.0+/-2.9, 17.0+/-2.9, 8.8+/-1.5, 5.7+/-2.3 and 65.0+/-5.2 (t = 11.9-26.1, P<0.01), respectively. Under TEM fairly differentiated Pc-3 cells were found. Thirty days after medication, tumors were shrunk and dried with scabs detached, and those in control group increased in size prominently with plenty of hypodermic blood vessels. In all animals the ILN were enlarged but in medicated animals they appeared later and smaller than those in control group. The extent of irradiative injury in ILN was positively correlated to the dosage of medication. Typical tumor cell apoptosis could be found under TEM in animals with intra-tumoral injection of low dosed 32P colloids. The peak of apoptosis occurred in 2.96 MBq group and 24 h after irradiation. In the course of irradiation-induced apoptosis, the value of Bcl-2/Bax was down regulated; Apo2.7 and caspase-3 protein expression were prominently increased dose dependently. 32P colloids intra-tumor injection having prominent anticancer effectiveness may reveal the ability of promoting cell differentiation. The low dose 32P colloids may induce human pancreatic carcinoma Pc-3 implanted tumor cell apoptosis; Apo2.7, caspase-3, Bcl-2 and Bax protein participated in regulating the process of irradiation induced cell apoptosis.

Efficient treatment of breast cancer xenografts with multifunctionalized iron oxide nanoparticles combining magnetic hyperthermia and anti-cancer drug delivery.

PubMed

Kossatz, Susanne; Grandke, Julia; Couleaud, Pierre; Latorre, Alfonso; Aires, Antonio; Crosbie-Staunton, Kieran; Ludwig, Robert; Dähring, Heidi; Ettelt, Volker; Lazaro-Carrillo, Ana; Calero, Macarena; Sader, Maha; Courty, José; Volkov, Yuri; Prina-Mello, Adriele; Villanueva, Angeles; Somoza, Álvaro; Cortajarena, Aitziber L; Miranda, Rodolfo; Hilger, Ingrid

2015-05-13

Tumor cells can effectively be killed by heat, e.g. by using magnetic hyperthermia. The main challenge in the field, however, is the generation of therapeutic temperatures selectively in the whole tumor region. We aimed to improve magnetic hyperthermia of breast cancer by using innovative nanoparticles which display a high heating potential and are functionalized with a cell internalization and a chemotherapeutic agent to increase cell death. The superparamagnetic iron oxide nanoparticles (MF66) were electrostatically functionalized with either Nucant multivalent pseudopeptide (N6L; MF66-N6L), doxorubicin (DOX; MF66-DOX) or both (MF66-N6LDOX). Their cytotoxic potential was assessed in a breast adenocarcinoma cell line MDA-MB-231. Therapeutic efficacy was analyzed on subcutaneous MDA-MB-231 tumor bearing female athymic nude mice. All nanoparticle variants showed an excellent heating potential around 500 W/g Fe in the alternating magnetic field (AMF, conditions: H=15.4 kA/m, f=435 kHz). We could show a gradual inter- and intracellular release of the ligands, and nanoparticle uptake in cells was increased by the N6L functionalization. MF66-DOX and MF66-N6LDOX in combination with hyperthermia were more cytotoxic to breast cancer cells than the respective free ligands. We observed a substantial tumor growth inhibition (to 40% of the initial tumor volume, complete tumor regression in many cases) after intratumoral injection of the nanoparticles in vivo. The proliferative activity of the remaining tumor tissue was distinctly reduced. The therapeutic effects of breast cancer magnetic hyperthermia could be strongly enhanced by the combination of MF66 functionalized with N6L and DOX and magnetic hyperthermia. Our approach combines two ways of tumor cell killing (magnetic hyperthermia and chemotherapy) and represents a straightforward strategy for translation into the clinical practice when injecting nanoparticles intratumorally.

Lymphatic Drainage from Renal Tumors In Vivo: A Prospective Sentinel Node Study Using SPECT/CT Imaging.

PubMed

Kuusk, Teele; De Bruijn, Roderick; Brouwer, Oscar R; De Jong, Jeroen; Donswijk, Maarten; Grivas, Nikolaos; Hendricksen, Kees; Horenblas, Simon; Prevoo, Warner; Valdés Olmos, Renato A; Van Der Poel, Henk G; Van Rhijn, Bas W G; Wit, Esther M; Bex, Axel

2018-06-01

Lymphatic drainage from renal tumors is unpredictable. In vivo drainage studies of primary lymphatic landing sites may reveal the variability and dynamics of lymphatic connections. The purpose of this study was to investigate the lymphatic drainage pattern of renal tumors in vivo with single photon emission/computerized tomography after intratumor radiotracer injection. We performed a phase II, prospective, single arm study to investigate the distribution of sentinel nodes from renal tumors on single photon emission/computerized tomography. Patients with cT1-3 (less than 10 cm) cN0M0 renal tumors of any subtype were enrolled in analysis. After intratumor ultrasound guided injection of 0.4 ml 99m Tc-nanocolloid we performed preoperative imaging of sentinel nodes with lymphoscintigraphy and single photon emission/computerized tomography. Sentinel and locoregional nonsentinel nodes were resected with a γ probe combined with a mobile γ camera. The primary study end point was the location of sentinel nodes outside the locoregional retroperitoneal templates on single photon emission/computerized tomography. Using a Simon minimax 2-stage design to detect a 25% extralocoregional retroperitoneal template location of sentinel nodes on imaging at α = 0.05 and 80% power at least 40 patients with sentinel node imaging on single photon emission/computerized tomography were needed. Of the 68 patients 40 underwent preoperative single photon emission/computerized tomography of sentinel nodes and were included in primary end point analysis. Lymphatic drainage outside the locoregional retroperitoneal templates was observed in 14 patients (35%). Eight patients (20%) had supradiaphragmatic sentinel nodes. Sentinel nodes from renal tumors were mainly located in the respective locoregional retroperitoneal templates. Simultaneous sentinel nodes were located outside the suggested lymph node dissection templates, including supradiaphragmatic sentinel nodes in more than a third of the patients. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Intratumoral heterogeneity on dedicated breast positron emission tomography predicts malignancy grade of breast cancer.

PubMed

Masumoto, Norio; Kadoya, Takayuki; Sasada, Shinsuke; Emi, Akiko; Arihiro, Koji; Okada, Morihito

2018-05-19

Dedicated breast positron emission tomography (DbPET) provides detailed high-resolution images and can detect intratumoral heterogeneity using 18 F-fluorodeoxyglucose (FDG). We aimed to evaluate the correlation between FDG uptake on DbPET and the clinicopathological features of breast cancer, particularly those with an intratumoral heterogeneous distribution of FDG on DbPET. We evaluated 195 consecutive patients with invasive breast cancer who underwent preoperative whole-body PET (WBPET) and DbPET concurrently between January 2016 and March 2017. The relationships between clinicopathological factors and the maximum standard uptake values (SUVmax) of DbPET and WBPET, including clinical stage, nuclear grade, Ki67 proliferation index, estrogen receptor (ER) and human epidermal growth factor receptor type 2 (HER2) statuses, and the intratumoral heterogeneous distribution of FDG on DbPET, were evaluated. The SUVmax of DbPET was significantly correlated with clinical T stage, N stage, nuclear grade, and Ki67 proliferation index (all p < 0.001) as well as the ER (p = 0.006) and HER2 (p = 0.040) statuses. Intratumoral heterogeneous distribution of FDG on DbPET was significantly related with high nuclear grade (p = 0.016) and high Ki67 proliferation index (p = 0.015) but not with clinical T stage, N stage, and ER and HER2 statuses. The SUVmax of DbPET correlates with clinicopathological factors and also WBPET does. In addition, intratumoral heterogeneity on DbPET provides predictive value for malignancy grade and could inform therapeutic decisions.

Imaging Intratumoral Convection: Pressure Dependent Enhancement in Chemotherapeutic Delivery to Solid Tumors

PubMed Central

Gade, Terence P.F.; Buchanan, Ian M.; Motley, Matthew W.; Mazaheri, Yousef; Spees, William M.; Koutcher, Jason A.

2014-01-01

Purpose Low molecular weight (LMW) chemotherapeutics are believed to reach tumors through diffusion across capillary beds as well as membrane transporters. Unexpectedly, the delivery of these agents appears to be augmented by reductions in tumor interstitial fluid pressure (TIFP), an effect typically associated with high molecular weight molecules which reach tumors principally through convection. We investigated the hypothesis that improved intratumoral convection can alter tumor metabolism and enhance the delivery of a LMW chemotherapeutic agent to solid tumors. Experimental Design For this purpose we applied 31P/19F MR spectroscopy and spectroscopic imaging to examine the influence of type I collagenase on tumor bioenergetics and the delivery of 5-fluorouracil (5FU) to HT29 human colorectal tumors grown subcutaneously in mice. Results Collagenase effected a 34% reduction in TIFP with an attendant disintegration of intratumoral collagen. Neither mice administered collagenase nor controls receiving PBS demonstrated changes in 31PMRS-measured tumor bioenergetics; however, a time-dependent increase in the content of extracellular inorganic phosphate (Pie) was observed in tumors of collagenase-treated animals. 31PMRSI demonstrated that this increase underscored a more homogeneous distribution of Pie in tumors of experimental mice. 19FMRS showed that these changes were associated with a 50% increase in 5FU uptake in tumors of experimental versus control animals; however, this increase resulted in an increase in 5FU catabolites rather than fluoronucleotide intermediates that are required for subsequent cytotoxicity. Conclusions These data indicate that the modulation of convective flow within tumors can improve the delivery of (LMW) chemotherapeutics and demonstrate the potential role for non-invasive imaging of this process in vivo. PMID:19118052

Phase I trial of preoperative intratumoral injection of immature dendritic cells and OK-432 for resectable pancreatic cancer patients.

PubMed

Endo, Hisahito; Saito, Takuro; Kenjo, Akira; Hoshino, Mika; Terashima, Masanori; Sato, Tetsu; Anazawa, Takayuki; Kimura, Takashi; Tsuchiya, Takao; Irisawa, Atsushi; Ohira, Hiromasa; Hikichi, Takuto; Takagi, Tadayuki; Gotoh, Mitsukazu

2012-07-01

To determine the feasibility, safety and histological change of preoperative endoscopic ultrasound-guided fine-needle injection (PEU-FNI) of immature DCs (iDCs) with OK-432 in pancreatic cancer patients. Nine patients enrolled in the trial (DC group) and were compared with 15 patients operated on without iDC injection (non-DC group). Adverse events of PEU-FNI and postoperative complications were evaluated according to CTC-AE ver.3.0 and the Clavien-Dindo classification/ISGPF definition, respectively. Histological changes within the tumor and lymph nodes were evaluated by immunohistochemical examination of infiltrating inflammatory cells (CD4+, CD8+, Foxp3+ and CD83+). There were no severe toxicities following PEU-FNI, except for one transient grade 3 fever, and there were no significant differences in the incidence of postoperative complications between the two groups. Colliquative necrosis and diffusely scattered TUNEL-positive cells were observed at the injection sites. CD83+ cells significantly accumulated in the regional lymph nodes of the DC group as well as Foxp3+ cells in the regional and distant lymph nodes. The two DC group patients, one of which was stage IV with distant lymph node metastasis, survived more than 5 years without requiring adjuvant theraphy. PEU-FNI was feasible and safe, and further study needs to confirm and enhance antitumor responses.

Regulating cancer associated fibroblasts with losartan-loaded injectable peptide hydrogel to potentiate chemotherapy in inhibiting growth and lung metastasis of triple negative breast cancer.

PubMed

Hu, Chunhua; Liu, Xiaoyu; Ran, Wei; Meng, Jia; Zhai, Yihui; Zhang, Pengcheng; Yin, Qi; Yu, Haijun; Zhang, Zhiwen; Li, Yaping

2017-11-01

Preoperative chemotherapy is effective in improving the prognosis of patients, but its efficacy is impeded by cancer associated fibroblasts (CAFs) that enhance the survival, growth, and metastasis of cancer cells. To inhibit the activity of CAFs, prolonged and localized drug exposure is necessary. Here, we report on the rational design, screening, and evaluation of an injectable peptide hydrogel as a local losartan depot aiming to inhibit CAFs and potentiate chemotherapy. We synthesized a set of peptide derivatives and found that C 16 -GNNQQNYKD-OH (C 16 -N) surpassed the others in hydrogel formation and drug encapsulation, due to its flexible hydrocarbon tail and interpeptide hydrogen bonding that allowed supramolecular self-assembly into long filaments with hydrophobic cores. C 16 -N co-assembled with losartan to form hydrogel from which losartan was sustainably released over 9 days. After intratumoral injection, the hydrogel could be retained in the tumor for more than 9 days, significantly inhibited the CAFs and collagen synthesis in orthotopic 4T1 tumors, and enhanced the efficacy of PEGylated doxorubicin-loaded liposomes (Dox-L) in inhibiting the tumor growth (64% vs. Dox-L alone) and lung metastasis (80% vs. Dox-L alone). These results provide important guiding principles for the rational design of injectable peptide hydrogels aiming to regulate CAFs and improve chemotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Analysis of cytotoxic activity of the CD4+ T lymphocytes generated by local immunotherapy.

PubMed Central

Katsumoto, Y.; Monden, T.; Takeda, T.; Haba, A.; Ito, Y.; Wakasugi, E.; Wakasugi, T.; Sekimoto, M.; Kobayashi, T.; Shiozaki, H.; Shimano, T.; Monden, M.

1996-01-01

We previously reported that the anti-tumour effect of OK-432 is considerably enhanced by its intratumoral injection together with fibrinogen. In the present study, we generated killer T cells by culturing tumour-infiltrating lymphocytes from thyroid cancer patients who had received this local immunotherapy. Phenotypic analysis revealed that the T cells were positive for CD3+, CD4+, Leu8-, CD45RO+ and T-cell receptor (TCR)alpha beta+, as well as showing strong surface expression of HLA-DR, CD25, LFA-1 and ICAM-1. The generated CD4+ T cells secreted interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, TNF-beta, and interleukin (IL)-6 (but not IL-4), and exhibited a high level of cytolytic activity against several tumour cell lines. The cytolytic activity of these T cells for Daudi cells was inhibited by preincubation with an anti-intercellular adhesion molecule (ICAM)-1 antibody, but not by preincubation with anti-TCR alpha beta, anti-CD2, or anti-LFA-1 antibodies. Pretreatment with anti-ICAM-1 antibody inhibited T-cell cytolytic activity, but not conjugation with target cells. In addition, incubation with immobilised anti-ICAM-1 enhanced the secretion of IFN-gamma by T cells. We conclude that ICAM-1 expressed on the effector cytotoxic CD4+ T lymphocytes delivers regulatory signals that enhance IFN-gamma secretion. PMID:8554971

Eradication of melanoma in vitro and in vivo via targeting with a Killer-Red-containing telomerase-dependent adenovirus.

PubMed

Takehara, Kiyoto; Yano, Shuya; Tazawa, Hiroshi; Kishimoto, Hiroyuki; Narii, Nobuhiro; Mizuguchi, Hiroyuki; Urata, Yasuo; Kagawa, Shunsuke; Fujiwara, Toshiyoshi; Hoffman, Robert M

2017-08-18

Melanoma is a highly recalcitrant cancer and transformative therapy is necessary for the cure of this disease. We recently developed a telomerase-dependent adenovirus containing the fluorescent protein Killer-Red. In the present report, we first determined the efficacy of Killer-Red adenovirus combined with laser irradiation on human melanoma cell lines in vitro. Cell viability of human melanoma cells was reduced in a dose-dependent and irradiation-time-dependent manner. We used an intradermal xenografted melanoma model in nude mice to determine efficacy of the Killer-Red adenovirus. Intratumoral injection of Killer-Red adenovirus, combined with laser irradiation, eradicated the melanoma indicating the potential of a new paradigm of cancer therapy.

Repeated onabotulinumtoxin-a injections provide better results than single injection in treatment of painful bladder syndrome.

PubMed

Kuo, Hann-Chorng

2013-01-01

Onabotulinumtoxin-A (BoNT-A) is effective for the treatment of interstitial cystitis/painful bladder syndrome (IC/PBS). However, long-term follow-up does not show successful outcome after a single injection. To evaluate the efficacy and safety of repeated intravesical BoNT-A injections for treatment of IC/PBS and compare the success rates among patient groups receiving different injection numbers. Prospective interventional study. Tertiary medical center. Intravesical injection of 100 U of BoNT-A was performed in 81 patients every 6 months for up to 4 times or until patients' symptoms significantly improved. Patients who received a single injection served as active controls. Measured parameters included O'Leary-Sant symptom indexes (ICSI) and problem indexes (ICPI), visual analogue score (VAS) for pain, voiding diary variables, urodynamic parameters, maximal bladder capacity under anesthesia, glomerulation grade, and global response assessment. Multiple measurements and Kaplan-Meier analysis were used for comparison of consecutive data and success rates among groups. Among 81 patients, 20 received single injections, 19 received 2 injections, 12 received 3 injections, and 30 received 4 injections. The mean (± standard deviation) of ICSI, ICPI, total scores, VAS, functional bladder capacity, and daytime frequency all showed significant improvement after repeated BoNT-A treatment with different injections. Significantly better success rates were noted in patients who received 4 repeated injections (P = 0.0242) and 3 injections (P = 0.050), compared to those who received a single injection. However, there was no significant difference of long-term success rates among patients who received 2, 3, and 4 injections. Lack of placebo control group is the main limitation. Repeated intravesical BoNT-A injections were safe and effective for pain relief and they increased bladder capacity and provided a better long-term success rate than a single injection did for treatment of IC/PBS.

Common experience modifies the reinforcing properties of methamphetamine-injected cage mates but not morphine-injected cage mates in C57 mice.

PubMed

Watanabe, Shigeru

2015-10-01

The aim of this study was to determine whether previous exposure to a drug affects the social facilitation of conditioned place preference (CPP) for a drug-injected cage mate. Twenty-two male C57/BL6J mice received drug injections (methamphetamine or morphine) and 22 male C57/BL6J mice received saline injections. All 44 mice then received CPP training, during which one compartment of a conventional CPP apparatus was associated with a drug-injected cage mate (stimulus mouse) and the other compartment was associated with a saline-injected cage mate (stimulus mouse). The subject mice did not receive any drug injection during this CPP training. Time spent in the compartment associated with the drug-injected cage mate was measured before and after training. Subject mice that had previously received methamphetamine injections showed an increase in the time spent in the compartment associated with the methamphetamine-injected cage mate after CPP training. This effect was not observed in subject mice that had previously received saline injections. Subject mice did not show an increase in the time spent in the compartment associated with the morphine-injected cage mate irrespective of whether they had previously received morphine or saline injections. Therefore, in agreement with previous reports, common experience with methamphetamine induced reinforcing properties, but that with morphine did not.

The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade

PubMed Central

Yamazaki, T; Pitt, J M; Vétizou, M; Marabelle, A; Flores, C; Rekdal, Ø; Kroemer, G; Zitvogel, L

2016-01-01

Intratumoral immunotherapies aim at reducing local immunosuppression, as well as reinstating and enhancing systemic anticancer T-cell functions, without inducing side effects. LTX-315 is a first-in-class oncolytic peptide-based local immunotherapy that meets these criteria by inducing a type of malignant cell death that elicits anticancer immune responses. Here, we show that LTX-315 rapidly reprograms the tumor microenvironment by decreasing the local abundance of immunosuppressive Tregs and myeloid-derived suppressor cells and by increasing the frequency of polyfunctional T helper type 1/type 1 cytotoxic T cells with a concomitant increase in cytotoxic T-lymphocyte antigen-4 (CTLA4) and drop in PD-1 expression levels. Logically, in tumors that were resistant to intratumoral or systemic CTLA4 blockade, subsequent local inoculation of LTX-315 cured the animals or caused tumor regressions with abscopal effects. This synergistic interaction between CTLA4 blockade and LTX-315 was reduced upon blockade of the β-chain of the interleukin-2 receptor (CD122). This preclinical study provides a strong rationale for administering the oncolytic peptide LTX-315 to patients who are receiving treatment with the CTLA4 blocking antibody ipilimumab. PMID:27082453

Role of intratumoral infiltrating macrophages after transarterial immunoembolization for hepatocellular carcinoma.

PubMed

Kenjo, Akira; Sato, Tetsu; Marubashi, Shigeru; Saito, Takuro; Tsuchiya, Takao; Kimura, Takashi; Sato, Naoya; Takahashi, Atsushi; Ohira, Hiromasa; Gotoh, Mitsukazu

2016-05-01

Preoperative transarterial immunoembolization (TIE) for hepatocellular carcinoma (HCC) is effective for preventing recurrence. We aimed to investigate the intratumoral and peritumoral M1 macrophage-induced immune response following TIE treatment. We compared 13 patients treated with TIE between 2003 and 2009 (TIE group) and 13 patients treated with surgery alone during the same period of time at our institute (control group) using an immunohistological study with CD68 and CD163 antibodies. No significant differences in clinicopathological characteristics, except for surgical time, were observed between the two groups. The 3-year recurrence-free survival outcome of the TIE group was quite different from that of the control group (100% vs. 38.5%, P = 0.034). In the histological investigation, lytic necrosis and coagulation necrosis of the main tumor along with the presence of multinuclear giant cells were observed in 10 of the 13 patients in the TIE group. The immunohistological study showed that not only the numbers of intratumoral CD68(+) cells, but also the numbers of intratumoral and peritumoral CD8(+) cells were significantly increased in the TIE group. The suppression of tumor recurrence induced by preoperative TIE might be induced by intratumoral M1 macrophages that are activated by OK-432 and fibrinogen. © 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Irinotecan Loaded in Eluting Beads: Preclinical Assessment in a Rabbit VX2 Liver Tumor Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rao, Pramod P.; Pascale, Florentina; Seck, Atman

2012-12-15

Purpose: The purpose of this study was to study the pharmacokinetics of irinotecan injected intravenously, intra-arterially, or loaded onto a delivery platform. Material and Methods: Fifty-four New Zealand White rabbits with VX2 liver tumor, divided in 3 groups of 17 rabbits, each received irinotecan either by intravenous (IV) route, intra-arterial hepatic (IA) route, or loaded on drug-eluting beads (DEBIRI). Animals were killed at 1, 6, and 24 h. Irinotecan and SN-38 concentrations were measured at different time points in serum, tumor, and normal liver.ResultsTwelve milligrams of irinotecan were injected IV and IA, whereas 6-16.5 mg were injected loaded onto DEBIRI.more » Normalized serum irinotecan reached a peak of 333 ng/ml (range 198.8-502.5) for IV, 327.1 ng/ml (range 277.1-495.6) for IA, and 189.7 ng/ml (range 111.1-261.9) for DEBIRI (P < 0.001) delivery. The area-under-the-curve value from 10 to 60 min of serum irinotecan concentration was significantly lower for DEBIRI (P = 0.0009). Tumor irinotecan levels for IV, IA, and DEBIRI (in ng/200 mg of tissue followed by ranges in parentheses) were, respectively, 23.6 (0.3-24.9), 36.5 (7.7-1914.1), and 20.2 (2.9-319) at 1 h; 4.2 (1-27.9), 99.3 (46.6-159.5), and 42.1 (11.3-189) at 6 h; and 2.7 (2.5-6.9), 18.3 (1.5-369.1), and 174.4 (3.4-5147.3) at 24 h (P = 0.02). At 24 h, tumor necrosis was 25% (10-30), 60% (40-91.25), and 95% (76.25-95) for IV, IA, and DEBIRI, respectively (P = 0.03). Conclusion: Compared with IV or IA, DEBIRI induces lower early serum levels of irinotecan, a high and prolonged intratumoral level of irinotecan, and a greater rate of tumor necrosis at 24 h. Further evaluation of the clinical benefit of DEBIRI is warranted.« less

Bone Marrow Mesenchymal Stem Cells Loaded With an Oncolytic Adenovirus Suppress the Anti-adenoviral Immune Response in the Cotton Rat Model

PubMed Central

Ahmed, Atique U; Rolle, Cleo E; Tyler, Matthew A; Han, Yu; Sengupta, Sadhak; Wainwright, Derek A; Balyasnikova, Irina V; Ulasov, Ilya V; Lesniak, Maciej S

2010-01-01

Oncolytic adenoviral virotherapy is an attractive treatment modality for cancer. However, following intratumoral injections, oncolytic viruses fail to efficiently migrate away from the injection site and are rapidly cleared by the immune system. We have previously demonstrated enhanced viral delivery and replicative persistence in vivo using human bone marrow–derived mesenchymal stem cells (MSCs) as delivery vehicles. In this study, we evaluated the immune response to adenovirus (Ad)-loaded MSCs using the semipermissive cotton rat (CR) model. First, we isolated MSCs from CR bone marrow aspirates. Real-time quantitative PCR analysis revealed that CR MSCs supported the replication of Ads in vitro. Moreover, we observed similar levels of suppression of T-cell proliferation in response to mitogenic stimulation, by MSCs alone and virus-loaded MSCs. Additionally, we found that MSCs suppressed the production of interferon-γ (IFN-γ) by activated T cells. In our in vivo model, CR MSCs enhanced the dissemination and persistence of Ad, compared to virus injection alone. Collectively, our data suggest that the use of MSCs as a delivery strategy for oncolytic Ad potentially offers a myriad of benefits, including improved delivery, enhanced dissemination, and increased persistence of viruses via suppression of the antiviral immune response. PMID:20588259

Intra-tumor heterogeneity in breast cancer has limited impact on transcriptomic-based molecular profiling.

PubMed

Karthik, Govindasamy-Muralidharan; Rantalainen, Mattias; Stålhammar, Gustav; Lövrot, John; Ullah, Ikram; Alkodsi, Amjad; Ma, Ran; Wedlund, Lena; Lindberg, Johan; Frisell, Jan; Bergh, Jonas; Hartman, Johan

2017-11-29

Transcriptomic profiling of breast tumors provides opportunity for subtyping and molecular-based patient stratification. In diagnostic applications the specimen profiled should be representative of the expression profile of the whole tumor and ideally capture properties of the most aggressive part of the tumor. However, breast cancers commonly exhibit intra-tumor heterogeneity at molecular, genomic and in phenotypic level, which can arise during tumor evolution. Currently it is not established to what extent a random sampling approach may influence molecular breast cancer diagnostics. In this study we applied RNA-sequencing to quantify gene expression in 43 pieces (2-5 pieces per tumor) from 12 breast tumors (Cohort 1). We determined molecular subtype and transcriptomic grade for all tumor pieces and analysed to what extent pieces originating from the same tumors are concordant or discordant with each other. Additionally, we validated our finding in an independent cohort consisting of 19 pieces (2-6 pieces per tumor) from 6 breast tumors (Cohort 2) profiled using microarray technique. Exome sequencing was also performed on this cohort, to investigate the extent of intra-tumor genomic heterogeneity versus the intra-tumor molecular subtype classifications. Molecular subtyping was consistent in 11 out of 12 tumors and transcriptomic grade assignments were consistent in 11 out of 12 tumors as well. Molecular subtype predictions revealed consistent subtypes in four out of six patients in this cohort 2. Interestingly, we observed extensive intra-tumor genomic heterogeneity in these tumor pieces but not in their molecular subtype classifications. Our results suggest that macroscopic intra-tumoral transcriptomic heterogeneity is limited and unlikely to have an impact on molecular diagnostics for most patients.

Tracking the Evolution of Non-Small-Cell Lung Cancer.

PubMed

Jamal-Hanjani, Mariam; Wilson, Gareth A; McGranahan, Nicholas; Birkbak, Nicolai J; Watkins, Thomas B K; Veeriah, Selvaraju; Shafi, Seema; Johnson, Diana H; Mitter, Richard; Rosenthal, Rachel; Salm, Max; Horswell, Stuart; Escudero, Mickael; Matthews, Nik; Rowan, Andrew; Chambers, Tim; Moore, David A; Turajlic, Samra; Xu, Hang; Lee, Siow-Ming; Forster, Martin D; Ahmad, Tanya; Hiley, Crispin T; Abbosh, Christopher; Falzon, Mary; Borg, Elaine; Marafioti, Teresa; Lawrence, David; Hayward, Martin; Kolvekar, Shyam; Panagiotopoulos, Nikolaos; Janes, Sam M; Thakrar, Ricky; Ahmed, Asia; Blackhall, Fiona; Summers, Yvonne; Shah, Rajesh; Joseph, Leena; Quinn, Anne M; Crosbie, Phil A; Naidu, Babu; Middleton, Gary; Langman, Gerald; Trotter, Simon; Nicolson, Marianne; Remmen, Hardy; Kerr, Keith; Chetty, Mahendran; Gomersall, Lesley; Fennell, Dean A; Nakas, Apostolos; Rathinam, Sridhar; Anand, Girija; Khan, Sajid; Russell, Peter; Ezhil, Veni; Ismail, Babikir; Irvin-Sellers, Melanie; Prakash, Vineet; Lester, Jason F; Kornaszewska, Malgorzata; Attanoos, Richard; Adams, Haydn; Davies, Helen; Dentro, Stefan; Taniere, Philippe; O'Sullivan, Brendan; Lowe, Helen L; Hartley, John A; Iles, Natasha; Bell, Harriet; Ngai, Yenting; Shaw, Jacqui A; Herrero, Javier; Szallasi, Zoltan; Schwarz, Roland F; Stewart, Aengus; Quezada, Sergio A; Le Quesne, John; Van Loo, Peter; Dive, Caroline; Hackshaw, Allan; Swanton, Charles

2017-06-01

Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10 -4 ), which remained significant in multivariate analysis. Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

Modality of tumor endothelial VEGFR2 silencing-mediated improvement in intratumoral distribution of lipid nanoparticles.

PubMed

Yamamoto, Shoshiro; Kato, Akari; Sakurai, Yu; Hada, Tomoya; Harashima, Hideyoshi

2017-04-10

The vascular endothelial growth factor (VEGF)-mediated enhancement in vascular permeability is considered to be a major factor in tumor-targeting delivery via the enhanced permeability and retention (EPR) effect. We previously reported that the silencing of the endothelial VEGF receptor (VEGFR2) by a liposomal siRNA system (RGD-MEND) resulted in an enhanced intratumoral distribution of polyethylene glycol (PEG)-modified liposomes (LPs) in a renal cell carcinoma, a type of hypervascularized cancer, although the inhibition of VEGF signaling would be expected to decrease the permeability of the tumor vasculature. We herein report that the enhancement in the intratumoral distribution of LPs by VEGFR2 inhibition was dependent on the vascular type of the tumor (stroma vessel type; SV and tumor vessel type; TV). In the case of TV-type tumors (renal cell carcinoma and hepatocellular carcinoma), inhibiting VEGFR2 improved intratumoral distribution, while no effect was found in the case of SV-type tumors (colorectal cancer). Moreover, through a comparison of the intratumoral distribution of LPs with a variety of physical properties (100nm vs 400nm, neutral vs negative vs positive), VEGFR2 inhibition was found to alter the tumor microenvironment, including heparan sulfate proteoglycans (HSPGs). In addition, the results regarding the effect of the size of nanoparticles indicated that VEGFR2 inhibition improved the penetration of nanoparticles through the vessel wall, but not via permeability, suggesting the involvement of an unknown mechanism. Our findings suggest that a combination of anti-angiogenic therapy and delivery via the EPR effect would be useful in certain cases, and that altering the tumor microenvironment by VEGFR2 blockade has a drastic effect on the intratumoral distribution of nanoparticles. Copyright © 2017 Elsevier B.V. All rights reserved.

Alteration of sensitivity of intratumor quiescent and total cells to gamma-rays following thermal neutron irradiation with or without 10B-compound.

PubMed

Masunaga, S; Ono, K; Suzuki, M; Sakurai, Y; Kobayashi, T; Takagaki, M; Kinashi, Y; Akaboshi, M

2000-02-01

Changes in the sensitivity of intratumor quiescent (Q) and total cells to gamma-rays following thermal neutron irradiation with or without 10B-compound were examined. 5-Bromo-2'-deoxyuridine (BrdU) was injected to SCC VII tumor-bearing mice intraperitoneally 10 times to label all the proliferating (P) tumor cells. As priming irradiation, thermal neutrons alone or thermal neutrons with 10B-labeled sodium borocaptate (BSH) or dl-p-boronophenylalanine (BPA) were administered. The tumor-bearing mice then received a series of gamma-ray radiation doses, 0 through 24 h after the priming irradiation. During this period, no BrdU was administered. Immediately after the second irradiation, the tumors were excised, minced, and trypsinized. Following incubation of tumor cells with cytokinesis blocker, the micronucleus (MN) frequency in cells without BrdU labeling (= Q cells at the time of priming irradiation) was determined using immunofluorescence staining for BrdU. The MN frequency in the total (P + Q) tumor cells was determined from the tumors that were not pretreated with BrdU before the priming irradiation. To determine the BrdU-labeled cell ratios in the tumors at the time of the second irradiation, each group also included mice that were continuously administered BrdU until just before the second irradiation using mini-osmotic pumps which had been implanted subcutaneously 5 days before the priming irradiation. In total cells, during the interval between the two irradiations, the tumor sensitivity to gamma-rays relative to that immediately after priming irradiation decreased with the priming irradiation ranking in the following order: thermal neutrons only > thermal neutrons with BSH > thermal neutrons with BPA. In contrast, in Q cells, during that time the sensitivity increased in the following order: thermal neutrons only < thermal neutrons with BSH < thermal neutrons with BPA. The longer the interval between the two irradiations, the higher was the BrdU-labeled cell ratio at the second irradiation. The labeled cell ratio at the same time point after each priming irradiation increased in the following order: thermal neutrons only < thermal neutrons with BSH < thermal neutrons with BPA. These findings indicated that the use of 10B-compound, especially BPA, in thermal neutron irradiation causes the recruitment from the Q to P population.

Effects of hyperthermia and calcium channel blocker co-therapy on mice injected with Meth A solid of Meth A ascites tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prince, R.N.

1986-01-01

A study was made to determine the effectiveness of treating tumor-injected mice with verapamil, a calcium antagonist, and hyperthermia. The co-treatment reduced the incidence of tumors in animals injected with Meth A solid cells. It was shown that the decrease in tumors corresponded to increases in natural killer (NK) cell activity measured in a /sup 51/Cr release assay, in the amount of anti-Meth A antibody measured in an immunofluorescence assay, and a decrease in the amount of intra-tumor cyclic AMP measured by radioimmunoassay in co-treated compared to untreated sarcoma-injected animals. A role of the immune system for mediating the preventionmore » of sarcoma growth was indicated by Winn assays. Splenocytes sensitized in vivo against Meth A solid cells for 14 days exhibited an enhanced cytotoxic activity against syngeneic target cells compared to untreated tumor-sensitized splenocytes following heat-drug co-treatment. It was established that the stimulation of cytotoxic T cells against a histocompatibility antigen (H-2/sup d/) present on Meth A sarcoma cells resulted in tumor cell lysis. Animals bearing established Meth A solid sarcomas did not manifest tumor regressions following the administration of co-treatment alone or the adoptive transfer of co-treated tumor-sensitized splenocytes. The growth of Meth A ascites and Meth A ascites-derived solid sarcomas, unlike Meth A solid cell tumors, were not prevented in Winn assays. Additionally, the lifespan of animals injected with Meth A ascites cells was reduced by 50% compared to animals injected with Meth A solid sarcoma cells.« less

Preparation and characterization of injectable Mitoxantrone poly (lactic acid)/fullerene implants for in vivo chemo-photodynamic therapy.

PubMed

Li, Zhi; Zhang, Fei-long; Pan, Li-li; Zhu, Xia-li; Zhang, Zhen-zhong

2015-08-01

Fullerene (C60) L-phenylalanine derivative attached with poly (lactic acid) (C60-phe-PLA) was developed to prepare injectable Mitoxantrone (MTX) multifunctional implants. C60-phe-PLA was self-assembled to form microspheres consisting of a hydrophilic antitumor drug (MTX) and a hydrophobic block (C60) by dispersion-solvent diffusion method. The self-assembled microspheres showed sustained release pattern almost 15days in vitro release experiments. According to the tissue distribution of C57BL mice after intratumoral administration of the microspheres, the MTX mainly distributed in tumors, and rarely in heart, liver, spleen, lung, and kidney. Photodynamic antitumor efficacy of blank microsphere was realized. Microspheres afforded high antitumor efficacy without obvious toxic effects to normal organs, owing to its significantly increased MTX tumor retention time, low MTX levels in normal organs and strong photodynamic activity of PLA-phe-C60. These C60-phe-PLA microspheres may be promising for the efficacy with minimal side effects in future treatment of solid tumors. Copyright © 2015 Elsevier B.V. All rights reserved.

Cytokine-enhanced vaccine and interferon-β plus suicide gene as combined therapy for spontaneous canine sarcomas.

PubMed

Finocchiaro, Liliana M E; Villaverde, Marcela S; Gil-Cardeza, María L; Riveros, María D; Glikin, Gerardo C

2011-10-01

Eleven soft tissue- and five osteosarcoma canine patients were subjected to: (i) periodic subcutaneous injection of irradiated xenogeneic cells secreting hGM-CSF and hIL-2 mixed with allogeneic or autologous tumor homogenates; and (ii) injections of cIFN-β and HSVtk-carrying lipoplexes and ganciclovir, marginal (after surgery) and/or intratumoral (in the case of partial tumor resection, local relapse or small surface tumors). This treatment alone (4 patients) or as surgery adjuvant (12 patients), was safe and well tolerated. In those patients presenting local disease (6/11), the suicide gene plus cIFN-β treatment induced local antitumor activity evidenced by the objective responses (3 complete, 2 partial) and stable diseases (2). In addition, the treatment prevented or delayed local relapse, regional metastases (lymph nodes developed only in 3/16) and distant metastases (0/16), suggesting a strong systemic antitumor immunity. The most encouraging result was the long survival times of 10 patients (>1 year, with good quality of life). Copyright © 2011 Elsevier Ltd. All rights reserved.

Exosomes derived from tumor cells genetically modified to express Mycobacterium tuberculosis antigen: a novel vaccine for cancer therapy.

PubMed

Koyama, Yoshiyuki; Ito, Tomoko; Hasegawa, Aya; Eriguchi, Masazumi; Inaba, Toshio; Ushigusa, Takahiro; Sugiura, Kikuya

2016-11-01

To examine the potential of exosomes derived from the tumor cells, which had been genetically modified to express a Mycobacterium tuberculosis antigen, as a cancer vaccine aimed at overcoming the weak immunogenicity of tumor antigens. We transfected B16 melanoma cells with a plasmid encoding the M. tuberculosis antigen, early secretory antigenic target-6 (ESAT-6). The secreted exosomes bearing both tumor-associated antigens and the pathogenic antigen (or their epitopes) were collected. When the exosomes were injected into foot pads of mice, they significantly (p < 0.05) evoked cellular immunity against both ESAT-6, and B16 tumor cells. Intra-tumoral injection of the exosomes significantly suppressed (p < 0.001) tumor growth in syngeneic B16 tumor-bearing mice, while the exosomes derived from the non-transfected B16 cells showed no effect on tumor growth, although both exosomes should have similar tumor antigens. Exosomes bearing both tumor antigens and the M. tuberculosis antigen (or their epitopes) have a high potential as a candidate for cancer vaccine to overcome the immune escape by tumor cells.

Efficacy and toxicity of plasmonic photothermal therapy (PPTT) using gold nanorods (GNRs) against mammary tumors in dogs and cats.

PubMed

Abdoon, Ahmed S; Al-Ashkar, Emad A; Kandil, Omaima M; Shaban, Ahmed M; Khaled, Hussein M; El Sayed, Mostafa A; El Shaer, Marwa M; Shaalan, Asharaf H; Eisa, Wael H; Eldin, Amina A Gamal; Hussein, Hany A; El Ashkar, Mohammad R; Ali, Moustafa R; Shabaka, Ali A

2016-11-01

Plasmonic photothermal therapy (PPTT) was introduced as a promising treatment of cancer. This work was conducted to evaluate the cytotoxic effect of intratumoral (IT) injection of 75μg gold nanorods (GNRs)/kg of body weight followed by direct exposure to 2 w/cm 2 near infra-red laser light for 10min on ablation of mammary tumor in 10 dogs and 6 cats. Complete blood count (CBC), liver and kidney function were checked before the start of treatment and one month after injection of GNRs. Results showed that 62.5% (10/16), 25% (4/16) and 12.5% (2/16) of treated animals showed complete remission, partial remission and no response, respectively. Tumor was relapsed in 4 cases of initially responding animals (25%). Overall survival rate was extended to 315.5±20.5days. GNRs have no toxic effect on blood profile, liver or kidney functions. In conclusion, GNRs can be safely used for treatment of mammary tumors in dogs and cats. Copyright © 2016 Elsevier Inc. All rights reserved.

The value of color Doppler imaging and intralesional steroid injection in pediatric orbital capillary hemangioma.

PubMed

Ke, Yifeng; Hao, Rui; He, Yanjin; Tam, Eric S; Li, Xiaorong

2014-05-01

To evaluate color Doppler imaging (CDI) as the primary imaging modality in the diagnosis of pediatric orbital capillary hemangioma. This is a retrospective study of 36 consecutive cases of orbital capillary hemangiomas between January 2006 and July 2011. Data on demographic details, clinical findings, gray-scale ultrasonography, CDI characteristics, treatment, and follow-up period were reviewed. The mean age of onset was 7 weeks. Twenty-nine (81%) lesions presented as eyelid masses, whereas seven (19%) presented as exophthalmos. Nineteen (53%) tumors were located on the upper eyelid, seven (19%) on the lower eyelid, six (17%) in the medial canthus, and one on both upper and lower eyelids. Ultrasonography depicted a heterogeneous, well-defined, irregular tumor with a low or moderate echogenicity. All lesions presented with abundant color blood flow on CDI. The intralesional blood flow had a mean peak systolic velocity of 37.5 ± 24.5 cm/second, and a mean resistance index of 0.69 ± 0.16, representing a shift in the pulse Doppler toward high velocity and high resistance. After a single intratumoral injection of betamethasone, 18 cases (50%) resolved. Additionally, 15 (42%) and four (11%) cases resolved after two injections and three injections, respectively. Only three (8%) masses persisted after three injections within the follow-up period. The blood flow characteristics of CDI play a vital role in the differentiation of orbital capillary hemangiomas from other orbital lesions. The availability and lack of adverse effects of CDI enable its utilization in the early clinical diagnosis of pediatric orbital capillary hemangioma. Copyright © 2014. Published by Elsevier B.V.

Intratumor Heterogeneity in Evolutionary Models of Tumor Progression

PubMed Central

Durrett, Rick; Foo, Jasmine; Leder, Kevin; Mayberry, John; Michor, Franziska

2011-01-01

With rare exceptions, human tumors arise from single cells that have accumulated the necessary number and types of heritable alterations. Each such cell leads to dysregulated growth and eventually the formation of a tumor. Despite their monoclonal origin, at the time of diagnosis most tumors show a striking amount of intratumor heterogeneity in all measurable phenotypes; such heterogeneity has implications for diagnosis, treatment efficacy, and the identification of drug targets. An understanding of the extent and evolution of intratumor heterogeneity is therefore of direct clinical importance. In this article, we investigate the evolutionary dynamics of heterogeneity arising during exponential expansion of a tumor cell population, in which heritable alterations confer random fitness changes to cells. We obtain analytical estimates for the extent of heterogeneity and quantify the effects of system parameters on this tumor trait. Our work contributes to a mathematical understanding of intratumor heterogeneity and is also applicable to organisms like bacteria, agricultural pests, and other microbes. PMID:21406679

Farnesylthiosalicylic acid-loaded lipid-polyethylene glycol-polymer hybrid nanoparticles for treatment of glioblastoma.

PubMed

Kaffashi, Abbas; Lüle, Sevda; Bozdağ Pehlivan, Sibel; Sarısözen, Can; Vural, İmran; Koşucu, Hüsnü; Demir, Taner; Buğdaycı, Kadir Emre; Söylemezoğlu, Figen; Karlı Oğuz, Kader; Mut, Melike

2017-08-01

We aimed to develop lipid-polyethylene glycol (PEG)-polymer hybrid nanoparticles, which have high affinity to tumour tissue with active ingredient, a new generation antineoplastic drug, farnesylthiosalicylic acid (FTA) for treatment of glioblastoma. Farnesylthiosalicylic acid-loaded poly(lactic-co-glycolic acid)-1,2 distearoyl-glycerol-3-phospho-ethanolamine-N [methoxy (PEG)-2000] ammonium salt (PLGA-DSPE-PEG) with or without 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) hybrid nanoparticles has been prepared and evaluated for in-vitro characterization. Cytotoxicity of FTA-loaded nanoparticles along with its efficacy on rat glioma-2 (RG2) cells was also evaluated both in vitro (in comparison with non-malignant cell line, L929) and in vivo. Scanning electron microscopy studies showed that all formulations prepared had smooth surface and spherical in shape. FTA and FTA-loaded nanoparticles have cytotoxic activity against RG2 glioma cell lines in cell culture studies, which further increases with addition of DOTAP. Magnetic resonance imaging and histopathologic evaluation on RG2 tumour cells in rat glioma model (49 female Wistar rats, 250-300 g) comparing intravenous and intratumoral injections of the drug have been performed and FTA-loaded nanoparticles reduced tumour size significantly in in-vivo studies, with higher efficiency of intratumoral administration than intravenous route. Farnesylthiosalicylic acid-loaded PLGA-DSPE-PEG-DOTAP hybrid nanoparticles are proven to be effective against glioblastoma in both in-vitro and in-vivo experiments. © 2017 Royal Pharmaceutical Society.

Contrast-enhanced color Doppler ultrasonography increases diagnostic accuracy for soft tissue tumors.

PubMed

Oebisu, Naoto; Hoshi, Manabu; Ieguchi, Makoto; Takada, Jun; Iwai, Tadashi; Ohsawa, Masahiko; Nakamura, Hiroaki

2014-10-01

Resolution of ultrasonography (US) has undergone marked development. Additionally, a new-generation contrast medium (Sonazoid) used for US is newly available. Contrast-enhanced US has been widely used for evaluating several types of cancer. In the present study, we evaluated the ability of color Doppler US (CDUS) and Sonazoid to differentiate between benign and malignant soft tissue tumors. A total of 180 patients (87 male, 93 female) were enrolled in the present study. The patient ages ranged from 1 to 91 years (mean 58.1±20.0 years). The maximum size, depth, tumor margins, shape, echogenicity and textural pattern were measured on gray-scale images. CDUS was used to evaluate the intratumoral blood flow with and without Sonazoid. Peak systolic flow velocity (Vp), mean flow velocity (Vm), resistivity index (RI) and pulsatility index (PI) of each detected intratumoral artery were automatically calculated with power Doppler US (PDUS). The present study included 118 benign and 62 malignant tumors. Statistical significances were found in size, depth, tumor margin and textural pattern but not in shape or echogenicity on gray-scale images. Before Sonazoid injection, CDUS findings showed 55% sensitivity, 77% specificity and 69% accuracy, whereas contrast-enhanced CDUS showed 87% sensitivity, 68% specificity and 74% accuracy. There were no statistically significant differences between malignant and benign tumors regarding the mean Vp, Vm, RI and PI values determined on PDUS. In conclusion, contrast-enhanced CDUS proved to be a reliable diagnostic tool for detecting malignant potential in soft tissue tumors.

Association between tumour infiltrating lymphocytes, histotype and clinical outcome in epithelial ovarian cancer.

PubMed

James, Fiona R; Jiminez-Linan, Mercedes; Alsop, Jennifer; Mack, Marie; Song, Honglin; Brenton, James D; Pharoah, Paul D P; Ali, H Raza

2017-09-20

There is evidence that some ovarian tumours evoke an immune response, which can be assessed by tumour infiltrating lymphocytes (TILs). To facilitate adoption of TILs as a clinical biomarker, a standardised method for their H&E visual evaluation has been validated in breast cancer. We sought to investigate the prognostic significance of TILs in a study of 953 invasive epithelial ovarian cancer tumour samples, both primary and metastatic, from 707 patients from the prospective population-based SEARCH study. TILs were analysed using a standardised method based on H&E staining producing a percentage score for stromal and intratumoral compartments. We used Cox regression to estimate hazard ratios of the association between TILs and survival. The extent of stromal and intra-tumoral TILs were correlated in the primary tumours (n = 679, Spearman's rank correlation = 0.60, P < 0.001) with a similar correlation in secondary tumours (n = 224, Spearman's rank correlation = 0.62, P < 0.001). There was a weak correlation between stromal TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.29, P < 0.001) and intra-tumoral TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.19, P = 0.0094). The extent of stromal TILs differed between histotypes (Pearson chi2 (12d.f.) 54.1, P < 0.0001) with higher levels of stromal infiltration in the high-grade serous and endometriod cases. A significant association was observed for higher intratumoral TIL levels and a favourable prognosis (HR 0.74 95% CI 0.55-1.00 p = 0.047). This study is the largest collection of epithelial ovarian tumour samples evaluated for TILs. We have shown that stromal and intratumoral TIL levels are correlated and that their levels correlate with clinical variables such as tumour histological subtype. We have also shown that increased levels of both intratumoral and stromal TILs are associated with a better prognosis; however, this is only statistically significant for intratumoral TILs. This study suggests that a clinically useful immune prognostic indicator in epithelial ovarian cancer could be developed using this technique.

Theoretical study of the influence of a heterogeneous activity distribution on intratumoral absorbed dose distribution.

PubMed

Bao, Ande; Zhao, Xia; Phillips, William T; Woolley, F Ross; Otto, Randal A; Goins, Beth; Hevezi, James M

2005-01-01

Radioimmunotherapy of hematopoeitic cancers and micrometastases has been shown to have significant therapeutic benefit. The treatment of solid tumors with radionuclide therapy has been less successful. Previous investigations of intratumoral activity distribution and studies on intratumoral drug delivery suggest that a probable reason for the disappointing results in solid tumor treatment is nonuniform intratumoral distribution coupled with restricted intratumoral drug penetrance, thus inhibiting antineoplastic agents from reaching the tumor's center. This paper describes a nonuniform intratumoral activity distribution identified by limited radiolabeled tracer diffusion from tumor surface to tumor center. This activity was simulated using techniques that allowed the absorbed dose distributions to be estimated using different intratumoral diffusion capabilities and calculated for tumors of varying diameters. The influences of these absorbed dose distributions on solid tumor radionuclide therapy are also discussed. The absorbed dose distribution was calculated using the dose point kernel method that provided for the application of a three-dimensional (3D) convolution between a dose rate kernel function and an activity distribution function. These functions were incorporated into 3D matrices with voxels measuring 0.10 x 0.10 x 0.10 mm3. At this point fast Fourier transform (FFT) and multiplication in frequency domain followed by inverse FFT (iFFT) were used to effect this phase of the dose calculation process. The absorbed dose distribution for tumors of 1, 3, 5, 10, and 15 mm in diameter were studied. Using the therapeutic radionuclides of 131I, 186Re, 188Re, and 90Y, the total average dose, center dose, and surface dose for each of the different tumor diameters were reported. The absorbed dose in the nearby normal tissue was also evaluated. When the tumor diameters exceed 15 mm, a much lower tumor center dose is delivered compared with tumors between 3 and 5 mm in diameter. Based on these findings, the use of higher beta-energy radionuclides, such as 188Re and 90Y is more effective in delivering a higher absorbed dose to the tumor center at tumor diameters around 10 mm.

Genomic and epigenomic heterogeneity of hepatocellular carcinoma

PubMed Central

Lin, De-Chen; Mayakonda, Anand; Dinh, Huy Q.; Huang, Pinbo; Lin, Lehang; Liu, Xiaoping; Ding, Ling-wen; Wang, Jie; Berman, Benjamin P.; Song, Er-Wei; Yin, Dong; Koeffler, H. Phillip

2017-01-01

Understanding the intratumoral heterogeneity of hepatocellular carcinoma (HCC) is instructive for developing personalized therapy and identifying molecular biomarkers. Here we applied whole-exome sequencing to 69 samples from 11 patients to resolve the genetic architecture of subclonal diversification. Spatial genomic diversity was found in all 11 HCC cases, with 29% of driver mutations being heterogeneous, including TERT, ARID1A, NOTCH2, and STAG2. Similar with other cancer types, TP53 mutations were always shared between all tumor regions i.e. located on the “trunk” of the evolutionary tree. In addition, we found that variants within several drug targets such as KIT, SYK and PIK3CA were mutated in a fully clonal manner, indicating their therapeutic potentials for HCC. Temporal dissection of mutational signatures suggested that mutagenic processes associated with exposure to aristolochic acid and aflatoxin might play a more important role in early, as opposed to late, stages of HCC development. Moreover, we observed extensive intratumoral epigenetic heterogeneity in HCC based on multiple independent analytical methods and showed that intratumoral methylation heterogeneity might play important roles in the biology of HCC cells. Our results also demonstrated prominent heterogeneity of intratumoral methylation even in a stable HCC genome. Together, these findings highlight widespread intratumoral heterogeneity at both the genomic and epigenomic levels in HCC and provide an important molecular foundation for better understanding the pathogenesis of this malignancy. PMID:28302680

Differentiating intratumoral melanocytes from Langerhans cells in nonmelanocytic pigmented skin tumors in vivo by label-free third-harmonic generation microscopy

NASA Astrophysics Data System (ADS)

Weng, Wei-Hung; Liao, Yi-Hua; Tsai, Ming-Rung; Wei, Ming-Liang; Huang, Hsin-Yi; Sun, Chi-Kuang

2016-07-01

Morphology and distribution of melanocytes are critical imaging information for the diagnosis of melanocytic lesions. However, how to image intratumoral melanocytes noninvasively in pigmented skin tumors is seldom investigated. Third-harmonic generation (THG) is shown to be enhanced by melanin, whereas high accuracy has been demonstrated using THG microscopy for in vivo differential diagnosis of nonmelanocytic pigmented skin tumors. It is thus desirable to investigate if label-free THG microscopy was capable to in vivo identify intratumoral melanocytes. In this study, histopathological correlations of label-free THG images with the immunohistochemical images stained with human melanoma black (HMB)-45 and cluster of differentiation 1a (CD1a) were made. The correlation results indicated that the intratumoral THG-bright dendritic-cell-like signals were endogenously derived from melanocytes rather than Langerhans cells (LCs). The consistency between THG-bright dendritic-cell-like signals and HMB-45 melanocyte staining showed a kappa coefficient of 0.807, 84.6% sensitivity, and 95% specificity. In contrast, a kappa coefficient of -0.37, 21.7% sensitivity, and 30% specificity were noted between the THG-bright dendritic-cell-like signals and CD1a staining for LCs. Our study indicates the capability of noninvasive label-free THG microscopy to differentiate intratumoral melanocytes from LCs, which is not feasible in previous in vivo label-free clinical-imaging modalities.

Using anti-VEGF McAb and magnetic nanoparticles as double-targeting vector for the radioimmunotherapy of liver cancer.

PubMed

Chen, Jing; Wu, Hua; Han, Deyan; Xie, Changsheng

2006-01-18

To study the biodistribution of a new radioimmunoconjugate-131I-anti-VEGF monoclonal antibody (Sc-7269)-Dextran Magnetic Nanoparticles (DMN) in nude mice bearing human liver cancer where an external magnetic field was focused on, and to evaluate its therapeutic effects and safety. Tumor Growth Delay (TGD) and tumor inhibition rate were observed as antitumor effect. Peripheral white blood cells counts and the loss of body weight were tested as an indicator of systemic toxicity. The results suggests that the radioimmunotherapy of intratumoral injection of 131I-Sc-7269-DMN may be safe and efficient for the treatment of liver cancer. Furthermore, the radioimmunotherapy using DMN as a 'carrier system' may be a highly potential approach in the treatment of other kind of tumors.

TLR7 agonist in combination with Salmonella as an effective antimelanoma immunotherapy.

PubMed

Vola, Magdalena; Mónaco, Amy; Bascuas, Thais; Rimsky, Geraldine; Agorio, Caroline Isabel; Chabalgoity, José Alejandro; Moreno, María

2018-03-22

We evaluated a novel approach combining the use of attenuated Salmonella immunotherapy with a Toll-like receptor agonist, imiquimod, in B16F1 melanoma-bearing mice. B16F1 melanoma-bearing mice were daily treated with topical imiquimod in combination with one intratumoral injection of attenuated Salmonella enterica serovar Typhimurium LVR01. The combined therapy resulted in retarded tumor growth and prolonged survival. Combination treatment led to an enhancement in the expression of pro-inflammatory cytokines and chemokines in the tumor microenvironment, with a Th1-skewed profile, resulting in a broad antitumor response. The induced immunity was effective in controlling the occurrence of metastasis. Salmonella LVR01 immunotherapy in combination with imiquimod is a novel approach that could be considered as an effective antimelanoma therapy.

Real-time infrared thermography detection of magnetic nanoparticle hyperthermia in a murine model under a non-uniform field configuration.

PubMed

Rodrigues, Harley F; Mello, Francyelli M; Branquinho, Luis C; Zufelato, Nicholas; Silveira-Lacerda, Elisângela P; Bakuzis, Andris F

2013-12-01

Magnetic nanoparticle hyperthermia consists of an increase of the temperature of magnetic nanoparticles (heat centres) due to the interaction of their magnetic moments with an alternating magnetic field. In vivo experiments using this method usually use a few fibre-optic thermometers inserted in the animal body to monitor the heat deposition. As a consequence, only a few points of the 3D temperature distribution can be monitored by this invasive procedure. It is the purpose of this work to show that non-invasive infrared thermography is able to detect, in real time, magnetic nanoparticle hyperthermia as well as monitor the harmful field-induced eddy currents in a murine model with a subcutaneous tumour. This surface temperature measurement method has the potential to give information about the intratumoral temperature. The non-invasive magnetic hyperthermia experiments were performed at 300 kHz in non-uniform field configuration conditions in healthy mice and murine tumour induced by sarcoma S180. A soft ferrite-based biocompatible magnetic colloid consisting of manganese-ferrite nanoparticles surface-coated with citric acid were used in the experiments, which were extensively characterised by several techniques (transmission electron microscopy (TEM), X-ray diffraction (XRD), vibrating sample magnetometer (VSM)). The amplitude of the alternating magnetic fields was obtained from measurements using an AC field probe at similar experimental conditions. The temperature measurements were obtained from an infrared thermal camera and a fibre-optic thermometer. Three-minute magnetic hyperthermia experiments revealed surface temperature increase as high as 11 °K in healthy and (5 °K in S180 tumour) animals when injecting subcutaneously 2 mg of magnetic nanoparticles (86 μL of magnetic fluid), in contrast to around 1.5 °K (for healthy) and 2.5 °K (for cancerous) animals in experiments without the colloid due to field-induced eddy currents at the animal surface. The thermographic temperature measurements were found to agree with the fibre-optic measurements within a 5% error, and were associated with the skin emissivity angle of dependence in the experimental set-up. On the other hand, a 30-min magnetic nanoparticle hyperthermia revealed surface temperature increases as high as 12 °K close to the injection site, while above 2-3 cm no significant temperature increase was observed. Curiously, the intratumoral temperature, monitored by a fibre-optic sensor, was found to be almost the same as the thermal camera surface temperature after achieving an equilibrium temperature regime. From the observed isotherms at the animal surface, using an analytical heat conduction model, taking into account surface conductance, we estimate a magnetic heating power of 0.45 W/cm(3) and a specific loss power (SLP) of 85 W/g for a field of the order of only 10 kA/m at the injection site region. The results indicate that infrared thermography may be a promising tool for both early cancer detection and for hyperthermia treatment (at least for subcutaneous tumours), since the method permits access to information about the intratumoral temperature during a real-time magnetic hyperthermia as well as to estimate the in vivo nanoparticles SLP.

Locally targeted delivery of a micron-size radiation therapy source using temperature-sensitive hydrogel.

PubMed

Kim, Yusung; Seol, Dong Rim; Mohapatra, Sucheta; Sunderland, John J; Schultz, Michael K; Domann, Frederick E; Lim, Tae-Hong

2014-04-01

To propose a novel radiation therapy (RT) delivery modality: locally targeted delivery of micron-size RT sources by using temperature-sensitive hydrogel (RT-GEL) as an injectable vehicle. Hydrogel is a water-like liquid at room temperature but gels at body temperature. Two US Food and Drug Administration-approved polymers were synthesized. Indium-111 (In-111) was used as the radioactive RT-GEL source. The release characteristics of In-111 from polymerized RT-GEL were evaluated. The injectability and efficacy of RT-GEL delivery to human breast tumor were tested using animal models with control datasets of RT-saline injection. As proof-of-concept studies, a total of 6 nude mice were tested by injecting 4 million tumor cells into their upper backs after a week of acclimatization. Three mice were injected with RT-GEL and 3 with RT-saline. Single-photon emission computed tomography (SPECT) and CT scans were performed on each mouse at 0, 24, and 48 h after injection. The efficacy of RT-GEL was determined by comparison with that of the control datasets by measuring kidney In-111 accumulation (mean nCi/cc), representing the distant diffusion of In-111. RT-GEL was successfully injected into the tumor by using a 30-gauge needle. No difficulties due to polymerization of hydrogel during injection and intratumoral pressure were observed during RT-GEL injection. No back flow occurred for either RT-GEL or RT-saline. The residual tumor activities of In-111 were 49% at 24 h (44% at 48 h, respectively) for RT-GEL and 29% (22%, respectively) for RT-saline. Fused SPECT-CT images of RT-saline showed considerable kidney accumulation of In-111 (2886%, 261%, and 262% of RT-GEL at 0, 24, and 48 h, respectively). RT-GEL was successfully injected and showed much higher residual tumor activity: 170% (200%, respectively), than that of RT-saline at 24 h (48 h, respectively) after injection with a minimal accumulation of In-111 to the kidneys. Preliminary data of RT-GEL as a delivery modality of a radiation source to a local tumor are promising. Published by Elsevier Inc.

Discontinuation rates and inter-injection interval for repeated intravesical botulinum toxin type A injections for detrusor overactivity.

PubMed

Veeratterapillay, Rajan; Harding, Chris; Teo, Luke; Vasdev, Nikhil; Abroaf, Ahmed; Dorkin, Trevor J; Pickard, Robert S; Hasan, Tahseen; Thorpe, Andrew C

2014-02-01

To report discontinuation rates, inter-injection interval and complication rates after repeated intravesical botulinum toxin type A for the treatment of detrusor overactivity. Patients with urodyamically proven detrusor overactivity who had two or more botulinum toxin type A injections in the period 2004-2011 at Freeman Hospital, Newcastle Upon Tyne, UK, were considered for the present study. Discontinuation rates, complication rates and interval between botulinum toxin type A treatments were retrospectively analyzed. Overall, 125 patients (median age 53 years, range 19-83 years) were included in the analysis. The female-to-male ratio was 2.4:1 and median follow up was 38 months. A total of 96 patients had idiopathic detrusor overactivity, whereas 29 had neurogenic detrusor overactivity. A total of 667 injections were carried out, with 125 patients receiving two injections, 60 receiving three injections, 28 receiving four injections, 14 receiving five injections, three receiving six injections, three receiving seven injections and two receiving eight injections. The mean interval (±standard deviation) between the first and second injection (n = 125) was 17.6 months (±10.4), between the second and third (n = 60) was 15.7 ± 7.4 months, between the third and fourth (n = 28) was 15.4 ± 8.6 months, and between the fourth and subsequent injections (n = 22) was 11.6 ± 4.5 months. A total of 26% required intermittent catheterization, and 18% developed recurrent urinary tract infections. There was a discontinuation rate of 25% at 60 months. Repeated botulinum toxin type A injections represent a safe and effective method for managing patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity. We have shown that the inter-injection interval remains unchanged up to five injections. © 2013 The Japanese Urological Association.

Whole-Lesion Apparent Diffusion Coefficient-Based Entropy-Related Parameters for Characterizing Cervical Cancers: Initial Findings.

PubMed

Guan, Yue; Li, Weifeng; Jiang, Zhuoran; Chen, Ying; Liu, Song; He, Jian; Zhou, Zhengyang; Ge, Yun

2016-12-01

This study aimed to develop whole-lesion apparent diffusion coefficient (ADC)-based entropy-related parameters of cervical cancer to preliminarily assess intratumoral heterogeneity of this lesion in comparison to adjacent normal cervical tissues. A total of 51 women (mean age, 49 years) with cervical cancers confirmed by biopsy underwent 3-T pelvic diffusion-weighted magnetic resonance imaging with b values of 0 and 800 s/mm 2 prospectively. ADC-based entropy-related parameters including first-order entropy and second-order entropies were derived from the whole tumor volume as well as adjacent normal cervical tissues. Intraclass correlation coefficient, Wilcoxon test with Bonferroni correction, Kruskal-Wallis test, and receiver operating characteristic curve were used for statistical analysis. All the parameters showed excellent interobserver agreement (all intraclass correlation coefficients  > 0.900). Entropy, entropy(H) 0 , entropy(H) 45 , entropy(H) 90 , entropy(H) 135 , and entropy(H) mean were significantly higher, whereas entropy(H) range and entropy(H) std were significantly lower in cervical cancers compared to adjacent normal cervical tissues (all P <.0001). Kruskal-Wallis test showed that there were no significant differences among the values of various second-order entropies including entropy(H) 0, entropy(H) 45 , entropy(H) 90 , entropy(H) 135 , and entropy(H) mean. All second-order entropies had larger area under the receiver operating characteristic curve than first-order entropy in differentiating cervical cancers from adjacent normal cervical tissues. Further, entropy(H) 45 , entropy(H) 90 , entropy(H) 135 , and entropy(H) mean had the same largest area under the receiver operating characteristic curve of 0.867. Whole-lesion ADC-based entropy-related parameters of cervical cancers were developed successfully, which showed initial potential in characterizing intratumoral heterogeneity in comparison to adjacent normal cervical tissues. Copyright © 2016 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

Intratumoral Vasculopathy in Leiomyoma Treated With Tranexamic Acid.

PubMed

Kudose, Satoru; Krigman, Hannah R

2017-07-01

Although intravascular thrombi and infarct-type necrosis have been reported in leiomyomas following tranexamic acid therapy, intratumoral vasculopathy resembling acute atherosis has not been reported to date in patients without exposure to gonadotropin receptor agonist. We describe a case of intratumoral vasculopathy resembling acute atherosis in a leiomyoma in a 49-year-old woman, with hereditary hemorrhagic telangiectasia and menorrhagia, treated with tranexamic acid. The patient had no exposure to gonadotropin receptor agonists. Pathologic examination of the hysterectomy specimen showed a 5.7-cm submucosal leiomyoma containing multiple arteries with fibrinoid change accompanied with abundant subintimal foamy macrophages and occasional luminal thrombi. The vascular media showed scant lymphocytic inflammation without necrosis. The leiomyoma contained numerous mast cells and edematous areas. Vessels outside of the leiomyoma showed neither fibrinoid changes nor inflammation. The patient is alive and well with no signs of systemic vasculitis. We demonstrate that intratumoral vasculopathy resembling acute atherosis may be seen in leiomyomas from patients taking tranexamic acid and postulate that this change results in vascular thrombosis, tumoral edema, and infarct-type necrosis.

Intratumor and Intertumor Heterogeneity in Melanoma.

PubMed

Grzywa, Tomasz M; Paskal, Wiktor; Włodarski, Paweł K

2017-12-01

Melanoma is a cancer that exhibits one of the most aggressive and heterogeneous features. The incidence rate escalates. A high number of clones harboring various mutations contribute to an exceptional level of intratumor heterogeneity of melanoma. It also refers to metastases which may originate from different subclones of primary lesion. Such component of the neoplasm biology is termed intertumor and intratumor heterogeneity. These levels of tumor heterogeneity hinder accurate diagnosis and effective treatment. The increasing number of research on the topic reflects the need for understanding limitation or failure of contemporary therapies. Majority of analyses concentrate on mutations in cancer-related genes. Novel high-throughput techniques reveal even higher degree of variations within a lesion. Consolidation of theories and researches indicates new routes for treatment options such as targets for immunotherapy. The demand for personalized approach in melanoma treatment requires extensive knowledge on intratumor and intertumor heterogeneity on the level of genome, transcriptome/proteome, and epigenome. Thus, achievements in exploration of melanoma variety are described in details. Particularly, the issue of tumor heterogeneity or homogeneity given BRAF mutations is discussed. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Relationship of mast cell density with lymphangiogenesis and prognostic parameters in breast carcinoma.

PubMed

Keser, Sevinc H; Kandemir, Nilufer O; Ece, Dilek; Gecmen, Gonca G; Gul, Aylin E; Barisik, Nagehan O; Sensu, Sibel; Buyukuysal, Cagatay; Barut, Figen

2017-04-01

In many cancers, mast cell density (MCD) in the tumor microenvironment is associated with tumor progression and, to a greater extent, angiogenesis. Our study was designed to investigate the correlation between MCD, tumor lymphangiogenesis, and several well-established prognostic parameters in breast cancer. One hundred and four cases of invasive breast carcinoma diagnosed in our clinic between 2007 and 2011 were included. Mast cells and lymphatic vessels were stained with toluidine blue and D2-40, respectively, and their densities were calculated in various areas of tumors and lymph nodes. The variables of MCD and lymphatic vessel density (LVD) were compared using prognostic parameters as well as with each other. As tumor size and volume increased, MCD increased comparably in metastatic lymph nodes; intratumoral and peritumoral LVD also increased. Lymphovascular invasion, lymphatic invasion, perineural invasion, and estrogen receptor positivity were positively related to intratumoral MCD. The relationship between peritumoral MCD and nontumoral breast tissue MCD was statistically significant. Stage was correlated with MCD in metastatic lymph nodes. Metastatic lymph node MCD and intratumoral MCD were also significantly related. Stage, lymphatic invasion, perineural invasion, lymphovascular invasion, and metastatic lymph node MCD were all correlated with intratumoral and/or peritumoral LVD. As nuclear grade increased, intratumoral LVD became higher. In breast carcinoma, MCD, depending on its location, was related to several prognostic parameters. Notably, mast cells may have at least some effect on lymphangiogenesis, which appears to be a predictor of tumor progression. Copyright © 2017. Published by Elsevier Taiwan.

Effects of tibolone on sulfatase pathway of estrogens metabolism and on growth of MCF-7 human breast tumors implanted in ovariectomized nude mice.

PubMed

Desreux, Joëlle; Kloosterboer, Helenius; Noël, Agnès; Frankenne, Francis; Lemaire, Madeleine; Putman, Monique; Foidart, Jean-Michel

2007-01-01

The benefits of estrogen plus progestin in healthy post-menopausal women remain uncertain. Tibolone, with its in vitro documented inhibitory effects on estrogens metabolism and its selective action on breast, may be an alternative that could favorably influence the health benefit of hormone replacement therapy. We studied the effect of tibolone on the tumor growth of MCF-7 cells implanted in 40 ovariectomized nude mice, receiving subcutaneous pellets of 17beta-estradiol, estrone, estrone-sulfate or vehicle, and daily gavages of tibolone or placebo. Tibolone, although used at high dose, did not stimulate nor inhibit the estrogen-induced tumors, nor the tumors in estrogen-deprived mice. Measurements of plasma levels of estrogens indicated that tibolone potently stimulated sulfotransferase activity, but intra-tumor levels of estrogens were not significantly modified by tibolone. This in vivo study performed with high dose of orally administered tibolone that allowed its hepatic conversion into active metabolites has shown no significant effect on breast tumors growth. Tibolone increased the circulating sulfated estrogens by its activity on the hepatic sulfation but not the intra-tumor levels of estrogens (free or sulfated). However, further studies of dose-response curve and molecular markers are needed to exclude definitely a stimulatory effect of tibolone on tumor growth.

Effective conversion of irinotecan to SN-38 after intratumoral drug delivery to an intracranial murine glioma model in vivo. Laboratory investigation.

PubMed

Wang, Weijun; Ghandi, Alex; Liebes, Leonard; Louie, Stan G; Hofman, Florence M; Schönthal, Axel H; Chen, Thomas C

2011-03-01

Irinotecan (CPT-11), a topoisomerase I inhibitor, is a cytotoxic agent with activity against malignant gliomas and other tumors. After systemic delivery, CPT-11 is converted to its active metabolite, SN-38, which displays significantly higher cytotoxic potency. However, the achievement of therapeutically effective plasma levels of CPT-11 and SN-38 is seriously complicated by variables that affect drug metabolism in the liver. Thus the capacity of CPT-11 to be converted to the active SN38 intratumorally in gliomas was addressed. For in vitro studies, 2 glioma cell lines, U87 and U251, were tested to determine the cytotoxic effects of CPT-11 and SN-38 in a dose-dependent manner. In vivo studies were performed by implanting U87 intracranially into athymic/nude mice. For a period of 2 weeks, SN-38, CPT-11, or vehicle was administered intratumorally by means of an osmotic minipump. One series of experiments measured the presence of SN-38 or CPT-11 in the tumor and surrounding brain tissues after 2 weeks' exposure to the drug. In a second series of experiments, after 2 weeks' exposure to the drug, the animals were maintained, in the absence of drug, until death. The survival curves were then calculated. The results show that the animals that had CPT-11 delivered intratumorally by the minipump expressed SN-38 in vivo. Furthermore, both CPT-11 and SN-38 accumulated at higher levels in tumor tissues compared with uninvolved brain. Intratumoral delivery of CPT-11 or SN-38 extended the average survival time of tumor-bearing animals from 22 days to 46 and 65 days, respectively. These results demonstrate that intratumorally administered CPT-11 can be effectively converted to SN-38 and this method of drug delivery is effective in extending the survival time of animals bearing malignant gliomas.

Long-term effect of anti-vascular endothelial growth factor injections on intraocular pressure

PubMed Central

Nariani, Ashiyana; Williams, Blake; Hariprasad, Seenu M

2016-01-01

Objective: There is a substantial debate in the ophthalmology community about whether anti-vascular endothelial growth factor (VEGF) injections result in a long-term increase in intraocular pressure (IOP). Design: We performed a retrospective study to investigate how the number and timing of intravitreal injections in patients with age-related macular degeneration (AMD) and diabetic macular edema (DME) affect IOP over time. Methods: We collected long-term IOP data on patients receiving anti-VEGF injections at our institution. Patients over the age of 40 years who received injections for AMD (n = 76) or DME (n = 55) were included. Patients were grouped according to indication as well as number of injections received (1–3, 4–6, 7–9, or 10+ injections). IOP measurements were then placed into time points (0–6, 6–12, 12–18, 18–24, or 24+ months) and compared to the preinjection average IOP. Results: For patients with DME, average preinjection IOP was 15.7 mmHg. At 24+ months after injection, the average IOP was 15.2 (P = 0.68) for patients receiving 1–3 injections, 16.8 (P = 0.23) for 4–6 injections, and 14.4 (P = 0.66) for 7–9 injections. For patients with AMD, average initial IOP was 15.6 mmHg. At 24+ months after injection, the average IOP was 12.6 (P = 0.97) for 1–3 injections, 14.9 (P = 0.96) for 4–6 injections, 14.8 (P = 0.84) for 7–9 injections, and 15.7 (P = 0.56) for 10+ injections. Conclusions: There was no increase in IOP over time for AMD or DME patients, regardless of how many injections they received. For patients receiving unilateral injections, there was no increase in IOP in the injected eye when compared to the noninjected eye. PMID:27853011

Medical Injection Use Among Adults and Adolescents Aged 15 to 64 Years in Kenya: Results From a National Survey

PubMed Central

Kimani, Daniel; Kamau, Rachel; Ssempijja, Victor; Robinson, Katherine; Oluoch, Tom; Njeru, Mercy; Mwangi, Jane; Njogu, David; Kim, Andrea A.

2016-01-01

Background Unsafe medical injections remain a potential route of HIV transmission in Kenya. We used data from a national survey in Kenya to study the magnitude of medical injection use, medication preference, and disposal of medical waste in the community. Methods The Kenya AIDS Indicator Survey 2012 was a nationally representative population-based survey. Among participants aged 15–64 years, data were collected regarding medical injections received in the year preceding the interview; blood samples were collected from participants for HIV testing. Results Of the 13,673 participants who answered questions on medical injections, 35.9% [95% confidence interval (CI): 34.5 to 37.3] reported receiving ≥1 injection in the past 12 months and 51.2% (95% CI: 49.7 to 52.8) preferred receiving an injection over a pill. Among those who received an injection from a health care provider, 95.9% (95% CI: 95.2 to 96.7) observed him/her open a new injection pack, and 7.4% (95% CI: 6.4 to 8.4) had seen a used syringe or needle near their home or community in the past 12 months. Men who had received ≥1 injection in the past 12 months (adjusted odds ratio, 3.2; 95% CI: 1.2 to 8.9) and women who had received an injection in the past 12 months, not for family planning purposes (adjusted odds ratio, 2.6; 95% CI: 1.2 to 5.5), were significantly more likely to be HIV infected compared with those who had not received medical injection in the past 12 months. Conclusions Injection preference may contribute to high rates of injections in Kenya. Exposure to unsafe medical waste in the community poses risks for injury and infection. We recommend that community- and facility-based injection safety strategies be integrated in disease prevention programs. PMID:24413041

Human dosimetry and preliminary tumor distribution of 18F-fluoropaclitaxel in healthy volunteers and newly diagnosed breast cancer patients using PET/CT.

PubMed

Kurdziel, Karen A; Kalen, Joseph D; Hirsch, Jerry I; Wilson, John D; Bear, Harry D; Logan, Jean; McCumisky, James; Moorman-Sykes, Kathy; Adler, Stephen; Choyke, Peter L

2011-09-01

(18)F-fluoropaclitaxel is a radiolabeled form of paclitaxel, a widely used chemotherapy agent. Preclinical data suggest that (18)F-fluoropaclitaxel may be a reasonable surrogate for measuring the uptake of paclitaxel. As a substrate of P-glycoprotein, a drug efflux pump associated with multidrug resistance, (18)F-fluoropaclitaxel may also be useful in identifying multidrug resistance and predicting tumor response for drugs other than paclitaxel. After informed consent was obtained, 3 healthy volunteers and 3 patients with untreated breast cancer (neoadjuvant chemotherapy candidates, tumor size > 2 cm) received an intravenous infusion of (18)F-fluoropaclitaxel and then underwent PET/CT. Healthy volunteers underwent serial whole-body imaging over an approximately 3-h interval, and organ (18)F residence times were determined from the time-activity curves uncorrected for decay to determine dosimetry. Radiation dose estimates were calculated using OLINDA/EXM software. For breast cancer patients, dynamic imaging of the primary tumor was performed for 60 min, followed by static whole-body scans at 1 and 2 h after injection. Dosimetry calculations showed that the gallbladder received the highest dose (229.50 μGy/MBq [0.849 rad/mCi]), followed by the small and large intestines (161.26 μGy/MBq [0.597 rad/mCi] and 184.59 μGy/MBq [0.683 rad/mCi]). The resultant effective dose was 28.79 μGy/MBq (0.107 rem/mCi). At approximately 1 h after injection, an average of 42% of the decay-corrected activity was in the gastrointestinal system, with a mean of 0.01% in the tumor. All 3 breast cancer patients showed retention of (18)F-fluoropaclitaxel and ultimately demonstrated a complete pathologic response (no invasive cancer in the breast or axillary nodes) to chemotherapy that included a taxane (either paclitaxel or docetaxel) at surgical resection. The tumor-to-background ratio increased with time to a maximum of 7.7 at 20 min. This study demonstrates the feasibility of using (18)F-fluoropaclitaxel PET/CT tumor imaging and provides radiation dosimetry measurements in humans. Although further study is needed, it is hoped that the measured intratumoral (18)F-fluoropaclitaxel distribution can serve as a surrogate for paclitaxel, and potentially other chemotherapeutic agent retention, in solid tumors.

The value of intratumoral heterogeneity of (18)F-FDG uptake to differentiate between primary benign and malignant musculoskeletal tumours on PET/CT.

PubMed

Nakajo, Masatoyo; Nakajo, Masayuki; Jinguji, Megumi; Fukukura, Yoshihiko; Nakabeppu, Yoshiaki; Tani, Atsushi; Yoshiura, Takashi

2015-01-01

The cumulative standardized uptake value (SUV)-volume histogram (CSH) was reported to be a novel way to characterize heterogeneity in intratumoral tracer uptake. This study investigated the value of fluorine-18 fludeoxyglucose ((18)F-FDG) intratumoral heterogeneity in comparison with SUV to discriminate between primary benign and malignant musculoskeletal (MS) tumours. The subjects comprised 85 pathologically proven MS tumours. The area under the curve of CSH (AUC-CSH) was used as a heterogeneity index, with lower values corresponding with increased heterogeneity. As 22 tumours were indiscernible on (18)F-FDG positron emission tomography, maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) and AUC-CSH were obtained in 63 positive tumours. The Mann-Whitney U test and receiver operating characteristic (ROC) analysis were used for analyses. The difference between benign (n = 35) and malignant tumours (n = 28) was significant in AUC-CSH (p = 0.004), but not in SUVmax (p = 0.168) and SUVmean (p = 0.879). The sensitivity, specificity and accuracy for diagnosing malignancy were 61%, 66% and 64% for SUVmax (optical threshold value, >6.9), 54%, 60% and 57% for SUVmean (optical threshold value, >3) and 61%, 86% and 75% for AUC-CSH (optical threshold value, ≤0.42), respectively. The area under the ROC curve was significantly higher in AUC-CSH (0.71) than SUVmax (0.60) (p = 0.018) and SUVmean (0.51) (p = 0.005). The heterogeneity index, AUC-CSH, has a higher diagnostic accuracy than SUV analysis in differentiating between primary benign and malignant MS tumours, although it is not sufficiently high enough to obviate histological analysis. AUC-CSH can assess the heterogeneity of (18)F-FDG uptake in primary benign and malignant MS tumours, with significantly greater heterogeneity associated with malignant MS tumours. AUC-CSH is more diagnostically accurate than SUV analysis in differentiating between benign and malignant MS tumours.

Improved Tumor Penetration and Single-Cell Targeting of Antibody-Drug Conjugates Increases Anticancer Efficacy and Host Survival.

PubMed

Cilliers, Cornelius; Menezes, Bruna; Nessler, Ian; Linderman, Jennifer; Thurber, Greg M

2018-02-01

Current antibody-drug conjugates (ADC) have made advances in engineering the antibody, linker, conjugation site, small-molecule payload, and drug-to-antibody ratio (DAR). However, the relationship between heterogeneous intratumoral distribution and efficacy of ADCs is poorly understood. Here, we compared trastuzumab and ado-trastuzumab emtansine (T-DM1) to study the impact of ADC tumor distribution on efficacy. In a mouse xenograft model insensitive to trastuzumab, coadministration of trastuzumab with a fixed dose of T-DM1 at 3:1 and 8:1 ratios dramatically improved ADC tumor penetration and resulted in twice the improvement in median survival compared with T-DM1 alone. In this setting, the effective DAR was lowered, decreasing the amount of payload delivered to each targeted cell but increasing the number of cells that received payload. This result is counterintuitive because trastuzumab acts as an antagonist in vitro and has no single-agent efficacy in vivo , yet improves the effectiveness of T-DM1 in vivo Novel dual-channel fluorescence ratios quantified single-cell ADC uptake and metabolism and confirmed that the in vivo cellular dose of T-DM1 alone exceeded the minimum required for efficacy in this model. In addition, this technique characterized cellular pharmacokinetics with heterogeneous delivery after 1 day, degradation and payload release by 2 days, and in vitro cell killing and in vivo tumor shrinkage 2 to 3 days later. This work demonstrates that the intratumoral distribution of ADC, independent of payload dose or plasma clearance, plays a major role in ADC efficacy. Significance: This study shows how lowering the drug-to-antibody ratio during treatment can improve the intratumoral distribution of a antibody-drug conjugate, with implications for improving the efficacy of this class of cancer drugs. Cancer Res; 78(3); 758-68. ©2017 AACR . ©2017 American Association for Cancer Research.

Targeting Promoter-Associated Noncoding RNA In Vivo.

PubMed

Civenni, Gianluca

2017-01-01

There are many classes of noncoding RNAs (ncRNAs), with wide-ranging functionalities (e.g., RNA editing, mediation of mRNA splicing, ribosomal function). MicroRNAs (miRNAs) and long ncRNAs (lncRNAs) are implicated in a wide variety of cellular processes, including the regulation of gene expression. Incorrect expression or mutation of lncRNAs has been reported to be associated with several disease conditions, such a malignant transformation in humans. Importantly, pivotal players in tumorigenesis and cancer progression, such as c-Myc, may be regulated by lncRNA at promoter level. The function of lncRNA can be reduced with antisense oligonucleotides that sequester or degrade mature lncRNAs. In alternative, lncRNA transcription can be blocked by small interference RNA (RNAi), which had acquired, recently, broad interested in clinical applications. In vivo-jetPEI™ is a linear polyethylenimine mediating nucleic acid (DNA, shRNA, siRNA, oligonucelotides) delivery with high efficiency. Different in vivo delivery routes have been validated: intravenous (IV), intraperitoneal (IP), intratumoral, subcutaneous, topical, and intrathecal. High levels of nucleic acid delivery are achieved into a broad range of tissues, such as lung, salivary glands, heart, spleen, liver, and prostate upon systemic administration. In addition, in vivo-jetPEI™ is also an efficient carrier for local gene and siRNA delivery such as intratumoral or topical application on the skin. After systemic injection, siRNA can be detected and the levels can be validated in target tissues by qRT-PCR. Targeting promoter-associated lncRNAs with siRNAs (small interfering RNAs) in vivo is becoming an exciting breakthrough for the treatment of human disease.

Syngeneic syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting.

PubMed

Siurala, Mikko; Vähä-Koskela, Markus; Havunen, Riikka; Tähtinen, Siri; Bramante, Simona; Parviainen, Suvi; Mathis, J Michael; Kanerva, Anna; Hemminki, Akseli

2016-05-01

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown promising yet sometimes suboptimal results in clinical trials for advanced cancer, underscoring the need for approaches improving efficacy and safety. Six implantable syngeneic tumor cell lines of the Syrian hamster were used to initiate TIL cultures. TIL generated from tumor fragments cultured in human interleukin-2 (IL-2) for 10 d were adoptively transferred into tumor-bearing hamsters with concomitant intratumoral injections of oncolytic adenovirus (Ad5-D24) for the assessment of antitumor efficacy. Pancreatic cancer (HapT1) and melanoma (RPMI 1846) TIL exhibited potent and tumor-specific cytotoxicity in effector-to-target (E/T) assays. MHC Class I blocking abrogated the cell killing of RPMI 1846 TIL, indicating cytotoxic CD8(+) T-cell activity. When TIL were combined with Ad5-D24 in vitro, HapT1 tumor cell killing was significantly enhanced over single agents. In vivo, the intratumoral administration of HapT1 TIL and Ad5-D24 resulted in improved tumor growth control compared with either treatment alone. Additionally, splenocytes derived from animals treated with the combination of Ad5-D24 and TIL killed autologous tumor cells more efficiently than monotherapy-derived splenocytes, suggesting that systemic antitumor immunity was induced. For the first time, TIL of the Syrian hamster have been cultured, characterized and used therapeutically together with oncolytic adenovirus for enhancing the efficacy of TIL therapy. Our results support human translation of oncolytic adenovirus as an enabling technology for adoptive T-cell therapy of solid tumors.

Combined dendritic cell cryotherapy of tumor induces systemic antimetastatic immunity.

PubMed

Machlenkin, Arthur; Goldberger, Ofir; Tirosh, Boaz; Paz, Adrian; Volovitz, Ilan; Bar-Haim, Erez; Lee, Sung-Hyung; Vadai, Ezra; Tzehoval, Esther; Eisenbach, Lea

2005-07-01

Cryotherapy of localized prostate, renal, and hepatic primary tumors and metastases is considered a minimally invasive treatment demonstrating a low complication rate in comparison with conventional surgery. The main drawback of cryotherapy is that it has no systemic effect on distant metastases. We investigated whether intratumoral injections of dendritic cells following cryotherapy of local tumors (cryoimmunotherapy) provides an improved approach to cancer treatment, combining local tumor destruction and systemic anticancer immunity. The 3LL murine Lewis lung carcinoma clone D122 and the ovalbumin-transfected B16 melanoma clone MO5 served as models for spontaneous metastasis. The antimetastatic effect of cryoimmunotherapy was assessed in the lung carcinoma model by monitoring mouse survival, lung weight, and induction of tumor-specific CTLs. The mechanism of cryoimmunotherapy was elucidated in the melanoma model using adoptive transfer of T cell receptor transgenic OT-I CTLs into the tumor-bearing mice, and analysis of Th1/Th2 responses by intracellular cytokine staining in CD4 and CD8 cells. Cryoimmunotherapy caused robust and tumor-specific CTL responses, increased Th1 responses, significantly prolonged survival and dramatically reduced lung metastasis. Although intratumor administration of dendritic cells alone increased the proliferation rate of CD8 cells, only cryoimmunotherapy resulted in the generation of effector memory cells. Furthermore, cryoimmunotherapyprotected mice that had survived primary MO5 tumors from rechallenge with parental tumors. These results present cryoimmunotherapy as a novel approach for systemic treatment of cancer. We envisage that cryotherapy of tumors combined with subsequent in situ immunotherapy by autologous unmodified immature dendritic cells can be applied in practice.

Risks of presurgical embolization of feeding arteries in 137 intracranial meningeal tumors.

PubMed

Law-ye, Bruno; Clarençon, Frédéric; Sourour, Nader-Antoine; Di Maria, Federico; Jean, Betty; Bonneville, Fabrice; Biondi, Alessandra; Iosif, Christina; Navarro, Soledad; Cornu, Philippe; Chiras, Jacques

2013-04-01

Embolization of extra-axial tumors has shown its effectiveness in reducing perisurgical blood loss. However, the complication rate of this procedure is poorly reported. We aimed to evaluate the rate of procedure-related complications and their risk factors. From 1998 to 2011, 193 consecutive patients (141 females, 52 males; mean age = 52.9 years) were referred to our institution for presurgical embolization of an extra-axial tumor (meningiomas: n = 178; solitary fibrous tumors: n = 3; other: n = 12). Of 193 patients, 137 (71 %) underwent 141 embolizations (by microparticles: n = 133; by glue: n = 8). The remaining 56 patients (29 %) were not embolized due to unstable catheterization or dangerous anastomosis. Occurrence of neurological deficit was systematically assessed during and after embolization. The risk factors of procedure-related neurological complications were evaluated. Neither intratumoral hemorrhage nor procedure-related death was reported. Two of the 137 patients (1.5 %) had ischemic events with permanent neurological deficit after microparticles embolization. One patient had cortical blindness and one had hemiparesis. Both complications involved the vertebrobasilar system. The first patient had direct intratumoral anastomosis between the middle and the posterior meningeal arteries (PMA); the second one had reflux in the vertebral artery during particles injection in the PMA. Occurrence of ischemic complication was not related to the size of the microparticles. Though embolization of meningeal tumors is considered as a safe technique, serious neurological complications may occur. Opening of dangerous anastomosis or uncontrolled reflux caused two neurological complications (1.5 %). The size of the microparticles was not associated with the occurrence of neurological event.

Syngeneic syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting

PubMed Central

Siurala, Mikko; Vähä-Koskela, Markus; Havunen, Riikka; Tähtinen, Siri; Bramante, Simona; Parviainen, Suvi; Mathis, J. Michael; Kanerva, Anna; Hemminki, Akseli

2016-01-01

ABSTRACT Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown promising yet sometimes suboptimal results in clinical trials for advanced cancer, underscoring the need for approaches improving efficacy and safety. Six implantable syngeneic tumor cell lines of the Syrian hamster were used to initiate TIL cultures. TIL generated from tumor fragments cultured in human interleukin-2 (IL-2) for 10 d were adoptively transferred into tumor-bearing hamsters with concomitant intratumoral injections of oncolytic adenovirus (Ad5-D24) for the assessment of antitumor efficacy. Pancreatic cancer (HapT1) and melanoma (RPMI 1846) TIL exhibited potent and tumor-specific cytotoxicity in effector-to-target (E/T) assays. MHC Class I blocking abrogated the cell killing of RPMI 1846 TIL, indicating cytotoxic CD8+ T-cell activity. When TIL were combined with Ad5-D24 in vitro, HapT1 tumor cell killing was significantly enhanced over single agents. In vivo, the intratumoral administration of HapT1 TIL and Ad5-D24 resulted in improved tumor growth control compared with either treatment alone. Additionally, splenocytes derived from animals treated with the combination of Ad5-D24 and TIL killed autologous tumor cells more efficiently than monotherapy-derived splenocytes, suggesting that systemic antitumor immunity was induced. For the first time, TIL of the Syrian hamster have been cultured, characterized and used therapeutically together with oncolytic adenovirus for enhancing the efficacy of TIL therapy. Our results support human translation of oncolytic adenovirus as an enabling technology for adoptive T-cell therapy of solid tumors. PMID:27467954

Enhancement of Intratumoral Chemotherapy with Cisplatin with or without Microwave Ablation and Lipiodol. Future Concept for Local Treatment in Lung Cancer.

PubMed

Hohenforst-Schmidt, Wolfgang; Zarogoulidis, Paul; Stopek, Joshua; Kosmidis, Efstratios; Vogl, Thomas; Linsmeier, Bernd; Tsakiridis, Kosmas; Lampaki, Sofia; Lazaridis, George; Mpakas, Andreas; Browning, Robert; Papaiwannou, Antonis; Drevelegas, Antonis; Baka, Sofia; Karavasilis, Vasilis; Mpoukovinas, Ioannis; Turner, J Francis; Zarogoulidis, Konstantinos; Brachmann, Johannes

2015-01-01

Novel therapies for lung cancer are being explored nowadays with local therapies being the tip of the arrow. Intratumoral chemotherapy administration and local microwave ablation have been investigated in several studies. It has been previously proposed that lipiodol has the ability to modify the microenvironment matrix. In our current study we investigated this theory in BALBC mice. In total 160 BALBC mice were divided in eight groups: a) control, b) cisplatin, c) microwave, d) microwave and lipiodol, e) cisplatin and lipiodol, f) microwave and cisplatin, g) lipiodol and h) lipiodol, cisplatin and microwave. Lewis lung carcinoma cell lines (10(6)) were injected into the right back leg of each mouse. After the 8th day, when the tumor volume was about 100mm(3) the therapy application was initiated, once per week for four weeks. Magnetic resonance imaging was performed for each tumor when a mouse died or when sacrificed if they were still alive by the end of the experiment (8-Canal multifunctional spool; NORAS MRI products, Gmbh, Germany). Imaging and survival revealed efficient tumor apoptosis for the groups b,c,d,e and f. However; severe toxicity was observed in group h and no follow up was available for this group after the second week of therapy administration. Lipiodol in its current form does assist in a more efficient way the distribution of cisplatin, as the microwave apoptotic effect. Future modification of lipiodol might provide a more efficient method of therapy enhancement. Combination of drug and microwave ablation is possible and has an efficient apoptotic effect.

A Chelator-Free Multifunctional [64Cu]-CuS Nanoparticle Platform for Simultaneous Micro-PET/CT Imaging and Photothermal Ablation Therapy

PubMed Central

Zhou, Min; Zhang, Rui; Huang, Miao; Lu, Wei; Song, Shaoli; Melancon, Marites P.; Tian, Mei; Liang, Dong; Li, Chun

2010-01-01

We synthesized and evaluated a novel class of chelator-free [64Cu]-CuS nanoparticles (NPs) suitable for both PET imaging and as photothermal coupling agents for photothermal ablation. [64Cu]-CuS NPs were simple to make, possessed excellent stability, and allowed robust noninvasive micro-PET imaging. Furthermore, CuS NPs displayed strong absorption in the near-infrared (NIR) region (peak 930 nm), passive targeting prefers the tumor site, and mediated ablation of U87 tumor cells upon exposure to NIR light both in vitro and in vivo after either intratumoral or intravenous injection. The combination of small diameter (~11 nm diameter), strong NIR absorption, and integration of 64Cu as a structural component makes [64Cu]-CuS NPs ideally suited for multifunctional molecular imaging and therapy. PMID:20942456

Oligodeoxynucleotides Expressing Polyguanosine Motifs Promote Anti-Tumor Activity through the Up-Regulation of IL-2

PubMed Central

Kobayashi, Nobuaki; Hong, Choongman; Klinman, Dennis M.; Shirota, Hidekazu

2012-01-01

The primary goal of cancer immunotherapy is to elicit an immune response capable of eliminating the tumor. One approach towards accomplishing that goal utilizes general (rather than tumor-specific) immunomodulatory agents to boost the number and activity of pre-existing cytotoxic T lymphocytes. We find that the intra-tumoral injection of poly-G ODN has such an effect, boosting anti-tumor immunity and promoting tumor regression. The anti-tumor activity of polyguanosine (poly-G) oligonucleotides (ODN) was mediated through CD8 T cells in a TLR9 independent manner. Mechanistically, poly-G ODN directly induced the phosphorylation of Lck (an essential element of the T cell signaling pathway), thereby enhancing the production of IL-2 and CD8 T cell proliferation. These findings establish poly-G ODN as a novel type of cancer immunotherapy. PMID:23296706

Encapsulated Stem Cells Loaded With Hyaluronidase-expressing Oncolytic Virus for Brain Tumor Therapy

PubMed Central

Martinez-Quintanilla, Jordi; He, Derek; Wakimoto, Hiroaki; Alemany, Ramon; Shah, Khalid

2015-01-01

Despite the proven safety of oncolytic viruses (OV) in clinical trials for glioblastoma (GBM), their efficacy has been hindered by suboptimal spreading within the tumor. We show that hyaluronan or hyaluronic acid (HA), an important component of extracellular matrix (ECM), is highly expressed in a majority of tumor xenografts established from patient-derived GBM lines that present both invasive and nodular phenotypes. Intratumoral injection of a conditionally replicating adenovirus expressing soluble hyaluronidase (ICOVIR17) into nodular GBM, mediated HA degradation and enhanced viral spread, resulting in a significant antitumor effect and mice survival. In an effort to translate OV-based therapeutics into clinical settings, we encapsulated human adipose-derived mesenchymal stem cells (MSC) loaded with ICOVIR17 in biocompatible synthetic extracellular matrix (sECM) and tested their efficacy in a clinically relevant mouse model of GBM resection. Compared with direct injection of ICOVIR17, sECM-MSC loaded with ICOVIR17 resulted in a significant decrease in tumor regrowth and increased mice survival. This is the first report of its kind revealing the expression of HA in GBM and the role of OV-mediated HA targeting in clinically relevant mouse model of GBM resection and thus has clinical implications. PMID:25352242

Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors.

PubMed

Song, Erwei; Zhu, Pengcheng; Lee, Sang-Kyung; Chowdhury, Dipanjan; Kussman, Steven; Dykxhoorn, Derek M; Feng, Yi; Palliser, Deborah; Weiner, David B; Shankar, Premlata; Marasco, Wayne A; Lieberman, Judy

2005-06-01

Delivery of small interfering RNAs (siRNAs) into cells is a key obstacle to their therapeutic application. We designed a protamine-antibody fusion protein to deliver siRNA to HIV-infected or envelope-transfected cells. The fusion protein (F105-P) was designed with the protamine coding sequence linked to the C terminus of the heavy chain Fab fragment of an HIV-1 envelope antibody. siRNAs bound to F105-P induced silencing only in cells expressing HIV-1 envelope. Additionally, siRNAs targeted against the HIV-1 capsid gene gag, inhibited HIV replication in hard-to-transfect, HIV-infected primary T cells. Intratumoral or intravenous injection of F105-P-complexed siRNAs into mice targeted HIV envelope-expressing B16 melanoma cells, but not normal tissue or envelope-negative B16 cells; injection of F105-P with siRNAs targeting c-myc, MDM2 and VEGF inhibited envelope-expressing subcutaneous B16 tumors. Furthermore, an ErbB2 single-chain antibody fused with protamine delivered siRNAs specifically into ErbB2-expressing cancer cells. This study demonstrates the potential for systemic, cell-type specific, antibody-mediated siRNA delivery.

Theranostic Nanoseeds for Efficacious Internal Radiation Therapy of Unresectable Solid Tumors

NASA Astrophysics Data System (ADS)

Moeendarbari, Sina; Tekade, Rakesh; Mulgaonkar, Aditi; Christensen, Preston; Ramezani, Saleh; Hassan, Gedaa; Jiang, Ruiqian; Öz, Orhan K.; Hao, Yaowu; Sun, Xiankai

2016-02-01

Malignant tumors are considered “unresectable” if they are adhere to vital structures or the surgery would cause irreversible damages to the patients. Though a variety of cytotoxic drugs and radiation therapies are currently available in clinical practice to treat such tumor masses, these therapeutic modalities are always associated with substantial side effects. Here, we report an injectable nanoparticle-based internal radiation source that potentially offers more efficacious treatment of unresectable solid tumors without significant adverse side effects. Using a highly efficient incorporation procedure, palladium-103, a brachytherapy radioisotope in clinical practice, was coated to monodispersed hollow gold nanoparticles with a diameter about 120 nm, to form 103Pd@Au nanoseeds. The therapeutic efficacy of 103Pd@Au nanoseeds were assessed when intratumorally injected into a prostate cancer xenograft model. Five weeks after a single-dose treatment, a significant tumor burden reduction (>80%) was observed without noticeable side effects on the liver, spleen and other organs. Impressively, >95% nanoseeds were retained inside the tumors as monitored by Single Photon Emission Computed Tomography (SPECT) with the gamma emissions of 103Pd. These findings show that this nanoseed-based brachytherapy has the potential to provide a theranostic solution to unresectable solid tumors.

Intra-tumor heterogeneity: lessons from microbial evolution and clinical implications

PubMed Central

2013-01-01

Multiple subclonal populations of tumor cells can coexist within the same tumor. This intra-tumor heterogeneity will have clinical implications and it is therefore important to identify factors that drive or suppress such heterogeneous tumor progression. Evolutionary biology can provide important insights into this process. In particular, experimental evolution studies of microbial populations, which exist as clonal populations that can diversify into multiple subclones, have revealed important evolutionary processes driving heterogeneity within a population. There are transferrable lessons that can be learnt from these studies that will help us to understand the process of intra-tumor heterogeneity in the clinical setting. In this review, we summarize drivers of microbial diversity that have been identified, such as mutation rate and environmental influences, and discuss how knowledge gained from microbial experimental evolution studies may guide us to identify and understand important selective factors that promote intra-tumor heterogeneity. Furthermore, we discuss how these factors could be used to direct and optimize research efforts to improve patient care, focusing on therapeutic resistance. Finally, we emphasize the need for longitudinal studies to address the impact of these potential tumor heterogeneity-promoting factors on drug resistance, metastatic potential and clinical outcome. PMID:24267946

Intratumoral gene therapy versus intravenous gene therapy for distant metastasis control with 2-diethylaminoethyl-dextran methyl methacrylate copolymer non-viral vector-p53.

PubMed

Baliaka, A; Zarogoulidis, P; Domvri, K; Hohenforst-Schmidt, W; Sakkas, A; Huang, H; Le Pivert, P; Koliakos, G; Koliakou, E; Kouzi-Koliakos, K; Tsakiridis, K; Chioti, A; Siotou, E; Cheva, A; Zarogoulidis, K; Sakkas, L

2014-02-01

Lung cancer still remains to be challenged by novel treatment modalities. Novel locally targeted routes of administration are a methodology to enhance treatment and reduce side effects. Intratumoral gene therapy is a method for local treatment and could be used either in early-stage lung cancer before surgery or at advanced stages as palliative care. Novel non-viral vectors are also in demand for efficient gene transfection to target local cancer tissue and at the same time protect the normal tissue. In the current study, C57BL/6 mice were divided into three groups: (a) control, (b) intravenous and (c) intatumoral gene therapy. The novel 2-Diethylaminoethyl-Dextran Methyl Methacrylate Copolymer Non-Viral Vector (Ryujyu Science Corporation) was conjugated with plasmid pSicop53 from the company Addgene for the first time. The aim of the study was to evaluate the safety and efficacy of targeted gene therapy in a Lewis lung cancer model. Indeed, although the pharmacokinetics of the different administration modalities differs, the intratumoral administration presented increased survival and decreased distant metastasis. Intratumoral gene therapy could be considered as an efficient local therapy for lung cancer.

DRUG-NEM: Optimizing drug combinations using single-cell perturbation response to account for intratumoral heterogeneity

PubMed Central

Anchang, Benedict; Davis, Kara L.; Fienberg, Harris G.; Bendall, Sean C.; Karacosta, Loukia G.; Tibshirani, Robert; Nolan, Garry P.; Plevritis, Sylvia K.

2018-01-01

An individual malignant tumor is composed of a heterogeneous collection of single cells with distinct molecular and phenotypic features, a phenomenon termed intratumoral heterogeneity. Intratumoral heterogeneity poses challenges for cancer treatment, motivating the need for combination therapies. Single-cell technologies are now available to guide effective drug combinations by accounting for intratumoral heterogeneity through the analysis of the signaling perturbations of an individual tumor sample screened by a drug panel. In particular, Mass Cytometry Time-of-Flight (CyTOF) is a high-throughput single-cell technology that enables the simultaneous measurements of multiple (>40) intracellular and surface markers at the level of single cells for hundreds of thousands of cells in a sample. We developed a computational framework, entitled Drug Nested Effects Models (DRUG-NEM), to analyze CyTOF single-drug perturbation data for the purpose of individualizing drug combinations. DRUG-NEM optimizes drug combinations by choosing the minimum number of drugs that produce the maximal desired intracellular effects based on nested effects modeling. We demonstrate the performance of DRUG-NEM using single-cell drug perturbation data from tumor cell lines and primary leukemia samples. PMID:29654148

Hilar cholangiocarcinoma with intratumoral calcification: A case report.

PubMed

Inoko, Kazuho; Tsuchikawa, Takahiro; Noji, Takehiro; Kurashima, Yo; Ebihara, Yuma; Tamoto, Eiji; Nakamura, Toru; Murakami, Soichi; Okamura, Keisuke; Shichinohe, Toshiaki; Hirano, Satoshi

2015-10-14

This report describes a rare case of hilar cholangiocarcinoma with intratumoral calcification that mimicked hepatolithiasis. A 73-year-old man presented to a local hospital with a calcified lesion in the hepatic hilum. At first, hepatolithiasis was diagnosed, and he underwent endoscopic stone extraction via the trans-papillary route. This treatment strategy failed due to biliary stricture. He was referred to our hospital, and further examination suggested the existence of cholangiocarcinoma. He underwent left hepatectomy with caudate lobectomy and extrahepatic bile duct resection. Pathological examination revealed hilar cholangiocarcinoma with intratumoral calcification, while no stones were found. To the best of our knowledge, only one case of calcified hilar cholangiocarcinoma has been previously reported in the literature. Here, we report a rare case of calcified hilar cholangiocarcinoma and reveal its clinicopathologic features.

Tocilizumab Injection

MedlinePlus

... of age or older after receiving certain immunotherapy infusions. Tocilizumab injection is in a class of medications ... you miss an appointment to receive a tocilizumab infusion, call your doctor.If you forget to inject ...

Synthesis and characterization of DNA nano-meso-microspheres as drug delivery carriers for intratumoral chemotherapy

NASA Astrophysics Data System (ADS)

Enriquez Schumacher, Iris Vanessa

Conventional cancer chemotherapy results in systemic toxicity which severely limits effectiveness and often adversely affects patient quality of life. There is a need to find new drugs and delivery methods for less toxic therapy. Previous studies concerning DNA complexing with chemotherapy drugs suggest unique opportunities for DNA as a mesosphere drug carrier. The overall objective of this research was devoted to the synthesis and evaluation of novel DNA-drug nano-mesospheres designed for localized chemotherapy via intratumoral injection. My research presents DNA nano-meso-microspheres (DNA-MS) that were prepared using a modified steric stabilization method originally developed in this lab for the preparation of albumin MS. DNA-MS were prepared with glutaraldehyde covalent crosslinking (genipin crosslinking was attempted) through the DNA base pairs. In addition, novel crosslinking of DNA-MS was demonstrated using chromium, gadolinium, or iron cations through the DNA phosphate groups. Covalent and ionic crosslinked DNA-MS syntheses yielded smooth and spherical particle morphologies with multimodal size distributions. Optimized DNA-MS syntheses produced particles with narrow and normal size distributions in the 50nm to 5mum diameter size range. In aqueous dispersions approximately 200% swelling was observed with dispersion stability for more than 48 hours. Typical process conditions included a 1550rpm initial mixing speed and particle filtration through 20mum filters to facilitate preparation. DNA-MS were in situ loaded during synthesis for the first time with mitoxantrone, 5-fluorouracil, and methotrexate. DNA-MS drug incorporation was 12%(w/w) for mitoxantrone, 9%(w/w) for methotrexate, and 5%(w/w) for 5-fluorouracil. In vitro drug release into phosphate buffered saline was observed for over 35 days by minimum sink release testing. The effect of gadolinium crosslink concentration on mitoxantrone release was evaluated at molar equivalences in the range of 20% to 120%. The most highly crosslinked DNA-MS exhibited the longest sustained release. The drug efficacy of mitoxantrone loaded DNA-MS was evaluated in vitro using a murine Lewis lung carcinoma cell line and a significant cytotoxic response was found at mitoxantrone doses as low as 1ppm. Drug release properties, DNA biodegradability, and observed cancer cell cytotoxicity of drug loaded DNA-MS suggest that they are appropriate for intratumoral chemotherapy evaluation aimed at improved and less toxic cancer therapy.

Intra-tumor genetic heterogeneity and mortality in head and neck cancer: analysis of data from the Cancer Genome Atlas.

PubMed

Mroz, Edmund A; Tward, Aaron D; Tward, Aaron M; Hammon, Rebecca J; Ren, Yin; Rocco, James W

2015-02-01

Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality. Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity's associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having oral-cavity or laryngeal cancers even when standard disease staging was taken into account. Prospective studies, however, will be required before MATH can be used prognostically in clinical trials or practice. Such studies will need to examine homogeneously treated HNSCC at specific head and neck subsites, and determine the influence of cancer therapy on MATH values. Analysis of MATH and outcome in human-papillomavirus-positive oropharyngeal squamous cell carcinoma is particularly needed. To our knowledge this study is the first to combine data from hundreds of patients, treated at multiple institutions, to document a relation between intra-tumor heterogeneity and overall survival in any type of cancer. We suggest applying the simply calculated MATH metric of heterogeneity to prospective studies of HNSCC and other tumor types.

Adjuvant immunotherapy of feline fibrosarcoma with recombinant feline interferon-omega.

PubMed

Hampel, Verena; Schwarz, Bianca; Kempf, Christine; Köstlin, Roberto; Schillinger, Ulrike; Küchenhoff, Helmut; Fenske, Nora; Brill, Thomas; Hirschberger, Johannes

2007-01-01

Recombinant feline interferon-omega (rFeIFN-omega) was tested as a treatment option for cats with fibrosarcoma to assess safety and feasibility. Treatment with rFeIFN-omega in cats with fibrosarcoma is safe and feasible. Twenty domestic cats. In an open-labeled uncontrolled clinical trial 12 injections of 1 x 10(6) U/kg rFeIFN-omega were administered over a 5-week period: the 1st through 4th injections were given intratumorally, and the 5th through 12th injections were administered subcutaneously at the tumor excision site. Wide surgical excision of the tumors was carried out after the 4th injection and before the 5th injection of rFeIFN-omega. A Common Terminology Criteria for Adverse Events (CTCAE) analysis was conducted. Flow cytometry of fibrosarcoma cells after incubation with rFeIFN-omega and recombinant feline interferon-gamma was performed to assess the biological effect of rFeIFN-omega. Changes in blood cell count, increases in serum aspartate-amino-transferase activity, serum bilirubin concentration, serum creatinine and serum electrolyte concentrations, weight loss, anorexia, increased body temperature, and reduced general condition were observed but were mostly minor (grade 1 and 2) and self limiting. Eosinophilia (P = .025), neutropenia (P = .021), and weight loss (P < .001) were statistically correlated with rFeIFN-omega-treatment (analysis of parameters before treatment and after 3 injections of rFeIFN-omega). Flow cytometry of 5 unrelated feline fibrosarcoma cell lines showed increased expression of major histocompatibility complex (MHC) class I molecules (P = .026) in response to in vitro incubation with rFeIFN-omega, whereas expression of MHC class II molecules was not affected significantly. RFeIFN-omega for the treatment of feline fibrosarcoma is safe, well tolerated, and can be easily performed in practice. To assess the efficacy of the treatment, it should be tested in a placebo-controlled trial.

Comprehensive Genetic Characterization of Intraprostatic Chronic Inflammation and Prostate Cancer in African American Men

DTIC Science & Technology

2017-09-01

with new methodologies of intratumoral phylogenetic analyses, will yield pivotal information in elucidating the key genes involved evolution of PCa...combined with both clinical and experimental genetic data produced by this study may empower patients and doctors to make personalized treatment decisions...sequencing, paired with new methodologies of intratumoral phylogenetic analyses, will yield pivotal information in elucidating the key genes involved

Influence of intra-tumoral heterogeneity on the evaluation of BCL2, E-cadherin, EGFR, EMMPRIN, and Ki-67 expression in tissue microarrays from breast cancer.

PubMed

Tramm, Trine; Kyndi, Marianne; Sørensen, Flemming B; Overgaard, Jens; Alsner, Jan

2018-01-01

The influence of intra-tumoral heterogeneity on the evaluation of immunohistochemical (IHC) biomarker expression may affect the analytical validity of new biomarkers substantially and hence compromise the clinical utility. The aim of this study was to examine the influence of intra-tumoral heterogeneity as well as inter-observer variability on the evaluation of various IHC markers with potential prognostic impact in breast cancer (BCL2, E-cadherin, EGFR, EMMPRIN and Ki-67). From each of 27 breast cancer patients, two tumor-containing paraffin blocks were chosen. Intra-tumoral heterogeneity was evaluated (1) within a single tumor-containing paraffin block ('intra-block agreement') by comparing information from a central, a peripheral tissue microarray (TMA) core and a whole slide section (WS), (2) between two different tumor-containing blocks from the same primary tumor ('inter-block agreement') by comparing information from TMA cores (central/peripheral) and WS. IHC markers on WS and TMA cores were evaluated by two observers independently, and agreements were estimated by Kappa statistics. For BCL2, E-cadherin and EGFR, an almost perfect intra- and inter-block agreement was found. EMMPRIN and Ki-67 showed a more heterogeneous expression with moderate to substantial intra-block agreements. For both stainings, there was a moderate inter-block agreement that improved slightly for EMMPRIN, when using WS instead of TMA cores. Inter-observer agreements were found to be almost perfect for BCL2, E-cadherin and EGFR (WS: κ > 0.82, TMAs: κ > 0.90), substantial for EMMPRIN (κ > 0.63), but only fair to moderate for Ki-67 (WS: κ = 0.54, TMAs: κ = 0.33). BCL2, E-cadherin and EGFR were found to be homogeneously expressed, whereas EMMPRIN and Ki-67 showed a more pronounced degree of intra-tumoral heterogeneity. The results emphasize the importance of securing the analytical validity of new biomarkers by examining the intra-tumoral heterogeneity of immunohistochemical stainings applied to TMA cores individually in each type of cancer.

The Impact of Peritumoral Retraction Clefting & Intratumoral Eosinophils on Overall Survival in Oral Squamous Carcinoma Patients.

PubMed

Jain, Dhruv; Tikku, Gargi; Bhadana, Pallavi; Dravid, Chandrashekhar; Grover, Rajesh Kumar

2017-10-18

This retrospective study aimed to investigate the impact of peritumoral retraction clefts (RC) and tumor-associated tissue eosinophilia (TATE) as predictors of overall survival (OS) in oral squamous cell carcinoma (OSCC) patients. Their relationships with tumor-factors were also examined. Eighty-seven OSCC cases (pTNM: I + II/III + IV; 32/55), post-curative surgery, comprised the study cohort. Three observers independently estimated the percent RC semi-quantitatively in the selected tumor sections. Additionally, stromal eosinophils were counted in ten consecutive high-power fields of intratumoral and peritumoral regions to evaluate the corresponding TATE. The percent RC ranged between 0% -90% (Mean ± SD: 16 ± 24%; Median: 5%). The stromal eosinophils were greater in peritumoral as compared to intratumoral region. The events of death and tumor recurrence were reached in 16 (18.4%) and 36 (41%) cases respectively. The 3-years OS was 69% [Median OS: 1880 days; Mean follow up: 471(Range; 36-1880) days]. Increased percent RC exhibited relationship with pathologic stage (pTNM III&IV), primary tumor (pT III&IV), tumor depth > 4 mm and categorical tumor recurrence. Additionally, peritumoral eosinophilic infiltrates increased with increasing tumor depths and muscle invasion. Kaplan-Meier curves revealed significantly reduced OS in OSCC cases exhibiting: increased percent RC (>2.5%), mild -moderate/absent intratumoral TATE (versus intense TATE) or categorical tumor recurrence. In subsequent multivariate tests, all the three variables retained significance. Additionally, intraclass correlation coefficient demonstrated acceptable internal consistency for the observers who estimated percent RC. In conclusion, RC and intratumoral TATE proved to be independent predictors of OS in our OSCC cohort. Additionally, increased percent RC pointed towards aggressive tumor behaviour.

Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs

PubMed Central

Du Four, Stephanie; Maenhout, Sarah K; Niclou, Simone P; Thielemans, Kris; Neyns, Bart; Aerts, Joeri L

2016-01-01

Melanoma brain metastases (MBM) occur in 10% to 50% of melanoma patients. They are often associated with a high morbidity and despite the improvements in the treatment of advanced melanoma, including immunotherapy, patients with MBM still have a poor prognosis. Antiangiogenic treatment was shown to reduce the immunosuppressive tumor microenvironment. Therefore we investigated the effect of the combination of VEGFR- and CTLA-4 blockade on the immune cells within the tumor microenvironment. In this study we investigated the effect of the combination of axitinib, a TKI against VEGFR-1, -2 and -3, with therapeutic inhibition of CTLA-4 in subcutaneous and intracranial mouse melanoma models. The combination of axitinib with αCTLA-4 reduced tumor growth and increased survival in both intracranial and subcutaneous models. Investigation of the splenic immune cells showed an increased number of CD4+ and CD8+ T cells after combination treatment. Moreover, combination treatment increased the number of intratumoral dendritic cells (DCs) and monocytic myeloid-derived suppressor cells (moMDSCs). When these immune cell populations were sorted from the subcutaneous and intracranial tumors of mice treated with axitinib+αCTLA-4, we observed an increased antigen-presenting function of DCs and a reduced suppressive capacity of moMDSCs on a per cell basis. Our results suggest that the combination of antiangiogenesis and checkpoint inhibition can lead to an enhanced antitumor effect leading to increased survival. We found that this effect is in part due to an enhanced antitumor immune response generated by an increased antigen-presenting function of intratumoral DCs in combination with a reduced suppressive capacity of intratumoral moMDSCs. PMID:27904768

Monitoring early response to chemoradiotherapy with 18F-FMISO dynamic PET in head and neck cancer.

PubMed

Grkovski, Milan; Lee, Nancy Y; Schöder, Heiko; Carlin, Sean D; Beattie, Bradley J; Riaz, Nadeem; Leeman, Jonathan E; O'Donoghue, Joseph A; Humm, John L

2017-09-01

There is growing recognition that biologic features of the tumor microenvironment affect the response to cancer therapies and the outcome of cancer patients. In head and neck cancer (HNC) one such feature is hypoxia. We investigated the utility of 18 F-fluoromisonidazole (FMISO) dynamic positron emission tomography (dPET) for monitoring the early microenvironmental response to chemoradiotherapy in HNC. Seventy-two HNC patients underwent FMISO dPET scans in a customized immobilization mask (0-30 min dynamic acquisition, followed by 10 min static acquisitions starting at ∼95 min and ∼160 min post-injection) at baseline and early into treatment where patients have already received one cycle of chemotherapy and anywhere from five to ten fractions of 2 Gy per fraction radiation therapy. Voxelwise pharmacokinetic modeling was conducted using an irreversible one-plasma two-tissue compartment model to calculate surrogate biomarkers of tumor hypoxia (k 3 and Tumor-to-Blood Ratio (TBR)), perfusion (K 1 ) and FMISO distribution volume (DV). Additionally, Tumor-to-Muscle Ratios (TMR) were derived by visual inspection by an experienced nuclear medicine physician, with TMR > 1.2 defining hypoxia. One hundred and thirty-five lesions in total were analyzed. TBR, k 3 and DV decreased on early response scans, while no significant change was observed for K 1 . The k 3 -TBR correlation decreased substantially from baseline scans (Pearson's r = 0.72 and 0.76 for mean intratumor and pooled voxelwise values, respectively) to early response scans (Pearson's r = 0.39 and 0.40, respectively). Both concordant and discordant examples of changes in intratumor k 3 and TBR were identified; the latter partially mediated by the change in DV. In 13 normoxic patients according to visual analysis (all having lesions with TMR = 1.2), subvolumes were identified where k 3 indicated the presence of hypoxia. Pharmacokinetic modeling of FMISO dynamic PET reveals a more detailed characterization of the tumor microenvironment and assessment of response to chemoradiotherapy in HNC patients than a single static image does. In a clinical trial where absence of hypoxia in primary tumor and lymph nodes would lead to de-escalation of therapy, the observed disagreement between visual analysis and pharmacokinetic modeling results would have affected patient management in <20% cases. While simple static PET imaging is easily implemented for clinical trials, the clinical applicability of pharmacokinetic modeling remains to be investigated.

Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors

PubMed Central

Barth, Rolf F.; Yang, Weilian; Wu, Gong; Swindall, Michele; Byun, Youngjoo; Narayanasamy, Sureshbabu; Tjarks, Werner; Tordoff, Kevin; Moeschberger, Melvin L.; Eriksson, Staffan; Binns, Peter J.; Riley, Kent J.

2008-01-01

The purpose of the present study was to evaluate the effectiveness of a 3-carboranyl thymidine analogue (3CTA), 3-[5-{2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl] thymidine, designated N5–2OH, for boron neutron capture therapy (BNCT) of brain tumors using the RG2 rat glioma model. Target validation was established using the thymidine kinase (TK) 1(+) wild-type, murine L929 cell line and its TK1(−) mutant counterpart, which were implanted s.c. (s.c.) into nude mice. Two intratumoral (i.t.) injections of 10B-enriched N5–2OH were administered to tumor-bearing mice at 2-hour intervals, after which BNCT was carried out at the Massachusetts Institute of Technology (MIT) Research Reactor. Thirty days after BNCT, mice bearing TK1(+) L929 tumors had a 15× reduction in tumor volume compared with TK1(−) controls. Based on these favorable results, BNCT studies were then initiated in rats bearing intracerebral (i.c.) RG2 gliomas, after i.c. administration of N5–2OH by Alzet osmotic pumps, either alone or in combination with i.v. (i.v.) boronophenylalanine (BPA), a drug that has been used clinically. The mean survival times (MSTs) of RG2 glioma bearing rats were 45.6 ± 7.2 days, 35.0 ± 3.3days, and 52.9 ± 8.9 days, respectively, for animals that received N5–2OH, BPA, or both. The differences between the survival plots of rats that received N5–2OH and BPA alone were highly significant (P = 0.0003). These data provide proof-of-principle that a 3CTA can function as a boron delivery agent for NCT. Further studies are planned to design and synthesize 3CTAs with enhanced chemical and biological properties, and increased therapeutic efficacy. PMID:18981415

Pain in adolescent girls receiving human papillomavirus vaccine with concomitantly administered vaccines.

PubMed

Walter, Emmanuel B; Kemper, Alex R; Dolor, Rowena J; Dunne, Eileen F

2015-02-01

Using the Faces Pain Scale - Revised, we assessed injection site pain 10 minutes after vaccination in young females randomized to receive either quadrivalent human papillomavirus vaccine (HPV4) before or after concomitantly administered vaccines. Although pain was modestly more after HPV4 injection than after other vaccines, the pain intensity after HPV4 injection was significantly less in those who received HPV4 before receiving other concomitant vaccines.

Non-Invasive Radiofrequency Field Treatment of 4T1 Breast Tumors Induces T-cell Dependent Inflammatory Response.

PubMed

Newton, Jared M; Flores-Arredondo, Jose H; Suki, Sarah; Ware, Matthew J; Krzykawska-Serda, Martyna; Agha, Mahdi; Law, Justin J; Sikora, Andrew G; Curley, Steven A; Corr, Stuart J

2018-02-22

Previous work using non-invasive radiofrequency field treatment (RFT) in cancer has demonstrated its therapeutic potential as it can increase intratumoral blood perfusion, localization of intravenously delivered drugs, and promote a hyperthermic intratumoral state. Despite the well-known immunologic benefits that febrile hyperthermia can induce, an investigation of how RFT could modulate the intra-tumoral immune microenvironment had not been studied. Thus, using an established 4T1 breast cancer model in immune competent mice, we demonstrate that RFT induces a transient, localized, and T-cell dependent intratumoral inflammatory response. More specifically we show that multi- and singlet-dose RFT promote an increase in tumor volume in immune competent Balb/c mice, which does not occur in athymic nude models. Further leukocyte subset analysis at 24, 48, and 120 hours after a single RFT show a rapid increase in tumoral trafficking of CD4+ and CD8+ T-cells 24 hours post-treatment. Additional serum cytokine analysis reveals an increase in numerous pro-inflammatory cytokines and chemokines associated with enhanced T-cell trafficking. Overall, these data demonstrate that non-invasive RFT could be an effective immunomodulatory strategy in solid tumors, especially for enhancing the tumoral trafficking of lymphocytes, which is currently a major hindrance of numerous cancer immunotherapeutic strategies.

Oncolytic virus therapies.

PubMed

Buonaguro, Franco Maria; Tornesello, Maria Lina; Izzo, Francesco; Buonaguro, Luigi

2012-11-01

Oncolytic virus (OV) therapy currently represents one of the most promising approaches to cancer treatment for their dual anticancer mechanisms: direct lysis of cancer cells (oncolytic feature) and activation of the immunosystem (cancer vaccine aspect). The latter demonstrates the advantage of a multi-target approach against multiple tumor-associated antigens. Since the 2005 SFDA (the Chinese FDA) approval for the clinical use of Oncorine™, the first human OV-based cancer treatment, more than 200 patents have been filed worldwide and several Phase I/II studies have been conducted. This patent review analyzes patents and clinical studies of the most promising OV products to highlight the pros and cons of this innovative anticancer approach, which is currently being tested in several cancers (i.e., hepatocellular carcinoma, melanoma and glioblastoma) by systemic as well as intratumoral injection. Clinical results, although effective only for a limited period of time, are encouraging. Combined treatments with radio or chemotherapeutic protocols are also in progress.

Magnetically-Responsive Nanoparticles for Vectored Delivery of Cancer Therapeutics

NASA Astrophysics Data System (ADS)

Klostergaard, Jim; Bankson, James; Woodward, Wendy; Gibson, Don; Seeney, Charles

2010-12-01

We propose that physical targeting of therapeutics to tumors using magnetically-responsive nanoparticles (MNPs) will enhance intratumoral drug levels compared to free drugs in an effort to overcome tumor resistance. We evaluated the feasibility of magnetic enhancement of tumor extravasation of systemically-administered MNPs in human xenografts implanted in the mammary fatpads of nude mice. Mice with orthotopic tumors were injected systemically with MNPs, with a focused magnetic field juxtaposed over the tumor. Magnetic resonance imaging and scanning electron microscopy both indicated successful tumor localization of MNPs. Next, MNPs were modified with poly-ethylene-glycol (PEG) and their clearance compared by estimating signal attenuation in liver due to iron accumulation. The results suggested that PEG substitution could retard the rate of MNP plasma clearance, which may allow greater magnetically-enhanced tumor localization. We propose that this technology is clinically scalable to many types of both superficial as well as some viscerable tumors with existing magnetic technology.

Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors.

PubMed

Xin, Gang; Schauder, David M; Jing, Weiqing; Jiang, Aimin; Joshi, Nikhil S; Johnson, Bryon; Cui, Weiguo

2017-01-24

Because of insufficient migration and antitumor function of transferred T cells, especially inside the immunosuppressive tumor microenvironment (TME), the efficacy of adoptive cell transfer (ACT) is much curtailed in treating solid tumors. To overcome these challenges, we sought to reenergize ACT (ReACT) with a pathogen-based cancer vaccine. To bridge ACT with a pathogen, we genetically engineered tumor-specific CD8 T cells in vitro with a second T-cell receptor (TCR) that recognizes a bacterial antigen. We then transferred these dual-specific T cells in combination with intratumoral bacteria injection to treat solid tumors in mice. The dual-specific CD8 T cells expanded vigorously, migrated to tumor sites, and robustly eradicated primary tumors. The mice cured from ReACT also developed immunological memory against tumor rechallenge. Mechanistically, we have found that this combined approach reverts the immunosuppressive TME and recruits CD8 T cells with an increased number and killing ability to the tumors.

Low electric field enhanced chemotherapy can cure mice with CT-26 colon carcinoma and induce anti-tumour immunity

PubMed Central

PLOTNIKOV, A; FISHMAN, D; TICHLER, T; KORENSTEIN, R; KEISARI, Y

2004-01-01

Low electric field cancer treatment − enhanced chemotherapy (LEFCT-EC) is a new anticancer treatment which utilizes a combination of chemotherapeutic agents and a low electric field. We investigated the antitumour effectiveness of this technique in a model of murine colon carcinoma (CT-26). The low electric field was applied to ∼65 mm3 intracutaneous tumours after intratumoral injection of 5FU, bleomycin or BCNU. We observed significant tumour size reduction and a prolongation of survival time. The complete cure of a significant fraction of animals treated by LEFCT-EC with 5FU (33%), bleomycin (51%) or BCNU (83%) was observed. Mice cured by LEFCT-EC developed resistance to a tumour challenge and their splenocytes had antitumour activity in vivo. Our results suggest that LEFCT-EC is an effective method for treatment of solid tumours. PMID:15544616

Low electric field enhanced chemotherapy can cure mice with CT-26 colon carcinoma and induce anti-tumour immunity.

PubMed

Plotnikov, A; Fishman, D; Tichler, T; Korenstein, R; Keisari, Y

2004-12-01

Low electric field cancer treatment-enhanced chemotherapy (LEFCT-EC) is a new anticancer treatment which utilizes a combination of chemotherapeutic agents and a low electric field. We investigated the antitumour effectiveness of this technique in a model of murine colon carcinoma (CT-26). The low electric field was applied to approximately 65 mm3 intracutaneous tumours after intratumoral injection of 5FU, bleomycin or BCNU. We observed significant tumour size reduction and a prolongation of survival time. The complete cure of a significant fraction of animals treated by LEFCT-EC with 5FU (33%), bleomycin (51%) or BCNU (83%) was observed. Mice cured by LEFCT-EC developed resistance to a tumour challenge and their splenocytes had antitumour activity in vivo. Our results suggest that LEFCT-EC is an effective method for treatment of solid tumours.

Gadolinium diethylenetriaminopentaacetic acid-loaded chitosan microspheres for gadolinium neutron-capture therapy.

PubMed

Saha, Tapan Kumar; Ichikawa, Hideki; Fukumori, Yoshinobu

2006-12-11

In order to provide a suitable device that would contain water-soluble drugs, highly water-soluble gadolinium diethylenetriaminopentaacetic acid-loaded chitosan microspheres (CMS-Gd-DTPA) were prepared by the emulsion method using glutaraldehyde as a cross-linker and Span 80 as a surfactant for gadolinium neutron-capture therapy of cancer. The gadolinium content and the mass median diameter of CMS-Gd-DTPA were estimated. The size and morphology of the CMS-Gd-DTPA were strongly influenced by the initial applied weight ratio of Gd-DTPA:chitosan. FTIR spectra showed that the electrostatic interaction between chitosan and Gd-DTPA accelerated the formation of gadolinium-enriched chitosan microspheres. Sufficient amounts of glutaraldehyde and Span 80 were necessary for producing discrete CMS-Gd-DTPA. The CMS-Gd-DTPA having a mass median diameter 11.7microm and 11.6% of gadolinium could be used in Gd-NCT following intratumoral injection.

Rationale of lymph node dissection for breast cancer--from the viewpoint of analysis of axillary lymphatic flow using activated carbon particle CH40.

PubMed

Sawai, K; Hagiwara, A; Shimotsuma, M; Sakakibara, T; Imanishi, T; Takemoto, Y; Takahashi, T

1996-03-01

In order to rationalize lymph node dissection for breast cancer, we reviewed regional lymphatic flow from the mesial and outer half of the breast using intra-tumoral injection of activated carbon particles (CH40). Seventy patients with breast cancer were included in this study. Cancers were located in the mesial half of the breast in 25 cases and in its outer half in 41 cases. Since regional lymph nodes were blackened by CH40, lymph node dissection was performed easily and small lymph nodes could be readily examined. The average number of resected nodes in each case was 29.4. When CH40 was injected into the mesial half of the breast, the rates of blackened nodes (number of macroscopically blackened lymph nodes/number of total removed lymph nodes) in the stations were 46.6% (No. 1a), 41.4% (No. 1b), 62.1% (No. 1c), 61.8% (No. 2), 69.2.% (No. 2h), and 65.6% (No. 3). When CH40 was injected into outer half of the breast, those were 62.0% (No. 1a), 64.3% (No. 1b), 68.7% (No. 1c), 75.3% (No. 2), and 67.8% (No. 2h). Regardless of tumor location, the rates of blackened nodes were high in each station. In conclusion, regardless of tumor location it is impossible to determine the level of axillary dissection for breast cancer. It should be all or nothing.

Strategies for improving chemotherapeutic delivery to solid tumors mediated by vascular permeability modulation

NASA Astrophysics Data System (ADS)

Roy Chaudhuri, Tista

An essential mode of distribution of blood-borne chemotherapeutic agents within a solid tumor is via the micro-circulation. Poor tumor perfusion, because of a lack of functional vasculature or a lack of microvessels, as well as low tumor vascular permeability, can prevent adequate deposition of even low molecular-weight agents into the tumor. The modulation of tumor vascular function and density can provides numerous strategies for improving intratumor deposition of chemotherapeutic agents. Here we investigated strategies to improve drug delivery to two tumor types that share in common poor drug delivery, but differ in the underlying cause. First, in an angiogenesis-driven brain tumor model of Glioblastoma, the vascular permeability barrier, along with poorly-functional vasculature, hinders drug delivery. A strategy of nanoparticle-based tumor 'priming' to attack the vascular permeability barrier, employing sterically stabilized liposomal doxorubicin (SSL-DXR), was investigated. Functional and histological evaluation of tumor vasculature revealed that after an initial period of depressed vascular permeability and vascular pruning 3--4 days after SSL-DXR administration, vascular permeability and perfusion were restored and then elevated after 5--7 days. As a result of tumor priming, deposition of subsequently-administered nanoparticles was enhanced, and the efficacy of temozolomide (TMZ), if administered during the window of elevated permeability, was increased. The sequenced regimen resulted in a persistent reduction of the tumor proliferative index and a 40% suppression of tumor volume, compared to animals that received both agents simultaneously. Second, in a hypovascular, pancreatic ductal adenocarcinoma model, disruption of tumor-stromal communication via sonic hedgehog (sHH) signaling pathway inhibition mediated an indirect vascular proliferation and a more than 2-fold increase in intratumor nanoparticle deposition. Enhanced delivery of SSL-DXR in tumors pre-treated with sHH-inhibitor led to a 90% lifespan extension in animals that received a single cycle of the combined regimen, and a 200% extension in animals receiving 3-cycles of treatment, compared to control animals or those receiving either of the agents alone. We surmise that direct or indirect modulation of tumor vasculature can provide new opportunities for combination therapies that could improve delivery and efficacy of both small- and large- molecular weight agents in treatment-resistant solid tumors.

Tumor Penetrating Theranostic Nanoparticles for Enhancement of Targeted and Image-guided Drug Delivery into Peritoneal Tumors following Intraperitoneal Delivery.

PubMed

Gao, Ning; Bozeman, Erica N; Qian, Weiping; Wang, Liya; Chen, Hongyu; Lipowska, Malgorzata; Staley, Charles A; Wang, Y Andrew; Mao, Hui; Yang, Lily

2017-01-01

The major obstacles in intraperitoneal (i.p.) chemotherapy of peritoneal tumors are fast absorption of drugs into the blood circulation, local and systemic toxicities, inadequate drug penetration into large tumors, and drug resistance. Targeted theranostic nanoparticles offer an opportunity to enhance the efficacy of i.p. therapy by increasing intratumoral drug delivery to overcome resistance, mediating image-guided drug delivery, and reducing systemic toxicity. Herein we report that i.p. delivery of urokinase plasminogen activator receptor (uPAR) targeted magnetic iron oxide nanoparticles (IONPs) led to intratumoral accumulation of 17% of total injected nanoparticles in an orthotopic mouse pancreatic cancer model, which was three-fold higher compared with intravenous delivery. Targeted delivery of near infrared dye labeled IONPs into orthotopic tumors could be detected by non-invasive optical and magnetic resonance imaging. Histological analysis revealed that a high level of uPAR targeted, PEGylated IONPs efficiently penetrated into both the peripheral and central tumor areas in the primary tumor as well as peritoneal metastatic tumor. Improved theranostic IONP delivery into the tumor center was not mediated by nonspecific macrophage uptake and was independent from tumor blood vessel locations. Importantly, i.p. delivery of uPAR targeted theranostic IONPs carrying chemotherapeutics, cisplatin or doxorubicin, significantly inhibited the growth of pancreatic tumors without apparent systemic toxicity. The levels of proliferating tumor cells and tumor vessels in tumors treated with the above theranostic IONPs were also markedly decreased. The detection of strong optical signals in residual tumors following i.p. therapy suggested the feasibility of image-guided surgery to remove drug-resistant tumors. Therefore, our results support the translational development of i.p. delivery of uPAR-targeted theranostic IONPs for image-guided treatment of peritoneal tumors.

Enhancement of Intratumoral Chemotherapy with Cisplatin with or without Microwave Ablation and Lipiodol. Future Concept for Local Treatment in Lung Cancer

PubMed Central

Hohenforst-Schmidt, Wolfgang; Zarogoulidis, Paul; Stopek, Joshua; Kosmidis, Efstratios; Vogl, Thomas; Linsmeier, Bernd; Tsakiridis, Kosmas; Lampaki, Sofia; Lazaridis, George; Mpakas, Andreas; Browning, Robert; Papaiwannou, Antonis; Drevelegas, Antonis; Baka, Sofia; Karavasilis, Vasilis; Mpoukovinas, Ioannis; Turner, J Francis; Zarogoulidis, Konstantinos; Brachmann, Johannes

2015-01-01

Novel therapies for lung cancer are being explored nowadays with local therapies being the tip of the arrow. Intratumoral chemotherapy administration and local microwave ablation have been investigated in several studies. It has been previously proposed that lipiodol has the ability to modify the microenvironment matrix. In our current study we investigated this theory in BALBC mice. In total 160 BALBC mice were divided in eight groups: a) control, b) cisplatin, c) microwave, d) microwave and lipiodol, e) cisplatin and lipiodol, f) microwave and cisplatin, g) lipiodol and h) lipiodol, cisplatin and microwave. Lewis lung carcinoma cell lines (106) were injected into the right back leg of each mouse. After the 8th day, when the tumor volume was about 100mm3 the therapy application was initiated, once per week for four weeks. Magnetic resonance imaging was performed for each tumor when a mouse died or when sacrificed if they were still alive by the end of the experiment (8-Canal multifunctional spool; NORAS MRI products, Gmbh, Germany). Imaging and survival revealed efficient tumor apoptosis for the groups b,c,d,e and f. However; severe toxicity was observed in group h and no follow up was available for this group after the second week of therapy administration. Lipiodol in its current form does assist in a more efficient way the distribution of cisplatin, as the microwave apoptotic effect. Future modification of lipiodol might provide a more efficient method of therapy enhancement. Combination of drug and microwave ablation is possible and has an efficient apoptotic effect. PMID:25663938

Transfer of allogeneic CD4+ T cells rescues CD8+ T cells in anti-PD-L1–resistant tumors leading to tumor eradication

PubMed Central

Arina, Ainhoa; Karrison, Theodore; Galka, Eva; Schreiber, Karin; Weichselbaum, Ralph R.; Schreiber, Hans

2017-01-01

Adoptively transferred CD8+ T cells can stabilize the size of solid tumors over long periods of time by exclusively recognizing antigen cross-presented on tumor stroma. However, these tumors eventually escape T cell–mediated growth control. The aim of this study was to eradicate such persistent cancers. In our model, the SIYRYYGL antigen is expressed by cancer cells that lack the MHC-I molecule Kb needed for direct presentation, but the antigen is picked up and cross-presented by tumor stroma. A single injection of antigen-specific 2C CD8+ T cells caused long-term inhibition of tumor growth, but without further intervention, tumors started to progress after approximately 3 months. Escape was associated with reduced numbers of circulating 2C cells. Tumor-infiltrating 2C cells produced significantly less TNFα and expressed more of the “exhaustion” markers PD-1 and Tim-3 than T cells from lymphoid organs. High-dose local ionizing radiation, depletion of myeloid-derived suppressor cells, infusions of additional 2C cells, and antibodies blocking PD-L1 did not prevent tumor escape. In contrast, adoptive transfer of allogeneic CD4+ T cells restored the numbers of circulating Ag-specific CD8+ T cells and their intratumoral function, resulting in tumor eradication. These CD4+ T cells had no antitumor effects in the absence of CD8+ T cells and recognized the alloantigen cross-presented on tumor stroma. CD4+ T cells might also be effective in cancer patients when PD1/PD-L1 blockade does not rescue intratumoral CD8+ T-cell function and tumors persist. PMID:28077434

Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity.

PubMed

Schettini, Jorge; Kidiyoor, Amritha; Besmer, Dahlia M; Tinder, Teresa L; Roy, Lopamudra Das; Lustgarten, Joseph; Gendler, Sandra J; Mukherjee, Pinku

2012-11-01

Monoclonal antibodies (mAbs) against tumor-associated antigens are useful anticancer agents. Antibody-dependent cellular cytotoxicity (ADCC) is one of the major mechanisms responsible for initiating natural killer cell (NK)-mediated killing of tumors. However, the regulation of ADCC via NK cells is poorly understood. We have investigated the cytolytic activity of NK cells against pancreatic cancer cells that were coated with an antibody directed against the human tumor antigen, Mucin-1 designated HMFG-2, either alone or conjugated to CpG oligodeoxynucleotide (CpG ODN). Conjugated antibodies were tested for their ability to elicit ADCC in vitro and in vivo against pancreatic cancer cells. NK cells cultured in the presence of immobilized CpG ODN, HMFG-2 Ab, or CpG ODN-conjugated HMFG-2 Ab were able to up-regulate perforin similarly. Interestingly, a significant higher ADCC was observed when CpG ODN-conjugated HMFG-2-coated tumor cells were co-cultured with NK cells compared to unconjugated HMFG-2 Ab or CpG ODN alone. Moreover, MyD88-deficient NK cells can perform ADCC in vitro. Furthermore, intratumoral injections of CpG ODN-conjugated HMFG-2 induced a significant reduction in tumor burden in vivo in an established model of pancreatic tumor in nude mice compared to CpG ODN or the HMFG-2 alone. Depletion of macrophages or NK cells before treatment confirmed that both cells were required for the anti-tumor response in vivo. Results also suggest that CpG ODN and HMFG-2 Ab could be sensed by NK cells on the mAb-coated tumor cells triggering enhanced ADCC in vitro and in vivo.

Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity

PubMed Central

Schettini, Jorge; Kidiyoor, Amritha; Besmer, Dahlia M.; Tinder, Teresa L.; Roy, Lopamudra Das; Lustgarten, Joseph; Gendler, Sandra J.

2013-01-01

Monoclonal antibodies (mAbs) against tumor-associated antigens are useful anticancer agents. Antibody-dependent cellular cytotoxicity (ADCC) is one of the major mechanisms responsible for initiating natural killer cell (NK)-mediated killing of tumors. However, the regulation of ADCC via NK cells is poorly understood. We have investigated the cytolytic activity of NK cells against pancreatic cancer cells that were coated with an antibody directed against the human tumor antigen, Mucin-1 designated HMFG-2, either alone or conjugated to CpG oligodeoxynucleotide (CpG ODN). Conjugated antibodies were tested for their ability to elicit ADCC in vitro and in vivo against pancreatic cancer cells. NK cells cultured in the presence of immobilized CpG ODN, HMFG-2 Ab, or CpG ODN-conjugated HMFG-2 Ab were able to up-regulate perforin similarly. Interestingly, a significant higher ADCC was observed when CpG ODN-conjugated HMFG-2-coated tumor cells were co-cultured with NK cells compared to unconjugated HMFG-2 Ab or CpG ODN alone. Moreover, MyD88-deficient NK cells can perform ADCC in vitro. Furthermore, intratumoral injections of CpG ODN-conjugated HMFG-2 induced a significant reduction in tumor burden in vivo in an established model of pancreatic tumor in nude mice compared to CpG ODN or the HMFG-2 alone. Depletion of macrophages or NK cells before treatment confirmed that both cells were required for the anti-tumor response in vivo. Results also suggest that CpG ODN and HMFG-2 Ab could be sensed by NK cells on the mAb-coated tumor cells triggering enhanced ADCC in vitro and in vivo. PMID:22543528

Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12Rβ2 or IL-18Rα

PubMed Central

Choi, I-K; Lee, J-S; Zhang, S-N; Park, J; Lee, K-M; Sonn, C H; Yun, C-O

2011-01-01

The oncolytic adenovirus (Ad) is currently being advanced as a promising antitumor remedy as it selectively replicates in tumor cells and can transfer and amplify therapeutic genes. Interleukin (IL)-12 induces a potent antitumor effect by promoting natural killer (NK) cell and cytotoxic T cell activities. IL-18 also augments cytotoxicity of NK cells and proliferation of T cells. This effect further enhances the function of IL-12 in a synergistic manner. Therefore, we investigated for the first time an effective cancer immunogene therapy of syngeneic tumors via intratumoral administration of oncolytic Ad co-expressing IL-12 and IL-18, RdB/IL-12/IL-18. Intratumoral administration of RdB/IL-12/IL-18 improved antitumor effects, as well as increased survival, in B16-F10 murine melanoma model. The ratio of T-helper type 1/2 cytokine as well as the levels of IL-12, IL-18, interferon-γ and granulocyte–macrophage colony-stimulating factor was markedly elevated in RdB/IL-12/IL-18-treated tumors. Mice injected with RdB/IL-12/IL-18 also showed enhanced cytotoxicity of tumor-specific immune cells. Consistent with these results, immense necrosis and infiltration of NK cells, as well as CD4+ and CD8+ T cells, were observed in RdB/IL-12/IL-18-treated tumor tissues. Importantly, tumors treated with RdB/IL-12/IL-18 showed an elevated number of T cells expressing IL-12Rβ2 or IL-18Rα. These results provide a new insight into therapeutic mechanisms of IL-12 plus IL-18 and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity. PMID:21451575

Canine transmissible venereal tumour: a morphological and immunohistochemical study of 11 tumours in growth phase and during regression after chemotherapy.

PubMed

Gonzalez, C M; Griffey, S M; Naydan, D K; Flores, E; Cepeda, R; Cattaneo, G; Madewell, B R

2000-05-01

Eleven dogs with canine transmissible venereal tumour (CTVT) were given vincristine sulphate chemotherapy to induce tumour regression. Biopsy specimens were collected from tumours during the growth phase, before chemotherapy, and again from the same dogs during the regression induced by chemotherapy. Laboratory assessment included cytology, histology, the number of tumour cells in relation to the number of intratumoral leucocytes, proliferative and apoptotic fractions of tumour cells, intratumoral vessel density, and fibrosis. The results revealed that during regression, tumour cell proliferation ceased, apoptosis increased, leucocytes increased (with increased proportion of T lymphocytes), tumour parenchyma collapsed around intratumoral vessels, and fibrosis increased. These results, which were similar to findings in dogs with spontaneous regression of CTVT, suggest that tumour immunity plays a role in tumour regression after modest chemotherapy. Copyright 2000 Harcourt Publishers Ltd.

Current status of intratumoral therapy for glioblastoma.

PubMed

Mehta, Ankit I; Linninger, Andreas; Lesniak, Maciej S; Engelhard, Herbert H

2015-10-01

With emerging drug delivery technologies becoming accessible, more options are expected to become available to patients with glioblastoma (GBM) in the near future. It is important for clinicians to be familiar with the underlying mechanisms and limitations of intratumoral drug delivery, and direction of recent research efforts. Tumor-adjacent brain is an extremely complex living matrix that creates challenges with normal tissue intertwining with tumor cells. For convection-enhanced delivery (CED), the role of tissue anisotropy for better predicting the biodistribution of the infusate has recently been studied. Computational predictive methods are now available to better plan CED therapy. Catheter design and placement—in addition to the agent being used—are critical components of any protocol. This paper overviews intratumoral therapies for GBM, highlighting key anatomic and physiologic perspectives, selected agents (especially immunotoxins), and some new developments such as the description of the glymphatic system.

Correlation of intra-tumor 18F-FDG uptake heterogeneity indices with perfusion CT derived parameters in colorectal cancer.

PubMed

Tixier, Florent; Groves, Ashley M; Goh, Vicky; Hatt, Mathieu; Ingrand, Pierre; Le Rest, Catherine Cheze; Visvikis, Dimitris

2014-01-01

Thirty patients with proven colorectal cancer prospectively underwent integrated 18F-FDG PET/DCE-CT to assess the metabolic-flow phenotype. Both CT blood flow parametric maps and PET images were analyzed. Correlations between PET heterogeneity and perfusion CT were assessed by Spearman's rank correlation analysis. Blood flow visualization provided by DCE-CT images was significantly correlated with 18F-FDG PET metabolically active tumor volume as well as with uptake heterogeneity for patients with stage III/IV tumors (|ρ|:0.66 to 0.78; p-value<0.02). The positive correlation found with tumor blood flow indicates that intra-tumor heterogeneity of 18F-FDG PET accumulation reflects to some extent tracer distribution and consequently indicates that 18F-FDG PET intra-tumor heterogeneity may be associated with physiological processes such as tumor vascularization.

Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas

PubMed Central

Mroz, Edmund A.; Tward, Aaron M.; Hammon, Rebecca J.; Ren, Yin; Rocco, James W.

2015-01-01

Background Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality. Methods and Findings Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity’s associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having oral-cavity or laryngeal cancers even when standard disease staging was taken into account. Prospective studies, however, will be required before MATH can be used prognostically in clinical trials or practice. Such studies will need to examine homogeneously treated HNSCC at specific head and neck subsites, and determine the influence of cancer therapy on MATH values. Analysis of MATH and outcome in human-papillomavirus-positive oropharyngeal squamous cell carcinoma is particularly needed. Conclusions To our knowledge this study is the first to combine data from hundreds of patients, treated at multiple institutions, to document a relation between intra-tumor heterogeneity and overall survival in any type of cancer. We suggest applying the simply calculated MATH metric of heterogeneity to prospective studies of HNSCC and other tumor types. PMID:25668320

Intratumoral administration of carboplatin bearing poly (ε-caprolactone) nanoparticles amalgamated with in situ gel tendered augmented drug delivery, cytotoxicity, and apoptosis in melanoma tumor.

PubMed

Bragta, Pallvi; Sidhu, Rupinder Kaur; Jyoti, Kiran; Baldi, Ashish; Jain, Upendra Kumar; Chandra, Ramesh; Madan, Jitender

2018-06-01

In a phase II clinical trial, carboplatin (CBDCA) displayed the response rate of 19% equivalent to dacarbazine in the treatment of malignant melanoma. However, besides desirable therapeutic profile, intravenous (i.v) administration of CBDCA delivers a subtherapeutic concentration at the target site. This entails administration of CBDCA through an alternate route by using nanovectors to achieve therapeutic efficacy in the treatment of melanoma. Carboplatin loaded poly(ε-caprolactone) nanoparticles (CBDCA-PCL-NPs) were formulated and amalgamated with chitosan-β-glycerophosphate gel (CBDCA-PCL-NPs-Gel) for intratumoral (i.t) administration. The mean particle size and zeta-potential of CBDCA-PCL-NPs were determined to be 54.5 ± 6.3-nm and -8.1 ± 0.9-mV, in addition to spherical shape of the nanoformulation. FT-IR spectroscopy denied any issue of chemical incompatibility between drug and polymer. XRD pattern indicated the amorphous lattice of CBDCA-PCL-NPs. The drug loading capacity of CBDCA-PCL-NPs-Gel was estimated to be 152 mg/1 ml. CBDCA-PCL-NPs-Gel demonstrated prolonged drug release up to 48 h. Furthermore, CBDCA-PCL-NPs-Gel displayed the IC 50 of 80.3-μM significantly (P < 0.05) lower than 162.8-μM of CBDCA-PCL-NPs and 248.5-μM of CBDCA solution in B16F1, melanoma cancer cells. CBDCA-PCL-NPs-Gel verified 80.2% of apoptosis significantly (P < 0.01) higher than 57.6% of CBDCA-PCL-NPs and 43.4% of CBDCA solution. Continuation to this, CBDCA-PCL-NPs-Gel significantly (P < 0.01) suppressed the tumor volume to 95.5 ± 8.4-mm 3 as compared to 178.9 ± 10.2-mm 3 of CBDCA solution injected i.t. and 210.6 ± 17.1-mm 3 displayed by CBDCA solution injected i.v. vis-à-vis 815.4 ± 17.1-mm 3 tumor volume of B16F1 tumor bearing C57BL6J mice. The promising preclinical results of CBDCA-PCL-NPs-Gel warrant further investigations under a set of stringent parameters for the treatment of melanoma. Copyright © 2018 Elsevier B.V. All rights reserved.

Cell Culture System for Analysis of Genetic Heterogeneity Within Hepatocellular Carcinomas and Response to Pharmacologic Agents.

PubMed

Gao, Qiang; Wang, Zhi-Chao; Duan, Meng; Lin, Yi-Hui; Zhou, Xue-Ya; Worthley, Daniel L; Wang, Xiao-Ying; Niu, Gang; Xia, Yuchao; Deng, Minghua; Liu, Long-Zi; Shi, Jie-Yi; Yang, Liu-Xiao; Zhang, Shu; Ding, Zhen-Bin; Zhou, Jian; Liang, Chun-Min; Cao, Ya; Xiong, Lei; Xi, Ruibin; Shi, Yong-Yong; Fan, Jia

2017-01-01

No targeted therapies have been found to be effective against hepatocellular carcinoma (HCC), possibly due to the large degree of intratumor heterogeneity. We performed genetic analyses of different regions of HCCs to evaluate levels of intratumor heterogeneity and associate alterations with responses to different pharmacologic agents. We obtained samples of HCCs (associated with hepatitis B virus infection) from 10 patients undergoing curative resection, before adjuvant therapy, at hospitals in China. We collected 4-9 spatially distinct samples from each tumor (55 regions total), performed histologic analyses, isolated cancer cells, and carried them low-passage culture. We performed whole-exome sequencing, copy-number analysis, and high-throughput screening of the cultured primary cancer cells. We tested responses of an additional 105 liver cancer cell lines to a fibroblast growth factor receptor (FGFR) 4 inhibitor. We identified a total of 3670 non-silent mutations (3192 missense, 94 splice-site variants, and 222 insertions or deletions) in the tumor samples. We observed considerable intratumor heterogeneity and branched evolution in all 10 tumors; the mean percentage of heterogeneous mutations in each tumor was 39.7% (range, 12.9%-68.5%). We found significant mutation shifts toward C>T and C>G substitutions in branches of phylogenetic trees among samples from each tumor (P < .0001). Of note, 14 of the 26 oncogenic alterations (53.8%) varied among subclones that mapped to different branches. Genetic alterations that can be targeted by existing pharmacologic agents (such as those in FGF19, DDR2, PDGFRA, and TOP1) were identified in intratumor subregions from 4 HCCs and were associated with sensitivity to these agents. However, cells from the remaining subregions, which did not have these alterations, were not sensitive to these drugs. High-throughput screening identified pharmacologic agents to which these cells were sensitive, however. Overexpression of FGF19 correlated with sensitivity of cells to an inhibitor of FGFR 4; this observation was validated in 105 liver cancer cell lines (P = .0024). By analyzing genetic alterations in different tumor regions of 10 HCCs, we observed extensive intratumor heterogeneity. Our patient-derived cell line-based model, integrating genetic and pharmacologic data from multiregional cancer samples, provides a platform to elucidate how intratumor heterogeneity affects sensitivity to different therapeutic agents. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Occurrence of intraocular air bubbles during intravitreal injections for retinopathy of prematurity.

PubMed

Sukgen, Emine Alyamac; Gunay, Murat; Kocluk, Yusuf

2017-02-01

This study aims to present five cases with retinopathy of prematurity (ROP) who were found to have intraocular air bubbles after intravitreal injection (IVI) treatment. The medical records of 148 infants who underwent IVI for ROP were retrospectively reviewed and the ones who demonstrated post-injection intraocular air bubble formation were recruited. Of the 148 patients (31 babies received ranibizumab, 20 babies received aflibercept, 97 babies received bevacizumab), five were found to have intraocular air bubbles right after the IVI. Two infants received intravitreal ranibizumab and three received intravitreal bevacizumab injections. Although intraocular pressure increased temporarily, no intraocular sterile or infective reactions were observed in the postoperative period. The air bubble was found to resorb spontaneously within 72 h. The occurrence rate of the intravitreal air bubbles in our series was 3.37 % despite previously not been reported in the literature. Due to the intravitreal air injection risk, it is important to be more careful while preparing the intravitreal medication before treatment in premature babies.

Combination therapy using intratumoral bacillus Calmette-Guerin (BCG) and vincristine in dogs with transmissible venereal tumours: therapeutic efficacy and histological changes.

PubMed

Mukaratirwa, S; Chitanga, S; Chimatira, T; Makuleke, C; Sayi, S T; Bhebhe, E

2009-06-01

Therapeutic efficacy and histological changes after bacillus Calmette-Guerin (BCG), vincristine and BCG/vincristine combination therapy of canine transmissible venereal tumours (CTVT) were studied. Twenty dogs with naturally occurring CTVT in the progression stage were divided into 4 groups and treated with intratumoral BCG, vincristine, BCG/vincristine combination therapy or intratumoral buffered saline (control group). Tumour sizes were determined weekly and tumour response to therapy was assessed. Tumour biopsies were taken weekly to evaluate histological changes. Complete tumour regression was observed in all the dogs treated with BCG, vincristine and BCG/vincristine combination therapy. BCG/vincristine combination therapy had a statistically significantly shorter regression time than BCG or vincristine therapy. No tumour regression was observed in the control group. Intratumoral BCG treatment resulted in the appearance of macrophages and increased numbers of tumour infiltrating lymphocytes (TILs) followed by tumour cell apoptosis and necrosis. Treatment with vincristine resulted in increased tumour cell apoptosis, reduction in the mitotic index and a decrease in the number of TILs. Tumours from dogs on BCG/vincristine combination were characterised by reduction in the mitotic index, and appearance of numerous TILs and macrophages followed by marked tumour cell apoptosis and necrosis. This study indicates that combined BCG and vincristine therapy is more effective than vincristine in treating CTVT, suggesting that the clinical course of this disease may be altered by immunochemotherapy.

Long-term outcome associated with intratumoral chemotherapy with cisplatin for cutaneous tumors in equidae: 573 cases (1995-2004).

PubMed

Théon, Alain P; Wilson, W David; Magdesian, K Gary; Pusterla, Nicola; Snyder, Jack R; Galuppo, Larry D

2007-05-15

To determine outcome associated with cutaneous tumors treated via intratumoral chemotherapy with cisplatin and identify risk factors affecting local tumor control and complications in equidae. Retrospective case series. 573 equidae with 630 cutaneous tumors. Medical records of horses, mules, donkeys, and ponies with cutaneous tumors treated via intratumoral chemotherapy with cisplatin were analyzed. 549 horses, 13 mules, 8 donkeys, and 3 ponies with 630 histologically confirmed cutaneous tumors were included. Tumors included sarcoids (n = 409), squamous cell carcinomas (151), soft tissue sarcomas (28), cutaneous lymphomas (26), and melanomas (16). Overall cure rate, defined as local control at 4 years, was 93.3%. For all tumor stages combined, cure rates after 1 course of treatment were 96.3% for sarcoids, 96% for lymphomas, 88% for squamous cell carcinomas, 85% for soft tissue sarcomas, and 81% for melanomas. Treatment protocol, tumor stage, and prior treatment were significant prognostic factors for tumor control. Treatment efficacy was lower for large tumors, those with gross postoperative residual disease, and those that had been treated previously with other modalities. Treatment was well tolerated. Local reactions were more likely to occur and to be more severe after the third and fourth treatment sessions. Results confirmed the value of intratumoral chemotherapy with cisplatin for treatment of cutaneous tumors in equidae. The results cannot be extrapolated to other formulations of cisplatin or other protocols that might be used.

Comparative prognostic relevance of breast intra-tumoral microvessel density evaluated by CD105 and CD146: A pilot study of 42 cases.

PubMed

Martinez, Leandro Marcelo; Labovsky, Vivian; Calcagno, María de Luján; Davies, Kevin Mauro; Rivello, Hernán Garcia; Wernicke, Alejandra; Calvo, Juan Carlos; Chasseing, Norma Alejandra

2016-04-01

Angiogenesis is a key process for metastatic progression. While it has been established that the evaluation of breast tumoral microvessel density by CD105 marker is a potential prognostic parameter, its evaluation by CD146 marker has been poorly studied. The purpose of this study was to compare the prognostic value of intra-tumoral microvessel density assayed by CD105 and CD146 in early breast cancer patients. 42 women with breast infiltrative ductal carcinoma (I and II-stages) were retrospectively reviewed. Intra-tumoral microvessel density was immunohistochemically examined using antibodies anti-CD105 and CD146 in paraffin-embedded tissues, and their association with classical prognostic-markers, metastatic recurrence, metastasis-free survival and overall survival was analyzed. High microvessel density assessed by CD146 was significantly associated with a higher risk of developing metastasis (p=0.0310) and a shorter metastasis-free survival (p=0.0197). In contrast, when we used the CD105-antibody, we did not find any significant association. Finally, CD146 showed to be an independent predictive indicator for metastasis-free survival (p=0.0055). Our data suggest that the intra-tumoral microvessel density evaluated by CD146 may be a more suitable predictor of metastatic development than that evaluated by CD105 in early breast cancer. Copyright © 2016 Elsevier GmbH. All rights reserved.

The Potential Role of Systemic Buffers in Reducing Intratumoral Extracellular pH and Acid-Mediated Invasion

PubMed Central

Silva, Ariosto S.; Yunes, Jose A.; Gillies, Robert J.; Gatenby, Robert A.

2013-01-01

A number of studies have shown that the extracellular pH (pHe) in cancers is typically lower than that in normal tissue and that an acidic pHe promotes invasive tumor growth in primary and metastatic cancers. Here, we investigate the hypothesis that increased systemic concentrations of pH buffers reduce intratumoral and peritumoral acidosis and, as a result, inhibit malignant growth. Computer simulations are used to quantify the ability of systemic pH buffers to increase the acidic pHe of tumors in vivo and investigate the chemical specifications of an optimal buffer for such purpose. We show that increased serum concentrations of the sodium bicarbonate (NaHCO3) can be achieved by ingesting amounts that have been used in published clinical trials. Furthermore, we find that consequent reduction of tumor acid concentrations significantly reduces tumor growth and invasion without altering the pH of blood or normal tissues. The simulations also show that the critical parameter governing buffer effectiveness is its pKa. This indicates that NaHCO3, with a pKa of 6.1, is not an ideal intratumoral buffer and that greater intratumoral pHe changes could be obtained using a buffer with a pKa of ~7. The simulations support the hypothesis that systemic pH buffers can be used to increase the tumor pHe and inhibit tumor invasion. PMID:19276380

Pulmonary emphysema and tumor microenvironment in primary lung cancer.

PubMed

Murakami, Junichi; Ueda, Kazuhiro; Sano, Fumiho; Hayashi, Masataro; Nishimoto, Arata; Hamano, Kimikazu

2016-02-01

To clarify the relationship between the presence of pulmonary emphysema and tumor microenvironment and their significance for the clinicopathologic aggressiveness of non-small cell lung cancer. The subjects included 48 patients with completely resected and pathologically confirmed stage I non-small cell lung cancer. Quantitative computed tomography was used to diagnose pulmonary emphysema, and immunohistochemical staining was performed to evaluate the matrix metalloproteinase (MMP) expression status in the intratumoral stromal cells as well as the microvessel density (MVD). Positive MMP-9 staining in the intratumoral stromal cells was confirmed in 17 (35%) of the 48 tumors. These 17 tumors were associated with a high MVD, frequent lymphovascular invasion, a high proliferative activity, and high postoperative recurrence rate (all, P < 0.05). The majority of the tumors (13 of 17) arose in patients with pulmonary emphysema (P = 0.02). Lung cancers arising from pulmonary emphysema were also associated with a high MVD, proliferative activity, and postoperative recurrence rate (all, P < 0.05). The MMP-9 expression in intratumoral stromal cells is associated with the clinicopathologic aggressiveness of lung cancer and is predominantly identified in tumors arising in emphysematous lungs. Further studies regarding the biological links between the intratumoral and extratumoral microenvironment will help to explain why lung cancers originating in emphysematous lung tissues are associated with a poor prognosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Magnetic Nanoliposomes as in Situ Microbubble Bombers for Multimodality Image-Guided Cancer Theranostics.

PubMed

Liu, Yang; Yang, Fang; Yuan, Chuxiao; Li, Mingxi; Wang, Tuantuan; Chen, Bo; Jin, Juan; Zhao, Peng; Tong, Jiayi; Luo, Shouhua; Gu, Ning

2017-02-28

Nanosized drug delivery systems have offered promising approaches for cancer theranostics. However, few are effective to simultaneously maximize tumor-specific uptake, imaging, and therapy in a single nanoplatform. Here, we report a simple yet stimuli-responsive anethole dithiolethione (ADT)-loaded magnetic nanoliposome (AML) delivery system, which consists of ADT, hydrogen sulfide (H 2 S) pro-drug, doped in the lipid bilayer, and superparamagnetic nanoparticles encapsulated inside. HepG2 cells could be effectively bombed after 6 h co-incubation with AMLs. For in vivo applications, after preferentially targeting the tumor tissue when spatiotemporally navigated by an external magnetic field, the nanoscaled AMLs can intratumorally convert to microsized H 2 S bubbles. This dynamic process can be monitored by magnetic resonance and ultrasound dual modal imaging. Importantly, the intratumoral generated H 2 S bubbles imaged by real-time ultrasound imaging first can bomb to ablate the tumor tissue when exposed to higher acoustic intensity; then as gasotransmitters, intratumoral generated high-concentration H 2 S molecules can diffuse into the inner tumor regions to further have a synergetic antitumor effect. After 7-day follow-up observation, AMLs with magnetic field treatments have indicated extremely significantly higher inhibitions of tumor growth. Therefore, such elaborately designed intratumoral conversion of nanostructures to microstructures has exhibited an improved anticancer efficacy, which may be promising for multimodal image-guided accurate cancer therapy.

Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity

PubMed Central

Erkes, Dan A; Xu, Guangwu; Daskalakis, Constantine; Zurbach, Katherine A; Wilski, Nicole A; Moghbeli, Toktam; Hill, Ann B; Snyder, Christopher M

2016-01-01

Cytomegalovirus is an attractive cancer vaccine platform because it induces strong, functional CD8+ T-cell responses that accumulate over time and migrate into most tissues. To explore this, we used murine cytomegalovirus expressing a modified gp100 melanoma antigen. Therapeutic vaccination by the intraperitoneal and intradermal routes induced tumor infiltrating gp100-specific CD8+ T-cells, but provided minimal benefit for subcutaneous lesions. In contrast, intratumoral infection of established tumor nodules greatly inhibited tumor growth and improved overall survival in a CD8+ T-cell-dependent manner, even in mice previously infected with murine cytomegalovirus. Although murine cytomegalovirus could infect and kill B16F0s in vitro, infection was restricted to tumor-associated macrophages in vivo. Surprisingly, the presence of a tumor antigen in the virus only slightly increased the efficacy of intratumoral infection and tumor-specific CD8+ T-cells in the tumor remained dysfunctional. Importantly, combining intratumoral murine cytomegalovirus infection with anti-PD-L1 therapy was synergistic, resulting in tumor clearance from over half of the mice and subsequent protection against tumor challenge. Thus, while a murine cytomegalovirus-based vaccine was poorly effective against established subcutaneous tumors, direct infection of tumor nodules unexpectedly delayed tumor growth and synergized with immune checkpoint blockade to promote tumor clearance and long-term protection. PMID:27434584

Shock wave induced sonoporation and gene transfer

NASA Astrophysics Data System (ADS)

Miller, Douglas L.

2003-10-01

During shockwave (SW) treatment, cavitation activity can be applied for cell killing. A bonus is that some surviving cells appear to be briefly permeabilized, or sonoporated, allowing them to take up large molecules including DNA. In vitro research has indicated that as the number of SW increased, survival declined exponentially but the number of sonoporated cells increased to better than 50% of survivors for 1000 SW. In vivo tests have demonstrated SW-induced tumor ablation could indeed be accompanied by the transfection of marker plasmids into mouse B16 melanoma tumors in vivo. With intratumor injection of plasmid DNA and air bubbles, significant results were obtained for only 400 SW. In a trial of cancer therapy, the effects of 500 SW combined with interleukin-12 immuno-gene therapy was observed on the progression of two mouse tumors, B16 melanoma and RENCA renal carcinoma. The combination of SW and IL-12 plasmid injection provided a statistically significant inhibition of tumor growth relative to SW alone for both tumor models, demonstrating feasibility for this treatment method. In the future, the development of intravenous gene delivery and improved transfection, together with image-guided ultrasound treatment, should lead to the clinical application of ultrasound enhanced gene therapy. [Work supported by NIH Grant No. EB002782.

Magnetic core mesoporous silica nanoparticles doped with dacarbazine and labelled with 99mTc for early and differential detection of metastatic melanoma by single photon emission computed tomography.

PubMed

Portilho, Filipe Leal; Helal-Neto, Edward; Cabezas, Santiago Sánchez; Pinto, Suyene Rocha; Dos Santos, Sofia Nascimento; Pozzo, Lorena; Sancenón, Félix; Martínez-Máñez, Ramón; Santos-Oliveira, Ralph

2018-02-27

Cancer is responsible for more than 12% of all causes of death in the world, with an annual death rate of more than 7 million people. In this scenario melanoma is one of the most aggressive ones with serious limitation in early detection and therapy. In this direction we developed, characterized and tested in vivo a new drug delivery system based on magnetic core-mesoporous silica nanoparticle that has been doped with dacarbazine and labelled with technetium 99 m to be used as nano-imaging agent (nanoradiopharmaceutical) for early and differential diagnosis and melanoma by single photon emission computed tomography. The results demonstrated the ability of the magnetic core-mesoporous silica to be efficiently (>98%) doped with dacarbazine and also efficiently labelled with 99mTc (technetium 99 m) (>99%). The in vivo test, using inducted mice with melanoma, demonstrated the EPR effect of the magnetic core-mesoporous silica nanoparticles doped with dacarbazine and labelled with technetium 99 metastable when injected intratumorally and the possibility to be used as systemic injection too. In both cases, magnetic core-mesoporous silica nanoparticles doped with dacarbazine and labelled with technetium 99 metastable showed to be a reliable and efficient nano-imaging agent for melanoma.

Retardation of Antigen Release from DNA Hydrogel Using Cholesterol-Modified DNA for Increased Antigen-Specific Immune Response.

PubMed

Umeki, Yuka; Saito, Masaaki; Takahashi, Yuki; Takakura, Yoshinobu; Nishikawa, Makiya

2017-10-01

Our previous study indicates that cationization of an antigen is effective for sustained release of both immunostimulatory DNA containing unmethylated cytosine-phosphate-guanine (CpG) dinucleotides, or CpG DNA, and antigen from a DNA hydrogel. Another approach to sustained antigen release would increase the applicability and versatility of the system. In this study, a hydrophobic interaction-based sustained release system of ovalbumin (OVA), a model antigen, from immunostimulatory CpG DNA hydrogel is developed by the use of cholesterol-modified DNA and urea-denatured OVA (udOVA). Cholesterol-modified DNA forms a hydrogel, Dgel(chol), and induces IL-6 mRNA expression in mouse skin after intradermal injection, as DNA without cholesterol does. Cholesterol-modified DNA associated with OVA and denaturation of OVA using urea increases the interaction. The release of udOVA from Dgel(chol) is significantly slower than that from DNA hydrogel with no cholesterol, Dgel. Moreover, intratumoral injections of udOVA/Dgel(chol) significantly inhibit the growth of EG7-OVA tumors in mice. These results indicate that sustained release of antigen from Dgel can be achieved by the combination of urea denaturation and cholesterol modification, and retardation of antigen release is effective to induce antigen-specific cancer immunity. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biodistribution of modular nanotransporter carrying Auger electron emitter and targeted at melanoma cells in murine tumor model

NASA Astrophysics Data System (ADS)

Vorontsova, M. S.; Morozova, N. B.; Karmakova, T. A.; Rosenkranz, A. A.; Slastnikova, T. A.; Petriev, V. M.; Smoryzanova, O. A.; Tischenko, V. K.; Yakubovskaya, R. I.; Kaprin, A. D.; Sobolev, A. S.

2017-09-01

Recombinant modular nanotransporter containing α-melanocyte-stimulating hormone peptide sequence (MNT-MSH) as a ligand module was designed for nucleus-targeted delivery of cytotoxic agents into melanoma cells. MNT-MSH radiolabeled with Auger electron emitter (111In-NOTA-MNT-MSH) showed a high antitumor efficacy in mice bearing syngeneic melanoma after intratumoral (i.t.) injection. This study is aimed at evaluating the biodistribution of the radioconjugate in melanoma tumor model in vivo. 111In-NOTA-MNT-MSH was administered i.t. in C57Bl/6j mice bearing subcutaneously implanted B16-F1 murine melanoma cells, expressing high levels of MCR1. The tissue uptake of radioactivity was determined ex vivo by γ-counter measurements. The intravenous route of administration did not provide a desirable level of radioactivity accumulation in the tumor, possibly, due to a high uptake of the transporter in liver tissue. After i.t. administration 111In-NOTA-MNT-MSH provided a high local retention of radionuclide, ranged from 400 to 350 %ID/g within at least 48 hours post-injection. MNT containing Auger electron emitter and α-MSH peptide as vector ligand could be a promising basis for radiopharmaceutical preparations intended for melanoma treatment.

Specific gene delivery to liver sinusoidal and artery endothelial cells.

PubMed

Abel, Tobias; El Filali, Ebtisam; Waern, Johan; Schneider, Irene C; Yuan, Qinggong; Münch, Robert C; Hick, Meike; Warnecke, Gregor; Madrahimov, Nodir; Kontermann, Roland E; Schüttrumpf, Jörg; Müller, Ulrike C; Seppen, Jurgen; Ott, Michael; Buchholz, Christian J

2013-09-19

Different types of endothelial cells (EC) fulfill distinct tasks depending on their microenvironment. ECs are therefore difficult to genetically manipulate ex vivo for functional studies or gene therapy. We assessed lentiviral vectors (LVs) targeted to the EC surface marker CD105 for in vivo gene delivery. The mouse CD105-specific vector, mCD105-LV, transduced only CD105-positive cells in primary liver cell cultures. Upon systemic injection, strong reporter gene expression was detected in liver where mCD105-LV specifically transduced liver sinusoidal ECs (LSECs) but not Kupffer cells, which were mainly transduced by nontargeted LVs. Tumor ECs were specifically targeted upon intratumoral vector injection. Delivery of the erythropoietin gene with mCD105-LV resulted in substantially increased erythropoietin and hematocrit levels. The human CD105-specific vector (huCD105-LV) transduced exclusively human LSECs in mice transplanted with human liver ECs. Interestingly, when applied at higher dose and in absence of target cells in the liver, huCD105-LV transduced ECs of a human artery transplanted into the descending mouse aorta. The data demonstrate for the first time targeted gene delivery to specialized ECs upon systemic vector administration. This strategy offers novel options to better understand the physiological functions of ECs and to treat genetic diseases such as those affecting blood factors.

Functionalized graphene oxide-based thermosensitive hydrogel for magnetic hyperthermia therapy on tumors

NASA Astrophysics Data System (ADS)

Zhu, Xiali; Zhang, Huijuan; Huang, Heqing; Zhang, Yingjie; Hou, Lin; Zhang, Zhenzhong

2015-09-01

A novel locally injectable, biodegradable, and thermo-sensitive hydrogel made from chitosan and β-glycerophosphate salt was prepared. It incorporated polyethylenimine (PEI)-modified super-paramagnetic graphene oxide (GO/IONP/PEI) as a form of minimally invasive treatment of cancer lesions by magnetically induced local hyperthermia. Doxorubicin (DOX) was mixed into the hydrogel which was pre-loaded on GO/IONP/PEI to create a drug delivery system DOX-GO/IONP/PEI-gel. In addition to the evaluation of in vitro and in vivo antitumor activities, the physicochemical properties, magnetic properties and DOX release profile of the DOX-GO/IONP/PEI-gel were determined. The aqueous solution of the hydrogel showed a sol-gel transition behavior depending on temperature changes. Magnetization loops indicated the super-paramagnetic properties of GO/IONP/PEI. Compared with free DOX, DOX-GO/IONP/PEI could efficiently pass through cell membranes, leading to more apoptosis and demonstrating higher antitumor efficacy on MCF-7 cells in vitro. Furthermore, DOX-GO/IONP/PEI-gel intratumorally injected (i.t.) showed high antitumor efficacy on tumor-bearing mice in vivo, with no obvious toxicity. The antitumor efficacy was higher when combined with an alternating magnetic field (AMF), showing that DOX-GO/IONP/PEI-gel under AMF has great potential for cancer magnetic hyperthermia therapy.

Injection practice in Kaski district, Western Nepal: a community perspective.

PubMed

Gyawali, Sudesh; Rathore, Devendra Singh; Shankar, Pathiyil Ravi; Kumar, Vikash K C; Maskey, Manisha; Jha, Nisha

2015-04-29

Previous studies have shown that unsafe injection practice is a major public health problem in Nepal but did not quantify the problem. The present community-based study was planned to: 1) quantify injection usage, 2) identify injection providers, 3) explore differences, if any, in injection usage and injection providers, and 4) study and compare people's knowledge and perception about injections between the urban and rural areas of Kaski district. A descriptive, cross-sectional mixed-methods study was conducted from July to November 2012, using a questionnaire based survey and focus group discussions (FGDs). A semi-structured questionnaire advocated by the World Health Organization was modified and administered to household heads and injection receivers in selected households and the FGDs were conducted using a topic guide. The district was divided into urban and rural areas and 300 households from each area were selected. Twenty FGDs were held. In 218 households (36.33%) [99 in urban and 119 in rural] one or more members received at least one injection. During the three month recall period, 258 subjects (10.44%) reported receiving injection(s) with a median of two injections. The average number of injections per person per year was calculated to be 2.37. Health care workers (34.8%), staff of medical dispensaries (37.7%), physicians (25.2%), and traditional healers (2.3%) were consulted by the respondents for their basic health care needs and for injections. Compared to urban respondents, more rural respondents preferred injections for fever (p < 0.001). People preferred injections due to injections being perceived by them as being powerful, fast-acting, and longer lasting than oral pills. More than 82% of respondents were aware of, and named, at least one disease transmitted by using unsterile syringes during injection administration or when syringes are shared between people. Less preference for injections and high awareness about the association between injections and injection-borne infections among the general population is encouraging for safe injection practice. However, respondents were not aware of the importance of having qualified injection providers for safe injections and were receiving injections from unqualified personnel.

Elimination of Topical Antibiotics for Intravitreous Injections and the Importance of Using Povidone-Iodine: Update From the Diabetic Retinopathy Clinical Research Network.

PubMed

Bhavsar, Abdhish R; Glassman, Adam R; Stockdale, Cynthia R; Jampol, Lee M

2016-10-01

This report provides updated endophthalmitis rates for eyes receiving intravitreous injections with and without povidone-iodine and rates with and without topical antibiotics from Diabetic Retinopathy Clinical Research Network clinical trials. Among 8 Diabetic Retinopathy Clinical Research Network clinical trials conducted from 2006 to 2015, 28 786 intravitreous injections were administered (3123 eyes), and 20 617 of those (2264 eyes) were administered between 2012 and 2015. Eleven cases of endophthalmitis occurred; 4 occurred between 2012 and 2015. Thirteen injections in 3 eyes from 2 participants were administered without povidone-iodine; both participants developed endophthalmitis in 1 eye. Of the remaining 28 773 injections (3120 eyes) performed with povidone-iodine, 9 cases of endophthalmitis occurred: 6 cases (0.05% of 11 565 injections) in eyes receiving topical antibiotics and 3 cases (0.02% of 17 208 injections) in eyes not receiving topical antibiotics (P = .17). While only a small number of eyes did not receive povidone-iodine just prior to an intravitreous injection, this report provides further evidence regarding the risk of endophthalmitis when povidone-iodine is not used before intravitreous injections. Exclusion of topical antibiotics was not associated with a higher risk of endophthalmitis. Continued use of povidone-iodine and consideration to eliminate topical antibiotics from injection procedures seems warranted.

Small-animal PET of tumor damage induced by photothermal ablation with 64Cu-bis-DOTA-hypericin.

PubMed

Song, Shaoli; Xiong, Chiyi; Zhou, Min; Lu, Wei; Huang, Qian; Ku, Geng; Zhao, Jun; Flores, Leo G; Ni, Yicheng; Li, Chun

2011-05-01

The purpose of this study was to investigate the potential application of small-molecular-weight (64)Cu-labeled bis-DOTA-hypericin in the noninvasive assessment of response to photothermal ablation therapy. Bis-DOTA-hypericin was labeled with (64)Cu with high efficiency (>95% without purification). Nine mice bearing subcutaneous human mammary BT474 tumors were used. Five mice were injected intratumorally with semiconductor CuS nanoparticles, followed by near-infrared laser irradiation 24 h later (12 W/cm(2) for 3 min), and 4 mice were not treated (control group). All mice were intravenously injected with (64)Cu-bis-DOTA-hypericin (24 h after laser treatment in treated mice). Small-animal PET images were acquired at 2, 6, and 24 h after radiotracer injection. All mice were killed immediately after the imaging session for biodistribution and histology study. In vitro cell uptake and surface plasmon resonance studies were performed to validate the small-animal PET results. (64)Cu-bis-DOTA-hypericin uptake was significantly higher in the treatment group than in the control group. The percentage injected dose per gram of tissue in the treated and control groups was 1.72 ± 0.43 and 0.76 ± 0.19, respectively (P = 0.017), at 24 h after injection. Autoradiography and histology results were consistent with selective uptake of the radiotracer in the necrotic zone of the tumor induced by photothermal ablation therapy. In vitro results showed that treated BT474 cells had a higher uptake of (64)Cu-bis-DOTA-hypericin than nontreated cells. Surface plasmon resonance study showed that bis-DOTA-hypericin had higher binding affinity to phosphatidylserine and phosphatidylethanolamine than to phosphatidylcholine. (64)Cu-bis-DOTA-hypericin has a potential to image thermal therapy-induced tumor cell damage. The affinity of (64)Cu-bis-DOTA-hypericin for injured tissues may be attributed to the breakdown of the cell membrane and exposure of phosphatidylserine or phosphatidylethanolamine to the radiotracer, which binds selectively to these phospholipids.

Human Dosimetry and Preliminary Tumor Distribution of (superscript)18F-Fluoropaclitaxel in Healthy Volunteers and Newly Diagnosed Breast Cancer Patients Using PET/CT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kurdziel, K.A.; Logan, J.; Kurdziel, K.A.

2011-08-17

{sup 18}F-fluoropaclitaxel is a radiolabeled form of paclitaxel, a widely used chemotherapy agent. Preclinical data suggest that {sup 18}F-fluoropaclitaxel may be a reasonable surrogate for measuring the uptake of paclitaxel. As a substrate of P-glycoprotein, a drug efflux pump associated with multidrug resistance, {sup 18}F-fluoropaclitaxel may also be useful in identifying multidrug resistance and predicting tumor response for drugs other than paclitaxel. After informed consent was obtained, 3 healthy volunteers and 3 patients with untreated breast cancer (neoadjuvant chemotherapy candidates, tumor size > 2 cm) received an intravenous infusion of {sup 18}F-fluoropaclitaxel and then underwent PET/CT. Healthy volunteers underwent serialmore » whole-body imaging over an approximately 3-h interval, and organ {sup 18}F residence times were determined from the time-activity curves uncorrected for decay to determine dosimetry. Radiation dose estimates were calculated using OLINDA/EXM software. For breast cancer patients, dynamic imaging of the primary tumor was performed for 60 min, followed by static whole-body scans at 1 and 2 h after injection. Dosimetry calculations showed that the gallbladder received the highest dose (229.50 {mu}Gy/MBq [0.849 rad/mCi]), followed by the small and large intestines (161.26 {mu}Gy/MBq [0.597 rad/mCi] and 184.59 {mu}Gy/MBq [0.683 rad/mCi]). The resultant effective dose was 28.79 {mu}Gy/MBq (0.107 rem/mCi). At approximately 1 h after injection, an average of 42% of the decay-corrected activity was in the gastrointestinal system, with a mean of 0.01% in the tumor. All 3 breast cancer patients showed retention of {sup 18}F-fluoropaclitaxel and ultimately demonstrated a complete pathologic response (no invasive cancer in the breast or axillary nodes) to chemotherapy that included a taxane (either paclitaxel or docetaxel) at surgical resection. The tumor-to-background ratio increased with time to a maximum of 7.7 at 20 min. This study demonstrates the feasibility of using {sup 18}F-fluoropaclitaxel PET/CT tumor imaging and provides radiation dosimetry measurements in humans. Although further study is needed, it is hoped that the measured intratumoral {sup 18}F-fluoropaclitaxel distribution can serve as a surrogate for paclitaxel, and potentially other chemotherapeutic agent retention, in solid tumors.« less

Positron emission tomography imaging of tumor angiogenesis and monitoring of antiangiogenic efficacy using the novel tetrameric peptide probe 64Cu-cyclam-RAFT-c(-RGDfK-)4.

PubMed

Jin, Zhao-Hui; Furukawa, Takako; Claron, Michael; Boturyn, Didier; Coll, Jean-Luc; Fukumura, Toshimitsu; Fujibayashi, Yasuhisa; Dumy, Pascal; Saga, Tsuneo

2012-12-01

64Cu-cyclam-RAFT-c(-RGDfK-)4 is a novel multimeric positron emission tomography (PET) probe for αVβ3 integrin imaging. Its uptake and αVβ3 expression in tumors showed a linear correlation. Since αVβ3 integrin is strongly expressed on activated endothelial cells during angiogenesis, we aimed to determine whether 64Cu-cyclam-RAFT-c(-RGDfK-)4 PET can be used to image tumor angiogenesis and monitor the antiangiogenic effect of a novel multi-targeted tyrosine kinase inhibitor, TSU-68. Athymic nude mice bearing human hepatocellular carcinoma HuH-7 xenografts, which expressed negligible αVβ3 levels on the tumor cells, received intraperitoneal injections of TSU-68 or the vehicle for 14 days. Antiangiogenic effects were determined at the end of therapy in terms of 64Cu-cyclam-RAFT-c(-RGDfK-)4 uptake evaluated using PET, biodistribution assay, and autoradiography, and they were compared with microvessel density (MVD) determined by CD31 immunostaining. 64Cu-cyclam-RAFT-c(-RGDfK-)4 PET enabled clear tumor visualization by targeting the vasculature, and the biodistribution assay indicated high tumor-to-blood and tumor-to-muscle ratios of 31.6 ± 6.3 and 6.7 ± 1.1, respectively, 3 h after probe injection. TSU-68 significantly slowed tumor growth and reduced MVD; these findings were consistent with a significant reduction in the tumor 64Cu-cyclam-RAFT-c(-RGDfK-)4 uptake. Moreover, a linear correlation was observed between tumor MVD and the corresponding standardized uptake value (SUV) (r = 0.829, P = 0.011 for SUV(mean); r = 0.776, P = 0.024 for SUV(max)) determined by quantitative PET. Autoradiography and immunostaining showed that the distribution of intratumoral radioactivity and tumor vasculature corresponded. We concluded that 64Cu-cyclam-RAFT-c(-RGDfK-)4 PET can be used for in vivo angiogenesis imaging and monitoring of tumor response to antiangiogenic therapy.

Fear of repeated injections in children younger than 4 years receiving subcutaneous allergy immunotherapy.

PubMed

de Vos, Gabriele; Shankar, Viswanathan; Nazari, Ramin; Kooragayalu, Shravan; Smith, Mitchell; Wiznia, Andrew; Rosenstreich, David

2012-12-01

Allergy immunotherapy during early childhood may have potential benefits for the prevention of asthma and allergy morbidity. However, subcutaneous immunotherapy has not yet been prospectively researched in children younger than 4 years, primarily because of safety concerns, including the fear and psychological distress young children may experience with repeated needle injections. To quantify fear in atopic children younger than 4 years with a history of wheezing who are receiving subcutaneous immunotherapy. Fear of injection was graded during a total of 788 immunotherapy injection visits in 18 children (age, 37 months; SD, 9 months) receiving subcutaneous allergy immunotherapy. The parent and the injection nurse assigned fear scores on a scale of 0 to 10 after each injection visit. At the time of analysis, children had a median of 49 injection visits (range, 12-88) during a median study period of 81.5 weeks (range, 15-165 weeks). Fifteen children (83%) lost their fear of injections during the study. A fear score of 0 was achieved after a mean of 8.4 visits (SD, 7.4). The more injection visits were missed, the more likely children were to retain fear of injections (hazard ratio, 0.13; 95% confidence interval, 0.02-1.02; P=.05). Age, adverse events, number of injections at each visit, and change of injection personnel were not associated with increased fear. Our analysis suggests that most children receiving weekly subcutaneous immunotherapy lose their fear of injections during the treatment course. Children with increased intervals between visits may be at higher risk of experiencing fear of injections. clinicaltrial.gov identifier NCT01028560. Copyright © 2012 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Monitoring of subsurface injection of wastes, Florida

USGS Publications Warehouse

Vecchioli, John

1979-01-01

Injection of waste liquids into Florida's subsurface is physically feasible in many places but should be accompanied by monitoring of the waste-receiving aquifer system in addition to the injection facility. Monitoring of the interaction of factors including hydrogeologic conditions, well construction, waste volumes and characteristics, and potable-water sources is desirable to assure that fresh-water resources are not being adversely affected. An effective aquifer-system monitoring program includes on-site wells located close to an injection well and open to the next-higher permeable stratum, satellite wells located hundreds to several thousands of feet from an injection well and open to the receiving aquifer, and regional wells located miles from individual injection wells and open to the receiving aquifer. An extensive aquifer-system monitoring program associated with two waste-injection facilities near Pensacola, Florida, has provided data which have aided hydrologists to understand the aquifer system's response to the injection and, accordingly, to evaluate the potential for affecting the area's fresh-water resources.

Limited utility of tissue micro-arrays in detecting intra-tumoral heterogeneity in stem cell characteristics and tumor progression markers in breast cancer.

PubMed

Kündig, Pascale; Giesen, Charlotte; Jackson, Hartland; Bodenmiller, Bernd; Papassotirolopus, Bärbel; Freiberger, Sandra Nicole; Aquino, Catharine; Opitz, Lennart; Varga, Zsuzsanna

2018-05-08

Intra-tumoral heterogeneity has been recently addressed in different types of cancer, including breast cancer. A concept describing the origin of intra-tumoral heterogeneity is the cancer stem-cell hypothesis, proposing the existence of cancer stem cells that can self-renew limitlessly and therefore lead to tumor progression. Clonal evolution in accumulated single cell genomic alterations is a further possible explanation in carcinogenesis. In this study, we addressed the question whether intra-tumoral heterogeneity can be reliably detected in tissue-micro-arrays in breast cancer by comparing expression levels of conventional predictive/prognostic tumor markers, tumor progression markers and stem cell markers between central and peripheral tumor areas. We analyzed immunohistochemical expression and/or gene amplification status of conventional prognostic tumor markers (ER, PR, HER2, CK5/6), tumor progression markers (PTEN, PIK3CA, p53, Ki-67) and stem cell markers (mTOR, SOX2, SOX9, SOX10, SLUG, CD44, CD24, TWIST) in 372 tissue-micro-array samples from 72 breast cancer patients. Expression levels were compared between central and peripheral tumor tissue areas and were correlated to histopathological grading. 15 selected cases additionally underwent RNA sequencing for transcriptome analysis. No significant difference in any of the analyzed between central and peripheral tumor areas was seen with any of the analyzed methods/or results that showed difference. Except mTOR, PIK3CA and SOX9 (nuclear) protein expression, all markers correlated significantly (p < 0.05) with histopathological grading both in central and peripheral areas. Our results suggest that intra-tumoral heterogeneity of stem-cell and tumor-progression markers cannot be reliably addressed in tissue-micro-array samples in breast cancer. However, most markers correlated strongly with histopathological grading confirming prognostic information as expression profiles were independent on the site of the biopsy was taken.

Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer

PubMed Central

Bilen, Mehmet Asim; Hess, Kenneth R.; Broaddus, Russell R.; Kopetz, Scott; Wei, Chongjuan; Pagliaro, Lance C.; Karam, Jose A.; Ward, John F.; Wood, Christopher G.; Rao, Priya; Tu, Zachary H.; General, Rosale; Chen, Adrienne H.; Nieto, Yago L.; Yeung, Sai‐ching J.; Lin, Sue‐Hwa; Logothetis, Christopher J.; Pisters, Louis L.

2016-01-01

BACKGROUND Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype. METHODS In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next‐generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations. RESULTS Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac‐seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected. CONCLUSIONS The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836–43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID:27018785

Interleukin-33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells.

PubMed

Jovanovic, Ivan P; Pejnovic, Nada N; Radosavljevic, Gordana D; Pantic, Jelena M; Milovanovic, Marija Z; Arsenijevic, Nebojsa N; Lukic, Miodrag L

2014-04-01

The role of IL-33/ST2 pathway in antitumor immunity is unclear. Using 4T1 breast cancer model we demonstrate time-dependent increase of endogenous IL-33 at both the mRNA and protein levels in primary tumors and metastatic lungs during cancer progression. Administration of IL-33 accelerated tumor growth and development of lung and liver metastases, which was associated with increased intratumoral accumulation of CD11b(+) Gr-1(+) TGF-β1(+) myeloid-derived suppressor cells (MDSCs) that expressed IL-13α1R, IL-13-producing Lin(-) Sca-1(+) ST2(+) innate lymphoid cells (ILCs) and CD4(+) Foxp3(+) ST2(+) IL-10(+) Tregs compared to untreated mice. Higher incidence of monocytic vs. granulocytic MDSCs and plasmocytoid vs. conventional dendritic cells (DCs) was present in mammary tumors of IL-33-treated mice. Intratumoral NKp46(+) NKG2D(+) and NKp46(+) FasL(+) cells were markedly reduced after IL-33 treatment, while phosphate-buffered saline-treated ST2-deficient mice had increased frequencies of these tumoricidal natural killer (NK) cells compared to untreated wild-type mice. IL-33 promoted intratumoral cell proliferation and neovascularization, which was attenuated in the absence of ST2. Tumor-bearing mice given IL-33 had increased percentages of splenic MDSCs, Lin(-) Sca-1(+) ILCs, IL-10-expressing CD11c(+) DCs and alternatively activated M2 macrophages and higher circulating levels of IL-10 and IL-13. A significantly reduced NK cell, but not CD8(+) T-cell cytotoxicity in IL-33-treated mice was observed and the mammary tumor progression was not affected when CD8(+) T cells were in vivo depleted. We show a previously unrecognized role for IL-33 in promoting breast cancer progression through increased intratumoral accumulation of immunosuppressive cells and by diminishing innate antitumor immunity. Therefore, IL-33 may be considered as an important mediator in the regulation of breast cancer progression. © 2013 UICC.

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

PubMed Central

Noordam, Lisanne; Sprengers, Dave; Boor, Patrick P. C.; Mancham, Shanta; Menon, Anand G.; Lange, Johan F.; Burger, Pim J. W. A.; Brandt, Alexandra; Galjart, Boris; Kwekkeboom, Jaap; Bruno, Marco J.

2018-01-01

ABSTRACT Purpose: Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology: Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC. Expression of inhibitory molecules was also analyzed on leukocytes isolated from paired resected metastatic liver tumors, tumor-free liver tissues, and blood of patients with mismatch repair-proficient LM-CRC. The effects of blocking inhibitory pathways on tumor-infiltrating T-cell responses were studied in ex vivo functional assays. Results: Mismatch repair-proficient LM-CRC showed higher expression of inhibitory receptors on intra-tumoral T-cells and contained higher proportions of CD8+ T-cells, dendritic cells and monocytes than mismatch repair-proficient primary CRC and/or PM-CRC. Inhibitory receptors LAG3, PD-1, TIM3 and CTLA4 were higher expressed on CD8+ T-cells, CD4+ T-helper and/or regulatory T-cells in LM-CRC tumors compared with tumor-free liver and blood. Antibody blockade of LAG3 or PD-L1 increased proliferation and effector cytokine production of intra-tumoral T-cells isolated from LM-CRC in response to both polyclonal and autologous tumor-specific stimulations. Higher LAG3 expression on intra-tumoral CD8+ T-cells associated with longer progression-free survival of LM-CRC patients. Conclusion: Mismatch repair-proficient LM-CRC may be more sensitive to immune checkpoint inhibitors than mismatch repair-proficient primary CRC. Blocking LAG3 enhances tumor-infiltrating T-cell responses of mismatch repair-proficient LM-CRC, and therefore may be a new promising immunotherapeutic target for LM-CRC.

Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer.

PubMed

Tu, Shi-Ming; Bilen, Mehmet Asim; Hess, Kenneth R; Broaddus, Russell R; Kopetz, Scott; Wei, Chongjuan; Pagliaro, Lance C; Karam, Jose A; Ward, John F; Wood, Christopher G; Rao, Priya; Tu, Zachary H; General, Rosale; Chen, Adrienne H; Nieto, Yago L; Yeung, Sai-Ching J; Lin, Sue-Hwa; Logothetis, Christopher J; Pisters, Louis L

2016-06-15

Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype. In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next-generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations. Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac-seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected. The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836-43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2016 American Cancer Society.

Peritumoral eosinophils predict recurrence in colorectal cancer.

PubMed

Harbaum, Lars; Pollheimer, Marion J; Kornprat, Peter; Lindtner, Richard A; Bokemeyer, Carsten; Langner, Cord

2015-03-01

In colorectal cancer, the presence and extent of eosinophil granulocyte infiltration may render important prognostic information. However, it remains unclear whether an increasing number of eosinophils might simply be linked to the overall inflammatory cell reaction or represent a self-contained, antitumoral mechanism that needs to be documented and promoted therapeutically. Peri- and intratumoral eosinophil counts were retrospectively assessed in 381 primary colorectal cancers from randomly selected patients. Tumors were diagnosed in American Joint Committee on Cancer (AJCC)/Union Internationale Contre le Cancer (UICC) stage I in 21%, stage II in 32%, stage III in 33%, and stage IV in 14%. Presence and extent of eosinophils was related to various histopathological parameters as well as patients' outcome. Overall, peri- and intratumoral eosinophils were observed in 86 and 75% cancer specimens. The peritumoral eosinophil count correlated strongly with the intratumoral eosinophil count (R=0.69; P<0.001) and with the intensity of the overall inflammatory cell reaction (R=0.318; P<0.001). Both increasing peri- and intratumoral eosinophil counts were significantly associated with lower T and N classification, better tumor differentiation, absence of vascular invasion, as well as improved progression-free and cancer-specific survival. However, only peritumoral eosinophils, but not intratumoral, were an independent prognosticator of favorable progression-free (hazard ratio 0.75; 95% confidence interval 0.58-0.98; P=0.04) and cancer-specific survival (hazard ratio 0.7; 95% confidence interval 0.52-0.93; P=0.01)-independent of the intensity of overall inflammatory cell reaction. This was also found for patients with AJCC/UICC stage II disease, wherein the presence of peritumoral eosinophils was significantly associated with favorable outcome. In conclusion, the number of peritumoral eosinophils had a significant favorable impact on prognosis of colorectal cancer patients independent of the overall tumor-associated inflammatory response. Evaluation of peritumoral eosinophils represents a promising readily assessable tool and should therefore routinely be commented on in the pathology report.

Vibration anesthesia for the reduction of pain with facial dermal filler injections.

PubMed

Mally, Pooja; Czyz, Craig N; Chan, Norman J; Wulc, Allan E

2014-04-01

Vibration anesthesia is an effective pain-reduction technique for facial cosmetic injections. The analgesic effect of this method was tested in this study during facial dermal filler injections. The study aimed to evaluate the safety and efficacy of vibration anesthesia for these facial injections. This prospective study analyzed 41 patients who received dermal filler injections to the nasolabial folds, tear troughs, cheeks, and other facial sites. The injections were administered in a randomly assigned split-face design. One side of the patient's face received vibration together with dermal filler injections, whereas the other side received dermal filler injections alone. The patients completed a posttreatment questionnaire pertaining to injection pain, adverse effects, and preference for vibration with future dermal filler injections. The patients experienced both clinically and statistically significant pain reduction when a vibration stimulus was co-administered with the dermal filler injections. No adverse events were reported. The majority of the patients (95 %) reported a preference for vibration anesthesia with subsequent dermal filler injections. Vibration is a safe and effective method of achieving anesthesia during facial dermal filler injections. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Endoscopic Injection of Low Dose Triamcinolone: a Simple, Minimally Invasive and Effective Therapy for Interstitial Cystitis with Hunner Lesions.

PubMed

Funaro, Michael G; King, Alexandra N; Stern, Joel N H; Moldwin, Robert M; Bahlani, Sonia

2018-05-18

To investigate the efficacy of low dose triamcinolone injection for effectiveness and durability in interstitial cystitis/bladder pain syndrome (IC/BPS) patients with Hunner Lesions (HL). Clinical data from patients with HL who underwent endoscopic submucosal injection of triamcinolone were reviewed: Demographics, pre/post operative pain and nocturia scores, and long-term clinical outcomes were assessed. Duration of response was estimated by time to repeat procedure. Kaplan-Meier estimator was used to evaluate time to repeat procedure. 36 patients who received injections of triamcinolone between 2011 and 2015 were included. Median age±SD of patients was 61.5±12.0 years 23; 28 (77.8%) of patients were female and 8 (22.2%) were male. 26 patients (72.2%) received only 1 set of injections, 8 (22.2%) received 2 sets of injections, and 2 (5.56%) received 3 or more sets of injections. Average time between injections in those receiving more than one set of injections was 344.9 days (median: 313.5, range: 77-714). Pre-procedural pain scores were 8.3±1.2 (mean±SD) on Likert pain scale (0-10), and mean post-procedural pain scores at approximately one month were 3.8±2.2 p<0.001. Mean pre-procedural nocturia bother scores were 7.5±2.0 and mean post-procedural nocturia bother scores were 5.1±2.5) p<0.001. Endoscopic submucosal injection of low dose triamcinolone in IC/BPS patients with HL is an effective and durable adjunct to existing treatment modalities. This approach is associated with low morbidity and can be performed on an outpatient basis. Copyright © 2018. Published by Elsevier Inc.

Periostin expression in intra-tumoral stromal cells is prognostic and predictive for colorectal carcinoma via creating a cancer-supportive niche

PubMed Central

Tan, Xiaojie; Ding, Yibo; Luo, Yanxin; Cai, Hui; Liu, Yan; Gao, Xianhua; Liu, Qizhi; Yu, Yongwei; Du, Yan; Wang, Hao; Ma, Liye; Wang, Jianping; Chen, Kun; Ding, Yanqing; Fu, Chuangang; Cao, Guangwen

2016-01-01

Periostin (POSTN) expression in cancer cells and circulation has been related to poor prognosis of colorectal carcinoma (CRC). However, the role of POSTN expressed in intra-tumoral stroma on CRC progression remains largely unknown. This study enrolled 1098 CRC patients who received surgical treatment in Shanghai and Guangzhou, Mainland China. In Shanghai cohort, immunohistochemistry score of stromal POSTN expression increased consecutively from adjacent mucosa, primary CRC tissues, to metastatic CRC tissues (P < 0.001), while medium- and high-stromal POSTN expression, rather than epithelial POSTN expression, independently predicted unfavorable prognoses of CRC, adjusted for covariates including TNM stage and postoperative chemotherapy in multivariate Cox models. The results in Shanghai cohort were faithfully replicated in Guangzhou cohort. Stromal POSTN expression dose-dependently predicted an unfavorable prognosis of stage III CRC patients with postoperative chemotherapy in both cohorts. POSTN derived from colonic fibroblasts or recombinant POSTN significantly promoted proliferation, anchorage independent growth, invasion, and chemo-resistance of CRC cells; whereas these effects were counteracted via targeting to PI3K/Akt or Wnt/β-catenin signaling pathway. CRC cell RKO-derived factor(s) significantly induced POSTN production in colonic fibroblasts and autocrine POSTN promoted proliferation, migration, and anchorage independent growth of fibroblasts. Conclusively, stromal POSTN is prognostic and predictive for CRC via creating a niche to facilitate cancer progression. Targeting POSTN-induced signaling pathways may be therapeutic options for metastatic or chemoresistant CRC. PMID:26556874

Intratumoral hemorrhage because of primary spinal mixed germ cell tumor presenting with atypical radiological features in an adult.

PubMed

Yamamoto, Junkoh; Takahashi, Mayu; Nakano, Yoshiteru; Saito, Takeshi; Kitagawa, Takehiro; Ueta, Kunihiro; Miyaoka, Ryo; Nakamura, Eiichiro; Nishizawa, Shigeru

2013-10-01

Germ cell tumors are known to arise in the central nervous system, usually in the intracranial regions. However, primary spinal mixed germ cell tumors are extremely rare. This is the first reported case of intratumoral hemorrhage because of a primary spinal mixed germ cell tumor consisting of germinoma and immature teratoma in the conus medullaris of an adult patient that presented with rapid changes on magnetic resonance image (MRI). We report this rare case and discuss the clinical manifestations of an intramedullary spinal mixed germ cell tumor in adult. A case report. A 42-year-old woman experienced buttock numbness, and a spinal cord tumor was observed on the conus medullaris on MRI. The patient was scheduled for an operation in 1 month, but she developed sudden-onset neurologic deterioration. Rapid progression of the tumor was observed on follow-up MRI. The tumor was removed by emergency surgery and was identified as a primary mixed germinoma and immature teratoma. The patient received adjuvant chemotherapy and radiotherapy after gross total resection. The neurologic deficit of the patient was relieved, and recurrence of the tumor was not observed 26 months after the surgery. We present this rare case and emphasize the necessity of precise diagnosis and early treatment of primary spinal germ cell tumor. Close observation on MRI is required after surgery, and adjuvant chemotherapy and radiotherapy should be considered according to the pathologic features. Copyright © 2013 Elsevier Inc. All rights reserved.

Heterogeneity of Glucose Metabolism in Esophageal Cancer Measured by Fractal Analysis of Fluorodeoxyglucose Positron Emission Tomography Image: Correlation between Metabolic Heterogeneity and Survival.

PubMed

Tochigi, Toru; Shuto, Kiyohiko; Kono, Tsuguaki; Ohira, Gaku; Tohma, Takayuki; Gunji, Hisashi; Hayano, Koichi; Narushima, Kazuo; Fujishiro, Takeshi; Hanaoka, Toshiharu; Akutsu, Yasunori; Okazumi, Shinichi; Matsubara, Hisahiro

2017-01-01

Intratumoral heterogeneity is a well-recognized characteristic feature of cancer. The purpose of this study is to assess the heterogeneity of the intratumoral glucose metabolism using fractal analysis, and evaluate its prognostic value in patients with esophageal squamous cell carcinoma (ESCC). 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) studies of 79 patients who received curative surgery were evaluated. FDG-PET images were analyzed using fractal analysis software, where differential box-counting method was employed to calculate the fractal dimension (FD) of the tumor lesion. Maximum standardized uptake value (SUVmax) and FD were compared with overall survival (OS). The median SUVmax and FD of ESCCs in this cohort were 13.8 and 1.95, respectively. In univariate analysis performed using Cox's proportional hazard model, T stage and FD showed significant associations with OS (p = 0.04, p < 0.0001, respectively), while SUVmax did not (p = 0.1). In Kaplan-Meier analysis, the low FD tumor (<1.95) showed a significant association with favorable OS (p < 0.0001). In wthe multivariate analysis among TNM staging, serum tumor markers, FD, and SUVmax, the FD was identified as the only independent prognostic factor for OS (p = 0.0006; hazards ratio 0.251, 95% CI 0.104-0.562). Metabolic heterogeneity measured by fractal analysis can be a novel imaging biomarker for survival in patients with ESCC. © 2016 S. Karger AG, Basel.

Intratumoral histologic heterogeneity of gliomas. A quantitative study.

PubMed

Paulus, W; Peiffer, J

1989-07-15

Quantitative data for intratumoral histologic heterogeneity were obtained by investigating ten small and ten large punched samples from 50 unembedded supratentorial gliomas. The 1000 samples were diagnosed according to the World Health Organization (WHO) classification and six histopathologic features associated with malignancy were evaluated (cellular density, nuclear pleomorphism, necroses, histologic architecture, vessels, and mitoses), each with defined gradations. The slides were read independently by two observers. The initially high interobserver variability (grade, 22.2%; type, 10.3%; and tumor presence/absence, 7.1%) was for the most part due to intermediate grades and types and was reduced to 1.7% after mutual review. Small samples showed lower mean grade than large samples and more often absence of tumor (7.6% versus 2.4%). Of all gliomas, 48% showed differently typed samples, 82% differently graded samples, and 62% benign and malignant grades. Intratumoral heterogeneity was higher for the necroses than for the other histopathologic features. Our results underscore the importance of extensive tissue sampling.

CT imaging of ovarian yolk sac tumor with emphasis on differential diagnosis

PubMed Central

Li, Yang-Kang; Zheng, Yu; Lin, Jian-Bang; Xu, Gui-Xiao; Cai, Ai-Qun; Zhou, Xiu-Guo; Zhang, Guo-Jun

2015-01-01

Ovarian yolk sac tumors (YSTs) are rare neoplasms. No radiological study has been done to compare the imaging findings between this type of tumor and other ovarian tumors. Here we analyzed the CT findings of 11 pathologically proven ovarian YSTs and compared their imaging findings with 18 other types of ovarian tumors in the same age range. Patient age, tumor size, tumor shape, ascites and metastasis of two groups did not differ significantly (P > 0.05). A mixed solid-cystic nature, intratumoral hemorrhage, marked enhancement and dilated intratumoral vessel of two groups differed significantly (P < 0.05). The area under the ROC curve of four significant CT features was 0.679, 0.707, 0.705, and 1.000, respectively. Multivariate logistic regression analysis identified two independent signs of YST: intratumoral hemorrhage and marked enhancement. Our results show that certain suggestive CT signs that may be valuable for improving the accuracy of imaging diagnosis of YST and may be helpful in distinguishing YST from other ovarian tumors. PMID:26074455

Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity.

PubMed

Nakagawa, Hidetoshi; Sido, Jessica M; Reyes, Edwin E; Kiers, Valerie; Cantor, Harvey; Kim, Hye-Jung

2016-05-31

Expression of the transcription factor Helios by Tregs ensures stable expression of a suppressive and anergic phenotype in the face of intense inflammatory responses, whereas Helios-deficient Tregs display diminished lineage stability, reduced FoxP3 expression, and production of proinflammatory cytokines. Here we report that selective Helios deficiency within CD4 Tregs leads to enhanced antitumor immunity through induction of an unstable phenotype and conversion of intratumoral Tregs into T effector cells within the tumor microenvironment. Induction of an unstable Treg phenotype is associated with enhanced production of proinflammatory cytokines by tumor-infiltrating but not systemic Tregs and significantly delayed tumor growth. Ab-dependent engagement of Treg surface receptors that result in Helios down-regulation also promotes conversion of intratumoral but not systemic Tregs into T effector cells and leads to enhanced antitumor immunity. These findings suggest that selective instability and conversion of intratumoral CD4 Tregs through genetic or Ab-based targeting of Helios may represent an effective approach to immunotherapy.

Loxoprofen sodium suppresses mouse tumor growth by inhibiting vascular endothelial growth factor.

PubMed

Kanda, Akio; Ebihara, Satoru; Takahashi, Hidenori; Sasaki, Hidetada

2003-01-01

There is increasing evidence to suggest the anti-tumor effects of non-steroidal anti-inflammatory drugs (NSAIDs). In this study it was shown that the most popular NSAID in Japan, loxoprofen sodium (LOX), inhibited in vivo growth of implanted Lewis lung carcinoma (LLC), whereas LOX did not affect the proliferation and viability of LLC cells in vitro. Intratumoral vessel density in LOX-treated mice was significantly lower than that of mice without treatment. Intratumoral expressions of vascular endothelial growth factor (VEGF) mRNA were attenuated by the LOX treatment. LOX suppressed both intratumoral and systemic VEGF protein in LLC-implanted mice. LOX also inhibited tubular formation of primary cultured human umbilical vein endothelial cells, presumably due to the inhibition of VEGF. In patients with advanced non-small cell lung cancer, LOX medication (120 mg/day) for a week significantly decreased the plasma VEGF level. These results suggest that LOX may have potent anti-cancer effects in patients with advanced NSCLC.

A population genetics perspective on the determinants of intra-tumor heterogeneity

PubMed Central

Hu, Zheng; Sun, Ruping; Curtis, Christina

2017-01-01

Cancer results from the acquisition of somatic alterations in a microevolutionary process that typically occurs over many years, much of which is occult. Understanding the evolutionary dynamics that are operative at different stages of progression in individual tumors might inform the earlier detection, diagnosis, and treatment of cancer. Although these processes cannot be directly observed, the resultant spatiotemporal patterns of genetic variation amongst tumor cells encode their evolutionary histories. Such intra-tumor heterogeneity is pervasive not only at the genomic level, but also at the transcriptomic, phenotypic, and cellular levels. Given the implications for precision medicine, the accurate quantification of heterogeneity within and between tumors has become a major focus of current research. In this review, we provide a population genetics perspective on the determinants of intra-tumor heterogeneity and approaches to quantify genetic diversity. We summarize evidence for different modes of evolution based on recent cancer genome sequencing studies and discuss emerging evolutionary strategies to therapeutically exploit tumor heterogeneity. PMID:28274726

Imaging Intratumor Heterogeneity: Role in Therapy Response, Resistance, and Clinical Outcome

PubMed Central

O’Connor, James P.B.; Rose, Chris J.; Waterton, John C.; Carano, Richard A.D.; Parker, Geoff J.M.; Jackson, Alan

2014-01-01

Tumors exhibit genomic and phenotypic heterogeneity which has prognostic significance and may influence response to therapy. Imaging can quantify the spatial variation in architecture and function of individual tumors through quantifying basic biophysical parameters such as density or MRI signal relaxation rate; through measurements of blood flow, hypoxia, metabolism, cell death and other phenotypic features; and through mapping the spatial distribution of biochemical pathways and cell signaling networks. These methods can establish whether one tumor is more or less heterogeneous than another and can identify sub-regions with differing biology. In this article we review the image analysis methods currently used to quantify spatial heterogeneity within tumors. We discuss how analysis of intratumor heterogeneity can provide benefit over more simple biomarkers such as tumor size and average function. We consider how imaging methods can be integrated with genomic and pathology data, rather than be developed in isolation. Finally, we identify the challenges that must be overcome before measurements of intratumoral heterogeneity can be used routinely to guide patient care. PMID:25421725

Two-dimensional gel analysis of protein expression in ovarian tumors shows a low degree of intratumoral heterogeneity.

PubMed

Alaiya, A A; Franzén, B; Moberger, B; Silfverswärd, C; Linder, S; Auer, G

1999-01-01

The process of tumor progression leads to the emergence of multiple clones, and to the development of tumor heterogeneity. One approach to the study of the extent of such heterogeneity is to examine the expression of marker proteins in different tumor areas. Two-dimensional gel electrophoresis (2-DE) is a powerful tool for such studies, since the expression of a large number of polypeptide markers can be evaluated. In the present study, tumor cells were prepared from human ovarian tumors and analyzed by 2-DE and PDQUEST. As judged from the analysis of two different areas in each of nine ovarian tumors, the intratumoral variation in protein expression was low. In contrast, large differences were observed when the protein profiles of different tumors were compared. The differences in gene expression between pairs of malignant carcinomas were slightly larger than the differences observed between pairs of benign tumors. We conclude that 2-DE analysis of intratumoral heterogeneity in ovarian cancer tissue indicates a low degree of heterogeneity.

An oncolytic measles virus-sensitive Group 3 medulloblastoma model in immune-competent mice.

PubMed

Lal, Sangeet; Carrera, Diego; Phillips, Joanna J; Weiss, William A; Raffel, Corey

2018-06-14

Oncolytic measles virus (MV) is effective in xenograft models of many tumor types in immune-compromised mice. However, no murine cell line exists that is tumorigenic, grows in immune-competent mice, and is killed by MV. The lack of such a model prevents an examination of the effect of the immune system on MV oncotherapy. Cerebellar stem cells from human CD46-transgenic immunocompetent mice were transduced to express Sendai virus C-protein, murine C-Myc, and Gfi1b proteins. The resultant cells were injected into the brain of NSG mice, and a cell line, called CSCG, was prepared from the resulting tumor. CSCG cells are highly proliferative, and express stem cell markers. These cells are permissive for replication of MV and are killed by the virus in a dose- and time-dependent manner. CSCG cells form aggressive tumors that morphologically resemble medulloblastoma when injected into the brains of immune-competent mice. On the molecular level, CSCG tumors overexpress natriuretic peptide receptor 3 and gamma-aminobutyric acid type A receptor alpha 5, markers of Group 3 medulloblastoma. A single intratumoral injection of MV‒green fluorescent protein resulted in complete tumor regression and prolonged survival of animals compared with treatments with phosphate buffered saline (P = 0.0018) or heat-inactivated MV (P = 0.0027). This immune-competent model provides the first platform to test therapeutic regimens of oncolytic MV for Group 3 medulloblastoma in the presence of anti-measles immunity. The strategy presented here can be used to make MV-sensitive murine models of any human tumor for which the driving mutations are known.

Thermoablation of Malignant Kidney Tumors Using Magnetic Nanoparticles: An In Vivo Feasibility Study in a Rabbit Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bruners, Philipp, E-mail: bruners@hia.rwth-aachen.d; Braunschweig, Till; Hodenius, Michael

2010-02-15

The objective of this study was to assess the technical feasibility of CT-guided magnetic thermoablation for the treatment of malignant kidney tumors in a VX2 tumor rabbit model. VX2 tumors were implanted into the kidneys of five rabbits and allowed to grow for 2 weeks. After preinterventional CT perfusion imaging, CT-guided injection of superparamagnetic iron oxide particles (300 {mu}l) was performed, followed by exposure of the animals to an alternating electromagnetic field for 15 min ({approx}0.32 kA/m). Then animals underwent CT perfusion imaging again. Afterward, animals were sacrificed and kidneys were dissected for macroscopic and histological evaluation. Changes in perfusionmore » before and after exposure to the alternating magnetic field were analyzed. In one animal no tumor growth could be detected so the animal was used for optimization of the ablation procedure including injection technique and peri-interventional cross-sectional imaging (CT, MRI). After image-guided intratumoral injection of ferrofluids, the depiction of nanoparticle distribution by CT correlated well with macroscopic evaluation of the dissected kidneys. MRI was limited due to severe susceptibility artefacts. Postinterventional CT perfusion imaging revealed a perfusion deficiency around the ferrofluid deposits. Histological workup showed different zones of thermal damage adjacent to the ferrofluid deposits. In conclusion, CT-guided magnetic thermoablation of malignant kidney tumors is technically feasible in an animal model and results in a perfusion deficiency indicating tumor necrosis as depicted by CT perfusion imaging and shown in histological evaluation.« less

A Reexamination of Active and Passive Tumor Targeting by Using Rod-Shaped Gold Nanocrystals and Covalently Conjugated Peptide Ligands

PubMed Central

Huang, Xiaohua; Peng, Xianghong; Wang, Yiqing; Wang, Yuxiang; Shin, Dong M.; El-Sayed, Mostafa A.; Nie, Shuming

2010-01-01

The targeted delivery of nanoparticles to solid tumors is one of the most important and challenging problems in cancer nanomedicine, but the detailed delivery mechanisms and design principles are still not well understood. Here we report quantitative tumor uptake studies for a class of elongated gold nanocrystals (called nanorods) that are covalently conjugated to tumor-targeting peptides. A major advantage in using gold as a “tracer” is that the accumulated gold in tumors and other organs can be quantitatively determined by elemental mass spectrometry (gold is not a natural element found in animals). Thus, colloidal gold nanorods are stabilized with a layer of polyethylene glycols (PEGs), and are conjugated to three different ligands: (i) a single-chain variable fragment (ScFv) peptide that recognizes the epidermal growth factor receptor (EGFR); (ii) an amino terminal fragment (ATF) peptide that recognizes the urokinase plasminogen activator receptor (uPAR); and (iii) a cyclic RGD peptide that recognizes the avb3 integrin receptor. Quantitative pharmacokinetic and biodistribution data show that these targeting ligands only marginally improve the total gold accumulation in xenograft tumor models in comparison with nontargeted controls, but their use could greatly alter the intracellular and extracellular nanoparticle distributions. When the gold nanorods are administered via intravenous injection, we also find that active molecular targeting of the tumor microenvironments (e.g., fibroblasts, macrophages, and vasculatures) does not significantly influence the tumor nanoparticle uptake. These results suggest that for photothermal cancer therapy, the preferred route of gold nanorod administration is intra-tumoral injection instead of intravenous injection. PMID:20863096

Intrathecal chemotherapy for refractory disseminated medulloblastoma.

PubMed

Yoshimura, Junichi; Nishiyama, Kenichi; Mori, Hiroshi; Takahashi, Hideaki; Fujii, Yukihiko

2008-05-01

To analyze the effect of intrathecal (IT) chemotherapy for disseminated medulloblastoma. Twenty-one patients received IT chemotherapy using the chemotherapeutic agents of methotrexate (MTX) and nitrosoureas (ACNU, MCNU) including nine patients for residual leptomeningeal lesions after initial surgery and radiation, and 12 for a recurrence with leptomeningeal dissemination. Of these 21 patients, 12 received a lumbar and/or ventricular bolus injection of the chemotherapeutic agents, one received the ventriculolumbar perfusion of the agents, and eight received both the perfusion and bolus injection. The doses ranged from 6-7 mg/m(2) of ACNU for perfusion and 3-3.5 mg/m(2) of ACNU, MCNU, or MTX for the bolus injection, and the cycles were administered from 3 to 12 times for perfusion and from 5 to 54 times for the bolus injection. The effects of chemotherapy were assessed by both radiological and cytological examinations, and the clinical symptoms were also assessed. Radiological and/or cytological responses were observed in 10 of 21 patients (47.6%), including seven cases demonstrating a complete remission. The 5-year overall survival rate and 5-year survival rate after dissemination were 61.5 and 46.4%, respectively. Five patients who received a lumbar bolus injection of nitrosoureas experienced paraplegia and double incontinence. One patient who received a ventricular injection of nitrosoureas experienced truncal ataxia. IT chemotherapy was found to be effective in some cases with refractory disseminated medulloblastoma and it seems to be an appropriate treatment choice for leptomeningeal recurrence. However, the frequent bolus injections of nitrosoureas should be avoided to prevent the side effects.

Tumor Heterogeneity in Breast Cancer

PubMed Central

Turashvili, Gulisa; Brogi, Edi

2017-01-01

Breast cancer is a heterogeneous disease and differs greatly among different patients (intertumor heterogeneity) and even within each individual tumor (intratumor heterogeneity). Clinical and morphologic intertumor heterogeneity is reflected by staging systems and histopathologic classification of breast cancer. Heterogeneity in the expression of established prognostic and predictive biomarkers, hormone receptors, and human epidermal growth factor receptor 2 oncoprotein is the basis for targeted treatment. Molecular classifications are indicators of genetic tumor heterogeneity, which is probed with multigene assays and can lead to improved stratification into low- and high-risk groups for personalized therapy. Intratumor heterogeneity occurs at the morphologic, genomic, transcriptomic, and proteomic levels, creating diagnostic and therapeutic challenges. Understanding the molecular and cellular mechanisms of tumor heterogeneity that are relevant to the development of treatment resistance is a major area of research. Despite the improved knowledge of the complex genetic and phenotypic features underpinning tumor heterogeneity, there has been only limited advancement in diagnostic, prognostic, or predictive strategies for breast cancer. The current guidelines for reporting of biomarkers aim to maximize patient eligibility for targeted therapy, but do not take into account intratumor heterogeneity. The molecular classification of breast cancer is not implemented in routine clinical practice. Additional studies and in-depth analysis are required to understand the clinical significance of rapidly accumulating data. This review highlights inter- and intratumor heterogeneity of breast carcinoma with special emphasis on pathologic findings, and provides insights into the clinical significance of molecular and cellular mechanisms of heterogeneity. PMID:29276709

A prospective randomized trial of 1 versus 2 injections during EUS-guided celiac plexus block for chronic pancreatitis pain.

PubMed

LeBlanc, Julia K; DeWitt, Jon; Johnson, Cynthia; Okumu, Wycliffe; McGreevy, Kathleen; Symms, Michelle; McHenry, Lee; Sherman, Stuart; Imperiale, Thomas

2009-04-01

The efficacy of 1-injection versus a 2-injections method of EUS-guided celiac plexus block (EUS-CPB) in patients with chronic pancreatitis is not known. To compare the clinical effectiveness and safety of EUS-CPB by using 1 versus 2 injections in patients with chronic pancreatitis and pain. The secondary aim is to identify factors that predict responsiveness. A prospective randomized study. EUS-CPB was performed by using bupivacaine and triamcinolone injected into 1 or 2 sites at the level of the celiac trunk during a single EUS-CPB procedure. Duration of pain relief, onset of pain relief, and complications. Fifty [corrected] subjects were enrolled (23 received 1 injection, 27 [corrected] received 2 injections). The median duration of pain relief in the 31 responders was 28 days (range 1-673 days). [corrected] Fifteen [corrected] of 23 (65%) [corrected] subjects who received 1 injection [corrected] had relief from pain compared with 16 of 27 (59%) [corrected] subjects who received 2 injections [corrected] (P = .67). [corrected] The median times to onset in the 1-injection and 2-injections groups were 21 and 14 days, respectively (P = .99). No correlation existed between duration of pain relief and time to onset of pain relief or onset within 24 hours. Age, sex, race, prior EUS-CPB, and smoking or alcohol history did not predict duration of pain relief. Telephone interviewers were not blinded. There was no difference in duration of pain relief or onset of pain relief in subjects with chronic pancreatitis and pain when the same total amount of medication was delivered in 1 or 2 injections during a single EUS-CPB procedure. Both methods were safe.

A protocol for the retina surgeon's safe initial intravitreal injections.

PubMed

Frenkel, Ronald E P; Haji, Shamim A; La, Melvin; Frenkel, Max P C; Reyes, Angela

2010-11-10

To determine the safety of a surgeon's initial consecutive intravitreal injections using a specific protocol and to review the complications that may be attributed to the injection procedure. A retrospective chart review. Fifty-nine patients (30 females, 29 males) received intravitreal injections of pegaptanib, bevacizumab, or ranibizumab as part of their treatment for neovascular age-related macular degeneration. The average patient age was 80 years. Twenty-two patients were diagnosed with or suspected of having glaucoma. Each patient received an average of 5.8 injections. The charts of 59 patients who received a total of 345 intravitreal injections (104 pegaptanib, 74 bevacizumab, 167 ranibizumab) were reviewed. All injections were performed in an office-based setting. Povidone-iodine, topical antibiotics, and eye speculum were used as part of the pre injection procedure. Vision and intraocular pressure were evaluated immediately following each injection. Incidence of post injection complications, including but not limited to endophthalmitis, retinal detachment, traumatic cataract, and vitreous hemorrhage. There were no cases of endophthalmitis, toxic reactions, traumatic cataracts, retinal detachment, or vitreous hemorrhage. There was one case each of lid swelling, transient floaters, retinal pigment epithelial tear, corneal edema, and corneal abrasion. There were five cases of transient no light perception following pegaptanib injections. The incidence of serious complications was very low for the intravitreal injections given. A surgeon's initial intravitreal injections may be performed with a very high degree of safety using this protocol.

Interaction of chronic food restriction and methylphenidate in sensation seeking of rats.

PubMed

Talishinsky, Aleksandr D; Nicolas, Celine; Ikemoto, Satoshi

2017-07-01

It is necessary to understand better how chronic food restriction (CFR) and psychostimulant drugs interact in motivated behavior unrelated to food or energy homeostasis. We examined whether CFR augments methylphenidate (MPH)-potentiated responding reinforced by visual sensation (VS) and whether repeated MPH injections or prolonged CFR further augments such responses. Before starting the following experiments, rats on a CFR diet received a limited daily ration in such a way that their body weights decreased to 85-90% of their original weights over 2 weeks. In experiment 1, rats on CFR and ad libitum diet received four injections of varying MPH doses (0, 2.5, 5, and 10 mg/kg). In experiment 2, CFR and ad libitum groups received repeated injections of MPH (2.5 mg/kg). In experiment 3, half of CFR rats received repeated injections of MPH (2.5 mg/kg), and the other half received saline, and following a 7-day abstinence, they all received the 2.5-mg/kg dose of MPH. CFR rats increased VS-reinforced responding more than ad libitum rats when they received MPH. Repeated injections of MPH with prolonged CFR further increased VS-reinforced responding. We found a double dissociation where prolonged CFR (3 vs. 6 weeks) made VS-reinforced responding, but not locomotor activity, more responsive to MPH, whereas repeated MPH injections made locomotor activity, but not VS-reinforced responding, more responsive to MPH. CFR markedly potentiates effects of MPH on VS-reinforced responding. The present study demonstrates that the longer CFR continues, the greater psychostimulant drugs augment behavioral interaction with salient stimuli.

Preclinical evaluation of IL2-based immunocytokines supports their use in combination with dacarbazine, paclitaxel and TNF-based immunotherapy.

PubMed

Pretto, Francesca; Elia, Giuliano; Castioni, Nadia; Neri, Dario

2014-09-01

Antibody-cytokine fusion proteins ("immunocytokines") represent a promising class of armed antibody products, which allow the selective delivery of potent pro-inflammatory payloads at the tumor site. The antibody-based selective delivery of interleukin-2 (IL2) is particularly attractive for the treatment of metastatic melanoma, an indication for which this cytokine received marketing approval from the US Food and drug administration. We used the K1735M2 immunocompetent syngeneic model of murine melanoma to study the therapeutic activity of F8-IL2, an immunocytokine based on the F8 antibody in diabody format, fused to human IL2. F8-IL2 was shown to selectively localize at the tumor site in vivo, following intravenous administration, and to mediate tumor growth retardation, which was potentiated by the combination with paclitaxel or dacarbazine. Combination treatment led to a substantially more effective tumor growth inhibition, compared to the cytotoxic drugs used as single agents, without additional toxicity. Analysis of the immune infiltrate revealed a significant accumulation of CD4(+) T cells 24 h after the administration of the combination. The fusion proteins F8-IL2 and L19-IL2, specific to the alternatively spliced extra domain A and extra domain B of fibronectin respectively, were also studied in combination with tumor necrosis factor (TNF)-based immunocytokines. The combination treatment was superior to the action of the individual immunocytokines and was able to eradicate neoplastic lesions after a single intratumoral injection, a procedure that is being clinically used for the treatment of Stage IIIC melanoma. Collectively, these data reinforce the rationale for the use of IL2-based immunocytokines in combination with cytotoxic agents or TNF-based immunotherapy for the treatment of melanoma patients.

Sustained Release Talazoparib Implants for Localized Treatment of BRCA1-deficient Breast Cancer

PubMed Central

Belz, Jodi E.; Kumar, Rajiv; Baldwin, Paige; Ojo, Noelle Castilla; Leal, Ana S.; Royce, Darlene B.; Zhang, Di; van de Ven, Anne L.; Liby, Karen T.; Sridhar, Srinivas

2017-01-01

Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre-clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1-deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0.8 mm diameter) loaded with subclinical dose (25 or 50 µg) Talazoparib were fabricated and characterized. In vitro studies with Brca1-deficient W780 and W0069 breast cancer cells were conducted to test sensitivity to PARP inhibition. The in vivo therapeutic efficacy of Talazoparib implants was assessed following a one-time intratumoral injection in Brca1Co/Co;MMTV-Cre;p53+/- mice and compared to drug-free implants and oral gavage. Immunohistochemistry studies were performed on tumor sections using PCNA and γ-H2AX staining. Sustained release of Talazoparib was observed over 28 days in vitro. Mice treated with Talazoparib implants showed statistically significant tumor growth inhibition compared to those receiving drug-free implants or free Talazoparib orally. Talazoparib implants were well-tolerated at both drug doses and resulted in less weight loss than oral gavage. PARP inhibition in mice treated with Talazoparib implants significantly increased double-stranded DNA damage and decreased tumor cell proliferation as shown by PCNA and γ-H2AX staining as compared to controls. These results demonstrate that localized and sustained delivery of Talazoparib via implants has potential to provide superior treatment outcomes at sub-clinical doses with minimal toxicity in patients with BRCA1 deficient tumors. PMID:29158830

Sustained Release Talazoparib Implants for Localized Treatment of BRCA1-deficient Breast Cancer.

PubMed

Belz, Jodi E; Kumar, Rajiv; Baldwin, Paige; Ojo, Noelle Castilla; Leal, Ana S; Royce, Darlene B; Zhang, Di; van de Ven, Anne L; Liby, Karen T; Sridhar, Srinivas

2017-01-01

Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre-clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1 -deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0.8 mm diameter) loaded with subclinical dose (25 or 50 µg) Talazoparib were fabricated and characterized. In vitro studies with Brca1 -deficient W780 and W0069 breast cancer cells were conducted to test sensitivity to PARP inhibition. The in vivo therapeutic efficacy of Talazoparib implants was assessed following a one-time intratumoral injection in Brca1 Co/Co ;MMTV-Cre;p53 +/- mice and compared to drug-free implants and oral gavage. Immunohistochemistry studies were performed on tumor sections using PCNA and γ-H2AX staining. Sustained release of Talazoparib was observed over 28 days in vitro . Mice treated with Talazoparib implants showed statistically significant tumor growth inhibition compared to those receiving drug-free implants or free Talazoparib orally. Talazoparib implants were well-tolerated at both drug doses and resulted in less weight loss than oral gavage. PARP inhibition in mice treated with Talazoparib implants significantly increased double-stranded DNA damage and decreased tumor cell proliferation as shown by PCNA and γ-H2AX staining as compared to controls. These results demonstrate that localized and sustained delivery of Talazoparib via implants has potential to provide superior treatment outcomes at sub-clinical doses with minimal toxicity in patients with BRCA1 deficient tumors.

Pan-cancer analysis of the extent and consequences of intratumor heterogeneity | Office of Cancer Genomics

Cancer.gov

Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) and PyClone to detect clones that are present at a ≥10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, ρ = 0.24-0.41; P < 0.001).

Intra-tumor heterogeneity of cancer cells and its implications for cancer treatment

PubMed Central

Sun, Xiao-xiao; Yu, Qiang

2015-01-01

Recent studies have revealed extensive genetic and non-genetic variation across different geographical regions of a tumor or throughout different stages of tumor progression, which is referred to as intra-tumor heterogeneity. Several causes contribute to this phenomenon, including genomic instability, epigenetic alteration, plastic gene expression, signal transduction, and microenvironmental differences. These variables may affect key signaling pathways that regulate cancer cell growth, drive phenotypic diversity, and pose challenges to cancer treatment. Understanding the mechanisms underlying this heterogeneity will support the development of effective therapeutic strategies. PMID:26388155

Cryopreserved human amniotic membrane injection for plantar fasciitis: a randomized, controlled, double-blind pilot study.

PubMed

Hanselman, Andrew E; Tidwell, John E; Santrock, Robert D

2015-02-01

Treatment options for plantar fasciitis have resulted in varied patient outcomes. The aim of this study was to compare a novel treatment, cryopreserved human amniotic membrane (c-hAM), to a traditional treatment, corticosteroid. Our hypothesis was that c-hAM would be safe and comparable to corticosteroids for plantar fasciitis in regard to patient outcomes. A randomized, controlled, double-blind, single-center pilot study was completed. Patients were randomized into one of 2 treatment groups: c-hAM or corticosteroid. Patients received an injection at their initial baseline visit with an option for a second injection at their first 6-week follow-up. Total follow-up was obtained for 12 weeks after the most recent injection. The primary outcome measurement was the Foot Health Status Questionnaire (FHSQ). The secondary outcome measurements were the Visual Analog Scale (VAS) and verbally reported percentage improvement. Data were analyzed between groups for the 2 different cohorts (1 injection versus 2 injections). Twenty-three patients had complete follow-up. Fourteen were randomized to receive corticosteroid and 9 were randomized to receive c-hAM. Three patients in each group received second injections. With the numbers available, the majority of outcome measurements showed no statistical difference between groups. The corticosteroid did, however, have greater FHSQ shoe fit improvement (P = .0244) at 6 weeks, FHSQ general health improvement (P = .0132) at 6 weeks, and verbally reported improvement (P = .041) at 12 weeks in the one-injection cohort. Cryopreserved hAM had greater FHSQ foot pain improvement (P = .0113) at 18 weeks in the 2-injection cohort. Cryopreserved hAM injection may be safe and comparable to corticosteroid injection for treatment of plantar fasciitis. This is a pilot study and requires further investigation. Level I, prospective randomized trial. © The Author(s) 2014.

Reinforcement of spinal anesthesia by epidural injection of saline: a comparison of hyperbaric and isobaric tetracaine.

PubMed

Yamazaki, Y; Mimura, M; Hazama, K; Namiki, A

2000-04-25

An epidural injection of saline was reported to extend spinal anesthesia because of a volume effect. The aim of this study was to evaluate the influence of the baricity of spinal local anesthetics upon the extension of spinal anesthesia by epidural injection of saline. Forty patients undergoing elective lower-limb surgery were randomly allocated to four groups of 10 patients each. Group A received no epidural injection after the spinal administration of hyperbaric tetracaine (dissolved in 10% glucose). Group B received an epidural injection of 8 ml of physiological saline 20 min after spinal hyperbaric tetracaine. Group C received no epidural injection after spinal isobaric tetracaine (dissolved in physiological saline). Group D received an epidural injection of 8 ml of saline 20 min after spinal isobaric tetracaine. The level of analgesia was examined by the pinprick method at 5-min intervals. The levels of analgesia 20 min after spinal anesthesia were significantly higher in hyperbaric groups than in isobaric groups [T5 (T2-L2) vs. T7 (T3-12)]. After epidural injection of saline, the levels of analgesia in groups B and D were significantly higher than in groups A and C. The segmental increases after epidural saline injection were 2 (0-3) in group B and 2 (1-7) in group D. Sensation in the sacral area remained 20 min after spinal block in one patient in group D; however, it disappeared after epidural saline injection. In this study, 8 ml of epidural saline extended spinal analgesia. However, there was no difference between the augmenting effect in isobaric and hyperbaric spinal anesthesia. We conclude that the reinforcement of spinal anesthesia by epidural injection of saline is not affected by the baricity of the spinal anesthetic solution used.

The effectiveness of repeat lumbar transforaminal epidural steroid injections.

PubMed

Murthy, Naveen S; Geske, Jennifer R; Shelerud, Randy A; Wald, John T; Diehn, Felix E; Thielen, Kent R; Kaufmann, Timothy J; Morris, Jonathan M; Lehman, Vance T; Amrami, Kimberly K; Carter, Rickey E; Maus, Timothy P

2014-10-01

The aim of this study was to determine 1) if repeat lumbar transforaminal epidural steroid injections (TFESIs) resulted in recovery of pain relief, which has waned since an index injection, and 2) if cumulative benefit could be achieved by repeat injections within 3 months of the index injection. Retrospective observational study with statistical modeling of the response to repeat TFESI. Academic radiology practice. Two thousand eighty-seven single-level TFESIs were performed for radicular pain on 933 subjects. Subjects received repeat TFESIs >2 weeks and <1 year from the index injection. Hierarchical linear modeling was performed to evaluate changes in continuous and categorical pain relief outcomes after repeat TFESI. Subgroup analyses were performed on patients with <3 months duration of pain (acute pain), patients receiving repeat injections within 3 months (clustered injections), and in patients with both acute pain and clustered injections. Repeat TFESIs achieved pain relief in both continuous and categorical outcomes. Relative to the index injection, there was a minimal but statistically significant decrease in pain relief in modeled continuous outcome measures with subsequent injections. Acute pain patients recovered all prior benefit with a statistically significant cumulative benefit. Patients receiving clustered injections achieved statistically significant cumulative benefit, of greater magnitude in acute pain patients. Repeat TFESI may be performed for recurrence of radicular pain with the expectation of recovery of most or all previously achieved benefit; acute pain patients will likely recover all prior benefit. Repeat TFESIs within 3 months of the index injection can provide cumulative benefit. Wiley Periodicals, Inc.

Editorial Commentary: Intra-articular Corticosteroid Injection at the Time of Knee Arthroscopy Is Not Recommended.

PubMed

Hunt, Timothy J

2016-01-01

In a population of Medicare patients undergoing knee arthroscopy, a significant increase in the incidence of postoperative infection at 3 and 6 months was found in patients who received an intra-articular corticosteroid injection at the time of knee arthroscopy compared with a matched control group that did not receive an injection. Intra-articular corticosteroid injection at the time of knee arthroscopy is not recommended. Copyright © 2016 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Tumor Necrosis Factor α‐Gene Therapy for an Established Murine Melanoma Using RGB (Arg‐Gly‐Asp) Fiber‐mutant Adenovirus Vectors

PubMed Central

Okada, Yuka; Nakagawa, Shinsaku; Mizuguchi, Hiroyuki; Takahashi, Koichi; Mizuno, Nobuyasu; Fujita, Takuya; Yamamoto, Akira; Hayakawa, Takao; Mayumi, Tadanori

2002-01-01

Although adenovirus vectors (Ad) provide high‐level transduction efficacy to many cell types, extremely high doses of Ad are required for sufficient gene transduction into several tumors, including melanoma. Here, we demonstrated that the expression of coxsackie‐adenovirus receptor, a primitive Ad‐receptor, was very low in murine and human melanoma cells. We also found that fiber‐mutant Ad containing the Arg‐Gly‐Asp (RGD) sequence in the fiber knob remarkably augmented gene transduction efficacy in melanoma cells by targeting αv‐integrins. In addition, intratumoral injection of RGD fiber‐mutant Ad containing the tumor necrosis factor α gene (AdRGD‐TNFα) revealed dramatic anti‐tumor efficacy through hemolytic necrosis in an established murine B16 BL6 melanoma model. Ad‐RGD‐TNFα required one‐tenth the dosage of Ad‐TNFα to induce an equal therapeutic effect. These results suggest that αv‐integrin‐targeted Ad will be a very powerful tool for the advancement of melanoma gene therapy. PMID:11985794

Structural alterations in tumor-draining lymph nodes before papillary thyroid carcinoma metastasis.

PubMed

Hinson, Andrew M; Massoll, Nicole A; Jolly, Lee Ann; Stack, Brendan C; Bodenner, Donald L; Franco, Aime T

2017-08-01

The purpose of this study was to define and characterize the thyroid tumor-draining lymph nodes in genetically engineered mice harboring thyroid-specific expression of oncogenic Braf V600E with and without Pten insufficiency. After intratumoral injection of methylene blue, the lymphatic drainage of the thyroid gland was visualized in real time. The thyroid gland/tumor was resected en bloc with the respiratory system for histological analysis. Although mice harboring Braf V600E mutations were smaller in body size compared with their wild-type (WT) littermates, the size of their thyroid glands and deep cervical lymph nodes were significantly larger. Additionally, the tumor-draining lymph nodes showed increased and enlarged lymphatic sinuses that were distributed throughout the cortex and medulla. Tumor-reactive lymphadenopathy and histiocytosis, but no frank metastases, were observed in all mice harboring Braf V600E mutations. The tumor-draining lymph nodes undergo significant structural alterations in immunocompetent mice, and this may represent a primer for papillary thyroid carcinoma (PTC) metastasis. © 2017 Wiley Periodicals, Inc.

Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors

PubMed Central

Xin, Gang; Schauder, David M.; Jing, Weiqing; Jiang, Aimin; Joshi, Nikhil S.; Johnson, Bryon; Cui, Weiguo

2017-01-01

Because of insufficient migration and antitumor function of transferred T cells, especially inside the immunosuppressive tumor microenvironment (TME), the efficacy of adoptive cell transfer (ACT) is much curtailed in treating solid tumors. To overcome these challenges, we sought to reenergize ACT (ReACT) with a pathogen-based cancer vaccine. To bridge ACT with a pathogen, we genetically engineered tumor-specific CD8 T cells in vitro with a second T-cell receptor (TCR) that recognizes a bacterial antigen. We then transferred these dual-specific T cells in combination with intratumoral bacteria injection to treat solid tumors in mice. The dual-specific CD8 T cells expanded vigorously, migrated to tumor sites, and robustly eradicated primary tumors. The mice cured from ReACT also developed immunological memory against tumor rechallenge. Mechanistically, we have found that this combined approach reverts the immunosuppressive TME and recruits CD8 T cells with an increased number and killing ability to the tumors. PMID:28069963

Hyperthermia mediated by dextran-coated La0.7Sr0.3MnO3 nanoparticles: in vivo studies

PubMed Central

Haghniaz, Reihaneh; Umrani, Rinku D; Paknikar, Kishore M

2016-01-01

Purpose The aim of this study was to evaluate radiofrequency-induced dextran-coated lanthanum strontium manganese oxide nanoparticles-mediated hyperthermia to be used for tumor regression in mice. Materials and methods Nanoparticles were injected intra-tumorally in melanoma-bearing C57BL/6J mice and were subjected to radiofrequency treatment. Results Hyperthermia treatment significantly inhibited tumor growth (~84%), increased survival (~50%), and reduced tumor proliferation in mice. Histopathological examination demonstrated immense cell death in treated tumors. DNA fragmentation, increased terminal deoxynucleotidyl transferase-dUTP nick end labeling signal, and elevated levels of caspase-3 and caspase-6 suggested apoptotic cell death. Enhanced catalase activity suggested reactive oxygen species-mediated cell death. Enhanced expression of heat shock proteins 70 and 90 in treated tumors suggested the possible development of “antitumor immunity”. Conclusion The dextran-coated lanthanum strontium manganese oxide-mediated hyperthermia can be used for the treatment of cancer. PMID:27175076

Biphasic magnetic nanoparticles-nanovesicle hybrids for chemotherapy and self-controlled hyperthermia.

PubMed

Gogoi, Manashjit; Sarma, Haladhar D; Bahadur, Dhirendra; Banerjee, Rinti

2014-05-01

The aim was to develop magnetic nanovesicles for chemotherapy and self-controlled hyperthermia that prevent overheating of tissues. Magnetic nanovesicles containing paclitaxel and a dextran-coated biphasic suspension of La0.75Sr0.25MnO3 and Fe3O4 nanoparticles (magnetic nanoparticles) were developed. Encapsulation efficiencies of magnetic nanoparticles and paclitaxel were 67 ± 5 and 83 ± 3%, respectively. Sequential release performed at 37°C for 1 h followed by 44°C for another 1 h (as expected for intratumoral injection), showed a cumulative release of 6.6% (109.6 µg), which was above the IC50 of the drug. In an alternating current magnetic field, the temperature remained controlled at 44°C and a synergistic cytotoxicity of paclitaxel and hyperthermia was observed in MCF-7 cells. Magnetic nanovesicles containing biphasic suspensions La0.75Sr0.25MnO3 and Fe3O4 nanoparticles encapsulating paclitaxel have potential for combined self-controlled hyperthermia and chemotherapy.

Ultrasound-mediated interferon {beta} gene transfection inhibits growth of malignant melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamaguchi, Kazuki; Department of Anatomy, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka City 814-0180; Feril, Loreto B., E-mail: ferilism@yahoo.com

2011-07-22

Highlights: {yields} Successful ultrasound-mediated transfection of melanoma (C32) cells with IFN-{beta} genes both in vitro and in vivo. {yields} Ultrasound-mediated IFN-{beta} transfection inhibited proliferation of melanoma cells in vitro. {yields} Ultrasound-mediated IFN-{beta} transfection inhibited melanoma tumor growth in vivo. -- Abstract: We investigated the effects of ultrasound-mediated transfection (sonotransfection) of interferon {beta} (IFN-{beta}) gene on melanoma (C32) both in vitro and in vivo. C32 cells were sonotransfected with IFN-{beta} in vitro. Subcutaneous C32 tumors in mice were sonicated weekly immediately after intra-tumor injection with IFN-{beta} genes mixed with microbubbles. Successful sonotransfection with IFN-{beta} gene in vitro was confirmed by ELISA,more » which resulted in C32 growth inhibition. In vivo, the growth ratio of tumors transfected with IFN-{beta} gene was significantly lower than the other experimental groups. These results may lead to a new method of treatment against melanoma and other hard-to-treat cancers.« less

Oncolytic Viral Therapy for Mesothelioma

PubMed Central

Pease, Daniel F.; Kratzke, Robert A.

2017-01-01

The limited effectiveness of conventional therapy for malignant pleural mesothelioma demands innovative approaches to this difficult disease. Even with aggressive multimodality treatment of surgery, radiation, and/or chemotherapy, the median survival is only 1–2 years depending on stage and histology. Oncolytic viral therapy has emerged in the last several decades as a rapidly advancing field of immunotherapy studied in a wide spectrum of malignancies. Mesothelioma makes an ideal candidate for studying oncolysis given the frequently localized pattern of growth and pleural location providing access to direct intratumoral injection of virus. Therefore, despite being a relatively uncommon disease, the multitude of viral studies for mesothelioma can provide insight for applying such therapy to other malignancies. This article will begin with a review of the general principles of oncolytic therapy focusing on antitumor efficacy, tumor selectivity, and immune system activation. The second half of this review will detail results of preclinical models and human studies for oncolytic virotherapy in mesothelioma. PMID:28884088

Prominent IL-12 production and tumor reduction in athymic nude mice after Toxoplasma gondii lysate antigen treatment.

PubMed

Pyo, Kyoung-Ho; Jung, Bong-Kwang; Xin, Chun-Feng; Lee, You-Won; Chai, Jong-Yil; Shin, Eun-Hee

2014-12-01

Toxoplasma gondii is an intracellular protozoan parasite that causes a Th1 cellular immunity. Our previous study showed that T. gondii lysate antigen (TLA) treatment in S180 tumor-bearing mice resulted in tumor reduction by suppressing CD31 expression, a marker of angiogenesis. In the present study, to investigate tumor suppressive effect of TLA under the absence of T lymphocytes, athymic nude mice were compared with euthymic mice in the anti-tumorigenic effect triggered by TLA in CT26 tumors. According to the results, intratumorally injected TLA reduced tumor growth and TIMP-1 level, a metastatic marker, in both euthymic and athymic mice. TLA treatment led to a sharp increase in IL-12 expression in serum cytokine profiling of athymic mice, and increased MyD88 signals in macrophages derived from the bone marrow, implying the activation of innate immunity. The selective induction of IL-12 by TLA treatment had an anti-tumorigenic effect.

Prominent IL-12 Production and Tumor Reduction in Athymic Nude Mice after Toxoplasma gondii Lysate Antigen Treatment

PubMed Central

Pyo, Kyoung-Ho; Jung, Bong-Kwang; Xin, Chun-Feng; Lee, You-Won; Chai, Jong-Yil

2014-01-01

Toxoplasma gondii is an intracellular protozoan parasite that causes a Th1 cellular immunity. Our previous study showed that T. gondii lysate antigen (TLA) treatment in S180 tumor-bearing mice resulted in tumor reduction by suppressing CD31 expression, a marker of angiogenesis. In the present study, to investigate tumor suppressive effect of TLA under the absence of T lymphocytes, athymic nude mice were compared with euthymic mice in the anti-tumorigenic effect triggered by TLA in CT26 tumors. According to the results, intratumorally injected TLA reduced tumor growth and TIMP-1 level, a metastatic marker, in both euthymic and athymic mice. TLA treatment led to a sharp increase in IL-12 expression in serum cytokine profiling of athymic mice, and increased MyD88 signals in macrophages derived from the bone marrow, implying the activation of innate immunity. The selective induction of IL-12 by TLA treatment had an anti-tumorigenic effect. PMID:25548411

A non-covalent peptide-based carrier for in vivo delivery of DNA mimics.

PubMed

Morris, May C; Gros, Edwige; Aldrian-Herrada, Gudrun; Choob, Michael; Archdeacon, John; Heitz, Frederic; Divita, Gilles

2007-01-01

The dramatic acceleration in identification of new nucleic-acid-based therapeutic molecules has provided new perspectives in pharmaceutical research. However, their development is limited by their poor cellular uptake and inefficient trafficking. Here we describe a short amphipathic peptide, Pep-3, that combines a tryptophan/phenylalanine domain with a lysine/arginine-rich hydrophilic motif. Pep-3 forms stable nano-size complexes with peptide-nucleic acid analogues and promotes their efficient delivery into a wide variety of cell lines, including primary and suspension lines, without any associated cytotoxicity. We demonstrate that Pep-3-mediated delivery of antisense-cyclin B1-charged-PNA blocks tumour growth in vivo upon intratumoral and intravenous injection. Moreover, we show that PEGylation of Pep-3 significantly improves complex stability in vivo and consequently the efficiency of antisense cyclin B1 administered intravenously. Given the biological characteristics of these vectors, we believe that peptide-based delivery technologies hold a true promise for therapeutic applications of DNA mimics.

A non-covalent peptide-based carrier for in vivo delivery of DNA mimics

PubMed Central

Morris, May C.; Gros, Edwige; Aldrian-Herrada, Gudrun; Choob, Michael; Archdeacon, John; Heitz, Frederic; Divita, Gilles

2007-01-01

The dramatic acceleration in identification of new nucleic-acid-based therapeutic molecules has provided new perspectives in pharmaceutical research. However, their development is limited by their poor cellular uptake and inefficient trafficking. Here we describe a short amphipathic peptide, Pep-3, that combines a tryptophan/phenylalanine domain with a lysine/arginine-rich hydrophilic motif. Pep-3 forms stable nano-size complexes with peptide-nucleic acid analogues and promotes their efficient delivery into a wide variety of cell lines, including primary and suspension lines, without any associated cytotoxicity. We demonstrate that Pep-3-mediated delivery of antisense-cyclin B1-charged-PNA blocks tumour growth in vivo upon intratumoral and intravenous injection. Moreover, we show that PEGylation of Pep-3 significantly improves complex stability in vivo and consequently the efficiency of antisense cyclin B1 administered intravenously. Given the biological characteristics of these vectors, we believe that peptide-based delivery technologies hold a true promise for therapeutic applications of DNA mimics. PMID:17341467

Peri-tumoral leakage during intra-tumoral convection-enhanced delivery has implications for efficacy of peri-tumoral infusion before removal of tumor.

PubMed

Yang, Xiaoliang; Saito, Ryuta; Nakamura, Taigen; Zhang, Rong; Sonoda, Yukihiko; Kumabe, Toshihiro; Forsayeth, John; Bankiewicz, Krystof; Tominaga, Teiji

2016-01-01

In cases of malignant brain tumors, infiltrating tumor cells that exist at the tumor-surrounding brain tissue always escape from cytoreductive surgery and, protected by blood-brain barrier (BBB), survive the adjuvant chemoradiotherapy, eventually leading to tumor recurrence. Local interstitial delivery of chemotherapeutic agents is a promising strategy to target these cells. During our effort to develop effective drug delivery methods by intra-tumoral infusion of chemotherapeutic agents, we found consistent pattern of leakage from the tumor. Here we describe our findings and propose promising strategy to cover the brain tissue surrounding the tumor with therapeutic agents by means of convection-enhanced delivery. First, the intracranial tumor isograft model was used to define patterns of leakage from tumor mass after intra-tumoral infusion of the chemotherapeutic agents. Liposomal doxorubicin, although first distributed inside the tumor, distributed diffusely into the surrounding normal brain once the leakage happen. Trypan blue dye was used to evaluate the distribution pattern of peri-tumoral infusions. When infused intra- or peri-tumorally, infusates distributed robustly into the tumor border. Subsequently, volume of distributions with different infusion scheduling; including intra-tumoral infusion, peri-tumoral infusion after tumor resection, peri-tumoral infusion without tumor removal with or without systemic infusion of steroids, were compared with Evans-blue dye. Peri-tumoral infusion without tumor removal resulted in maximum volume of distribution. Prior use of steroids further increased the volume of distribution. Local interstitial drug delivery targeting tumor surrounding brain tissue before tumor removal should be more effective when targeting the invading cells.

Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor Regression in Vivo

PubMed Central

Checkley, L. Allyson; Rudolph, Michael C.; Wellberg, Elizabeth A.; Giles, Erin D.; Wahdan-Alaswad, Reema S.; Houck, Julie A.; Edgerton, Susan M.; Thor, Ann D.; Schedin, Pepper; Anderson, Steven M.; MacLean, Paul S.

2017-01-01

Several epidemiological studies have associated metformin treatment with a reduction in breast cancer incidence in pre-diabetic and type II diabetic populations. Uncertainty exists regarding which patient populations and/or tumor subtypes will benefit from metformin treatment, and most preclinical in vivo studies have given little attention to the cellular pharmacology of intratumoral metformin uptake. Epidemiological reports consistently link western-style high fat diets, which drive overweight and obesity, with increased risk of breast cancer. We used a rat model of high fat diet (HFD) induced overweight and mammary carcinogenesis to define intratumoral factors that confer metformin sensitivity. Mammary tumors were initiated with N-methyl-N-nitrosourea (MNU), and rats were randomized into metformin-treated (2 mg/ml drinking water) or control groups (water only) for 8 weeks. Two-thirds of existing mammary tumors responded to metformin treatment with decreased tumor volumes (p<0.05), reduced proliferative index (p<0.01), and activated AMPK (p<0.05). Highly responsive tumors accumulated 3-fold greater metformin amounts (p<0.05) that were positively correlated with organic cation transporter-2 (OCT2) protein expression (r=0.57, P=0.038). Importantly, intratumoral metformin concentration negatively associated with tumor volume (P=0.03), and each 10 pmol increase in intratumoral metformin predicted >0.11 cm3 reduction in tumor volume. Metformin treatment also decreased proinflammatory arachidonic acid >1.5 fold in responsive tumors (P=0.023). Collectively, these preclinical data provide evidence for a direct effect of metformin in vivo and suggest that OCT2 expression may predict metformin uptake and tumor response. PMID:28154203

Improved Intratumoral Oxygenation Through Vascular Normalization Increases Glioma Sensitivity to Ionizing Radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGee, Mackenzie C.; Hamner, J. Blair; Williams, Regan F.

2010-04-15

Purpose: Ionizing radiation, an important component of glioma therapy, is critically dependent on tumor oxygenation. However, gliomas are notable for areas of necrosis and hypoxia, which foster radioresistance. We hypothesized that pharmacologic manipulation of the typically dysfunctional tumor vasculature would improve intratumoral oxygenation and, thus, the antiglioma efficacy of ionizing radiation. Methods and Materials: Orthotopic U87 xenografts were treated with either continuous interferon-beta (IFN-beta) or bevacizumab, alone, or combined with cranial irradiation (RT). Tumor growth was assessed by quantitative bioluminescence imaging; the tumor vasculature using immunohistochemical staining, and tumor oxygenation using hypoxyprobe staining. Results: Both IFN-beta and bevaziumab profoundly affectedmore » the tumor vasculature, albeit with different cellular phenotypes. IFN-beta caused a doubling in the percentage of area of perivascular cell staining, and bevacizumab caused a rapid decrease in the percentage of area of endothelial cell staining. However, both agents increased intratumoral oxygenation, although with bevacizumab, the effect was transient, being lost by 5 days. Administration of IFN-beta or bevacizumab before RT was significantly more effective than any of the three modalities as monotherapy or when RT was administered concomitantly with IFN-beta or bevacizumab or 5 days after bevacizumab. Conclusion: Bevacizumab and continuous delivery of IFN-beta each induced significant changes in glioma vascular physiology, improving intratumoral oxygenation and enhancing the antitumor activity of ionizing radiation. Additional investigation into the use and timing of these and other agents that modify the vascular phenotype, combined with RT, is warranted to optimize cytotoxic activity.« less

Computerized Dental Injection Fear Treatment

PubMed Central

Heaton, L.J.; Leroux, B.G.; Ruff, P.A.; Coldwell, S.E.

2013-01-01

One in four adults reports a clinically significant fear of dental injections, leading many to avoid dental care. While systematic desensitization is the most common therapeutic method for treating specific phobias such as fear of dental injections, lack of access to trained therapists, as well as dentists’ lack of training and time in providing such a therapy, means that most fearful individuals are not able to receive the therapy needed to be able to receive necessary dental treatment. Computer Assisted Relaxation Learning (CARL) is a self-paced computerized treatment based on systematic desensitization for dental injection fear. This multicenter, block-randomized, dentist-blind, parallel-group study conducted in 8 sites in the United States compared CARL with an informational pamphlet in reducing fear of dental injections. Participants completing CARL reported significantly greater reduction in self-reported general and injection-specific dental anxiety measures compared with control individuals (p < .001). Twice as many CARL participants (35.3%) as controls (17.6%) opted to receive a dental injection after the intervention, although this was not statistically significant. CARL, therefore, led to significant changes in self-reported fear in study participants, but no significant differences in the proportion of participants having a dental injection (ClinicalTrials.gov, NCT00609648). PMID:23690352

Soft tissue and intra-articular injection of bupivacaine, epinephrine, and morphine has a beneficial effect after total knee arthroplasty.

PubMed

Lombardi, Adolph V; Berend, Keith R; Mallory, Thomas H; Dodds, Kathleen L; Adams, Joanne B

2004-11-01

The purpose of this study was to determine if an intraoperative intraarticular and soft-tissue injection of local anaesthetic, epinephrine, and morphine has a beneficial effect for total knee arthroplasty. A control group of 138 patients (181 knees) received no intraoperative injection. The study group of 171 patients (197 knees) received intraoperative injection of 0.25% bupivacaine with epinephrine and morphine with 2/3 injected into the soft tissues and 1/3 injected into the joint. Patients having bilateral simultaneous procedures received a divided dose. The pain treatment protocol otherwise was identical. Pain, sedation, rescue narcotic usage, narcotic reversal and blood loss were examined. Pain levels during the immediate postoperative period, blood loss, and bleeding indices were reduced with injection. Considerably more control patients required rescue doses of narcotics. Preemptive analgesia with soft tissue and intra-articular injection of long-acting local anesthetic with epinephrine and morphine provides better pain control in the immediate postoperative period, decreases blood loss, and decreases the need for rescue narcotics and reversal agents. This simple, inexpensive method provides an effective adjunct to a multimodal approach in improving the postoperative course of primary total knee arthroplasty.

The effectiveness of a mail reminder system for depot medroxyprogesterone injections.

PubMed

Madlon-Kay, D J

1996-04-01

To determine if a mail reminder system leads to an increase in the percentage of depot medroxyprogesterone acetate (Depo-Provera) injections administered on time, the charts of 184 women were reviewed. The reminder postcard included the due dates of both the next medroxyprogesterone injection and the next Papanicolaou test. Timeliness of injections improved with the reminder system from 64% administered on time to 76% (P < .02). Injections given late despite the reminders were late a mean of 8 days. Injections given late before the reminder system began were late a mean of 20 days (P < .05). If injections given during the injection's 14-day "grace" period are included, the on-time rate improved from 87% to 96% with the reminder system (P < .005). The reminder system was not effective in ensuring annual Papanicolaou testing. Vigilance is needed to ensure that women receiving medroxyprogesterone injections also receive timely Papanicolaou testing.

Effects of intracerebroventricular injections of free fatty acids, lysophospholipids, or platelet activating factor in a mouse model of orofacial pain.

PubMed

Vahidy, Wajiha H; Ong, Wei-Yi; Farooqui, Akhlaq A; Yeo, Jin-Fei

2006-10-01

The present study was carried out to determine the effects of central nervous free fatty acids, lysophospholipids, or platelet activating factor (PAF), in a mouse facial carrageenan injection model of orofacial pain. Mice that received intracerebroventricular (I.C.V.) injection of arachidonic acid or oleic acid showed significantly reduced allodynia and behavioral responses to von Frey hair stimulation of a carrageenan-injected area of the face, at 8 h post-injection, compared to controls that received I.C.V. injection of vehicle. In contrast to free fatty acids, increased responses were observed in mice at 72 h after I.C.V. lysophosphatidic acid or lysophosphatidylcholine injection, and at 8 and 24 h after PAF injection, compared vehicle injected controls. Information regarding pro-nociceptive effect of specific brain lipids may be a useful basis for further studies to explore mechanism.

The role of cyclophosphamide in enhancing antitumor efficacy of an adenovirus oncolytic vector in subcutaneous Syrian hamster tumors

PubMed Central

Young, Brittany A.; Spencer, Jacqueline F.; Ying, Baoling; Tollefson, Ann E.; Toth, Karoly; Wold, William S. M.

2013-01-01

We have previously reported that intratumoral injection of VRX-007—an Ad5-based vector overexpressing ADP (Adenovirus Death Protein)—can suppress the growth of subcutaneous HaK (hamster renal cancer) tumors. VRX-007 replication and tumor growth inhibition are enhanced when the hamsters are immunosuppressed by a high dose of cyclophosphamide (CP), an immunosuppressive and chemotherapeutic agent. Here we report that continuous immunosuppression with CP was not required for increased oncolytic activity of VRX-007 because short-term dosing or continuous dosing with the drug yielded similar antitumor results. Prolonged viral replication was found only in animals on continuous CP treatment. We used 007-Luc, a replication-competent, luciferase-expressing vector similar to VRX-007 to investigate the replication of the vector over time. Tumor growth inhibition was similar in hamsters given CP treatment either one week before or one week after 007-Luc injection, which suggests that CP exerts its antitumor efficacy independently of vector therapy. 007-Luc did not spread far from the inoculation site, even in immunosuppressed, CP-treated animals. Our results indicate that the enhanced effectiveness that is produced by the combination of VRX-007 and CP therapies is due to their two independent mechanisms and that they do not have to be given simultaneously for the improved outcome shown. PMID:23928731

The role of cyclophosphamide in enhancing antitumor efficacy of an adenovirus oncolytic vector in subcutaneous Syrian hamster tumors.

PubMed

Young, B A; Spencer, J F; Ying, B; Tollefson, A E; Toth, K; Wold, W S M

2013-09-01

We have previously reported that intratumoral injection of VRX-007--an Ad5 (a species C adenovirus)-based vector overexpressing adenovirus death protein--can suppress the growth of subcutaneous HaK (hamster renal cancer) tumors. VRX-007 replication and tumor growth inhibition are enhanced when the hamsters are immunosuppressed by a high dose of cyclophosphamide (CP), an immunosuppressive and chemotherapeutic agent. Here, we report that continuous immunosuppression with CP was not required for increased oncolytic activity of VRX-007 because short-term dosing or continuous dosing with the drug yielded similar antitumor results. Prolonged viral replication was found only in animals on continuous CP treatment. We used 007-Luc, a replication-competent, luciferase-expressing vector similar to VRX-007, to investigate the replication of the vector over time. Tumor growth inhibition was similar in hamsters given CP treatment either 1 week before or 1 week after 007-Luc injection, which suggests that CP exerts its antitumor efficacy independently of vector therapy. 007-Luc did not spread far from the inoculation site, even in immunosuppressed, CP-treated animals. Our results indicate that the enhanced effectiveness that is produced by the combination of VRX-007 and CP therapies is due to their two independent mechanisms and that they do not have to be given simultaneously for the improved outcome.

The oncolytic peptide LTX-315 triggers immunogenic cell death

PubMed Central

Zhou, H; Forveille, S; Sauvat, A; Yamazaki, T; Senovilla, L; Ma, Y; Liu, P; Yang, H; Bezu, L; Müller, K; Zitvogel, L; Rekdal, Ø; Kepp, O; Kroemer, G

2016-01-01

LTX-315 is a cationic amphilytic peptide that preferentially permeabilizes mitochondrial membranes, thereby causing partially BAX/BAK1-regulated, caspase-independent necrosis. Based on the observation that intratumorally injected LTX-315 stimulates a strong T lymphocyte-mediated anticancer immune response, we investigated whether LTX-315 may elicit the hallmarks of immunogenic cell death (ICD), namely (i) exposure of calreticulin on the plasma membrane surface, (ii) release of ATP into the extracellular space, (iii) exodus of HMGB1 from the nucleus, and (iv) induction of a type-1 interferon response. Using a panel of biosensor cell lines and robotized fluorescence microscopy coupled to automatic image analysis, we observed that LTX-315 induces all known ICD characteristics. This conclusion was validated by several independent methods including immunofluorescence stainings (for calreticulin), bioluminescence assays (for ATP), immunoassays (for HMGB1), and RT-PCRs (for type-1 interferon induction). When injected into established cancers, LTX-315 caused a transiently hemorrhagic focal necrosis that was accompanied by massive release of HMGB1 (from close-to-all cancer cells), as well as caspase-3 activation in a fraction of the cells. LTX-315 was at least as efficient as the positive control, the anthracycline mitoxantrone (MTX), in inducing local inflammation with infiltration by myeloid cells and T lymphocytes. Collectively, these results support the idea that LTX-315 can induce ICD, hence explaining its capacity to mediate immune-dependent therapeutic effects. PMID:26962684

The oncolytic peptide LTX-315 triggers immunogenic cell death.

PubMed

Zhou, H; Forveille, S; Sauvat, A; Yamazaki, T; Senovilla, L; Ma, Y; Liu, P; Yang, H; Bezu, L; Müller, K; Zitvogel, L; Rekdal, Ø; Kepp, O; Kroemer, G

2016-03-10

LTX-315 is a cationic amphilytic peptide that preferentially permeabilizes mitochondrial membranes, thereby causing partially BAX/BAK1-regulated, caspase-independent necrosis. Based on the observation that intratumorally injected LTX-315 stimulates a strong T lymphocyte-mediated anticancer immune response, we investigated whether LTX-315 may elicit the hallmarks of immunogenic cell death (ICD), namely (i) exposure of calreticulin on the plasma membrane surface, (ii) release of ATP into the extracellular space, (iii) exodus of HMGB1 from the nucleus, and (iv) induction of a type-1 interferon response. Using a panel of biosensor cell lines and robotized fluorescence microscopy coupled to automatic image analysis, we observed that LTX-315 induces all known ICD characteristics. This conclusion was validated by several independent methods including immunofluorescence stainings (for calreticulin), bioluminescence assays (for ATP), immunoassays (for HMGB1), and RT-PCRs (for type-1 interferon induction). When injected into established cancers, LTX-315 caused a transiently hemorrhagic focal necrosis that was accompanied by massive release of HMGB1 (from close-to-all cancer cells), as well as caspase-3 activation in a fraction of the cells. LTX-315 was at least as efficient as the positive control, the anthracycline mitoxantrone (MTX), in inducing local inflammation with infiltration by myeloid cells and T lymphocytes. Collectively, these results support the idea that LTX-315 can induce ICD, hence explaining its capacity to mediate immune-dependent therapeutic effects.

Frequency of booster injections of allergoids.

PubMed

Norman, P S; Creticos, P S; Marsh, D G

1990-01-01

In 1982, 43 ragweed-sensitive patients receiving maintenance injections of full doses of ragweed allergoid were selected for a study of the immunologic and clinical efficacy of booster injections only four times a year. These patients had participated for 2 to 7 years as part of a trial of mixes of up to four allergoids to common pollens in the mid-Atlantic area tailored to each patient's skin test sensitivity. They were divided into a group (21 patients) to receive injections every 3 months and a group (22 patients) to receive injections about every 6 weeks (eight injections per year). Patients were rerandomized after 1 year so that half of each original group switched to the alternate treatment, and this program was continued until after the ragweed season of 1985. Thirty-four patients were still under study the last year. Doses, per injection, were 100 allergoid units (1 allergoid unit equals 100 PNU) of each allergen in the mixture. Symptom scores during the 8 weeks of each of the four ragweed seasons were not significantly higher in the 3-month treated group. IgG antibody levels to Amb a I (antigen E) were followed until early 1984 and were not significantly different in the two groups, even though the 6-week treated patients received a two times higher cumulative dose per year. Rates of local and systemic reactions (percent of injections eliciting reactions) were not different in the groups, which means that the 3-month treated group had about half as many reactions by virtue of taking half as many injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet-rich plasma for chronic lateral epicondylitis: is one injection sufficient?

PubMed

Glanzmann, Michael C; Audigé, Laurent

2015-12-01

Chronic lateral epicondylitis is generally treated using nonsurgical methods including physiotherapy and infiltrations of cortisone or platelet-rich plasma (PRP). The latter is known for its simple application as well as associated low risk of adverse events, which lend to its widespread use in treating various musculoskeletal conditions. There is limited evidence on the effectiveness of PRP injections to optimally treat chronic lateral epicondylitis. This study explored the effectiveness of single or repeated injections for patients with symptoms that spanned 6 months or more and were unresponsive to alternate conservative measures. Patients with chronic lateral epicondylitis received PRP injections in 4-week intervals that were complemented with standardized physical therapy. Patient-reported outcomes based on the patient-rated elbow evaluation (PREE), quick disabilities of the arm, shoulder and hand (qDASH), and EuroQol (five dimensions) 3-level version (EQ5D3L) questionnaires were documented at each visit including 6 months after the first injection. These outcomes were compared between patients receiving 1 vs. 2 or 3 PRP injections. Sixty-two patients received one (n = 36) or more (n = 26) PRP injections. The mean baseline to 6-month follow-up scores of the PREE and qDASH questionnaires improved significantly from 54.0 to 23.0 and 50.3 to 20.7, respectively. The mean baseline EQ5D3L-visual analogue scale score improved from 62.5 to 82.9 by 6 months post-injection. These outcomes did not significantly differ between the patients who received varying numbers of injections. Patients with chronic lateral epicondylitis reported significant pain relief and gain in function as well as quality of life 6 months after localized PRP treatment. A single PRP injection may be sufficient.

Botulinum Toxin Dosing Trends in Spasmodic Dysphonia Over a 20-year Period.

PubMed

Namin, Arya W; Christopher, Kara M; Eisenbeis, John F

2017-01-01

The study aims to (1) identify the botulinum toxin (BTX) dosing trend in a cohort of patients who received at least 20 injections for the treatment of adductor spasmodic dysphonia (ADSD), (2) describe two distinct BTX dosing trends in treating ADSD (a "classic" dosing trend that initially decreases before stabilizing, and a "fluctuating" dosing trend), and (3) determine if patients with the "classic" dosing trend differed in age or in dosing intervals from those with the "fluctuating" dosing trend. This is a retrospective case series. Of 149 patients who received a total of 2484 BTX injections for the treatment of spasmodic dysphonia in 1993-2013, 49 patients received at least 20 injections. The BTX dose and the interval between doses were recorded. The mean dose of injections 1-20 was determined. The age at initial injection, initial dose, and interval in days between treatments were compared for the "fluctuating" and "classic" groups. The cohort exhibits a significant decrease in dose during the first 10-15 injections. The "fluctuating" group had a significantly shorter interval between injections (mean interval = 97.09 days, SD = 29.41; mean interval = 136.90 days, SD = 43.76, P = 0.002). The mean age at initial dose was not significantly different between the "classic" and "fluctuating" groups. The average BTX dose of patients with ADSD who receive long-term injections significantly decreases during the initial 10-15 injections before stabilizing. Patients who exhibit the "fluctuating" dosing pattern have a significantly shorter interval between injections than those with the "classic" dosing pattern. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Long-acting oxytetracycline prophylaxis to protect susceptible cattle introduced into an area of Kenya with endemic East Coast fever.

PubMed

Chumo, R S; Irvin, A D; Morzaria, S P; Katende, J; Purnell, R E

1989-03-04

Two field trials were carried out in successive years at the Ngong Veterinary Farm, Kenya, in which young cattle, previously unexposed to tick-borne diseases, were introduced into an area with endemic East Coast fever while protected by a series of injections of a long-acting oxytetracycline. In 1984, 12 animals which received injections of 20 mg/kg of the drug on days 0, 7, 14 and 21 after introduction, together with 12 untreated controls, were exposed without tick control until clinical disease occurred. All 12 control animals contracted East Coast fever by day 24 and 10 of them died. Five of the 12 injected animals had detectable parasites, and one of them required antitheilerial treatment. In 1985, four groups of 10 calves were introduced. One group received injections of 20 mg/kg of oxytetracycline on days 7 and 14, one group received injections on days 7, 14 and 21, and a third group received injections on days 7, 12 and 17; the fourth group (controls) had no treatment until clinical disease occurred. By day 35 all the control animals had contracted the disease and one had died despite antitheilerial treatment. Three injections of oxytetracycline suppressed the disease so that mild reactions occurred in only four animals in each group, but two injections failed to prevent severe reactions in two animals and mild reactions in four others.(ABSTRACT TRUNCATED AT 250 WORDS)

Intratumoral peripheral small papillary tufts: a diagnostic clue of renal tumors associated with Birt-Hogg-Dubé syndrome.

PubMed

Kuroda, Naoto; Furuya, Mitsuko; Nagashima, Yoji; Gotohda, Hiroko; Moritani, Suzuko; Kawakami, Fumi; Imamura, Yoshiaki; Bando, Yoshimi; Takahashi, Masayuki; Kanayama, Hiro-omi; Ota, Satoshi; Michal, Michal; Hes, Ondrej; Nakatani, Yukio

2014-06-01

In this article, we searched for the common histologic characteristic of renal tumors in patients with Birt-Hogg-Dubé syndrome (BHDS). We selected 6 patients with histologically confirmed renal tumor in BHDS. Germline FLCN gene mutation has been identified in 5 patients. Multifocality and bilaterality of the renal tumors were pathologically or radiologically confirmed in 5 and 2 cases, respectively. Histologic subtypes of the dominant tumor included 3 previously described hybrid oncocytic tumors, one composite chromophobe/papillary/clear cell renal cell carcinoma (RCC) and one unclassified RCC resembling hybrid chromophobe/clear cell RCC. In one case, chromophobe RCC and clear cell RCC were separately observed. Small papillary lesions located in the peripheral area of the tumor, which we designated as intratumoral peripheral small papillary tufts, were identified in all patients. In conclusion, multifocality/bilaterality of renal tumors, discordance of histologic subtypes, and the presence of intratumoral peripheral small papillary tufts may be important clues to identify BHDS-associated renal tumors. Copyright © 2014 Elsevier Inc. All rights reserved.

Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma.

PubMed

Wallin, Jeffrey J; Bendell, Johanna C; Funke, Roel; Sznol, Mario; Korski, Konstanty; Jones, Suzanne; Hernandez, Genevive; Mier, James; He, Xian; Hodi, F Stephen; Denker, Mitchell; Leveque, Vincent; Cañamero, Marta; Babitski, Galina; Koeppen, Hartmut; Ziai, James; Sharma, Neeraj; Gaire, Fabien; Chen, Daniel S; Waterkamp, Daniel; Hegde, Priti S; McDermott, David F

2016-08-30

Anti-tumour immune activation by checkpoint inhibitors leads to durable responses in a variety of cancers, but combination approaches are required to extend this benefit beyond a subset of patients. In preclinical models tumour-derived VEGF limits immune cell activity while anti-VEGF augments intra-tumoral T-cell infiltration, potentially through vascular normalization and endothelial cell activation. This study investigates how VEGF blockade with bevacizumab could potentiate PD-L1 checkpoint inhibition with atezolizumab in mRCC. Tissue collections are before treatment, after bevacizumab and after the addition of atezolizumab. We discover that intra-tumoral CD8(+) T cells increase following combination treatment. A related increase is found in intra-tumoral MHC-I, Th1 and T-effector markers, and chemokines, most notably CX3CL1 (fractalkine). We also discover that the fractalkine receptor increases on peripheral CD8(+) T cells with treatment. Furthermore, trafficking lymphocyte increases are observed in tumors following bevacizumab and combination treatment. These data suggest that the anti-VEGF and anti-PD-L1 combination improves antigen-specific T-cell migration.

Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma

PubMed Central

Wallin, Jeffrey J.; Bendell, Johanna C.; Funke, Roel; Sznol, Mario; Korski, Konstanty; Jones, Suzanne; Hernandez, Genevive; Mier, James; He, Xian; Hodi, F. Stephen; Denker, Mitchell; Leveque, Vincent; Cañamero, Marta; Babitski, Galina; Koeppen, Hartmut; Ziai, James; Sharma, Neeraj; Gaire, Fabien; Chen, Daniel S.; Waterkamp, Daniel; Hegde, Priti S.; McDermott, David F.

2016-01-01

Anti-tumour immune activation by checkpoint inhibitors leads to durable responses in a variety of cancers, but combination approaches are required to extend this benefit beyond a subset of patients. In preclinical models tumour-derived VEGF limits immune cell activity while anti-VEGF augments intra-tumoral T-cell infiltration, potentially through vascular normalization and endothelial cell activation. This study investigates how VEGF blockade with bevacizumab could potentiate PD-L1 checkpoint inhibition with atezolizumab in mRCC. Tissue collections are before treatment, after bevacizumab and after the addition of atezolizumab. We discover that intra-tumoral CD8+ T cells increase following combination treatment. A related increase is found in intra-tumoral MHC-I, Th1 and T-effector markers, and chemokines, most notably CX3CL1 (fractalkine). We also discover that the fractalkine receptor increases on peripheral CD8+ T cells with treatment. Furthermore, trafficking lymphocyte increases are observed in tumors following bevacizumab and combination treatment. These data suggest that the anti-VEGF and anti-PD-L1 combination improves antigen-specific T-cell migration. PMID:27571927

Imaging intratumor heterogeneity: role in therapy response, resistance, and clinical outcome.

PubMed

O'Connor, James P B; Rose, Chris J; Waterton, John C; Carano, Richard A D; Parker, Geoff J M; Jackson, Alan

2015-01-15

Tumors exhibit genomic and phenotypic heterogeneity, which has prognostic significance and may influence response to therapy. Imaging can quantify the spatial variation in architecture and function of individual tumors through quantifying basic biophysical parameters such as CT density or MRI signal relaxation rate; through measurements of blood flow, hypoxia, metabolism, cell death, and other phenotypic features; and through mapping the spatial distribution of biochemical pathways and cell signaling networks using PET, MRI, and other emerging molecular imaging techniques. These methods can establish whether one tumor is more or less heterogeneous than another and can identify subregions with differing biology. In this article, we review the image analysis methods currently used to quantify spatial heterogeneity within tumors. We discuss how analysis of intratumor heterogeneity can provide benefit over more simple biomarkers such as tumor size and average function. We consider how imaging methods can be integrated with genomic and pathology data, instead of being developed in isolation. Finally, we identify the challenges that must be overcome before measurements of intratumoral heterogeneity can be used routinely to guide patient care. ©2014 American Association for Cancer Research.

Intratumoral heterogeneity of the epigenome

PubMed Central

Song, Jun S.; Costello, Joseph F.

2016-01-01

Investigation into intratumoral heterogeneity (ITH) of the epigenome is in a formative stage. The patterns of tumor evolution inferred from epigenetic ITH and genetic ITH are remarkably similar, suggesting widespread co-dependency of these disparate mechanisms. The biological and clinical relevance of epigenetic ITH are becoming more apparent. Rare tumor cells with unique and reversible epigenetic states may drive drug resistance, and the degree of epigenetic ITH at diagnosis may predict patient outcome. This perspective presents these current concepts and clinical implications of epigenetic ITH, and the experimental and computational techniques at the forefront of ITH exploration. PMID:27070699

Chaos synchronization communication using extremely unsymmetrical bidirectional injections.

PubMed

Zhang, Wei Li; Pan, Wei; Luo, Bin; Zou, Xi Hua; Wang, Meng Yao; Zhou, Zhi

2008-02-01

Chaos synchronization and message transmission between two semiconductor lasers with extremely unsymmetrical bidirectional injections (EUBIs) are discussed. By using EUBIs, synchronization is realized through injection locking. Numerical results show that if the laser subjected to strong injection serves as the receiver, chaos pass filtering (CPF) of the system is similar to that of unidirectional coupled systems. Moreover, if the other laser serves as the receiver, a stronger CPF can be obtained. Finally, we demonstrate that messages can be extracted successfully from either of the two transmission directions of the system.

Combined treatment, based on lysomustine administration with mesenchymal stem cells expressing cytosine deaminase therapy, leads to pronounced murine Lewis lung carcinoma growth inhibition.

PubMed

Krassikova, Lyudmila S; Karshieva, Saida S; Cheglakov, Ivan B; Belyavsky, Alexander V

2016-09-01

The combination of stem cell-based gene therapy with chemotherapy comprises an advantageous strategy that results in a reduction of system toxicity effects and an improvement in the general efficacy of treatment. In the present study, we estimated the efficacy of adipose tissue-derived mesenchymal stem cells (AT-MSCs) expressing cytosine deaminase (CDA) combined with lysomustine chemotherapy in mice bearing late stage Lewis lung carcinoma (LLC). Adipose tissue-derived mesenchymal stem cells were transfected with non-insert plasmid construct transiently expressing fused cytosine deaminase-uracil phosphoribosyltransferase protein (CDA/UPRT) or the same construct fused with Herpes Simplex Virus Type1 tegument protein VP22 (CDA/UPRT/VP22). Systemic administration of 5-fluorocytosine (5FC) and lysomustine was implemented after a single intratumoral injection of transfected AT-MSCs. We demonstrated that direct intratumoral transplantation of AT-MSCs expressing CDA/UPRT or CDA/UPRT/VP22 followed by systemic administration of 5FC resulted in a significant tumor growth inhibition. There was a 56% reduction in tumor volume in mice treated by AT-MSCs-CDA/UPRT + 5FC or with AT-MSCs-CDA/UPRT/VP22 + 5FC compared to control animals grafted with lung carcinoma alone. Transplantation of AT-MSCs-CDA/UPRT + 5FC and AT-MSCs-CDA/UPRT/VP22 + 5FC prolonged the life span of mice bearing LLC by 27% and 31%, respectively. Co-administration of lysomustine and AT-MSCs-CDA/UPRT + 5FC led to tumor growth inhibition (by 86%) and life span extension (by 60%) compared to the control group. Our data indicate that a combination CDA/UPRT-expressing AT-MSCs with lysomustine has a superior antitumor effect in the murine lung carcinoma model compared to monotherapies with transfected AT-MSCs or lysomustine alone, possibly because of a synergistic effect of the combination therapy. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Impediments to enhancement of CPT-11 anticancer activity by E. coli directed beta-glucuronidase therapy.

PubMed

Hsieh, Yuan-Ting; Chen, Kai-Chuan; Cheng, Chiu-Min; Cheng, Tian-Lu; Tao, Mi-Hua; Roffler, Steve R

2015-01-01

CPT-11 is a camptothecin analog used for the clinical treatment of colorectal adenocarcinoma. CPT-11 is converted into the therapeutic anti-cancer agent SN-38 by liver enzymes and can be further metabolized to a non-toxic glucuronide SN-38G, resulting in low SN-38 but high SN-38G concentrations in the circulation. We previously demonstrated that adenoviral expression of membrane-anchored beta-glucuronidase could promote conversion of SN-38G to SN-38 in tumors and increase the anticancer activity of CPT-11. Here, we identified impediments to effective tumor therapy with E. coli that were engineered to constitutively express highly active E. coli beta-glucuronidase intracellularly to enhance the anticancer activity of CPT-11. The engineered bacteria, E. coli (lux/βG), could hydrolyze SN-38G to SN-38, increased the sensitivity of cultured tumor cells to SN-38G by about 100 fold and selectively accumulated in tumors. However, E. coli (lux/βG) did not more effectively increase CPT-11 anticancer activity in human tumor xenografts as compared to non-engineered E. coli. SN-38G conversion to SN-38 by E. coli (lux/βG) appeared to be limited by slow uptake into bacteria as well as by segregation of E. coli in necrotic regions of tumors that may be relatively inaccessible to systemically-administered drug molecules. Studies using a fluorescent glucuronide probe showed that significantly greater glucuronide hydrolysis could be achieved in mice pretreated with E. coli (lux/βG) by direct intratumoral injection of the glucuronide probe or by intratumoral lysis of bacteria to release intracellular beta-glucuronidase. Our study suggests that the distribution of beta-glucuronidase, and possibly other therapeutic proteins, in the tumor microenvironment might be an important barrier for effective bacterial-based tumor therapy. Expression of secreted therapeutic proteins or induction of therapeutic protein release from bacteria might therefore be a promising strategy to enhance anti-tumor activity.

Trans sodium crocetinate: functional neuroimaging studies in a hypoxic brain tumor.

PubMed

Sheehan, Jason P; Popp, Britney; Monteith, Stephen; Toulmin, Sushila; Tomlinson, Jennifer; Martin, Jessica; Cifarelli, Christopher P; Lee, Dae-Hee; Park, Deric M

2011-10-01

Intratumoral hypoxia is believed to be exhibited in high-grade gliomas. Trans sodium crocetinate (TSC) has been shown to increase oxygen diffusion to hypoxic tissues. In this research, the authors use oxygen-sensitive PET studies to evaluate the extent of hypoxia in vivo in a glioblastoma model and the effect of TSC on the baseline oxygenation of the tumor. The C6 glioma cells were stereotactically implanted in the right frontal region of rat brains. Formation of intracranial tumors was confirmed on MR imaging. Animals were injected with Copper(II) diacetyl-di(N4-methylthiosemicarbazone) (Cu-ATSM) and then either TSC or saline (6 rats each). Positron emission tomography imaging was performed, and relative uptake values were computed to determine oxygenation within the tumor and normal brain parenchyma. Additionally, TSC or saline was infused into the animals, and carbonic anhydrase 9 (CA9) and hypoxia-inducing factor-1α (HIF-1α) protein expression were measured 1 day afterward. On PET imaging, all glioblastoma tumors demonstrated a statistically significant decrease in uptake of Cu-ATSM compared with the contralateral cerebral hemisphere (p = 0.000002). The mean relative uptake value of the tumor was 3900 (range 2203-6836), and that of the contralateral brain tissue was 1017 (range 488-2304). The mean relative hypoxic tumor volume for the saline group and TSC group (6 rats each) was 1.01 ± 0.063 and 0.69 ± 0.062, respectively (mean ± SEM, p = 0.002). Infusion of TSC resulted in a 31% decrease in hypoxic volume. Immunoblot analysis revealed expression of HIF-1α and CA9 in all tumor specimens. Some glioblastomas exhibit hypoxia that is demonstrable on oxygen-specific PET imaging. It appears that TSC lessens intratumoral hypoxia on functional imaging. Further studies should explore relative hypoxia in glioblastoma and the potential therapeutic gains that can be achieved by lessening hypoxia during delivery of adjuvant treatment.

Magnetically assisted intraperitoneal drug delivery for cancer chemotherapy.

PubMed

Shamsi, Milad; Sedaghatkish, Amir; Dejam, Morteza; Saghafian, Mohsen; Mohammadi, Mehdi; Sanati-Nezhad, Amir

2018-11-01

Intraperitoneal (IP) chemotherapy has revived hopes during the past few years for the management of peritoneal disseminations of digestive and gynecological cancers. Nevertheless, a poor drug penetration is one key drawback of IP chemotherapy since peritoneal neoplasms are notoriously resistant to drug penetration. Recent preclinical studies have focused on targeting the aberrant tumor microenvironment to improve intratumoral drug transport. However, tumor stroma targeting therapies have limited therapeutic windows and show variable outcomes across different cohort of patients. Therefore, the development of new strategies for improving the efficacy of IP chemotherapy is a certain need. In this work, we propose a new magnetically assisted strategy to elevate drug penetration into peritoneal tumor nodules and improve IP chemotherapy. A computational model was developed to assess the feasibility and predictability of the proposed active drug delivery method. The key tumor pathophysiology, including a spatially heterogeneous construct of leaky vasculature, nonfunctional lymphatics, and dense extracellular matrix (ECM), was reconstructed in silico. The transport of intraperitoneally injected magnetic nanoparticles (MNPs) inside tumors was simulated and compared with the transport of free cytotoxic agents. Our results on magnetically assisted delivery showed an order of magnitude increase in the final intratumoral concentration of drug-coated MNPs with respect to free cytotoxic agents. The intermediate MNPs with the radius range of 200-300 nm yield optimal magnetic drug targeting (MDT) performance in 5-10 mm tumors while the MDT performance remains essentially the same over a large particle radius range of 100-500 nm for a 1 mm radius small tumor. The success of MDT in larger tumors (5-10 mm in radius) was found to be markedly dependent on the choice of magnet strength and tumor-magnet distance while these two parameters were less of a concern in small tumors. We also validated in silico results against experimental results related to tumor interstitial hypertension, conventional IP chemoperfusion, and magnetically actuated movement of MNPs in excised tissue.

Impediments to Enhancement of CPT-11 Anticancer Activity by E. coli Directed Beta-Glucuronidase Therapy

PubMed Central

Hsieh, Yuan-Ting; Chen, Kai-Chuan; Cheng, Chiu-Min; Cheng, Tian-Lu; Tao, Mi-Hua; Roffler, Steve R.

2015-01-01

CPT-11 is a camptothecin analog used for the clinical treatment of colorectal adenocarcinoma. CPT-11 is converted into the therapeutic anti-cancer agent SN-38 by liver enzymes and can be further metabolized to a non-toxic glucuronide SN-38G, resulting in low SN-38 but high SN-38G concentrations in the circulation. We previously demonstrated that adenoviral expression of membrane-anchored beta-glucuronidase could promote conversion of SN-38G to SN-38 in tumors and increase the anticancer activity of CPT-11. Here, we identified impediments to effective tumor therapy with E. coli that were engineered to constitutively express highly active E. coli beta-glucuronidase intracellularly to enhance the anticancer activity of CPT-11. The engineered bacteria, E. coli (lux/βG), could hydrolyze SN-38G to SN-38, increased the sensitivity of cultured tumor cells to SN-38G by about 100 fold and selectively accumulated in tumors. However, E. coli (lux/βG) did not more effectively increase CPT-11 anticancer activity in human tumor xenografts as compared to non-engineered E. coli. SN-38G conversion to SN-38 by E. coli (lux/βG) appeared to be limited by slow uptake into bacteria as well as by segregation of E. coli in necrotic regions of tumors that may be relatively inaccessible to systemically-administered drug molecules. Studies using a fluorescent glucuronide probe showed that significantly greater glucuronide hydrolysis could be achieved in mice pretreated with E. coli (lux/βG) by direct intratumoral injection of the glucuronide probe or by intratumoral lysis of bacteria to release intracellular beta-glucuronidase. Our study suggests that the distribution of beta-glucuronidase, and possibly other therapeutic proteins, in the tumor microenvironment might be an important barrier for effective bacterial-based tumor therapy. Expression of secreted therapeutic proteins or induction of therapeutic protein release from bacteria might therefore be a promising strategy to enhance anti-tumor activity. PMID:25688562

AS30D Model of Hepatocellular Carcinoma: Tumorigenicity and Preliminary Characterization by Imaging, Histopathology, and Immunohistochemistry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thompson, Scott M.; Callstrom, Matthew R.; Knudsen, Bruce

This study was designed to determine the tumorigenicity of the AS30D HCC cell line following orthotopic injection into rat liver and preliminarily characterize the tumor model by both magnetic resonance imaging (MRI) and ultrasound (US) as well as histopathology and immunohistochemistry.MaterialsAS30D cell line in vitro proliferation was assessed by using MTT assay. Female rats (N = 5) underwent injection of the AS30D cell line into one site in the liver. Rats subsequently underwent MR imaging at days 7 and 14 to assess tumor establishment and volume. One rat underwent US of the liver at day 7. Rats were euthanized atmore » day 7 or 14 and livers were subjected to gross, histopathologic (H and E), and immunohistochemical (CD31) analysis to assess for tumor growth and neovascularization. AS30D cell line demonstrated an in vitro doubling time of 33.2 {+-} 5.3 h. MR imaging demonstrated hyperintense T2-weighted and hypointense T1-weighted lesions with tumor induction in five of five and three of three sites at days 7 and 14, respectively. The mean (SD) tumor volume was 126.1 {+-} 36.2 mm{sup 3} at day 7 (N = 5). US of the liver demonstrated a well-circumscribed, hypoechoic mass and comparison of tumor dimensions agreed well with MRI. Analysis of H and E- and CD31-stained sections demonstrated moderate-high grade epithelial tumors with minimal tumor necrosis and evidence of diffuse intratumoral and peritumoral neovascularization by day 7. AS30D HCC cell line is tumorigenic following orthotopic injection into rat liver and can be used to generate an early vascularizing, slower-growing rat HCC tumor model.« less

Microseismic Monitoring of the Mounds Drill Cuttings Injection Tests

DOE Office of Scientific and Technical Information (OSTI.GOV)

Branagan, P.T.; Mahrer, K.D.; Moschovidis, Z.A.

This paper describes the microseismic mapping of repeated injections of drill cuttings into two separate formations at a test site near Mounds, OK. Injections were performed in sandstone and shale formations at depths of 830 and 595 m, respectively. Typical injection disposal was simulated using multiple small-volume injections over a three-day period, with long shut-in periods interspersed between the injections. Microseismic monitoring was achieved using a 5-level array of wireline-run, triaxial- accelerometer receivers in a monitor well 76 m from the disposed well. Results of the mapped microseismic locations showed that the disposal domti W= generally aligns with the majormore » horizontal stress with some variations in azimuth and that wide variations in height and length growth occurred with continued injections. These experiments show that the cuttings injection process cm be adequately monitored from a downhole, wireline-run receiver array, thus providing process control and environmental assurance.« less

Reducing intraocular-pressure spike after intravitreal-bevacizumab injection with ocular decompression using a sterile cotton swab soaked in proparacaine 0.5%: A quasi-experimental study.

PubMed

Qureshi, Naveed A; Mansoor, Hassan; Ahmad, Sabihuddin; Zafar, Sarah; Asif, Muhammad

2016-01-01

The study was conducted to determine the effect of preinjection ocular decompression by a cotton swab soaked in local anesthetic on the immediate postinjection rise in intraocular pressure (IOP) after intravitreal bevacizumab (IVB). A nonrandomized, quasi-experimental interventional study was conducted at Al-Shifa Trust Eye Hospital, Pakistan, from August 1, 2013 to July 31, 2014. One hundred ( n = 100) patients receiving 0.05-mL IVB injection for the first time were assigned to two preinjection anesthetic methods: one with ocular decompression using a sterile cotton swab soaked in proparacaine 0.5%, and the other without ocular decompression using proparacaine 0.5% eyedrops. The IOP was recorded in the eye receiving IVB at three time intervals: Time 1 (preinjection), Time 2 (immediately after injection), and Time 3 (30 minutes after injection). There was a significant difference in the mean IOP change (between Time 1 and Time 2) for the group injected with ocular decompression [ M = 1.00, standard deviation (SD) = 1.47] and the group injected without ocular decompression ( M = 5.00, SD = 2.38; t (68) = 9.761, p < 0.001). There was also a significant difference in the mean IOP change (between Time 1 and Time 3) for the group injected with ocular decompression ( M = 0.428, SD = 1.58) and the group injected without ocular decompression ( M = 4.318, SD = 3.34; t (58) = 7.111, p < 0.001). Patients receiving IVB injections with ocular-decompression soaking in proparacaine 0.5% experience significantly lower postinjection IOP spike, and that too for a considerably shorter duration as compared to those receiving IVB without ocular decompression.

Intradiskal methylene blue treatment for diskogenic low back pain.

PubMed

Levi, David S; Horn, Scott; Walko, Edward

2014-11-01

Low back pain is a leading cause of pain and disability. The intervertebral disk has been identified as the most common source of chronic low back pain. Although prior treatments directed at intervertebral disks have been disappointing, recent studies show promising improvement of pain and function after a single intradiskal injection of methylene blue. To assess changes in pain and function in patients with diskogenic low back pain, diagnosed by diskography, after an intradiskal injection of methylene blue. Prospective trial. Patients diagnosed with diskogenic pain by diskography underwent a single treatment of intradiskal injection of methylene blue, determined by prior provocation diskography. Pain and function measurements were completed at baseline and 1, 2, and 6 months after treatment. Treatment was considered a categorical success based on a 30% improvement in pain according to a visual analog scale (VAS) and function on the Oswestry Disability Index (ODI). Treatment was considered a categorical failure if less than 30% improvement in pain and function was achieved or if the patient pursued other invasive treatment options during the trial period. Sixteen patients received the intradiskal methylene blue injection. Eleven patients received a single-level injection, 4 patients received a 2-level injection, and one patient received injections at 3 levels. For the VAS, at 1, 2, and 6 months after the injection, the categorical success rates were 25%, 21%, and 25%, respectively. For the ODI, at 1, 2 and 6 months after the injection, the categorical success rates were 25%, 21%, and 33%, respectively. The overall categorical success rates at 1, 2, and 6 months after the injection were 19%, 21%, and 25%, respectively. This small trial did not demonstrate overall clinical success of intradiskal methylene blue injection for patients diagnosed with diskogenic pain by diskography. Copyright © 2014 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

Monte Carlo simulation of radiation transport and dose deposition from locally released gold nanoparticles labeled with 111In, 177Lu or 90Y incorporated into tissue implantable depots

NASA Astrophysics Data System (ADS)

Lai, Priscilla; Cai, Zhongli; Pignol, Jean-Philippe; Lechtman, Eli; Mashouf, Shahram; Lu, Yijie; Winnik, Mitchell A.; Jaffray, David A.; Reilly, Raymond M.

2017-11-01

Permanent seed implantation (PSI) brachytherapy is a highly conformal form of radiation therapy but is challenged with dose inhomogeneity due to its utilization of low energy radiation sources. Gold nanoparticles (AuNP) conjugated with electron emitting radionuclides have recently been developed as a novel form of brachytherapy and can aid in homogenizing dose through physical distribution of radiolabeled AuNP when injected intratumorally (IT) in suspension. However, the distribution is unpredictable and precise placement of many injections would be difficult. Previously, we reported the design of a nanoparticle depot (NPD) that can be implanted using PSI techniques and which facilitates controlled release of AuNP. We report here the 3D dose distribution resulting from a NPD incorporating AuNP labeled with electron emitters (90Y, 177Lu, 111In) of different energies using Monte Carlo based voxel level dosimetry. The MCNP5 Monte Carlo radiation transport code was used to assess differences in dose distribution from simulated NPD and conventional brachytherapy sources, positioned in breast tissue simulating material. We further compare these dose distributions in mice bearing subcutaneous human breast cancer xenografts implanted with 177Lu-AuNP NPD, or injected IT with 177Lu-AuNP in suspension. The radioactivity distributions were derived from registered SPECT/CT images and time-dependent dose was estimated. Results demonstrated that the dose distribution from NPD reduced the maximum dose 3-fold when compared to conventional seeds. For simulated NPD, as well as NPD implanted in vivo, 90Y delivered the most homogeneous dose distribution. The tumor radioactivity in mice IT injected with 177Lu-AuNP redistributed while radioactivity in the NPD remained confined to the implant site. The dose distribution from radiolabeled AuNP NPD were predictable and concentric in contrast to IT injected radiolabeled AuNP, which provided irregular and temporally variant dose distributions. The use of NPD may serve as an intermediate between PSI and radiation delivered by radiolabeled AuNP by providing a controlled method to improve delivery of prescribed doses as well as homogenize dose from low penetrating electron sources.

Vapocoolant Anesthesia for Cosmetic Facial Rejuvenation Injections: A Randomized, Prospective, Split-Face Trial.

PubMed

Zeiderman, Matthew R; Kelishadi, Shahrooz Sean; Tutela, John Paul; Rao, Arun; Chowdhry, Saeed; Brooks, Ronald M; Wilhelmi, Bradon J

2018-01-01

Background: Minimally invasive cosmetic procedures are the most commonly performed aesthetic techniques by plastic surgeons. Patients are interested in a pain-free experience. Surgeons desire patient satisfaction and time-efficient utilization of office staff and resources. Clinical evidence exists for use of vapocoolant technology to reduce pain associated with intravenous cannulation in the pediatric population and in hemodialysis patients. Applying vapocoolant technology to facial rejuvenation is a novel approach to decrease pain associated with neurotoxin or filler injection. Methods: A randomized, prospective study was conducted, testing 15 subjects receiving filler injections and another 15 patients receiving neurotoxin injections using a split-face model. The vapocoolant spray used was composed of a 95:5 ratio of 1,1,1,3,3-pentafluoropropane and 1,1,1,2-tetrafluoroethane. Within each group, individual patients randomly received injection (filler or neurotoxin) alone versus injection (filler or neurotoxin) plus vapocoolant on an equivalent half of his or her face. An independent examiner recorded from each patient on a scale of 1 to 10 perceived pain for injection alone versus injection plus vapocoolant spray. Results were calculated as a percentage change of pain scores experienced after injection for each person between the control (nonvapocoolant) and treatment (vapocoolant) sides of the face. Results: Vapocoolant spray at the time of cosmetic facial injections leads to a 59% decrease in perceived pain score with neurotoxin injections (range, 0%-100% change) and 64% decrease in perceived pain score with filler injections (range, 0%-100% change). These results were statistically significant with P < .05. Conclusion: Vapocoolant spray reduces pain associated with facial rejuvenation procedures.

Physician-Industry Interactions and Anti-Vascular Endothelial Growth Factor Use Among US Ophthalmologists.

PubMed

Taylor, Stanford C; Huecker, Julia B; Gordon, Mae O; Vollman, David E; Apte, Rajendra S

2016-08-01

The publication of the US Physician Payments Sunshine Act provides insight into the financial relationship between physicians and the pharmaceutical industry. This added transparency creates new opportunities of using objective data to better understand prior research that implicates pharmaceutical promotions as an important factor in a physician's decision-making process. To assess the association between reported industry payments and physician-prescribing habits by comparing the use of anti-vascular endothelial growth factor (VEGF) intravitreal injections by US ophthalmologists to the industry payments these same physicians received. This study reviews data from the Centers for Medicare & Medicaid Services (CMS) 2013 Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File and the CMS-sponsored August through December 2013 Open Payments program (Physician Payments Sunshine Act). Ophthalmologists who prescribe anti-VEGF injections for all indications were analyzed. Association between industry payments reportedly received and the number and type of anti-VEGF injections administered. A total of 3011 US ophthalmologists were reimbursed by CMS for 2.2 million anti-VEGF injections in 2013. Of these physicians, 38.0% reportedly received $1.3 million in industry payments for ranibizumab and aflibercept. Analysis revealed positive associations between increasing numbers of reported industry payments and total injection use (r = 0.24; 95% CI, 0.22-0.26; P < .001), aflibercept and ranibizumab injection use (r = 0.32; 95% CI, 0.29-0.34; P < .001), and percentage of injections per physician that were aflibercept or ranibizumab (r = 0.27; 95% CI, 0.25-0.29; P < .001). A smaller association was noted between greater number of industry payments and bevacizumab injection use (r = 0.07; 95% CI, 0.04-0.09; P < .001). Similar associations were found between the total dollars of reported industry payments received to injection use. Subgroup analysis further revealed that physicians receiving $1 to $25 in reported industry benefits were more likely than those not receiving industry payments to perform a greater percentage of their injections with aflibercept and ranibizumab. Among ophthalmologists who prescribe anti-VEGF medications, there is a positive association between reported pharmaceutical payments and increased use of aflibercept and ranibizumab injections. As is inherent to the design of correlation studies, this analysis cannot determine whether the payments reported caused the increased use, are a result of the increased use, or are merely associated with some other factor that causes the increased use.

Effect of intravenous drug administration mode on drug distribution in a tumor slab: a finite Fourier transform analysis.

PubMed

Subramaniam, B; Claudius, J S

1990-03-08

Cancer therapy using chemotherapeutic drugs frequently involves injection of the drug into the body through some intravenous mode of administration, viz, continuous (drip) infusion or single/multiple bolus injection(s). An understanding of the effect of the various modes of administration upon tumor penetration of drug is essential to rational design of drug therapy. This paper investigates drug penetration into a model tumor of slab geometry (between two capillaries) in which the overall transport rate of drug is limited by intra-tumor transport characterized by an effective diffusion coefficient. Employing the method of Finite Fourier Transforms (FFT), analytical solutions have been obtained for transient drug distribution in both the plasma and the tumor following three modes of administration, viz, continuous infusion, single bolus injection and equally-spaced equal-dose multiple bolus injections, of a given amount of drug. The qualitative trends exhibited by the plasma drug distribution profiles are consistent with reported experimental studies. Two concepts, viz, the dimensionless decay constant and the plasma/tumor drug concentration trajectories, are found to be particularly useful in the rational design of drug therapy. The dimensionless decay constant provides a measure of the rate of drug decay in the plasma relative to the rate of drug diffusion into the tumor and is thus characteristic of the tumor/drug system. The magnitude of this parameter dictates the choice of drug administration mode for minimizing drug decay in the plasma while simultaneously maximizing drug transport into the tumor. The concentration trajectories provide a measure of the plasma drug concentration relative to the tumor drug concentration at various times following injection. When the tumor drug concentration exceeds the plasma drug concentration, the drug will begin to diffuse out of the tumor. Knowledge of the time at which this diffusion reversal occurs is especially useful for optimum scheduling of subsequent bolus injections in a multiple bolus dosing regimen. There are no reported applications of the FFT method to solve repeated input functions in either the chemical engineering or pharmaceutical science literature. Thus, the application of FFT method to solve multiple bolus injections is a unique one. Use of this FFT based analysis as a predictor tool can limit the number of costly experiments which are being done now to achieve this purpose. Even though the model in its present form is simplified, the analysis thereof has nevertheless led to a better understanding of the various factors that must be taken into account for rational design of drug therapy.

Efficacy and safety of collagenase clostridium histolyticum in the treatment of proximal interphalangeal joints in dupuytren contracture: combined analysis of 4 phase 3 clinical trials.

PubMed

Badalamente, Marie A; Hurst, Lawrence C; Benhaim, Prosper; Cohen, Brian M

2015-05-01

To examine the results of proximal interphalangeal (PIP) joint contractures from 4 phase 3 clinical trials of collagenase clostridium histolyticum (CCH) injection for Dupuytren contracture. Patients enrolled in Collagenase Option for Reduction of Dupuytren I/II and JOINT I/II with one or more PIP joint contractures (20° to 80°) received CCH 0.58 mg/0.20 mL or placebo (Collagenase Option for Reduction of Dupuytren I/II only) injected directly into a palpable cord. The percentage of PIP joints achieving clinical success (0° to 5° of full extension), clinical improvement (50% or more reduction in baseline contracture), and range of motion improvement at 30 days after the first and last CCH injections was assessed. The PIP joint contractures were classified into low (40° or less) and high (more than 40°) baseline severity. Adverse events were recorded. A total of 506 adults (mean age, 63 ± 10 y; 80% male) received 1,165 CCH injections in 644 PIP joint cords (mean, 1.6 injections/cord). Most patients (60%) received 1 injection, with 24%, 16%, and 1% receiving 2, 3, and 4 injections, respectively. Clinical success and clinical improvement occurred in 27% and 49% of PIP joints after one injection and in 34% and 58% after the last injection. Patients with lower baseline severity showed greater improvement and response was comparable between fingers, as were improvements in range of motion. Adverse events occurring in more than 10% of patients were peripheral edema (58%), contusion (38%), injection site hemorrhage (23%), injection site pain (21%), injection site swelling (16%), and tenderness (13%). This incidence was consistent with data reported in phase 3 trials. Two tendon ruptures occurred. No further ruptures occurred after a modified injection technique was adopted. Collagenase clostridium histolyticum was effective and well tolerated in the short term in patients with Dupuytren PIP joint contractures. Therapeutic II. Copyright © 2015 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Histologic Assessment of Intratumoral Lymphoplasmacytic Infiltration Is Useful in Predicting Prognosis of Patients with Hepatocellular Carcinoma.

PubMed

Hayashi, Akimasa; Shibahara, Junji; Misumi, Kento; Arita, Junichi; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Kokudo, Norihiro; Fukayama, Masashi

2016-01-01

In the present study, we investigated the clinicopathologic significance of intratumoral lymphoplasmacytic infiltration in a large cohort of patients with solitary hepatocellular carcinoma (HCC). Based on examination of hematoxylin and eosin-stained sections, significant infiltration was defined as dense lymphoplasmacytic infiltration, either multifocal or diffuse, in 2 or more fields under low-power magnification. Of 544 cases, 216 (39.7%) were positive for significant infiltration (HCC-LI group), while 328 (60.3%) were negative (HCC-NLI group). There were no significant between-group differences in patient age, sex, or background etiology. The lower incidence of Child-Pugh stage B (P = 0.001) and lower level of indocyanine green retention rate at 15 minutes (P < 0.001) in the HCC-LI group indicated better liver function in this group. Histologically, tumors were significantly smaller in size in the HCC-LI group than in the HCC-NLI group (P < 0.001). In addition, prominent neutrophilic infiltration, interstitial fibrosis and tumor steatosis were significantly more frequent (P < 0.001) in the HCC-LI group, while tumor necrosis was significantly less frequent (P = 0.008). Kaplan-Meier analyses revealed that overall and recurrence-free survival were significantly better in the HCC-LI group (P < 0.001). Multivariate Cox regression analysis showed that intratumoral lymphoplasmacytic infiltration was independently prognostic of both overall and recurrence-free survival (P < 0.001), with absence of infiltration showing high Cox-hazard ratios for poor prognosis. In conclusion, intratumoral lymphoplasmacytic infiltration, as determined by assessment of hematoxylin and eosin-stained slides, was significantly associated with the clinical and pathologic features of HCC and has profound prognostic importance.

Histologic Assessment of Intratumoral Lymphoplasmacytic Infiltration Is Useful in Predicting Prognosis of Patients with Hepatocellular Carcinoma

PubMed Central

Hayashi, Akimasa; Shibahara, Junji; Misumi, Kento; Arita, Junichi; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Kokudo, Norihiro; Fukayama, Masashi

2016-01-01

In the present study, we investigated the clinicopathologic significance of intratumoral lymphoplasmacytic infiltration in a large cohort of patients with solitary hepatocellular carcinoma (HCC). Based on examination of hematoxylin and eosin-stained sections, significant infiltration was defined as dense lymphoplasmacytic infiltration, either multifocal or diffuse, in 2 or more fields under low-power magnification. Of 544 cases, 216 (39.7%) were positive for significant infiltration (HCC-LI group), while 328 (60.3%) were negative (HCC-NLI group). There were no significant between-group differences in patient age, sex, or background etiology. The lower incidence of Child-Pugh stage B (P = 0.001) and lower level of indocyanine green retention rate at 15 minutes (P < 0.001) in the HCC-LI group indicated better liver function in this group. Histologically, tumors were significantly smaller in size in the HCC-LI group than in the HCC-NLI group (P < 0.001). In addition, prominent neutrophilic infiltration, interstitial fibrosis and tumor steatosis were significantly more frequent (P < 0.001) in the HCC-LI group, while tumor necrosis was significantly less frequent (P = 0.008). Kaplan-Meier analyses revealed that overall and recurrence-free survival were significantly better in the HCC-LI group (P < 0.001). Multivariate Cox regression analysis showed that intratumoral lymphoplasmacytic infiltration was independently prognostic of both overall and recurrence-free survival (P < 0.001), with absence of infiltration showing high Cox-hazard ratios for poor prognosis. In conclusion, intratumoral lymphoplasmacytic infiltration, as determined by assessment of hematoxylin and eosin-stained slides, was significantly associated with the clinical and pathologic features of HCC and has profound prognostic importance. PMID:27195977

Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies.

PubMed

Monjazeb, Arta M; Kent, Michael S; Grossenbacher, Steven K; Mall, Christine; Zamora, Anthony E; Mirsoian, Annie; Chen, Mingyi; Kol, Amir; Shiao, Stephen L; Reddy, Abhinav; Perks, Julian R; T N Culp, William; Sparger, Ellen E; Canter, Robert J; Sckisel, Gail D; Murphy, William J

2016-09-01

Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term "rebound immune suppression," limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy. We examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial. In murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy, CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8(+) T-cell-dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects. These results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation. Clin Cancer Res; 22(17); 4328-40. ©2016 AACR. ©2016 American Association for Cancer Research.

Association between lysyl oxidase and fibrotic focus in relation with inflammation in breast cancer

PubMed Central

Jeong, Young Ju; Park, Sung Hwan; Mun, Sung Hee; Kwak, Sang Gyu; Lee, Sun-Jae; Oh, Hoon Kyu

2018-01-01

We hypothesized that lysyl oxidase (LOX) contributes to the formation of fibrotic focus (FF) in association with inflammation and serves a significant role in breast carcinogenesis. In the present study, the association between the expression of LOX family members and FF with regards to with inflammation was analyzed, and the prognostic significance of LOX and FF in breast cancer was investigated. Immunohistochemical staining for LOX, LOX-like protein (LOXL) 1, LOXL2 and LOXL3 was performed in primary breast cancer tissues. The status of FF within the tumor was assessed, including size and grade. Levels of inflammatory markers, intratumoral and peritumoral lymphocyte infiltration were also evaluated. The clinicopathological characteristics were evaluated from the medical records of patients. In the present study, the expression of LOX family members was not associated with the presence of FF. FF was identified to be associated with intratumoral and peritumoral inflammation, tumor stage, larger tumor size, lymph node metastasis, high histologic grade, and p53 expression. LOX and LOXL3 were associated with intratumoral, and peritumoral inflammation. Furthermore, LOXL1 was associated with intratumoral inflammation and interleukin-4. In addition, LOX was associated with cluster of differentiation 8+ T cells. LOXL3 was associated with expression of ER and PR, and molecular subtype. In the survival analysis, overall survival time was statistically significantly longer in the FF-negative compared with that in the FF-positive group. In conclusion, it was demonstrated that FF and the expression of LOX family members were associated with inflammation in breast cancer. FF was associated with poor prognostic markers of breast cancer. Further studies are required to clarify the mechanisms underlying the association between the LOX family, FF and inflammation in breast cancer. PMID:29434955

Comparison of Two Anesthetic Methods for Intravitreal Ozurdex Injection

PubMed Central

Karabaş, V. Levent; Özkan, Berna; Koçer, Çiğdem Akdağ; Altıntaş, Özgül; Pirhan, Dilara; Yüksel, Nurşen

2015-01-01

Purpose. To determine whether subconjunctival lidocaine injection maintains additional anesthetic effect during intravitreal Ozurdex injection. Methods. 63 patients who were diagnosed as central or branch retinal vein occlusion and planned to receive Ozurdex injection for macular edema were prospectively included in the study. The patients were randomized into one of the two anesthetic groups. The first group received topical proparacaine drop and lidocaine applied pledget. The second group received subconjunctival lidocaine injection in addition to the anesthetics in group 1. Results. Mean pain score was 1.90 ± 2.39 in group 1 and 1.71 ± 2.09 in group 2 (p = 0.746). Mean subconjunctival hemorrhage grade was 1.67 ± 0.17 in group 1 and 0.90 ± 0.14 in group 2 (p = 0.001). There was no relationship between the amount of subconjunctival hemorrhage and pain score of the patients. Conclusions. There was no difference in pain scores between the two anesthetic methods. The addition of subconjunctival lidocaine injection offered no advantage in pain relief compared to lidocaine-applied pledgets. PMID:25949822

Comparison of two anesthetic methods for intravitreal ozurdex injection.

PubMed

Karabaş, V Levent; Özkan, Berna; Koçer, Çiğdem Akdağ; Altıntaş, Özgül; Pirhan, Dilara; Yüksel, Nurşen

2015-01-01

Purpose. To determine whether subconjunctival lidocaine injection maintains additional anesthetic effect during intravitreal Ozurdex injection. Methods. 63 patients who were diagnosed as central or branch retinal vein occlusion and planned to receive Ozurdex injection for macular edema were prospectively included in the study. The patients were randomized into one of the two anesthetic groups. The first group received topical proparacaine drop and lidocaine applied pledget. The second group received subconjunctival lidocaine injection in addition to the anesthetics in group 1. Results. Mean pain score was 1.90 ± 2.39 in group 1 and 1.71 ± 2.09 in group 2 (p = 0.746). Mean subconjunctival hemorrhage grade was 1.67 ± 0.17 in group 1 and 0.90 ± 0.14 in group 2 (p = 0.001). There was no relationship between the amount of subconjunctival hemorrhage and pain score of the patients. Conclusions. There was no difference in pain scores between the two anesthetic methods. The addition of subconjunctival lidocaine injection offered no advantage in pain relief compared to lidocaine-applied pledgets.

Out-of-Pocket Household Expenditures on Medical Injections in Cambodia.

PubMed

Ozawa, Sachiko; Yemeke, Tatenda T; Tawah, Alie F; Kulkarni, Vivek; Villar Uribe, Manuela

2018-02-09

Cambodia has one of the highest rates of overall medical injection usage worldwide. Therapeutic injections, which are often unnecessary, contribute to the spread of blood-borne diseases. This study describes injection practices and associated household expenditures in rural northwest Cambodia. We assessed care-seeking patterns of surveyed adult family members who sought healthcare in the previous 30 days, including location of care, medical injection use, and out-of-pocket household expenditures for treatment. A regression model was used to explore the impact of injection use on out-of-pocket household expenditures. Among 480 households sampled, 298 included members who had been sick within the previous 30 days; a total of 342 episodes of care had been sought. Private providers accounted for over 66% (n = 226) of all episodes of care, with public and informal providers accounting for 20% (n = 69) and 14% (n = 47), respectively. Injections were administered in over 120 (35%) episodes of care, with 81% of injections administered by private providers. Patients who received injections incurred total out-of-pocket household expenditures that were, on average, 126,590 Cambodian Riel (KHR) (US$31.65) higher than those who did not receive injections (p < 0.01), equivalent to nearly half of the country's total annual health expenditure per capita. Receiving injections and perceived severity of illness were significantly associated with higher out-of-pocket household expenditures. This study found high levels of medical injection use, particularly among private healthcare providers, which was significantly associated with high healthcare expenditures. Reducing the number of medical injections would not only reduce disease transmission risk but also contribute to reduced healthcare costs and greater financial protection.

Investigation of new dyes for chromovitrectomy: preclinical biocompatibility of trisodium, orangell and methyl violet.

PubMed

Badaro, Emmerson; Souza-Lima, Rodrigo A; Novais, Eduardo A; Maia, Mauricio; Hirai, Flávio; Meyer, Carsten H; Farah, Michel Eid; Rodrigues, Eduardo B

2015-01-01

To investigate the retinal toxicity by electroretinography (ERG), clinical examination and histology after intravitreal injection of biological stains in two concentrations: Trisodium (0.50 g/L and 1.00 g/L), Orangell (0.25 g/L and 1.00 g/L) and Methyl Violet (0.50 g/L and 1.00 g/L). Eighteen New-Zealand albinos rabbits were assigned in six groups (n = 3 in each group). The animals in group 1 received Trisodium in the dose of 0.50 g/L and group 2 received 1.00 g/L; Group 3 received Orangell in the dose of 0.25 g/L and group 4 received 1.00 g/L; Group 5 received Methyl Violet in the dose of 1.00 g/L and group 6 received 0.50 g/L. A volume of 0.05 mL of dye was injected in the right eyes, whereas the left eyes received the same volume of balanced salt solution (BSS) as control. ERG recordings and clinical examination were performed at baseline and seven days after intravitreal injection. The ERG responses at one week after injection were compared with baseline levels. A decrease in the post-injection amplitude of more than 50% was considered remarkable. After the 7-day follow-up, rabbits were euthanized and eye enucleated for light microscopy (LM) histological evaluation. At clinical examination by indirect ophthalmoscopy seven days after dye injection, all eyes were negative for cataract, hemorrhage, retinal detachment, and intraocular opacities. Amplitude analysis of maximum scotopic b-wave showed no significant reduction in either dye injected or control eyes. Neither dye nor BSS caused significant retinal alteration on LM at doses tested. Trisodium, Orangell and Methyl Violet can be applied in future studies in order to prove the capacity to stain preretinal tissues and vitreous without toxicity. The three dyes did not induce significant ERG amplitude reduction or LM alterations in this preliminary experimental research. Trisodium, Orangell and Methyl Violet may be potentially useful vital dyes for ocular surgery, and deserve further investigation.

Inhibition of CSF1 Receptor Improves the Anti-tumor Efficacy of Adoptive Cell Transfer Immunotherapy

PubMed Central

Tsui, Christopher; Xu, Jingying; Robert, Lídia; Wu, Lily; Graeber, Thomas; West, Brian L.; Bollag, Gideon; Ribas, Antoni

2013-01-01

Colony stimulating factor-1 (CSF-1) recruits tumor-infiltrating myeloid cells (TIMs) that suppress tumor immunity, including M2 macrophages and myeloid derived suppressor cells (MDSC). The CSF-1 receptor (CSF-1R) is a tyrosine kinase that is targetable by small molecule inhibitors such as PLX3397. In this study, we used a syngeneic mouse model of BRAFV600E-driven melanoma to evaluate the ability of PLX3397 to improve the efficacy of adoptive T-cell therapy (ACT). In this model, we found that combined treatment produced superior anti-tumor responses compared with single treatments. In mice receiving the combined treatment, a dramatic reduction of TIMs and a skewing of MHCIIlow to MHCIIhi macrophages was observed. Further, mice receiving the combined treatment exhibited an increase in tumor-infiltrating lymphocytes (TILs) and T cells, as revealed by real-time imaging in vivo. In support of these observations, TILs from these mice released higher levels of IFN-γ. In conclusion, CSF-1R blockade with PLX3397 improved the efficacy of ACT immunotherapy by inhibiting the intratumoral accumulation of immune suppressive macrophages. PMID:24247719

The syringe gap: an assessment of sterile syringe need and acquisition among syringe exchange program participants in New York City

PubMed Central

Heller, Daliah I; Paone, Denise; Siegler, Anne; Karpati, Adam

2009-01-01

Background Programmatic data from New York City syringe exchange programs suggest that many clients visit the programs infrequently and take few syringes per transaction, while separate survey data from individuals using these programs indicate that frequent injecting – at least daily – is common. Together, these data suggest a possible "syringe gap" between the number of injections performed by users and the number of syringes they are receiving from programs for those injections. Methods We surveyed a convenience sample of 478 injecting drug users in New York City at syringe exchange programs to determine whether program syringe coverage was adequate to support safer injecting practices in this group. Results Respondents reported injecting a median of 60 times per month, visiting the syringe exchange program a median of 4 times per month, and obtaining a median of 10 syringes per transaction; more than one in four reported reusing syringes. Fifty-four percent of participants reported receiving fewer syringes than their number of injections per month. Receiving an inadequate number of syringes was more frequently reported by younger and homeless injectors, and by those who reported public injecting in the past month. Conclusion To improve syringe coverage and reduce syringe sharing, programs should target younger and homeless drug users, adopt non-restrictive syringe uptake policies, and establish better relationships with law enforcement and homeless services. The potential for safe injecting facilities should be explored, to address the prevalence of public injecting and resolve the 'syringe gap' for injecting drug users. PMID:19138414

A randomized, double-blind, controlled study of ultrasound-guided corticosteroid injection into the joint of patients with inflammatory arthritis.

PubMed

Cunnington, Joanna; Marshall, Nicola; Hide, Geoff; Bracewell, Claire; Isaacs, John; Platt, Philip; Kane, David

2010-07-01

Most corticosteroid injections into the joint are guided by the clinical examination (CE), but up to 70% are inaccurately placed, which may contribute to an inadequate response. The aim of this study was to investigate whether ultrasound (US) guidance improves the accuracy and clinical outcome of joint injections as compared with CE guidance in patients with inflammatory arthritis. A total of 184 patients with inflammatory arthritis and an inflamed joint (shoulder, elbow, wrist, knee, or ankle) were randomized to receive either US-guided or CE-guided corticosteroid injections. Visual analog scales (VAS) for assessment of function, pain, and stiffness of the target joint, a modified Health Assessment Questionnaire, and the EuroQol 5-domain questionnaire were obtained at baseline and at 2 weeks and 6 weeks postinjection. The erythrocyte sedimentation rate and C-reactive protein level were measured at baseline and 2 weeks. Contrast injected with the steroid was used to assess the accuracy of the joint injection. One-third of CE-guided injections were inaccurate. US-guided injections performed by a trainee rheumatologist were more accurate than the CE-guided injections performed by more senior rheumatologists (83% versus 66%; P = 0.010). There was no significant difference in clinical outcome between the group receiving US-guided injections and the group receiving CE-guided injections. Accurate injections led to greater improvement in joint function, as determined by VAS scores, at 6 weeks, as compared with inaccurate injections (30.6 mm versus 21.2 mm; P = 0.030). Clinicians who used US guidance reliably assessed the accuracy of joint injection (P < 0.001), whereas those who used CE guidance did not (P = 0.29). US guidance significantly improves the accuracy of joint injection, allowing a trainee to rapidly achieve higher accuracy than more experienced rheumatologists. US guidance did not improve the short-term outcome of joint injection.

Effect of muscle injection site on preanaesthetic sedation in dogs.

PubMed

Self, I A; Hughes, J M L; Kenny, D A; Clutton, R E

2009-03-14

The demeanour of 122 dogs was assessed, and a mixture of 0.025 mg/kg acepromazine and 0.3 mg/kg morphine was injected intramuscularly into one of four randomly assigned muscle sites (cervical epaxial, triceps brachii, middle gluteal and quadriceps femoris) and the dogs' reactions to the injections were assessed. The development of sedation and the occurrence of side effects were assessed after 10, 20 and 30 minutes, and each dog's reaction to venous catheterisation was scored. All the dogs became similarly sedated after 30 minutes. The degree of sedation and the incidence of side effects were independent of the injection site, but the dogs receiving intragluteal injections had lower sedation scores after 10 minutes. The dogs' demeanour had no effect on their response to venous catheterisation. The dogs receiving an injection into the postural quadriceps and triceps muscles showed more marked reactions than those injected into the non-postural cervical epaxial and gluteal muscles.

Sodium Ferric Gluconate Injection

MedlinePlus

Sodium ferric gluconate injection is used to treat iron-deficiency anemia (a lower than normal number of ... are also receiving the medication epoetin (Epogen, Procrit). Sodium ferric gluconate injection is in a class of ...

Metaplastic thymoma with myasthenia gravis presumably caused by an accumulation of intratumoral immature T cells: a case report.

PubMed

Tajima, Shogo; Yanagiya, Masahiro; Sato, Masaaki; Nakajima, Jun; Fukayama, Masashi

2015-01-01

Among human neoplasms, thymomas are well known for their association with paraneoplastic autoimmune diseases such as myasthenia gravis. However, regarding rare metaplastic thymoma, only one case of an association with myasthenia gravis has been reported. Here, we present the second case of a 44-year-old woman with metaplastic thymoma associated with myasthenia gravis. In metaplastic thymoma, intratumoral terminal deoxynucleotidyl transferase-positive T-cells (immature T-cells) are generally scarce, while they were abundant in the present case. We believe that these immature T-cells could be related to the occurrence of myasthenia gravis.

Intratumoral heterogeneity and clonal evolution in blood malignancies and solid tumors.

PubMed

Varela, Ignacio; Menendez, Pablo; Sanjuan-Pla, Alejandra

2017-09-12

This meeting held at the University of Barcelona in March 2017, brought together scientists and clinicians worldwide to discuss current and future clinico-biological implications of intratumoral heterogeneity (ITH) and subclonal evolution in cancer diagnosis, patient stratification, and treatment resistance in diagnosis, treatment and follow-up. There was consensus that both longitudinal and tumor multi-region studies in matched samples are needed to better understand the dynamics of ITH. The contribution of the epigenome and microenvironment to ITH and subclone evolution remains understudied. It was recommended to combine computational, pathology and imaging tools to study the role of the microenvironment in subclone selection/evolution.

Colorectal cancer cells suppress CD4+ T cells immunity through canonical Wnt signaling.

PubMed

Sun, Xuan; Liu, Suoning; Wang, Daguang; Zhang, Yang; Li, Wei; Guo, Yuchen; Zhang, Hua; Suo, Jian

2017-02-28

Understanding how colorectal cancer escapes from immunosurveillance and immune attack is important for developing novel immunotherapies for colorectal cancer. In this study we evaluated the role of canonical Wnt signaling in the regulation of T cell function in a mouse colorectal cancer model. We found that colorectal cancer cells expressed abundant Wnt ligands, and intratumoral T cells expressed various Frizzled proteins. Meanwhile, both active β-catenin and total β-catenin were elevated in intratumoral T cells. In vitro study indicated that colorectal cancer cells suppressed IFN-γ expression and increased IL-17a expression in activated CD4+ T cells. However, the cytotoxic activity of CD8+ T cells was not altered by colorectal cancer cells. To further evaluate the importance of Wnt signaling for CD4+ T cell-mediated cancer immunity, β-catenin expression was enforced in CD4+ T cells using lentiviral transduction. In an adoptive transfer model, enforced expression of β-catenin in intratumoral CD4+ T cells increased IL-17a expression, enhanced proliferation and inhibited apoptosis of colorectal cancer cells. Taken together, our study disclosed a new mechanism by which colorectal cancer impairs T cell immunity.

Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity.

PubMed

Overacre-Delgoffe, Abigail E; Chikina, Maria; Dadey, Rebekah E; Yano, Hiroshi; Brunazzi, Erin A; Shayan, Gulidanna; Horne, William; Moskovitz, Jessica M; Kolls, Jay K; Sander, Cindy; Shuai, Yongli; Normolle, Daniel P; Kirkwood, John M; Ferris, Robert L; Delgoffe, Greg M; Bruno, Tullia C; Workman, Creg J; Vignali, Dario A A

2017-06-01

Regulatory T cells (T regs ) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral T reg stability and function but is dispensable for peripheral immune tolerance. T reg -restricted Nrp1 deletion results in profound tumor resistance due to T reg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of T reg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1 + T regs correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1 -/- ) and wild-type (Nrp1 +/+ ) T regs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1 -/- T regs produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type T regs , boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced T reg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting T reg fragility may be efficacious. Copyright © 2017 Elsevier Inc. All rights reserved.

Endogenous molecular network reveals two mechanisms of heterogeneity within gastric cancer.

PubMed

Li, Site; Zhu, Xiaomei; Liu, Bingya; Wang, Gaowei; Ao, Ping

2015-05-30

Intratumor heterogeneity is a common phenomenon and impedes cancer therapy and research. Gastric cancer (GC) cells have generally been classified into two heterogeneous cellular phenotypes, the gastric and intestinal types, yet the mechanisms of maintaining two phenotypes and controlling phenotypic transition are largely unknown. A qualitative systematic framework, the endogenous molecular network hypothesis, has recently been proposed to understand cancer genesis and progression. Here, a minimal network corresponding to such framework was found for GC and was quantified via a stochastic nonlinear dynamical system. We then further extended the framework to address the important question of intratumor heterogeneity quantitatively. The working network characterized main known features of normal gastric epithelial and GC cell phenotypes. Our results demonstrated that four positive feedback loops in the network are critical for GC cell phenotypes. Moreover, two mechanisms that contribute to GC cell heterogeneity were identified: particular positive feedback loops are responsible for the maintenance of intestinal and gastric phenotypes; GC cell progression routes that were revealed by the dynamical behaviors of individual key components are heterogeneous. In this work, we constructed an endogenous molecular network of GC that can be expanded in the future and would broaden the known mechanisms of intratumor heterogeneity.

Androgen biosynthesis in castration-resistant prostate cancer

PubMed Central

Penning, Trevor M

2014-01-01

Prostate cancer is the second leading cause of death in adult males in the USA. Recent advances have revealed that the fatal form of this cancer, known as castration-resistant prostate cancer (CRPC), remains hormonally driven despite castrate levels of circulating androgens. CRPC arises as the tumor undergoes adaptation to low levels of androgens by either synthesizing its own androgens (intratumoral androgens) or altering the androgen receptor (AR). This article reviews the major routes to testosterone and dihydrotestosterone synthesis in CRPC cells and examines the enzyme targets and progress in the development of isoform-specific inhibitors that could block intratumoral androgen biosynthesis. Because redundancy exists in these pathways, it is likely that inhibition of a single pathway will lead to upregulation of another so that drug resistance would be anticipated. Drugs that target multiple pathways or bifunctional agents that block intratumoral androgen biosynthesis and antagonize the AR offer the most promise. Optimal use of enzyme inhibitors or AR antagonists to ensure maximal benefits to CRPC patients will also require application of precision molecular medicine to determine whether a tumor in a particular patient will be responsive to these treatments either alone or in combination. PMID:24829267

Endogenous molecular network reveals two mechanisms of heterogeneity within gastric cancer

PubMed Central

Li, Site; Zhu, Xiaomei; Liu, Bingya; Wang, Gaowei; Ao, Ping

2015-01-01

Intratumor heterogeneity is a common phenomenon and impedes cancer therapy and research. Gastric cancer (GC) cells have generally been classified into two heterogeneous cellular phenotypes, the gastric and intestinal types, yet the mechanisms of maintaining two phenotypes and controlling phenotypic transition are largely unknown. A qualitative systematic framework, the endogenous molecular network hypothesis, has recently been proposed to understand cancer genesis and progression. Here, a minimal network corresponding to such framework was found for GC and was quantified via a stochastic nonlinear dynamical system. We then further extended the framework to address the important question of intratumor heterogeneity quantitatively. The working network characterized main known features of normal gastric epithelial and GC cell phenotypes. Our results demonstrated that four positive feedback loops in the network are critical for GC cell phenotypes. Moreover, two mechanisms that contribute to GC cell heterogeneity were identified: particular positive feedback loops are responsible for the maintenance of intestinal and gastric phenotypes; GC cell progression routes that were revealed by the dynamical behaviors of individual key components are heterogeneous. In this work, we constructed an endogenous molecular network of GC that can be expanded in the future and would broaden the known mechanisms of intratumor heterogeneity. PMID:25962957

Anesthetic efficacy of the supplemental intraosseous injection of 3% mepivacaine in irreversible pulpitis.

PubMed

Reisman, D; Reader, A; Nist, R; Beck, M; Weaver, J

1997-12-01

To determine the efficacy of a supplemental intraosseous injection of 3% mepivacaine in mandibular posterior teeth with irreversible pulpitis. Intraosseous injection pain, subjective heart rate increase, and pain ratings during endodontic treatment were also assessed. Forty-eight patients with irreversible pulpitis received conventional inferior alveolar nerve blocks. Electric pulp testing was used to determine pulpal anesthesia. Patients who were positive to the pulp testing, or negative to pulp testing but felt pain during endodontic treatment, received an intraosseous injection of 1.8 ml of 3% mepivacaine. A second intraosseous injection of 3% mepivacaine (1.8 ml) was given if the first injection was unsuccessful. Seventy-five percent of patients required an initial intraosseous injection because of failure to gain pulpal anesthesia. The inferior alveolar block was 25% successful; the first intraosseous injection increased success to 80%. A second intraosseous injection further increased success to 98%. These differences were significant (p < 0.05). Eight percent (4/48) of the initial intraosseous injections resulted in solution being expressed into the oral cavity: these were considered technique failures. For mandibular posterior teeth with irreversible pulpitis, a supplemental intraosseous injection of 3% mepivacaine increased anesthetic success. A second intraosseous injection, when necessary, further improved success.

Lidocaine Injection in the Intramuscular Innervation Zone Can Effectively Treat Chronic Neck Pain Caused by MTrPs in the Trapezius Muscle.

PubMed

Xie, Peng; Qin, Bangyong; Yang, Fangjiu; Yu, Tian; Yu, Jin; Wang, Jiang; Zheng, Hong

2015-01-01

An increasing number of people suffer from neck pain due to life style and prolonged use of computers. Research has revealed that myofascial trigger points (MTrPs) and the intramuscular innervation zone (IZ) are involved in neck pain. MTrPs are induced mainly by IZ dysfunction of the affected skeletal muscle and the 2 do not overlap in location. The question is whether injection treatment in MTrPs or in the IZ is more effective to relieve MTrPs-associated pains. The precise location and body-surface map of the intramuscular IZ in the trapezius muscle and a clinical injection study in the IZ may provide a useful answer to the question. This study aimed to investigate the efficacy of lidocaine injection in the intramuscular IZ for the treatment of chronic neck pain caused by MTrPs in the trapezius muscle. Prospective observational study, approved by the local research ethics. University hospital, departments of Anesthesiology and Anatomy. First, for the determination of IZ distribution and body-surface mapping, a modified intramuscular Sihler's neural staining technique was applied to elucidate nerve distribution patterns of the trapezius muscle. Then, 120 patients with myofascial pain syndrome (MPS) of the trapezius muscle were randomly divided into 5 groups for analysis. Group 1 (n = 24) received injections of saline (0.9% NaCl) at the MTrPs. Group 2 (n = 24) received injections of 0.5% lidocaine at the MTrPs. Group 3 (n = 24) received injections of saline (0.9% NaCl) at the mid-upper trapezius (Point E). Group 4 (n = 24) received injections of 0.5% lidocaine at Point E. Group 5 (n = 24) received a combined injection of 0.5% lidocaine treatment at both Point E and the lower trapezius (Point F). The injection dose was 4 mL at each injection site. All patients received injections once a week for 4 weeks. The visual analogue scale (VAS) and the frequency of painful days per month (FPD) were obtained before treatment and at 2, 4, and 6 months after treatment. The intramuscular terminal nerve branches presented a "dendritic" distribution in the trapezius muscle and were connected with each other to form an S-shaped IZ belt in the middle of the muscle belly. Compared with the MTrP injection group, lidocaine-injection therapy in the IZ significantly reduced the degree and frequency of neck pain in patients at 6 months after treatment, especially the combined lidocaine-injection therapy in the IZ of both the mid-upper trapezius and the lower trapezius are more effective (all P < 0.05). This study confirms that lidocaine-injection therapy in the IZ significantly reduces the degree and frequency of neck pain in patients at 6 months after treatment. The combined lidocaine-injection therapy in the IZ of both the mid-upper trapezius and the lower trapezius is more effective. In addition, this study establishes a clear distribution map of intramuscular nerves that will be conducive to the future use of chemical blockers and electrical stimulation in the nervous system in treating MPS of the trapezius muscle. The small number of patients and the short duration of follow-up.

123I-labeled HIV-1 tat peptide radioimmunoconjugates are imported into the nucleus of human breast cancer cells and functionally interact in vitro and in vivo with the cyclin-dependent kinase inhibitor, p21(WAF-1/Cip-1).

PubMed

Hu, Meiduo; Chen, Paul; Wang, Judy; Scollard, Deborah A; Vallis, Katherine A; Reilly, Raymond M

2007-03-01

To evaluate the internalization and nuclear translocation of (123)I-tat-peptide radioimmunoconjugates in MDA-MB-468 breast cancer cells and their ability to interact with the cyclin-dependent kinase inhibitor, p21(WAF-1/Cip-1). Peptides [GRKKRRQRRRPPQGYGC] harboring the nuclear-localizing sequence from HIV tat domain were conjugated to anti-p21(WAF-1/Cip-1) antibodies. Immunoreactivity was assessed by Western blot using lysate from MDA-MB-468 cells exposed to EGF to induce p21(WAF-1/Cip-1). Internalization and nuclear translocation were measured. The ability of tat-anti-p21(WAF-1/Cip-1) to block G(1)-S phase arrest in MDA-MB-468 cells caused by EGF-induced p21(WAF-1/Cip-1) was evaluated. Tumor and normal tissue uptake were determined at 48 h p.i. in athymic mice implanted s.c. with MDA-MB-468 xenografts injected intratumorally with EGF. There was 13.4+/-0.2% of radioactivity internalized by MDA-MB-468 cells incubated with (123)I-tat-anti-p21(WAF-1/Cip-1) and 34.6+/-3.1% imported into the nucleus. Tat-anti-p21(WAF-1/Cip-1)(8 muM) decreased the proportion of EGF-treated cells in G(1) phase from 81.9+/-0.7% to 46.1+/-0.7% (p<0.001), almost restoring the G(1) phase fraction to that of unexposed cells (25.8+/-0.2%). Non-specific tat-mouse IgG did not block EGF-induced G(1)-S phase arrest. Tumor uptake of radioactivity was higher in mice injected with EGF to induce p21(WAF-1/Cip-1) than in mice not receiving EGF (3.1+/-0.4% versus 1.8+/-0.2% ID/g; p=0.04). Western blot analysis of tumors revealed a threefold increase in the p21(WAF-1/Cip-1)/beta-actin ratio. We conclude that intracellular and nuclear epitopes in cancer cells can be functionally targeted with tat-radioimmunoconjugates to exploit many more epitopes for imaging and radiotherapeutic applications than have previously been accessible.

Study of Methylene Blue Ototoxicity in the Guinea Pig.

PubMed

Belhassen, Sarah; Alzahrani, Musaed; Nader, Marc-Elie; Gaboury, Louis; Saliba, Issam

2017-11-01

Methylene blue is widely used in the medical field, especially as a blue dye for staining. It is also used as a photosensitizing agent in antimicrobial photodynamic therapy, which once photoactivated is effective for the eradication of several multi-resistant bacteria. The objective of this study was to investigate the ototoxic potential of methylene blue and precise its use in otology. It was a prospective animal study performed on guinea pigs in our tertiary medical center. We divided the animals into two groups: an experimental group and a control group, who underwent a series of three intratympanic (IT) injections. In the control group (n = 10), they received injections of gentamicin in one ear (positive control) and normal saline in the contralateral ear (negative control). The experimental group (n = 10) received injections of methylene blue in one ear, compared to injections of normal saline in the contralateral ear. We conducted auditory-evoked brainstem response (ABR) before and 1 week after the injection series. Once this is completed, the cochlea was dissected and caspase-3 was analyzed by immunohistochemistry. The mean difference of hearing loss in the methylene blue group compared to normal saline was 1.50 dB, and it was not shown to be statistically significant (P = 0.688). For the positive control group, which received IT injections of gentamicin, the mean threshold of hearing loss difference for all the frequencies combined was 66.25 dB (P < 0.001). Furthermore, uptake of caspase-3 by immunohistochemistry (apoptotic marker) was negative in our group, which received injections of methylene blue. In light of our results, IT injections of methylene blue did not demonstrate an ototoxic potential. We recommend further studies to precise its use in the otologic field.

Study of Methylene Blue Ototoxicity in the Guinea Pig

PubMed Central

Belhassen, Sarah; Alzahrani, Musaed; Nader, Marc-Elie; Gaboury, Louis; Saliba, Issam

2017-01-01

Background Methylene blue is widely used in the medical field, especially as a blue dye for staining. It is also used as a photosensitizing agent in antimicrobial photodynamic therapy, which once photoactivated is effective for the eradication of several multi-resistant bacteria. The objective of this study was to investigate the ototoxic potential of methylene blue and precise its use in otology. Methods It was a prospective animal study performed on guinea pigs in our tertiary medical center. We divided the animals into two groups: an experimental group and a control group, who underwent a series of three intratympanic (IT) injections. In the control group (n = 10), they received injections of gentamicin in one ear (positive control) and normal saline in the contralateral ear (negative control). The experimental group (n = 10) received injections of methylene blue in one ear, compared to injections of normal saline in the contralateral ear. We conducted auditory-evoked brainstem response (ABR) before and 1 week after the injection series. Once this is completed, the cochlea was dissected and caspase-3 was analyzed by immunohistochemistry. Results The mean difference of hearing loss in the methylene blue group compared to normal saline was 1.50 dB, and it was not shown to be statistically significant (P = 0.688). For the positive control group, which received IT injections of gentamicin, the mean threshold of hearing loss difference for all the frequencies combined was 66.25 dB (P < 0.001). Furthermore, uptake of caspase-3 by immunohistochemistry (apoptotic marker) was negative in our group, which received injections of methylene blue. Conclusion In light of our results, IT injections of methylene blue did not demonstrate an ototoxic potential. We recommend further studies to precise its use in the otologic field. PMID:29038666

Effect of breeding protocols and reproductive tract score on reproductive performance of dairy heifers and economic outcome of breeding programs.

PubMed

Stevenson, J L; Rodrigues, J A; Braga, F A; Bitente, S; Dalton, J C; Santos, J E P; Chebel, R C

2008-09-01

The objectives of this study were to evaluate the effect of reproductive protocols and reproductive tract score on reproductive performance of dairy heifers and economic outcomes of breeding programs. Holstein heifers (n = 534), 13 +/- 1 mo of age, were randomly assigned to 1 of 4 reproductive protocols. On the day of enrollment (d 0), heifers were palpated per rectum and received a score according to the maturity of their reproductive tract (1 = prepubertal; 2 = peripubertal; and 3 = puber-tal). Estrous detection-control heifers (CON, n = 146) received no treatment and were inseminated on detection of estrus for 28 d. Prostaglandin F(2alpha)-treated heifers (PGED, n = 137) received 1 injection of PGF(2alpha) on d 0 and were inseminated on detection of estrus; heifers not in-seminated by d 14 received a second injection of PGF(2alpha) and were observed for estrus and artificial insemination (AI) for an additional 14 d. Heifers enrolled in the estrous detection-timed AI (EDTAI, n = 140) treatment received a controlled internal drug-release (CIDR) insert on d 0, and 7 d later, the CIDR was removed and all heifers received an injection of PGF(2alpha), heifers received AI on detection of estrus, and those not inseminated by 72 h after PGF(2alpha) received an injection of GnRH concurrent with AI. Heifers in the GnRH-timed AI (GTAI, n = 111) treatment received 1 injection of GnRH on d 0, on d 6 heifers received a CIDR insert and injections of GnRH and PGF(2alpha), on d 13 the CIDR was removed and heifers received an injection of PGF(2alpha), and 48 h later all heifers received an injection of GnRH and AI. Pregnancy was diagnosed at 32 +/- 3 and 62 +/- 3 d after AI. Cost of reproductive protocols and their economic outcomes were calculated for a 28 d period beginning at enrollment. Heifers in the PGED treatment were inseminated at a faster rate than CON heifers. A smaller proportion of prepubertal and peripubertal heifers were inseminated within 14 d of enrollment compared with pubertal heifers. Pregnancy per AI of CON and PGED heifers was greater compared with EDTAI and GTAI heifers. Proportion of GTAI heifers pregnant at the end of the 28-d breeding program was or tended to be smaller compared with PGED and CON heifers, respectively. Heifers in the CON and PGED treatments had the smallest cost per pregnancy followed by heifers in the EDTAI and GTAI treatments, respectively. When different scenarios were evaluated, however, the mean cost per pregnancy was smallest for PGED heifers. Cost per pregnancy generated was greatest for prepubertal heifers, whereas pubertal heifers had the smallest cost per pregnancy generated. Treatment of dairy heifers with PGF(2alpha) every 14 d until insemination and pregnancy results in the best economic outcomes, and screening heifers according to RTS may prove beneficial to identify heifers that may not be pubertal and would have compromised reproductive and economic performance in a breeding program.

Fifteen-second skin icing using a frozen gel pack is effective for reducing goserelin injection pain.

PubMed

Naya, Yoshio; Hagiwara, Nobuhisa; Takeuchi, Ichiro; Mori, Masaru; Inagaki, Akinori; Nakanouchi, Tsuneyuki; Mikami, Kazuya

2014-01-01

The efficacy of skin icing to reduce the pain of goserelin injection has been reported. We investigated the optimal icing time with a frozen gel pack and its effectiveness. Abdominal skin temperatures of 49 healthy volunteers were measured after application of the frozen gel pack for 10, 15 and 30 s, and it was decided that a 15-second icing was adequate. For 55 consecutive patients who received goserelin (10.8 mg) injection, pain was evaluated employing a visual analog scale (VAS). The first injection was administered routinely. A second injection was administered after skin icing in 27 of 55 patients who wanted to try icing. At the time of the third injection, all patient decided whether they were to receive icing or the routine method. After icing, VAS scores decreased in 20 of 27 patients. At the third injection, 18 patients requested icing. When a patient complains of injection pain, the icing method should be considered for pain reduction. 2014 S. Karger AG, Basel.

Levoleucovorin Injection

MedlinePlus

... injection is used to prevent harmful effects of methotrexate (Rheumatrex, Trexall) when methotrexate is used to to treat certain types of ... people who have accidentally received an overdose of methotrexate or similar medications. Levoleucovorin injection is in a ...

Needle-less local anesthesia: clinical evaluation of the effectiveness of the jet anesthesia Injex in local anesthesia in dentistry.

PubMed

Dabarakis, Nikolaos N; Alexander, Veis; Tsirlis, Anastasios T; Parissis, Nikolaos A; Nikolaos, Maroufidis

2007-01-01

To clinically evaluate the jet injection Injex (Rösch AG Medizintechnik) using 2 different anesthetic solutions, and to compare the jet injection and the standard needle injection techniques. Of the 32 patients in the study, 10 received mepivacaine 3% anesthetic solution by means of the jet injection technique, while the remaining 22 patients received lidocaine 2% with epinephrine 1:80,000 by the same method. The 14 patients in whom pulp anesthesia was achieved were selected for an additional evaluation of the pulp reaction using standard needle injection anesthesia. The differences between the 2 compounds with Injex were statistically evaluated by means of independent-samples t test analysis. The differences between subgroups receiving both jet injection and needle injection anesthesia were evaluated by means of paired t test analysis. The administration of mepivacaine 3% using Injex did not achieve pulp anesthesia in any of the 10 patients, although the soft tissue anesthesia was successful. The administration of lidocaine with epinephrine using Injex resulted in pulp anesthesia in only 14 patients; soft tissue anesthesia was observed in all patients of this group. There was no statistically significant difference between Injex and the needle injection technique in onset of anesthesia. However, the duration of anesthesia was significantly longer for the needle infiltration group than for the Injex injection group. The anesthetic solution should be combined with a vasoconstriction agent when the Injex technique is implemented.

Functional imaging to monitor vascular and metabolic response in canine head and neck tumors during fractionated radiotherapy.

PubMed

Rødal, Jan; Rusten, Espen; Søvik, Åste; Skogmo, Hege Kippenes; Malinen, Eirik

2013-10-01

Radiotherapy causes alterations in tumor biology, and non-invasive early assessment of such alterations may become useful for identifying treatment resistant disease. The purpose of the current work is to assess changes in vascular and metabolic features derived from functional imaging of canine head and neck tumors during fractionated radiotherapy. Material and methods. Three dogs with spontaneous head and neck tumors received intensity-modulated radiotherapy (IMRT). Contrast-enhanced cone beam computed tomography (CE-CBCT) at the treatment unit was performed at five treatment fractions. Dynamic (18)FDG-PET (D-PET) was performed prior to the start of radiotherapy, at mid-treatment and at 3-12 weeks after the completion of treatment. Tumor contrast enhancement in the CE-CBCT images was used as a surrogate for tumor vasculature. Vascular and metabolic tumor parameters were further obtained from the D-PET images. Changes in these tumor parameters were assessed, with emphasis on intra-tumoral distributions. Results. For all three patients, metabolic imaging parameters obtained from D-PET decreased from the pre- to the inter-therapy session. Correspondingly, for two of three patients, vascular imaging parameters obtained from both CE-CBCT and D-PET increased. Only one of the tumors showed a clear metabolic response after therapy. No systematic changes in the intra-tumor heterogeneity in the imaging parameters were found. Conclusion. Changes in vascular and metabolic parameters could be detected by the current functional imaging methods. Vascular tumor features from CE-CBCT and D-PET corresponded well. CE-CBCT is a potential method for easy response assessment when the patient is at the treatment unit.

5-Aminolevulinic Acid Induced Fluorescence Is a Powerful Intraoperative Marker for Precise Histopathological Grading of Gliomas with Non-Significant Contrast-Enhancement

PubMed Central

Widhalm, Georg; Kiesel, Barbara; Woehrer, Adelheid; Traub-Weidinger, Tatjana; Preusser, Matthias; Marosi, Christine; Prayer, Daniela; Hainfellner, Johannes A.; Knosp, Engelbert; Wolfsberger, Stefan

2013-01-01

Background Intraoperative identification of anaplastic foci in diffusely infiltrating gliomas (DIG) with non-significant contrast-enhancement on MRI is indispensible to avoid histopathological undergrading and subsequent treatment failure. Recently, we found that 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence can visualize areas with increased proliferative and metabolic activity in such gliomas intraoperatively. As treatment of DIG is predominantely based on histopathological World Health Organisation (WHO) parameters, we analyzed whether PpIX fluorescence can detect anaplastic foci according to these criteria. Methods We prospectively included DIG patients with non-significant contrast-enhancement that received 5-ALA prior to resection. Intraoperatively, multiple samples from PpIX positive and negative intratumoral areas were collected using a modified neurosurgical microscope. In all samples, histopathological WHO criteria and proliferation rate were assessed and correlated to the PpIX fluorescence status. Results A total of 215 tumor specimens were collected in 59 patients. Of 26 WHO grade III gliomas, 23 cases (85%) showed focal PpIX fluorescence, whereas 29 (91%) of 33 WHO grade II gliomas were PpIX negative. In intratumoral areas with focal PpIX fluorescence, mitotic rate, cell density, nuclear pleomorphism, and proliferation rate were significantly higher than in non-fluorescing areas. The positive predictive value of focal PpIX fluorescence for WHO grade III histology was 85%. Conclusions Our study indicates that 5-ALA induced PpIX fluorescence is a powerful marker for intraoperative identification of anaplastic foci according to the histopathological WHO criteria in DIG with non-significant contrast-enhancement. Therefore, application of 5-ALA optimizes tissue sampling for precise histopathological diagnosis independent of brain-shift. PMID:24204718

Development and validation of a novel predictive scoring model for microvascular invasion in patients with hepatocellular carcinoma.

PubMed

Zhao, Hui; Hua, Ye; Dai, Tu; He, Jian; Tang, Min; Fu, Xu; Mao, Liang; Jin, Huihan; Qiu, Yudong

2017-03-01

Microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) cannot be accurately predicted preoperatively. This study aimed to establish a predictive scoring model of MVI in solitary HCC patients without macroscopic vascular invasion. A total of 309 consecutive HCC patients who underwent curative hepatectomy were divided into the derivation (n=206) and validation cohort (n=103). A predictive scoring model of MVI was established according to the valuable predictors in the derivation cohort based on multivariate logistic regression analysis. The performance of the predictive model was evaluated in the derivation and validation cohorts. Preoperative imaging features on CECT, such as intratumoral arteries, non-nodular type of HCC and absence of radiological tumor capsule were independent predictors for MVI. The predictive scoring model was established according to the β coefficients of the 3 predictors. Area under receiver operating characteristic (AUROC) of the predictive scoring model was 0.872 (95% CI, 0.817-0.928) and 0.856 (95% CI, 0.771-0.940) in the derivation and validation cohorts. The positive and negative predictive values were 76.5% and 88.0% in the derivation cohort and 74.4% and 88.3% in the validation cohort. The performance of the model was similar between the patients with tumor size ≤5cm and >5cm in AUROC (P=0.910). The predictive scoring model based on intratumoral arteries, non-nodular type of HCC, and absence of the radiological tumor capsule on preoperative CECT is of great value in the prediction of MVI regardless of tumor size. Copyright © 2017 Elsevier B.V. All rights reserved.

Mechanism and Natural Course of Tumor Involution in Hepatocellular Carcinoma Following Transarterial Ethanol Ablation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Simon Chun Ho, E-mail: simonyu@cuhk.edu.hk; Lau, Tiffany Wing Wa; Tang, Peggy

PurposeTo evaluate the microvascular distribution of lipiodol–ethanol, the histological change of the tumor lesion, and the status of tumor involution over time in hepatocellular carcinoma (HCC) following transarterial ethanol ablation (TEA), in lesions that showed CT evidence of complete tumor response.Materials and methodsPatients with unresectable HCC were treated (183 patients, 242 lesions) with TEA using lipiodol–ethanol mixture (LEM) mixed in 2:1 ratio by volume and followed with CT at 3-month intervals for a median of 14.1 months. Liver tumors (n = 131) that showed CT evidence of complete tumor response, defined as the absence of any enhancing tumor throughout the follow-up period, weremore » included. The surgical specimens of five patients who subsequently received partial hepatectomy were available for histological assessment. The microvascular distribution of LEM and the degree of tumor necrosis were analyzed. Tumor involution over time was assessed with CT in lesions that showed complete response.ResultsLipid stain revealed lipiodol infiltration throughout arterioles, intratumoral sinusoidal spaces, tumor capsule, and peritumoral portal venules. Complete tumor necrosis (100 %) occurred in all 5 surgical specimens. The median (IQR) percentage tumor volume compared to baseline volumes at 12, 36, and 60 months was 32 % (23.5–52.5 %), 22 % (8–31 %), and 13.5 % (6–21.5 %), respectively.ConclusionIntrahepatic HCC lesion that showed CT evidence of complete tumor response following TEA is associated with histological evidence of LEM infiltration throughout the intratumoral and peritumoral vasculature and complete tumor necrosis, as well as sustained reduction in tumor volume over time.« less

Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases.

PubMed

Ng, Charlotte K Y; Bidard, Francois-Clement; Piscuoglio, Salvatore; Geyer, Felipe C; Lim, Raymond S; de Bruijn, Ino; Shen, Ronglai; Pareja, Fresia; Berman, Samuel H; Wang, Lu; Pierga, Jean-Yves; Vincent-Salomon, Anne; Viale, Agnes; Norton, Larry; Sigal, Brigitte; Weigelt, Britta; Cottu, Paul; Reis-Filho, Jorge S

2017-08-01

Purpose: Paired primary breast cancers and metachronous metastases after adjuvant treatment are reported to differ in their clonal composition and genetic alterations, but it is unclear whether these differences stem from the selective pressures of the metastatic process, the systemic therapies, or both. We sought to define the repertoire of genetic alterations in breast cancer patients with de novo metastatic disease who had not received local or systemic therapy. Experimental Design: Up to two anatomically distinct core biopsies of primary breast cancers and synchronous distant metastases from nine patients who presented with metastatic disease were subjected to high-depth whole-exome sequencing. Mutations, copy number alterations and their cancer cell fractions, and mutation signatures were defined using state-of-the-art bioinformatics methods. All mutations identified were validated with orthogonal methods. Results: Genomic differences were observed between primary and metastatic deposits, with a median of 60% (range 6%-95%) of shared somatic mutations. Although mutations in known driver genes including TP53, PIK3CA , and GATA3 were preferentially clonal in both sites, primary breast cancers and their synchronous metastases displayed spatial intratumor heterogeneity. Likely pathogenic mutations affecting epithelial-to-mesenchymal transition-related genes, including SMAD4, TCF7L2 , and TCF4 ( ITF2 ), were found to be restricted to or enriched in the metastatic lesions. Mutational signatures of trunk mutations differed from those of mutations enriched in the primary tumor or the metastasis in six cases. Conclusions: Synchronous primary breast cancers and metastases differ in their repertoire of somatic genetic alterations even in the absence of systemic therapy. Mutational signature shifts might contribute to spatial intratumor genetic heterogeneity. Clin Cancer Res; 23(15); 4402-15. ©2017 AACR . ©2017 American Association for Cancer Research.

5-Aminolevulinic acid induced fluorescence is a powerful intraoperative marker for precise histopathological grading of gliomas with non-significant contrast-enhancement.

PubMed

Widhalm, Georg; Kiesel, Barbara; Woehrer, Adelheid; Traub-Weidinger, Tatjana; Preusser, Matthias; Marosi, Christine; Prayer, Daniela; Hainfellner, Johannes A; Knosp, Engelbert; Wolfsberger, Stefan

2013-01-01

Intraoperative identification of anaplastic foci in diffusely infiltrating gliomas (DIG) with non-significant contrast-enhancement on MRI is indispensible to avoid histopathological undergrading and subsequent treatment failure. Recently, we found that 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence can visualize areas with increased proliferative and metabolic activity in such gliomas intraoperatively. As treatment of DIG is predominantely based on histopathological World Health Organisation (WHO) parameters, we analyzed whether PpIX fluorescence can detect anaplastic foci according to these criteria. We prospectively included DIG patients with non-significant contrast-enhancement that received 5-ALA prior to resection. Intraoperatively, multiple samples from PpIX positive and negative intratumoral areas were collected using a modified neurosurgical microscope. In all samples, histopathological WHO criteria and proliferation rate were assessed and correlated to the PpIX fluorescence status. A total of 215 tumor specimens were collected in 59 patients. Of 26 WHO grade III gliomas, 23 cases (85%) showed focal PpIX fluorescence, whereas 29 (91%) of 33 WHO grade II gliomas were PpIX negative. In intratumoral areas with focal PpIX fluorescence, mitotic rate, cell density, nuclear pleomorphism, and proliferation rate were significantly higher than in non-fluorescing areas. The positive predictive value of focal PpIX fluorescence for WHO grade III histology was 85%. Our study indicates that 5-ALA induced PpIX fluorescence is a powerful marker for intraoperative identification of anaplastic foci according to the histopathological WHO criteria in DIG with non-significant contrast-enhancement. Therefore, application of 5-ALA optimizes tissue sampling for precise histopathological diagnosis independent of brain-shift.

Canine (Pet Dog) Tumor Microsurgery and Intratumoral Concentration and Safety of Metronomic Chlorambucil for Spontaneous Glioma: A Phase I Clinical Trial.

PubMed

Bentley, R Timothy; Thomovsky, Stephanie A; Miller, Margaret A; Knapp, Deborah W; Cohen-Gadol, Aaron A

2018-06-04

Metronomic (daily low-dose) chlorambucil requires further study before use in human patients with glioma. The aim of this study was to investigate distribution and safety of metronomic chlorambucil in naturally occurring canine glioma. Eight client-owned (pet) dogs with newly diagnosed spontaneous glioma were prospectively enrolled. Chlorambucil was administered preoperatively at 4 mg/m 2 every 24 hours for ≥3 days and continued postoperatively until death or dose-limiting adverse events. Chlorambucil concentrations in the surgical glioma specimen, cerebrospinal fluid, and serum were analyzed. Dogs additionally received lomustine postoperatively. Dogs were monitored for seizures, myoclonus, cytopenias, and tumor recurrence. Complete microsurgical resection was achieved in 7 oligodendrogliomas and 1 astrocytoma (6 high grade, 2 low grade). Median surgical glioma specimen chlorambucil concentration was 0.52 ng/g (range, 0-2.62 ng/g), or 37% (range, 0%-178%) of serum concentration. Median cerebrospinal fluid concentration was 0.1 ng/mL (range, 0-0.3 ng/mL). Chlorambucil was not associated with increase in seizure activity. Six dogs displayed prolonged seizure-free intervals. There was no myoclonus. Three dogs developed asymptomatic thrombocytopenia after 8-12 months of chlorambucil. Median progression-free survival was 253 days (range, 63-860 days). Median overall survival was 257 days (range, 64-860 days). The presence of intratumoral chlorambucil indicated an altered blood-brain barrier that varied from case to case. Despite sporadic previous reports of neurotoxicity, prolonged seizure-free intervals supported a high safety margin at this dose in this species. Metronomic chlorambucil was well tolerated. Spontaneous canine glioma offers a robust preclinical model. Copyright © 2018 Elsevier Inc. All rights reserved.

Fractal analysis of the susceptibility weighted imaging patterns in malignant brain tumors during antiangiogenic treatment: technical report on four cases serially imaged by 7 T magnetic resonance during a period of four weeks.

PubMed

Di Ieva, Antonio; Matula, Christian; Grizzi, Fabio; Grabner, Günther; Trattnig, Siegfried; Tschabitscher, Manfred

2012-01-01

The need for new and objective indexes for the neuroradiologic follow-up of brain tumors and for monitoring the effects of antiangiogenic strategies in vivo led us to perform a technical study on four patients who received computerized analysis of tumor-associated vasculature with ultra-high-field (7 T) magnetic resonance imaging (MRI). The image analysis involved the application of susceptibility weighted imaging (SWI) to evaluate vascular structures. Four patients affected by recurrent malignant brain tumors were enrolled in the present study. After the first 7-T SWI MRI procedure, the patients underwent antiangiogenic treatment with bevacizumab. The imaging was repeated every 2 weeks for a period of 4 weeks. The SWI patterns visualized in the three MRI temporal sequences were analyzed by means of a computer-aided fractal-based method to objectively quantify their geometric complexity. In two clinically deteriorating patients we found an increase of the geometric complexity of the space-filling properties of the SWI patterns over time despite the antiangiogenic treatment. In one patient, who showed improvement with the therapy, the fractal dimension of the intratumoral structure decreased, whereas in the fourth patient, no differences were found. The qualitative changes of the intratumoral SWI patterns during a period of 4 weeks were quantified with the fractal dimension. Because SWI patterns are also related to the presence of vascular structures, the quantification of their space-filling properties with fractal dimension seemed to be a valid tool for the in vivo neuroradiologic follow-up of brain tumors. Copyright © 2012 Elsevier Inc. All rights reserved.

Clinical Outcomes of Intravitreal Preservative-Free Triamcinolone Preparation (Triesence®) for Cystoid Macular Oedema and Inflammation in Patients with Uveitis.

PubMed

Steeples, Laura R; Anand, Nitin; Moraji, Jiten; Jones, Nicholas P

2017-03-20

To assess the outcomes of intravitreal benzyl alcohol-free triamcinolone acetonide suspension in uveitis-related macular oedema. Single-center retrospective cohort study of 66 injections to 44 eyes of 40 patients. Uveitis diagnosis, systemic and local therapy, intraocular pressure (IOP), central retinal thickness (CRT), number of injections, time to re-injection and side-effects were noted during 6-months minimum follow-up. Sixty eight percent of eyes received a single injection. 18% required 2 injections, and 13% received ≥3 injections with mean time to second and third injections of 25.5 and 52.7 weeks, respectively. 90% of injections were unilateral. Mean CRT reduced, and by 12-weeks visual acuity improvement >0.3logMar was achieved in 46%. Cataract progression (47%) and IOP>21 mmHg (45%) were the commonest adverse events. Preservative-free triamcinolone is an additional option for uveitis-related macular oedema, particularly in unilateral cases, with favorable CRT and visual outcomes. Repeat injections may be necessary, and the period of efficacy varies between eyes.

Orthotopic glioblastoma stem-like cell xenograft model in mice to evaluate intra-arterial delivery of bevacizumab: from bedside to bench.

PubMed

Burkhardt, Jan-Karl; Hofstetter, Christoph P; Santillan, Alejandro; Shin, Benjamin J; Foley, Conor P; Ballon, Douglas J; Pierre Gobin, Y; Boockvar, John A

2012-11-01

Bevacizumab (BV), a humanized monocolonal antibody directed against vascular endothelial growth factor (VEGF), is a standard intravenous (IV) treatment for recurrent glioblastoma multiforme (GBM), that has been introduced recently as an intra-arterial (IA) treatment modality in humans. Since preclinical models have not been reported, we sought to develop a tumor stem cell (TSC) xenograft model to investigate IA BV delivery in vivo. Firefly luciferase transduced patient TSC were injected into the cortex of 35 nude mice. Tumor growth was monitored weekly using bioluminescence imaging. Mice were treated with either intraperitoneal (IP) or IA BV, with or without blood-brain barrier disruption (BBBD), or with IP saline injection (controls). Tumor tissue was analyzed using immunohistochemistry and western blot techniques. Tumor formation occurred in 31 of 35 (89%) mice with a significant signal increase over time (p=0.018). Post mortem histology revealed an infiltrative growth of TSC xenografts in a similar pattern compared to the primary human GBM. Tumor tissue analyzed at 24 hours after treatment revealed that IA BV treatment with BBBD led to a significantly higher intratumoral BV concentration compared to IA BV alone, IP BV or controls (p<0.05). Thus, we have developed a TSC-based xenograft mouse model that allows us to study IA chemotherapy. However, further studies are needed to analyze the treatment effects after IA BV to assess tumor progression and overall animal survival. Copyright © 2012 Elsevier Ltd. All rights reserved.

Therapeutic potential of targeting microRNA-10b in established intracranial glioblastoma: first steps toward the clinic.

PubMed

Teplyuk, Nadiya M; Uhlmann, Erik J; Gabriely, Galina; Volfovsky, Natalia; Wang, Yang; Teng, Jian; Karmali, Priya; Marcusson, Eric; Peter, Merlene; Mohan, Athul; Kraytsberg, Yevgenya; Cialic, Ron; Chiocca, E Antonio; Godlewski, Jakub; Tannous, Bakhos; Krichevsky, Anna M

2016-03-01

MicroRNA-10b (miR-10b) is a unique oncogenic miRNA that is highly expressed in all GBM subtypes, while absent in normal neuroglial cells of the brain. miR-10b inhibition strongly impairs proliferation and survival of cultured glioma cells, including glioma-initiating stem-like cells (GSC). Although several miR-10b targets have been identified previously, the common mechanism conferring the miR-10b-sustained viability of GSC is unknown. Here, we demonstrate that in heterogeneous GSC, miR-10b regulates cell cycle and alternative splicing, often through the non-canonical targeting via 5'UTRs of its target genes, including MBNL1-3, SART3, and RSRC1. We have further assessed the inhibition of miR-10b in intracranial human GSC-derived xenograft and murine GL261 allograft models in athymic and immunocompetent mice. Three delivery routes for the miR-10b antisense oligonucleotide inhibitors (ASO), direct intratumoral injections, continuous osmotic delivery, and systemic intravenous injections, have been explored. In all cases, the treatment with miR-10b ASO led to targets' derepression, and attenuated growth and progression of established intracranial GBM. No significant systemic toxicity was observed upon ASO administration by local or systemic routes. Our results indicate that miR-10b is a promising candidate for the development of targeted therapies against all GBM subtypes. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Poly(ornithine-co-arginine-co-glycine-co-aspartic Acid): Preparation via NCA Polymerization and its Potential as a Polymeric Tumor-Penetrating Agent.

PubMed

Yu, Haiyang; Tang, Zhaohui; Zhang, Dawei; Song, Wantong; Duan, Taicheng; Gu, Jingkai; Chen, Xuesi

2015-06-01

A novel random copolypeptide of ornithine, arginine, glycine, and aspartic acid [Poly(ornithine-co-arginine-co-glycine-co-aspartic acid), Poly(O,R,G,D)] has been prepared through ring-opening polymerization of N-δ-carbobenzoxy-l-ornithine N-carboxyanhydride [Orn(Cbz)-NCA)], l-glycine N-carboxyanhydride (Gly-NCA) and β-benzyl l-aspartate N-carboxyanhydride [Asp(Bn)-NCA], following by subsequent deprotection and guanidization. The structure of Poly(O,R,G,D) was confirmed by nuclear magnetic resonance (NMR) spectroscopy and gel permeation chromatography (GPC). Low cytotoxicity of Poly(O,R,G,D) was confirmed from MTT assay. The Poly(O,R,G,D) contain some internal sequences of RXXR (X = O, R, G, or D) that could be proteolytically cleaved to expose the cryptic CendR element and bind to Neuropilin-1. This would lead to vascular and tissue permeabilization. Therefore trypsin-cleaved Poly(O,R,G,D) increase the vascular leakage of Evans blue from dermal microvessels at the injection site in vivo skin permeability assay. The intratumoral injection of the Poly(O,R,G,D) significantly enhanced the concentration of cisplatin-loaded nanoparticles in MCF-7 solid tumors. These results show that Poly(O,R,G,D) could increase the vascular leakage and tissue penetration of nanoparticles in a solid tumor and can be used as a potential polymeric tumor-penetrating agent. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Phosphatidylserine-targeted liposome for enhanced glioma-selective imaging.

PubMed

Zhang, Liang; Habib, Amyn A; Zhao, Dawen

2016-06-21

Phosphatidylserine (PS), which is normally intracellular, becomes exposed on the outer surface of viable endothelial cells (ECs) of tumor vasculature. Utilizing a PS-targeting antibody, we have recently established a PS-targeted liposomal (PS-L) nanoplatform that has demonstrated to be highly tumor-selective. Because of the vascular lumen-exposed PS that is immediately accessible without a need to penetrate the intact blood brain barrier (BBB), we hypothesize that the systemically administered PS-L binds specifically to tumor vascular ECs, becomes subsequently internalized into the cells and then enables its cargos to be efficiently delivered to glioma parenchyma. To test this, we exploited the dual MRI/optical imaging contrast agents-loaded PS-L and injected it intravenously into mice bearing intracranial U87 glioma. At 24 h, both in vivo optical imaging and MRI depicted enhanced tumor contrast, distinct from the surrounding normal brain. Intriguingly, longitudinal MRI revealed temporal and spatial intratumoral distribution of the PS-L by following MRI contrast changes, which appeared punctate in tumor periphery at an earlier time point (4 h), but became clustering and disseminated throughout the tumor at 24 h post injection. Importantly, glioma-targeting specificity of the PS-L was antigen specific, since a control probe of irrelevant specificity showed minimal accumulation in the glioma. Together, these results indicate that the PS-L nanoplatform enables the enhanced, glioma-targeted delivery of imaging contrast agents by crossing the tumor BBB efficiently, which may also serve as a useful nanoplatform for anti-glioma drugs.

Evaluating the Anticancer Properties of Liposomal Copper in a Nude Mouse Xenograft Model of Human Prostate Cancer: Formulation, In Vitro, In Vivo, Histology and Tissue Distribution Studies

PubMed Central

Wang, Yan; Zeng, San; Lin, Tien-Min; Krugner-Higby, Lisa; Lyman, Doug; Steffen, Dana; Xiong, May P.

2014-01-01

Purpose Although copper (Cu) complexes have been investigated as anticancer agents, there has been no description of Cu itself as a cancer killing agent. A stealth liposomal Cu formulation (LpCu) was studied in vitro and in vivo. Methods LpCu was evaluated in prostate cancer origin PC-3 cells by a metabolic cytotoxicity assay, by monitoring reactive oxygen species (ROS), and by flow cytometry. LpCu efficacy was evaluated in vivo using intratumoral and intravenous injections into mice bearing PC-3 xenograft tumors. Toxicology was assessed by performing hematological and blood biochemistry assays, and tissue histology and Cu distribution was investigated by elemental analysis. Results LpCu and free Cu salts displayed similar levels of cell metabolic toxicity and ROS. Flow cytometry indicated that the mechanisms of cell death were both apoptosis and necrosis. Animals injected i.t. with 3.5 mg/kg or i.v. with 3.5 and 7.0 mg/kg LpCu exhibited significant tumor growth inhibition. Kidney and eye were the main organs affected by Cu-mediated toxicities, but spleen and liver were the major organs of Cu deposition. Conclusions LpCu was effective at reducing tumor burden in the xenograft prostate cancer model. There was histological evidence of Cu toxicity in kidneys and eyes of animals treated at the maximum tolerated dose of LpCu 7.0 mg/kg. PMID:24848339

The Expression of Distress by Children Receiving Medical Treatment.

ERIC Educational Resources Information Center

Ballard, Brenda D.; Gipson, Martin

The nature of children's distress reactions to medical treatment is examined in terms of age and sex differences and initial normative data are provided. Predominately white, middle class children, ages 1 to 11, were observed while receiving allergy treatment injections. Males were observed on 453 injection occasions while females were observed on…

Impact of Clinical Practice Guidelines on Use of Intra-Articular Hyaluronic Acid and Corticosteroid Injections for Knee Osteoarthritis.

PubMed

Bedard, Nicholas A; DeMik, David E; Glass, Natalie A; Burnett, Robert A; Bozic, Kevin J; Callaghan, John J

2018-05-16

The efficacy of corticosteroid and hyaluronic acid injections for knee osteoarthritis has been questioned. The purpose of this study was to determine the impact of the American Academy of Orthopaedic Surgeons (AAOS) clinical practice guidelines on the use of these injections in the United States and determine if utilization differed by provider specialty. Patients with knee osteoarthritis were identified within the Humana database from 2007 to 2015, and the percentage of patients receiving a knee injection relative to the number of patients having an encounter for knee osteoarthritis was calculated and was trended for the study period. The impact of each edition of the AAOS clinical practice guidelines on injection use was evaluated with segmented regression analysis. Injection trends were also analyzed relative to the specialty of the provider performing the injection. Of 1,065,175 patients with knee osteoarthritis, 405,101 (38.0%) received a corticosteroid injection and 137,005 (12.9%) received a hyaluronic acid injection. The rate of increase in hyaluronic acid use, per 100 patients with knee osteoarthritis, decreased from 0.15 to 0.07 injection per quarter year (p = 0.02) after the first clinical practice guideline, and the increase changed to a decrease at a rate of -0.12 injection per quarter (p < 0.001) after the second clinical practice guideline. After the first clinical practice guideline, the rate of increase in utilization of corticosteroids, per 100 patients with knee osteoarthritis, significantly lessened to 0.12 injection per quarter (p < 0.001), and after the second clinical practice guideline, corticosteroid injection use plateaued (p = 0.72). The trend in use of hyaluronic acid injections by orthopaedic surgeons and pain specialists decreased with time following the second-edition clinical practice guideline but did not change for primary care physicians or nonoperative musculoskeletal providers. Subtle but significant changes in hyaluronic acid and corticosteroid injections occurred following the publication of both clinical practice guidelines. Although the clinical practice guidelines did impact injection use, given the high costs of these injections and their questionable clinical efficacy, further interventions beyond publishing clinical practice guidelines are needed to encourage higher-value care for patients with knee osteoarthritis.

A potentized homeopathic drug, Arsenicum Album 200, can ameliorate genotoxicity induced by repeated injections of arsenic trioxide in mice.

PubMed

Banerjee, P; Biswas, S J; Belon, P; Khuda-Bukhsh, A R

2007-09-01

Groundwater arsenic contamination has become a menacing global problem. No drug is available until now to combat chronic arsenic poisoning. To examine if a potentized homeopathic remedy, Arsenicum Album-200, can effectively combat chronic arsenic toxicity induced by repeated injections of Arsenic trioxide in mice, the following experimental design was adopted. Mice (Mus musculus) were injected subcutaneously with 0.016% arsenic trioxide at the rate of 1 ml/100 g body weight, at an interval of 7 days until they were killed at day 30, 60, 90 or 120 and were divided into three groups: (i) one receiving a daily dose of Arsenicum Album-200 through oral administration, (ii) one receiving the same dose of diluted succussed alcohol (Alcohol-200) and (iii) another receiving neither drug, nor succussed alcohol. The remedy or the placebo, as the case may be, was fed from the next day onwards after injection until the day before the next injection, and the cycle was repeated until the mice were killed. Two other control groups were also maintained: one receiving only normal diet, and the other receiving normal diet and succussed alcohol. Several toxicity assays, such as cytogenetical (chromosome aberrations, micronuclei, mitotic index, sperm head anomaly) and biochemical (acid and alkaline phosphatases, lipid peroxidation), were periodically made. Compared with controls, the drug fed mice showed reduced toxicity at statistically significant levels in respect of all the parameters studied, thereby indicating protective potentials of the homeopathic drug against chronic arsenic poisoning.

Laser multiplexing system

DOEpatents

Johnson, Steve A.; English, Jr., Ronald Edward; White, Ronald K.

2001-01-01

A plurality of copper lasers, as radiant power sources, emits a beam of power carrying radiation. A plurality of fiber injection assemblies receives power from the plurality of copper lasers and injects such power into a plurality of fibers for individually transmitting the received power to a plurality of power-receiving devices. The power-transmitting fibers of the system are so arranged that power is delivered therethrough to each of the power-receiving devices such that, even if a few of the radiant power sources and/or fibers fail, the power supply to any of the power receiving devices will not completely drop to zero but will drop by the same proportionate amount.

Safety and effectiveness of a single and repeat intramuscular injection of a GnRH vaccine (GonaCon™) in adult female domestic cats.

PubMed

Vansandt, L M; Kutzler, M A; Fischer, A E; Morris, K N; Swanson, W F

2017-04-01

Sterilization is a key strategy to reduce the number of domestic cats entering and killed in shelters each year. However, surgical sterilization is expensive and labour-intensive and cannot fully address the 70 million free-roaming cats estimated to exist in the United States. GonaCon™ is a gonadotropin-releasing hormone vaccine originally developed for use as a wildlife immunocontraceptive. An earlier formulation was tested in domestic cats and found to be safe and effective for long-term contraception. However, the current Environmental Protection Agency (EPA)-registered formulation consists of a different antigen-carrier protein and increased antigen concentration and has never been tested in cats. A pilot study was undertaken to evaluate the short-term safety of a single GonaCon immunization, assess the consequences of vaccinated cats receiving an accidental second GonaCon injection and determine the humoral immune response to immunization. During Phase 1, cats in Group A (n = 3) received a single intramuscular injection of GonaCon and Group B (n = 3) received a single intramuscular injection of saline. During Phase 2, Group A received a second GonaCon injection and Group B received their initial GonaCon injection. All cats developed GnRH antibodies within 30 days of vaccine administration. The endpoint titre (1:1,024,000) was similar among all cats, and levels remained high throughout the duration of the study. Four cats developed a sterile, painless, self-limiting mass at the site of injection. The mean number of days to mass development was 110.3 (range, 18-249 days). In conclusion, this preliminary study suggests that the EPA-registered GonaCon formulation is safe for continued testing in domestic cats, an accidental revaccination should not increase the risk of a vaccine reaction and the EPA-registered formulation effectively elicits a strong humoral immune response. © 2016 Blackwell Verlag GmbH.

Curcumin-loaded chitosan-alginate-STPP nanoparticles ameliorate memory deficits and reduce glial activation in pentylenetetrazol-induced kindling model of epilepsy.

PubMed

Hashemian, Mona; Anissian, Diana; Ghasemi-Kasman, Maryam; Akbari, Atefeh; Khalili-Fomeshi, Mohsen; Ghasemi, Shahram; Ahmadi, Fatemeh; Moghadamnia, Ali Akbar; Ebrahimpour, Anahita

2017-10-03

Despite several beneficial effects of curcumin, its medical application has been hampered due to low water solubility. To improve the aqueous solubility of curcumin, it has been loaded on chitosan (CS)-alginate (ALG) - sodium tripolyphosphate (STPP) nanoparticles (NPs). Then, the effect of curcumin NPs on memory improvement and glial activation was investigated in pentylenetetrazol (PTZ)-induced kindling model. Male NMRI mice have received the daily injection of curcumin NPs at dose of 12.5 or 25mg/kg. All interventions were injected intraperitoneally (i.p), 10days before PTZ administration and the injections were continued until 1h before each PTZ injection. Spatial learning and memory was evaluated using Morris water maze test after the 7th PTZ injection. Animals have received 10 injections of PTZ and then, brain tissues were removed for histological evaluation. Nissl staining was used to determine the level of cell death in hippocampus and immunostaining method was performed against NeuN and GFAP/Iba1 for assessment of neuronal density and glial activation respectively. Behavioral results showed that curcumin NPs exhibit anticonvulsant activity and prevent cognitive impairment in fully kindled animals. The level of cell death and glial activation reduced in animals which have received curcumin NPs compared to those received free curcumin. To conclude, these findings suggest that curcumin NPs effectively ameliorate memory impairment and attenuate the level of activated glial cells in a mice model of chronic epilepsy. Copyright © 2017. Published by Elsevier Inc.

Computationally Guided Photothermal Tumor Therapy Using Long-Circulating Gold Nanorod Antennas

PubMed Central

Maltzahn, Geoffrey von; Park, Ji-Ho; Agrawal, Amit; Bandaru, Nanda Kishor; Das, Sarit K.; Sailor, Michael J.; Bhatia, Sangeeta N.

2009-01-01

Plasmonic nanomaterials have the opportunity to considerably improve the specificity of cancer ablation by i.v. homing to tumors and acting as antennas for accepting externally applied energy. Here, we describe an integrated approach to improved plasmonic therapy composed of multimodal nanomaterial optimization and computational irradiation protocol development. We synthesized polyethylene glycol (PEG)-protected gold nanorods (NR) that exhibit superior spectral bandwidth, photothermal heat generation per gram of gold, and circulation half-life in vivo (t1/2, ~17 hours) compared with the prototypical tunable plasmonic particles, gold nanoshells, as well as ~2-fold higher X-ray absorption than a clinical iodine contrast agent. After intratumoral or i.v. administration, we fuse PEG-NR biodistribution data derived via noninvasive X-ray computed tomography or ex vivo spectrometry, respectively, with four-dimensional computational heat transport modeling to predict photothermal heating during irradiation. In computationally driven pilot therapeutic studies, we show that a single i.v. injection of PEG-NRs enabled destruction of all irradiated human xenograft tumors in mice. These studies highlight the potential of integrating computational therapy design with nanotherapeutic development for ultraselective tumor ablation. PMID:19366797

Enzyme-directed assembly of nanoparticles in tumors monitored by in vivo whole animal imaging and ex vivo super-resolution fluorescence imaging.

PubMed

Chien, Miao-Ping; Carlini, Andrea S; Hu, Dehong; Barback, Christopher V; Rush, Anthony M; Hall, David J; Orr, Galya; Gianneschi, Nathan C

2013-12-18

Matrix metalloproteinase enzymes, overexpressed in HT-1080 human fibrocarcinoma tumors, were used to guide the accumulation and retention of an enzyme-responsive nanoparticle in a xenograft mouse model. The nanoparticles were prepared as micelles from amphiphilic block copolymers bearing a simple hydrophobic block and a hydrophilic peptide brush. The polymers were end-labeled with Alexa Fluor 647 dyes leading to the formation of labeled micelles upon dialysis of the polymers from DMSO/DMF to aqueous buffer. This dye-labeling strategy allowed the presence of the retained material to be visualized via whole animal imaging in vivo and in ex vivo organ analysis following intratumoral injection into HT-1080 xenograft tumors. We propose that the material is retained by virtue of an enzyme-induced accumulation process whereby particles change morphology from 20 nm spherical micelles to micrometer-scale aggregates, kinetically trapping them within the tumor. This hypothesis is tested here via an unprecedented super-resolution fluorescence analysis of ex vivo tissue slices confirming a particle size increase occurs concomitantly with extended retention of responsive particles compared to unresponsive controls.

The administration of IL-12/GM-CSF and Ig-4-1BB ligand markedly decreases murine floor of mouth squamous cell cancer.

PubMed

Adappa, Nithin D; Sung, Chi-Kwang; Choi, Bryan; Huang, Tian-Gui; Genden, Eric M; Shin, Edward J

2008-09-01

To assess immune-based gene therapy in a murine floor of mouth (FOM) squamous cell carcinoma (SCC) model. In vitro and in vivo testing of immune therapy for SCC. Multiple SCC lines were infected by using advRSV-interleukin-12 (IL-12) and advCMV-interleukin-12/granulocyte macrophage colony-stimulating factor (IL-12/GM-CSF) and monitored for production of IL-12 and GM-CSF. Intratumoral injections of viral vectors were administered with systemic Ig-4-1BB ligand in an orthotopic murine FOM SCC model and followed for tumor size and survival. In vitro, all cell lines produced substantial levels of IL-12 and GM-CSF. In vivo, tumors treated with advCMV-IL-12/GM-CSF and Ig-4-1BBL showed a striking reduction in tumor volume (vs control P<0.0001) and improved median survival (38 days vs 19 days for control, P<0.0001). Combination immune-based therapies effectively improve survival in mice bearing FOM SCC over single-modality therapy.

Tumor detection and elimination by a targeted gallium corrole

PubMed Central

Agadjanian, Hasmik; Ma, Jun; Rentsendorj, Altan; Valluripalli, Vinod; Hwang, Jae Youn; Mahammed, Atif; Farkas, Daniel L.; Gray, Harry B.; Gross, Zeev; Medina-Kauwe, Lali K.

2009-01-01

Sulfonated gallium(III) corroles are intensely fluorescent macrocyclic compounds that spontaneously assemble with carrier proteins to undergo cell entry. We report in vivo imaging and therapeutic efficacy of a tumor-targeted corrole noncovalently assembled with a heregulin-modified protein directed at the human epidermal growth factor receptor (HER). Systemic delivery of this protein-corrole complex results in tumor accumulation, which can be visualized in vivo owing to intensely red corrole fluorescence. Targeted delivery in vivo leads to tumor cell death while normal tissue is spared. These findings contrast with the effects of doxorubicin, which can elicit cardiac damage during therapy and required direct intratumoral injection to yield similar levels of tumor shrinkage compared with the systemically delivered corrole. The targeted complex ablated tumors at >5 times a lower dose than untargeted systemic doxorubicin, and the corrole did not damage heart tissue. Complexes remained intact in serum and the carrier protein elicited no detectable immunogenicity. The sulfonated gallium(III) corrole functions both for tumor detection and intervention with safety and targeting advantages over standard chemotherapeutic agents. PMID:19342490

Glaucoma filtration surgery following sustained elevation of intraocular pressure secondary to intravitreal anti-VEGF injections.

PubMed

Skalicky, Simon E; Ho, Ivan; Agar, Ashish; Bank, Allan

2012-07-01

To document cases of sustained elevation of intraocular pressure (IOP) while receiving intravitreal anti-vascular endothelial growth factor (VEGF) agents and subsequent management. A retrospective series of all cases managed by the authors and colleagues was performed. Six patients developed sustained elevated IOP; five received ranibizumab and one bevacizumab. Four received unilateral and two received bilateral injections. Two had preexisting primary open-angle glaucoma and one had pseudoexfoliative glaucoma, all with stable IOP prior to anti-VEGF treatment. Angles were open in all cases. Peak IOP averaged 43 mm Hg (range: 34 to 60 mm Hg). The mean number of injections preceding the IOP increase was 10 (range: 1 to 20). Four patients required trabeculectomy, one selective laser trabeculoplasty, and one multiple topical medications. A sustained increase in IOP requiring glaucoma filtering surgery is a rare but important treatment complication for patients receiving intravitreal anti-VEGF therapy, especially those with preexisting glaucoma or glaucoma risk factors. Copyright 2012, SLACK Incorporated.

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future.

PubMed

McGranahan, Nicholas; Swanton, Charles

2017-02-09

Intratumor heterogeneity, which fosters tumor evolution, is a key challenge in cancer medicine. Here, we review data and technologies that have revealed intra-tumor heterogeneity across cancer types and the dynamics, constraints, and contingencies inherent to tumor evolution. We emphasize the importance of macro-evolutionary leaps, often involving large-scale chromosomal alterations, in driving tumor evolution and metastasis and consider the role of the tumor microenvironment in engendering heterogeneity and drug resistance. We suggest that bold approaches to drug development, harnessing the adaptive properties of the immune-microenvironment while limiting those of the tumor, combined with advances in clinical trial-design, will improve patient outcome. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Treatment of severe motion sickness with antimotion sickness drug injections

NASA Technical Reports Server (NTRS)

Graybiel, Ashton; Lackner, James R.

1987-01-01

This report concerns the use of intramuscular injections of scopolamine, promethazine, and dramamine to treat severely motion sick individuals participating in parabolic flight experiments. The findings indicate that a majority of individuals received benefit from 50-mg injections of promethazine or 0.5 mg-injections of scopolamine. By contrast, 50-mg injections of dramamine and 25-mg injections of promethazine were nonbeneficial. The use of antimotion drug injections for treating space motion sickness is discussed.

Impact of transforming growth factor-beta1 on atrioventricular node conduction modification by injected autologous fibroblasts in the canine heart.

PubMed

Bunch, T Jared; Mahapatra, Srijoy; Bruce, G Keith; Johnson, Susan B; Miller, Dylan V; Horne, Benjamin D; Wang, Xiao-Li; Lee, Hon-Chi; Caplice, Noel M; Packer, Douglas L

2006-05-30

Atrioventricular (AV) nodal ablation for management of atrial fibrillation (AF) is irreversible and requires permanent pacemaker implantation. We hypothesized that as an alternative, implantation of autologous fibroblasts in the perinodal region would focally modify AV nodal conduction and that this modulation would be enhanced by pretreatment with transforming growth factor-beta1 (TGF-beta1), a stimulant of fibroblasts. Skin biopsies were taken from 12 mongrel dogs, and derived fibroblasts were dissociated and grown in culture for 2 weeks. Multiple injections (0.25 mL) were made through an 8F NOGA catheter along the fast/slow AV nodal pathways as guided by an electroanatomic mapping system. Seven dogs received fibroblasts alone (1x10(6) cells/mL), 7 dogs received TGF-beta1 (5 microg), 4 dogs received fibroblasts and TGF-beta1 (1x10(6) cells/mL+5 microg), and 4 dogs received saline only. AV node function was assessed at baseline and after 4 weeks. Saline (80 mL) with assigned therapy (0.25 mL per injection) was injected into the peri-AV nodal region in each dog. At baseline, the AH interval (66+/-3 ms) and the average RR interval (331+/-17 ms) in pacing-induced AF were similar in each cohort. The increase in AH interval in normal sinus rhythm was longer after fibroblast (23+/-4 versus 5+/-5 ms; P=0.05) and fibroblast plus TGF-beta1 (50+/-5 versus 5+/-5 ms; P<0.001) injections than with saline alone, with similar findings during high right atrium and distal coronary sinus pacing. The AH interval was not significantly increased after TGF-beta1 injections. The AH interval was significantly longer after fibroblast plus TGF-beta1 injections than with either therapy (TGF-beta1 or fibroblasts) alone. The RR interval during AF was increased in dogs that received fibroblasts alone (110+/-36 versus -41+/-34 ms) and to a greater extent with the addition of TGF-beta1 (294+/-108 versus -41+/-34 ms). No AV block was seen in any cohort at 4 weeks. Labeled fibroblasts that expressed vimentin were identified in all dogs that received cell injections at 4 weeks. AV nodal modification can be achieved with injected fibroblasts without the creation of AV block. The effect on AV node conduction is substantially enhanced by pretreatment of fibroblasts with TGF-beta1. These data have therapeutic potential for the management of rapid ventricular rate during AF without pacemaker implantation.

Cardiovascular effects of intraosseous injections of 2 percent lidocaine with 1:100,000 epinephrine and 3 percent mepivacaine.

PubMed

Replogle, K; Reader, A; Nist, R; Beck, M; Weaver, J; Meyers, W J

1999-05-01

Because a number of patients have reported an increase in heart rate with the intraosseous, or i.o., injection, it is important to evaluate changes in the cardiovascular system with this injection technique. The purpose of this study was to determine the cardiovascular effects of an i.o. injection of 2 percent lidocaine with 1:100,000 epinephrine and 3 percent mepivacaine. With the use of a repeated-measures design, the authors randomly assigned 42 subjects to receive i.o. injections of 1.8 milliliters of 2 percent lidocaine with 1:100,000 epinephrine or 1.8 mL of 3 percent mepivacaine in a double-blinded manner at two appointments. At each appointment the authors monitored electrocardiographic findings, cardiac rate, systolic and diastolic blood pressure, and mean arterial pressure before, during and after administration of anesthetic solutions. With the 2 percent lidocaine with 1:100,000 epinephrine solution, 28 (67 percent) of 42 subjects experienced an increase in heart rate that might be attributed to the effect of the epinephrine. In 22 (79 percent) of these subjects, the heart rate returned to within 5 beats of baseline values within four minutes after solution deposition. The authors found no significant increase in heart rate in subjects receiving the 3 percent mepivacaine. No significant differences (P > .05) were found in mean diastolic, mean systolic or mean arterial blood pressure values between the subjects receiving 2 percent lidocaine with 1:100,000 epinephrine and those receiving 3 percent mepivacaine. The majority of subjects receiving the i.o. injection of the 2 percent lidocaine-epinephrine solution experienced a transient increase in heart rate. No significant increase in heart rate was seen with the i.o. injection of 3 percent mepivacaine. While patients would likely notice the heart rate increase with the lidocaine-epinephrine solution, it would not be clinically significant in most healthy patients. In patients whose medical condition, drug therapies or epinephrine sensitivity suggests caution, 3 percent mepivacaine is a good alternative for i.o. injections.

Spatiotemporal changes of seismic attenuation caused by injected CO2 at the Frio-II pilot site, Dayton, TX, USA

NASA Astrophysics Data System (ADS)

Zhu, Tieyuan; Ajo-Franklin, Jonathan B.; Daley, Thomas M.

2017-09-01

A continuous active source seismic monitoring data set was collected with crosswell geometry during CO2 injection at the Frio-II brine pilot, near Liberty, TX. Previous studies have shown that spatiotemporal changes in the P wave first arrival time reveal the movement of the injected CO2 plume in the storage zone. To further constrain the CO2 saturation, particularly at higher saturation levels, we investigate spatial-temporal changes in the seismic attenuation of the first arrivals. The attenuation changes over the injection period are estimated by the amount of the centroid frequency shift computed by local time-frequency analysis. We observe that (1) at receivers above the injection zone seismic attenuation does not change in a physical trend; (2) at receivers in the injection zone attenuation sharply increases following injection and peaks at specific points varying with distributed receivers, which is consistent with observations from time delays of first arrivals; then, (3) attenuation decreases over the injection time. The attenuation change exhibits a bell-shaped pattern during CO2 injection. Under Frio-II field reservoir conditions, White's patchy saturation model can quantitatively explain both the P wave velocity and attenuation response observed. We have combined the velocity and attenuation change data in a crossplot format that is useful for model-data comparison and determining patch size. Our analysis suggests that spatial-temporal attenuation change is not only an indicator of the movement and saturation of CO2 plumes, even at large saturations, but also can quantitatively constrain CO2 plume saturation when used jointly with seismic velocity.

Effects of dexpanthenol and N-acetylcysteine pretreatment in rats before renal ischemia/reperfusion injury.

PubMed

Sen, Huseyin; Deniz, Suleyman; Yedekci, A Erturk; Inangil, Gokhan; Muftuoglu, Tuba; Haholu, Aptullah; Ozkan, Sezai

2014-11-01

We investigated the anti-inflammatory and protective effects of concomitant use of dexpanthenol (DXP) and N-acetylcysteine (NAC) induced ischemia/reperfusion (I/R) injury of kidney. Forty rats were randomly divided into 5 groups. In all groups except for Group 1(Sham), renal arteries bilaterally occluded with vascular clamp for IR injury. Group 1(Sham), received a single dose of 10 mL/kg isotonic saline daily by intraperitoneal (IP) injection for three days. Group 2(IR), received a single dose of 10 mL/kg isotonic saline daily by IP injection for three days. Group 3(IR + NAC), received 300 mg/kg NAC daily by IP injection for three days. Group 4(IR + DXP), received 500 mg/kg DXP daily by IP injection for three days. Group 5(IR + NAC + DXP), received 500 mg/kg DXP and 300 mg/kg NAC daily by IP injection for three days. Serum urea (BUN), creatinine (Cr) and neutrophil gelatinase-associated lipocalin (NGAL, lipocalin 2, siderocalin) levels were measured as kidney function tests. TNF-α levels were measured as inflammatory marker. Tissue sections were evaluated histopathologically under light microscopy. IR + NAC + DXP group received both NAC and DXP before induction of renal I/R and as the biochemical and histopathological data revealed the results of the IR + NAC + DXP group and sham group were similar. Biochemically and histopathologically, combined use of NAC and DXP has better results when each of them used alone. We concluded that concomitant use of DXP and NAC plays a major role against I/R injury and may be useful in acute treatment of I/R induced renal failure.

Intra-articular decorin influences the fibrosis genetic expression profile in a rabbit model of joint contracture.

PubMed

Abdel, M P; Morrey, M E; Barlow, J D; Grill, D E; Kolbert, C P; An, K N; Steinmann, S P; Morrey, B F; Sanchez-Sotelo, J

2014-01-01

The goal of this study was to determine whether intra-articular administration of the potentially anti-fibrotic agent decorin influences the expression of genes involved in the fibrotic cascade, and ultimately leads to less contracture, in an animal model. A total of 18 rabbits underwent an operation on their right knees to form contractures. Six limbs in group 1 received four intra-articular injections of decorin; six limbs in group 2 received four intra-articular injections of bovine serum albumin (BSA) over eight days; six limbs in group 3 received no injections. The contracted limbs of rabbits in group 1 were biomechanically and genetically compared with the contracted limbs of rabbits in groups 2 and 3, with the use of a calibrated joint measuring device and custom microarray, respectively. There was no statistical difference in the flexion contracture angles between those limbs that received intra-articular decorin versus those that received intra-articular BSA (66° vs 69°; p = 0.41). Likewise, there was no statistical difference between those limbs that received intra-articular decorin versus those who had no injection (66° vs 72°; p = 0.27). When compared with BSA, decorin led to a statistically significant increase in the mRNA expression of 12 genes (p < 0.01). In addition, there was a statistical change in the mRNA expression of three genes, when compared with those without injection. In this model, when administered intra-articularly at eight weeks, 2 mg of decorin had no significant effect on joint contractures. However, our genetic analysis revealed a significant alteration in several fibrotic genes. Cite this article: Bone Joint Res 2014;3:82-8.

Experience of Anti-VEGF Treatment and Clinical Levels of Depression and Anxiety in Patients With Wet Age-Related Macular Degeneration.

PubMed

Senra, Hugo; Balaskas, Konstantinos; Mahmoodi, Neda; Aslam, Tariq

2017-05-01

To investigate detailed patient experiences specific to receiving vascular endothelial growth factor inhibitors (anti-VEGF) for wet age-related macular degeneration (wAMD), and to acquire a snapshot of the frequency of clinically significant levels of depression, anxiety, and posttraumatic stress among patients and levels of burden in patients' carers. Observational cross-sectional mixed-methods study. Three hundred patients with wAMD receiving anti-VEGF treatment and 100 patient carers were recruited. Qualitative data on patients' experience of treatment were collected using a structured survey. Standardized validated questionnaires were used to quantify clinically significant levels of anxiety, depression, and posttraumatic stress, as well as cognitive function and carers' burden. Qualitative data showed that 56% of patients (n = 132) reported anxiety related to anti-VEGF treatment. The main sources of anxiety were fear of going blind owing to intravitreal injections and concerns about treatment effectiveness, rather than around pain. From validated questionnaires, 17% of patients (n = 52) showed clinical levels of anxiety and 12% (n = 36) showed clinical levels of depression. Depression levels, but not anxiety, were significantly higher in patients who received up to 3 injections compared with patients who received from 4 to 12 injections (analysis of variance [ANOVA] P = .027) and compared with patients who received more than 12 injections (ANOVA P = .001). Anti-VEGF treatment is often experienced with some anxiety related to treatment, regardless of the number of injections received. Clinical levels of depression seem to be more frequent in patients at early stages of anti-VEGF treatment. Strategies to improve patient experience of treatment and minimize morbidity are suggested. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Hair Follicle Generation by Injections of Adult Human Follicular Epithelial and Dermal Papilla Cells into Nude Mice

PubMed Central

Nilforoushzadeh, Mohammadali; Rahimi Jameh, Elham; Jaffary, Fariba; Abolhasani, Ehsan; Keshtmand, Gelavizh; Zarkob, Hajar; Mohammadi, Parvaneh; Aghdami, Nasser

2017-01-01

Objective Dermal papilla and hair epithelial stem cells regulate hair formation and the growth cycle. Damage to or loss of these cells can cause hair loss. Although several studies claim to reconstitute hairs using rodent cells in an animal model, additional research is needed to develop a stable human hair follicle reconstitution protocol. In this study, we have evaluated hair induction by injecting adult cultured human dermal papilla cells and a mixture of hair epithelial and dermal papilla cells in a mouse model. Materials and Methods In this experimental study, discarded human scalp skins were used to obtain dermal papilla and hair epithelial cells. After separation, cells were cultured and assessed for their characteristics. We randomly allocated 15 C57BL/6 nude mice into three groups that received injections in their dorsal skin. The first group received cultured dermal papilla cells, the second group received a mixture of cultured epithelial and dermal papilla cells, and the third group (control) received a placebo [phosphate-buffered saline (PBS-)]. Results Histopathologic examination of the injection sites showed evidence of hair growth in samples that received cells compared with the control group. However, the group that received epithelial and dermal papilla cells had visible evidence of hair growth. PKH tracing confirmed the presence of transplanted cells in the new hair. Conclusion Our data showed that injection of a combination of adult human cultured dermal papilla and epithelial cells could induce hair growth in nude mice. This study emphasized that the combination of human adult cultured dermal papilla and epithelial cells could induce new hair in nude mice. PMID:28670518

Hypermutable DNA chronicles the evolution of human colon cancer

PubMed Central

Naxerova, Kamila; Brachtel, Elena; Salk, Jesse J.; Seese, Aaron M.; Power, Karen; Abbasi, Bardia; Snuderl, Matija; Chiang, Sarah; Kasif, Simon; Jain, Rakesh K.

2014-01-01

Intratumor genetic heterogeneity reflects the evolutionary history of a cancer and is thought to influence treatment outcomes. Here we report that a simple PCR-based assay interrogating somatic variation in hypermutable polyguanine (poly-G) repeats can provide a rapid and reliable assessment of mitotic history and clonal architecture in human cancer. We use poly-G repeat genotyping to study the evolution of colon carcinoma. In a cohort of 22 patients, we detect poly-G variants in 91% of tumors. Patient age is positively correlated with somatic mutation frequency, suggesting that some poly-G variants accumulate before the onset of carcinogenesis during normal division in colonic stem cells. Poorly differentiated tumors have fewer mutations than well-differentiated tumors, possibly indicating a shorter mitotic history of the founder cell in these cancers. We generate poly-G mutation profiles of spatially separated samples from primary carcinomas and matched metastases to build well-supported phylogenetic trees that illuminate individual patients’ path of metastatic progression. Our results show varying degrees of intratumor heterogeneity among patients. Finally, we show that poly-G mutations can be found in other cancers than colon carcinoma. Our approach can generate reliable maps of intratumor heterogeneity in large numbers of patients with minimal time and cost expenditure. PMID:24753616

Vaccine-instructed intratumoral IFN-γ enables regression of autochthonous mouse prostate cancer in allogeneic T-cell transplantation.

PubMed

Hess Michelini, Rodrigo; Manzo, Teresa; Sturmheit, Tabea; Basso, Veronica; Rocchi, Martina; Freschi, Massimo; Listopad, Joanna; Blankenstein, Thomas; Bellone, Matteo; Mondino, Anna

2013-08-01

Vaccination can synergize with transplantation of allogeneic hematopoietic stem cells to cure hematologic malignancies, but the basis for this synergy is not understood to the degree where such approaches could be effective for treating solid tumors. We investigated this issue in a transgenic mouse model of prostate cancer treated by transplantation of a nonmyeloablative MHC-matched, single Y chromosome-encoded, or multiple minor histocompatibility antigen-mismatched hematopoietic cell preparation. Here, we report that tumor-directed vaccination after allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion is essential for acute graft versus tumor responses, tumor regression, and prolonged survival. Vaccination proved essential for generation of CD8(+) IFN-γ(+) tumor-directed effector cells in secondary lymphoid organs and also for IFN-γ(+) upregulation at the tumor site, which in turn instructed local expression of proinflammatory chemokines and intratumoral recruitment of donor-derived T cells for disease regression. Omitting vaccination, transplanting IFN-γ-deficient donor T cells, or depleting alloreactive T cells all compromised intratumoral IFN-γ-driven inflammation and lymphocyte infiltration, abolishing antitumor responses and therapeutic efficacy of the combined approach. Our findings argue that posttransplant tumor-directed vaccination is critical to effectively direct donor T cells to the tumor site in cooperation with allogeneic hematopoietic cell transplantation. ©2013 AACR.

A gastrointestinal stromal tumor of the jejunum presenting with an intratumoral abscess: A case report and a literature review.

PubMed

Ito, Soichi; Tsuchitani, Yuma; Kim, Yuro; Hashimoto, Souhei; Miura, Yuichi; Uemura, Takuji; Katsura, Kazunori; Abe, Takayuki; Sato, Koichiro; Kato, Hirotaka

2018-05-29

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The small intestine is the second-most frequent location where GISTs occur after the stomach. Attention should be paid to small intestinal GISTs because they infrequently present with acute abdomen, which necessitates emergency surgery. This report describes a patient with a small intestinal GIST developing a giant intratumoral abscess, in whom emergency surgery was performed. A 56-year-old woman presented with worsening abdominal pain. Computed tomography scan showed an approximately 9.5 cm × 9 cm tumor bearing a thick and hypervascularized wall with an internal air-fluid level. Emergency laparotomy revealed the tumor originated from the jejunum, and partial resection of the jejunum was performed. A large amount of pus was contained inside the tumor. Immunohistochemically, the tumor was diagnosed as a high risk GIST of the Cjejunum, and imatinib mesylate was initiated. When an intratumoral abscess in the abdomen is confirmed, GISTs should be listed as differential diagnosis. Complete surgical resetcion with careful handling and adjuvant chemotherapy with imatinib mesylate are considered to be important for this state. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Tumor Heterogeneity: Mechanisms and Bases for a Reliable Application of Molecular Marker Design

PubMed Central

Diaz-Cano, Salvador J.

2012-01-01

Tumor heterogeneity is a confusing finding in the assessment of neoplasms, potentially resulting in inaccurate diagnostic, prognostic and predictive tests. This tumor heterogeneity is not always a random and unpredictable phenomenon, whose knowledge helps designing better tests. The biologic reasons for this intratumoral heterogeneity would then be important to understand both the natural history of neoplasms and the selection of test samples for reliable analysis. The main factors contributing to intratumoral heterogeneity inducing gene abnormalities or modifying its expression include: the gradient ischemic level within neoplasms, the action of tumor microenvironment (bidirectional interaction between tumor cells and stroma), mechanisms of intercellular transference of genetic information (exosomes), and differential mechanisms of sequence-independent modifications of genetic material and proteins. The intratumoral heterogeneity is at the origin of tumor progression and it is also the byproduct of the selection process during progression. Any analysis of heterogeneity mechanisms must be integrated within the process of segregation of genetic changes in tumor cells during the clonal expansion and progression of neoplasms. The evaluation of these mechanisms must also consider the redundancy and pleiotropism of molecular pathways, for which appropriate surrogate markers would support the presence or not of heterogeneous genetics and the main mechanisms responsible. This knowledge would constitute a solid scientific background for future therapeutic planning. PMID:22408433

Quantitative image variables reflect the intratumoral pathologic heterogeneity of lung adenocarcinoma.

PubMed

Choi, E-Ryung; Lee, Ho Yun; Jeong, Ji Yun; Choi, Yoon-La; Kim, Jhingook; Bae, Jungmin; Lee, Kyung Soo; Shim, Young Mog

2016-10-11

We aimed to compare quantitative radiomic parameters from dual-energy computed tomography (DECT) of lung adenocarcinoma and pathologic complexity.A total 89 tumors with clinical stage I/II lung adenocarcinoma were prospectively included. Fifty one radiomic features were assessed both from iodine images and non-contrast images of DECT datasets. Comprehensive histologic subtyping was evaluated with all surgically resected tumors. The degree of pathologic heterogeneity was assessed using pathologic index and the number of mixture histologic subtypes in a tumor. Radiomic parameters were correlated with pathologic index. Tumors were classified as three groups according to the number of mixture histologic subtypes and radiomic parameters were compared between the three groups.Tumor density and 50th through 97.5th percentile Hounsfield units (HU) of histogram on non-contrast images showed strong correlation with the pathologic heterogeneity. Radiomic parameters including 75th and 97.5th percentile HU of histogram, entropy, and inertia on 1-, 2- and 3 voxel distance on non-contrast images showed incremental changes while homogeneity showed detrimental change according to the number of mixture histologic subtypes (all Ps < 0.05).Radiomic variables from DECT of lung adenocarcinoma reflect pathologic intratumoral heterogeneity, which may help in the prediction of intratumoral heterogeneity of the whole tumor.

Intratumoral and peritumoral lymphovascular invasion detected by D2-40 immunohistochemistry correlates with metastasis in primary cutaneous Merkel cell carcinoma.

PubMed

Al-Rohil, Rami N; Milton, Denái R; Nagarajan, Priyadharsini; Curry, Jonathan L; Feldmeyer, Laurence; Torres-Cabala, Carlos A; Ivan, Doina; Prieto, Victor G; Tetzlaff, Michael T; Aung, Phyu P

2018-07-01

Primary cutaneous Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy in which lymphovascular invasion (LVI) correlates with more aggressive phenotype. The prognostic significance of LVI detected by D2-40 immunohistochemistry (IHC) in MCC remains controversial. We aimed to determine how LVI detected by D2-40 IHC compares with LVI detected by hematoxylin and eosin (H&E) staining in predicting MCC metastasis. Clinical and histopathologic features of MCCs diagnosed and treated in 2002 to 2015 were assembled and included 58 MCC tumors from 58 patients. H&E-stained tissue sections and D2-40 IHC studies were reviewed. When LVI was present, the location (peritumoral or intratumoral) and the size of the largest invaded vessel were recorded. LVI findings by H&E staining and D2-40 IHC were compared with each other and with histologic features and clinical outcomes. H&E staining showed LVI in 37 of 58 cases; D2-40 IHC confirmed LVI in 30 of these cases but failed to confirm LVI in 7. D2-40 IHC also detected 14 cases of LVI not identified on H&E staining. Histologically, D2-40-detected LVI was associated with infiltrative growth pattern and nonbrisk lymphoid infiltrate (P = .005 and P = .055, respectively). There was a statistically significant difference between the frequency of detection of peritumoral LVI by H&E in comparison to D2-40 IHC (P = .0009). MCCs in which D2-40 IHC-detected both intratumoral and peritumoral LVI were typically larger than MCCs without (mean, 24.5 mm versus 17.3 mm; P = .03) and more frequently metastasized (87% versus 51%; P = .03). D2-40 IHC detection of both intratumoral and peritumoral LVI is associated with metastasis. Copyright © 2018 Elsevier Inc. All rights reserved.

Intratumoral Agreement of High-Resolution Magic Angle Spinning Magnetic Resonance Spectroscopic Profiles in the Metabolic Characterization of Breast Cancer

PubMed Central

Park, Vivian Youngjean; Yoon, Dahye; Koo, Ja Seung; Kim, Eun-Kyung; Kim, Seung Il; Choi, Ji Soo; Park, Seho; Park, Hyung Seok; Kim, Suhkmann; Kim, Min Jung

2016-01-01

Abstract High-resolution magic angle spinning (HR-MAS) magnetic resonance (MR) spectroscopy data may serve as a biomarker for breast cancer, with only a small volume of tissue sample required for assessment. However, previous studies utilized only a single tissue sample from each patient. The aim of this study was to investigate whether intratumoral location and biospecimen type affected the metabolic characterization of breast cancer assessed by HR-MAS MR spectroscopy This prospective study was approved by the institutional review board and informed consent was obtained. Preoperative core-needle biopsies (CNBs), central, and peripheral surgical tumor specimens were prospectively collected under ultrasound (US) guidance in 31 patients with invasive breast cancer. Specimens were assessed with HR-MAS MR spectroscopy. The reliability of metabolite concentrations was evaluated and multivariate analysis was performed according to intratumoral location and biospecimen type. There was a moderate or higher agreement between the relative concentrations of 94.3% (33 of 35) of metabolites in the center and periphery, 80.0% (28 of 35) of metabolites in the CNB and central surgical specimens, and 82.9% (29 of 35) of metabolites between all 3 specimen types. However, there was no significant agreement between the concentrations of phosphocholine (PC) and phosphoethanolamine (PE) in the center and periphery. The concentrations of several metabolites (adipate, arginine, fumarate, glutamate, PC, and PE) had no significant agreement between the CNB and central surgical specimens. In conclusion, most HR-MAS MR spectroscopic data do not differ based on intratumoral location or biospecimen type. However, some metabolites may be affected by specimen-related variables, and caution is recommended in decision-making based solely on metabolite concentrations, particularly PC and PE. Further validation through future studies is needed for the clinical implementation of these biomarkers based on data from a single tissue sample. PMID:27082613

Impact of Circulating Cholesterol Levels on Growth and Intratumoral Androgen Concentration of Prostate Tumors

PubMed Central

Pelton, Kristine; Freeman, Michael R.; Montgomery, R. Bruce

2012-01-01

Prostate cancer (PCa) is the second most common cancer in men. Androgen deprivation therapy (ADT) leads to tumor involution and reduction of tumor burden. However, tumors eventually reemerge that have overcome the absence of gonadal androgens, termed castration resistant PCa (CRPC). Theories underlying the development of CRPC include androgen receptor (AR) mutation allowing for promiscuous activation by non-androgens, AR amplification and overexpression leading to hypersensitivity to low androgen levels, and/or tumoral uptake and conversion of adrenally derived androgens. More recently it has been proposed that prostate tumor cells synthesize their own androgens through de novo steroidogenesis, which involves the step-wise synthesis of androgens from cholesterol. Using the in vivo LNCaP PCa xenograft model, previous data from our group demonstrated that a hypercholesterolemia diet potentiates prostatic tumor growth via induction of angiogenesis. Using this same model we now demonstrate that circulating cholesterol levels are significantly associated with tumor size (R = 0.3957, p = 0.0049) and intratumoral levels of testosterone (R = 0.41, p = 0.0023) in LNCaP tumors grown in hormonally intact mice. We demonstrate tumoral expression of cholesterol uptake genes as well as the spectrum of steroidogenic enzymes necessary for androgen biosynthesis from cholesterol. Moreover, we show that circulating cholesterol levels are directly correlated with tumoral expression of CYP17A, the critical enzyme required for de novo synthesis of androgens from cholesterol (R = 0.4073, p = 0.025) Since hypercholesterolemia does not raise circulating androgen levels and the adrenal gland of the mouse synthesizes minimal androgens, this study provides evidence that hypercholesterolemia increases intratumoral de novo steroidogenesis. Our results are consistent with the hypothesis that cholesterol-fueled intratumoral androgen synthesis may accelerate the growth of prostate tumors, and suggest that treatment of CRPC may be optimized by inclusion of cholesterol reduction therapies in conjunction with therapies targeting androgen synthesis and the AR. PMID:22279565

Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer

NASA Astrophysics Data System (ADS)

Kos, Petra; Lächelt, Ulrich; Herrmann, Annika; Mickler, Frauke Martina; Döblinger, Markus; He, Dongsheng; Krhač Levačić, Ana; Morys, Stephan; Bräuchle, Christoph; Wagner, Ernst

2015-03-01

Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target-specificity of the formed polyplexes. Implementation of endosomal escape-promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor.Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target-specificity of the formed polyplexes. Implementation of endosomal escape-promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr06556e

Dirhenium decacarbonyl-loaded PLLA nanoparticles: influence of neutron irradiation and preliminary in vivo administration by the TMT technique.

PubMed

Hamoudeh, Misara; Fessi, Hatem; Mehier, Henri; Faraj, Achraf Al; Canet-Soulas, Emmanuelle

2008-02-04

In a previous study, we have described the elaboration of PLLA-based nanoparticles loaded with non radioactive dirhenium decacarbonyl [Re(2)(CO)(10)], a novel neutron-activatable radiopharmaceutical dosage form for intra-tumoral radiotherapy. These nanoparticles are designed for a neutron irradiation which can be carried out in a nuclear reactor facility. This new paper describes the neutron irradiation influence on these Re(2)(CO)(10)-loaded PLLA nanoparticles. The loaded nanoparticles with 23% (w/w) of metallic rhenium have shown to remain stable and separated and to keep out their sphericity at the lower neutron flux (1x10(11)n/cm(2)/s for 0.5h) which was used for rhenium content determination (neutron activation analysis, NAA). However, when loaded nanoparticles were irradiated at the higher neutron flux (1.45x10(13)n/cm(2)/s, 1h), they have shown to be partially coagglomerated and some pores appeared at their surface. Furthermore, DSC results showed a decrease in the PLLA melting point and melting enthalpy in both blank and loaded nanoparticles indicating a decrease in polymer crystallinity. In addition, the polymer molecular weights (M(n), M(w)) decreased after irradiation but without largely affecting the polymer polydispersity index (P.I.) which indicated that an irradiation-induced PLLA chain scission had occurred in a random way. The XRD patterns of irradiated PLLA provided another proof of polymer loss of crystallinity. FTIR spectra results have shown that irradiated nanoparticles retained the chemical identity of the used Re(2)(CO)(10) and PLLA despite the reduction in polymer crystallinity and molecular weight. Nanoparticles suspending after irradiation became also more difficult, but it was properly achievable by adding PVA (1%) and ethanol (10%) into the dispersing medium. Moreover, after 24h incubation of different irradiated nanoparticles in two different culture mediums, visual examination did not show bacterial growth indicating that applied neutron irradiation, yielding an absorbed dose of 450kGy, can be a terminal method for nanoparticles sterilisation. Thereafter, in a preliminary in vivo experiment, superparamagnetic non radioactive nanoparticles loaded with Re(2)(CO)(10) and oleic-acid coated magnetite have been successfully injected into a mice animal model via targeted multi therapy (TMT) technique which would be our selected administration method for future in vivo studies. In conclusion, although some induced neutron irradiation damage to nanoparticles occurs, dirhenium decacarbonyl-loaded PLLA nanoparticles retain their chemical identity and remain almost as re-dispersible and injectable nanoparticles by the TMT technique. These nanoparticles represent a novel interesting candidate for local intra-tumoral radiotherapy.

Hypo-fractionated radiation, magnetic nanoparticle hyperthermia and a viral immunotherapy treatment of spontaneous canine cancer

NASA Astrophysics Data System (ADS)

Hoopes, P. Jack; Moodie, Karen L.; Petryk, Alicia A.; Petryk, James D.; Sechrist, Shawntel; Gladstone, David J.; Steinmetz, Nicole F.; Veliz, Frank A.; Bursey, Alicea A.; Wagner, Robert J.; Rajan, Ashish; Dugat, Danielle; Crary-Burney, Margaret; Fiering, Steven N.

2017-02-01

It has recently been shown that cancer treatments such as radiation and hyperthermia, which have conventionally been viewed to have modest immune based anti-cancer effects, may, if used appropriately stimulate a significant and potentially effective local and systemic anti-cancer immune effect (abscopal effect) and improved prognosis. Using eight spontaneous canine cancers (2 oral melanoma, 3 oral amelioblastomas and 1 carcinomas), we have shown that hypofractionated radiation (6 x 6 Gy) and/or magnetic nanoparticle hyperthermia (2 X 43°C / 45 minutes) and/or an immunogenic virus-like nanoparticle (VLP, 2 x 200 μg) are capable of delivering a highly effective cancer treatment that includes an immunogenic component. Two tumors received all three therapeutic modalities, one tumor received radiation and hyperthermia, two tumors received radiation and VLP, and three tumors received only mNP hyperthermia. The treatment regimen is conducted over a 14-day period. All patients tolerated the treatments without complication and have had local and distant tumor responses that significantly exceed responses observed following conventional therapy (surgery and/or radiation). The results suggest that both hypofractionated radiation and hyperthermia have effective immune responses that are enhanced by the intratumoral VLP treatment. Molecular data from these tumors suggest Heat Shock Protein (HSP) 70/90, calreticulin and CD47 are targets that can be exploited to enhance the local and systemic (abscopal effect) immune potential of radiation and hyperthermia cancer treatment.

Tetanus toxoid vaccination coverage and differential between urban and rural areas of Bangladesh.

PubMed

Rahman, Mosiur

2009-04-01

Government commitment and support from a range of partnerships have led to a massive increase in tetanus toxoid immunization coverage among women of childbearing age, ensuring that both mothers and babies are protected against tetanus infection in Bangladesh. In order to control and eliminate the vaccine preventable diseases it is important to know the vaccination coverage. The major objective of this study is to determine the complete vaccination rate and the predictors that influence vaccination of mothers during pregnancy and to see whether there is any gap lies between the women of urban and rural areas regarding the tetanus toxoid injection receiving. This study utilizes the data extracted from Bangladesh Demographic and Health Survey 2004 (BDHS).To meets the objectives this study considers bivariate and multivariate analysis. The study represents that 88 per cent urban mothers and 84 per cent rural mothers receive tetanus toxoid injection during their pregnancy period. Logistic regression model is adjusted by wealth index, mother's age at last birth, education, husband's occupation, ever using contraception, fertility preference, wanted last child, having permission to go to hospital/health center, telling about pregnancy complications and mass media exposure for receiving TT injection. All these explanatory variables come out to be as significant determinants of receiving TT injection for all mothers as well as for rural mothers in Bangladesh. On the other hand ever using contraception, wanted last child, telling about pregnancy complications, mass media exposure and wealth index are the significant determinants of receiving TT injection for mothers of urban area.

Uroprotective mechanism of quercetin against cyclophosphamide-induced urotoxicity: Effect on oxidative stress and inflammatory markers.

PubMed

Sherif, Iman O

2018-05-18

The urotoxicity is a common complication associated with patients receiving cyclophosphamide (CYP). This study was designed to investigate the uroprotective mechanism of quercetin (Quer) flavonoid against CYP induced urotoxicity via determination of oxidative stress markers as well as inflammatory mediators in bladder tissue. Forty male Wistar rats were divided into four groups; Normal group: received saline for 10 days. Quer control group: received quercetin 50 mg/kg/day for 10 days. CYP group: received saline for 10 days and injected with a single dose of 150 mg/kg CYP intraperitoneal (i.p) at day 8. The Quer + CYP group: received Quer 50 mg/kg/day for 10 days plus CYP 150 mg/kg i.p. injection at day 8. The CYP injection produced a significant elevation in bladder contents of malondialdehyde (MDA), and nitric oxide (NO), and bladder protein levels and expressions of tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) in addition to the upregulation of cyclooxygenase-2 (COX-2) bladder gene expression. Also, CYP injection showed a marked reduction in bladder levels of catalase, superoxide dismutase (SOD), and IL-10 when compared with normal group. Moreover, histopathological examination of the bladder showed degenerative alterations, severe edema, and inflammation following CYP injection. Quer attenuated the biochemical markers and histopathological changes induced by CYP. The uroprotective effect of Quer was exerted by restoring the balance between oxidative/antioxidative status and pro-/anti-inflammatory cytokines via its antioxidant and anti-inflammatory activities. © 2018 Wiley Periodicals, Inc.

Deltoid Injections of Risperidone Long-acting Injectable in Patients with Schizophrenia

PubMed Central

Quiroz, Jorge A.; Rusch, Sarah; Thyssen, An; Kushner, Stuart

2011-01-01

Background Risperidone long-acting injectable was previously approved for treatment of schizophrenia as biweekly injections in the gluteal muscle only. We present data on local injection-site tolerability and safety of risperidone long-acting injectable and comparability of systemic exposure of deltoid versus gluteal injections. Methods Risperidone long-acting injectable was administered in an open-label, single-dose, two-way crossover study, with patients randomized to receive either 25mg gluteal/37.5mg deltoid crossover in two treatment periods or 50mg gluteal/50mg deltoid injections crossover; each treatment period was separated by an 85-day observation period (Study 1) and an open-label, multiple-dose study (4 sequential 37.5mg or 50mg deltoid injections every 2 weeks) (Study 2). The pharmacokinetic results from both the studies have already been published. Results In Study 1 (n=170), the majority of patients had no local injection-site findings, based on investigator and patient-rated evaluations. In Study 2 (n=53), seven of the 51 patients who received at least two deltoid injections discontinued (primary endpoint). However, none of the discontinuations were due to injection-site related reasons. The 90-percent upper confidence limit of the true proportion of injection-site issue withdrawals was 5.7 percent. No moderate or severe injection-site reactions were reported. Conclusion Intramuscular injections via the deltoid and gluteal sites are equivalent routes of administration of risperidone long-acting injectable with respect to local injection-site tolerability. The overall safety and tolerability profile of risperidone long-acting injectable was comparable when administered as an intramuscular injection in the deltoid (37.5mg and 50mg) and gluteal (25mg and 50mg) sites. PMID:21779538

Parenteral Medication Prescriptions, Dispensing and Administration Habits in Mongolia

PubMed Central

Dorj, Gereltuya; Sunderland, Bruce; Hendrie, Delia; Parsons, Richard

2014-01-01

High levels of injection prescribing were reported in Mongolia. Understanding the factors influencing the injection prescribing is essential to reduce their inappropriate use. The study evaluated the views, experiences and attitudes of community members associated with the prescribing of injections in Mongolia. A structured questionnaire focusing on respondents' characteristics, experiences and views about injections was developed and administered face-to-face to community members in Ulaanbaatar, Mongolia. Standard descriptive statistics were used to summarize demographic data and responses to the questionnaires. Dependant variables were compared using Kruskal-Wallis Tests for independence. Statistical analyses were performed using SPSS Version 21.0. Six hundred participants were approached and the response rate was 79% (n = 474). Almost half of the respondents were aged between 31 and 50 (n = 228, 48.1%) and 40.9% of respondents were male (n = 194). Most respondents were from Ulaanbaatar city (n = 407, 85.7%). All respondents had received injections in the past and 268 (56.5%) had received injection in the past year. The most common reason for having an injection in the past year was reported as treatment of a disease (n = 163, 60.8%), or for administration of vitamins (n = 70, 26.1%). Injections were prescribed by a doctor (n = 353, 74.9%), dispensed by a pharmacist (n = 283, 59.7%) and administered by a nurse (n = 277, 54.9%). Only 16% of all respondents had the expectation of receiving injections when they visited a doctor (n = 77). An important perception regarding injections was that they hastened the recovery process (n = 269, 56.8%). When asked their opinion about therapeutic injections, 40% of all respondents agreed that injections were a better medicine (n = 190) than oral medications, with older respondents strongly agreeing (p<0.001). Based on this total sample, approximately 1891 injections per 1000 patients were administered. The excessive injection use seems to be promoted by inappropriate prescribing, dispensing and administration of medication by doctors and others. PMID:25531766

Rilonacept in the treatment of subacromial bursitis: A randomized, non-inferiority, unblinded study versus triamcinolone acetonide.

PubMed

Carroll, Matthew B; Motley, Spencer A; Wohlford, Susanna; Ramsey, Bryan C

2015-12-01

Subacromial bursitis is caused by inflammation of the bursa that separates the superior surface of the supraspinatus tendon from the overlying coraco-acromial ligament and acromion. While multiple cytokines are implicated, interleukin-1 beta appears to play a prominent role. Rilonacept, an interleukin-1 trap, may be an alternative to corticosteroid injection for the management of this condition. This single center, randomized, non-inferiority, unblinded study recruited 33 subjects over 9 months. Twenty subjects received 160mg intrabursal injection of rilonacept and 13 received a 6mL mixture of lidocaine, bupivacaine, and 80mg triamcinolone acetonide. QuickDASH, subject reported pain, and adverse events were recorded at time of injection, 2 days later, 2 weeks later, and 4 weeks later. Primary outcome was improvement in QuickDASH 4 weeks post-injection. Secondary outcomes were improvement in subject reported pain and occurrence of adverse events at 4 weeks. Both study groups were equally matched for age, gender, ethnicity, and site of bursa injection. Both medications demonstrated a statistically significant improvement in QuickDASH 4 weeks post-injection, but triamcinolone acetonide injection offered greater improvement (P=0.004). Both medications demonstrated improvement in subject reported pain but between group comparison at 4 weeks showed that triamcinolone was superior (P=0.044). No statistically significant differences in adverse events were noted between groups, but subjects who received rilonacept experienced more episodes of diarrhea and headache. While improvement in QuickDASH and pain was noted with a single intrabursal injection of rilonacept at 4 weeks, injection with triamcinolone acetonide was more efficacious. This trial was registered with www.clinicaltrials.gov (NCT01830699). Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits.

PubMed

Labrador Velandia, Sonia; Di Lauro, Salvatore; Alonso-Alonso, Maria Luz; Tabera Bartolomé, Soraya; Srivastava, Girish Kumar; Pastor, José Carlos; Fernandez-Bueno, Ivan

2018-01-01

To evaluate the feasibility, safety, and biocompatibility of intravitreal injection of human mesenchymal stem cells (MSCs) in immunocompetent pigmented rabbits. Thirty-two pigmented rabbits (24 females, 8 males; Chinchilla-New Zealand White) were divided into 8 groups of 4 animals. Commercially prepared human MSCs were injected (0.05 ml) into the post-lens vitreous of the right eyes. Groups 1 and 4 received isotonic medium (Ringer lactate-based), groups 2, 5, 7, and 8 received a low dose of 15 × 10 6 cells/ml. Groups 3 and 6 received a high dose of 30 × 10 6 cells/ml. Clinical signs were evaluated and scored before MSCs injection and weekly for 2 or 6 weeks. Animals were sacrificed at 2 or 6 weeks after injection. Eyes, liver, spleen, and gonads were assessed by histology and by fluorescent in situ hybridization to evaluate survival and extraocular migration of MSCs. There were no relevant clinical findings between control and MSC-injected rabbit eyes at any time point. There were also no relevant histological findings between control and MSC-injected rabbits related to ocular, liver, spleen, or gonad tissues modifications. MSCs survived intravitreally for at least 2 weeks after injection. Extraocular migration of MSCs was not detected. MSCs are safe and well-tolerated when administered intravitreally at a dose of 15 × 10 6 cells/ml in pigmented rabbits. These findings enable future research to explore the intravitreal use of commercially prepared allogenic human MSCs in clinical trials of retinal diseases.

Will a single periarticular lidocaine-corticosteroid injection improve the clinical efficacy of intraarticular hyaluronic acid treatment of symptomatic knee osteoarthritis?

PubMed

Ertürk, Cemil; Altay, Mehmet Akif; Altay, Nuray; Kalender, Ali Murat; Öztürk, İbrahim Avşin

2016-11-01

A local injection of corticosteroid-lidocaine into the periarticular soft tissue structures is used commonly for rapid pain relief. It is hypothesized that knee pain associated with knee osteoarthritis would be relieved quickly and effectively in patients receiving intraarticular hyaluronic acid combined with a periarticular lidocaine-corticosteroid injection. To test this hypothesis, the clinical effect of the combined treatment with hyaluronic acid injection alone in patients with symptomatic knee osteoarthritis as compared in this prospective single-blinded randomized trial. This study included 70 patients. Group 1 (n = 35) received intraarticular hyaluronic acid injections only, whereas group 2 (n = 35) received intraarticular hyaluronic acid injections combined with a single local injection of corticosteroid-lidocaine. Injections were administered to the most painful areas of the anterior or posterior medial condyle of the femur or tibia. The outcome was measured by independent assessors (blinded to treatment) using a linear VAS pain scale and WOMAC and HSS knee scores. Assessments were performed at baseline and at 1, 3, 6, 12, 26, and 52 weeks. During the first 3 weeks, group 2 patients showed significantly better all scores than did group 1 patients (p < 0.01). However, no significant differences were detected at 6, 12, 26 or 52 weeks (n.s.). The combined treatment may lead to earlier pain relief compared with intraarticular hyaluronic acid alone in patients with knee osteoarthritis and can be considered a useful adjunctive treatment modality. This combined method may provide early return to patient's daily activity. Therapeutic study, Level I.

Alternating Bi-Weekly Intravitreal Ranibizumab and Bevacizumab for Refractory Neovascular Age-Related Macular Degeneration with Pigment Epithelial Detachment.

PubMed

Witkin, Andre J; Rayess, Nadim; Garg, Sunir J; Maguire, Joseph I; Storey, Philip; Kaiser, Richard S; Hsu, Jason; Vander, James F; Ho, Allen C

2017-01-01

To describe visual and anatomical outcomes following bi-weekly intravitreal ranibizumab/bevacizumab injections in eyes with refractory neovascular age-related macular degeneration (AMD) and pigment epithelial detachment (PED). Retrospective, consecutive, interventional case series. Eighteen patients diagnosed with neovascular AMD that were refractory to anti-VEGF therapy and received alternating biweekly ranibizumab/bevacizumab injections were included. Patients with neovascular AMD and PED that were refractory to at least 11 monthly ranibizumab or bevacizumab injections were included in this study at a large, single retina practice. Following inclusion, patients received four bi-weekly alternating ranibizumab/bevacizumab intravitreal injections. After completing a course of four bi-weekly injections, patients were treated with variable regimens of intravitreal anti-vascular endothelial growth factor (VEGF) therapy. The primary outcomes of the study included change in visual acuity (VA) and central foveal thickness (CFT) at eight weeks follow-up. Study eyes had previously received a mean of 22 intravitreal anti-VEGF injections. At enrollment, mean VA was 20/95 and mean CFT was 455 µm. After four bi-weekly anti-VEGF injections, mean VA improved to 20/65 (p < 0.001), and mean CFT decreased to 387 µm (p = 0.029). In patients with PED, there was a mean 27.9% reduction in height (p = 0.046) at eight weeks' follow-up. Four injections of bi-weekly alternating ranibizumab/bevacizumab improved visual acuity and reduced macular thickness in a number of patients with refractory neovascular AMD and PED.

Targeted Cancer Therapy: Correlative Light-Electron Microscopy Shows RGD-Targeted ZnO Nanoparticles Dissolve in the Intracellular Environment of Triple Negative Breast Cancer Cells and Cause Apoptosis with Intratumor Heterogeneity (Adv. Healthcare Mater. 11/2016).

PubMed

Othman, Basmah A; Greenwood, Christina; Abuelela, Ayman F; Bharath, Anil A; Chen, Shu; Theodorou, Ioannis; Douglas, Trevor; Uchida, Maskai; Ryan, Mary; Merzaban, Jasmeen S; Porter, Alexandra E

2016-06-01

On page 1310 J. S. Merzaban, A. E. Porter, and co-workers present fluorescently labeled RGD-targeted ZnO nanoparticles (NPs; green) for the targeted delivery of cytotoxic ZnO to integrin αvβ3 receptors expressed on triple negative breast cancer cells. Correlative light-electron microscopy shows that NPs dissolve into ionic Zn(2+) (blue) upon uptake and cause apoptosis (red) with intra-tumor heterogeneity, thereby providing a possible strategy for targeted breast cancer therapy. Cover design by Ivan Gromicho. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Designing and building oncolytic viruses

PubMed Central

Maroun, Justin; Muñoz-Alía, Miguel; Ammayappan, Arun; Schulze, Autumn; Peng, Kah-Whye; Russell, Stephen

2017-01-01

Oncolytic viruses (OVs) are engineered and/or evolved to propagate selectively in cancerous tissues. They have a dual mechanism of action; direct killing of infected cancer cells cross-primes anticancer immunity to boost the killing of uninfected cancer cells. The goal of the field is to develop OVs that are easily manufactured, efficiently delivered to disseminated sites of cancer growth, undergo rapid intratumoral spread, selectively kill tumor cells, cause no collateral damage and pose no risk of transmission in the population. Here we discuss the many virus engineering strategies that are being pursued to optimize delivery, intratumoral spread and safety of OVs derived from different virus families. With continued progress, OVs have the potential to transform the paradigm of cancer care. PMID:29387140

Radiomics in Oncological PET/CT: Clinical Applications.

PubMed

Lee, Jeong Won; Lee, Sang Mi

2018-06-01

18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is widely used for staging, evaluating treatment response, and predicting prognosis in malignant diseases. FDG uptake and volumetric PET parameters such as metabolic tumor volume have been used and are still used as conventional PET parameters to assess biological characteristics of tumors. However, in recent years, additional features derived from PET images by computational processing have been found to reflect intratumoral heterogeneity, which is related to biological tumor features, and to provide additional predictive and prognostic information, which leads to the concept of radiomics. In this review, we focus on recent clinical studies of malignant diseases that investigated intratumoral heterogeneity on PET/CT, and we discuss its clinical role in various cancers.

Phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate in dogs with naturally occurring malignant tumors.

PubMed

Cai, Shuang; Zhang, Ti; Forrest, W C; Yang, Qiuhong; Groer, Chad; Mohr, Eva; Aires, Daniel J; Axiak-Bechtel, Sandra M; Flesner, Brian K; Henry, Carolyn J; Selting, Kimberly A; Tate, Deborah; Swarz, Jeffrey A; Bryan, Jeffrey N; Forrest, M Laird

2016-09-01

OBJECTIVE To conduct a phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate (HA-Pt) in dogs with naturally occurring malignant tumors. ANIMALS 18 healthy rats, 9 healthy mice, and 16 dogs with cancer. PROCEDURES HA-Pt was prepared and tested by inductively coupled plasma mass spectrometry; DNA-platinum adduct formation and antiproliferation effects of cisplatin and HA-Pt were compared in vitro. Effects of cisplatin (IV) and HA-Pt (SC) in rodents were tested by clinicopathologic assays. In the clinical trial, dogs with cancer received 1 to 4 injections of HA-Pt (10 to 30 mg/m(2), intratumoral or peritumoral, q 3 wk). Blood samples were collected for pharmacokinetic analysis; CBC, serum BUN and creatinine concentration measurement, and urinalysis were conducted before and 1 week after each treatment. Some dogs underwent hepatic enzyme testing. Tumors were measured before the first treatment and 3 weeks after each treatment to assess response. RESULTS No adverse drug effects were detected in pretrial assessments in rodents. Seven of 16 dogs completed the study; 3 had complete tumor responses, 3 had stable disease, and 1 had progressive disease. Three of 7 dogs with oral and nasal squamous cell carcinoma (SCC) that completed the study had complete responses. Myelosuppression and cardiotoxicosis were identified in 6 and 2 dogs, respectively; none had nephrotoxicosis. Four of 5 dogs with hepatic enzymes assessed had increased ALT activities, attributed to diaquated cisplatin products in the HA-Pt. Pharmacokinetic data fit a 3-compartment model. CONCLUSIONS AND CLINICAL RELEVANCE HA-Pt treatment resulted in positive tumor responses in some dogs, primarily those with SCC. The adverse effect rate was high. IMPACT FOR HUMAN MEDICINE Oral SCC in dogs has characteristics similar to human head and neck SCC; these results could be useful in developing human treatments.

Preliminary evaluation of the Highland Rim aquifer system in Tennessee for receiving injected wastes

USGS Publications Warehouse

Bradley, M.W.

1986-01-01

The EPA has authority under the Safe Drinking Water Act to protect underground sources of drinking water from contamination by deep well injection. An aquifer, however, may be exempted from protection and used for injected wastes where the aquifer meets criteria established in the Agency 's Underground Injection Control program. The Highland Rim aquifer system in Tennessee consists of Mississippian age carbonate rocks and occurs from the Valley and Ridge of East Tennessee to west of the Tennessee River. This aquifer contains potable water and is an important source of drinking water for municipal and domestic supplies on the Highland Rim. The Highland Rim aquifer system under parts of the Cumberland Plateau is not currently used as a source of drinking water and is not expected to be used in the future. These areas meet parts of the EPA 's Underground Injection Control criteria for exempting aquifers to receive injected waste. (Author 's abstract)

Antisense imaging of epidermal growth factor-induced p21(WAF-1/CIP-1) gene expression in MDA-MB-468 human breast cancer xenografts.

PubMed

Wang, Judy; Chen, Paul; Mrkobrada, Marko; Hu, Meiduo; Vallis, Katherine A; Reilly, Raymond M

2003-09-01

Molecular imaging of the expression of key genes which determine the response to DNA damage following cancer treatment may predict the effectiveness of a particular treatment strategy. A prominent early response gene for DNA damage is the gene encoding p21(WAF-1/CIP-1), a cyclin-dependent kinase inhibitor that regulates progression through the cell cycle. In this study, we explored the feasibility of imaging p21(WAF-1/CIP-1) gene expression at the mRNA level using an 18-mer phosphorothioated antisense oligodeoxynucleotide (ODN) labeled with (111)In. The known induction of the p21(WAF-1/CIP-1) gene in MDA-MB-468 human breast cancer cells following exposure to epidermal growth factor (EGF) was used as an experimental tool. Treatment of MDA-MB-468 cells in vitro with EGF (20 n M) increased the ratio of p21(WAF-1/CIP-1) mRNA/beta-actin mRNA threefold within 2 h as measured by the reverse transcription polymerase chain reaction (RT-PCR). A concentration-dependent inhibition of EGF-induced p21(WAF-1/CIP-1) protein expression was achieved in MDA-MB-468 cells by treatment with antisense ODNs with up to a tenfold decrease observed at 1 microM. There was a fourfold lower inhibition of p21(WAF-1/CIP-1) protein expression by control sense or random sequence ODNs. Intratumoral injections of EGF (15 microg/dayx3 days) were employed to induce p21(WAF-1/CIP-1) gene expression in MDA-MB-468 xenografts implanted subcutaneously into athymic mice. RT-PCR of explanted tumors showed a threefold increased level of p21(WAF-1/CIP-1) mRNA compared with normal saline-treated tumors. Successful imaging of EGF-induced p21(WAF-1/CIP-1) gene expression in MDA-MB-468 xenografts was achieved at 48 h post injection of (111)In-labeled antisense ODNs (3.7 MBq; 2 microg). Tumors displaying basal levels of p21(WAF-1/CIP-1) gene expression in the absence of EGF treatment could not be visualized. Biodistribution studies showed a significantly higher tumor accumulation of (111)In-labeled antisense ODNs in the presence of EGF induction of the p21(WAF-1/CIP-1) gene (0.32%+/-0.06% injected dose/g) compared with normal saline-treated control mice (0.11%+/-0.07% injected dose/g). The tumor/blood ratio for antisense ODNs in the presence of EGF induction of the p21(WAF-1/CIP-1) gene (4.87+/-0.87) was also significantly higher than for control random sequence ODNs (2.14+/-0.69) or for mice receiving antisense ODNs but not treated with EGF (2.07+/-0.37). We conclude that antisense imaging of upregulated p21(WAF-1/CIP-1) gene expression is feasible and could represent a promising new molecular imaging strategy for monitoring tumor response in cancer patients. To our knowledge, this study also describes the first report of molecular imaging of the upregulated expression of a downstream gene target of the EGFR, a transmembrane tyrosine kinase receptor.

Rates of fuel discharge as affected by the design of fuel-injection systems for internal-combustion engines

NASA Technical Reports Server (NTRS)

Gelalles, A G; Marsh, E T

1933-01-01

Using the method of weighing fuel collected in a receiver during a definite interval of the injection period, rates of discharge were determined, and the effects noted, when various changes were made in a fuel-injection system. The injection system consisted primarily of a by-pass controlled fuel pump and an automatic injection valve. The variables of the system studied were the pump speed, pump-throttle setting, discharge-orifice diameter, injection-valve opening and closing pressures, and injection-tube length and diameter.

Intratumoral iron oxide nanoparticle hyperthermia and radiation cancer treatment

NASA Astrophysics Data System (ADS)

Hoopes, P. J.; Strawbridge, R. R.; Gibson, U. J.; Zeng, Q.; Pierce, Z. E.; Savellano, M.; Tate, J. A.; Ogden, J. A.; Baker, I.; Ivkov, R.; Foreman, A. R.

2007-02-01

The potential synergism and benefit of combined hyperthermia and radiation for cancer treatment is well established, but has yet to be optimized clinically. Specifically, the delivery of heat via external arrays /applicators or interstitial antennas has not demonstrated the spatial precision or specificity necessary to achieve appropriate a highly positive therapeutic ratio. Recently, antibody directed and possibly even non-antibody directed iron oxide nanoparticle hyperthermia has shown significant promise as a tumor treatment modality. Our studies are designed to determine the effects (safety and efficacy) of iron oxide nanoparticle hyperthermia and external beam radiation in a murine breast cancer model. Methods: MTG-B murine breast cancer cells (1 x 106) were implanted subcutaneous in 7 week-old female C3H/HeJ mice and grown to a treatment size of 150 mm3 +/- 50 mm3. Tumors were then injected locally with iron oxide nanoparticles and heated via an alternating magnetic field (AMF) generator operated at approximately 160 kHz and 400 - 550 Oe. Tumor growth was monitored daily using standard 3-D caliper measurement technique and formula. specific Mouse tumors were heated using a cooled, 36 mm diameter square copper tube induction coil which provided optimal heating in a 1 cm wide region in the center of the coil. Double dextran coated 80 nm iron oxide nanoparticles (Triton Biosystems) were used in all studies. Intra-tumor, peri-tumor and rectal (core body) temperatures were continually measured throughout the treatment period. Results: Preliminary in vivo nanoparticle-AMF hyperthermia (167 KHz and 400 or 550 Oe) studies demonstrated dose responsive cytotoxicity which enhanced the effects of external beam radiation. AMF associated eddy currents resulted in nonspecific temperature increases in exposed tissues which did not contain nanoparticles, however these effects were minor and not injurious to the mice. These studies also suggest that iron oxide nanoparticle hyperthermia is more effective than non-nanoparticle tumor heating techniques when similar thermal doses are applied. Initial electron and light microscopy studies of iron oxide nanoparticle and AMF exposed tumor cells show a rapid uptake of particles and acute cytotoxicity following AMF exposure.

30 CFR 250.124 - Will MMS approve gas injection into the cap rock containing a sulphur deposit?

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 2 2010-07-01 2010-07-01 false Will MMS approve gas injection into the cap... SHELF General Performance Standards § 250.124 Will MMS approve gas injection into the cap rock containing a sulphur deposit? To receive the Regional Supervisor's approval to inject gas into the cap rock...

Healthcare Utilization and Costs of Knee or Hip Replacements versus Pain-Relief Injections

PubMed Central

Pasquale, Margaret K.; Louder, Anthony M.; Cheung, Raymond Y.; Reiners, Andrew T.; Mardekian, Jack; Sanchez, Robert J.; Goli, Veerainder

2015-01-01

Background Given the dramatic increase in total knee and hip replacement procedures among the US population aged 45 years and older, there is a need to compare the downstream healthcare utilization and costs between patients who undergo joint replacement and those who receive intraarticular injections as a low-cost alternative. Objective To compare changes in osteoarthritis (OA)-related healthcare utilization and costs for Medicare members with OA who underwent knee or hip replacement versus those receiving steroid or viscosupplementation injections. Methods Medicare members aged ≥45 years diagnosed with OA were identified for this retrospective longitudinal study. Data were compared for patients who underwent primary knee or hip replacement surgery between July 1, 2007, and June 30, 2012, and those receiving injection of pain-relief medication during the same period. The date of joint replacement surgery was considered the index date. For the comparison cohort, the index date was 180 days postinjection of the first intraarticular injection. Medical and pharmacy claims were examined longitudinally in 90-day increments, from 180 days preindex until 360 days postindex. Difference-in-difference analyses were conducted to compare the change in OA-related healthcare costs, postindex versus preindex, between the study cohorts. Time-to-event analyses were used to measure rates of readmissions and venous thromboembolism (VTE). Results The mean age was 70.7 years for patients with knee replacement, 71.7 years for those with hip replacement, and 71.1 years for those receiving pain-relief injection (P <.0001). The RxRisk-V comorbidity index scores were 4.7, 4.4, and 4.8, respectively (P <.0001). Difference-in-difference analyses indicated that decreases in OA-related costs were greater for the joint replacement cohorts (coefficient for knee replacement*time: −0.603; hip replacement*time: −0.438; P <.001 for both) than for the comparison cohort. The VTE rates were 5.6% (knee) and 5.1% (hip) postsurgery versus 1.4% (knee) and 1.3% (hip) presurgery. Conclusion The overall difference-in-difference results showed a greater decrease in healthcare utilization and costs for the members with joint replacement than for those receiving injection. PMID:26557232

Efficacy of pressure topical anaesthesia in punctal occlusion by diathermy

PubMed Central

Law, R W K; Li, R T H; Lam, D S C; Lai, J S M

2005-01-01

Aims: To prospectively compare the efficacy and safety of pressure topical anaesthesia in punctal occlusion by using cautery in the treatment of dry eye syndrome (DES) with that of conventional treatment by using needle injection of anaesthetic agents. Methods: In a randomised controlled trial, 18 consecutive adult patients with DES requiring punctal occlusion were recruited over a 10 month period. Consenting patients were randomised into two groups. Group A patients received pressure topical anaesthesia in the right eye followed by injection anaesthesia in the left eye. Group B was vice versa. Punctal occlusion using cautery was performed in each eye after a specified time following the application of anaesthesia. The main outcome measures were the pain experienced during application of anaesthesia and that during punctal occlusion. Results: 36 eyes of 18 patients were randomised to receive injection anaesthesia in one eye and pressure topical anaesthesia in the other. Nine patients (nine females) were in group A and nine patients (seven females, two males) in group B. The mean age of group A patients was 45.3 (SD 13.5) years, and that of group B patients was 55.6 (12.6) years. The two groups were comparable in terms of mean age (p = 0.117) and mean pain score for pressure topical anaesthesia application (p = 0.612), injection anaesthesia application (p = 0.454), diathermy in pressure anaesthetised eyes (p = 0.113), and diathermy in injection anaesthetised eyes (p = 0.289). Paired t test was used to compare the mean pain score for pressure topical anaesthesia application (16.8 (24.8)) with those for injection anaesthesia application (56.7 (30.0)). 18 eyes of 18 patients were compared with the fellow eye of the same 18 patients. The mean pain score for injection anaesthesia was greater than for pressure topical anaesthesia application (p<0.0001) (statistical power = 0.87). No statistically significant difference was found in the mean pain score for diathermy for eyes that received pressure topical anaesthesia (20.5 (27.5)) compared with eyes that received injection anaesthesia (23.1 (26.3)) (p = 0.760) (statistical power = 0.96). All 18 patients preferred pressure topical anaesthesia to injection anaesthesia. Conclusion: Injection anaesthesia for punctal occlusion is more painful than pressure topical anaesthesia application. However, the pain experienced during diathermy application for punctal occlusion is similar between pressure anaesthetised eyes and injection anaesthetised eyes. Pressure topical anaesthesia is a less painful (in terms of anaesthesia application) but equally effective alternative to conventional injection anaesthesia when used for punctal occlusion. PMID:16234451

Efficacy of pressure topical anaesthesia in punctal occlusion by diathermy.

PubMed

Law, R W K; Li, R T H; Lam, D S C; Lai, J S M

2005-11-01

To prospectively compare the efficacy and safety of pressure topical anaesthesia in punctal occlusion by using cautery in the treatment of dry eye syndrome (DES) with that of conventional treatment by using needle injection of anaesthetic agents. In a randomised controlled trial, 18 consecutive adult patients with DES requiring punctal occlusion were recruited over a 10 month period. Consenting patients were randomised into two groups. Group A patients received pressure topical anaesthesia in the right eye followed by injection anaesthesia in the left eye. Group B was vice versa. Punctal occlusion using cautery was performed in each eye after a specified time following the application of anaesthesia. The main outcome measures were the pain experienced during application of anaesthesia and that during punctal occlusion. 36 eyes of 18 patients were randomised to receive injection anaesthesia in one eye and pressure topical anaesthesia in the other. Nine patients (nine females) were in group A and nine patients (seven females, two males) in group B. The mean age of group A patients was 45.3 (SD 13.5) years, and that of group B patients was 55.6 (12.6) years. The two groups were comparable in terms of mean age (p=0.117) and mean pain score for pressure topical anaesthesia application (p=0.612), injection anaesthesia application (p=0.454), diathermy in pressure anaesthetised eyes (p=0.113), and diathermy in injection anaesthetised eyes (p=0.289). Paired t test was used to compare the mean pain score for pressure topical anaesthesia application (16.8 (24.8)) with those for injection anaesthesia application (56.7 (30.0)). 18 eyes of 18 patients were compared with the fellow eye of the same 18 patients. The mean pain score for injection anaesthesia was greater than for pressure topical anaesthesia application (p<0.0001) (statistical power=0.87). No statistically significant difference was found in the mean pain score for diathermy for eyes that received pressure topical anaesthesia (20.5 (27.5)) compared with eyes that received injection anaesthesia (23.1 (26.3)) (p=0.760) (statistical power=0.96). All 18 patients preferred pressure topical anaesthesia to injection anaesthesia. Injection anaesthesia for punctal occlusion is more painful than pressure topical anaesthesia application. However, the pain experienced during diathermy application for punctal occlusion is similar between pressure anaesthetised eyes and injection anaesthetised eyes. Pressure topical anaesthesia is a less painful (in terms of anaesthesia application) but equally effective alternative to conventional injection anaesthesia when used for punctal occlusion.

Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts

PubMed Central

Zhu, Yin; Cheng, Ming; Yang, Zhen; Zeng, Chun-Yan; Chen, Jiang; Xie, Yong; Luo, Shi-Wen; Zhang, Kun-He; Zhou, Shu-Feng; Lu, Nong-Hua

2014-01-01

Mesenchymal stem cells (MSCs) have been recognized as promising delivery vehicles for gene therapy of tumors. Gastric cancer is the third leading cause of worldwide cancer mortality, and novel treatment modalities are urgently needed. NK4 is an antagonist of hepatocyte growth factor receptors (Met) which are often aberrantly activated in gastric cancer and thus represent a useful candidate for targeted therapies. This study investigated MSC-delivered NK4 gene therapy in nude mice bearing gastric cancer xenografts. MSCs were transduced with lentiviral vectors carrying NK4 complementary DNA or enhanced green fluorescent protein (GFP). Such transduction did not change the phenotype of MSCs. Gastric cancer xenografts were established in BALB/C nude mice, and the mice were treated with phosphate-buffered saline (PBS), MSCs-GFP, Lenti-NK4, or MSCs-NK4. The tropism of MSCs toward gastric cancer cells was determined by an in vitro migration assay using MKN45 cells, GES-1 cells and human fibroblasts and their presence in tumor xenografts. Tumor growth, tumor cell apoptosis and intratumoral microvessel density of tumor tissue were measured in nude mice bearing gastric cancer xenografts treated with PBS, MSCs-GFP, Lenti-NK4, or MSCs-NK4 via tail vein injection. The results showed that MSCs migrated preferably to gastric cancer cells in vitro. Systemic MSCs-NK4 injection significantly suppressed the growth of gastric cancer xenografts. MSCs-NK4 migrated and accumulated in tumor tissues after systemic injection. The microvessel density of tumor xenografts was decreased, and tumor cellular apoptosis was significantly induced in the mice treated with MSCs-NK4 compared to control mice. These findings demonstrate that MSC-based NK4 gene therapy can obviously inhibit the growth of gastric cancer xenografts, and MSCs are a better vehicle for NK4 gene therapy than lentiviral vectors. Further studies are warranted to explore the efficacy and safety of the MSC-based NK4 gene therapy in animals and cancer patients. PMID:25525335

Thawing frozen shoulder by steroid injection.

PubMed

Pushpasekaran, Narendran; Kumar, Narender; Chopra, R K; Borah, Diganta; Arora, Sumit

2017-01-01

Frozen shoulder is not an uncommon disorder, and steroid injection into the glenohumeral (GH) joint is one of the most well-known approaches for the frozen shoulder. However, their results have been varied with beneficial effects or no additional advantage. With the understanding about the pathological changes taking place in frozen shoulder and the biomechanics involved, we wanted to evaluate the short- and long-term efficacy of steroid injection by a novel three-site (NTS) injection technique and compare it with the single-site injection (SSI). This was a prospective study with 85 patients including all stages and randomized into two groups. SSI group received steroid injection through posterior approach. NTS group received the same dose of steroid in diluted doses at three sites (posterior capsule, subacromial and subcoracoid). Second sitting was repeated after 3 weeks. Both groups had received the same physiotherapy. The patients were evaluated by CONSTANT score at initial, 3 week, 6 week and 6 month. NTS group patients had significant pain relief and early improvement in activities of daily living ( p < 0.005). Both groups had improvement in shoulder movements but with NTS group, early near-normal scores were attained and sustained after 6 months. About 43% in SSI group could not attain near-normal levels and had relapses. The three-site approach to steroid instillation in frozen shoulder is a safe method and provides early recovery and better improvement in shoulder function with less relapses.

Generation of a CW local oscillator signal using a stabilized injection locked semiconductor laser

NASA Astrophysics Data System (ADS)

Pezeshki, Jonah Massih

In high speed-communications, it is desirable to be able to detect small signals while maintaining a low bit-error rate. Conventional receivers for high-speed fiber optic networks are Amplified Direct Detectors (ADDs) that use erbium-doped fiber amplifiers (EDFAs) before the detector to achieve a suitable sensitivity. In principle, a better method for obtaining the maximum possible signal to noise ratio is through the use of homodyne detection. The major difficulty in implementing a homodyne detection system is the generation of a suitable local oscillator signal. This local oscillator signal must be at the same frequency as the received data signal, as well as be phase coherent with it. To accomplish this, a variety of synchronization techniques have been explored, including Optical Phase-Lock Loops (OPLL), Optical Injection Locking (OIL) with both Fabry-Perot and DFB lasers, and an Optical Injection Phase-Lock Loop (OIPLL). For this project I have implemented a method for regenerating a local oscillator from a portion of the received optical signal. This regenerated local oscillator is at the same frequency, and is phase coherent with, the received optical signal. In addition, we show that the injection locking process can be electronically stabilized by using the modulation transfer ratio of the slave laser as a monitor, given either a DFB or Fabry-Perot slave laser. We show that this stabilization technique maintains injection lock (given a locking range of ˜1GHz) for laser drift much greater than what is expected in a typical transmission system. In addition, we explore the quality of the output of the slave laser, and analyze its suitability as a local oscillator signal for a homodyne receiver.

A Vibration Device to Control Injection Discomfort.

PubMed

Shaefer, Jeffry R; Lee, Stephanie J; Anderson, Nina K

2017-06-01

Pain from local anesthesia injections can be reduced by distraction and counter-stimulation techniques. This study investigated the DentalVibe® Injection Comfort System (third-generation, DV3), developed to lessen anesthesia pain through pulsed vibration, a form of counter-stimulation. The aim of the study was to evaluate both the efficacy of DV3 in reducing pain and discomfort from intraoral long buccal (LB) and inferior alveolar nerve (IAN) injections and the time needed to achieve complete anesthesia during an IAN block. The study enrolled 60 subjects, 30 men and 30 women, aged 21 to 32 years, who rated both injection pain on a visual analog scale and discomfort, unpleasantness, and difficulty in enduring the injection on a modified symptom severity index. Each subject received bilateral LB injections and an IAN block. Using block design, the third-generation DV (DV3) was randomly assigned to either the first or second LB injection and to 30 subjects on their third injection, the IAN block. No topical anesthesia was applied. Subjects receiving DV3 reported significantly less pain, discomfort, unpleasantness, and difficulty in enduring LB and IAN injections (P < .05), regardless of whether DV3 was used on the first or second LB injection. Time to complete anesthesia was not significantly different (P > .05) when DV3 was used on IAN block injections. The DV3 significantly (P < .02) reduced pain/discomfort from anesthetic injections in this pilot study, in which many subjects were either dental or medical students familiar with performing and enduring injections. More studies are warranted on layperson populations.

Triple Therapy of HER2+ Cancer Using Radiolabeled Multifunctional Iron Oxide Nanoparticles and Alternating Magnetic Field.

PubMed

Zolata, Hamidreza; Afarideh, Hossein; Davani, Fereydoun Abbasi

2016-11-01

By using radio-labeled multifunctional superparamagnetic iron oxide nanoparticles (SPIONs) and an alternating magnetic field (AMF), we carried out targeted hyperthermia, drug delivery, radio-immunotherapy (RIT), and controlled chemotherapy of cancer tumors. We synthesized and characterized Indium-111-labeled, Trastuzumab and Doxorubicin (DOX)-conjugated APTES-PEG-coated SPIONs in our previous work. Then, we evaluated their capability in SPECT/MRI (single photon emission computed tomography/magnetic resonance imaging) dual modal molecular imaging, targeting, and controlled release. In this research, AMF was introduced to evaluate therapeutic effects of magnetic hyperthermia on radionuclide-chemo therapy of HER2 + cells and tumor (HER2 + )-bearing mice. In vitro and in vivo experiments using synthesized complex were repeated under an AMF (f: 100 KHz, H: 280 Gs). Instead of an intra-tumor injection in most hyperthermia experiments, SPIONs were injected to the tail vein, based on our delivery strategies. For magnetic delivery, we held a permanent Nd-B-Fe magnet near the tumor region. The results showed that simultaneous magnetic hyperthermia enhanced SKBR3 cancer cells, killing by 24%, 28%, 33%, and 80% at 48 hours post-treatment for treated cells with (1) bare SPIONs; (2) antibody-conjugated, DOX-free, surface-modified SPIONs; (3) 111 In-labeled, antibody-conjugated surface-modified SPIONs; and (4) 111 In-labeled, antibody- and DOX-conjugated surface-modified SPIONs, respectively. Moreover, tumor volume inhibitory rate was 85% after a 28 day period of treatment. By using this method, multimodal imaging-guided, targeted hyperthermia, RIT, and controlled chemotherapy could be achievable in the near future.

Disabled infectious single cycle herpes simplex virus (DISC-HSV) is a candidate vector system for gene delivery/expression of GM-CSF in human prostate cancer therapy.

PubMed

Parkinson, Richard J; Mian, Shahid; Bishop, Michael C; Gray, Trevor; Li, Geng; McArdle, Stephanie E B; Ali, Selman; Rees, Robert C

2003-06-15

DISC-HSV is a replication incompetent herpes simplex virus that is a highly efficient vector for the transduction of genes in vivo and in vitro. We examine the ability of DISC-HSV to infect human prostate cancer cell-lines and xenograft tumor models, and induce expression of reporter and therapeutic cytokine genes. Infection was confirmed by cellular staining for the beta-galactosidase reporter gene product, and by EM. Human GM-CSF production following DISC-hGMCSF infection was measured using ELISA. The metabolic activity of infected cells was determined by NADP/NADPH assay. Cell death was estimated by cell-cycle analysis using flow cytometry with propidium iodide staining. Infection of DU145, PC3 and LNCaP cells with DISC-HSV was dose dependent. Cells infected with DISC-hGM-CSF released significant levels of hGM-CSF for 3 days. NADP/NADPH assay suggested that infected cells continued to be metabolically active for 3 days post-infection, which was consistent with flow cytometry findings that cell death did not occur within 7 days of infection. Tumor xenografts injected with DISC-HSV expressed beta-galactosidase, and intracellular viral particles were demonstrated using EM. We have previously reported the rejection of established tumors following intra-tumoral injection of DISC-GMCSF. This study demonstrates the ability of DISC-HSV to infect prostate cancer and express GMCSF at significant levels. We suggest that prostate cancer is a potential target for therapy using DISC-HSV containing GM-CSF. Copyright 2003 Wiley-Liss, Inc.

Serotype chimeric oncolytic adenovirus coding for GM-CSF for treatment of sarcoma in rodents and humans.

PubMed

Bramante, Simona; Koski, Anniina; Kipar, Anja; Diaconu, Iulia; Liikanen, Ilkka; Hemminki, Otto; Vassilev, Lotta; Parviainen, Suvi; Cerullo, Vincenzo; Pesonen, Saila K; Oksanen, Minna; Heiskanen, Raita; Rouvinen-Lagerström, Noora; Merisalo-Soikkeli, Maiju; Hakonen, Tiina; Joensuu, Timo; Kanerva, Anna; Pesonen, Sari; Hemminki, Akseli

2014-08-01

Sarcomas are a relatively rare cancer, but often incurable at the late metastatic stage. Oncolytic immunotherapy has gained attention over the past years, and a wide range of oncolytic viruses have been delivered via intratumoral injection with positive safety and promising efficacy data. Here, we report preclinical and clinical results from treatment of sarcoma with oncolytic adenovirus Ad5/3-D24-GMCSF (CGTG-102). Ad5/3-D24-GMCSF is a serotype chimeric oncolytic adenovirus coding for human granulocyte-macrophage colony-stimulating factor (GM-CSF). The efficacy of Ad5/3-D24-GMCSF was evaluated on a panel of soft-tissue sarcoma (STS) cell lines and in two animal models. Sarcoma specific human data were also collected from the Advanced Therapy Access Program (ATAP), in preparation for further clinical development. Efficacy was seen in both in vitro and in vivo STS models. Fifteen patients with treatment-refractory STS (13/15) or primary bone sarcoma (2/15) were treated in ATAP, and treatments appeared safe and well-tolerated. A total of 12 radiological RECIST response evaluations were performed, and two cases of minor response, six cases of stable disease and four cases of progressive disease were detected in patients progressing prior to virus treatment. Overall, the median survival time post treatment was 170 days. One patient is still alive at 1,459 days post virus treatment. In summary, Ad5/3-D24-GMCSF appears promising for the treatment of advanced STS; a clinical trial for treatment of refractory injectable solid tumors including STS is ongoing. © 2013 UICC.

Near-infrared emitting fluorescent nanocrystals-labeled natural killer cells as a platform technology for the optical imaging of immunotherapeutic cells-based cancer therapy

NASA Astrophysics Data System (ADS)

Taik Lim, Yong; Cho, Mi Young; Noh, Young-Woock; Chung, Jin Woong; Chung, Bong Hyun

2009-11-01

This study describes the development of near-infrared optical imaging technology for the monitoring of immunotherapeutic cell-based cancer therapy using natural killer (NK) cells labeled with fluorescent nanocrystals. Although NK cell-based immunotherapeutic strategies have drawn interest as potent preclinical or clinical methods of cancer therapy, there are few reports documenting the molecular imaging of NK cell-based cancer therapy, primarily due to the difficulty of labeling of NK cells with imaging probes. Human natural killer cells (NK92MI) were labeled with anti-human CD56 antibody-coated quantum dots (QD705) for fluorescence imaging. FACS analysis showed that the NK92MI cells labeled with anti-human CD56 antibody-coated QD705 have no effect on the cell viability. The effect of anti-human CD56 antibody-coated QD705 labeling on the NK92MI cell function was investigated by measuring interferon gamma (IFN- γ) production and cytolytic activity. Finally, the NK92MI cells labeled with anti-human CD56 antibody-coated QD705 showed a therapeutic effect similar to that of unlabeled NK92MI cells. Images of intratumorally injected NK92MI cells labeled with anti-human CD56 antibody-coated could be acquired using near-infrared optical imaging both in vivo and in vitro. This result demonstrates that the immunotherapeutic cells labeled with fluorescent nanocrystals can be a versatile platform for the effective tracking of injected therapeutic cells using optical imaging technology, which is very important in cell-based cancer therapies.

Fructose-fed streptozotocin-injected rat: an alternative model for type 2 diabetes.

PubMed

Wilson, Rachel D; Islam, Md Shahidul

2012-01-01

The main objective of the study was to develop an alternative non-genetic rat model for type 2 diabetes (T2D). Six-week-old male Sprague-Dawley rats (190.56 ± 23.60 g) were randomly divided into six groups, namely: Normal Control (NC), Diabetic Control (DBC), Fructose-10 (FR10), Fructose-20 (FR20), Fructose-30 (FR30) and Fructose-40 (FR40) and were fed a normal rat pellet diet ad libitum for 2 weeks. During this period, the two control groups received normal drinking water whilst the fructose groups received 10, 20, 30 and 40% fructose in drinking water ad libitum, respectively. After two weeks of dietary manipulation, all groups except the NC group received a single injection (i.p.) of streptozotocin (STZ) (40 mg/kg b.w.) dissolved in citrate buffer (pH 4.4). The NC group received only a vehicle buffer injection (i.p.). One week after the STZ injection, animals with non-fasting blood glucose levels > 300 mg/dl were considered as diabetic. Three weeks after the STZ injection, the animals in FR20, FR30 and FR40 groups were eliminated from the study due to the severity of diabetes and the FR10 group was selected for the remainder of the 11 weeks experimental period. The significantly (p < 0.05) higher fluid intake, blood glucose, serum lipids, liver glycogen, liver function enzymes and insulin resistance (HOMA-IR) and significantly (p < 0.05) lower body weight, oral glucose tolerance, number of pancreatic β-cells and pancreatic β-cell functions (HOMA-β) of FR10 group demonstrate that the 10% fructose-fed followed by 40 mg/kg of BWSTZ injected rat can be a new and alternative model for T2D.

Minireview: SLCO and ABC Transporters: A Role for Steroid Transport in Prostate Cancer Progression

PubMed Central

Cho, Eunpi; Montgomery, R. Bruce

2014-01-01

Androgens play a critical role in the development and progression of prostate cancer (PCa), and androgen deprivation therapy via surgical or medical castration is front-line therapy for patients with advanced PCa. However, intratumoral testosterone levels are elevated in metastases from patients with castration-resistant disease, and residual intratumoral androgens have been implicated in mediating ligand-dependent mechanisms of androgen receptor activation. The source of residual tissue androgens present despite castration has not been fully elucidated, but proposed mechanisms include uptake and conversion of adrenal androgens, such as dehdroepiandrosterone to testosterone and dihydrotestosterone, or de novo androgen synthesis from cholesterol or progesterone precursors. In this minireview, we discuss the emerging evidence that suggests a role for specific transporters in mediating transport of steroids into or out of prostate cells, thereby influencing intratumoral androgen levels and PCa development and progression. We focus on the solute carrier and ATP binding cassette gene families, which have the most published data for a role in PCa-related steroid transport, and review the potential impact of genetic variation on steroid transport activity and PCa outcomes. Continued assessment of transport activity in PCa models and human tumor tissue is needed to better delineate the different roles these transporters play in physiologic and neoplastic settings, and in order to determine whether targeting the uptake of steroid substrates by specific transporters may be a clinically feasible therapeutic strategy. PMID:25147980

Nerve Growth Factor Expression Is Not Associated with Perineural Invasion in Extrahepatic Cholangiocarcinoma.

PubMed

Urabe, Kazuhide; Murakami, Yoshiaki; Kondo, Naru; Uemura, Kenichiro; Hashimoto, Yasushi; Nakagawa, Naoya; Sasaki, Hayato; Hiyama, Eiso; Takahashi, Shinya; Sueda, Taijiro

2016-03-01

Although the presence of perineural invasion has been recognized as a poor prognostic factor in extrahepatic cholangiocarcinoma, the molecular mechanisms of perineural invasion in extrahepatic cholangiocarcinoma remain unclear. Nerve growth factor has been reported to be a candidate predictive biomarker of perineural invasion in some cancers. To investigate the impact of intratumoral nerve growth factor expression in resected extrahepatic cholangiocarcinoma on survival. Intratumoral nerve growth factor expression was investigated immunohistochemically in 112 patients with resected extrahepatic cholangiocarcinoma. Associations between nerve growth factor expression and clinicopathological factors were statistically evaluated, and risk factors for poor survival were analyzed using univariate and multivariate analyses. High and low nerve growth factor expression was observed in 62 (55%) and 50 (45%) patients, respectively. For all 112 patients, no significant correlation was found between nerve growth factor expression and presence of perineural invasion (P = 0.942). Moreover, nerve growth factor expression was not associated with recurrence-free survival (P = 0.861) and overall survival (P = 0.973). In multivariate analysis, lymph node metastasis (P = 0.004) was identified as an independent risk factor for early recurrence and the presence of perineural invasion (P = 0.002) and lymph node metastasis (P < 0.001) was identified as independent risk factors for poor survival. Intratumoral nerve growth factor expression is not associated with perineural invasion or recurrence-free and overall survival in patients with resected extrahepatic cholangiocarcinoma.

Noninvasive visualization of in vivo release and intratumoral distribution of surrogate MR contrast agent using the dual MR contrast technique.

PubMed

Onuki, Yoshinori; Jacobs, Igor; Artemov, Dmitri; Kato, Yoshinori

2010-09-01

A direct evaluation of the in vivo release profile of drugs from carriers is a clinical demand in drug delivery systems, because drug release characterized in vitro correlates poorly with in vivo release. The purpose of this study is to demonstrate the in vivo applicability of the dual MR contrast technique as a useful tool for noninvasive monitoring of the stability and the release profile of drug carriers, by visualizing in vivo release of the encapsulated surrogate MR contrast agent from carriers and its subsequent intratumoral distribution profile. The important aspect of this technique is that it incorporates both positive and negative contrast agents within a single carrier. GdDTPA, superparamagnetic iron oxide nanoparticles, and 5-fluorouracil were encapsulated in nano- and microspheres composed of poly(D,L-lactide-co-glycolide), which was used as a model carrier. In vivo studies were performed with orthotopic xenograft of human breast cancer. The MR-based technique demonstrated here has enabled visualization of the delivery of carriers, and release and intratumoral distribution of the encapsulated positive contrast agent. This study demonstrated proof-of-principle results for the noninvasive monitoring of in vivo release and distribution profiles of MR contrast agents, and thus, this technique will make a great contribution to the field. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

FUNCTIONAL SUBCLONE PROFILING FOR PREDICTION OF TREATMENT-INDUCED INTRA-TUMOR POPULATION SHIFTS AND DISCOVERY OF RATIONAL DRUG COMBINATIONS IN HUMAN GLIOBLASTOMA

PubMed Central

Reinartz, Roman; Wang, Shanshan; Kebir, Sied; Silver, Daniel J.; Wieland, Anja; Zheng, Tong; Küpper, Marius; Rauschenbach, Laurèl; Fimmers, Rolf; Shepherd, Timothy M.; Trageser, Daniel; Till, Andreas; Schäfer, Niklas; Glas, Martin; Hillmer, Axel M.; Cichon, Sven; Smith, Amy A.; Pietsch, Torsten; Liu, Ying; Reynolds, Brent A.; Yachnis, Anthony; Pincus, David W.; Simon, Matthias; Brüstle, Oliver; Steindler, Dennis A.; Scheffler, Björn

2016-01-01

Purpose Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and inter-individual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacological sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential anti-glioblastoma compounds. A more comprehensive intra-tumoral analysis revealed that stable genetic and phenotypic characteristics of co-existing subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacological profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions Our data provide a previously unrecognized strategy for revealing functional consequences of intra-tumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma. PMID:27521447

High Variation of Intravitreal Injection Rates and Medicare Anti-Vascular Endothelial Growth Factor Payments per Injection in the United States.

PubMed

Erie, Jay C; Barkmeier, Andrew J; Hodge, David O; Mahr, Michael A

2016-06-01

To estimate geographic variation of intravitreal injection rates and Medicare anti-vascular endothelial growth factor (VEGF) drug costs per injection in aging Americans. Observational cohort study using 2013 Medicare claims database. United States fee-for-service (FFS) Part B Medicare beneficiaries and their providers. Medicare Provider Utilization and Payment Data furnished by the Centers for Medicare and Medicaid Services was used to identify all intravitreal injection claims and anti-VEGF drug claims among FFS Medicare beneficiaries in all 50 states and the District of Columbia in 2013. The rate of FFS Medicare beneficiaries receiving intravitreal injections and the mean Medicare-allowed drug payment per anti-VEGF injection was calculated nationally and for each state. Geographic variations were evaluated by using extremal quotient, coefficient of variation, and systematic component of variance (SCV). Rate of FFS Medicare Part B beneficiaries receiving intravitreal injections (Current Procedural Terminology [CPT] code, 67028), nationally and by state; mean Medicare-allowed drug payment per anti-VEGF injection (CPT code, 67028; and treatment-specific J-codes, J0178, J2778, J9035, J3490, and J3590) nationally and by state. In 2013, the rate of FFS Medicare beneficiaries receiving intravitreal injections varied widely by 7-fold across states (range by state, 4 per 1000 [Wyoming]-28 per 1000 [Utah]), averaging 19 per 1000 beneficiaries. The mean SCV was 8.5, confirming high nonrandom geographic variation. There were more than 2.1 million anti-VEGF drug claims, totaling more than $2.3 billion in Medicare payments for anti-VEGF agents in 2013. The mean national Medicare drug payment per anti-VEGF injection varied widely by 6.2-fold across states (range by state, $242 [South Carolina]-$1509 [Maine]), averaging $1078 per injection. Nationally, 94% of injections were office based and 6% were facility based. High variation was observed in intravitreal injection rates and in Medicare drug payments per anti-VEGF injection across the United States in 2013. Identifying factors that contribute to high variation may help the ophthalmology community to optimize further the delivery and use of anti-VEGF agents. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Do flexible inter-injection intervals improve the effects of botulinum toxin A treatment in reducing impairment and disability in patients with spasticity?

PubMed

Trompetto, Carlo; Marinelli, Lucio; Mori, Laura; Puce, Luca; Pelosin, Elisa; Serrati, Carlo; Fattapposta, Francesco; Rinalduzzi, Steno; Abbruzzese, Giovanni; Currà, Antonio

2017-05-01

In patients treated with botulinum toxin-A (BoNT-A), toxin-directed antibody formation was related to the dosage and frequency of injections, leading to the empirical adoption of minimum time intervals between injections of 3months or longer. However, recent data suggest that low immunogenicity of current BoNT-A preparations could allow more frequent injections. Our hypothesis is that a short time interval between injections may be safe and effective in reducing upper limb spasticity and related disability. IncobotulinumtoxinA was injected under ultrasound guidance in spastic muscles of 11 subjects, who were evaluated just before BoNT-A injection (T0), and 1month (T1), 2months (T2) and 4months (T3) after injecting. At T1, in the case of persistent disability related to spasticity interfering with normal activities, patients received an additional toxin dose. Seven subjects received the additional dose at T1 because of persistent disability; 4 of them had a decrease of disability 1month later (T2). Rethinking the injection scheme for BoNT-A treatment may have a major impact in the management of spasticity and related disability. Future studies with larger sample sizes are warranted to confirm that injection schedules with short time intervals should no longer be discouraged in clinical practice. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bupivacaine injection remodels extraocular muscles and corrects comitant strabismus.

PubMed

Miller, Joel M; Scott, Alan B; Danh, Kenneth K; Strasser, Dirk; Sane, Mona

2013-12-01

To evaluate the clinical effectiveness and anatomic changes resulting from bupivacaine injection into extraocular muscles to treat comitant horizontal strabismus. Prospective, observational clinical series. Thirty-one comitant horizontal strabismus patients. Nineteen patients with esotropia received bupivacaine injections in the lateral rectus muscle, and 12 patients with exotropia received bupivacaine injections in the medial rectus. Sixteen of these, with large strabismus angles, also received botulinum type A toxin injections in the antagonist muscle at the same treatment session. A second treatment was given to 13 patients who had residual strabismus after the first treatment. Clinical alignment measures and muscle volume, maximum cross-sectional area, and shape derived from magnetic resonance imaging, with follow-up examinations for up to 3 years. At an average of 15.3 months after the final treatment, original misalignment was reduced by 10.5 prism diopters (Δ; 6.0°) with residual deviations of 10Δ or less in 53% of patients. A single treatment with bupivacaine alone reduced misalignment at 11.3 months by 4.7Δ (2.7°) with residual deviations of 10Δ or less in 50% of patients. Alignment corrections were remarkably stable over follow-ups for as long as 3 years. Six months after bupivacaine injection, muscle volume had increased by 6.6%, and maximum cross-sectional area had increased by 8.5%, gradually relaxing toward pretreatment values thereafter. Computer modeling with Orbit 1.8 (Eidactics, San Francisco, CA) suggested that changes in agonist and antagonist muscle lengths were responsible for the enduring changes in eye alignment. Bupivacaine injection alone or together with botulinum toxin injection in the antagonist muscle improves eye alignment in comitant horizontal strabismus by inducing changes in rectus muscle structure and length. Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Key drivers of visual acuity gains in neovascular age-related macular degeneration in real life: findings from the AURA study.

PubMed

Holz, Frank G; Tadayoni, Ramin; Beatty, Stephen; Berger, Alan; Cereda, Matteo Giuseppe; Hykin, Philip; Staurenghi, Giovanni; Wittrup-Jensen, Kim; Altemark, Andreas; Nilsson, Jonas; Kim, Kun; Sivaprasad, Sobha

2016-12-01

To identify predictive markers for the outcomes of anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration (nAMD). AURA was a retrospective, observational, multicentre study that monitored the 2-year outcomes following intravitreal ranibizumab treatment in patients with nAMD. Using stepwise regression analysis, we evaluated the association between visual acuity outcomes, baseline characteristics and resource utilisation in order to determine which variables are significantly linked to outcomes in AURA. We also examined the relationship between visual acuity outcomes and number of injections received. Analyses were performed using data from year 1 (n=1695) and year 2 completers (n=1184). Logistic analysis showed that baseline visual acuity score, age at start of therapy, number of ophthalmoscopies and optical coherence tomography (OCT) (combined) and number of injections (ranibizumab) were significant (p<0.05) prognostic factors for vision maintenance (loss <15 letters) or vision gain (≥15 letters). Patients who received >7 injections (in 1 year) or >14 injections (over 2 years) gained more letters and demonstrated greater vision maintenance (loss of <15 letters) than patients who received fewer injections. There was a significant (p<0.05) association between number of injections and national reimbursement schemes and OCT. A number of factors that are predictive of treatment outcomes in a real-life setting were identified. Notably, the decline of treatment benefits may be linked to number of injections and a failure to visit clinicians and receive OCT as required. These findings may be helpful in guiding ophthalmologist treatment decisions under limited time and financial constraints. NCT01447043. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Women's injection drug practices in their own words: a qualitative study.

PubMed

Tuchman, Ellen

2015-03-07

There are significant gender differences in injection drug practices and relative risks involved for women who inject drug compared with men. This qualitative study aims to explore the social, contextual, and behavioral dimensions of injecting practices among women who inject drugs. Participants were selected by purposive venue-based sampling from a syringe exchange program in 2012-2013. In-depth interviews were conducted with 26 women to elicit detailed perspectives regarding injection drug use practices and women-focused decision-making. All interviews were transcribed verbatim and analyzed with Atlas.ti. Participant's mean age was 43.2 years, 48% Caucasian, 36% African American, and 16% Latina, poorly educated, mostly single, and heroin self-injectors. Three themes emerged; a) transitioning from non-injection to injection drug use; b) patterns and variations of initiation to injecting; and c) shifting toward autonomy or reliance on others. Women were predominantly influenced to transition to injection drug use by other women with their claims that injecting was a way to curtail their daily drug expenditure. More than half the women received their first injection from another woman in their social network rather than a male sexual partner. Self-injecting women exhibited agency around the circumstances of injection safety and potential risks. Other women revealed that their inability to inject themselves could and did make them dependent on others for unsafe injection practices. The finding that many women were influenced to transition to injection drug use and receive the first injection from a woman is contrary to literature claims that male sexual partners introduce and initiate women to injection drug use. Self-injecting women possessed capacity to act in a way that produced the results they wanted, not sharing prepared drugs or injecting equipment. In stark contrast, women assisted with injections could and did make them vulnerable to unsafe injecting. Findings support early prevention strategies that discourage women's transition from non-injection to injection and development of female peer-driven experiential interventions to dispel myths for non-injection women and to increase personal capability to self-inject for women who require assistance with injecting, to reduce injection-related harm.

A chance to stop and breathe: participants’ experiences in the North American Opiate Medication Initiative clinical trial

PubMed Central

2014-01-01

Background The North American Opiate Medication Initiative (NAOMI) clinical trial compared the effectiveness of injectable diacetylmorphine (DAM) or hydromorphone (HDM) to oral methadone maintenance treatment (MMT). This study aimed to determine participants’ perceptions of treatment delivered in NAOMI. Methods A qualitative sub-study was conducted with 29 participants (12 female): 18 (62.1%) received injectable DAM or HDM and 11 (37.9%) received MMT. A phenomenological theoretical framework was used. Semi-structured interviews were audio-recorded and transcribed verbatim. A thematic analysis was used over successive phases and was driven by the semantic meanings of the data. Results Participants receiving injectable medications suggested that the supervised delivery model was stringent but provided valuable stability to their lives. Females discussed the adjustment required for the clinical setting, while males focused on the challenging clinic schedule and its impact on employment abilities. Participants receiving MMT described disappointment with being randomized to this treatment; however, positive aspects, including the quick titration time and availability of auxiliary services, were also discussed. Conclusion Treatment with injectable DAM (or HDM) is preferred by participants and considered effective in reducing the burden of opioid dependency. Engaging patients in research regarding their perceptions of treatment provides a comprehensive assessment of treatment needs and barriers. Clinical trial registration NCT00175357 PMID:25262567

OnabotulinumtoxinA Injection

MedlinePlus

... older than 18 years of age with chronic migraine (severe, throbbing headaches that are sometimes accompanied by ... limb spasticity, urinary incontinence, overactive bladder, or chronic migraine, you may receive additional injections every 3 to ...

Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia.

PubMed

Landau, Dan A; Clement, Kendell; Ziller, Michael J; Boyle, Patrick; Fan, Jean; Gu, Hongcang; Stevenson, Kristen; Sougnez, Carrie; Wang, Lili; Li, Shuqiang; Kotliar, Dylan; Zhang, Wandi; Ghandi, Mahmoud; Garraway, Levi; Fernandes, Stacey M; Livak, Kenneth J; Gabriel, Stacey; Gnirke, Andreas; Lander, Eric S; Brown, Jennifer R; Neuberg, Donna; Kharchenko, Peter V; Hacohen, Nir; Getz, Gad; Meissner, Alexander; Wu, Catherine J

2014-12-08

Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of 104 primary chronic lymphocytic leukemias (CLLs). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylation disorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories. Copyright © 2014 Elsevier Inc. All rights reserved.

Locally disordered methylation forms the basis of intra-tumor methylome variation in chronic lymphocytic leukemia

PubMed Central

Landau, Dan A.; Clement, Kendell; Ziller, Michael J.; Boyle, Patrick; Fan, Jean; Gu, Hongcang; Stevenson, Kristen; Sougnez, Carrie; Wang, Lili; Li, Shuqiang; Kotliar, Dylan; Zhang, Wandi; Ghandi, Mahmoud; Garraway, Levi; Fernandes, Stacey M.; Livak, Kenneth J.; Gabriel, Stacey; Gnirke, Andreas; Lander, Eric S.; Brown, Jennifer R.; Neuberg, Donna; Kharchenko, Peter V.; Hacohen, Nir; Getz, Gad; Meissner, Alexander; Wu, Catherine J.

2014-01-01

SUMMARY Intra-tumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of 104 primary chronic lymphocytic leukemias (CLL). Compared to 26 normal B cell samples, CLLs consistently displayed higher intra-sample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylation disorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories. PMID:25490447