Science.gov

Sample records for adult solid tumors

  1. Clofarabine in Adult Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2014-02-04

    Solid Tumors; Leukemia, Lymphocytic, Acute, Pediatric; Leukemia, Lymphocytic, Acute, Adult; Leukemia, Myelocytic, Acute, Pediatric; Leukemia, Myelocytic, Acute, Adult; Myelodysplastic Syndromes, Adult

  2. Vaccine Therapy Plus Biological Therapy in Treating Adults With Metastatic Solid Tumors

    ClinicalTrials.gov

    2013-06-19

    Colorectal Cancer; Endometrial Cancer; Head and Neck Cancer; Liver Cancer; Lung Cancer; Melanoma (Skin); Pancreatic Cancer; Testicular Germ Cell Tumor; Unspecified Adult Solid Tumor, Protocol Specific

  3. A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors

    PubMed Central

    Blumenthal, Gideon M.; Gills, Joell J.; Ballas, Marc S.; Bernstein, Wendy B.; Komiya, Takefumi; Dechowdhury, Roopa; Morrow, Betsy; Root, Hyejeong; Chun, Guinevere; Helsabeck, Cynthia; Steinberg, Seth M.; LoPiccolo, Jaclyn; Kawabata, Shigeru; Gardner, Erin R.; Figg, William D.; Dennis, Phillip A.

    2014-01-01

    Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin. PMID:25327558

  4. Brain tumor - primary - adults

    MedlinePlus

    ... Vestibular schwannoma (acoustic neuroma) - adults; Meningioma - adults; Cancer - brain tumor (adults) ... Primary brain tumors include any tumor that starts in the brain. Primary brain tumors can start from brain cells, ...

  5. Chemotherapy in Treating Patients With Solid Tumors

    ClinicalTrials.gov

    2013-07-01

    Bladder Cancer; Breast Cancer; Colorectal Cancer; Esophageal Cancer; Head and Neck Cancer; Kidney Cancer; Lung Cancer; Ovarian Cancer; Prostate Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  6. Targeted therapeutics in treatment of children and young adults with solid tumors: an expert survey and review of the literature.

    PubMed

    Grunewald, T G P; Greulich, N; Kontny, U; Frühwald, M; Rutkowski, S; Kordes, U; Scheurlen, W; Schmidt, W; Stachel, D; Metzler, M; Mittler, U; Graf, N; Benesch, M; Burdach, S

    2012-04-01

    Although prognosis of children with solid tumors is steadily improving, long-term survival is not achievable in all patients, especially in patients with recurrent or refractory disease. Despite the increasing number of targeted therapeutics (TT), only very few TT have been introduced into clinical protocols. Accordingly, clinical experience concerning the efficacy and safety of these drugs is limited. This may possibly discourage oncologists from administering TT to children.We performed a comprehensive review of the literature to identify TT that may be considered for treatment of children and young adults with solid tumors. Moreover, we interviewed an expert panel of the Society for Pediatric Oncology and Hematology (GPOH) using questionnaires in a modified Delphi process in order to describe the experts' experiences in the use of these TT.Among 30 TT identified to be possibly useful in children and young adults, imatinib, bevacizumab and rapamycin were most widely used. These drugs were reported as having mostly little to no severe adverse events and seem to induce at least partial responses in a subset of patients. In addition, our study confirms and expands the present knowledge about adverse events and the potential efficacy of 5 other commonly used TT in this population.This information may be useful for oncologists when administering these TT to children and young adults with solid tumors. Controlled clinical trials are urgently needed to test their safety and efficacy.

  7. High-throughput genomic profiling of adult solid tumors reveals novel insights into cancer pathogenesis.

    PubMed

    Hartmaier, Ryan J; Albacker, Lee; Chmielecki, Juliann; Bailey, Mark; He, Jie; Goldberg, Michael; Ramkissoon, Shakti; Suh, James; Elvin, Julia A; Chiacchia, Samuel; Frampton, Garrett M; Ross, Jeffrey S; Miller, Vincent; Stephens, Philip J; Lipson, Doron

    2017-02-24

    Genomic profiling is widely predicted to become a standard of care in clinical oncology, but more effective data sharing to accelerate progress in precision medicine will be required. Here we describe cancer-associated genomic profiles from 18,004 unique adult cancers. The dataset was composed of 162 tumor subtypes including multiple rare and uncommon tumors. Comparison of alteration frequencies to The Cancer Genome Atlas (TCGA) identified some differences and suggested an enrichment of treatment-refractory samples in breast and lung cancer cohorts. To illustrate novelty within the dataset, we surveyed the genomic landscape of rare diseases and identified an increased frequency of NOTCH1 alterations in adenoid cystic carcinomas compared to previous studies. Analysis of tumor suppressor gene patterns revealed disease specificity for certain genes but broad inactivation of others. We identified multiple potentially druggable, novel and known kinase fusions in diseases beyond those in which they are currently recognized. Analysis of variants of unknown significance identified an enrichment of SMAD4 alterations in colon cancer and other rare alterations predicted to have functional impact. Analysis of established, clinically relevant alterations highlighted the spectrum of molecular changes for which testing is currently recommended, as well as opportunities for expansion of indications for use of approved targeted therapies. Overall, this dataset presents a new resource with which to investigate rare alterations and diseases, validate clinical relevance, and identify novel therapeutic targets.

  8. High-Dose Thiotepa Plus Peripheral Stem Cell Transplantation in Treating Patients With Refractory Solid Tumors

    ClinicalTrials.gov

    2013-03-06

    Brain and Central Nervous System Tumors; Childhood Germ Cell Tumor; Extragonadal Germ Cell Tumor; Ovarian Cancer; Retinoblastoma; Testicular Germ Cell Tumor; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

  9. A Trial of PT2977 Tablets In Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2016-12-22

    Advanced Solid Tumors; Solid Tumor; Solid Carcinoma; Solid Tumor, Adult; ccRCC; RCC, Clear Cell Adenocarcinoma; RCC; Kidney Cancer; Clear Cell Renal Cell Carcinoma; Renal Cell Carcinoma, Metastatic; Renal Cell Carcinoma Recurrent; Renal Cell Carcinoma, Clear Cell Adenocarcinoma

  10. C-Reactive Protein Is an Important Biomarker for Prognosis Tumor Recurrence and Treatment Response in Adult Solid Tumors: A Systematic Review

    PubMed Central

    Shrotriya, Shiva; Walsh, Declan; Bennani-Baiti, Nabila; Thomas, Shirley; Lorton, Cliona

    2015-01-01

    Purpose A systematic literature review was done to determine the relationship between elevated CRP and prognosis in people with solid tumors. C-reactive protein (CRP) is a serum acute phase reactant and a well-established inflammatory marker. We also examined the role of CRP to predict treatment response and tumor recurrence. Methods MeSH (Medical Subject Heading) terms were used to search multiple electronic databases (PubMed, EMBASE, Web of Science, SCOPUS, EBM-Cochrane). Two independent reviewers selected research papers. We also included a quality Assessment (QA) score. Reports with QA scores <50% were excluded. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) methodology was utilized for this review (S1 PRISMA Checklist). Results 271 articles were identified for final review. There were 45% prospective studies and 52% retrospective. 264 had intermediate QA score (≥50% but <80%); Seven were adequate (80% -100%); A high CRP was predictive of prognosis in 90% (245/271) of studies—80% of the 245 studies by multivariate analysis, 20% by univariate analysis. Many (52%) of the articles were about gastrointestinal malignancies (GI) or kidney malignancies. A high CRP was prognostic in 90% (127 of 141) of the reports in those groups of tumors. CRP was also prognostic in most reports in other solid tumors primary sites. Conclusions A high CRP was associated with higher mortality in 90% of reports in people with solid tumors primary sites. This was particularly notable in GI malignancies and kidney malignancies. In other solid tumors (lung, pancreas, hepatocellular cancer, and bladder) an elevated CRP also predicted prognosis. In addition there is also evidence to support the use of CRP to help decide treatment response and identify tumor recurrence. Better designed large scale studies should be conducted to examine these issues more comprehensively. PMID:26717416

  11. A Phase I Study of Veliparib in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas

    PubMed Central

    Kummar, Shivaani; Ji, Jiuping; Morgan, Robert; Lenz, Heinz-Josef; Puhalla, Shannon L.; Belani, Chandra P.; Gandara, David R.; Allen, Deborah; Kiesel, Brian; Beumer, Jan H.; Newman, Edward M.; Rubinstein, Larry; Chen, Alice; Zhang, Yiping; Wang, Lihua; Kinders, Robert J.; Parchment, Ralph E.; Tomaszewski, Joseph E.; Doroshow, James H.

    2012-01-01

    Purpose Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. Poly(ADP-ribose) polymerase (PARP) inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies. Experimental Design Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics; measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMCs); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTCs). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days. Results Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels; γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration. Conclusions The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared to single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma. PMID:22307137

  12. High-Dose Chemotherapy, Total-Body Irradiation, and Autologous Stem Cell Transplantation or Bone Marrow Transplantation in Treating Patients With Hematologic Cancer or Solid Tumors

    ClinicalTrials.gov

    2013-05-07

    Breast Cancer; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Testicular Germ Cell Tumor; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

  13. Levofloxacin to Prevent Infection Following Chemotherapy in Treating Patients With Solid Tumors or Lymphoma

    ClinicalTrials.gov

    2013-08-01

    Brain and Central Nervous System Tumors; Breast Cancer; Extragonadal Germ Cell Tumor; Infection; Lung Cancer; Lymphoma; Ovarian Cancer; Small Intestine Cancer; Testicular Germ Cell Tumor; Unspecified Adult Solid Tumor, Protocol Specific

  14. A Phase I Study of the SMAC-Mimetic Birinapant in Adults with Refractory Solid Tumors or Lymphoma.

    PubMed

    Amaravadi, Ravi K; Schilder, Russell J; Martin, Lainie P; Levin, Myron; Graham, Martin A; Weng, David E; Adjei, Alex A

    2015-11-01

    The inhibitor of apoptosis (IAP) family of antiapoptotic proteins has been identified as a target for small molecule inhibitors in cancer. Second mitochondrial-derived activator of caspases (SMAC) efficiently and naturally antagonizes IAPs, and preclinical studies have determined that SMAC mimetics have potent anticancer properties. Here, we report a first-in-human trial designed to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics/pharmacodynamics (PK/PD) of birinapant, a novel SMAC mimetic. Patients with advanced solid tumors or lymphoma were enrolled in a 3+3 dose escalation design with birinapant administered intravenously from 0.18 to 63 mg/m(2) once weekly every 3 of 4 weeks. Fifty patients were enrolled to 12 dose cohorts. Birinapant 47 mg/m(2) was determined to be the MTD. At 63 mg/m(2), dose-limiting toxicities included headache, nausea, and vomiting. Two cases of Bell's palsy (grade 2) also occurred at 63 mg/m(2). Birinapant had a plasma half-life of 30 to 35 hours and accumulated in tumor tissue. Birinapant suppressed cIAP1 and increased apoptosis in peripheral blood mononuclear cells and tumor tissue. Prolonged stable disease was observed in 3 patients: non-small cell lung cancer (5 months), colorectal cancer (5 months), and liposarcoma (9 months). Two patients with colorectal cancer had radiographic evidence of tumor shrinkage. In conclusion, birinapant was well tolerated with an MTD of 47 mg/m(2) and exhibited favorable PK and PD properties. Several patients demonstrated stable disease and evidence of antitumor activity. These results support the ongoing clinical trials of birinapant in patients with cancer.

  15. Decitabine in Treating Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2013-02-06

    Male Breast Cancer; Recurrent Bladder Cancer; Recurrent Breast Cancer; Recurrent Melanoma; Stage III Melanoma; Stage IV Bladder Cancer; Stage IV Breast Cancer; Stage IV Melanoma; Unspecified Adult Solid Tumor, Protocol Specific

  16. Delivering nanomedicine to solid tumors

    PubMed Central

    Jain, Rakesh K.; Stylianopoulos, Triantafyllos

    2011-01-01

    Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. While the enhanced permeability and retention effect has served as a key rationale for using nanoparticles to treat solid tumors, it does not enable uniform delivery of these particles to all regions of tumors in sufficient quantities. This heterogeneous distribution of therapeutics is a result of physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. These barriers are likely to be responsible for the modest survival benefit offered by many FDA-approved nanotherapeutics and must be overcome for the promise of nanomedicine in patients to be realized. Here, we review these barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers. Finally, we discuss design considerations for optimizing the delivery of nanoparticles to tumors. PMID:20838415

  17. Everolimus and Vatalanib in Treating Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2017-03-21

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Pheochromocytoma; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Recurrent Melanoma; Recurrent Neuroendocrine Carcinoma of the Skin; Recurrent Non-small Cell Lung Cancer; Recurrent Pheochromocytoma; Recurrent Renal Cell Cancer; Somatostatinoma; Stage III Neuroendocrine Carcinoma of the Skin; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Stage IV Renal Cell Cancer; Thyroid Gland Medullary Carcinoma; Unspecified Adult Solid Tumor, Protocol Specific

  18. Irinotecan and Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases From Solid Tumors

    ClinicalTrials.gov

    2010-03-15

    Brain and Central Nervous System Tumors; Cognitive/Functional Effects; Long-term Effects Secondary to Cancer Therapy in Adults; Long-term Effects Secondary to Cancer Therapy in Children; Poor Performance Status; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

  19. Busulfan, Melphalan, Topotecan Hydrochloride, and a Stem Cell Transplant in Treating Patients With Newly Diagnosed or Relapsed Solid Tumor

    ClinicalTrials.gov

    2016-11-04

    Solid Tumor; Adult Central Nervous System Germ Cell Tumor; Adult Rhabdomyosarcoma; Childhood Central Nervous System Germ Cell Tumor; Childhood Soft Tissue Sarcoma; Ewing Sarcoma; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Ovarian Mixed Germ Cell Tumor; Previously Untreated Childhood Rhabdomyosarcoma; Recurrent Adult Brain Tumor; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Extragonadal Germ Cell Tumor; Recurrent Extragonadal Non-seminomatous Germ Cell Tumor; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Neuroblastoma; Recurrent Ovarian Germ Cell Tumor; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

  20. Combination Chemotherapy in Treating Patients With Recurrent, Refractory, or Metastatic Solid Tumors or Lymphomas

    ClinicalTrials.gov

    2012-03-21

    Colorectal Cancer; Esophageal Cancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer; Liver Cancer; Lung Cancer; Lymphoma; Pancreatic Cancer; Small Intestine Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  1. Potential Biomarkers for Bevacizumab-Induced High Blood Pressure in Patients With Solid Tumor

    ClinicalTrials.gov

    2012-02-23

    Breast Cancer; Cardiovascular Complications; Colorectal Cancer; Fallopian Tube Cancer; Head and Neck Cancer; Lung Cancer; Ovarian Cancer; Peritoneal Cavity Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  2. Warburg's effect on solid tumors.

    PubMed

    El Imad, Talal; El Khoury, Lara; Geara, Abdallah Sassine

    2014-11-01

    Lactic acidosis is the result of imbalance between the systemic formation of lactate and its hepatic metabolism. In cancer patients, lactic acidosis is mainly associated with hematologic malignancies (leukemia and lymphomas) and the mechanism is known as Warburg's effect. We report a 76-year-old male known to have hypertension and coronary artery disease, who presented with abdominal distension and lactic acidosis. His initial evaluation showed multiple liver masses that were biopsied and the patient was diagnosed with undifferentiated carcinoma of unknown primary, involving the liver. The patient had progression of lactic acidosis leading to his death on day-15. As the lactic acidosis was not in the setting of hypoxia or hemodynamic instability, we made the diagnosis of malignancy-associated type B lactic acidosis, also known as the Warburg's effect. Warburg's effect can occur in solid cancer if the tumor involves the liver. It has bad prognostic implications. The use of intravenous bicarbonate as a temporary measure is of controversial benefit, as it can potentially worsen the metabolic acidosis and its use should be limited to patients with very low pH. In cancer patients, the use of lactatebased intravenous fluids can be potentially harmful and can increase the risk of tumor metastasis, at least in animal malignancy models.

  3. ABT-751 in Treating Young Patients With Refractory Solid Tumors

    ClinicalTrials.gov

    2012-03-14

    Brain and Central Nervous System Tumors; Childhood Germ Cell Tumor; Extragonadal Germ Cell Tumor; Kidney Cancer; Liver Cancer; Neuroblastoma; Ovarian Cancer; Sarcoma; Unspecified Childhood Solid Tumor, Protocol Specific

  4. Role of Bcl-3 in solid tumors

    PubMed Central

    2011-01-01

    Bcl-3 is an established oncogene in hematologic malignancies, such as B-cell chronic lymphocytic leukemias. Nevertheless, recent research has shown that it also participates in progression of diverse solid tumors. The present review summarizes the current knowledge of Bcl3 role in solid tumors progression, including some new insights in its possible molecular mechanisms of action. PMID:22195643

  5. Solid renal masses in adults

    PubMed Central

    Mittal, Mahesh Kumar; Sureka, Binit

    2016-01-01

    With the ever increasing trend of using cross-section imaging in today's era, incidental detection of small solid renal masses has dramatically multiplied. Coincidentally, the number of asymptomatic benign lesions being detected has also increased. The role of radiologists is not only to identify these lesions, but also go a one step further and accurately characterize various renal masses. Earlier detection of small renal cell carcinomas means identifying at the initial stage which has an impact on prognosis, patient management and healthcare costs. In this review article we share our experience with the typical and atypical solid renal masses encountered in adults in routine daily practice. PMID:28104933

  6. Brain and Spinal Cord Tumors in Adults

    MedlinePlus

    ... Search Search En Español Category Cancer A-Z Brain and Spinal Cord Tumors in Adults If you have a brain or spinal cord tumor or are close to ... cope. Here you can find out all about brain and spinal cord tumors in adults, including risk ...

  7. Solid pseudopapillary tumor of the pancreas.

    PubMed

    Schlarb, Haley C; Schlarb, Alexander C; Ubert, H Adam; Schlarb, Christopher A

    2015-01-01

    Solid pseudopapillary tumor is a rare tumor accounting for 1-2% of exocrine neoplasms involving the pancreas. This typically benign tumor is predominately found in young females of non-Caucasian descent between the second and fourth decades of life. Despite the reported increasing incidence of this neoplasm, many physicians are unfamiliar with this tumor, which may lead to uncertainty of diagnosis and treatment. While further delineating the clinical and imaging features of this tumor, we present two cases with review of the literature.

  8. Pediatric solid tumor genomics and developmental pliancy.

    PubMed

    Chen, X; Pappo, A; Dyer, M A

    2015-10-08

    Pediatric solid tumors are remarkably diverse in their cellular origins, developmental timing and clinical features. Over the last 5 years, there have been significant advances in our understanding of the genetic lesions that contribute to the initiation and progression of pediatric solid tumors. To date, over 1000 pediatric solid tumors have been analyzed by Next-Generation Sequencing. These genomic data provide the foundation to launch new research efforts to address one of the fundamental questions in cancer biology-why are some cells more susceptible to malignant transformation by particular genetic lesions at discrete developmental stages than others? Because of their developmental, molecular, cellular and genetic diversity, pediatric solid tumors provide an ideal platform to begin to answer this question. In this review, we highlight the diversity of pediatric solid tumors and provide a new framework for studying the cellular and developmental origins of pediatric cancer. We also introduce a new unifying concept called cellular pliancy as a possible explanation for susceptibility to cancer and the developmental origins of pediatric solid tumors.

  9. Emerging Trends for Radioimmunotherapy in Solid Tumors

    PubMed Central

    Gupta, Suprit; Kaur, Sukhwinder; Ponnusamy, Moorthy P.

    2013-01-01

    Abstract Due to its ability to target both known and occult lesions, radioimmunotherapy (RIT) is an attractive therapeutic modality for solid tumors. Poor tumor uptake and undesirable pharmacokinetics, however, have precluded the administration of radioimmunoconjugates at therapeutically relevant doses thereby limiting the clinical utility of RIT. In solid tumors, efficacy of RIT is further compromised by heterogeneities in blood flow, tumor stroma, expression of target antigens and radioresistance. As a result significant efforts have been invested toward developing strategies to overcome these impediments. Further, there is an emerging interest in exploiting short-range, high energy α-particle emitting radionuclides for the eradication of minimal residual and micrometastatic disease. As a result several modalities for localized therapy and models of minimal disease have been developed for preclinical evaluation. This review provides a brief update on the recent efforts toward improving the efficacy of RIT for solid tumors, and development of RIT strategies for minimal disease associated with solid tumors. Further, some of promising approaches to improve tumor targeting, which showed promise in the past, but have now been ignored are also discussed. PMID:23844555

  10. Radiofrequency Ablation Therapy for Solid Tumors

    SciTech Connect

    Kam, Anthony

    2002-12-04

    Surgical resection, systemic chemotherapy, and local radiation have been the conventional treatments for localized solid cancer. Because certain patients are not candidates for tumor resection and because many tumors are poorly responsive to chemotherapy and radiation, there has been an impetus to develop alternative therapies. Radiofrequency ablation (RFA) is a minimally invasive therapy for localized solid cancers that has gained considerable attention in the last 12 years. Advantages of minimally invasive therapies over surgery include less recovery time, lower morbidity and mortality, eligibility of more patients, and lower cost. RFA has been applied most extensively to inoperable hepatic tumors. It is investigational for tumors in the kidney, lung, bone, breast, and adrenal gland. This colloquium will review the mechanism, techniques, limitations, and clinical applications of RFA. The ultimate role that RFA will play in cancer therapy will depend on the results of long-term follow-up and prospective randomized trials.

  11. FAU in Treating Patients With Advanced Solid Tumors or Lymphoma

    ClinicalTrials.gov

    2014-01-06

    Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  12. Chemotherapy in Treating Patients With Refractory Advanced Solid Tumors or Hematologic Cancer

    ClinicalTrials.gov

    2013-06-20

    Bladder Cancer; Breast Cancer; Colorectal Cancer; Gastric Cancer; Head and Neck Cancer; Kidney Cancer; Leukemia; Lung Cancer; Melanoma (Skin); Ovarian Cancer; Prostate Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  13. Irinotecan and Alisertib in Treating Patients With Advanced Solid Tumors or Colorectal Cancer

    ClinicalTrials.gov

    2016-12-20

    Mucinous Adenocarcinoma of the Colon; Mucinous Adenocarcinoma of the Rectum; Recurrent Colon Cancer; Recurrent Rectal Cancer; Signet Ring Adenocarcinoma of the Colon; Signet Ring Adenocarcinoma of the Rectum; Stage IIIA Colon Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  14. Alisertib and Gemcitabine Hydrochloride in Treating Patients With Solid Tumors or Pancreatic Cancer

    ClinicalTrials.gov

    2017-01-19

    Acinar Cell Adenocarcinoma of the Pancreas; Duct Cell Adenocarcinoma of the Pancreas; Recurrent Pancreatic Cancer; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  15. Propranolol Hydrochloride in Treating Patients With Locally Recurrent or Metastatic Solid Tumors That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2016-09-28

    Male Breast Cancer; Recurrent Melanoma; Stage IV Breast Cancer; Stage IV Melanoma; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Unspecified Adult Solid Tumor, Protocol Specific; Hepatocellular Carcinoma

  16. Carcinomatous meningitis: Leptomeningeal metastases in solid tumors

    PubMed Central

    Le Rhun, Emilie; Taillibert, Sophie; Chamberlain, Marc C.

    2013-01-01

    Leptomeningeal metastasis (LM) results from metastatic spread of cancer to the leptomeninges, giving rise to central nervous system dysfunction. Breast cancer, lung cancer, and melanoma are the most frequent causes of LM among solid tumors in adults. An early diagnosis of LM, before fixed neurologic deficits are manifest, permits earlier and potentially more effective treatment, thus leading to a better quality of life in patients so affected. Apart from a clinical suspicion of LM, diagnosis is dependent upon demonstration of cancer in cerebrospinal fluid (CSF) or radiographic manifestations as revealed by neuraxis imaging. Potentially of use, though not commonly employed, today are use of biomarkers and protein profiling in the CSF. Symptomatic treatment is directed at pain including headache, nausea, and vomiting, whereas more specific LM-directed therapies include intra-CSF chemotherapy, systemic chemotherapy, and site-specific radiotherapy. A special emphasis in the review discusses novel agents including targeted therapies, that may be promising in the future management of LM. These new therapies include anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib in nonsmall cell lung cancer, anti-HER2 monoclonal antibody trastuzumab in breast cancer, anti-CTLA4 ipilimumab and anti-BRAF tyrosine kinase inhibitors such as vermurafenib in melanoma, and the antivascular endothelial growth factor monoclonal antibody bevacizumab are currently under investigation in patients with LM. Challenges of managing patients with LM are manifold and include determining the appropriate patients for treatment as well as the optimal route of administration of intra-CSF drug therapy. PMID:23717798

  17. Multistep, effective drug distribution within solid tumors

    PubMed Central

    Shemi, Amotz; Khvalevsky, Elina Zorde; Gabai, Rachel Malka; Domb, Abraham; Barenholz, Yechezkel

    2015-01-01

    The distribution of drugs within solid tumors presents a long-standing barrier for efficient cancer therapies. Tumors are highly resistant to diffusion, and the lack of blood and lymphatic flows suppresses convection. Prolonged, continuous intratumoral drug delivery from a miniature drug source offers an alternative to both systemic delivery and intratumoral injection. Presented here is a model of drug distribution from such a source, in a multistep process. At delivery onset the drug mainly affects the closest surroundings. Such ‘priming’ enables drug penetration to successive cell layers. Tumor ‘void volume’ (volume not occupied by cells) increases, facilitating lymphatic perfusion. The drug is then transported by hydraulic convection downstream along interstitial fluid pressure (IFP) gradients, away from the tumor core. After a week tumor cell death occurs throughout the entire tumor and IFP gradients are flattened. Then, the drug is transported mainly by ‘mixing’, powered by physiological bulk body movements. Steady state is achieved and the drug covers the entire tumor over several months. Supporting measurements are provided from the LODER™ system, releasing siRNA against mutated KRAS over months in pancreatic cancer in-vivo models. LODER™ was also successfully employed in a recent Phase 1/2 clinical trial with pancreatic cancer patients. PMID:26416413

  18. Sunitinib in Treating Young Patients With Refractory Solid Tumors

    ClinicalTrials.gov

    2014-01-27

    Central Nervous System Metastases; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Embryonal Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Recurrent Childhood Central Nervous System Embryonal Tumor; Unspecified Childhood Solid Tumor, Protocol Specific

  19. Combination Chemotherapy in Treating Young Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2013-05-01

    Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Embryonal Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Unspecified Childhood Solid Tumor, Protocol Specific

  20. Study of the Glutaminase Inhibitor CB-839 in Solid Tumors

    ClinicalTrials.gov

    2016-08-18

    Solid Tumors; Triple-Negative Breast Cancer; Non Small Cell Lung Cancer; Renal Cell Carcinoma; Mesothelioma; Fumarate Hydratase (FH)-Deficient Tumors; Succinate Dehydrogenase (SDH)-Deficient Gastrointestinal Stromal Tumors (GIST); Succinate Dehydrogenase (SDH)-Deficient Non-gastrointestinal Stromal Tumors; Tumors Harboring Isocitrate Dehydrogenase-1 (IDH1) and IDH2 Mutations; Tumors Harboring Amplifications in the cMyc Gene

  1. Targeting BET bromodomain proteins in solid tumors

    PubMed Central

    Sahai, Vaibhav; Redig, Amanda J.; Collier, Katharine A.; Eckerdt, Frank D.; Munshi, Hidayatullah G.

    2016-01-01

    There is increasing interest in inhibitors targeting BET (bromodomain and extra-terminal) proteins because of the association between this family of proteins and cancer progression. BET inhibitors were initially shown to have efficacy in hematologic malignancies; however, a number of studies have now shown that BET inhibitors can also block progression of non-hematologic malignancies. In this Review, we summarize the efficacy of BET inhibitors in select solid tumors; evaluate the role of BET proteins in mediating resistance to current targeted therapies; and consider potential toxicities of BET inhibitors. We also evaluate recently characterized mechanisms of resistance to BET inhibitors; summarize ongoing clinical trials with these inhibitors; and discuss potential future roles of BET inhibitors in patients with solid tumors. PMID:27283767

  2. Destruction of solid tumors by immune cells

    NASA Astrophysics Data System (ADS)

    López, Álvaro G.; Seoane, Jesús M.; Sanjuán, Miguel A. F.

    2017-03-01

    The fractional cell kill is a mathematical expression describing the rate at which a certain population of cells is reduced to a fraction of itself. In order to investigate the fractional cell kill that governs the rate at which a solid tumor is lysed by a cell population of cytotoxic CD8+ T cells (CTLs), we present several in silico simulations and mathematical analyses. When the CTLs eradicate efficiently the tumor cells, the models predict a correlation between the morphology of the tumors and the rate at which they are lysed. However, when the effectiveness of the immune cells is decreased, the mathematical function fails to reproduce the process of lysis. This limit is thoroughly discussed and a new fractional cell kill is proposed.

  3. Patterns of Chromosomal Aberrations in Solid Tumors

    PubMed Central

    Grade, Marian; Difilippantonio, Michael J.

    2016-01-01

    Chromosomal abnormalities are a defining feature of solid tumors. Such cytogenetic alterations are mainly classified into structural chromosomal aberrations and copy number alterations, giving rise to aneuploid karyotypes. The increasing detection of these genetic changes allowed the description of specific tumor entities and the associated patterns of gene expression. In fact, tumor-specific landscapes of gross genomic copy number changes, including aneuploidies of entire chromosome arms and chromosomes result in a global deregulation of the transcriptome of cancer cells. Furthermore, the molecular characterization of cytogenetic abnormalities has provided insights into the mechanisms of tumorigenesis and has, in a few instances, led to the clinical implementation of effective diagnostic and prognostic tools, as well as treatment strategies that target a specific genetic abnormality. PMID:26376875

  4. Ixabepilone in Treating Young Patients With Refractory Solid Tumors

    ClinicalTrials.gov

    2014-11-13

    Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Alveolar Childhood Rhabdomyosarcoma; Childhood Synovial Sarcoma; Embryonal Childhood Rhabdomyosarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors

  5. Cixutumumab in Treating Patients With Relapsed or Refractory Solid Tumors

    ClinicalTrials.gov

    2015-03-18

    Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Childhood Hepatoblastoma; Childhood Synovial Sarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Adrenocortical Carcinoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive; Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Retinoblastoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors

  6. Advances in Cancer Immunotherapy in Solid Tumors

    PubMed Central

    Menon, Smitha; Shin, Sarah; Dy, Grace

    2016-01-01

    Immunotherapy is heralded as one of the most important advances in oncology. Until recently, only limited immunotherapeutic options were available in selected immunogenic cancers like melanoma and renal cell carcinomas. Nowadays, there is an improved understanding that anti-tumor immunity is controlled by a delicate balance in the tumor microenvironment between immune stimulatory and immune inhibitory pathways. Either by blocking the inhibitory pathways or stimulating the activating pathways that regulate cytotoxic lymphocytes, anti-tumor immunity can be enhanced leading to durable anti-tumor responses. Drugs which block the immune regulatory checkpoints namely the PD-1/PDL1 and CTLA 4 pathway have shown tremendous promise in a wide spectrum of solid and hematological malignancies, significantly improving overall survival in newly diagnosed and heavily pretreated patients alike. Hence there is renewed enthusiasm in the field of immune oncology with current research focused on augmenting responses to checkpoint inhibitors by combination therapy as well as studies looking at other immune modulators and adoptive T cell therapy. In this article, we highlight the key clinical advances and concepts in immunotherapy with particular emphasis on checkpoint inhibition as well as the future direction in this field. PMID:27886124

  7. Characterization of cell suspensions from solid tumors

    SciTech Connect

    Pallavicini, M.

    1985-07-10

    The desirable features of cells in suspension will necessarily be dependent upon the use for which the cells were prepared. Adequate cell yield or recovery is defined by the measurement to be performed. Retention of cellular morphology is important for microscopic identification of cell types in a heterogenous cell suspension, and may be used to determine whether the cells in suspension are representative of those in the tumor in situ. Different dispersal protocols may yield cells with different degrees of clonogenicity, as well as altered biochemical features, such as loss of cellular proteins, surface antigens, nucleotide pools, etc. The quality of the cell suspension can be judged by the degree of cell clumping and level of cellular debris, both of which impact on flow cytometric measurements and studies in which the number of cells be known accurately. Finally, if the data measured on the cells in suspension are to be extrapolated to phenomena occurring in the tumor in situ, it is desirable that the cells in suspension are representative of those in the solid tumor in vivo. This report compares characteristics of tumor cell suspensions obtained by different types of selected disaggregation methods. 33 refs., 2 figs., 4 tabs.

  8. MR-guided High Intensity Focused Ultrasound (HIFU) on Pediatric Solid Tumors

    ClinicalTrials.gov

    2017-02-27

    Relapsed Pediatric Solid Tumors; Refractory Pediatric Solid Tumors; Tumors Located in Bone or Soft Tissue in Close Proximity to Bone; Rhabdomyosarcoma; Ewing Sarcoma; Osteosarcoma; Neuroblastoma; Wilms Tumor; Hepatic Tumor; Germ Cell Tumor

  9. Therapy of leptomeningeal metastasis in solid tumors.

    PubMed

    Mack, F; Baumert, B G; Schäfer, N; Hattingen, E; Scheffler, B; Herrlinger, U; Glas, M

    2016-02-01

    Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors. Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction. In cases of suspected LM, the highest diagnostic sensitivity is provided by the combination of CSF cytology and contrast-enhanced MRI (cranial as well as complete spine). The therapeutic spectrum includes radiotherapy of the clinically involved region as well as systemic and intrathecal chemotherapy. The choice of treatment modalities depends on the type of LM (non-adherent tumor cells in the CSF vs. nodular contrast-enhancing tumor growth), additional systemic involvement (uncontrolled vs. controlled systemic disease) and additional involvement of the CNS parenchyma (LM as the only CNS involvement vs. LM+parenchymal CNS metastases). Larger contrast-enhancing nodular LM or symptomatic lesions of the spine may be treated with radiotherapy. In case of uncontrolled systemic disease, the treatment regimen should include systemic chemotherapy. The choice of systemic treatment should take into account the histology of the primary tumor. Intrathecal chemotherapy is most important in cases of LM of the non-adherent type. There are three substances for routine use for intrathecal chemotherapy: methotrexate, cytarabine, and thiotepa. Liposomal cytarabine shows advantages in terms of longer injection intervals, a sufficient distribution in the entire subarachnoid space after lumbar administration and improved quality-of-life. The role of new agents (e.g. rituximab and trastuzumab) for intrathecal therapy is still unclear.

  10. Immunoconjugates against solid tumors: mind the gap.

    PubMed

    Ricart, A D

    2011-04-01

    The objective of immunoconjugate development is to combine the specificity of immunoglobulins with the efficacy of cytotoxic molecules. This therapeutic approach has been validated in hematologic malignancies; however, several obstacles to achieving efficacy in treating solid tumors have been identified. These include insufficient specificity of targets and poor antibody delivery, most specifically to the tumor core. Heterogeneous antigen expression, imperfect vascular supply, and elevated interstitial fluid pressure have been suggested as the factors responsible for the poor delivery of antibodies. Promising immunoconjugates are in development: immunoconjugates targeting the prostate-specific membrane antigen, trastuzumab-DM1, lorvotuzumab mertansine, and SS1P. Advances in cancer biology and antibody engineering may overcome some of the challenges. New small antibody formats, such as single-chain Fv, Fab, and diabodies, may improve penetration within tumor masses. Nevertheless, the cost of treatment might require justification in terms of demonstrable improvement in quality of life in addition to efficacy; further economic evaluation might be necessary before this approach can replace the current standards of care in clinical practice.

  11. Autocrine growth factors and solid tumor malignancy.

    PubMed Central

    Walsh, J. H.; Karnes, W. E.; Cuttitta, F.; Walker, A.

    1991-01-01

    The ability of malignant cells to escape the constraint that normally regulate cell growth and differentiation has been a primary focus of attention for investigators of cancer cell biology. An outcome of this attention has been the discovery that the protein products of oncogenes play a role in the activation of growth signal pathways. A second outcome, possibly related to abnormal oncogene expression, has been the discovery that malignant cells frequently show an ability to regulate their own growth by the release of autocrine growth modulatory substances. Most important, the growth of certain malignant cell types has been shown to depend on autocrine growth circuits. A malignant tumor whose continued growth depends on the release of an autocrine growth factor may be vulnerable to treatment with specific receptor antagonists or immunoneutralizing antibodies designed to break the autocrine circuit. Information is rapidly emerging concerning autocrine growth factors in selected human solid tissue malignancy. Images PMID:1926844

  12. Entinostat and Sorafenib Tosylate in Treating Patients With Advanced or Metastatic Solid Tumors or Refractory or Relapsed Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-09-18

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; Recurrent Adult Acute Myeloid Leukemia; Unspecified Adult Solid Tumor, Protocol Specific

  13. Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 and Temsirolimus in Treating Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2014-05-29

    Endometrial Papillary Serous Carcinoma; Recurrent Endometrial Carcinoma; Recurrent Renal Cell Cancer; Stage III Endometrial Carcinoma; Stage III Renal Cell Cancer; Stage IV Endometrial Carcinoma; Stage IV Renal Cell Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  14. Temozolomide and O6-benzylguanine in Treating Children With Solid Tumors

    ClinicalTrials.gov

    2015-04-28

    Brain and Central Nervous System Tumors; Childhood Germ Cell Tumor; Extragonadal Germ Cell Tumor; Kidney Cancer; Liver Cancer; Neuroblastoma; Ovarian Cancer; Sarcoma; Unspecified Childhood Solid Tumor, Protocol Specific

  15. Population Pharmacokinetics of Selumetinib and Its Metabolite N-desmethyl-selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low-Grade Gliomas.

    PubMed

    Patel, Y T; Daryani, V M; Patel, P; Zhou, D; Fangusaro, J; Carlile, D J; Martin, P D; Aarons, L; Stewart, C F

    2017-03-22

    Selumetinib (AZD6244, ARRY-142886), a mitogen activated protein kinases (MEK1 and 2) inhibitor, has been granted orphan drug designation for differentiated thyroid cancer. The primary aim of this analysis was to characterize the population pharmacokinetics of selumetinib and its active metabolite N-desmethyl-selumetinib in patients with cancer. Concentration-time data from adult and pediatric clinical trials were pooled to develop a population pharmacokinetic model using a sequential approach where selumetinib and N-desmethyl-selumetinib data were modeled separately. A sequential zero- and first-order absorption with lag time with a two-compartment model for selumetinib and a two-compartment model for N-desmethyl-selumetinib best described the concentration-time data. Intrapatient variability in absorption was higher than interpatient variability. The apparent drug clearance (CL/F) from the central compartment was 13.5 L/hr (RSE 4.9%). Significant covariates for CL/F were age, alanine aminotransferase, and body surface area. This study confirms that flat dosing is appropriate in adults, whereas body-surface area based dosing should be used in pediatric patients.

  16. Disseminated Cerebrospinal Embryonal Tumor in the Adult

    PubMed Central

    Armocida, Daniele; Caporlingua, Federico; Lapadula, Gennaro; Elefante, Grazia Maria; Antonelli, Manila; Salvati, Maurizio

    2016-01-01

    Introduction. According to the 2016 World Health Organization classification of Tumors of the Central Nervous System, the term Primitive Neuroectodermal Tumor has been replaced by the term Embryonal Tumor (ET). We present a case of disseminated cerebrospinal ET presenting in an adult patient. Illustrative Case. A 49-year-old male presenting with low back pain, dysuria, and hypoesthesia of the lower extremities referred to our emergency department. Brain and whole spine contrast-enhanced MRI documented a diffusively disseminated heterogeneous neoplasm with intradural extra- and intramedullary involvement of the cervicothoracic tract and cauda equina. A primary biopsy of the lumbosacral localization was performed through L5 bilateral laminectomy. Histologic diagnosis was Embryonal Tumor Not Otherwise Specified. The patient underwent chemotherapy with postoperative adjuvant alternating Vincristine-Doxorubicin-Ifosfamide (VAI) and Ifosfamide-Etoposide (IE). Discussion. Spinal ETs are exceedingly rare especially when presenting in the adult patient. Neurosurgical and oncologic management is still unclear. When feasible, surgical removal should always be performed to obtain a histologic diagnosis. Postoperative adjuvant therapy might entail both chemo- and radiotherapy; however a consensus on this matter is still lacking. PMID:27818821

  17. MORAb-004 in Treating Young Patients With Recurrent or Refractory Solid Tumors or Lymphoma

    ClinicalTrials.gov

    2016-01-07

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  18. Immunotherapeutics for Pediatric Solid Tumors | NCI Technology Transfer Center | TTC

    Cancer.gov

    The National Cancer Institute’s Pediatric Oncology Branch seeks partners interested in licensing or collaborative research to co-develop new immunotherapeutic agents based on chimeric antigen receptor (CARs) for the treatment of pediatric solid tumors.

  19. A Study Evaluating MM-310 in Patients With Solid Tumors

    ClinicalTrials.gov

    2017-03-23

    Solid Tumors; Urothelial Carcinoma; Gastric Carcinoma; Squamous Cell Carcinoma of the Head and Neck; Ovarian Cancer; Pancreatic Ductal Adenocarcinoma; Prostate Adenocarcinoma; Non-small Cell Lung Cancer; Small Cell Lung Cancer; Triple Negative Breast Cancer; Endometrial Carcinoma; Soft Tissue Sarcoma

  20. Cilengitide (EMD 121974) in Treating Patients With Advanced Solid Tumors or Lymphoma

    ClinicalTrials.gov

    2013-01-23

    Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific

  1. Trebananib And Temsirolimus in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2015-10-05

    Adult Solid Neoplasm; Lung Carcinoid Tumor; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Renal Cell Carcinoma; Recurrent Uterine Corpus Sarcoma; Stage III Renal Cell Cancer; Stage IIIB Uterine Sarcoma; Stage IIIC Uterine Sarcoma; Stage IV Renal Cell Cancer; Stage IVA Uterine Sarcoma; Stage IVB Uterine Sarcoma

  2. Abemaciclib in Children With DIPG or Recurrent/Refractory Solid Tumors

    ClinicalTrials.gov

    2017-02-10

    Diffuse Intrinsic Pontine Glioma; Brain Tumor, Recurrent; Solid Tumor, Recurrent; Neuroblastoma, Recurrent, Refractory; Ewing Sarcoma, Recurrent, Refractory; Rhabdomyosarcoma, Recurrent, Refractory; Osteosarcoma, Recurrent, Refractory; Rhabdoid Tumor, Recurrent, Refractory

  3. Veliparib, Oxaliplatin, and Capecitabine in Treating Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2014-04-01

    Adenocarcinoma of the Pancreas; Adenocarcinoma of the Stomach; BRCA1 Mutation Carrier; BRCA2 Mutation Carrier; Ovarian Mucinous Cystadenocarcinoma; Recurrent Breast Cancer; Recurrent Colon Cancer; Recurrent Gastric Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Gastric Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Pancreatic Cancer; Stage IV Rectal Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  4. Therapeutic potential of bacteria against solid tumors.

    PubMed

    Hatzikirou, Haralampos; Lopez Alfonso, Juan Carlos; Leschner, Sara; Weiss, Siegfried; Meyer-Hermann, Michael

    2017-02-15

    Intentional bacterial infections can produce efficacious anti-tumor responses in mice, rats, dogs and humans. However, low overall success rates and intense side-effects prevent such approaches from being employed clinically. In this work, we titered bacteria and/or the pro-inflammatory cytokine TNF-α in a set of established murine models of cancer. To interpret the experiments conducted, we considered and calibrated a tumor-effector cell recruitment model under the influence of functional tumor-associated vasculature. In this model, bacterial infections and TNF-α enhanced immune activity and altered vascularization in the tumor bed. Information to predict bacterial therapy outcomes was provided by pre-treatment tumor size and the underlying immune recruitment dynamics. Notably, increasing bacterial loads did not necessarily produce better long-term tumor control, suggesting that tumor sizes affected optimal bacterial loads. Short-term treatment responses were favored by high concentrations of effector cells post-injection, such as induced by higher bacterial loads, but in the longer term did not correlate with an effective restoration of immune surveillance. Overall, our findings suggested that a combination of intermediate bacterial loads with low levels TNF-α administration could enable more favorable outcomes elicited by bacterial infections in tumor-bearing subjects.

  5. Dasatinib, Ifosfamide, Carboplatin, and Etoposide in Treating Young Patients With Metastatic or Recurrent Malignant Solid Tumors

    ClinicalTrials.gov

    2017-02-10

    Brain and Central Nervous System Tumors; Childhood Germ Cell Tumor; Extragonadal Germ Cell Tumor; Kidney Cancer; Liver Cancer; Lymphoma; Neuroblastoma; Ovarian Cancer; Sarcoma; Testicular Germ Cell Tumor; Unspecified Childhood Solid Tumor, Protocol Specific

  6. Improving delivery and efficacy of nanomedicines in solid tumors: Role of tumor priming

    PubMed Central

    Wang, Jie; Lu, Ze; Gao, Yue; Wientjes, M. Guillaume; Au, Jessie L.-S.

    2013-01-01

    Effectiveness of nanomedicines in cancer therapy is limited in part by inadequate delivery and transport in tumor interstitium. This report reviews the experimental approaches to improve nanomedicines delivery and transport in solid tumors. These approaches include tumor vasculature normalization, interstitial fluid pressure modulation, enzymatic extracellular matrix degradation, and apoptosis-inducing tumor priming technology. We advocate the latter approach due to its ease and practicality (accomplished with standard-of-care chemotherapy such as paclitaxel) and tumor selectivity. Examples of applying tumor priming to deliver nanomedicines and to design drug/RNAi-loaded carriers are discussed. PMID:22077464

  7. The Childhood Solid Tumor Network: A new resource for the developmental biology and oncology research communities.

    PubMed

    Stewart, Elizabeth; Federico, Sara; Karlstrom, Asa; Shelat, Anang; Sablauer, Andras; Pappo, Alberto; Dyer, Michael A

    2016-03-15

    Significant advances have been made over the past 25 years in our understanding of the most common adult solid tumors such as breast, colon, lung and prostate cancer. Much less is known about childhood solid tumors because they are rare and because they originate in developing organs during fetal development, childhood and adolescence. It can be very difficult to study the cellular origins of pediatric solid tumors in developing organs characterized by rapid proliferative expansion, growth factor signaling, developmental angiogenesis, programmed cell death, tissue reorganization and cell migration. Not only has the etiology of pediatric cancer remained elusive because of their developmental origins, but it also makes it more difficult to treat. Molecular targeted therapeutics that alter developmental pathway signaling may have devastating effects on normal organ development. Therefore, basic research focused on the mechanisms of development provides an essential foundation for pediatric solid tumor translational research. In this article, we describe new resources available for the developmental biology and oncology research communities. In a companion paper, we present the detailed characterization of an orthotopic xenograft of a pediatric solid tumor derived from sympathoadrenal lineage during development.

  8. Solid tumor therapy by selectively targeting stromal endothelial cells

    PubMed Central

    Liu, Shihui; Liu, Jie; Ma, Qian; Cao, Liu; Fattah, Rasem J.; Yu, Zuxi; Bugge, Thomas H.; Finkel, Toren; Leppla, Stephen H.

    2016-01-01

    Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors. PMID:27357689

  9. PET Radiotracers for Imaging the Proliferative Status of Solid Tumors

    PubMed Central

    Mach, Robert H.; Dehdashti, Farrokh; Wheeler, Kenneth T.

    2009-01-01

    Synopsis Two different strategies have been developed for imaging the proliferative status of solid tumors with the functional imaging technique, Positron Emission Tomography (PET). The first strategy uses carbon-11 labeled thymidine and/or, more recently, fluorine-18 labeled thymidine analogs. These agents are a substrate for the enzyme thymidine kinase-1 (TK-1) and provide a pulse label of the number of cells in S phase. The second method for imaging the proliferative status of a tumor uses radiolabeled ligands that bind to the sigma-2 receptor which has a 10-fold higher density in proliferating (P) tumor cells versus quiescent (Q) tumor cells. This article compares and contrasts the two different strategies for imaging the proliferative status of solid tumors, and describes the strengths and weaknesses of each approach. PMID:20046891

  10. Irinotecan in Treating Children With Refractory Solid Tumors

    ClinicalTrials.gov

    2013-06-13

    Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood Infratentorial Ependymoma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Unspecified Childhood Solid Tumor, Protocol Specific

  11. Characterization and differentiation of three solid tumors using quantitative ultrasound

    NASA Astrophysics Data System (ADS)

    Oelze, Michael L.; O'Brien, William D.; Zachary, James F.

    2004-05-01

    Three kinds of solid tumors were acquired and scanned in vivo ultrasonically. The first tumor series (fibroadenoma) was acquired from tumors that had spontaneously developed in rats. The second tumor series was acquired by culturing a carcinoma cell line (4T1-MMT) in culture media and injecting the cells into Balb/c mice. The third tumor was acquired by transplanting a soft-tissue sarcoma cell line (EHS) into C57BL mice. The tumors were allowed to grow to 1 cm in size and then scanned ultrasonically. The scatterer properties of average scatterer diameter and acoustic concentration were estimated using a Gaussian form factor from the backscattered ultrasound measured from the tumors. Parametric images of the tumors were constructed utilizing estimated scatterer properties for regions of interest inside the tumors. The parametric images showed distinct differences between the various tumor types. Quantitatively, the tumors could be distinguished through feature analysis plots of average scatterer size versus acoustic concentration. Comparison with photomicrographs of the tumors showed structures similar in size to the ultrasound estimates. [Work supported by NIH Grant F32 CA96419 to MLO and by the University of Illinois Research Board.

  12. Barriers to drug delivery in solid tumors

    PubMed Central

    Sriraman, Shravan Kumar; Aryasomayajula, Bhawani; Torchilin, Vladimir P

    2014-01-01

    Over the last decade, significant progress has been made in the field of drug delivery. The advent of engineered nanoparticles has allowed us to circumvent the initial limitations to drug delivery such as pharmacokinetics and solubility. However, in spite of significant advances to tumor targeting, an effective treatment strategy for malignant tumors still remains elusive. Tumors possess distinct physiological features which allow them to resist traditional treatment approaches. This combined with the complexity of the biological system presents significant hurdles to the site-specific delivery of therapeutic drugs. One of the key features of engineered nanoparticles is that these can be tailored to execute specific functions. With this review, we hope to provide the reader with a clear understanding and knowledge of biological barriers and the methods to exploit these characteristics to design multifunctional nanocarriers, effect useful dosing regimens and subsequently improve therapeutic outcomes in the clinic. PMID:25068098

  13. Effect of tumor shape and size on drug delivery to solid tumors

    PubMed Central

    2012-01-01

    Tumor shape and size effect on drug delivery to solid tumors are studied, based on the application of the governing equations for fluid flow, i.e., the conservation laws for mass and momentum, to physiological systems containing solid tumors. The discretized form of the governing equations, with appropriate boundary conditions, is developed for predefined tumor geometries. The governing equations are solved using a numerical method, the element-based finite volume method. Interstitial fluid pressure and velocity are used to show the details of drug delivery in a solid tumor, under an assumption that drug particles flow with the interstitial fluid. Drug delivery problems have been most extensively researched in spherical tumors, which have been the simplest to examine with the analytical methods. With our numerical method, however, more complex shapes of the tumor can be studied. The numerical model of fluid flow in solid tumors previously introduced by our group is further developed to incorporate and investigate non-spherical tumors such as prolate and oblate ones. Also the effects of the surface area per unit volume of the tissue, vascular and interstitial hydraulic conductivity on drug delivery are investigated. PMID:22534172

  14. 17-DMAG in Treating Patients With Metastatic or Unresectable Solid Tumors or Lymphomas

    ClinicalTrials.gov

    2013-01-24

    Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenstr

  15. MS-275 and Isotretinoin in Treating Patients With Metastatic or Advanced Solid Tumors or Lymphomas

    ClinicalTrials.gov

    2013-01-23

    Adult Grade III Lymphomatoid Granulomatosis; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  16. Harnessing the potential of epigenetic therapy to target solid tumors

    PubMed Central

    Ahuja, Nita; Easwaran, Hariharan; Baylin, Stephen B.

    2014-01-01

    Epigenetic therapies may play a prominent role in the future management of solid tumors. This possibility is based on the clinical efficacy of existing drugs in treating defined hematopoietic neoplasms, paired with promising new data from preclinical and clinical studies that examined these agents in solid tumors. We suggest that current drugs may represent a targeted therapeutic approach for reprogramming solid tumor cells, a strategy that must be pursued in concert with the explosion in knowledge about the molecular underpinnings of normal and cancer epigenomes. We hypothesize that understanding targeted proteins in the context of their enzymatic and scaffolding functions and in terms of their interactions in complexes with proteins that are targets of new drugs under development defines the future of epigenetic therapies for cancer. PMID:24382390

  17. 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.

  18. Vorinostat in Treating Patients With Metastatic or Unresectable Solid Tumors or Lymphoma and Liver Dysfunction

    ClinicalTrials.gov

    2014-02-21

    IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  19. Chimeric antigen receptor T-cell therapy for solid tumors

    PubMed Central

    Newick, Kheng; Moon, Edmund; Albelda, Steven M

    2016-01-01

    Chimeric antigen receptor (CAR) T cells are engineered constructs composed of synthetic receptors that direct T cells to surface antigens for subsequent elimination. Many CAR constructs are also manufactured with elements that augment T-cell persistence and activity. To date, CAR T cells have demonstrated tremendous success in eradicating hematological malignancies (e.g., CD19 CARs in leukemias). This success is not yet extrapolated to solid tumors, and the reasons for this are being actively investigated. Here in this mini-review, we discuss some of the key hurdles encountered by CAR T cells in the solid tumor microenvironment. PMID:27162934

  20. Tanespimycin and Bortezomib in Treating Patients With Advanced Solid Tumors or Lymphomas

    ClinicalTrials.gov

    2014-02-21

    T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  1. PXD101 and Bortezomib in Treating Patients With Advanced Solid Tumors or Lymphomas

    ClinicalTrials.gov

    2013-05-01

    Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  2. [Oncolytic virotherapy for human solid tumors].

    PubMed

    Fujiwara, Toshiyoshi

    2009-05-01

    Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. Telomerase activation is considered to be a critical step in carcinogenesis, and its activity correlates closely with human telomerase reverse transcriptase(hTERT)expression. We constructed an attenuated adenovirus 5 vector(Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1 genes. Telomelysin replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human cells lacking telomerase activity. We further modified the E3 region of OBP-301 to contain green fluorescent protein(GFP)gene for monitoring viral replication(TelomeScan, OBP-401). When TelomeScan was intratumorally injected into human tumors orthotopically implanted into the rectum in mice, para-aortic lymph node metastasis could be visualized at laparotomy with a three-chip color cooled charged-coupled device camera. This article reviews recent highlights in this rapidly evolving field of cancer therapeutic and diagnostic approaches using telomerase-specific oncolytic adenoviruses.

  3. Pharmacotherapy for Adults with Tumors of the Central Nervous System

    PubMed Central

    Schor, Nina F.

    2009-01-01

    Tumors of the adult central nervous system are among the most common and most chemoresistant neoplasms. Malignant tumors of the brain and spinal cord collectively account for approximately 1.3% of all cancers and 2.2% of all cancer-related deaths. Novel pharmacological approaches to nervous system tumors are urgently needed. This review presents the current approaches and challenges to successful pharmacotherapy of adults with malignant tumors of the central nervous system and discusses novel approaches aimed at overcoming these challenges. PMID:19091301

  4. Myeloid Cells as Targets for Therapy in Solid Tumors

    PubMed Central

    Cotechini, Tiziana; Medler, Terry R.; Coussens, Lisa M.

    2016-01-01

    It is well established that cancer development ensues based on reciprocal interactions between genomically altered neoplastic cells and diverse populations of recruited “host” cells co-opted to support malignant progression. Among the host cells recruited into tumor microenvironments, several subtypes of myeloid cells, including macrophages, monocytes, dendritic cells, and granulocytes contribute to tumor development by providing tumor-promoting factors as well as a spectrum of molecules that suppress cytotoxic activities of T lymphocytes. Based on compelling preclinical data revealing that inhibition of critical myeloid-based programs leads to tumor suppression, novel immune-based therapies and approaches are now entering the clinic for evaluation. This review discusses mechanisms underlying protumorigenic programming of myeloid cells and discusses how targeting of these has potential to attenuate solid tumor progression via the induction and of mobilization CD8+ cytotoxic T cell immunity. PMID:26222088

  5. Targeted radionuclide therapy for solid tumors: An overview

    SciTech Connect

    De Nardo, Sally J.

    2006-10-01

    Although radioimmunotherapy (RIT) has been effective in non-Hodgkin's lymphoma (NHL) as a single agent, solid tumors have shown less clinically significant therapeutic response to RIT alone. The clinical impact of RIT or other forms of targeted radionuclide therapy for solid tumors depends on the development of a high therapeutic index (TI) for the tumor vs. normal tissue effect, and the implementation of RIT as part of synergistic combined modality therapy (CMRIT). Preclinical and clinical studies have provided a wealth of information, and new prototypes or paradigms have shed light on future possibilities in many instances. Evidence suggests that combination and sequencing of RIT in CMRIT appropriately can provide effective treatment for many solid tumors. Vascular targets provide RIT enhancement opportunities and nanoparticles may prove to be effective carriers for RIT combined with intracellular drug delivery or alternating magnetic frequency (AMF) induced thermal tumor necrosis. The sequence and timing of combined modality treatments will be of critical importance to achieve synergy for therapy while minimizing toxicity. Fortunately, the radionuclide used for RIT also provides a signal useful for nondestructive quantitation of the influence of sequence and timing of CMRIT on events in animals and patients. This can be readily accomplished clinically using quantitative high-resolution imaging (e.g., positron emission tomography [PET])

  6. Genetic Testing Plus Irinotecan in Treating Patients With Solid Tumors or Lymphoma

    ClinicalTrials.gov

    2013-01-23

    Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific

  7. 3-AP and Gemcitabine in Treating Patients With Advanced Solid Tumors or Lymphoma

    ClinicalTrials.gov

    2013-09-27

    -cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  8. FGFR3-TACC3 fusion in solid tumors: mini review

    PubMed Central

    Costa, Ricardo; Carneiro, Benedito A.; Taxter, Timothy; Tavora, Fabio A.; Kalyan, Aparna; Pai, Sachin A.; Chae, Young Kwang; Giles, Francis J.

    2016-01-01

    Fibroblast growth factor receptors (FGFR) are transmembrane kinase proteins with growing importance in cancer biology given the frequency of molecular alterations and vast interface with multiple other signaling pathways. Furthermore, numerous FGFR inhibitors in clinical development demonstrate the expanding therapeutic relevance of this pathway. Indeed, results from early phase clinical trials already indicate that a subset of patients with advanced tumors derive benefit from FGFR targeted therapies. FGFR gene aberrations and FGFR gene rearrangements are relatively rare in solid malignancies. The recently described FGFR3-TACC3 fusion protein has a constitutively active tyrosine kinase domain and promotes aneuploidy. We summarize the prevalence data on FGFR3-TACC3 fusions among different histological tumor types and the preliminary evidence that this rearrangement represents a targetable molecular aberration in some patients with solid tumors. PMID:27409839

  9. Review of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in solid tumors excluding breast cancer

    PubMed Central

    Karadurmus, Nuri; Sahin, Ugur; Basgoz, Bilgin Bahadir; Arpaci, Fikret; Demirer, Taner

    2016-01-01

    Solid tumors in adults constitute a heterogeneous group of malignancy originating from various organ systems. Solid tumors are not completely curable by chemotherapy, even though some subgroups are very chemo-sensitive. Recently, oncologists have focused on the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with reduced intensity conditioning (RIC) for the treatment of some refractory solid tumors. After the demonstration of allogeneic graft-versus-leukemia effect in patients with hematological malignancies who received allo-HSCT, investigators evaluated this effect in patients with refractory metastatic solid tumors. According to data from experimental animal models and preliminary clinical trials, a graft-versus-tumor (GvT) effect may also be observed in the treatment of some solid tumors (e.g., renal cell cancer, colorectal cancer, etc.) after allo-HSCT with RIC. The use of RIC regimens offers an opportunity of achieving full-donor engraftment with GvT effect, as well as, a reduced transplant-related mortality. Current literature suggests that allo-HSCT with RIC might become a choice for elderly and medically fragile patients with refractory metastatic solid tumors. PMID:28058217

  10. Preclinical evaluation of engineered oncolytic herpes simplex virus for the treatment of pediatric solid tumors.

    PubMed

    Megison, Michael L; Gillory, Lauren A; Stewart, Jerry E; Nabers, Hugh C; Mroczek-Musulman, Elizabeth; Waters, Alicia M; Coleman, Jennifer M; Kelly, Virginia; Markert, James M; Gillespie, G Yancey; Friedman, Gregory K; Beierle, Elizabeth A

    2014-01-01

    Recently, investigators showed that mice with syngeneic murine gliomas that were treated with a neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ134.5 gene, enabling replication in tumor cells but precluding infection of normal cells. Previous studies have shown antitumor effects of other oHSV against a number of adult tumors including hepatocellular carcinoma and renal cell carcinoma. The purpose of the current study was to investigate the oncolytic potential of M002 against difficult to treat pediatric liver and kidney tumors. We showed that the oHSV, M002, infected, replicated, and decreased cell survival in hepatoblastoma, malignant rhabdoid kidney tumor, and renal sarcoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly increased survival and decreased tumor growth. Finally, these studies showed that the primary entry protein for oHSV, CD111 (nectin-1) was present in human hepatoblastoma and malignant rhabdoid kidney tumor specimens. We concluded that M002 effectively targeted these rare aggressive tumor types and that M002 may have potential for use in children with unresponsive or relapsed pediatric solid tumors.

  11. Primitive Neuroectodermal Tumor with Glioblastoma Multiforme Components in an Adult: A Collision Tumor.

    PubMed

    Forbes, Victoria; Vredenburgh, James

    2016-01-11

    We report a rare case of a central nervous system collision tumor in a 40-year-old woman. Histopathological examination of her large temporal tumor revealed two different components making up the tumor tissue. The predominant component of the tumor was found to be a primitive neuroectodermal tumor. The other component was glioblastoma multiforme. Both of these tumors carry a poor prognosis, and primitive neuroectodermal tumors are extremely uncommon in adults. Central nervous system neoplasms with the combined features of both primitive neuroectodermal tumor and malignant glioma are very rare and represent a diagnostic and treatment predicament. The patient underwent surgical resection, radiation therapy, and chemotherapy targeting both the primitive neuroectodermal tumor and glioblastoma. Our patient has been fortunate in not showing any sign of recurrence and will celebrate the third anniversary since her diagnosis this January.

  12. Infections in Cancer Patients with Solid Tumors: A Review.

    PubMed

    Rolston, Kenneth V I

    2017-03-01

    Solid tumors are much more common than hematologic malignancies. Although severe and prolonged neutropenia is uncommon, several factors increase the risk of infection in patients with solid tumors, and the presence of multiple risk factors in the same patient is not uncommon. These include obstruction (most often caused by progression of the tumor), disruption of natural anatomic barriers such as the skin and mucosal surfaces, and treatment-related factors such as chemotherapy, radiation, diagnostic and/or therapeutic surgical procedures, and the increasing use of medical devices such as various catheters, stents, and prostheses. Common sites of infection include the skin and skin structures (including surgical site infections), the bloodstream (including infections associated with central venous catheters), the lungs, the hepato-biliary and intestinal tracts, and the urinary tract, and include distinct clinical syndromes such as post-obstructive pneumonia, obstructive uropathy, and neutropenic enterocolitis. The epidemiology of most of these infections is changing with resistant organisms [MRSA, Pseudomonas aeruginosa, extended spectrum beta-lactamase (ESBL)-producing organisms] being isolated more often than in the past. Polymicrobial infections now predominate when deep tissue sites are involved. Conservative management of most of these infections (antibiotics, fluid and electrolyte replacement, bowel rest when needed) is generally effective, with surgical intervention being reserved for the drainage of deep abscesses, or to deal with complications such as intestinal obstruction or hemorrhage. Infected prostheses often need to be removed. Reactivation of certain viral infections (HBV, HCV, and occasionally CMV) has become an important issue, and screening, prevention and treatment strategies are being developed. Infection prevention, infection control, and antimicrobial stewardship are important strategies in the overall management of infections in patients with

  13. Potential of epigenetic therapies in the management of solid tumors

    PubMed Central

    Valdespino, Victor; Valdespino, Patricia M

    2015-01-01

    Cancer is a complex disease with both genetic and epigenetic origins. The growing field of epigenetics has contributed to our understanding of oncogenesis and tumor progression, and has allowed the development of novel therapeutic drugs. First-generation epigenetic inhibitor drugs have obtained modest clinical results in two types of hematological malignancy. Second-generation epigenetic inhibitors are in development, and have intrinsically greater selectivity for their molecular targets. Solid tumors are more genetic and epigenetically complex than hematological malignancies, but the transcriptome and epigenome biomarkers have been identified for many of these malignancies. This solid tumor molecular aberration profile may be modified using specific or quasi-specific epidrugs together with conventional and innovative anticancer treatments. In this critical review, we briefly analyze the strategies to select the targeted epigenetic changes, enumerate the second-generation epigenetic inhibitors, and describe the main signs indicating the potential of epigenetic therapies in the management of solid tumors. We also highlight the work of consortia or academic organizations that support the undertaking of human epigenetic therapeutic projects as well as some examples of transcriptome/epigenome profile determination in clinical assessment of cancer patients treated with epidrugs. There is a good chance that epigenetic therapies will be able to be used in patients with solid tumors in the future. This may happen soon through collaboration of diverse scientific groups, making the selection of targeted epigenetic aberration(s) more rapid, the design and probe of drug candidates, accelerating in vitro and in vivo assays, and undertaking new cancer epigenetic-therapy clinical trails. PMID:26346546

  14. A Dose Escalation Study in Adult Patients With Advanced Solid Malignancies

    ClinicalTrials.gov

    2017-03-20

    Advanced Solid Tumors With Alterations of FGFR1, 2 and or 3; Squamous Lung Cancer With FGFR1 Amplification; Bladder Cancer With FGFR3 Mutation or Fusion; Advanced Solid Tumors With FGFR1 Amplication; Advanced Solid Tumors With FGFR2 Amplication; Advanced Solid Tumors With FGFR3 Mutation

  15. AFP464 in Treating Patients With Metastatic or Refractory Solid Tumors That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2014-02-21

    Male Breast Cancer; Recurrent Breast Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Primary Peritoneal Cavity Cancer; Recurrent Renal Cell Cancer; Stage IV Breast Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Primary Peritoneal Cavity Cancer; Stage IV Renal Cell Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  16. Clinical application of adoptive T cell therapy in solid tumors

    PubMed Central

    Zang, Yi-Wen; Gu, Xiao-Dong; Xiang, Jian-Bin; Chen, Zong-You

    2014-01-01

    As an emerging therapeutic approach, adoptive T cell therapy shown promise in advanced solid malignancies. The results obtained in patients with metastatic melanoma and kidney cancer are encouraging because of the visible clinical benefits and limited adverse effects. Recently, the genetically-modified T cells expressing specific T cell receptors or chimeric antigen receptors are just now entering the clinical arena and show great potential for high avidity to tumor-associated antigens and long-lasting anti-tumor responses. However, continued investigations are necessary to improve the cell product quality so as to decrease adverse effects and clinical costs, and make adoptive T cell therapy a tool of choice for solid malignancies. PMID:24912947

  17. SB-715992 in Treating Patients With Metastatic or Unresectable Solid Tumors or Hodgkin's or Non-Hodgkin's Lymphoma

    ClinicalTrials.gov

    2013-01-11

    Adult Grade III Lymphomatoid Granulomatosis; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  18. The Multifaceted Roles of B Cells in Solid Tumors: Emerging Treatment Opportunities.

    PubMed

    Flynn, Nicole J; Somasundaram, Rajasekharan; Arnold, Kimberly M; Sims-Mourtada, Jennifer

    2017-04-01

    The influence of tumor infiltrating lymphocytes on tumor growth and response to therapy is becoming increasingly apparent. While much work has focused on the role of T cell responses in anti-tumor immunity, the role of B cells in solid tumors is much less understood. Tumor infiltrating B cells have been found in a variety of solid tumors, including breast, ovarian, prostate, melanoma, and colorectal cancer. The function of B cells in solid tumors is controversial, with many studies reporting a pro-tumor effect, while other studies demonstrate a role for B cells in the anti-tumor immune response. In this review, we discuss the prognostic ability of B cells in solid tumors as well as the mechanisms by which B cells can either promote or suppress anti-tumor immunity. Additionally, we review current therapeutic strategies that may target both pro- and anti-tumor B cells.

  19. Chemophototherapy: An Emerging Treatment Option for Solid Tumors

    PubMed Central

    Luo, Dandan; Carter, Kevin A.; Miranda, Dyego

    2016-01-01

    Near infrared (NIR) light penetrates human tissues with limited depth, thereby providing a method to safely deliver non‐ionizing radiation to well‐defined target tissue volumes. Light‐based therapies including photodynamic therapy (PDT) and laser‐induced thermal therapy have been validated clinically for curative and palliative treatment of solid tumors. However, these monotherapies can suffer from incomplete tumor killing and have not displaced existing ablative modalities. The combination of phototherapy and chemotherapy (chemophototherapy, CPT), when carefully planned, has been shown to be an effective tumor treatment option preclinically and clinically. Chemotherapy can enhance the efficacy of PDT by targeting surviving cancer cells or by inhibiting regrowth of damaged tumor blood vessels. Alternatively, PDT‐mediated vascular permeabilization has been shown to enhance the deposition of nanoparticulate drugs into tumors for enhanced accumulation and efficacy. Integrated nanoparticles have been reported that combine photosensitizers and drugs into a single agent. More recently, light‐activated nanoparticles have been developed that release their payload in response to light irradiation to achieve improved drug bioavailability with superior efficacy. CPT can potently eradicate tumors with precise spatial control, and further clinical testing is warranted. PMID:28105389

  20. Local iontophoretic administration of cytotoxic therapies to solid tumors

    PubMed Central

    Byrne, James D.; Jajja, Mohammad R. N.; O’Neill, Adrian T.; Bickford, Lissett R.; Keeler, Amanda W.; Hyder, Nabeel; Wagner, Kyle; Deal, Allison; Little, Ryan E.; Moffitt, Richard A.; Stack, Colleen; Nelson, Meredith; Brooks, Christopher R.; Lee, William; Luft, J. Chris; Napier, Mary E.; Darr, David; Anders, Carey K.; Stack, Richard; Tepper, Joel E.; Wang, Andrew Z.; Zamboni, William C.; Yeh, Jen Jen; DeSimone, Joseph M.

    2015-01-01

    Parenteral and oral routes have been the traditional methods of administering cytotoxic agents to cancer patients. Unfortunately, the maximum potential effect of these cytotoxic agents has been limited because of systemic toxicity and poor tumor perfusion. In an attempt to improve the efficacy of cytotoxic agents while mitigating their side effects, we have developed modalities for the localized iontophoretic delivery of cytotoxic agents. These iontophoretic devices were designed to be implanted proximal to the tumor with external control of power and drug flow. Three distinct orthotopic mouse models of cancer and a canine model were evaluated for device efficacy and toxicity. Orthotopic patient-derived pancreatic cancer xenografts treated biweekly with gemcitabine via the device for 7 weeks experienced a mean log2 fold change in tumor volume of −0.8 compared to a mean log2 fold change in tumor volume of 1.1 for intravenous (IV) gemcitabine, 3.0 for IV saline, and 2.6 for device saline groups. The weekly coadministration of systemic cisplatin therapy and transdermal device cisplatin therapy significantly increased tumor growth inhibition and doubled the survival in two aggressive orthotopic models of breast cancer. The addition of radiotherapy to this treatment further extended survival. Device delivery of gemcitabine in dogs resulted in more than 7-fold difference in local drug concentrations and 25-fold lower systemic drug levels than the IV treatment. Overall, these devices have potential paradigm shifting implications for the treatment of pancreatic, breast, and other solid tumors. PMID:25653220

  1. Prevention of infection in adult travelers after solid organ transplantation.

    PubMed

    Kotton, Camille Nelson; Ryan, Edward T; Fishman, Jay A

    2005-01-01

    Increasing numbers of solid organ transplant recipients are traveling to the developing world. Many of these individuals either do not seek or do not receive optimal medical care prior to travel. This review considers risks of international travel to adult solid organ transplant recipients and the use of vaccines and prophylactic agents in this population.

  2. Mast cells as targets for immunotherapy of solid tumors.

    PubMed

    Oldford, Sharon A; Marshall, Jean S

    2015-01-01

    Mast cells have historically been studied mainly in the context of allergic disease. In recent years, we have come to understand the critical importance of mast cells in tissue remodeling events and their role as sentinel cells in the induction and development of effective immune responses to infection. Studies of the role of mast cells in tumor immunity are more limited. The pro-tumorigenic role of mast cells has been widely reported. However, mast cell infiltration predicts improved prognosis in some cancers, suggesting that their prognostic value may be dependent on other variables. Such factors may include the nature of local mast cell subsets and the various activation stimuli present within the tumor microenvironment. Experimental models have highlighted the importance of mast cells in orchestrating the anti-tumor events that follow immunotherapies that target innate immunity. Mast cells are long-lived tissue resident cells that are abundant around many solid tumors and are radiation resistant making them unique candidates for combined treatment modalities. This review will examine some of the key roles of mast cells in tumor immunity, with a focus on potential immunotherapeutic interventions that harness the sentinel role of mast cells.

  3. Cross-talk among myeloid-derived suppressor cells, macrophages, and tumor cells impacts the inflammatory milieu of solid tumors

    PubMed Central

    Beury, Daniel W.; Parker, Katherine H.; Nyandjo, Maeva; Sinha, Pratima; Carter, Kayla A.; Ostrand-Rosenberg, Suzanne

    2014-01-01

    MDSC and macrophages are present in most solid tumors and are important drivers of immune suppression and inflammation. It is established that cross-talk between MDSC and macrophages impacts anti-tumor immunity; however, interactions between tumor cells and MDSC or macrophages are less well studied. To examine potential interactions between these cells, we studied the impact of MDSC, macrophages, and four murine tumor cell lines on each other, both in vitro and in vivo. We focused on IL-6, IL-10, IL-12, TNF-α, and NO, as these molecules are produced by macrophages, MDSC, and many tumor cells; are present in most solid tumors; and regulate inflammation. In vitro studies demonstrated that MDSC-produced IL-10 decreased macrophage IL-6 and TNF-α and increased NO. IL-6 indirectly regulated MDSC IL-10. Tumor cells increased MDSC IL-6 and vice versa. Tumor cells also increased macrophage IL-6 and NO and decreased macrophage TNF-α. Tumor cell-driven macrophage IL-6 was reduced by MDSC, and tumor cells and MDSC enhanced macrophage NO. In vivo analysis of solid tumors identified IL-6 and IL-10 as the dominant cytokines and demonstrated that these molecules were produced predominantly by stromal cells. These results suggest that inflammation within solid tumors is regulated by the ratio of tumor cells to MDSC and macrophages and that interactions of these cells have the potential to alter significantly the inflammatory milieu within the tumor microenvironment. PMID:25170116

  4. Developing vascular and hypoxia based theranostics in solid tumors

    NASA Astrophysics Data System (ADS)

    Koonce, Nathan A.

    Tissue hypoxia was recognized for its biological attenuating effects on ionizing radiation over a century ago and is a characteristic feature of many solid tumors. Clinical and experimental evidence indicates tumor hypoxia plays diverse and key roles in tumor progression, angiogenesis, and resistance to chemotherapy/radiotherapy. Hypoxia has known effects on progression and resistance to several standard treatment approaches and the significant history of study might suggest diagnostic imaging and therapeutic interventions would be routine in oncological practice. Curiously, this is not the case and the research results involved in this report will attempt to better understand and contribute to why this gap in knowledge exists and a rationale for harnessing the potential of detecting and targeting hypoxia. Despite the addition of oxygen and reversal of hypoxia being known as the best radiosensitizer, hypoxia remains unexploited in clinical cancer therapy. The studies reported herein detail development of a novel imaging technique to detect a subtype of tumor hypoxia, vascular hypoxia or hypoxemia, with a 17-fold increase (p<0.05) in uptake of pimonidazole targeted microbubbles observed compared to controls. This technique creates the potential to study the role of hypoxemia in progression and therapeutic response. Additionally, description of a nanoparticle-based therapy that targets tumor areas associated with tumor hypoxia and the tumor microenvironment in general is reported. TNF-loaded nanoparticles combined with radiotherapy resulted in a 5.25-fold growth delay that was found to be synergistic (p<0.05) and suggests clinical evaluation is warranted. An additional study to evaluate an approach to use thermal ablation of intratumoral hypoxia by an image-guided technique developed in our group is described along with a sequence dependence of radiation preceding ablation. A final study on the use of galectin-1 antagonist to significantly decrease (p<0.05) hypoxia

  5. Clinical Significance of Serum Biomarkers in Pediatric Solid Mediastinal and Abdominal Tumors

    PubMed Central

    Sandoval, John A.; Malkas, Linda H.; Hickey, Robert J.

    2012-01-01

    Childhood cancer is the leading cause of death by disease among U.S. children between infancy and age 15. Despite successes in treating solid tumors such as Wilms tumor, disappointments in the outcomes of high-risk solid tumors like neuroblastoma have precipitated efforts towards the early and accurate detection of these malignancies. This review summarizes available solid tumor serum biomarkers with a special focus on mediastinal and abdominal cancers in children. PMID:22312308

  6. Exploiting hypoxia in solid tumors to achieve oncolysis.

    PubMed

    Payne, Anthony G

    2007-01-01

    Chemo- and radio-resistant cancer cells within solid tumors undermine the effectiveness of these approaches to achieving oncolysis. These resistant cells and clusters of cells typically thrive at low oxygen tensions and are reliant on anaerobic metabolic pathways that churn out lactate. This hypoxic state is one that can be exploited and in this paper a novel method is advanced involving tumor cell infiltration by bifidobacterium species which should bring about prodigious lactate synthesis; concomitant blocking of its enzymatic degradation by urea as well as export (from the cell) by use of quercetin; depletion of ATP using exogenous thyroid; and compromised oxidative catabolism of free fatty acids and amino acids via oral intake of l-hydroxycitrate, melatonin and nontoxic NDGA. This "anaerobic pathway cocktail", it is hypothesized, will bring about a profound reduction in intracellular pH and a compromised state of cellular energetics sufficient to effect oncolysis.

  7. Enhanced radiation lethality in partially synchronized solid mouse tumors

    SciTech Connect

    Todoroki, T.; Koike, S.; Tsunemoto, H.; Watanabe, I.

    1982-12-01

    We studied the combined effects of local irradiation on in vivo partially synchronized solid mouse tumors. Syngeneic fibrosarcoma cells were transplanted s.c. into the thighs of C3H/He mice. When the tumors grew to 179 cu mm in volume, 1-beta-D-arabinofuranosylcytosine (ara-C) was repeatedly injected i.p. followed by a single injection of vinblastine sulfate at 5 hr after the end of the ara-C treatment. The mitotic indexes increased from 4% in control to 22 to 23% at 5 hr after the ara-C treatment, and the level continued for another 5 hr. Further treatment with vinblastine sulfate after the ara-C injections resulted in more effective accumulation of mitotic cells, i.e., 30% at the sixth hr. The tumor was locally irradiated with a single dose of 3000 rads of gamma-rays at the maximum level of mitotic index. The results indicated a synergistic inhibition of tumor growth and an 84% prolongation of the 50% survival day beyond that of the nontreated control mice.

  8. Pancreatic solid cystic desmoid tumor: case report and literature review.

    PubMed

    Xu, Bin; Zhu, Ling-Hua; Wu, Jia-Guo; Wang, Xian-Fa; Matro, Erik; Ni, Jun-Jun

    2013-12-14

    Desmoid tumors (DTs) are nonmetastatic, locally aggressive neoplasms with a high rate of postoperative recurrence. Pancreatic DTs are especially rare; only a few cases have been reported to date. This paper describes a case of a sporadic cystic DT of the pancreas managed successfully with central pancreatectomy, with no signs of recurrence 40 mo after surgery. According to the literature, this is the first reported case in China of a pancreatic DT presenting as a solid cystic lesion, as well as the first pancreatic DT managed with central pancreatectomy and pancreaticogastrostomy. We report the case for its rarity and emphasize disease management by concerted application of clinical, pathological, radiological and immunohistochemical analyses.

  9. RO4929097 and Capecitabine in Treating Patients With Refractory Solid Tumors

    ClinicalTrials.gov

    2014-11-06

    Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Colon Cancer; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Rectal Cancer; Stage III Small Lymphocytic Lymphoma; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Rectal Cancer; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  10. Clinical development of VEGF signaling pathway inhibitors in childhood solid tumors.

    PubMed

    Glade Bender, Julia; Yamashiro, Darrell J; Fox, Elizabeth

    2011-01-01

    Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers.

  11. Increased IMP dehydrogenase gene expression in solid tumor tissues and tumor cell lines

    SciTech Connect

    Collart, F.R.; Chubb, C.B.; Mirkin, B.L.; Huberman, E.

    1992-07-10

    IMP dehydrogenase, a regulatory enzyme of guanine nucleotide biosynthesis, may play a role in cell proliferation and malignancy. To assess this possibility, we examined IMP dehydrogenase expression in a series of human solid tumor tissues and tumor cell lines in comparison with their normal counterparts. Increased IMP dehydrogenase gene expression was observed in brain tumors relative to normal brain tissue and in sarcoma cells relative to normal fibroblasts. Similarly, in several B- and T-lymphoid leukemia cell lines, elevated levels of IMP dehydrogenase mRNA and cellular enzyme were observed in comparison with the levels in peripheral blood lymphocytes. These results are consistent with an association between increased IMP dehydrogenase expression and either enhanced cell proliferation or malignant transformation.

  12. Mutation-associated fusion cancer genes in solid tumors.

    PubMed

    Kaye, Frederic J

    2009-06-01

    Chromosomal translocations and fusion oncogenes serve as the ultimate biomarker for clinicians as they show specificity for distinct histopathologic malignancies while simultaneously encoding an etiologic mutation and a therapeutic target. Previously considered a minor mutational event in epithelial solid tumors, new methodologies that do not rely on the detection of macroscopic cytogenetic alterations, as well as access to large series of annotated clinical material, are expanding the inventory of recurrent fusion oncogenes in both common and rare solid epithelial tumors. Unexpectedly, related assays are also revealing a high number of tandem or chimeric transcripts in normal tissues including, in one provocative case, a template for a known fusion oncogene. These observations may force us to reassess long-held views on the definition of a gene. They also raise the possibility that some rearrangements might represent constitutive forms of a physiological chimeric transcript. Defining the chimeric transcriptome in both health (transcription-induced chimerism and intergenic splicing) and disease (mutation-associated fusion oncogenes) will play an increasingly important role in the diagnosis, prognosis, and therapy of patients with cancer.

  13. Is the NBN gene mutation I171V a potential risk factor for malignant solid tumors in children?

    PubMed

    Nowak, Jerzy; Mosor, Maria; Nowicka, Karina; Rembowska, Jolanta; Januszkiewicz, Danuta

    2011-08-01

    NBN gene is considered as one of the low-to-moderate cancer susceptibility gene. At least 4 germline NBN mutations have been found in several malignancies in adults. In our studies, we observed the high incidence of germline mutation I171V of NBN gene in breast, colorectal, larynx cancer, and in multiple primary tumors. In this study, we would like to answer the question whether I171V germline mutation of NBN gene may constitute risk factor for solid tumors in children. The frequency of this mutation has been analyzed in patients with neuroblastoma (n=66), Wilms tumor (n=54), medulloblastoma (n=57), and rhabdomyosarcoma (n=82) hospitalized in Pediatric Oncology, Hematology and Bone Marrow Transplantation Department in the years between 1987 and 2010. About 2947 anonymous blood samples collected on Guthrie cards drawn from the newborn screening program of the Wielkopolska region have been used as controls. All the patients and controls came from the same geographical region. I171V mutation of the NBN gene has been observed in 5 controls. Among children with solid tumors only in 1 child with medulloblastoma I171V variant has been found. In conclusion, I171V germline mutation in contrary to adults cannot be considered as a risk factor for children malignancies. However, owing to low number of patients with solid tumors the possibility of a Type II error may exist.

  14. Evaluation of the effects of methotrexate released from polymeric implants in solid Ehrlich tumor.

    PubMed

    de Fátima Pereira, Adriana; Mara da Costa, Vivian; Cristina Magalhães Santos, Millene; Maciel de A Ribeiro, Rosy Iara; Gabriela Silva, Ana; Carmo Horta Pinto, Flávia; Vieira Teixeira Vidigal, Paula; Rodrigues Da Silva, Gisele

    2014-04-01

    In this study, the effects of the controlled and sustained release of methotrexate from poly(ɛ-caprolactone) implants were evaluated in the solid Ehrlich tumor. The drug locally leached from the implantable devices was capable of reducing the tumor growth and the necrotic areas of the tumor site. Furthermore, the methotrexate exerted its anti-tumor effect probably by the recruitment of neutrophils at the tumor site, which assisted in modulating the growth of the tumor. The polymeric implants containing methotrexate could be a chemotherapic alternative to treat locally solid tumors with lower systemic side effects.

  15. Secondary neoplasms after radiotherapy for a childhood solid tumor.

    PubMed

    Paulino, Arnold C; Fowler, B Zach

    2005-03-01

    This study was conducted to determine the outcome of patients who develop a second neoplasm after radiotherapy (RT) for a childhood solid tumor. From 1956 to 1998, 429 children with a malignant solid tumor were treated at a single radiation oncology facility. The medical records and radiotherapy charts were reviewed to determine if the patient developed a secondary neoplasm after treatment for malignancy. Twenty-three (5.4%) patients developed a secondary neoplasm. There were 12 males and 11 females with a median age at RT of 6.6 years (range, 2 months to 20 years). There were 14 malignant neoplasms in 13 (3.0%) and 14 benign neoplasms in 11 patients (2.6%). The types of initial solid tumors treated with RT were Ewing sarcoma in 6, Wilms tumor in 6, medulloblastoma in 5, neuroblastoma in 3, and other in 3. Median RT dose was 45 Gy (range, 12.3 to 60 Gy) using 4 MV in 9, 1.25 MV in 8, 250 KV in 4, and 6 MV photons in 1 patient. One child was treated using 15-MeV electrons. Fourteen had chemotherapy. Median follow-up was 23.2 years (range, 5.3 to 44.4 years). For the 14 malignant neoplasms, the median time interval from initial tumor to second malignancy was 10.1 years. The 14 second malignant neoplasms (SMN) were osteosarcoma in 3, breast carcinoma in 2, melanoma in 2, malignant fibrous histiocytoma in 1, dermatofibrosarcoma in 1, leiomyosarcoma in 1, mucoepidermoid carcinoma in 1, colon cancer in 1, chronic myelogenous leukemia in 1, and basal cell carcinoma in 1. Ten of the 14 SMN (71%) were at the edge or inside the RT field. The 5- and 10-year overall survival rate after diagnosis of an SMN was 69.2%; it was 70% for children with a SMN at the edge or inside the RT field and 66.7% for those outside of the RT field. The 14 benign neoplasms appeared at a median time of 16.9 years and included cervical intraepithelial neoplasia in 3, osteochondroma in 3, thyroid adenoma in 1, duodenal adenoma in 1, lipoma in 1, cherry angioma in 1, uterine leiomyoma in 1, ovarian

  16. Life Satisfaction in Adult Survivors of Childhood Brain Tumors

    PubMed Central

    Crom, Deborah B.; Li, Zhenghong; Brinkman, Tara M.; Hudson, Melissa M.; Armstrong, Gregory T.; Neglia, Joseph; Ness, Kirsten K.

    2014-01-01

    Adult survivors of childhood brain tumors experience multiple, significant, life-long deficits as a consequence of their malignancy and therapy. Current survivorship literature documents the substantial impact such impairments have on survivors’ physical health and quality of life. Psychosocial reports detail educational, cognitive, and emotional limitations characterizing survivors as especially fragile, often incompetent, and unreliable in evaluating their circumstances. Anecdotal data suggests some survivors report life experiences similar to those of healthy controls. The aim of our investigation was to determine whether life satisfaction in adult survivors of childhood brain tumors differs from that of healthy controls and to identify potential predictors of life satisfaction in survivors. This cross-sectional study compared 78 brain tumor survivors with population–based matched controls. Chi-square tests, t-tests, and linear regression models were used to investigate patterns of life satisfaction and identify potential correlates. Results indicated life satisfaction of adult survivors of childhood brain tumors was similar to that of healthy controls. Survivors’ general health expectations emerged as the primary correlate of life satisfaction. Understanding life satisfaction as an important variable will optimize the design of strategies to enhance participation in follow-up care, reduce suffering, and optimize quality of life in this vulnerable population. PMID:25027187

  17. Life satisfaction in adult survivors of childhood brain tumors.

    PubMed

    Crom, Deborah B; Li, Zhenghong; Brinkman, Tara M; Hudson, Melissa M; Armstrong, Gregory T; Neglia, Joseph; Ness, Kirsten K

    2014-01-01

    Adult survivors of childhood brain tumors experience multiple, significant, lifelong deficits as a consequence of their malignancy and therapy. Current survivorship literature documents the substantial impact such impairments have on survivors' physical health and quality of life. Psychosocial reports detail educational, cognitive, and emotional limitations characterizing survivors as especially fragile, often incompetent, and unreliable in evaluating their circumstances. Anecdotal data suggest some survivors report life experiences similar to those of healthy controls. The aim of our investigation was to determine whether life satisfaction in adult survivors of childhood brain tumors differs from that of healthy controls and to identify potential predictors of life satisfaction in survivors. This cross-sectional study compared 78 brain tumor survivors with population-based matched controls. Chi-square tests, t tests, and linear regression models were used to investigate patterns of life satisfaction and identify potential correlates. Results indicated that life satisfaction of adult survivors of childhood brain tumors was similar to that of healthy controls. Survivors' general health expectations emerged as the primary correlate of life satisfaction. Understanding life satisfaction as an important variable will optimize the design of strategies to enhance participation in follow-up care, reduce suffering, and optimize quality of life in this vulnerable population.

  18. Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors

    ClinicalTrials.gov

    2017-03-15

    Malignant Melanoma; Medullary Thyroid Cancer; Glioblastoma; Large Cell Neuroendocrine Carcinoma; Neuroendocrine Prostate Cancer; High Grade Gastroenteropancreatic Neuroendocrine Carcinoma; Other Neuroendocrine Carcinoma; Other Solid Tumors

  19. Erlotinib in Treating Patients With Solid Tumors and Liver or Kidney Dysfunction

    ClinicalTrials.gov

    2013-01-15

    ; Stage III Pancreatic Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Anal Cancer; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Bladder Cancer; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Pancreatic Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Stage IVA Cervical Cancer; Stage IVB Cervical Cancer; Unspecified Adult Solid Tumor, Protocol Specific; Untreated Metastatic Squamous Neck Cancer With Occult Primary

  20. Aflac ST0901 CHOANOME - Sirolimus in Solid Tumors

    ClinicalTrials.gov

    2016-04-11

    Ewing's Sarcoma; Osteosarcoma; Astrocytoma; Atypical Teratoid/Rhabdoid Tumor; Ependymoma; Germ Cell Tumor; Glioma; Medulloblastoma; Rhabdoid Tumor; Retinoblastoma; Clear Cell Sarcoma; Renal Cell Carcinoma; Wilms Tumor; Hepatoblastoma; Neuroblastoma; Rhabdomyosarcoma

  1. Bevacizumab and Cediranib Maleate in Treating Patients With Metastatic or Unresectable Solid Tumor, Lymphoma, Intracranial Glioblastoma, Gliosarcoma or Anaplastic Astrocytoma

    ClinicalTrials.gov

    2014-02-14

    Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  2. Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions)

    ClinicalTrials.gov

    2017-04-05

    Breast Cancer; Cholangiocarcinoma; Colorectal Cancer; Head and Neck Neoplasms; Lymphoma, Large-Cell, Anaplastic; Melanoma; Neuroendocrine Tumors; Non-Small Cell Lung Cancer; Ovarian Cancer; Pancreatic Cancer; Papillary Thyroid Cancer; Primary Brain Tumors; Renal Cell Carcinoma; Sarcomas; Salivary Gland Cancers; Adult Solid Tumor

  3. Ixabepilone in Treating Young Patients With Solid Tumors or Leukemia That Haven't Responded to Therapy

    ClinicalTrials.gov

    2012-03-14

    Brain and Central Nervous System Tumors; Childhood Germ Cell Tumor; Extragonadal Germ Cell Tumor; Kidney Cancer; Leukemia; Liver Cancer; Neuroblastoma; Ovarian Cancer; Sarcoma; Unspecified Childhood Solid Tumor, Protocol Specific

  4. Ultrasound mediated delivery of drugs and genes to solid tumors.

    PubMed

    Frenkel, Victor

    2008-06-30

    It has long been shown that therapeutic ultrasound can be used effectively to ablate solid tumors, and a variety of cancers are presently being treated in the clinic using these types of ultrasound exposures. There is, however, an ever-increasing body of preclinical literature that demonstrates how ultrasound energy can also be used non-destructively for increasing the efficacy of drugs and genes for improving cancer treatment. In this review, a summary of the most important ultrasound mechanisms will be given with a detailed description of how each one can be employed for a variety of applications. This includes the manner by which acoustic energy deposition can be used to create changes in tissue permeability for enhancing the delivery of conventional agents, as well as for deploying and activating drugs and genes via specially tailored vehicles and formulations.

  5. Ultrasound mediated delivery of drugs and genes to solid tumors

    PubMed Central

    Frenkel, Victor

    2008-01-01

    It has long been shown that therapeutic ultrasound can be used effectively to ablate solid tumors, and a variety of cancers are presently being treated in the clinic using these types of ultrasound exposures. There is, however, an ever-increasing body of preclinical literature that demonstrates how ultrasound energy can also be used non-destructively for increasing the efficacy of drugs and genes for improving cancer treatment. In this review, a summary of the most important ultrasound mechanisms will be given with a detailed description of how each one can be employed for a variety of applications. This includes the manner by which acoustic energy deposition can be used to create changes in tissue permeability for enhancing the delivery of conventional agents, as well as for deploying and activating drugs and genes via specially tailored vehicles and formulations. PMID:18474406

  6. PXD101 and 17-N-Allylamino-17-Demethoxygeldanamycin in Treating Patients With Metastatic or Unresectable Solid Tumors or Lymphoma

    ClinicalTrials.gov

    2013-05-15

    Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  7. Sorafenib in Treating Patients With Metastatic or Unresectable Solid Tumors, Multiple Myeloma, or Non-Hodgkin's Lymphoma With or Without Impaired Liver or Kidney Function

    ClinicalTrials.gov

    2013-01-04

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  8. Gossypol, Paclitaxel, and Carboplatin in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2013-01-09

    ; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  9. Vorinostat and Decitabine in Treating Patients With Advanced Solid Tumors or Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-08-26

    ; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  10. A poly(l-glutamic acid)-combretastatin A4 conjugate for solid tumor therapy: Markedly improved therapeutic efficiency through its low tissue penetration in solid tumor.

    PubMed

    Liu, Tianzhou; Zhang, Dawei; Song, Wantong; Tang, Zhaohui; Zhu, Jiaming; Ma, Zhiming; Wang, Xudong; Chen, Xuesi; Tong, Ti

    2017-02-03

    Combretastatin A4 (CA4) is a leading agent in vascular disrupting strategies for tumor therapy. Although many small-molecule prodrugs of CA4 have been developed to improve its solubility, the overall therapeutic efficiency is moderate. A key reason for this is the reversible effect that CA4 has on tubulin as well as its rapid clearance from plasma and tissues. In this study, we proposed a poly(l-glutamic acid)-CA4 conjugate (PLG-CA4) nanomedicine to fulfill the requirements for fully liberating the potential of CA4 on tumor therapy. Enhanced accumulation and retention of CA4 in tumor tissue, especially, high distribution and gradual release around tumor blood vessels resulted in prolonged vascular disruption and markedly enhanced therapeutic efficiency. We examined and compared the therapeutic effect of PLG-CA4 and commercial combretastatin-A4 phosphate (CA4P) in a murine colon C26 tumor. PLG-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, the PLG-CA4 was mainly distributed around the tumor vessels because of its low tissue penetration in solid tumor. Pathology tests showed that PLG-CA4 treatment resulted in persistent vascular disruption and tumor damage 72h after a single injection, this in contrast to CA4P treatment, which showed quick relapse at an equal dose. Tumor suppression tests showed that PLG-CA4 treatment resulted in a tumor suppression rate of 74%, which indicates a significant advantage when compared to tumor suppression rate of the CA4P group, which was 24%. This is the first time that an advantage of the polymeric CA4 nanomedicine with low tissue penetration for solid tumor therapy has been shown. Thus, the results presented in this study provide a new idea for enhancing the tumor therapeutic effect of vascular disrupting agents.

  11. Phenylalanine-coupled solid lipid nanoparticles for brain tumor targeting

    NASA Astrophysics Data System (ADS)

    Kharya, Parul; Jain, Ashish; Gulbake, Arvind; Shilpi, Satish; Jain, Ankit; Hurkat, Pooja; Majumdar, Subrata; Jain, Sanjay K.

    2013-11-01

    The purpose of this study is to investigate the targeting potential of amino acid (phenylalanine)-coupled solid lipid nanoparticles (SLN) loaded with ionically complexed doxorubicin HCl (Dox). Ionic complexation was used to enhance the loading efficiency and release characteristics of water soluble form of Dox. l-Type amino acid transporters (LAT1) are highly expressed on blood brain barrier as well as on many brain cancer cells, thus targeting LAT1 using phenylalanine improved anticancer activity of prepared nanocarrier. The phenylalanine-coupled SLN were characterized by fourier transform infrared spectroscopy, scanning electron microscope, transmission electron microscopy, particle size, zeta potential, entrapment efficiency and in vitro release. The particle size of the resulting SLN was found to be in the range of 163.3 ± 5.2 to 113.0 ± 2.6 nm, with a slightly negative surface charge. In ex vivo study on C6 glioma cell lines, the cellular cytotoxicity of the SLN was highly increased when coupled with phenylalanine. In addition, stealthing sheath of PEG present on the surface of the SLN enhanced the cellular uptake of the SLN on C6 glioma cell line. Results of biodistribution and fluorescence studies clearly revealed that phenylalanine-coupled SLN could deliver high amount of drug into the brain tumor cells and showed the brain-targeting potential.

  12. NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy?

    PubMed

    Cantoni, Claudia; Huergo-Zapico, Leticia; Parodi, Monica; Pedrazzi, Marco; Mingari, Maria Cristina; Moretta, Alessandro; Sparatore, Bianca; Gonzalez, Segundo; Olive, Daniel; Bottino, Cristina; Castriconi, Roberta; Vitale, Massimo

    2016-01-01

    Several evidences suggest that NK cells can patrol the body and eliminate tumors in their initial phases but may hardly control established solid tumors. Multiple factors, including the transition of tumor cells towards a proinvasive/prometastatic phenotype, the immunosuppressive effect of the tumor microenvironment, and the tumor structure complexity, may account for limited NK cell efficacy. Several putative mechanisms of NK cell suppression have been defined in these last years; conversely, the cross talk between NK cells and tumor cells undergoing different transitional phases remains poorly explored. Nevertheless, recent in vitro studies and immunohistochemical analyses on tumor biopsies suggest that NK cells could not only kill tumor cells but also influence their evolution. Indeed, NK cells may induce tumor cells to change the expression of HLA-I, PD-L1, or NKG2D-L and modulate their susceptibility to the immune response. Moreover, NK cells may be preferentially located in the borders of tumor masses, where, indeed, tumor cells can undergo Epithelial-to-Mesenchymal Transition (EMT) acquiring prometastatic phenotype. Finally, the recently highlighted role of HMGB1 both in EMT and in amplifying the recruitment of NK cells provides further hints on a possible effect of NK cells on tumor progression and fosters new studies on this issue.

  13. NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy?

    PubMed Central

    Huergo-Zapico, Leticia; Parodi, Monica; Pedrazzi, Marco; Mingari, Maria Cristina; Sparatore, Bianca; Gonzalez, Segundo; Olive, Daniel; Bottino, Cristina

    2016-01-01

    Several evidences suggest that NK cells can patrol the body and eliminate tumors in their initial phases but may hardly control established solid tumors. Multiple factors, including the transition of tumor cells towards a proinvasive/prometastatic phenotype, the immunosuppressive effect of the tumor microenvironment, and the tumor structure complexity, may account for limited NK cell efficacy. Several putative mechanisms of NK cell suppression have been defined in these last years; conversely, the cross talk between NK cells and tumor cells undergoing different transitional phases remains poorly explored. Nevertheless, recent in vitro studies and immunohistochemical analyses on tumor biopsies suggest that NK cells could not only kill tumor cells but also influence their evolution. Indeed, NK cells may induce tumor cells to change the expression of HLA-I, PD-L1, or NKG2D-L and modulate their susceptibility to the immune response. Moreover, NK cells may be preferentially located in the borders of tumor masses, where, indeed, tumor cells can undergo Epithelial-to-Mesenchymal Transition (EMT) acquiring prometastatic phenotype. Finally, the recently highlighted role of HMGB1 both in EMT and in amplifying the recruitment of NK cells provides further hints on a possible effect of NK cells on tumor progression and fosters new studies on this issue. PMID:27294158

  14. GTI-2040 and Docetaxel in Treating Patients With Recurrent, Metastatic, or Unresectable Locally Advanced Non-Small Cell Lung Cancer, Prostate Cancer, or Other Solid Tumors

    ClinicalTrials.gov

    2013-01-23

    Recurrent Non-small Cell Lung Cancer; Recurrent Prostate Cancer; Stage III Prostate Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Prostate Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  15. APN401 in Treating Patients With Melanoma, Kidney Cancer, Pancreatic Cancer, or Other Solid Tumors That Are Metastatic or Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2017-01-17

    Recurrent Melanoma; Recurrent Pancreatic Cancer; Recurrent Renal Cell Cancer; Stage III Pancreatic Cancer; Stage III Renal Cell Cancer; Stage IIIA Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma; Stage IV Pancreatic Cancer; Stage IV Renal Cell Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  16. Talazoparib and HSP90 Inhibitor AT13387 in Treating Patients With Metastatic Advanced Solid Tumor or Recurrent Ovarian, Fallopian Tube, Primary Peritoneal, or Triple Negative Breast Cancer

    ClinicalTrials.gov

    2016-07-22

    Adult Solid Neoplasm; Estrogen Receptor Negative; Fallopian Tube Serous Neoplasm; HER2/Neu Negative; Ovarian Serous Adenocarcinoma; Ovarian Serous Tumor; Primary Peritoneal Serous Adenocarcinoma; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Triple-Negative Breast Carcinoma

  17. Phase 1 Clinical Trial of Ipilimumab In Pediatric Patients With Advanced Solid Tumors

    PubMed Central

    Merchant, Melinda S.; Wright, Matthew; Baird, Kristin; Wexler, Leonard H.; Rodriguez-Galindo, Carlos; Bernstein, Donna; Delbrook, Cindy; Lodish, Maya; Bishop, Rachel; Wolchok, Jedd D.; Streicher, Howard; Mackall, Crystal L.

    2016-01-01

    Purpose Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase 1 protocol. Experimental Design This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects ≤21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10mg/m2 intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity. Results Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n=12), sarcoma (n=17), or other refractory solid tumors (n= 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5mg/kg and 10mg/kg dose levels. Pharmacokinetics revealed a half–life of 8-15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T cell populations. Six subjects had confirmed stable disease for 4-10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma). Conclusions Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune related toxicities had an increased overall survival compared to those who showed no evidence of breaking tolerance. PMID:26534966

  18. High-Dose Chemotherapy With or Without Total-Body Irradiation Followed by Autologous Stem Cell Transplant in Treating Patients With Hematologic Cancer or Solid Tumors

    ClinicalTrials.gov

    2017-03-30

    Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Neuroblastoma; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Regional Neuroblastoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  19. Structure of solid tumors and their vasculature: Implications for therapy with monoclonal antibodies

    SciTech Connect

    Dvorak, H.F.; Nagy, J.A.; Dvorak, A.M. )

    1991-03-01

    Delivery of monoclonal antibodies to solid tumors is a vexing problem that must be solved if these antibodies are to realize their promise in therapy. Such success as has been achieved with monoclonal antibodies is attributable to the local hyperpermeability of the tumor vasculature, a property that favors antibody extravasation at tumor sites and that is mediated by a tumor-secreted vascular permeability factor. However, leaky tumor blood vessels are generally some distance removed from target tumor cells, separated by stroma and by other tumor cells that together represent significant barriers to penetration by extravasated monoclonal antibodies. For this reason, alternative approaches may be attractive. These include the use of antibody-linked cytotoxins, which are able to kill tumor cells without immediate contact, and direction of antibodies against nontumor cell targets, for example, antigens unique to the tumor vascular endothelium or to tumor stroma. 50 refs.

  20. Growth delay effect of combined interstitial hyperthermia and brachytherapy in a rat solid tumor model.

    PubMed

    Papadopoulos, D; Kimler, B F; Estes, N C; Durham, F J

    1989-01-01

    The rat mammary AC33 solid tumor model was used to investigate the efficacy of interstitial hyperthermia and/or brachytherapy. Subcutaneous flank tumors were heated with an interstitial microwave (915 MHz) antenna to a temperature of 43 +/- 0.5 degrees C for 45 min for two treatments, three days apart, and/or implanted with Ir-192 seeds for three days (-25 Gy tumor dose). Following treatments, tumors were measured 2 to 3 times per week. Hyperthermia alone produced a modest delay in tumor volume regrowth, while brachytherapy was substantially more effective. The combination produced a improvement in tumor regrowth delay compared to brachytherapy alone.

  1. Flavopiridol in Treating Children With Relapsed or Refractory Solid Tumors or Lymphomas

    ClinicalTrials.gov

    2013-07-01

    Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Retinoblastoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

  2. A Phase I Trial and Pharmacokinetic Study of Sorafenib in Children with Refractory Solid Tumors or Leukemias: A Children’s Oncology Group Phase I Consortium Report

    PubMed Central

    Widemann, Brigitte C.; Kim, AeRang; Fox, Elizabeth; Baruchel, Sylvain; Adamson, Peter C.; Ingle, Ashish M.; Bender, Julia Glade; Burke, Michael; Weigel, Brenda; Stempak, Diana; Balis, Frank M.; Blaney, Susan M.

    2012-01-01

    Purpose To determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of sorafenib in children with refractory extracranial solid tumors and evaluate the tolerability of the solid tumor MTD in children with refractory leukemias. Experimental Design Sorafenib was administered orally every 12 hours for consecutive 28-day cycles. Pharmacokinetics (day 1 and steady-state) and pharmacodynamics were conducted during cycle 1. Results Of 65 patients enrolled, 60 were eligible. In the solid tumor cohort (n = 49), 4 of 6 patients experienced a DLT [hypertension, pain, rash/urticaria, thrombocytopenia, alanine aminotransferase (ALT)/ aspartate aminotransferase (AST)] at the starting dose (150 mg/m2/dose) which resulted in de-escalation to 105 mg/m2/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m2/ dose for solid tumors and 150 mg/m2/dose for leukemias. Sorafenib exposure was highly variable between patients but was within the ranges reported in adults. The apparent sorafenib clearance increased with patient age. Diarrhea, rash, fatigue, and increased ALT/AST were the most common sorafenib-related toxicities. Stable disease for 4 or more cycles was observed in 14 solid tumor patients, and 2 patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (FLT3ITD) experienced a decrease in bone marrow blasts to less than 5%. Conclusions The recommended phase II dose of sorafenib administered every 12 hours continuously for children with solid tumors is 200 mg/m2/dose and 150 mg/m2/dose for children with leukemias. Sorafenib toxicities and distribution in children are similar to adults. The activity of sorafenib in children with AML and FLT3ITD is currently being evaluated, and a phase II study for select solid tumors is ongoing. PMID:22962440

  3. Cisplatin Nephrotoxicity and Longitudinal Growth in Children With Solid Tumors

    PubMed Central

    Jiménez-Triana, Clímaco Andres; Castelán-Martínez, Osvaldo D.; Rivas-Ruiz, Rodolfo; Jiménez-Méndez, Ricardo; Medina, Aurora; Clark, Patricia; Rassekh, Rod; Castañeda-Hernández, Gilberto; Carleton, Bruce; Medeiros, Mara

    2015-01-01

    Abstract Cisplatin, a major antineoplastic drug used in the treatment of solid tumors, is a known nephrotoxin. This retrospective cohort study evaluated the prevalence and severity of cisplatin nephrotoxicity in 54 children and its impact on height and weight. We recorded the weight, height, serum creatinine, and electrolytes in each cisplatin cycle and after 12 months of treatment. Nephrotoxicity was graded as follows: normal renal function (Grade 0); asymptomatic electrolyte disorders, including an increase in serum creatinine, up to 1.5 times baseline value (Grade 1); need for electrolyte supplementation <3 months and/or increase in serum creatinine 1.5 to 1.9 times from baseline (Grade 2); increase in serum creatinine 2 to 2.9 times from baseline or need for electrolyte supplementation for more than 3 months after treatment completion (Grade 3); and increase in serum creatinine ≥3 times from baseline or renal replacement therapy (Grade 4). Nephrotoxicity was observed in 41 subjects (75.9%). Grade 1 nephrotoxicity was observed in 18 patients (33.3%), Grade 2 in 5 patients (9.2%), and Grade 3 in 18 patients (33.3%). None had Grade 4 nephrotoxicity. Nephrotoxicity patients were younger and received higher cisplatin dose, they also had impairment in longitudinal growth manifested as statistically significant worsening on the height Z Score at 12 months after treatment. We used a multiple logistic regression model using the delta of height Z Score (baseline-12 months) as dependent variable in order to adjust for the main confounder variables such as: germ cell tumor, cisplatin total dose, serum magnesium levels at 12 months, gender, and nephrotoxicity grade. Patients with nephrotoxicity Grade 1 where at higher risk of not growing (OR 5.1, 95% CI 1.07–24.3, P = 0.04). The cisplatin total dose had a significant negative relationship with magnesium levels at 12 months (Spearman r = −0.527, P = <0.001). PMID:26313789

  4. Ascitic and solid Ehrlich tumor inhibition by Chenopodium ambrosioides L. treatment.

    PubMed

    Nascimento, Flávia R F; Cruz, Gustavo V B; Pereira, Paulo Vitor S; Maciel, Márcia C G; Silva, Lucilene A; Azevedo, Ana Paula S; Barroqueiro, Elizabeth S B; Guerra, Rosane N M

    2006-04-25

    The leaves of Chenopodium ambrosioides L. [Chenopodiaceae] ('mastruz') have been indicated for the treatment of several diseases, among which the cancer. There are no results focusing the effect of C. ambrosioides treatment on tumor development in vivo. The aim of this study was to investigate the effect of treatment with C. ambrosioides on Ehrlich tumor development. Swiss mice were treated by intraperitoneal route (i.p.) with hydroalcoholic extract from leaves of C. ambrosioides (5 mg/kg) or with PBS (control group) 48 h before or 48 h later the Ehrlich tumor implantation. The tumor cells were implanted on the left footpad (solid tumor) or in the peritoneal cavity (ascitic tumor). To determine the solid tumor growth, footpad was measured each 2 days until the fourteenth day, when the feet were weighed. Ascitic tumor development was evaluated after 8 days of tumor implantation by quantification of the ascitic fluid volume and tumor cell number. The i.p. administration of C. ambrosioides extract before or after the tumor implantation significantly inhibited the solid and ascitic Ehrlich tumor forms. This inhibition was observed in ascitic tumor cell number, in the ascitic volume, in the tumor-bearing foot size and foot weight when compared to control mice. The treatments also increased the survival of tumor-bearing mice. In conclusion, C. ambrosioides has a potent anti-tumoral effect which was evident with a small dose and even when the treatment was given two days after the tumor implantation. This effect is probably related with anti-oxidant properties of C. ambrosioides.

  5. LAPTM4B: an oncogene in various solid tumors and its functions

    PubMed Central

    Meng, Y; Wang, L; Chen, D; Chang, Y; Zhang, M; XU, J-J; Zhou, R; Zhang, Q-Y

    2016-01-01

    The oncogene Lysosome-associated protein transmembrane-4β (LAPTM4B) gene was identified, and the polymorphism region in the 5′-UTR of this gene was certified to be associated with tumor susceptibility. LAPTM4B-35 protein was found to be highly expressed in various solid tumors and could be a poor prognosis marker. The functions of LAPTM4B in solid tumors were also explored. It is suggested that LAPTM4B could promote the proliferation of tumor cells, boost invasion and metastasis, resist apoptosis, initiate autophagy and assist drug resistance. PMID:27212036

  6. Percutaneous cytologic diagnosis of solid pseudopapillary tumors of pancreas in children.

    PubMed

    Tlili, Yemen; Thiesse, Philippe; Lemaistre, Anne I; Dubois, Remi; Faure-Conter, Cecile

    2013-03-01

    Solid pseudopapillary tumors of the pancreas, formerly known as Frantz tumors, are rare exocrine tumors that electively affect young women in their second and third decades of life, and are rarely observed in children. Histologic confirmation is nevertheless desirable before proceeding with treatment of pancreatic lesions, as appropriate treatment can range from conservative to ablative surgery. Here, we report 3 cases of solid pseudopapillary tumors of the pancreas and we postulate that percutaneous cytologic sample analysis (instead of biopsy) may be sufficient to reach an accurate diagnosis and eliminate differential diagnosis.

  7. Lenvatinib: Role in thyroid cancer and other solid tumors.

    PubMed

    Cabanillas, Maria E; Habra, Mouhammed Amir

    2016-01-01

    Despite recent breakthroughs in treatment of advanced thyroid cancers, prognoses remain poor. Treatment of advanced, progressive disease remains challenging, with limited treatment options. Small-molecule tyrosine kinase inhibitors, including vandetanib, cabozantinib, sorafenib, and lenvatinib, which are now FDA-approved for thyroid cancer, have shown clinical benefit in advanced thyroid cancer. Lenvatinib is approved for treatment of locally recurrent or metastatic, progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). It has been studied in phase II and III trials for treatment of advanced RAI-refractory DTC, and in a phase II trial for medullary thyroid cancer (MTC). Lenvatinib targets vascular endothelial growth factor receptors 1-3 (VEGFR1-3), fibroblast growth factor receptors 1-4 (FGFR-1-4), RET, c-kit, and platelet-derived growth factor receptor α (PDGFRα). Its antitumor activity may be due to antiangiogenic properties and direct antitumor effects. Lenvatinib has demonstrated antitumor activity in a variety of solid tumors, including MTC, in phase I and II clinical trials. In a phase II study in advanced RAI-refractory DTC, lenvatinib-treated patients achieved a 50% response rate (RR), with median progression-free survival (PFS) of 12.6 months. In a phase III trial in RAI-refractory DTC, median PFS in lenvatinib-treated patients was 18.3 months, with a 65% overall RR, versus 3.6 months in placebo-treated patients, with a 2% RR. Adverse events occurring in >50% of patients included hypertension, diarrhea, fatigue/asthenia, and decreased appetite. Lenvatinib is a promising new agent for treatment of patients with advanced thyroid cancer.

  8. Tumor vessel destruction resulting from high-intensity focused ultrasound in patients with solid malignancies.

    PubMed

    Wu, Feng; Chen, Wen-Zhi; Bai, Jin; Zou, Jian-Zhong; Wang, Zhi-Long; Zhu, Hui; Wang, Zhi-Biao

    2002-04-01

    The purpose of this study was to explore the sequential imaging and histologic alterations of tumor blood vessels in the patient with solid malignancies after extracorporeal treatment of high-intensity focused ultrasound (HIFU). A total of 164 patients underwent extracorporeal HIFU ablation of malignant solid tumors. After HIFU treatment, enhanced magnetic resonance imaging (MRI), color Doppler ultrasound (US) imaging, dynamic radionuclide scanning, digital subtraction angiography, and histologic study were performed to monitor the response of tumor vessels to HIFU ablation. Compared with tumor images in the patients before HIFU, clinical images showed an abrupt interruption, followed by the cessation of blood flow within the tumor vessels after HIFU treatment. The histologic examination indicated that not only the treated tumor cells showed coagulative necrosis, but also small tumor vessels were severely damaged by the HIFU treatment. The results strongly imply that the damaged tumor vessels might play a critical role in secondary tumor cell death, and then indirectly strengthen the destructive force of focused US beams on tumor tissue. It is concluded that tumor vessel damage can be induced by HIFU, which may be a promising strategy in the treatment of patients with solid malignancies.

  9. Immune Surveillance Against a Solid Tumor Fails because of Immunological Ignorance

    NASA Astrophysics Data System (ADS)

    Ochsenbein, Adrian F.; Klenerman, Paul; Karrer, Urs; Ludewig, Burkhard; Pericin, Marcus; Hengartner, Hans; Zinkernagel, Rolf M.

    1999-03-01

    Many peripheral solid tumors such as sarcomas and carcinomas express tumor-specific antigens that can serve as targets for immune effector T cells. Nevertheless, overall immune surveillance against such tumors seems relatively inefficient. We studied immune surveillance against a s.c. sarcoma expressing a characterized viral tumor antigen. Surprisingly, the tumor cells were capable of inducing a protective cytotoxic T cell response if transferred as a single-cell suspension. However, if they were transplanted as small tumor pieces, tumors readily grew. Tumor growth correlated strictly with (i) failure of tumor cells to reach the draining lymph nodes and (ii) absence of primed cytotoxic T cells. Cytotoxic T cells were not tolerant or deleted because a tumor antigen-specific cytotoxic T cell response was readily induced in lymphoid tissue by immunization with virus or with tumor cells even in the presence of large tumors. Established tumors were rejected by vaccine-induced effector T cells if effector T cells were maintained by prolonged or repetitive vaccination, but not by single-dose vaccination. Thus, in addition to several other tumor-promoting parameters, some antigenic peripheral sarcomas--and probably carcinomas--may grow not because they anergize or tolerize tumor-specific T cells, but because such tumors are immunologically dealt with as if they were in a so-called immunologically privileged site and are ignored for too long.

  10. [Clinical features of solid malignant tumors in childhood].

    PubMed

    Koshinaga, Tsugumichi; Ohashi, Kensuke; Sugitou, Kiminobu; Ikeda, Tarou

    2013-07-01

    The pathogenesis of pediatric malignant tumors is associated with congenital abnormalities. Oncogenes and antioncogenes are identified in some of these cases. Neuroblastoma arises from the adrenal medulla and sympathetic ganglia. Most neuroblastomas produce catecholamine. Urinary vanillylmandelic acid(VMA)and homovanillic acid(HVA), metabolites of catecholamine, are sensitive tumor markers. Risk stratification according to tumor stage and a combination of prognostic factors helps determine the appropriate therapeutic strategy in clinical settings. Nephroblastoma(Wilms tumor)is the most common pediatric renal tumor and is often accompanied by congenital anomalies. Surgical resection of the tumor and the involved kidney is the initial treatment recommendation in the US and Japan. Consecutive chemotherapy and radiotherapy are administered after surgical staging and a definite histopathological diagnosis. Prognosis is relatively good for most nephroblastoma cases with a favorable histology. In addition to nephroblastoma, clear cell sarcoma of the kidney, characterized by a tendency to metastasize to the bone, is a renal tumor with poor prognosis. Rhabdoid tumor of the kidney is another tumor type; however, its pathogenesis is still unknown and it is associated with extremely poor prognosis because of the lack of effective therapeutic measures. Hepatoblastoma is the most common malignant liver tumor. The serum alpha-fetoprotein level is the most effective tumor marker. Complete surgical resection of the involved liver lobe is the definitive approach for cure. Preoperative chemotherapy increases the possibility of complete surgical resection. High-risk patients have a poor prognosis.

  11. Solid tumor penetration by integrin-mediated pegylated poly(trimethylene carbonate) nanoparticles loaded with paclitaxel.

    PubMed

    Jiang, Xinyi; Xin, Hongliang; Gu, Jijin; Xu, Ximing; Xia, Weiyi; Chen, Shuo; Xie, Yike; Chen, Liangcen; Chen, Yanzuo; Sha, Xianyi; Fang, Xiaoling

    2013-02-01

    Limited penetration of antineoplastic agents is one of the contributing factors for chemotherapy failure of many solid tumors. In order to enhance drug penetration into solid cancer, especially, into the avascular regions inside tumors, we proposed cyclic RGD peptide functionalized PEGylated poly(trimethylene carbonate) nanoparticles (c(RGDyK)-NP). By integrin-mediated transcytosis and enhanced drug permeation, c(RGDyK)-NP could access the neoplastic cells distant from blood vessels, and consequently, avoiding the capability of cancer regeneration from these tumor cells. In the present study, the solid tumor penetration, homing specificity and anticancer efficacy were evaluated both on the ex vivo 3D tumor spheroids and on the subcutaneous xenograft mice model. In comparison with conventional nanoparticles (NP/PTX) and Taxol, c(RGDyK)-NP/PTX showed the strongest penetration and accumulation into 3D tumor spheroids, a marked tumor-homing specificity in vivo and the greatest tumor growth inhibitory effect in vitro and in vivo. Histochemistry analysis revealed that no obvious histopathological abnormalities or lesions were observed in major organs after intravenous administration with the treatment doses. In conclusion, cyclic RGD peptide-conjugated PEG-PTMC nanoparticle could facilitate drug penetration and accumulation in tumor tissues and may be a promising vehicle for enhancing the chemotherapy of solid cancers.

  12. Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs.

    PubMed

    Kirson, Eilon D; Giladi, Moshe; Gurvich, Zoya; Itzhaki, Aviran; Mordechovich, Daniel; Schneiderman, Rosa S; Wasserman, Yoram; Ryffel, Bernhard; Goldsher, Dorit; Palti, Yoram

    2009-01-01

    Tumor treating fields (TTFields) are low intensity, intermediate frequency, alternating electric fields used to treat cancerous tumors. This novel treatment modality effectively inhibits the growth of solid tumors in vivo and has shown promise in pilot clinical trials in patients with advanced stage solid tumors. TTFields were tested for their potential to inhibit metastatic spread of solid tumors to the lungs in two animal models: (1) Mice injected with malignant melanoma cells (B16F10) into the tail vein, (2) New Zealand White rabbits implanted with VX-2 tumors within the kidney capsule. Mice and rabbits were treated using two-directional TTFields at 100-200 kHz. Animals were either monitored for survival, or sacrificed for pathological and histological analysis of the lungs. The total number of lung surface metastases and the absolute weight of the lungs were both significantly lower in TTFields treated mice then in sham control mice. TTFields treated rabbits survived longer than sham control animals. This extension in survival was found to be due to an inhibition of metastatic spread, seeding or growth in the lungs of TTFields treated rabbits compared to controls. Histologically, extensive peri- and intra-tumoral immune cell infiltration was seen in TTFields treated rabbits only. These results raise the possibility that in addition to their proven inhibitory effect on the growth of solid tumors, TTFields may also have clinical benefit in the prevention of metastatic spread from primary tumors.

  13. Cardiac Safety Study of Entinostat in Men and Women With Advanced Solid Tumors

    ClinicalTrials.gov

    2017-02-24

    Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Digestive System Neoplasms; Endocrine Gland Neoplasms; Carcinoma, Non-Small-Cell Lung; Lung Diseases; Breast Neoplasms; Breast Diseases; Renal Neoplasm; Solid Tumors

  14. Continuation Study of Entinostat in Combination With Pembrolizumab in Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2017-02-24

    Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Digestive System Neoplasms; Endocrine Gland Neoplasms; Carcinoma, Non-Small-Cell Lung; Lung Diseases; Breast Diseases; Renal Neoplasm; Solid Tumors

  15. Lenalidomide in Treating Young Patients With Relapsed or Refractory Solid Tumors or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2014-06-10

    Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Ringed Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Secondary Myelodysplastic Syndromes; Unspecified Childhood Solid Tumor, Protocol Specific

  16. Study of LOXO-101 in Subjects With NTRK Fusion Positive Solid Tumors (NAVIGATE)

    ClinicalTrials.gov

    2017-03-23

    Carcinoma, Non-Small-Cell Lung; Thyroid Neoplasms; Sarcoma; Colorectal Neoplasms; Salivary Gland Neoplasms; Biliary Tract Neoplasms; Brain Neoplasm, Primary; Carcinoma, Ductal, Breast; Melanoma; Solid Tumors; Glioblastoma; Bile Duct Neoplasms; Astrocytoma; Head and Neck Squamous Cell Carcinoma; Pontine Glioma

  17. Role of constitutive behavior and tumor-host mechanical interactions in the state of stress and growth of solid tumors.

    PubMed

    Voutouri, Chrysovalantis; Mpekris, Fotios; Papageorgis, Panagiotis; Odysseos, Andreani D; Stylianopoulos, Triantafyllos

    2014-01-01

    Mechanical forces play a crucial role in tumor patho-physiology. Compression of cancer cells inhibits their proliferation rate, induces apoptosis and enhances their invasive and metastatic potential. Additionally, compression of intratumor blood vessels reduces the supply of oxygen, nutrients and drugs, affecting tumor progression and treatment. Despite the great importance of the mechanical microenvironment to the pathology of cancer, there are limited studies for the constitutive modeling and the mechanical properties of tumors and on how these parameters affect tumor growth. Also, the contribution of the host tissue to the growth and state of stress of the tumor remains unclear. To this end, we performed unconfined compression experiments in two tumor types and found that the experimental stress-strain response is better fitted to an exponential constitutive equation compared to the widely used neo-Hookean and Blatz-Ko models. Subsequently, we incorporated the constitutive equations along with the corresponding values of the mechanical properties - calculated by the fit - to a biomechanical model of tumor growth. Interestingly, we found that the evolution of stress and the growth rate of the tumor are independent from the selection of the constitutive equation, but depend strongly on the mechanical interactions with the surrounding host tissue. Particularly, model predictions - in agreement with experimental studies - suggest that the stiffness of solid tumors should exceed a critical value compared with that of the surrounding tissue in order to be able to displace the tissue and grow in size. With the use of the model, we estimated this critical value to be on the order of 1.5. Our results suggest that the direct effect of solid stress on tumor growth involves not only the inhibitory effect of stress on cancer cell proliferation and the induction of apoptosis, but also the resistance of the surrounding tissue to tumor expansion.

  18. Evolution and morphology of microenvironment-enhanced malignancy of three-dimensional invasive solid tumors

    NASA Astrophysics Data System (ADS)

    Jiao, Yang; Torquato, Salvatore

    2013-05-01

    The emergence of invasive and metastatic behavior in malignant tumors can often lead to fatal outcomes for patients. The collective malignant tumor behavior resulting from the complex tumor-host interactions and the interactions between the tumor cells is currently poorly understood. In this paper, we employ a cellular automaton (CA) model to investigate microenvironment-enhanced malignant behaviors and morphologies of in vitro avascular invasive solid tumors in three dimensions. Our CA model incorporates a variety of microscopic-scale tumor-host interactions, including the degradation of the extracellular matrix by the malignant cells, nutrient-driven cell migration, pressure buildup due to the deformation of the microenvironment by the growing tumor, and its effect on the local tumor-host interface stability. Moreover, the effects of cell-cell adhesion on tumor growth are explicitly taken into account. Specifically, we find that while strong cell-cell adhesion can suppress the invasive behavior of the tumors growing in soft microenvironments, cancer malignancy can be significantly enhanced by harsh microenvironmental conditions, such as exposure to high pressure levels. We infer from the simulation results a qualitative phase diagram that characterizes the expected malignant behavior of invasive solid tumors in terms of two competing malignancy effects: the rigidity of the microenvironment and cell-cell adhesion. This diagram exhibits phase transitions between noninvasive and invasive behaviors. We also discuss the implications of our results for the diagnosis, prognosis, and treatment of malignant tumors.

  19. Ispinesib in Treating Young Patients With Relapsed or Refractory Solid Tumors or Lymphoma

    ClinicalTrials.gov

    2013-01-15

    Childhood Burkitt Lymphoma; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Spinal Cord Neoplasm; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Unspecified Childhood Solid Tumor, Protocol Specific

  20. Overcoming the challenges in the effective delivery of chemotherapies to CNS solid tumors

    PubMed Central

    Sarin, Hemant

    2011-01-01

    Locoregional therapies, such as surgery and intratumoral chemotherapy, do not effectively treat infiltrative primary CNS solid tumors and multifocal metastatic solid tumor disease of the CNS. It also remains a challenge to treat such CNS malignant solid tumor disease with systemic chemotherapies, although these lipid-soluble small-molecule drugs demonstrate potent cytotoxicity in vitro. Even in the setting of a ‘normalized’ tumor microenvironment, small-molecule drugs do not accumulate to effective concentrations in the vast majority of tumor cells, which is due to the fact that small-molecule drugs have short blood half-lives. It has been recently shown that drug-conjugated spherical lipid-insoluble nanoparticles within the 7–10 nm size range can deliver therapeutic concentrations of drug fraction directly into individual tumor cells following systemic administration, since these functionalized particles maintain peak blood concentrations for several hours and are smaller than the physiologic upper limit of pore size in the VEGF-derived blood capillaries of solid tumors, which is approximately 12 nm. In this article, the physiologic and ultrastructural basis of this novel translational approach for the treatment of CNS, as well as non-CNS, solid cancers is reviewed. PMID:22163071

  1. Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting.

    PubMed

    Zhu, Charles; Sempkowski, Michelle; Holleran, Timothy; Linz, Thomas; Bertalan, Thomas; Josefsson, Anders; Bruchertseifer, Frank; Morgenstern, Alfred; Sofou, Stavroula

    2017-06-01

    Diffusion limitations on the penetration of nanocarriers in solid tumors hamper their therapeutic use when labeled with α-particle emitters. This is mostly due to the α-particles' relatively short range (≤100 μm) resulting in partial tumor irradiation and limited killing. To utilize the high therapeutic potential of α-particles against solid tumors, we designed non-targeted, non-internalizing nanometer-sized tunable carriers (pH-tunable liposomes) that are triggered to release, within the slightly acidic tumor interstitium, highly-diffusive forms of the encapsulated α-particle generator Actinium-225 ((225)Ac) resulting in more homogeneous distributions of the α-particle emitters, improving uniformity in tumor irradiation and increasing killing efficacies. On large multicellular spheroids (400 μm-in-diameter), used as surrogates of the avascular areas of solid tumors, interstitially-releasing liposomes resulted in best growth control independent of HER2 expression followed in performance by (a) the HER2-targeting radiolabeled antibody or (b) the non-responsive liposomes. In an orthotopic human HER2-negative mouse model, interstitially-releasing (225)Ac-loaded liposomes resulted in the longest overall and median survival. This study demonstrates the therapeutic potential of a general strategy to bypass the diffusion-limited transport of radionuclide carriers in solid tumors enabling interstitial release from non-internalizing nanocarriers of highly-diffusing and deeper tumor-penetrating molecular forms of α-particle emitters, independent of cell-targeting.

  2. Metabolic reprogramming: a new relevant pathway in adult adrenocortical tumors

    PubMed Central

    Longatto-Filho, Adhemar; Faria, André M.; Fragoso, Maria C. B. V.; Lovisolo, Silvana M.; Lerário, Antonio M.; Almeida, Madson Q.

    2015-01-01

    Adrenocortical carcinomas (ACCs) are complex neoplasias that may present unexpected clinical behavior, being imperative to identify new biological markers that can predict patient prognosis and provide new therapeutic options. The main aim of the present study was to evaluate the prognostic value of metabolism-related key proteins in adrenocortical carcinoma. The immunohistochemical expression of MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX was evaluated in a series of 154 adult patients with adrenocortical neoplasia and associated with patients' clinicopathological parameters. A significant increase in was found for membranous expression of MCT4, GLUT1 and CAIX in carcinomas, when compared to adenomas. Importantly MCT1, GLUT1 and CAIX expressions were significantly associated with poor prognostic variables, including high nuclear grade, high mitotic index, advanced tumor staging, presence of metastasis, as well as shorter overall and disease free survival. In opposition, MCT2 membranous expression was associated with favorable prognostic parameters. Importantly, cytoplasmic expression of CD147 was identified as an independent predictor of longer overall survival and cytoplasmic expression of CAIX as an independent predictor of longer disease-free survival. We provide evidence for a metabolic reprogramming in adrenocortical malignant tumors towards the hyperglycolytic and acid-resistant phenotype, which was associated with poor prognosis. PMID:26587828

  3. Fluorodeoxyglucose-based positron emission tomography imaging to monitor drug responses in solid tumors.

    PubMed

    Newbold, Andrea; Martin, Ben P; Cullinane, Carleen; Bots, Michael

    2014-10-01

    Positron emission tomography (PET) is used to monitor the uptake of the labeled glucose analogue fluorodeoxyglucose (¹⁸F-FDG) by solid tumor cells, a process generally believed to reflect viable tumor cell mass. The use of ¹⁸F-FDG exploits the high demand for glucose in tumor cells, and serves to document over time the response of a solid tumor to an inducer of apoptosis. The apoptosis inducer crizotinib is a small-molecule inhibitor of c-Met, a receptor tyrosine kinase that is often dysregulated in human tumors. In this protocol, we describe how to monitor the response of a solid tumor to crizotinib. Human gastric tumor cells (GTL-16 cells) are injected into recipient mice and, on tumor formation, the mice are treated with crizotinib. The tracer ¹⁸F-FDG is then injected into the mice at several time points, and its uptake is monitored using PET. Because ¹⁸F-FDG uptake varies widely among different tumor models, preliminary experiments should be performed with each new model to determine its basal level of ¹⁸F-FDG uptake. Verifying that the basal level of uptake is sufficiently above background levels will assure accurate quantitation. Because ¹⁸F-FDG uptake is not a direct measure of apoptosis, it is advisable to carry out an additional direct method to show the presence of apoptotic cells.

  4. A Rare Case of Primary Anterior Mediastinal Yolk Sac Tumor in an Elderly Adult Male

    PubMed Central

    Nakhla, Sammy G.; Sundararajan, Srinath

    2016-01-01

    Mediastinal germ cell tumors are extragonadal germ cell tumors (EGGCTs) commonly seen in children and young adults. They are more common in men. Clinically they are classified as teratomas, seminomas, and nonseminomatous germ cell tumors. Primary mediastinal yolk sac neoplasm is an extremely rare tumor. We present here a very rare case of primary yolk sac tumor of the anterior mediastinum in a 73-year-old male. Mediastinal germ cell tumors have a worse prognosis than gonadal germ cell tumors. Chemotherapy followed by adjuvant surgery improves overall response in EGGCTs. However, comorbidities can render treatment with chemotherapy and surgery challenging in elderly patients. PMID:27144043

  5. A mathematical model of the enhanced permeability and retention effect for liposome transport in solid tumors.

    PubMed

    Stapleton, Shawn; Milosevic, Michael; Allen, Christine; Zheng, Jinzi; Dunne, Michael; Yeung, Ivan; Jaffray, David A

    2013-01-01

    The discovery of the enhanced permeability and retention (EPR) effect has resulted in the development of nanomedicines, including liposome-based formulations of drugs, as cancer therapies. The use of liposomes has resulted in substantial increases in accumulation of drugs in solid tumors; yet, significant improvements in therapeutic efficacy have yet to be achieved. Imaging of the tumor accumulation of liposomes has revealed that this poor or variable performance is in part due to heterogeneous inter-subject and intra-tumoral liposome accumulation, which occurs as a result of an abnormal transport microenvironment. A mathematical model that relates liposome accumulation to the underlying transport properties in solid tumors could provide insight into inter and intra-tumoral variations in the EPR effect. In this paper, we present a theoretical framework to describe liposome transport in solid tumors. The mathematical model is based on biophysical transport equations that describe pressure driven fluid flow across blood vessels and through the tumor interstitium. The model was validated by direct comparison with computed tomography measurements of tumor accumulation of liposomes in three preclinical tumor models. The mathematical model was fit to liposome accumulation curves producing predictions of transport parameters that reflect the tumor microenvironment. Notably, all fits had a high coefficient of determination and predictions of interstitial fluid pressure agreed with previously published independent measurements made in the same tumor type. Furthermore, it was demonstrated that the model attributed inter-subject heterogeneity in liposome accumulation to variations in peak interstitial fluid pressure. These findings highlight the relationship between transvascular and interstitial flow dynamics and variations in the EPR effect. In conclusion, we have presented a theoretical framework that predicts inter-subject and intra-tumoral variations in the EPR effect

  6. A Mathematical Model of the Enhanced Permeability and Retention Effect for Liposome Transport in Solid Tumors

    PubMed Central

    Stapleton, Shawn; Milosevic, Michael; Allen, Christine; Zheng, Jinzi; Dunne, Michael; Yeung, Ivan; Jaffray, David A.

    2013-01-01

    The discovery of the enhanced permeability and retention (EPR) effect has resulted in the development of nanomedicines, including liposome-based formulations of drugs, as cancer therapies. The use of liposomes has resulted in substantial increases in accumulation of drugs in solid tumors; yet, significant improvements in therapeutic efficacy have yet to be achieved. Imaging of the tumor accumulation of liposomes has revealed that this poor or variable performance is in part due to heterogeneous inter-subject and intra-tumoral liposome accumulation, which occurs as a result of an abnormal transport microenvironment. A mathematical model that relates liposome accumulation to the underlying transport properties in solid tumors could provide insight into inter and intra-tumoral variations in the EPR effect. In this paper, we present a theoretical framework to describe liposome transport in solid tumors. The mathematical model is based on biophysical transport equations that describe pressure driven fluid flow across blood vessels and through the tumor interstitium. The model was validated by direct comparison with computed tomography measurements of tumor accumulation of liposomes in three preclinical tumor models. The mathematical model was fit to liposome accumulation curves producing predictions of transport parameters that reflect the tumor microenvironment. Notably, all fits had a high coefficient of determination and predictions of interstitial fluid pressure agreed with previously published independent measurements made in the same tumor type. Furthermore, it was demonstrated that the model attributed inter-subject heterogeneity in liposome accumulation to variations in peak interstitial fluid pressure. These findings highlight the relationship between transvascular and interstitial flow dynamics and variations in the EPR effect. In conclusion, we have presented a theoretical framework that predicts inter-subject and intra-tumoral variations in the EPR effect

  7. Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors

    PubMed Central

    Nayak, Lakshmi; Fleisher, Martin; Gonzalez-Espinoza, Rita; Lin, Oscar; Panageas, Katherine; Reiner, Anne; Liu, Chhui-Mei; DeAngelis, Lisa M.

    2013-01-01

    Objective: To evaluate the utility of rare cell capture technology (RCCT) in the diagnosis of leptomeningeal metastasis (LM) from solid tumors through identification of circulating tumor cells (CTCs) in the CSF. Methods: In this pilot study, CSF samples from 60 patients were analyzed. The main patient cohort consisted of 51 patients with solid tumors undergoing lumbar puncture for clinical suspicion of LM. Those patients underwent initial MRI evaluation and had CSF analyzed through conventional cytology and for the presence of CTCs using RCCT, based on immunomagnetic platform enrichment utilizing anti–epithelial cell adhesion molecule antibody-covered magnetic nanoparticles. An additional 9 patients with CSF pleocytosis but without solid tumors were separately analyzed to ensure accurate differentiation between CTCs and leukocytes. Results: Among the 51 patients with solid tumors, 15 patients fulfilled criteria for LM. CSF CTCs were found in 16 patients (median 20.7 CTCs/mL, range 0.13 to >150), achieving a sensitivity of 100% as compared with 66.7% for conventional cytology and 73.3% for MRI. One patient had a false-positive CSF CTC result (specificity = 97.2%); however, that patient eventually met LM criteria 6 months after the tap. CSF CTCs were not found in any of the additional 9 patients with CSF pleocytosis. Conclusion: RCCT is an accurate, novel method for the detection of LM in solid tumors, potentially providing earlier diagnostic confirmation and sparing patients from repeat lumbar punctures. PMID:23553479

  8. Vorinostat and Bortezomib in Treating Young Patients With Refractory or Recurrent Solid Tumors, Including Central Nervous System Tumors and Lymphoma

    ClinicalTrials.gov

    2013-07-01

    Childhood Burkitt Lymphoma; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Germ Cell Tumor; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Medulloepithelioma; Childhood Meningioma; Childhood Mixed Glioma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Childhood Oligodendroglioma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

  9. Pembrolizumab and Ziv-aflibercept in Treating Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2017-04-04

    Adult Solid Neoplasm; Metastatic Melanoma; Metastatic Renal Cell Cancer; Recurrent Colorectal Carcinoma; Recurrent Melanoma; Recurrent Ovarian Carcinoma; Recurrent Renal Cell Carcinoma; Stage IV Ovarian Cancer; Stage IVA Colorectal Cancer; Stage IVB Colorectal Cancer

  10. Gadd45 in modulation of solid tumors and leukemia.

    PubMed

    Hoffman, Barbara; Liebermann, Dan A

    2013-01-01

    The stress response gadd45 gene family participates in cell cycle control, cell survival, apoptosis, maintenance of genomic stability, DNA repair, and active DNA demethylation, in response to environmental and physiological stress including oncogenic stress. Given these diverse functions, it is anticipated that gadd45 genes can influence the initiation and progression of malignancy and the response to different treatments. This chapter will provide an overview of how the different members of the gadd45 gene family are expressed in different tumors and leukemia, how this may impact on progression of disease, and what happens when expression is manipulated. Studies from human tumor/leukemia samples, cell lines, and animal models are included in this review. An overriding theme is that each of the gadd45 genes has both tumor suppressor and tumor promoter functions, dependent on the tissue/cell type and transforming event.

  11. A Rare Breast Tumor Confused with Ductal Carcinoma in Situ, Primary Solid Neuroendocrine Carcinoma

    PubMed Central

    Alıcı, Ömer; Aydoğdu, Serap Korkmaz

    2014-01-01

    The concept of pure neuroendocrine breast tumors was initially defined by Sapino et al. There are three sub-types of these tumors: solid, small cell/oat cell, and large cell neuroendocrine carcinomas. To diagnose neuroendocrine tumors, more than half of the tumor cells must have neuroendocrine differentiation. The possibility of metastatic neuroendocrine carcinoma must always be excluded in the differential diagnosis. In addition, it should be considered that solid neuroendocrine (NE) carcinomas can be confused with ductal carcinoma in situ due to their similar morphologic appearance. In this article, a patient with primary solid neuroendocrine breast cancer who had been diagnosed with ductal carcinoma in situ at another center was presented along with morphological and immunohistochemical features.

  12. New Strategies for the Treatment of Solid Tumors with CAR-T Cells.

    PubMed

    Zhang, Hao; Ye, Zhen-Long; Yuan, Zhen-Gang; Luo, Zheng-Qiang; Jin, Hua-Jun; Qian, Qi-Jun

    2016-01-01

    Recent years, we have witnessed significant progresses in both basic and clinical studies regarding novel therapeutic strategies with genetically engineered T cells. Modification with chimeric antigen receptors (CARs) endows T cells with tumor specific cytotoxicity and thus induce anti-tumor immunity against malignancies. However, targeting solid tumors is more challenging than targeting B-cell malignancies with CAR-T cells because of the histopathological structure features, specific antigens shortage and strong immunosuppressive environment of solid tumors. Meanwhile, the on-target/off-tumor toxicity caused by relative expression of target on normal tissues is another issue that should be reckoned. Optimization of the design of CAR vectors, exploration of new targets, addition of safe switches and combination with other treatments bring new vitality to the CAR-T cell based immunotherapy against solid tumors. In this review, we focus on the major obstacles limiting the application of CAR-T cell therapy toward solid tumors and summarize the measures to refine this new cancer therapeutic modality.

  13. Oxaliplatin and Irinotecan in Treating Young Patients With Refractory Solid Tumors or Lymphomas

    ClinicalTrials.gov

    2013-06-04

    Childhood Burkitt Lymphoma; Childhood Central Nervous System Germ Cell Tumor; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway Glioma; Recurrent Colon Cancer; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Melanoma; Recurrent Nasopharyngeal Cancer; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

  14. FR901228 in Treating Children With Refractory or Recurrent Solid Tumors or Leukemia

    ClinicalTrials.gov

    2013-01-15

    Blastic Phase Chronic Myelogenous Leukemia; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Chronic Myelogenous Leukemia; Childhood Craniopharyngioma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Spinal Cord Neoplasm; Childhood Supratentorial Ependymoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Refractory Chronic Lymphocytic Leukemia; Relapsing Chronic Myelogenous Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

  15. Vaccine Therapy and Pembrolizumab in Treating Patients With Solid Tumors That Have Failed Prior Therapy

    ClinicalTrials.gov

    2017-03-30

    Adult Solid Neoplasm; Bladder Carcinoma; Colon Carcinoma; Estrogen Receptor Negative; Head and Neck Squamous Cell Carcinoma; Hepatocellular Carcinoma; HER2/Neu Negative; Melanoma; Non-Small Cell Lung Carcinoma; Pancreatic Carcinoma; Progesterone Receptor Negative; Rectal Carcinoma; Renal Cell Carcinoma; Soft Tissue Sarcoma; Triple-Negative Breast Carcinoma; TP53 Gene Mutation; Unresectable Solid Neoplasm

  16. Clinical actionability enhanced through deep targeted sequencing of solid tumors

    PubMed Central

    Chen, Ken; Meric-Bernstam, Funda; Zhao, Hao; Zhang, Qingxiu; Ezzeddine, Nader; Tang, Lin-ya; Qi, Yuan; Mao, Yong; Chen, Tenghui; Chong, Zechen; Zhou, Wanding; Zheng, Xiaofeng; Johnson, Amber; Aldape, Kenneth D.; Routbort, Mark J.; Luthra, Rajyalakshmi; Kopetz, Scott; Davies, Michael A.; de Groot, John; Moulder, Stacy; Vinod, Ravi; Farhangfar, Carol J.; Shaw, Kenna Mills; Mendelsohn, John; Mills, Gordon B.; Eterovic, Agda Karina

    2015-01-01

    Background Further advances of targeted cancer therapy require comprehensive in-depth profiling of somatic mutations that are present in subpopulations of tumor cells in a clinical tumor sample. However, it is unclear to what extent such intra-tumor heterogeneity is present and whether it may affect clinical decision making. To unravel this challenge, we established a deep targeted sequencing platform to identify potentially actionable DNA alterations in tumor samples. Methods We assayed 515 FFPE tumor samples and matched germline (475 patients) from 11 disease sites by capturing and sequencing all the exons in 201 cancer related genes. Mutations, indels and copy number data were reported. Results We obtained a 1000-fold average sequencing depth and identified 4794 non-synonymous mutations in the samples analyzed, which 15.2% were present at less than 10% allele frequency. Most of these low level mutations occurred at known oncogenic hotspots and are likely functional. Identifying low level mutations improved identification of mutations in actionable genes in 118 (24.84%) patients, among which 47 (9.8%) would otherwise be unactionable. In addition, acquiring ultra-high depth also ensured a low false discovery rate (less than 2.2%) from FFPE samples. Conclusion Our results were as accurate as a commercially available CLIA-compliant hotspot panel, but allowed the detection of a higher number of mutations in actionable genes. Our study revealed the critical importance of acquiring and utilizing high depth in profiling clinical tumor samples and presented a very useful platform for implementing routine sequencing in a cancer care institution. PMID:25626406

  17. A strategy to identify genes associated with circulating solid tumor cell survival in peripheral blood.

    PubMed Central

    Fournier, M. V.; Carvalho, M. G.; Pardee, A. B.

    1999-01-01

    Efforts in metastasis research have centered on the phenotypic and genetic differences between primary site and metastatic site tumors. However, genes that may be used as molecular markers of metastasis in circulating tumor cells remain unidentified. Genes regulating the dissemination and survival of solid tumor cells in the blood, as well as their adaptation to new environments, could be candidates for unique metastatic tumor markers. Differential display (DD) was conducted to compare the blood of tumor-free individuals with the blood of patients with lung, breast, and colon cancers. Twenty-one up-expressed genes in the tumor patient blood samples but none in the tumor-free donor blood samples were identified. Nine of these samples were isolated, amplified, and directly sequenced. A gene AB-1 homologous to a Bcl-2 family member, which might function as an apoptosis inhibitor, was identified. The overexpression of an apoptosis inhibitor in blood from patients with metastatic tumors might be correlated with the capability of solid tumor cells to survive in peripheral blood. This is the first demonstration of the usefulness of comparing control and patient blood samples by DD to find novel potential genetic markers identifying metastasis in the blood. http://link.springer-ny. com/link/service/journals/00020/bibs/5n5p313.html Images Fig. 1 Fig. 2 Fig. 3 PMID:10390547

  18. Bacteria-mediated in vivo delivery of quantum dots into solid tumor

    SciTech Connect

    Liu, Ying; Zhou, Mei; Luo, Dan; Wang, Lijun; Hong, Yuankai; Yang, Yepeng; Sha, Yinlin

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer New approach using the probiotic Bifidobacterium bifidum as a vehicle to deliver QDs into the deep tissue of solid tumors in vivo was achieved. Black-Right-Pointing-Pointer Bifidobacterium bifidum delivery system has intrinsic biocompatibility. Black-Right-Pointing-Pointer The targeting efficacy was improved by folic acids. -- Abstract: Semiconductor nanocrystals, so-called quantum dots (QDs), promise potential application in bioimaging and diagnosis in vitro and in vivo owing to their high-quality photoluminescence and excellent photostability as well as size-tunable spectra. Here, we describe a biocompatible, comparatively safe bacteria-based system that can deliver QDs specifically into solid tumor of living animals. In our strategy, anaerobic bacterium Bifidobacterium bifidum (B. bifidum) that colonizes selectively in hypoxic regions of animal body was successfully used as a vehicle to load with QDs and transported into the deep tissue of solid tumors. The internalization of lipid-encapsuled QDs into B. bifidum was conveniently carried by electroporation. To improve the efficacy and specificity of tumor targeting, the QDs-carrying bacterium surface was further conjugated with folic acids (FAs) that can bind to the folic acid receptor overexpressed tumor cells. This new approach opens a pathway for delivering different types of functional cargos such as nanoparticles and drugs into solid tumor of live animals for imaging, diagnosis and therapy.

  19. Glucocorticoid receptor expression in 20 solid tumor types using immunohistochemistry assay

    PubMed Central

    Block, Thaddeus S; Murphy, Tiffany I; Munster, Pamela N; Nguyen, Dat P; Lynch, Frank J

    2017-01-01

    Background Glucocorticoid receptor (GR) activity plays a role in many aspects of human physiology and may play a crucial role in chemotherapy resistance in a wide variety of solid tumors. A novel immunohistochemistry (IHC) based assay has been previously developed and validated in order to assess GR immunoreactivity in triple-negative breast cancer. The current study investigates the standardized use of this validated assay to assess GR expression in a broad range of solid tumor malignancies. Methods Archived formalin-fixed paraffin-embedded tumor bank samples (n=236) from 20 different solid tumor types were analyzed immunohistochemically. Nuclear staining was reported based on the H-score method using differential intensity scores (0, 1+, 2+, or 3+) with the percent stained (out of at least 100 carcinoma cells) recorded at each intensity. Results GR was expressed in all tumor types that had been evaluated. Renal cell carcinoma, sarcoma, cervical cancer, and melanoma were those with the highest mean H-scores, indicating high levels of GR expression. Colon, endometrial, and gastric cancers had lower GR staining percentages and intensities, resulting in the lowest mean H-scores. Conclusion A validated IHC assay revealed GR immunoreactivity in all solid tumor types studied and allowed for standardized comparison of reactivity among the different malignancies. Impact Baseline expression levels of GR may be a useful biomarker when pharmaceutically targeting GR in research or clinical setting. PMID:28293120

  20. Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors.

    PubMed

    Yu, Man; Lee, Carol; Wang, Marina; Tannock, Ian F

    2015-10-01

    Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined the effects of the PPI lansoprazole to modify the activity of doxorubicin. To gain insight into its mechanisms, we studied the effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole showed concentration-dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances the therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors.

  1. Pazopanib Hydrochloride in Treating Young Patients With Solid Tumors That Have Relapsed or Not Responded to Treatment

    ClinicalTrials.gov

    2013-09-27

    Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Embryonal Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Metastatic Childhood Soft Tissue Sarcoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Childhood Visual Pathway Glioma; Unspecified Childhood Solid Tumor, Protocol Specific

  2. Superior Performance of Aptamer in Tumor Penetration over Antibody: Implication of Aptamer-Based Theranostics in Solid Tumors

    PubMed Central

    Xiang, Dongxi; Zheng, Conglong; Zhou, Shu-Feng; Qiao, Shuxi; Tran, Phuong Ha-Lien; Pu, Chunwen; Li, Yong; Kong, Lingxue; Kouzani, Abbas Z.; Lin, Jia; Liu, Ke; Li, Lianhong; Shigdar, Sarah; Duan, Wei

    2015-01-01

    Insufficient penetration of therapeutic agents into tumor tissues results in inadequate drug distribution and lower intracellular concentration of drugs, leading to the increase of drug resistance and resultant failure of cancer treatment. Targeted drug delivery to solid tumors followed by complete drug penetration and durable retention will significantly improve clinical outcomes of cancer therapy. Monoclonal antibodies have been commonly used in clinic for cancer treatment, but their limitation of penetrating into tumor tissues still remains because of their large size. Aptamers, as “chemical antibodies”, are 15-20 times smaller than antibodies. To explore whether aptamers are superior to antibodies in terms of tumor penetration, we carried out the first comprehensive study to compare the performance of an EpCAM aptamer with an EpCAM antibody in theranostic applications. Penetration and retention were studied in in vitro three-dimensional tumorspheres, in vivo live animal imaging and mouse colorectal cancer xenograft model. We found that the EpCAM aptamer can not only effectively penetrate into the tumorsphere cores but can also be retained by tumor sphere cells for at least 24 h, while limited tumor penetration by EpCAM antibody was observed after 4 h incubation. As observed from in vivo live animal imaging, EpCAM aptamers displayed a maximum tumor uptake at around 10 min followed by a rapid clearance after 80 min, while the signal of peak uptake and disappearance of antibody appeared at 3 h and 6 h after intravenous injection, respectively. The signal of PEGylated EpCAM aptamers in xenograft tumors was sustained for 26 h, which was 4.3-fold longer than that of the EpCAM antibody. Consistently, there were 1.67-fold and 6.6-fold higher accumulation of PEGylated aptamer in xenograft tumors than that of antibody, at 3 h and 24 h after intravenous administration, respectively. In addition, the aptamer achieved at least a 4-time better tumor penetration in

  3. Superior Performance of Aptamer in Tumor Penetration over Antibody: Implication of Aptamer-Based Theranostics in Solid Tumors.

    PubMed

    Xiang, Dongxi; Zheng, Conglong; Zhou, Shu-Feng; Qiao, Shuxi; Tran, Phuong Ha-Lien; Pu, Chunwen; Li, Yong; Kong, Lingxue; Kouzani, Abbas Z; Lin, Jia; Liu, Ke; Li, Lianhong; Shigdar, Sarah; Duan, Wei

    2015-01-01

    Insufficient penetration of therapeutic agents into tumor tissues results in inadequate drug distribution and lower intracellular concentration of drugs, leading to the increase of drug resistance and resultant failure of cancer treatment. Targeted drug delivery to solid tumors followed by complete drug penetration and durable retention will significantly improve clinical outcomes of cancer therapy. Monoclonal antibodies have been commonly used in clinic for cancer treatment, but their limitation of penetrating into tumor tissues still remains because of their large size. Aptamers, as "chemical antibodies", are 15-20 times smaller than antibodies. To explore whether aptamers are superior to antibodies in terms of tumor penetration, we carried out the first comprehensive study to compare the performance of an EpCAM aptamer with an EpCAM antibody in theranostic applications. Penetration and retention were studied in in vitro three-dimensional tumorspheres, in vivo live animal imaging and mouse colorectal cancer xenograft model. We found that the EpCAM aptamer can not only effectively penetrate into the tumorsphere cores but can also be retained by tumor sphere cells for at least 24 h, while limited tumor penetration by EpCAM antibody was observed after 4 h incubation. As observed from in vivo live animal imaging, EpCAM aptamers displayed a maximum tumor uptake at around 10 min followed by a rapid clearance after 80 min, while the signal of peak uptake and disappearance of antibody appeared at 3 h and 6 h after intravenous injection, respectively. The signal of PEGylated EpCAM aptamers in xenograft tumors was sustained for 26 h, which was 4.3-fold longer than that of the EpCAM antibody. Consistently, there were 1.67-fold and 6.6-fold higher accumulation of PEGylated aptamer in xenograft tumors than that of antibody, at 3 h and 24 h after intravenous administration, respectively. In addition, the aptamer achieved at least a 4-time better tumor penetration in xenograft

  4. Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions.

    PubMed

    Pedrosa, Ana-Rita; Trindade, Alexandre; Carvalho, Catarina; Graça, José; Carvalho, Sandra; Peleteiro, Maria C; Adams, Ralf H; Duarte, António

    2015-09-15

    Angiogenesis is an essential process required for tumor growth and progression. The Notch signaling pathway has been identified as a key regulator of the neo-angiogenic process. Jagged-1 (Jag1) is a Notch ligand required for embryonic and retinal vascular development, which direct contribution to the regulation of tumor angiogenesis remains to be fully characterized. The current study addresses the role of endothelial Jagged1-mediated Notch signaling in the context of tumoral angiogenesis in two different mouse tumor models: subcutaneous Lewis Lung Carcinoma (LLC) tumor transplants and the autochthonous Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP). The role of endothelial Jagged1 in tumor growth and neo-angiogenesis was investigated with endothelial-specific Jag1 gain- and loss-of-function mouse mutants (eJag1OE and eJag1cKO). By modulating levels of endothelial Jag1, we observed that this ligand regulates tumor vessel density, branching, and perivascular maturation, thus affecting tumor vascular perfusion. The pro-angiogenic function is exerted by its ability to positively regulate levels of Vegfr-2 while negatively regulating Vegfr-1. Additionally, endothelial Jagged1 appears to exert an angiocrine function possibly by activating Notch3/Hey1 in tumor cells, promoting proliferation, survival and epithelial-to-mesenchymal transition (EMT), potentiating tumor development. These findings provide valuable mechanistic insights into the role of endothelial Jagged1 in promoting solid tumor development and support the notion that it may constitute a promising target for cancer therapy.

  5. Favorable alteration of tumor microenvironment by immunomodulatory cytokines for efficient T-cell therapy in solid tumors.

    PubMed

    Tähtinen, Siri; Kaikkonen, Saija; Merisalo-Soikkeli, Maiju; Grönberg-Vähä-Koskela, Susanna; Kanerva, Anna; Parviainen, Suvi; Vähä-Koskela, Markus; Hemminki, Akseli

    2015-01-01

    Unfavorable ratios between the number and activation status of effector and suppressor immune cells infiltrating the tumor contribute to resistance of solid tumors to T-cell based therapies. Here, we studied the capacity of FDA and EMA approved recombinant cytokines to manipulate this balance in favor of efficient anti-tumor responses in B16.OVA melanoma bearing C57BL/6 mice. Intratumoral administration of IFN-α2, IFN-γ, TNF-α, and IL-2 significantly enhanced the anti-tumor effect of ovalbumin-specific CD8+ T-cell (OT-I) therapy, whereas GM-CSF increased tumor growth in association with an increase in immunosuppressive cell populations. None of the cytokines augmented tumor trafficking of OT-I cells significantly, but injections of IFN-α2, IFN-γ and IL-2 increased intratumoral cytokine secretion and recruitment of endogenous immune cells capable of stimulating T-cells, such as natural killer and maturated CD11c+ antigen-presenting cells. Moreover, IFN-α2 and IL-2 increased the levels of activated tumor-infiltrating CD8+ T-cells concomitant with reduction in the CD8+ T-cell expression of anergy markers CTLA-4 and PD-1. In conclusion, intratumoral administration of IFN-α2, IFN-γ and IL-2 can lead to immune sensitization of the established tumor, whereas GM-CSF may contribute to tumor-associated immunosuppression. The results described here provide rationale for including local administration of immunostimulatory cytokines into T-cell therapy regimens. One appealing embodiment of this would be vectored delivery which could be advantageous over direct injection of recombinant molecules with regard to efficacy, cost, persistence and convenience.

  6. Favorable Alteration of Tumor Microenvironment by Immunomodulatory Cytokines for Efficient T-Cell Therapy in Solid Tumors

    PubMed Central

    Tähtinen, Siri; Kaikkonen, Saija; Merisalo-Soikkeli, Maiju; Grönberg-Vähä-Koskela, Susanna; Kanerva, Anna; Parviainen, Suvi; Vähä-Koskela, Markus; Hemminki, Akseli

    2015-01-01

    Unfavorable ratios between the number and activation status of effector and suppressor immune cells infiltrating the tumor contribute to resistance of solid tumors to T-cell based therapies. Here, we studied the capacity of FDA and EMA approved recombinant cytokines to manipulate this balance in favor of efficient anti-tumor responses in B16.OVA melanoma bearing C57BL/6 mice. Intratumoral administration of IFN-α2, IFN-γ, TNF-α, and IL-2 significantly enhanced the anti-tumor effect of ovalbumin-specific CD8+ T-cell (OT-I) therapy, whereas GM-CSF increased tumor growth in association with an increase in immunosuppressive cell populations. None of the cytokines augmented tumor trafficking of OT-I cells significantly, but injections of IFN-α2, IFN-γ and IL-2 increased intratumoral cytokine secretion and recruitment of endogenous immune cells capable of stimulating T-cells, such as natural killer and maturated CD11c+ antigen-presenting cells. Moreover, IFN-α2 and IL-2 increased the levels of activated tumor-infiltrating CD8+ T-cells concomitant with reduction in the CD8+ T-cell expression of anergy markers CTLA-4 and PD-1. In conclusion, intratumoral administration of IFN-α2, IFN-γ and IL-2 can lead to immune sensitization of the established tumor, whereas GM-CSF may contribute to tumor-associated immunosuppression. The results described here provide rationale for including local administration of immunostimulatory cytokines into T-cell therapy regimens. One appealing embodiment of this would be vectored delivery which could be advantageous over direct injection of recombinant molecules with regard to efficacy, cost, persistence and convenience. PMID:26107883

  7. An overview of viral oncology in Italy - report from the Pavia meeting on solid tumors.

    PubMed

    Perfetti, Vittorio; Ricotti, Mattia; Buonaguro, Franco; Tirelli, Umberto; Pedrazzoli, Paolo

    2012-09-05

    This is a report on some of the research activities currently ongoing in Italy as outlined at the "Viruses and solid tumors" meeting jointly organized by the Oncology Sections of IRCCS Policlinico "San Matteo" (Pavia) and IRCCS National Cancer Institute (Aviano), held in Pavia, Italy, on October 2011. Experts from the various disciplines involved in the study of the complex relationships between solid tumors and viruses met to discuss recent developments in the field and to report their personal contributions to the specified topics. Secondary end point was to establish a multidisciplinary work group specifically devoted to solid tumors and infectious agents, aimed to identify areas of common interest, promoting and establishing collaborative projects and programs, and to coordinate clinical and research activities. The group, which will be named IVOG (Italian Viral Oncology Group), will operate under the patronage of the various scientific societies of interest.

  8. WEE1 Inhibitor MK-1775 and Irinotecan Hydrochloride in Treating Younger Patients With Relapsed or Refractory Solid Tumors

    ClinicalTrials.gov

    2017-03-13

    Childhood Central Nervous System Neoplasm; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Embryonal Tumor, Not Otherwise Specified; Recurrent Malignant Solid Neoplasm; Recurrent Neuroblastoma

  9. Pregnancy following Radical Resection of Solid Pseudopapillary Tumor of the Pancreas

    PubMed Central

    O'Brien, James M.; Hagopian, Ellen; Matulewicz, Theodore

    2014-01-01

    Solid pseudopapillary tumor of the pancreas is a rare tumor seen in predominately young women and carries a low malignant potential. We discuss a patient, who presented to our high risk clinic, with a clinical history of solid pseudopapillary tumor of the pancreas, predating her pregnancy. The patient had undergone previous surgery and imaging which had excluded recurrence of disease; however, increased attention was paid to the patient during her pregnancy secondary to elevated hormonal levels of progesterone, which any residual disease would have a heightened sensitivity to. In cases of pregnant patients with a history of pancreatic tumors, a multidisciplinary approach with maternal fetal medicine, medicine, and general surgery is appropriate and can result in a healthy mother and healthy term infant. PMID:25349752

  10. High-intensity focused ultrasound for the treatment of solid tumor: Chinese clinical experience

    NASA Astrophysics Data System (ADS)

    Takeuchi, Akira; Zhang, Hong; Sun, Kun; Hasumura, Hiromi; Liu, Botao; Fu, Yurui; Yang, Zaocheng

    2006-05-01

    As a non-invasive modality, high-intensity focused ultrasound (HIFU) therapy has been received an interest for the treatment of solid tumor. There are some makers of HIFU for the equipment in China. The Sonic CZ901 is developed from the Mianyang stream that has a great advantage for guiding by color Doppler ultrasound imaging. For the research about possibility of this equipment, we evaluate the clinical usefulness to the solid tumor of HIFU treatment at Wujing general hospital in Beijing. We elucidate the result in 28 cases with benign and malignant tumor (Uterine myoma:16, Benign prostatic hypertrophy:5, Benign breast tumor:2, Breast cancer:1, Retroperitoneal tumor:1, Pheochromocytoma:1, Liver cancer: 2) . After 14˜90days, all cases show the reduction of tumor size (Max.3.2cm, Min.1.6cm, :Mean 2.2cm reduced), and the blood flow of tumor completely reduced in 7/23, partially reduced in16/23. Clinical symptoms disappeared in 7, clearly improved in 14, improved in 7. All treatments had no adverse event except for two cases of liver cancer. They felt an abdominal pain that controllable by medicine and it improved within 6hours. It is concluded that HIFU with guide by ultrasound imaging is very safe, painless and effective as the anti-tumor treatment.

  11. Handling of solid brain tumor tissue for protein analysis.

    PubMed

    Ericsson, Christer; Nistér, Monica

    2011-01-01

    Optimal protein analysis requires unfixed tissue samples. We suggest handling the brain tumor tissue sterilely and coldly (on ice) for as short time as possible prior to processing, but for no more than 8 h. This simple protocol results in apparently intact morphology, immunoreactivity, protein integrity, and protein phosphorylation with the criteria we apply. Sample handling for Pathological Anatomical Diagnosis (PAD) and for protein analysis can be one and the same.

  12. Detection of BRAF mutations from solid tumors using Tumorplex™ technology

    PubMed Central

    Yo, Jacob; Hay, Katie S.L.; Vinayagamoorthy, Dilanthi; Maryanski, Danielle; Carter, Mark; Wiegel, Joseph; Vinayagamoorthy, Thuraiayah

    2015-01-01

    Allele specific multiplex sequencing (Tumorplex™) is a new molecular platform for the detection of single base mutation in tumor biopsies with high sensitivity for clinical testing. Tumorplex™ is a novel modification of Sanger sequencing technology that generates both mutant and wild type nucleotide sequences simultaneously in the same electropherogram. The molecular weight of the two sequencing primers are different such that the two sequences generated are separated, thus eliminating possible suppression of mutant signal by the more abundant wild type signal. Tumorplex™ platform technology was tested using BRAF mutation V600E. These studies were performed with cloned BRAF mutations and genomic DNA extracted from tumor cells carrying 50% mutant allele. The lower limit of detection for BRAF V600E was found to be 20 genome equivalents (GE) using genomic DNA extracted from mutation specific cell lines. Sensitivity of the assay was tested by challenging the mutant allele with wild type allele at 20 GE, and was able to detect BRAF mutant signal at a GE ration of 20:1 × 107 (mutant to wild-type). This level of sensitivity can detect low abundance of clonal mutations in tumor biopsies and eliminate the need for cell enrichment. • Tumorplex™ is a single tube assay that permits the recognition of mutant allele without suppression by wildtype signal. • Tumorplex™ provides a high level of sensitivity. • Tumorplex™ can be used with small sample size with mixed population of cells carrying heterogeneous gDNA. PMID:26258049

  13. Detection of BRAF mutations from solid tumors using Tumorplex™ technology.

    PubMed

    Yo, Jacob; Hay, Katie S L; Vinayagamoorthy, Dilanthi; Maryanski, Danielle; Carter, Mark; Wiegel, Joseph; Vinayagamoorthy, Thuraiayah

    2015-01-01

    Allele specific multiplex sequencing (Tumorplex™) is a new molecular platform for the detection of single base mutation in tumor biopsies with high sensitivity for clinical testing. Tumorplex™ is a novel modification of Sanger sequencing technology that generates both mutant and wild type nucleotide sequences simultaneously in the same electropherogram. The molecular weight of the two sequencing primers are different such that the two sequences generated are separated, thus eliminating possible suppression of mutant signal by the more abundant wild type signal. Tumorplex™ platform technology was tested using BRAF mutation V600E. These studies were performed with cloned BRAF mutations and genomic DNA extracted from tumor cells carrying 50% mutant allele. The lower limit of detection for BRAF V600E was found to be 20 genome equivalents (GE) using genomic DNA extracted from mutation specific cell lines. Sensitivity of the assay was tested by challenging the mutant allele with wild type allele at 20 GE, and was able to detect BRAF mutant signal at a GE ration of 20:1 × 10(7) (mutant to wild-type). This level of sensitivity can detect low abundance of clonal mutations in tumor biopsies and eliminate the need for cell enrichment. •Tumorplex™ is a single tube assay that permits the recognition of mutant allele without suppression by wildtype signal.•Tumorplex™ provides a high level of sensitivity.•Tumorplex™ can be used with small sample size with mixed population of cells carrying heterogeneous gDNA.

  14. Albumin-bound paclitaxel in solid tumors: clinical development and future directions.

    PubMed

    Kundranda, Madappa N; Niu, Jiaxin

    2015-01-01

    Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free formulation of paclitaxel that was initially developed more than a decade ago to overcome toxicities associated with the solvents used in the formulation of standard paclitaxel and to potentially improve efficacy. Nab-paclitaxel has demonstrated an advantage over solvent-based paclitaxel by being able to deliver a higher dose of paclitaxel to tumors and decrease the incidence of serious toxicities, including severe allergic reactions. To date, nab-paclitaxel has been indicated for the treatment of three solid tumors in the USA. It was first approved for the treatment of metastatic breast cancer in 2005, followed by locally advanced or metastatic non-small-cell lung cancer in 2012, and most recently for metastatic pancreatic cancer in 2013. Nab-paclitaxel is also under investigation for the treatment of a number of other solid tumors. This review highlights key clinical efficacy and safety outcomes of nab-paclitaxel in the solid tumors for which it is currently indicated, discusses ongoing trials that may provide new data for the expansion of nab-paclitaxel's indications into other solid tumors, and provides a clinical perspective on the use of nab-paclitaxel in practice.

  15. Albumin-bound paclitaxel in solid tumors: clinical development and future directions

    PubMed Central

    Kundranda, Madappa N; Niu, Jiaxin

    2015-01-01

    Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free formulation of paclitaxel that was initially developed more than a decade ago to overcome toxicities associated with the solvents used in the formulation of standard paclitaxel and to potentially improve efficacy. Nab-paclitaxel has demonstrated an advantage over solvent-based paclitaxel by being able to deliver a higher dose of paclitaxel to tumors and decrease the incidence of serious toxicities, including severe allergic reactions. To date, nab-paclitaxel has been indicated for the treatment of three solid tumors in the USA. It was first approved for the treatment of metastatic breast cancer in 2005, followed by locally advanced or metastatic non-small-cell lung cancer in 2012, and most recently for metastatic pancreatic cancer in 2013. Nab-paclitaxel is also under investigation for the treatment of a number of other solid tumors. This review highlights key clinical efficacy and safety outcomes of nab-paclitaxel in the solid tumors for which it is currently indicated, discusses ongoing trials that may provide new data for the expansion of nab-paclitaxel’s indications into other solid tumors, and provides a clinical perspective on the use of nab-paclitaxel in practice. PMID:26244011

  16. In-vivo imaging of nanoshell extravasation from solid tumor vasculature by photoacoustic microscopy

    NASA Astrophysics Data System (ADS)

    Li, Meng-Lin; Schwartz, Jon A.; Wang, James; Stoica, George; Wang, Lihong V.

    2007-02-01

    In this study, high resolution reflection-mode (backward-mode) photoacoustic microscopy (PAM) is used to noninvasively image progressive extravasation and accumulation of nanoshells within a solid tumor in vivo. This study takes advantage of the strong near-infrared absorption of nanoshells, a novel type of optically tunable gold nanoparticles that tend to extravasate from leaky tumor vasculatures (i.e., passive targeting) via the "enhanced permeability and retention" effect due to their nanoscale size. Tumors were grown in immunocompetent BALB/c mice by subcutaneous inoculation of CT26.wt murine colon carcinoma cells. PEGylated nanoshells with a peak optical absorption at ~800 nm were intravenously administered. Pre-scans prior to nanoshell injection were taken using a 584-nm laser source to highlight blood content and an 800-nm laser source to mark the background limit for nanoshell accumulation. After injection, the three-dimensional nanoshell distribution inside the tumor was monitored by PAM for 7 hours. Experimental results show that nanoshell accumulation is heterogeneous in tumors: more concentrated within the tumor cortex and largely absent from the tumor core. This correlates with others' observation that drug delivery within tumor cores is ineffective because of both high interstitial pressure and tendency to necrosis of tumor cores. Since nanoshells have been recently applied to thermal therapy for subcutaneous tumors, we anticipate that PAM will be important to this therapeutic technique.

  17. Use of Arsenic Trioxide as an Antivascular and Thermosensitizing Agent in Solid Tumors1

    PubMed Central

    Griffin, Robert J; Lee, Sang H; Rood, Kelly L; Stewart, Michael J; Lyons, John C; Lew, Young S; Park, Heonjoo; Song, Chang W

    2000-01-01

    Abstract Arsenic trioxide, As2O3 (ATO), has been found to be an effective chemotherapy drug for acute promyelocytic leukemia but its effect on solid tumors has not been fully explored. In the present report, we describe our observation that ATO is a potent antivascular agent and that it markedly enhances the effect of hyperthermia on tumors. The tumor blood perfusion in SCK tumors of A/J mice and FSall tumors of C3H mice was significantly suppressed for up to 24 hours after an i.p. injection of 8 mg/kg ATO. ATO was also found to be able to increase the thermosensitivity of tumor cells in vitro. As a probable consequence of these effects, ATO treatment markedly increased the tumor growth delay caused by hyperthermia at 41.5–42.5°C. Immunohistochemical staining of tumor tissue revealed that the expression levels of several adhesion molecules and TNFα are noticeably increased in tumors 2–6 hours after systemic ATO treatment. It is concluded that ATO is potentially useful to enhance the effect of hyperthermia on tumors at a clinically relevant temperature. PMID:11228548

  18. Chemokines, costimulatory molecules and fusion proteins for the immunotherapy of solid tumors.

    PubMed

    Lechner, Melissa G; Russell, Sarah M; Bass, Rikki S; Epstein, Alan L

    2011-11-01

    In this article, the role of chemokines and costimulatory molecules in the immunotherapy of experimental murine solid tumors and immunotherapy used in ongoing clinical trials are presented. Chemokine networks regulate physiologic cell migration that may be disrupted to inhibit antitumor immune responses or co-opted to promote tumor growth and metastasis in cancer. Recent studies highlight the potential use of chemokines in cancer immunotherapy to improve innate and adaptive cell interactions and to recruit immune effector cells into the tumor microenvironment. Another critical component of antitumor immune responses is antigen priming and activation of effector cells. Reciprocal expression and binding of costimulatory molecules and their ligands by antigen-presenting cells and naive lymphocytes ensures robust expansion, activity and survival of tumor-specific effector cells in vivo. Immunotherapy approaches using agonist antibodies or fusion proteins of immunomodulatory molecules significantly inhibit tumor growth and boost cell-mediated immunity. To localize immune stimulation to the tumor site, a series of fusion proteins consisting of a tumor-targeting monoclonal antibody directed against tumor necrosis and chemokines or costimulatory molecules were generated and tested in tumor-bearing mice. While several of these reagents were initially shown to have therapeutic value, combination therapies with methods to delete suppressor cells had the greatest effect on tumor growth. In conclusion, a key conclusion that has emerged from these studies is that successful immunotherapy will require both advanced methods of immunostimulation and the removal of immunosuppression in the host.

  19. Targeting Mitochondrial Function to Treat Quiescent Tumor Cells in Solid Tumors

    PubMed Central

    Zhang, Xiaonan; de Milito, Angelo; Olofsson, Maria Hägg; Gullbo, Joachim; D’Arcy, Padraig; Linder, Stig

    2015-01-01

    The disorganized nature of tumor vasculature results in the generation of microenvironments characterized by nutrient starvation, hypoxia and accumulation of acidic metabolites. Tumor cell populations in such areas are often slowly proliferating and thus refractory to chemotherapeutical drugs that are dependent on an active cell cycle. There is an urgent need for alternative therapeutic interventions that circumvent growth dependency. The screening of drug libraries using multicellular tumor spheroids (MCTS) or glucose-starved tumor cells has led to the identification of several compounds with promising therapeutic potential and that display activity on quiescent tumor cells. Interestingly, a common theme of these drug screens is the recurrent identification of agents that affect mitochondrial function. Such data suggest that, contrary to the classical Warburg view, tumor cells in nutritionally-compromised microenvironments are dependent on mitochondrial function for energy metabolism and survival. These findings suggest that mitochondria may represent an “Achilles heel” for the survival of slowly-proliferating tumor cells and suggest strategies for the development of therapy to target these cell populations. PMID:26580606

  20. Hydrodynamics and convection enhanced macromolecular fluid transport in soft biological tissues: Application to solid tumor.

    PubMed

    Dey, Bibaswan; Sekhar, G P Raja

    2016-04-21

    This work addresses a theoretical framework for transvascular exchange and extravascular transport of solute macromolecules through soft interstitial space inside a solid tumor. Most of the soft biological tissues show materialistic properties similar to deformable porous material. They exhibit mechanical behavior towards the fluid motion since the solid phase of the tumor tissue gets compressed by the drag force that is associated with the extracellular fluid flow. This paper presents a general view about the transvascular and interstitial transport of solute nutrients inside a tumor in the macroscopic level. Modified Starling׳s equation is used to describe transvascular nutrient transport. On the macroscopic level, motion of extracellular fluid within the tumor interstitium is modeled with the help of biphasic mixture theory and a spherical symmetry solution is given as a simpler case. This present model describes the average interstitial fluid pressure (IFP), extracellular fluid velocity (EFV) and flow rate of extracellular fluid, as well as the deformation of the solid phase of the tumor tissue as an immediate cause of extracellular fluid flow. When the interstitial transport is diffusion dominated, an analytical treatment of advection-diffusion-reaction equation finds the overall nutrient distribution. We propose suitable criteria for the formation of necrosis within the tumor interstitium. This study introduces some parameters that represent the nutrient supply from tumor blood vessels into the tumor extracellular space. These transport parameters compete with the reversible nutrient metabolism of the tumor cells present in the interstitium. The present study also shows that the effectiveness factor corresponding to a first order nutrient metabolism may reach beyond unity if the strength of the distributive solute source assumes positive non-zero values.

  1. 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

  2. Novel Antibody Therapeutics Targeting Mesothelin In Solid Tumors

    PubMed Central

    Zhao, Xiao-Yan; Subramanyam, Babu; Sarapa, Nenad; Golfier, Sven; Dinter, Harald

    2016-01-01

    Abstract: Background Monoclonal antibodies have become attractive clinical anti-cancer drugs in the last 3 decades due to their targeting specificity and suitable pharmacokinetic properties. Mesothelin is a tumor-associated antigen with limited expression in normal tissues. It is frequently over-expressed on the cell membrane of a number of epithelial malignancies (e.g. mesothelioma, pancreatic, ovarian, lung, triple negative breast and gastric cancers). Methods Mesothelin is validated as a suitable antibody target for cancer therapy. A number of novel antibody therapeutics targeting mesothelin in development are compared and their mechanisms of action are also discussed. Both basic science and clinical data are provided to give a complete veiw of how an agent is developed from bench to bedside. Results Novel antibody therapeutics, including unconjugated monoclonal antibodies, recombinant immunotoxins and antibody-drug conjugates, targeting mesothelin exert anti-tumor activities by different mechanisms of action. Based on the convincing preclinical data generated with these molecules, the antibody therapeutics have been brought into early clinical evaluation where initial promising results were obtained. Conclusion These antibody therapeutics directed against mesothelin are expected to have different safety profiles, based on their different mechanism of action. Further clinical development will reveal which of these molecules shows the best efficacy and widest therapeutic window and thus is best suited to bring benefit to the patients. PMID:27853672

  3. Prognostic value of FOXQ1 in patients with malignant solid tumors: a meta-analysis

    PubMed Central

    Cui, Xiaohai; Zhang, Jing; Lv, Jiajun; Yan, Yan; Liu, Xu; Wang, Jizhao; Lv, Yi; Zhang, Jia

    2017-01-01

    Background Forkhead box Q1 (FOXQ1, also known as HFH1), a member of the forkhead transcription factor family, has been demonstrated to be overexpressed in multiple tumors and is thought to be an indicator of poor clinical outcomes. Methods A meta-analysis using qualified relevant literature was performed to evaluate the prognostic significance of FOXQ1 in various malignant solid tumors. A search of electronic databases was conducted in MEDLINE, Embase, and the Cochrane Library to identify relevant studies published from 1966 to July 30, 2016, and the studies were identified by further evaluation. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for analyses were assessed to investigate the association between FOXQ1 expression and overall survival (OS) of patients with malignant solid tumors. Results A total of 1,520 patients from six studies (seven cohorts) with multiple malignant solid tumors were included. For OS, high FOXQ1 expression could significantly predict worse outcome with the pooled HR of 1.38 (95% CI: 1.17–1.59; P<0.001). The subgroup analysis suggested that the elevated levels of FOXQ1 appear to be associated with worse OS in hepatocellular carcinoma (HR =1.34; 95% CI: 1.11–1.57; P<0.001) and other cancers (HR =1.62; 95% CI: 1.09–2.14; P<0.001). Conclusion This meta-analysis indicated that the high expression of FOXQ1 is associated with an adverse OS in malignant solid tumors, suggesting that FOXQ1 may be a predictor of poor prognosis for the development of malignant solid tumors. PMID:28367060

  4. A hybrid cellular automaton model of solid tumor growth and bioreductive drug transport.

    PubMed

    Kazmi, Nabila; Hossain, M A; Phillips, Roger M

    2012-01-01

    Bioreductive drugs are a class of hypoxia selective drugs that are designed to eradicate the hypoxic fraction of solid tumors. Their activity depends upon a number of biological and pharmacological factors and we used a mathematical modeling approach to explore the dynamics of tumor growth, infusion, and penetration of the bioreductive drug Tirapazamine (TPZ). An in-silico model is implemented to calculate the tumor mass considering oxygen and glucose as key microenvironmental parameters. The next stage of the model integrated extra cellular matrix (ECM), cell-cell adhesion, and cell movement parameters as growth constraints. The tumor microenvironments strongly influenced tumor morphology and growth rates. Once the growth model was established, a hybrid model was developed to study drug dynamics inside the hypoxic regions of tumors. The model used 10, 50 and 100 \\mu {\\rm M} as TPZ initial concentrations and determined TPZ pharmacokinetic (PK) (transport) and pharmacodynamics (cytotoxicity) properties inside hypoxic regions of solid tumor. The model results showed that diminished drug transport is a reason for TPZ failure and recommend the optimization of the drug transport properties in the emerging TPZ generations. The modeling approach used in this study is novel and can be a step to explore the behavioral dynamics of TPZ.

  5. Evading anti-angiogenic therapy: resistance to anti-angiogenic therapy in solid tumors

    PubMed Central

    Dey, Nandini; De, Pradip; Brian, Leyland-Jones

    2015-01-01

    Vascular endothelial growth factor (VEGF) dependent tumor angiogenesis is an essential step for the initiation and promotion of tumor progression. The hypothesis that VEGF-driven tumor angiogenesis is necessary and sufficient for metastatic progression of the tumor, has been the major premise of the use of anti-VEGF therapy for decades. While the success of anti-VEGF therapy in solid tumors has led to the success of knowledge-based-therapies over the past several years, failures of this therapeutic approach due to the development of inherent/acquired resistance has led to the increased understanding of VEGF-independent angiogenesis. Today, tumor-angiogenesis is not a synonymous term to VEGF-dependent function. The extensive study of VEGF-independent angiogenesis has revealed several key factors responsible for this phenomenon including the role of myeloid cells, and the contribution of entirely new phenomenon like vascular mimicry. In this review, we will present the cellular and molecular factors related to the development of anti-angiogenic resistance following anti-VEGF therapy in different solid tumors. PMID:26692917

  6. SN-38-loaded nanofiber matrices for local control of pediatric solid tumors after subtotal resection surgery.

    PubMed

    Monterrubio, Carles; Pascual-Pasto, Guillem; Cano, Francisco; Vila-Ubach, Monica; Manzanares, Alejandro; Schaiquevich, Paula; Tornero, Jose A; Sosnik, Alejandro; Mora, Jaume; Carcaboso, Angel M

    2016-02-01

    In addition to surgery, local tumor control in pediatric oncology requires new treatments as an alternative to radiotherapy. SN-38 is an anticancer drug with proved activity against several pediatric solid tumors including neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. Taking advantage of the extremely low aqueous solubility of SN-38, we have developed a novel drug delivery system (DDS) consisting of matrices made of poly(lactic acid) electrospun polymer nanofibers loaded with SN-38 microcrystals for local release in difficult-to-treat pediatric solid tumors. To model the clinical scenario, we conducted extensive preclinical experiments to characterize the biodistribution of the released SN-38 using microdialysis sampling in vivo. We observed that the drug achieves high concentrations in the virtual space of the surgical bed and penetrates a maximum distance of 2 mm within the tumor bulk. Subsequently, we developed a model of subtotal tumor resection in clinically relevant pediatric patient-derived xenografts and used such models to provide evidence of the activity of the SN-38 DDS to inhibit tumor regrowth. We propose that this novel DDS could represent a potential future strategy to avoid harmful radiation therapy as a primary tumor control together with surgery.

  7. nab-Paclitaxel as a potential partner with checkpoint inhibitors in solid tumors

    PubMed Central

    Soliman, Hatem H

    2017-01-01

    Tumors recognized by the host immune system are associated with better survival. However, the immune system is often suppressed in patients with established tumor burden. Stimulating the immune system to detect and kill tumor cells has been a challenge in cancer therapy for some time. Recently, novel cancer immunotherapies, such as immune checkpoint inhibitors, monoclonal antibodies, and vaccine therapies, have emerged as promising therapeutic approaches for many solid tumors. However, for some tumors, immunotherapy alone has not provided significant benefits, and some may even be fully resistant to immunotherapy. It has been suggested that the immune system may require “priming” before an immunotherapy can elicit an immune response. Although chemotherapies are believed to be immunosuppressive, when given at the right dose and sequence these agents may provide this “priming” effect for the immune system. In addition to direct cytotoxic killing of tumor cells, standard chemotherapeutic agents can elicit immunogenicity through various mechanisms. This review highlights the general immunomodulatory properties of chemotherapy agents. It also provides a rationale for combined therapy with nab-paclitaxel and immune checkpoint inhibitors. Recent clinical trial data with these combination regimens in solid tumors are presented, along with a summary of ongoing trials. PMID:28053544

  8. Intensive chemotherapy as salvage treatment for solid tumors: focus on germ cell cancer

    PubMed Central

    Selle, F.; Gligorov, J.; Richard, S.; Khalil, A.; Alexandre, I.; Avenin, D.; Provent, S.; Soares, D.G.; Lotz, J.P.

    2014-01-01

    Germ cell tumors present contrasting biological and molecular features compared to many solid tumors, which may partially explain their unusual sensitivity to chemotherapy. Reduced DNA repair capacity and enhanced induction of apoptosis appear to be key factors in the sensitivity of germ cell tumors to cisplatin. Despite substantial cure rates, some patients relapse and subsequently die of their disease. Intensive doses of chemotherapy are used to counter mechanisms of drug resistance. So far, high-dose chemotherapy with hematopoietic stem cell support for solid tumors is used only in the setting of testicular germ cell tumors. In that indication, high-dose chemotherapy is given as the first or late salvage treatment for patients with either relapsed or progressive tumors after initial conventional salvage chemotherapy. High-dose chemotherapy is usually given as two or three sequential cycles using carboplatin and etoposide with or without ifosfamide. The administration of intensive therapy carries significant side effects and can only be efficiently and safely conducted in specialized referral centers to assure optimum patient care outcomes. In breast and ovarian cancer, most studies have demonstrated improvement in progression-free survival (PFS), but overall survival remained unchanged. Therefore, most of these approaches have been dropped. In germ cell tumors, clinical trials are currently investigating novel therapeutic combinations and active treatments. In particular, the integration of targeted therapies constitutes an important area of research for patients with a poor prognosis. PMID:25493378

  9. Differentiation of solid pancreatic tumors by using dynamic contrast-enhanced MRI

    NASA Astrophysics Data System (ADS)

    Choi, Seung Joon; Kim, Hyung Sik; Park, Hyunjin

    2014-01-01

    Distinguishing among different solid pancreatic tumor types, pancreatic ductal adenocarcinomas, neuroendocrine tumors (NETs), and solid pseudopapillary tumors (SPTs) is important, as the treatment options are vastly different. This study compared characteristics of solid pancreatic tumors by using dynamic contrast enhanced magnetic resonance imaging (MRI). Fifty patients underwent MR imaging of pancreatic masses with a histopathology that was later confirmed as an adenocarcinoma (n = 27), a NET (n = 16), and a SPT (n = 7). For qualitative analysis, two reviewers evaluated the morphologic features of the tumors: locations, margins, shapes, contained products, pancreatic ductal dilatation, and grade of signal intensity (SI). For the quantitative analysis, all phases of the MR images were co-registered using proprietary image registration software; thus, a region of interest (ROI) defined on one phase could be re-applied in other phases. The following four ratios were considered: tumor-to-uninvolved pancreas SI ratio, percent SI change, tumor-touninvolved pancreas enhancement index, and arterial-to-delayed washout rate. The areas under the receiver operating characteristic (ROC) curves were assessed for the four ratios. Adenocarcinomas had ill-defined margins, irregular shapes, and ductal dilatation compared with NETs and SPTs (P < 0.001). The tumor-to-uninvolved pancreas ratio on all dynamic phases was significantly higher for NETs than for both adenocarcinomas and SPTs (P < 0.05). Percentage SI changes of pancreatic tumors on the pancreatic and the portal venous phases were significantly higher for NETs than for both adenocarcinomas and SPTs (P < 0.05). A significant difference between NETs and adenocarcinomas was also found with respect to the tumor-to-uninvolved pancreas enhancement index and arterial-to-delayed washout rate. The percentage SI changes in the pancreatic phase and the arterial-to-delayed washout rate best distinguished between adenocarcinomas and

  10. A Study of CDX-1127 (Varlilumab) in Patients With Select Solid Tumor Types or Hematologic Cancers

    ClinicalTrials.gov

    2017-01-23

    CD27 Expressing B-cell Malignancies for Example Hodgkin's Lymphoma; Chronic Lymphocytic Leukemia; Mantle Cell Lymphoma; Marginal Zone B Cell Lymphoma); Any T-cell Malignancy; Solid Tumors (Metastatic Melanoma, Renal (Clear) Cell Carcinoma; Hormone-refractory Prostate Adenocarcinoma, Ovarian Cancer; Colorectal Adenocarcinoma, Non-small Cell Lung Cancer); Burkett's Lymphoma; Primary Lymphoma of the Central Nervous System

  11. Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects.

    PubMed

    Maruyama, Kazuo

    2011-03-18

    The success of an effective drug delivery system using liposomes for solid tumor targeting based on EPR effects is highly dependent on both size ranging from 100-200 nm in diameter and prolonged circulation half-life in the blood. A major development was the synthesis of PEG-liposomes with a prolonged circulation time in the blood. Active targeting of immunoliposomes to the solid tumor tissue can be achieved by the Fab' fragment which is better than whole IgG in terms of designing PEG-immunoliposomes with prolonged circulation. For intracellular targeting delivery to solid tumors based on EPR effects, transferrin-PEG-liposomes can stay in blood circulation for a long time and extravasate into the extravascular of tumor tissue by the EPR effect as PEG-liposomes. The extravasated transferrin-PEG-liposomes can maintain anti cancer drugs in interstitial space for a longer period, and deliver them into the cytoplasm of tumor cells via transferrin receptor-mediated endocytosis. Transferrin-PEG-liposomes improve the safety and efficacy of anti cancer drug by both passive targeting by prolonged circulation and active targeting by transferrin.

  12. Transient Mild Hyperthermia Induces E-selectin Mediated Localization of Mesoporous Silicon Vectors in Solid Tumors

    PubMed Central

    Kirui, Dickson K.; Mai, Juahua; Palange, Anna-Lisa; Qin, Guoting; van de Ven, Anne L.; Liu, Xuewu; Shen, Haifa; Ferrari, Mauro

    2014-01-01

    Background Hyperthermia treatment has been explored as a strategy to overcome biological barriers that hinder effective drug delivery in solid tumors. Most studies have used mild hyperthermia treatment (MHT) to target the delivery of thermo-sensitive liposomes carriers. Others have studied its application to permeabilize tumor vessels and improve tumor interstitial transport. However, the role of MHT in altering tumor vessel interfacial and adhesion properties and its relationship to improved delivery has not been established. In the present study, we evaluated effects of MHT treatment on tumor vessel flow dynamics and expression of adhesion molecules and assessed enhancement in particle localization using mesoporous silicon vectors (MSVs). We also determined the optimal time window at which maximal accumulation occur. Results In this study, using intravital microscopy analyses, we showed that temporal mild hyperthermia (∼1 W/cm2) amplified delivery and accumulation of MSVs in orthotopic breast cancer tumors. The number of discoidal MSVs (1000×400 nm) adhering to tumor vasculature increased 6-fold for SUM159 tumors and 3-fold for MCF-7 breast cancer tumors. By flow chamber experiments and Western blotting, we established that a temporal increase in E-selectin expression correlated with enhanced particle accumulation. Furthermore, MHT treatment was shown to increase tumor perfusion in a time-dependent fashion. Conclusions Our findings reveal that well-timed mild hyperthermia treatment can transiently elevate tumor transport and alter vascular adhesion properties and thereby provides a means to enhance tumor localization of non-thermally sensitive particles such as MSVs. Such enhancement in accumulation could be leveraged to increase therapeutic efficacy and reduce drug dosing in cancer therapy. PMID:24558362

  13. CAR T-cell intrinsic PD-1 checkpoint blockade: A two-in-one approach for solid tumor immunotherapy.

    PubMed

    Chen, Nan; Morello, Aurore; Tano, Zachary; Adusumilli, Prasad S

    2017-01-01

    PD-L1/2 expression in solid tumors inhibits chimeric antigen receptor (CAR) T-cell efficacy. A PD-1 dominant negative receptor expressed in CAR T cells provides cell-intrinsic checkpoint blockade and augments antitumor efficacy. A combinatorial immunotherapeutic strategy of combining CAR T cells with checkpoint blockade is a promising treatment approach for solid tumors.

  14. Identification of recurrent regulated alternative splicing events across human solid tumors

    PubMed Central

    Danan-Gotthold, Miri; Golan-Gerstl, Regina; Eisenberg, Eli; Meir, Keren; Karni, Rotem; Levanon, Erez Y.

    2015-01-01

    Cancer is a complex disease that involves aberrant gene expression regulation. Discriminating the modified expression patterns driving tumor biology from the many that have no or little contribution is important for understanding cancer molecular basis. Recurrent deregulation patterns observed in multiple cancer types are enriched for such driver events. Here, we studied splicing alterations in hundreds of matched tumor and normal RNA-seq samples of eight solid cancer types. We found hundreds of cassette exons for which splicing was altered in multiple cancer types and identified a set of highly frequent altered splicing events. Specific splicing regulators, including RBFOX2, MBNL1/2 and QKI, appear to account for many splicing alteration events in multiple cancer types. Together, our results provide a first global analysis of regulated splicing alterations in cancer and identify common events with a potential causative role in solid tumor development. PMID:25908786

  15. [Molecular detection of minimal residual disease in melanoma and solid tumors].

    PubMed

    Vázquez, Valeria; Otero, Laura L; Laurent, Viviana E; Gabri, Mariano R; Gómez, Daniel E; Alonso, Daniel F

    2009-01-01

    The availability of highly sensitive and specific methods for the detection of minimal residual disease in patients with solid tumors may have important prognostic and therapeutic implications. One of the most widely used methods for the molecular detection of cancer cells is the RT-PCR technique, which leads to the amplification of tissue-specific mRNA. It was firstly applied in the detection of circulating tumor cells in peripheral blood of patients with advanced melanoma; and soon it was adapted for the detection of minimal residual disease in other solid tumors. The aim of the present review is to evaluate the published data since the first study in 1991 and to analyze the clinical value of the findings obtained. The importance of sample handling and standardization of RT-PCR procedures is also discussed.

  16. Hydrodynamic Tail Vein Injection as a Simple Tool for Yielding Extended Transgene Expression in Solid Tumors.

    PubMed

    Takayama, Takuma; Ukawa, Masami; Kanazawa, Yuki; Ando, Hidenori; Shimizu, Taro; Ishida, Tatsuhiro

    2016-01-01

    Hydrodynamic tail vein injection was considered an in vivo transfection method that yields a higher level of gene expression mainly in the liver. This method has been applied to cancer gene therapy targeting both hepatic and non-hepatic cancers. However, intratumor transgene expression in non-hepatic tumors has not been well studied. In this study, we showed an extended transgene expression of β-galactosidase (LacZ), a nonsecretory protein, in a subcutaneously implanted murine solid tumor following the hydrodynamic injection of plasmid DNA (LacZ pDNA). Our result may indicate that the hydrodynamic injection method is a powerful tool that can be used to gain transgene expression not only in the liver but also in solid tumors.

  17. Use of Cancer-Specific Genomic Rearrangements to Quantify Disease Burden in Plasma from Patients with Solid Tumors

    PubMed Central

    McBride, David J.; Orpana, Arto K.; Sotiriou, Christos; Joensuu, Heikki; Stephens, Philip J.; Mudie, Laura J.; Hämälaïnen, Eija; Stebbings, Lucy A.; Andersson, Leif C.; Flanagan, Adrienne M.; Durbecq, Virginie; Ignatiadis, Michail; Kallioniemi, Olli; Heckman, Caroline A.; Alitalo, Kari; Edgren, Henrik; Futreal, P. Andrew; Stratton, Michael R.; Campbell, Peter J.

    2011-01-01

    Detection of recurrent somatic rearrangements routinely allows monitoring of residual disease burden in leukemias, but is not used for most solid tumors. However, next-generation sequencing now allows rapid identification of patient-specific rearrangements in solid tumors. We mapped genomic rearrangements in three cancers and showed that PCR assays for rearrangements could detect a single copy of the tumor genome in plasma without false positives. Disease status, drug responsiveness, and incipient relapse could be serially assessed. In future, this strategy could be readily established in diagnostic laboratories, with major impact on monitoring of disease status and personalizing treatment of solid tumors. PMID:20725990

  18. Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors.

    PubMed

    McBride, David J; Orpana, Arto K; Sotiriou, Christos; Joensuu, Heikki; Stephens, Philip J; Mudie, Laura J; Hämäläinen, Eija; Stebbings, Lucy A; Andersson, Leif C; Flanagan, Adrienne M; Durbecq, Virginie; Ignatiadis, Michail; Kallioniemi, Olli; Heckman, Caroline A; Alitalo, Kari; Edgren, Henrik; Futreal, P Andrew; Stratton, Michael R; Campbell, Peter J

    2010-11-01

    Detection of recurrent somatic rearrangements routinely allows monitoring of residual disease burden in leukemias, but is not used for most solid tumors. However, next-generation sequencing now allows rapid identification of patient-specific rearrangements in solid tumors. We mapped genomic rearrangements in three cancers and showed that PCR assays for rearrangements could detect a single copy of the tumor genome in plasma without false positives. Disease status, drug responsiveness, and incipient relapse could be serially assessed. In future, this strategy could be readily established in diagnostic laboratories, with major impact on monitoring of disease status and personalizing treatment of solid tumors.

  19. Targeting cancer stem cells in solid tumors by vitamin D

    PubMed Central

    Jae Young, So; Nanjoo, Suh

    2014-01-01

    Cancer stem cells (CSCs) are a small subset of cells that may be responsible for initiation, progression and recurrence of tumors. Recent studies have demonstrated that CSCs are highly tumorigenic and resistant to conventional chemotherapies, making them a promising target for the development of preventive/therapeutic agents. A single or combination of various markers, such as CD44, EpCAM, CD49f, CD133, CXCR4, ALDH-1 and CD24, were utilized to isolate CSCs fromvarious types of human cancers. Notch, Hedgehog, Wnt, and TGF-β signalingregulate self-renewal and differentiation of normal stem cells andare aberrantly activated in CSCs. In addition, many studies have demonstrated that these stem cell-associated signaling pathways are required for the maintenance of CSCs in differentmalignancies, including breast, colorectal, prostate and pancreatic cancers. Accumulating evidence hasshowninhibitory effects of vitamin D and its analogs on the cancer stem cell signaling pathways, suggesting vitamin D as a potential preventive/therapeutic agent against CSCs.In this review, we summarize recent findings about the roles of Notch, Hedgehog, Wnt, and TGF-β signaling in CSCs as well as the effects of vitamin D on these stem cell signaling pathways. PMID:25460302

  20. 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.

  1. Theranostic Nanoseeds for Efficacious Internal Radiation Therapy of Unresectable Solid Tumors

    PubMed Central

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

    2016-01-01

    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. PMID:26852805

  2. Innovative delivery of siRNA to solid tumors by super carbonate apatite.

    PubMed

    Wu, Xin; Yamamoto, Hirofumi; Nakanishi, Hiroyuki; Yamamoto, Yuki; Inoue, Akira; Tei, Mitsuyoshi; Hirose, Hajime; Uemura, Mamoru; Nishimura, Junichi; Hata, Taishi; Takemasa, Ichiro; Mizushima, Tsunekazu; Hossain, Sharif; Akaike, Toshihiro; Matsuura, Nariaki; Doki, Yuichiro; Mori, Masaki

    2015-01-01

    RNA interference (RNAi) technology is currently being tested in clinical trials for a limited number of diseases. However, systemic delivery of small interfering RNA (siRNA) to solid tumors has not yet been achieved in clinics. Here, we introduce an in vivo pH-sensitive delivery system for siRNA using super carbonate apatite (sCA) nanoparticles, which is the smallest class of nanocarrier. These carriers consist simply of inorganic ions and accumulate specifically in tumors, yet they cause no serious adverse events in mice and monkeys. Intravenously administered sCA-siRNA abundantly accumulated in the cytoplasm of tumor cells at 4 h, indicating quick achievement of endosomal escape. sCA-survivin-siRNA induced apoptosis in HT29 tumors and significantly inhibited in vivo tumor growth of HCT116, to a greater extent than two other in vivo delivery reagents. With innovative in vivo delivery efficiency, sCA could be a useful nanoparticle for the therapy of solid tumors.

  3. Phase I study of a systemically delivered p53 nanoparticle in advanced solid tumors.

    PubMed

    Senzer, Neil; Nemunaitis, John; Nemunaitis, Derek; Bedell, Cynthia; Edelman, Gerald; Barve, Minal; Nunan, Robert; Pirollo, Kathleen F; Rait, Antonina; Chang, Esther H

    2013-05-01

    Selective delivery of therapeutic molecules to primary and metastatic tumors is optimal for effective cancer therapy. A liposomal nanodelivery complex (scL) for systemic, tumor-targeting delivery of anticancer therapeutics has been developed. scL employs an anti-transferrin receptor (TfR), scFv as the targeting molecule. Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, is present in most human cancers. Rather than being transiently permissive for tumor initiation, persistence of p53 dysfunction is a continuing requirement for maintaining tumor growth. Herein, we report results of a first-in-man Phase I clinical trial of restoration of the normal human tumor suppressor gene p53 using the scL nanocomplex (SGT-53). Minimal side effects were observed in this trial in patients with advanced solid tumors. Furthermore, the majority of patients demonstrated stable disease. One patient with adenoid cystic carcinoma had his status changed from unresectable to resectable after one treatment cycle. More significantly, we observed an accumulation of the transgene in metastatic tumors, but not in normal skin tissue, in a dose-related manner. These results show not only that systemically delivered SGT-53 is well tolerated and exhibits anticancer activity, but also supply evidence of targeted tumor delivery of SGT-53 to metastatic lesions.

  4. Immunohistochemistry as potential diagnostic pitfall in the most common solid tumors of children and adolescents.

    PubMed

    Magro, Gaetano; Longo, Francesca Romana; Angelico, Giuseppe; Spadola, Saveria; Amore, Flavia Francesca; Salvatorelli, Lucia

    2015-01-01

    Making a correct diagnosis when dealing with a small round blue cell tumor (SRBCT) of children and adolescents may be relatively straightforward if the tumor arises in the typical clinical setting and the classic pathologic features are all recognizable. However it is widely known that diagnostic difficulties may arise because of: (i) many tumors share overlapping morphological and/or immunohistochemical features; (ii) considerable clinical, pathologic, and immunohistochemical variations do exist; (iii) the increasing use of small biopsies in daily practice makes the diagnosis of these neoplasms more challenging. Accordingly, immunohistochemical analyses are currently mandatory in establishing the correct diagnosis. In this regard there is the need to identify more sensitive and specific immunomarkers useful in the distinction of the several tumor entities. Over the last decades, several markers, such as CD99, WT1 protein, desmin, myogenin, NB84, and INI1 have been identified, providing a considerable help in recognition of the most common solid tumors (ESW/pPNET, rhabdomyosarcoma, neuroblastoma, Wilms' tumor, desmoplastic small round cell tumor; malignant rhabdoid tumor) in children and adolescents. However, at the same time, their unusual, unexpected expression can result in a misinterpretation of the immunohistochemical results, especially by pathologists who are not familiar with oncologic pediatric pathology. Therefore the present review focuses on the potential immunohistochemical pitfalls which should be kept in mind by pathologists to prevent diagnostic errors when dealing with SRBCTs.

  5. Phase I Study of a Systemically Delivered p53 Nanoparticle in Advanced Solid Tumors

    PubMed Central

    Senzer, Neil; Nemunaitis, John; Nemunaitis, Derek; Bedell, Cynthia; Edelman, Gerald; Barve, Minal; Nunan, Robert; Pirollo, Kathleen F; Rait, Antonina; Chang, Esther H

    2013-01-01

    Selective delivery of therapeutic molecules to primary and metastatic tumors is optimal for effective cancer therapy. A liposomal nanodelivery complex (scL) for systemic, tumor-targeting delivery of anticancer therapeutics has been developed. scL employs an anti-transferrin receptor (TfR), scFv as the targeting molecule. Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, is present in most human cancers. Rather than being transiently permissive for tumor initiation, persistence of p53 dysfunction is a continuing requirement for maintaining tumor growth. Herein, we report results of a first-in-man Phase I clinical trial of restoration of the normal human tumor suppressor gene p53 using the scL nanocomplex (SGT-53). Minimal side effects were observed in this trial in patients with advanced solid tumors. Furthermore, the majority of patients demonstrated stable disease. One patient with adenoid cystic carcinoma had his status changed from unresectable to resectable after one treatment cycle. More significantly, we observed an accumulation of the transgene in metastatic tumors, but not in normal skin tissue, in a dose-related manner. These results show not only that systemically delivered SGT-53 is well tolerated and exhibits anticancer activity, but also supply evidence of targeted tumor delivery of SGT-53 to metastatic lesions. PMID:23609015

  6. Pediatric Adrenocortical Tumors: What They Can Tell Us on Adrenal Development and Comparison with Adult Adrenal Tumors

    PubMed Central

    Lalli, Enzo; Figueiredo, Bonald C.

    2015-01-01

    Adrenocortical tumors (ACT) in children are very rare and are most frequently diagnosed in the context of the Li-Fraumeni syndrome, a multiple cancer syndrome linked to germline mutations of the tumor suppressor gene TP53 with loss of heterozygosity in the tumors. A peak of children ACT incidence is present in the states of southern Brazil, where they are linked to the high prevalence in the population of a specific TP53 mutation (R337H). Children ACT have specific features distinguishing them from adult tumors in their pathogenetic mechanisms, genomic profiles, and prognosis. Epidemiological and molecular evidence suggests that in most cases they are derived from the fetal adrenal. PMID:25741319

  7. Wildtype adult stem cells, unlike tumor cells, are resistant to cellular damages in Drosophila.

    PubMed

    Ma, Meifang; Zhao, Hang; Zhao, Hanfei; Binari, Richard; Perrimon, Norbert; Li, Zhouhua

    2016-03-15

    Adult stem cells or residential progenitor cells are critical to maintain the structure and function of adult tissues (homeostasis) throughout the lifetime of an individual. Mis-regulation of stem cell proliferation and differentiation often leads to diseases including cancer, however, how wildtype adult stem cells and cancer cells respond to cellular damages remains unclear. We find that in the adult Drosophila midgut, intestinal stem cells (ISCs), unlike tumor intestinal cells, are resistant to various cellular damages. Tumor intestinal cells, unlike wildtype ISCs, are easily eliminated by apoptosis. Further, their proliferation is inhibited upon autophagy induction, and autophagy-mediated tumor inhibition is independent of caspase-dependent apoptosis. Interestingly, inhibition of tumorigenesis by autophagy is likely through the sequestration and degradation of mitochondria, as compromising mitochondria activity in these tumor models mimics the induction of autophagy and increasing the production of mitochondria alleviates the tumor-suppression capacity of autophagy. Together, these data demonstrate that wildtype adult stem cells and tumor cells show dramatic differences in sensitivity to cellular damages, thus providing potential therapeutic implications targeting tumorigenesis.

  8. Effect of microvascular distribution and its density on interstitial fluid pressure in solid tumors: A computational model.

    PubMed

    Mohammadi, M; Chen, P

    2015-09-01

    Solid tumors with different microvascular densities (MVD) have been shown to have different outcomes in clinical studies. Other studies have demonstrated the significant correlation between high MVD, elevated interstitial fluid pressure (IFP) and metastasis in cancers. Elevated IFP in solid tumors prevents drug macromolecules reaching most cancerous cells. To overcome this barrier, antiangiogenesis drugs can reduce MVD within the tumor and lower IFP. A quantitative approach is essential to compute how much reduction in MVD is required for a specific tumor to reach a desired amount of IFP for drug delivery purposes. Here we provide a computational framework to investigate how IFP is affected by the tumor size, the MVD, and location of vessels within the tumor. A general physiologically relevant tumor type with a heterogenous vascular structure surrounded by normal tissue is utilized. Then the continuity equation, Darcy's law, and Starling's equation are applied in the continuum mechanics model, which can calculate IFP for different cases of solid tumors. High MVD causes IFP elevation in solid tumors, and IFP distribution correlates with microvascular distribution within tumor tissue. However, for tumors with constant MVD but different microvascular structures, the average values of IFP were found to be the same. Moreover, for a constant MVD and vascular distribution, an increase in tumor size leads to increased IFP.

  9. Solid pseudopapillary tumor of pancreas: A lesser known entity-diagnosis and pitfalls: A case report

    PubMed Central

    Singh, Anshu; Mohan, Gyanendra; Chaturvedi, Sunanda; Sarangi, Lalatendu

    2016-01-01

    Solid pseudopapillary tumor (SPT) is a rare pancreatic neoplasm with a reported incidence of 0.1% to 2.7% of all pancreatic tumors. Because radiological presentation of pancreatic tumors is quite overlapping, distinctive features in fine needle aspiration cytology (FNAC) helps in its diagnosis preoperatively. Being a low-grade malignancy presenting predominantly in young females, correct preoperative diagnosis minimizes the need of extensive surgery. SPT carries good prognosis without any adjuvant chemotherapy/radiotherapy in most cases, even in the presence of metastatic disease. On the other hand, aggressive surgical resection is required for ductal adenocarcinoma which is more common pancreatic tumor (90%). We report here a case of a 49-year-old female diagnosed as SPT. The importance of the need for the radiologist, pathologist, and surgeon to be familiar with SPT is highlighted so that it is more often diagnosed as there are significant therapeutic and prognostic implications. PMID:28028341

  10. Improved tumor targeting and antitumor activity of camptothecin loaded solid lipid nanoparticles by preinjection of blank solid lipid nanoparticles.

    PubMed

    Jang, Dong-Jin; Moon, Cheol; Oh, Euichaul

    2016-05-01

    This study aimed to enhance the in vivo antitumor effects of camptothecin (CPT), a strong antitumor agent whose delivery is limited by poor aqueous solubility and instability of the active lactone form. CPT was loaded into sterically stabilized, solid lipid nanoparticles (CPT-SLNs) formulated for intravenous administration. The influence of preinjected blank SLNs on the tumor targeting, pharmacokinetics and antitumor activity of CPT-SLNs was investigated. The CPT-SLNs composed of trilaurin-based lipid matrix containing poloxamer188 and pegylated phospholipid as stabilizers were prepared by hot homogenization method and evaluated for in vitro characteristics and in vivo performance. The CPT-SLNs showed an in vitro long-term sustained release pattern and effectively protected the CPT lactone form from hydrolysis under physiological conditions. Notable tumor targeting and tumor growth inhibition were observed after intravenous administration of CPT-SLNs to mice with subcutaneous transplants of CT26 carcinoma cells. In pharmacokinetic studies in rats, CPT-SLNs markedly elevated plasma CPT level and prolonged blood circulation compared to free CPT. Nonetheless, high uptake of CPT-SLNs by reticuloendothelial system (RES)-rich tissues resulted in limited tumor targeting of CPT-SLNs and plasma CPT levels. Preinjection of blank SLNs before administration of CPT-SLNs to tumor-bearing mice substantially reduced the accumulation of CPT-SLNs in RES organs. This led to significantly enhanced tumor targeting, improved pharmacokinetic parameters and increased antitumor efficacy of CPT-SLNs. These results suggested that the in vivo antitumor effects of CPT-SLNs could be further enhanced by preinjection of blank SLNs. Therefore, CPT-SLNs with preinjected blank SLNs could be a potential approach for stable and effective CPT-based cancer therapy.

  11. Early treatment with metformin induces resistance against tumor growth in adult rats.

    PubMed

    Trombini, Amanda B; Franco, Claudinéia Cs; Miranda, Rosiane A; de Oliveira, Júlio C; Barella, Luiz F; Prates, Kelly V; de Souza, Aline A; Pavanello, Audrei; Malta, Ananda; Almeida, Douglas L; Tófolo, Laize P; Rigo, Kesia P; Ribeiro, Tatiane As; Fabricio, Gabriel S; de Sant'Anna, Juliane R; Castro-Prado, Marialba Aa; de Souza, Helenir Medri; de Morais, Hely; Mathias, Paulo Cf

    2015-01-01

    It is known that antidiabetic drug metformin, which is used worldwide, has anti-cancer effects and can be used to prevent cancer growth. We tested the hypothesis that tumor cell growth can be inhibited by early treatment with metformin. For this purpose, adult rats chronically treated with metformin in adolescence or in adulthood were inoculated with Walker 256 carcinoma cells. Adult rats that were treated with metformin during adolescence presented inhibition of tumor growth, and animals that were treated during adult life did not demonstrate any changes in tumor growth. Although we do not have data to disclose a molecular mechanism to the preventive metformin effect, we present, for the first time, results showing that cancer growth in adult life is dependent on early life intervention, thus supporting a new therapeutic prevention for cancer.

  12. Loss of heterozygosity and SOSTDC1 in adult and pediatric renal tumors

    PubMed Central

    2010-01-01

    Background Deletions within the short arm of chromosome 7 are observed in approximately 25% of adult and 10% of Wilms pediatric renal tumors. Within Wilms tumors, the region of interest has been delineated to a 2-Mb minimal region that includes ten known genes. Two of these ten candidate genes, SOSTDC1 and MEOX2, are particularly relevant to tumor development and maintenance. This finding, coupled with evidence that SOSTDC1 is frequently downregulated in adult renal cancer and regulates both Wingless-Int (Wnt)- and bone morphogenetic protein (BMP)-induced signaling, points to a role for SOSTDC1 as a potential tumor suppressor. Methods To investigate this hypothesis, we interrogated the Oncomine database to examine the SOSTDC1 levels in adult renal clear cell tumors and pediatric Wilms tumors. We then performed single nucleotide polymorphism (SNP) and sequencing analyses of SOSTDC1 in 25 pediatric and 36 adult renal tumors. Immunohistochemical staining of patient samples was utilized to examine the impact of SOSTDC1 genetic aberrations on SOSTDC1 protein levels and signaling. Results Within the Oncomine database, we found that SOSTDC1 levels were reduced in adult renal clear cell tumors and pediatric Wilms tumors. Through SNP and sequencing analyses of 25 Wilms tumors, we identified four with loss of heterozygosity (LOH) at 7p and three that affected SOSTDC1. Of 36 adult renal cancers, we found five with LOH at 7p, two of which affected SOSTDC1. Immunohistochemical analysis of SOSTDC1 protein levels within these tumors did not reveal a relationship between these instances of SOSTDC1 LOH and SOSTDC1 protein levels. Moreover, we could not discern any impact of these genetic alterations on Wnt signaling as measured by altered beta-catenin levels or localization. Conclusions This study shows that genetic aberrations near SOSTDC1 are not uncommon in renal cancer, and occur in adult as well as pediatric renal tumors. These observations of SOSTDC1 LOH, however, did not

  13. Discovery of structural alterations in solid tumor oligodendroglioma by single molecule analysis

    PubMed Central

    2013-01-01

    Background Solid tumors present a panoply of genomic alterations, from single base changes to the gain or loss of entire chromosomes. Although aberrations at the two extremes of this spectrum are readily defined, comprehensive discernment of the complex and disperse mutational spectrum of cancer genomes remains a significant challenge for current genome analysis platforms. In this context, high throughput, single molecule platforms like Optical Mapping offer a unique perspective. Results Using measurements from large ensembles of individual DNA molecules, we have discovered genomic structural alterations in the solid tumor oligodendroglioma. Over a thousand structural variants were identified in each tumor sample, without any prior hypotheses, and often in genomic regions deemed intractable by other technologies. These findings were then validated by comprehensive comparisons to variants reported in external and internal databases, and by selected experimental corroborations. Alterations range in size from under 5 kb to hundreds of kilobases, and comprise insertions, deletions, inversions and compound events. Candidate mutations were scored at sub-genic resolution and unambiguously reveal structural details at aberrant loci. Conclusions The Optical Mapping system provides a rich description of the complex genomes of solid tumors, including sequence level aberrations, structural alterations and copy number variants that power generation of functional hypotheses for oligodendroglioma genetics. PMID:23885787

  14. Solid pseudopapillary tumor: an invasive case report of primary ovarian origin and review of the literature

    PubMed Central

    He, Shuqian; Yang, Xiaoqing; Zhou, Ping; Cheng, Yuxia; Sun, Qing

    2015-01-01

    Solid pseudopapillary neoplasm occurring as a primary tumor outside the pancreas is a rare event. We report a case of an ovarian primary occurring with an ill-defined cystic mass in a 39-year-old woman. The morphologic and immunohistochemical features of the ovarian neoplasm described in this report are compatible with those of solid pseudopapillary neoplasm of the pancreas. Histologically, the tumor cells of the case we report infiltrate into the ovarian parenchyma. Because of the diagnosis is not clear before surgery, the patient had a reoccurrence two months after the operation in which laparoscopic simple ovarian cystectomy and part ovarian tissue removal, followed by the right salpingo-oophorectomy. The case herein confirms that solid pseudopapillary neoplasm of the ovary belongs to the class of low-grade malignant tumor with certain invasiveness. The diagnosis should be taken into serious consideration in order to avoid missed diagnosis and delay treatment. Through this case we have a better understanding of the biological behavior of solid pseudopapillary neoplasm of the ovary. PMID:26339451

  15. Epidemiology of Brain Tumors.

    PubMed

    McNeill, Katharine A

    2016-11-01

    Brain tumors are the commonest solid tumor in children, leading to significant cancer-related mortality. Several hereditary syndromes associated with brain tumors are nonfamilial. Ionizing radiation is a well-recognized risk factor for brain tumors. Several industrial exposures have been evaluated for a causal association with brain tumor formation but the results are inconclusive. A casual association between the common mutagens of tobacco, alcohol, or dietary factors has not yet been established. There is no clear evidence that the incidence of brain tumors has changed over time. This article presents the descriptive epidemiology of the commonest brain tumors of children and adults.

  16. Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors

    PubMed Central

    Fox, Alan J.; Hiemenz, Matthew C.; Lieberman, David B.; Sukhadia, Shrey; Li, Barnett; Grubb, Joseph; Candrea, Patrick; Ganapathy, Karthik; Zhao, Jianhua; Roth, David; Alley, Evan; Loren, Alison; Morrissette, Jennifer J. D.

    2016-01-01

    As our understanding of the driver mutations necessary for initiation and progression of cancers improves, we gain critical information on how specific molecular profiles of a tumor may predict responsiveness to therapeutic agents or provide knowledge about prognosis. At our institution a tumor genotyping program was established as part of routine clinical care, screening both hematologic and solid tumors for a wide spectrum of mutations using two next-generation sequencing (NGS) panels: a custom, 33 gene hematological malignancies panel for use with peripheral blood and bone marrow, and a commercially produced solid tumor panel for use with formalin-fixed paraffin-embedded tissue that targets 47 genes commonly mutated in cancer. Our workflow includes a pathologist review of the biopsy to ensure there is adequate amount of tumor for the assay followed by customized DNA extraction is performed on the specimen. Quality control of the specimen includes steps for quantity, quality and integrity and only after the extracted DNA passes these metrics an amplicon library is generated and sequenced. The resulting data is analyzed through an in-house bioinformatics pipeline and the variants are reviewed and interpreted for pathogenicity. Here we provide a snapshot of the utility of each panel using two clinical cases to provide insight into how a well-designed NGS workflow can contribute to optimizing clinical outcomes. PMID:27684276

  17. A cellular automata model for avascular solid tumor growth under the effect of therapy

    NASA Astrophysics Data System (ADS)

    Reis, E. A.; Santos, L. B. L.; Pinho, S. T. R.

    2009-04-01

    Tumor growth has long been a target of investigation within the context of mathematical and computer modeling. The objective of this study is to propose and analyze a two-dimensional stochastic cellular automata model to describe avascular solid tumor growth, taking into account both the competition between cancer cells and normal cells for nutrients and/or space and a time-dependent proliferation of cancer cells. Gompertzian growth, characteristic of some tumors, is described and some of the features of the time-spatial pattern of solid tumors, such as compact morphology with irregular borders, are captured. The parameter space is studied in order to analyze the occurrence of necrosis and the response to therapy. Our findings suggest that transitions exist between necrotic and non-necrotic phases (no-therapy cases), and between the states of cure and non-cure (therapy cases). To analyze cure, the control and order parameters are, respectively, the highest probability of cancer cell proliferation and the probability of the therapeutic effect on cancer cells. With respect to patterns, it is possible to observe the inner necrotic core and the effect of the therapy destroying the tumor from its outer borders inwards.

  18. Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors.

    PubMed

    Fox, Alan J; Hiemenz, Matthew C; Lieberman, David B; Sukhadia, Shrey; Li, Barnett; Grubb, Joseph; Candrea, Patrick; Ganapathy, Karthik; Zhao, Jianhua; Roth, David; Alley, Evan; Loren, Alison; Morrissette, Jennifer J D

    2016-09-20

    As our understanding of the driver mutations necessary for initiation and progression of cancers improves, we gain critical information on how specific molecular profiles of a tumor may predict responsiveness to therapeutic agents or provide knowledge about prognosis. At our institution a tumor genotyping program was established as part of routine clinical care, screening both hematologic and solid tumors for a wide spectrum of mutations using two next-generation sequencing (NGS) panels: a custom, 33 gene hematological malignancies panel for use with peripheral blood and bone marrow, and a commercially produced solid tumor panel for use with formalin-fixed paraffin-embedded tissue that targets 47 genes commonly mutated in cancer. Our workflow includes a pathologist review of the biopsy to ensure there is adequate amount of tumor for the assay followed by customized DNA extraction is performed on the specimen. Quality control of the specimen includes steps for quantity, quality and integrity and only after the extracted DNA passes these metrics an amplicon library is generated and sequenced. The resulting data is analyzed through an in-house bioinformatics pipeline and the variants are reviewed and interpreted for pathogenicity. Here we provide a snapshot of the utility of each panel using two clinical cases to provide insight into how a well-designed NGS workflow can contribute to optimizing clinical outcomes.

  19. Low energy scatter due to in-situ irradiation of solid tumors in laboratory rats

    SciTech Connect

    Ritenour, E.R. Jr.

    1980-01-01

    A study of the pattern of scattered radiation in laboratory rat cadavers during irradiation of solid tumors on the animals' flanks was performed. The animals were wrapped in a lead shield having a circular cutout through which the tumor protruded. Irradiations were performed with a 250 kVp 15ma X-ray machine with a measured half value layer of 1.39 mmCu. Lead shielding was of sufficient thickness to attenuate essentially all of the beam. The absorbed dose measured in the animal was then due to internal scatter from the tumor. Arrays of thermoluminescent dosimeters (TLDs) were placed beneath the skin of 17 animals bearing a solid tumor (hepatoma H-4-II-E). Absorbed dose was seen to vary isotropically, decreasing as the inverse distance squared from the tumor. Analysis of experimental error played a major role in this study. A pilot study resulted in standard errors that were 35% of the mean absorbed dose measurements. A careful reassessment of methods of manipulating the animals and the dosimetry system resulted in a reduction in standard error to 14% of the mean for small groups (less than 10 animals).

  20. Solid pseudopapillary tumor of pancreas in a male child: a diagnosis by fine needle aspiration cytology.

    PubMed

    Nasit, Jitendra Gordhanbhai; Jetly, Dhaval; Shah, Manoj

    2013-07-01

    Solid pseudopapillary tumor (SPT) is an uncommon pancreatic neoplasm with low malignant potential. It occurs predominantly in young women. It is very rare in males and nonrelated pediatrics. In children, SPT commonly present as abdominal mass and pain. A 10-year-old male presented with progressively growing palpable tumor in upper abdomen. SPT of pancreas is diagnosed on preoperative fine needle aspiration cytology. This was subsequently confirmed by histopathology and immunohistochemistry. Due to rarity, SPT is not the first option to rule out, especially in children. Preoperative cytological diagnosis of SPT helps in management of this surgically curable neoplasm with good prognosis.

  1. Comparison of the EORTC criteria and PERCIST in solid tumors: a pooled analysis and review

    PubMed Central

    Kim, Jung Han

    2016-01-01

    Two sets of response criteria using PET are currently available to monitor metabolic changes in solid tumors: the criteria developed by the European Organization for Research and Treatment of Cancer (EORTC criteria) and the PET Response Criteria in Solid Tumors (PERCIST). We conducted this pooled study to investigate the strength of agreement between the EORTC criteria and PERCIST in the assessment of tumor response. We surveyed MEDLINE, EMBASE and PUBMED for articles with terms of the EORTC criteria and PERCIST between 2009 and January 2016. We searched for all the references of relevant articles and reviews using the ‘related articles’ feature in the PUBMED. There were six articles with the data on the comparison of the EORTC criteria and PERCIST. A total of 348 patients were collected; 190 (54.6%) with breast cancer, 81 with colorectal cancer, 45 with lung cancer, 14 with basal cell carcinoma in the skin, 12 with stomach cancer, and 6 with head and neck cancer. The agreement of tumor response between the EORTC criteria and PERCIST was excellent (k = 0.946). Of 348 patients, only 12 (3.4%) showed disagreement between the two criteria in the assessment of tumor response. The shift of tumor response between the EORTC criteria and PERCIST occurred mostly in patients with PMR and SMD. The estimated overall response rates were not significantly different between the two criteria (72.7% by EORTC vs. 73.6% by PERCIST). In conclusion, this pooled analysis demonstrates that the EORTC criteria and PERCIST showed almost perfect agreement in the assessment of tumor response. PMID:27517621

  2. Treatment of solid tumors by interstitial release of recoiling short-lived alpha emitters

    NASA Astrophysics Data System (ADS)

    Arazi, L.; Cooks, T.; Schmidt, M.; Keisari, Y.; Kelson, I.

    2007-08-01

    A new method utilizing alpha particles to treat solid tumors is presented. Tumors are treated with interstitial radioactive sources which continually release short-lived alpha emitting atoms from their surface. The atoms disperse inside the tumor, delivering a high dose through their alpha decays. We implement this scheme using thin wire sources impregnated with 224Ra, which release by recoil 220Rn, 216Po and 212Pb atoms. This work aims to demonstrate the feasibility of our method by measuring the activity patterns of the released radionuclides in experimental tumors. Sources carrying 224Ra activities in the range 10-130 kBq were used in experiments on murine squamous cell carcinoma tumors. These included gamma spectroscopy of the dissected tumors and major organs, Fuji-plate autoradiography of histological tumor sections and tissue damage detection by Hematoxylin-Eosin staining. The measurements focused on 212Pb and 212Bi. The 220Rn/216Po distribution was treated theoretically using a simple diffusion model. A simplified scheme was used to convert measured 212Pb activities to absorbed dose estimates. Both physical and histological measurements confirmed the formation of a 5-7 mm diameter necrotic region receiving a therapeutic alpha-particle dose around the source. The necrotic regions shape closely corresponded to the measured activity patterns. 212Pb was found to leave the tumor through the blood at a rate which decreased with tumor mass. Our results suggest that the proposed method, termed DART (diffusing alpha-emitters radiation therapy), may potentially be useful for the treatment of human patients.

  3. The long-term side effects of radiation therapy for benign brain tumors in adults

    SciTech Connect

    al-Mefty, O.; Kersh, J.E.; Routh, A.; Smith, R.R. )

    1990-10-01

    Radiation therapy plays an integral part in managing intracranial tumors. While the risk:benefit ratio is considered acceptable for treating malignant tumors, risks of long-term complications of radiotherapy need thorough assessment in adults treated for benign tumors. Many previously reported delayed complications of radiotherapy can be attributed to inappropriate treatment or to the sensitivity of a developing child's brain to radiation. Medical records, radiological studies, autopsy findings, and follow-up information were reviewed for 58 adult patients (31 men and 27 women) treated between 1958 and 1987 with radiotherapy for benign intracranial tumors. Patient ages at the time of irradiation ranged from 21 to 87 years (mean 47.7 years). The pathology included 46 pituitary adenomas, five meningiomas, four glomus jugulare tumors, two pineal area tumors, and one craniopharyngioma. Average radiation dosage was 4984 cGy (range 3100 to 7012 cGy), given in an average of 27.2 fractions (range 15 to 45 fractions), over a period averaging 46.6 days. The follow-up period ranged from 3 to 31 years (mean 8.1 years). Findings related to tumor recurrence or surgery were excluded. Twenty-two patients had complications considered to be delayed side effects of radiotherapy. Two patients had visual deterioration developing 3 and 6 years after treatment; six had pituitary dysfunction; and 17 had varying degrees of parenchymal changes of the brain, occurring mostly in the temporal lobes and relating to the frequent presentation of pituitary tumors. One clival tumor with the radiographic appearance of a meningioma, developed 30 years post-irradiation for acromegaly. This study unveils considerable delayed sequelae of radiotherapy in a series of adult patients receiving what is considered safe treatment for benign brain tumors. 163 refs.

  4. Antiproliferative activity of epi-cercosporin in human solid tumor cell lines.

    PubMed

    Trigos, Angel; Espinoza, César; Martínez, Maricela; Márquez, Olivia; León, Leticia G; Padrón, José M; Norted, Manuel; Fernández, José J

    2013-02-01

    From cultures of Cercospora piaropi, a phytopathogenic fungus isolated from symptomatic leaves of water hyacinth was obtained a red compound, which, according to the spectroscopic data, was epi-cercosporin. It showed in vitro antiproliferative activity against the panel of human solid tumor cells HBL-100, HeLa, SW1573 and WiDr. Cell cycle studies revealed that epi-cercosporin induces accumulation of cells in G2/M phase.

  5. Detection and Identification of Hematologic Malignancies and Solid Tumors by an Electrochemical Technique

    PubMed Central

    Zhang, Bowen; Zhang, Xiaoping; Wang, Xuemei; Cheng, Jian; Chen, Baoan

    2016-01-01

    Purpose Develop and evaluate an electrochemical method to identify healthy individuals, malignant hematopathic patients and solid tumor patients by detecting the leukocytes in whole-blood. Methods A total of 114 individual blood samples obtained from our affiliated hospital in China (June 2015- August 2015) were divided into three groups: healthy individuals (n = 35), hematologic malignancies (n = 41) and solid tumors (n = 38). An electrochemical workstation system was used to measure differential pulse voltammetry due to the different electrochemical behaviors of leukocytes in blood samples. Then, one-way analysis of variance (ANOVA) was applied to analyze the scanning curves and to compare the peak potential and peak current. Results The scanning curve demonstrated the specific electrochemical behaviors of the blank potassium ferricyanide solution and that mixed with blood samples in different groups. Significant differences in mean peak potentials of mixture and shifts (ΔEp (mV)) were observed of the three groups (P< = 0.001). 106.00±9.00 and 3.14±7.48 for Group healthy individuals, 120.90±11.18 and 18.10±8.81 for Group hematologic malignancies, 136.84±11.53 and 32.89±10.50 for Group solid tumors, respectively. In contrast, there were no significant differences in the peak currents and shifts. Conclusions The newly developed method to apply the electrochemical workstation system to identify hematologic malignancies and solid tumors with good sensitivity and specificity might be effective, suggesting a potential utility in clinical application. PMID:27115355

  6. Normal tissue and solid tumor effects of hyperthermia in animal models and clinical trials.

    PubMed

    Storm, F K; Harrison, W H; Elliott, R S; Morton, D L

    1979-06-01

    Localized hyperthermia therapy by high-energy radio-frequency waves was evaluated in malignant and adjacent normal tissue of 30 patients with 10 types of cancer. Hyperthermia was delivered to superficial and deep visceral cancers in awake patients who had refractory disease. Histological and clinical responses were recorded serially. Toxicity tests in dogs, sheep, and pigs showed that progressive necrosis of normal and cancer tissue occurred at temperatures above 45 degrees C (113 degrees F). However, as normal tissues approached this temperature, intrinsic heat dissipation occurred (possibly due to augmented blood flow) so that temperatures below 45 degrees C could be maintained, whereas most solid tumors did not have this adaptive capacity and could be heated to 50 degrees C (122 degrees F) with virtually no injury to normal organs, s.c. tissue, or skin. To date, 69 treatments have been administered to 36 tumors in the 30 patients. Selective heating was observed in both primary and metastatic tumors located in surface tissues and internal organs. Response appeared to be related to tumor size in that differential heating was possible more often in the larger lesions. In tumors successfully heated, moderate to marked necrosis occurred. Radio-frequency hyperthermia appears to be a safe and potentially useful form of therapy for selected cancer patients. While other cancer treatments are more effective for small tumors, hyperthermia may be uniquely beneficial against larger lesions.

  7. Photodynamic Nanomedicine in the Treatment of Solid Tumors: Perspectives and Challenges

    PubMed Central

    Master, Alyssa; Livingston, Megan; Gupta, Anirban Sen

    2013-01-01

    Photodynamic therapy (PDT) is a promising treatment strategy where activation of photosensitizer drugs with specific wavelengths of light results in energy transfer cascades that ultimately yield cytotoxic reactive oxygen species which can render apoptotic and necrotic cell death. Without light the photosensitizer drugs are minimally toxic and the photoactivating light itself is non-ionizing. Therefore, harnessing this mechanism in tumors provides a safe and novel way to selectively eradicate tumor with reduced systemic toxicity and side effects on healthy tissues. For successful PDT of solid tumors, it is necessary to ensure tumor-selective delivery of the photosensitizers, as well as, the photoactivating light and to establish dosimetric correlation of light and drug parameters to PDT-induced tumor response. To this end, the nanomedicine approach provides a promising way towards enhanced control of photosensitizer biodistribution and tumor-selective delivery. In addition, refinement of nanoparticle designs can also allow incorporation of imaging agents, light delivery components and dosimetric components. This review aims at describing the current state-of-the-art regarding nanomedicine strategies in PDT, with a comprehensive narrative of the research that has been carried out in vitro and in vivo, with a discussion of the nanoformulation design aspects and a perspective on the promise and challenges of PDT regarding successful translation into clinical application. PMID:23474028

  8. A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

    ClinicalTrials.gov

    2017-01-17

    Malignant Rhabdoid Tumors (MRT); Rhabdoid Tumors of the Kidney (RTK); Atypical Teratoid Rhabdoid Tumors (ATRT); Selected Tumors With Rhabdoid Features; Synovial Sarcoma; INI1-negative Tumors; Malignant Rhabdoid Tumor of Ovary; Renal Medullary Carcinoma; Epithelioid Sarcoma; Any Solid Tumor With an EZH2 GOF Mutation

  9. Induction of oncogene addiction shift to NF-{kappa}B by camptothecin in solid tumor cells

    SciTech Connect

    Togano, Tomiteru; Sasaki, Masataka; Watanabe, Mariko; Nakashima, Makoto; Tsuruo, Takashi; Umezawa, Kazuo; Higashihara, Masaaki; Watanabe, Toshiki; Horie, Ryouichi

    2009-12-04

    The biological basis of the resistance of solid tumor cells to chemotherapy is not well understood. While addressing this problem, we found that gastric cancer cell line St-4/CPT, lung cancer cell line A549/CPT, and colon cancer cell line HT-29/CPT, all of which are resistant to camptothecin (CPT), showed strong and constitutive nuclear factor (NF)-{kappa}B activity driven by I{kappa}B kinase compared with their parental cell lines St-4, A549, and HT-29. A new NF-{kappa}B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), reduced viability and induced apoptosis in St-4/CPT, A549/CPT, and HT-29/CPT cell lines, while their parental cell lines were resistant to DHMEQ. The results in this study present an example of the shift in signals that support the survival of solid tumor cells to NF-{kappa}B during the acquisition of resistance to CPT. The results also indicate that solid tumor cells that become resistant to chemotherapy may be more easily treated by NF-{kappa}B inhibitors.

  10. Solid variant of orbital angioleiomyoma: An unusual tumor at an unusual site

    PubMed Central

    Nair, Akshay Gopinathan; Jain, Vandana; Gopinathan, Indumati; Murthy, Anuradha

    2016-01-01

    We describe the clinicopathological features of a solid variant of orbital angioleiomyoma. A review of clinical records, diagnostic, and radiographic studies combined with histopathological evaluation with standard histochemical staining and immunohistochemistry was conducted. A 22-year-old male patient presented with a mass in the region of the left lacrimal gland that was gradually increasing over the past 2 years. Radiological and clinical examinations showed no signs suspicious of a malignancy and fine needle aspiration cytology was inconclusive. Therefore, an excision biopsy was performed. On histopathological examination, the picture was consistent with a benign spindle cell tumor. Immunohistochemistry showed positivity for CD 34 and CD 31 (markers for vascular endothelium). The tumor also showed positivity for smooth muscle actin and Ki-67 proliferative index was low. Angioleiomyomas are rarely encountered in the orbit and has features seen in leiomyoma as well as some vascular tumor elements. In most cases, surgical excision is usually curative. PMID:27488159

  11. Targeting solid tumors via T cell receptor complementarity-determining region 3delta in an engineered antibody.

    PubMed

    Wang, Zhun; Zhang, Tie; Hu, Hongbo; Zhang, Huiyuan; Yang, Zhi; Cui, Lianxian; He, Wei

    2008-12-18

    Human Vdelta2 gammadelta T lymphocytes killed multiple solid tumors, even displaying comparable therapeutic efficacy with anti-tumor chemical-cis-platinum in an adoptive experiment in both nude and SCID murine model shown in present study. We previously found that T cell receptor (TCR) gammadelta recognize tumors via complementarity-determining region 3 (CDR3), briefly named as CDR3delta. Based on characteristics of specific binding of CDR3delta to tumor targets, we developed a novel tumor-targeting antibody, whose CDR3 in heavy chain is replaced by CDR3delta sequence derived from human ovarian carcinoma (OEC) infiltrating gammadelta T cells (gammadeltaTILs). This CDR3delta-grafted antibody OT3 exhibited specific binding activities to OEC line SKOV3 both in vitro and in vivo, which included specific binding to several tumor cell lines, interacting with heat shock protein (HSP) 60 and triggering ADCC against tumors in vitro, as well as displaying tumor imaging by radioisotope 99mTc-labeled antibody OT3 in vivo. Moreover, immunotoxin OT3-DT, CDR3delta-grafted antibody OT3 chemically conjugated with diphtheria toxin (DT) showed the anti-tumor effect on the growth of several solid tumors including OEC, cervix adenocarcinoma, hepatocellular carcinoma, and rectum adenocarcinoma to various extents in nude mice. Therefore, we have found and confirmed a novel therapeutic strategy for targeting solid tumors, making use of immune recognition characteristics of gammadelta T cells.

  12. Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors

    PubMed Central

    Solakoglu, Oender; Maierhofer, Christine; Lahr, Georgia; Breit, Elisabeth; Scheunemann, Peter; Heumos, Isabella; Pichlmeier, Uwe; Schlimok, Günter; Oberneder, Ralph; Köllermann, Manfred W.; Köllermann, Jens; Speicher, Michael R.; Pantel, Klaus

    2002-01-01

    Bone marrow is a major homing site for circulating epithelial tumor cells. The present study was aimed to assess the proliferative capacity of occult metastatic cells in bone marrow of patients with operable solid tumors especially with regard to their clinical outcome. We obtained bone marrow aspirates from 153 patients with carcinomas of the prostate (n = 46), breast (n = 45), colon (n = 33), and kidney (n = 29). Most of the patients (87%) had primary disease with no clinical signs of overt metastases [tumor-node-metastasis (TNM)-stage UICC (Union Internationale Contre le Cancer) I-III]. After bone marrow was cultured for 21–102 days under special cell culture conditions, viable epithelial cells were detected by cytokeratin staining in 124 patients (81%). The cultured epithelial cells harbored Ki-ras2 mutations and numerical chromosomal aberrations. The highest median number of expanded tumor cells was observed in prostate cancer (2,619 per flask). There was a significant positive correlation between the number of expanded tumor cells and the UICC-stage of the patients (P = 0.03) or the presence of overt metastases (P = 0.04). Moreover, a strong expansion of tumor cells was correlated to an increased rate of cancer-related deaths (P = 0.007) and a reduced survival of the patients (P = 0.006). In conclusion, the majority of cancer patients have viable tumor cells in their bone marrow at primary tumor diagnosis, and the proliferative potential of these cells determines the clinical outcome. PMID:11854519

  13. Detection and specific targeting of hypoxic regions within solid tumors: current preclinical and clinical strategies.

    PubMed

    Bache, M; Kappler, M; Said, H M; Staab, A; Vordermark, D

    2008-01-01

    Poor oxygenation of solid tumors is a major indicator of adverse prognosis after standard treatment, e.g. radiotherapy. This observation founded on intratumoral pO(2) electrode measurements has been supported more recently by studies of injected hypoxia markers (pimonidazole, EF5) or hypoxia-related proteins (hypoxia-inducible factor-1alpha, carbonic anhydrase IX) detected immunohistochemically. Alternative approaches include imaging of tumor hypoxia by nuclear medicine studies and the measurement of hypoxia-related proteins (osteopontin) in patient plasma. Low oxygen levels as found in tumors are rarely observed in normal tissues. The presence of hypoxic tumor cells is therefore regarded not only as an adverse prognostic factor but as an opportunity for tumor-specific treatment. Classic approaches to normalize tumor oxygenation involve the breathing of modified gas mixtures and pharmacologic modification of blood flow as in the "accelerated radiotherapy, carbogen, nicotinamide" (ARCON) scheme. Specific killing of hypoxic tumor cells can potentially be achieved by hypoxia-selective cytotoxins (model substance tirapazamine), which has shown promise in head and neck cancer. Direct targeting of hypoxia-related molecules such as hypoxia-inducible factor-1alpha, the central regulator of the hypoxic response in tumor cells, is an attractive approach currently tested in preclinical models. For clinical applications, the appropriate combination of hypoxia detection for patient selection with a hypoxia-specific treatment is essential. A therapeutic benefit has been suggested for the selection of patients by plasma osteopontin level and treatment with the hypoxic radiosensitizer nimorazole in addition to radiotherapy, for selection by F-misonidazole positron-emission tomography (PET) and treatment with tirapazamine in addition to chemoradiation and for selection by pimonidazole immunohistochemistry and ARCON treatment, all in head and neck cancer.

  14. Intussusception secondary to a carcinoid tumor in an adult patient☆

    PubMed Central

    Wiener-Carrillo, Isidoro; González-Alvarado, Carlos; Cervantes-Valladolid, Mario; Echaverry-Navarrete, Denis; Zubieta-O’Farrill, Gregorio; Gudiño-Chávez, Andrés

    2014-01-01

    INTRODUCTION Intussusception in adult patients represents 5% of all intussusceptions and 1–5% of bowel obstructions in adults. In contrast to pediatric patients, 90% of the time, in adults, it's caused by well-established pathologic mechanisms, such as carcinoma, polyps, diverticula, Meckel diverticula, stenosis, or benign neoplasms. Small intestine intussusceptions are more frequent, but colonic intussusceptions are caused 50% of the time by malignant neoplasms, especially adenocarcinoma. PRESENTATION OF CASE We present a 70-year-old woman, with no relevant familial history, who presented with a 3-day symptomatology consisting of epigastric, colic, diffuse, abdominal pain of moderate intensity, which progressed till reaching a severe intensity, also referring abdominal distension, nausea, and gastrointestinal-content vomits. DISCUSSION In adult patients, the exact mechanism of intussusception is unknown in 8–20% of the cases, however, secondary intussusception can occur with any lesion of the intestinal wall or any irritant factor in its lumen that alters normal peristaltic activity and that could serve as a trigger to start an intussusception of one bowel segment over another the most common site is the small intestine. CONCLUSION Intussusception represents an unusual problem in adult patients; it requires a high clinical suspicion, mainly as a differential diagnosis in patients with intestinal obstruction, and it clinically presents as a subacute or chronic illness. CT represents the most useful diagnostic tool. An attempt to perform reduction procedures in small intestine intussusceptions can be done, however, in ileocolic or colonic intussusceptions, a formal resection of the segment is recommended. PMID:24727207

  15. Rationally Repurposing Ruxolitinib (Jakafi®) as a Solid Tumor Therapeutic

    PubMed Central

    Tavallai, Mehrad; Booth, Laurence; Roberts, Jane L.; Poklepovic, Andrew; Dent, Paul

    2016-01-01

    We determined whether the approved myelofibrosis drug ruxolitinib (Jakafi®), an inhibitor of Janus kinases 1/2 (JAK1 and JAK2), could be repurposed as an anti-cancer agent for solid tumors. Ruxolitinib synergistically interacted with dual ERBB1/2/4 inhibitors to kill breast as well as lung, ovarian and brain cancer cells. Knock down of JAK1/2 or of ERBB1/2/3/4 recapitulated on-target drug effects. The combination of (ruxolitinib + ERBB1/2/4 inhibitor) rapidly inactivated AKT, mTORC1, mTORC2, STAT3, and STAT5, and activated eIF2α. In parallel, the drug combination reduced expression of MCL-1, BCL-XL, HSP90, HSP70, and GRP78, and increased expression of Beclin1. Activated forms of STAT3, AKT, or mTOR prevented the drug-induced decline in BCL-XL, MCL-1, HSP90, and HSP70 levels. Over-expression of chaperones maintained AKT/mTOR activity in the presence of drugs and protected tumor cells from the drug combination. Expression of dominant negative eIF2α S51A prevented the increase in Beclin1 expression and protected tumor cells from the drug combination. Loss of mTOR activity was associated with increased ATG13 S318 phosphorylation and with autophagosome formation. Autophagosomes initially co-localized with mitochondria and subsequently with lysosomes. Knock down of Beclin1 suppressed: drug-induced mitophagy; the activation of the toxic BH3 domain proteins BAX and BAK; and tumor cell killing. Knock down of apoptosis-inducing factor (AIF) protected tumor cells from the drug combination, whereas blockade of caspase 9 signaling did not. The drug combination released AIF into the cytosol and increased nuclear AIF: eIF3A co-localization. A 4-day transient exposure of orthotopic tumors to (ruxolitinib + afatinib) profoundly reduced mammary tumor growth over the following 35 days. Re-grown tumors exhibited high levels of BAD S112 phosphorylation and activation of ERK1/2 and NFκB. Our data demonstrate that mitophagy is an essential component of (ruxolitinib

  16. Antitumor activity of tumor necrosis factor-alpha conjugated with polyvinylpyrrolidone on solid tumors in mice.

    PubMed

    Kamada, H; Tsutsumi, Y; Yamamoto, Y; Kihira, T; Kaneda, Y; Mu, Y; Kodaira, H; Tsunoda, S I; Nakagawa, S; Mayumi, T

    2000-11-15

    We attempted the development of a novel polymer conjugation to further improve the therapeutic potency of antitumor cytokines compared with PEGylation for clinical application. Compared with native tumor necrosis factor (TNF)-alpha in vitro, specific bioactivities of polyvinyl-pyrrolidone (PVP)-modified TNF-alphas (PVP-TNF-alphas) were decreased by increasing the degree of PVP attachment. PVP-TNF-alpha fraction 3, Mr 101,000, had the most effective antitumor activity of the various PVP-TNF-alphas in vivo. PVP-TNF-alpha fraction 3 had >200-fold higher antitumor effect than native TNF-alpha, and the antitumor activity of PVP-TNF-alpha fraction 3 was >2-fold higher than that of MPEG-TNF-alpha (Mr 108,000), which had the highest antitumor activity among the polyethylene glycol (PEG)-conjugated TNF-alphas. Additionally, a high dose of native TNF-alpha induced toxic side effects such as body weight reduction, piloerection. and tissue inflammation, whereas no side effects were observed after i.v. administration of PVP-TNF-alpha fraction 3. The plasma half-life of PVP-TNF-alpha fraction 3 (360 min) was about 80- and 3-fold longer than those of native TNF-alpha (4.6 mm) and MPEG-TNF-alpha (122 min), respectively. The mechanism of increased antitumor effect in vivo caused the prolongation of plasma half-life and increase in stability. These results suggested that PVP is a useful polymeric modifier for bioconjugation of TNF-alpha to increase its antitumor potency, and multifunctionally bioconjugated TNF-alpha may be a potentiated antitumor agent for clinical use.

  17. Tumor-targeted delivery of paclitaxel using low density lipoprotein-mimetic solid lipid nanoparticles.

    PubMed

    Kim, Jin-Ho; Kim, Youngwook; Bae, Ki Hyun; Park, Tae Gwan; Lee, Jung Hee; Park, Keunchil

    2015-04-06

    Water-insoluble anticancer drugs, including paclitaxel, present severe clinical side effects when administered to patients, primarily associated with the toxicity of reagents used to solubilize the drugs. In efforts to develop alternative formulations of water-insoluble anticancer drugs suitable for intravenous administration, we developed biocompatible anticancer therapeutic solid lipid nanoparticles (SLNs), mimicking the structure and composition of natural particles, low-density lipoproteins (LDLs), for tumor-targeted delivery of paclitaxel. These therapeutic nanoparticles contained water-insoluble paclitaxel in the core with tumor-targeting ligand covalently conjugated on the polyethylene glycol (PEG)-modified surface (targeted PtSLNs). In preclinical human cancer xenograft mouse model studies, the paclitaxel-containing tumor-targeting SLNs exhibited pronounced in vivo stability and enhanced biocompatibility. Furthermore, these SLNs had superior antitumor activity to in-class nanoparticular therapeutics in clinical use (Taxol and Genexol-PM) and yielded long-term complete responses. The in vivo targeted antitumor activities of the SLN formulations in a mouse tumor model suggest that LDL-mimetic SLN formulations can be utilized as a biocompatible, tumor-targeting platform for the delivery of various anticancer therapeutics.

  18. Separation of high and low metastatic subpopulations from solid tumors by centrifugal elutriation.

    PubMed

    Onoda, J M; Nelson, K K; Grossi, I M; Umbarger, L A; Taylor, J D; Honn, K V

    1988-02-01

    We have isolated from murine solid tumors (B16a) subpopulations of cells possessing high and low metastatic potential. Tumors were dispersed by collagenase treatment. The resulting heterogeneous population of cells (i.e., viable and non-viable tumor cells and host cells) were separated by centrifugal elutriation. Four of the fractions (100, 180, 260, 340) contained tumor cells of high viability (greater than 95%) and high purity (less than 1% host cell contamination). The four fractions were characterized by flow cytometry and found to differ in distribution of cells in G1, S and G2. The cell populations were also found to differ in metastatic potential as determined by their ability to form lung colonies following intravenous injection. The 340 fraction was approximately 5-fold more metastatic than the 100 fraction. We also observed that cells from the 100 fraction failed to induce platelet aggregation whereas cells from the 340 fraction induced significant platelet aggregation. These observations demonstrate that cells of B16a tumors are heterogeneous for phenotypic characteristics (i.e., metastatic potential; platelet aggregation, etc.) and that their ability to induce platelet aggregation is positively correlated with metastatic potential.

  19. [High-dose chemotherapy as a strategy to overcome drug resistance in solid tumors].

    PubMed

    Selle, Frédéric; Gligorov, Joseph; Soares, Daniele G; Lotz, Jean-Pierre

    2016-10-01

    The concept of high-doses chemotherapy was developed in the 1980s based on in vitro scientific observations. Exposure of tumor cells to increasing concentrations of alkylating agents resulted in increased cell death in a strong dose-response manner. Moreover, the acquired resistance of tumor cells could be overcome by dose intensification. In clinic, dose intensification of alkylating agents resulted in increased therapeutic responses, however associated with significant hematological toxicity. Following the development of autologous stem cells transplantation harvesting from peripheral blood, the high-doses of chemotherapy, initially associated with marked toxic effects, could be more easily tolerated. As a result, the approach was evaluated in different types of solid tumors, including breast, ovarian and germ cell tumors, small cell lung carcinoma, soft tissue sarcomas and Ewing sarcoma. To date, high-doses chemotherapy with hematopoietic stem cells support is only used as a salvage therapy to treat poor prognosis germ cell tumors patients with chemo-sensitive disease. Regarding breast and ovarian cancer, high-doses chemotherapy should be considered only in the context of clinical trials. However, intensive therapy as an approach to overcome resistance to standard treatments is still relevant. Numerous efforts are still ongoing to identify novel therapeutic combinations and active treatments to improve patients' responses.

  20. Chimeric antigen receptor T cells: a novel therapy for solid tumors.

    PubMed

    Yu, Shengnan; Li, Anping; Liu, Qian; Li, Tengfei; Yuan, Xun; Han, Xinwei; Wu, Kongming

    2017-03-29

    The chimeric antigen receptor T (CAR-T) cell therapy is a newly developed adoptive antitumor treatment. Theoretically, CAR-T cells can specifically localize and eliminate tumor cells by interacting with the tumor-associated antigens (TAAs) expressing on tumor cell surface. Current studies demonstrated that various TAAs could act as target antigens for CAR-T cells, for instance, the type III variant epidermal growth factor receptor (EGFRvIII) was considered as an ideal target for its aberrant expression on the cell surface of several tumor types. CAR-T cell therapy has achieved gratifying breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. The third generation of CAR-T demonstrates increased antitumor cytotoxicity and persistence through modification of CAR structure. In this review, we summarized the preclinical and clinical progress of CAR-T cells targeting EGFR, human epidermal growth factor receptor 2 (HER2), and mesothelin (MSLN), as well as the challenges for CAR-T cell therapy.

  1. Concurrent intrathecal methotrexate and liposomal cytarabine for leptomeningeal metastasis from solid tumors: a retrospective cohort study.

    PubMed

    Scott, Brian J; van Vugt, Vincent A; Rush, Toni; Brown, Tiffany; Chen, Clark C; Carter, Bob S; Schwab, Richard; Fanta, Paul; Helsten, Teresa; Bazhenova, Lyudmila; Parker, Barbara; Pingle, Sandeep; Saria, Marlon G; Brown, Bradley D; Piccioni, David E; Kesari, Santosh

    2014-09-01

    Leptomeningeal metastasis (LM) from solid tumors is typically a late manifestation of systemic cancer with limited survival. Randomized trials comparing single agent intrathecal methotrexate to liposomal cytarabine have shown similar efficacy and tolerability. We hypothesized that combination intrathecal chemotherapy would be a safe and tolerable option in solid tumor LM. We conducted a retrospective cohort study of combination IT chemotherapy in solid tumor LM at a single institution between April 2010 and July 2012. In addition to therapies directed at active systemic disease, each subject received IT liposomal cytarabine plus IT methotrexate with dexamethasone premedication. Patient characteristics, survival outcomes and toxicities were determined by systematic chart review. Thirty subjects were treated during the study period. The most common cancer types were breast 15 (50 %), glioblastoma 6 (20 %), and lung 5 (17 %). Cytologic clearance was achieved in 6 (33 %). Median non-glioblastoma overall survival was 30.2 weeks (n = 18; range 3.9-73.4), and did not differ significantly by tumor type. Median time to neurologic progression was 7 weeks (n = 8; range 0.9-57), with 10 subjects (56 %) experiencing death from systemic disease without progression of LM. Age less than 60 was associated with longer overall survival (p = 0.01). Six (21 %) experienced grade III toxicities during treatment, most commonly meningitis 2 (7 %). Combination IT chemotherapy was feasible in this small retrospective cohort. Prospective evaluation is necessary to determine tolerability, the impact on quality of life and neurocognitive outcomes or any survival benefit when compared to single agent IT chemotherapy.

  2. Efficacy of 68Ga-DOTATOC Positron Emission Tomography (PET) CT in Children and Young Adults With Brain Tumors

    ClinicalTrials.gov

    2016-09-07

    Acoustic Schwannoma; Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Tumor; Adult Craniopharyngioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade I Meningioma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Subependymal Giant Cell Astrocytoma; Adult Subependymoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Supratentorial Ependymoma; Meningeal Melanocytoma; Newly Diagnosed Childhood Ependymoma; Recurrent Adult Brain Tumor; Recurrent Childhood Anaplastic Astrocytoma; Recurrent Childhood Anaplastic Oligoastrocytoma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Diffuse Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Fibrillary Astrocytoma; Recurrent Childhood Gemistocytic Astrocytoma; Recurrent Childhood Giant Cell Glioblastoma; Recurrent Childhood Glioblastoma; Recurrent Childhood Gliomatosis Cerebri; Recurrent Childhood Gliosarcoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood

  3. Comparative methylome analysis in solid tumors reveals aberrant methylation at chromosome 6p in nasopharyngeal carcinoma

    PubMed Central

    Dai, Wei; Cheung, Arthur Kwok Leung; Ko, Josephine Mun Yee; Cheng, Yue; Zheng, Hong; Ngan, Roger Kai Cheong; Ng, Wai Tong; Lee, Anne Wing Mui; Yau, Chun Chung; Lee, Victor Ho Fu; Lung, Maria Li

    2015-01-01

    Altered patterns of DNA methylation are key features of cancer. Nasopharyngeal carcinoma (NPC) has the highest incidence in Southern China. Aberrant methylation at the promoter region of tumor suppressors is frequently reported in NPC; however, genome-wide methylation changes have not been comprehensively investigated. Therefore, we systematically analyzed methylome data in 25 primary NPC tumors and nontumor counterparts using a high-throughput approach with the Illumina HumanMethylation450 BeadChip. Comparatively, we examined the methylome data of 11 types of solid tumors collected by The Cancer Genome Atlas (TCGA). In NPC, the hypermethylation pattern was more dominant than hypomethylation and the majority of de novo methylated loci were within or close to CpG islands in tumors. The comparative methylome analysis reveals hypermethylation at chromosome 6p21.3 frequently occurred in NPC (false discovery rate; FDR=1.33 × 10−9), but was less obvious in other types of solid tumors except for prostate and Epstein–Barr virus (EBV)-positive gastric cancer (FDR<10−3). Bisulfite pyrosequencing results further confirmed the aberrant methylation at 6p in an additional patient cohort. Evident enrichment of the repressive mark H3K27me3 and active mark H3K4me3 derived from human embryonic stem cells were found at these regions, indicating both DNA methylation and histone modification function together, leading to epigenetic deregulation in NPC. Our study highlights the importance of epigenetic deregulation in NPC. Polycomb Complex 2 (PRC2), responsible for H3K27 trimethylation, is a promising therapeutic target. A key genomic region on 6p with aberrant methylation was identified. This region contains several important genes having potential use as biomarkers for NPC detection. PMID:25924914

  4. Phase I, multicenter, open-label, dose-escalation study of sonidegib in Asian patients with advanced solid tumors.

    PubMed

    Minami, Hironobu; Ando, Yuichi; Ma, Brigette Buig Yue; Hsiang Lee, Jih-; Momota, Hiroyuki; Fujiwara, Yutaka; Li, Leung; Fukino, Koichi; Ito, Koji; Tajima, Takeshi; Mori, Asuka; Lin, Chia-Chi

    2016-10-01

    Sonidegib is a selective inhibitor of Smoothened receptor, which is a key regulator of the Hedgehog signaling pathway. The purpose of this study was to determine the maximum tolerated dose based on dose-limiting toxicity (DLT) and the recommended dose (RD) of sonidegib in Asian patients with advanced solid tumors. This was an open-label, single-arm, multicenter, two-group, parallel, dose-escalation, phase I study undertaken in Asian patients; group 1 included patients from Japan and group 2 included patients from Hong Kong and Taiwan. Dose escalation was guided by a Bayesian logistic regression model dependent on DLTs in cycle 1 and other safety findings. A total of 45 adult Asian patients with confirmed advanced solid tumors were enrolled. Group 1 included 21 patients (12 treated with 400 mg q.d. [once daily] and 9 treated with 600 mg q.d.) and group 2 included 24 patients (12 treated with 400 mg q.d., 8 treated with 600 mg q.d., and 4 treated with 800 mg q.d.). Elevation in creatine kinase was the DLT in both groups. The most common adverse events suspected to be related to sonidegib in both patient groups were increase in creatine kinase levels, myalgia, fatigue, and abnormal hepatic function. The RD of 400 mg q.d. was defined in both groups. Difference in tolerability was noted between the East Asian patients and Western population. The RD in East Asian patients (400 mg q.d.) was lower than in patients from Europe and the USA (800 mg q.d. and 250 mg twice daily). (Registered with Clinicaltrials.gov: NCT01208831.).

  5. Prognostic Significance of the Metabolic Marker Hexokinase-2 in Various Solid Tumors: A Meta-Analysis

    PubMed Central

    Liu, Yulin; Wu, Ke; Shi, Liang; Xiang, Fan; Tao, Kaixiong; Wang, Guobin

    2016-01-01

    Objective Recently, numerous studies have reported that hexokinase-2 (HK2) is aberrantly expressed in cancer, indicating that HK2 plays a pivotal role in the development and progression of cancer. However, its prognostic significance in solid tumor remains unclear. Accordingly, we performed a meta-analysis to assess the prognostic value of HK2 in solid tumor. Methods Eligible studies were identified using PubMed, Embase, and Web of Science databases. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) or progression-free survival (PFS)/disease-free survival (DFS)/relapse-free survival (RFS) were estimated with random effects or fixed effects models, respectively. Subgroup analysis was also performed according to patients’ ethnicities, tumor types, detection methods, and analysis types. Results Data from 21 included studies with 2532 patients were summarized. HK2 overexpression was significantly associated with worse OS (pooled HR = 1.90, 95% CI = 1.51–2.38, p < 0.001) and PFS (pooled HR = 2.91, 95% CI = 2.02–4.22, p < 0.001) in solid tumor. As to a specific form of cancer, the negative effect of HK2 on OS was observed in hepatocellular carcinoma (pooled HR = 2.06, 95% CI = 1.67–2.54, p < 0.001), gastric cancer (pooled HR = 1.72, 95% CI = 1.09–2.71, p = 0.020), colorectal cancer (pooled HR = 2.89, 95% CI = 1.62–5.16, p < 0.001), but not in pancreatic cancer (pooled HR = 1.13, 95% CI = 0.28–4.66, p = 0.864). No publication bias was found in the included studies for OS (Begg’s test, p = 0.325; Egger’s test, p = 0.441). Conclusion In this meta-analysis, we identified that elevated HK2 expression was significantly associated with shorter OS and PFS in patients with solid tumor, but the association varies according to cancer type. PMID:27824926

  6. Auto Transplant for High Risk or Relapsed Solid or CNS Tumors

    ClinicalTrials.gov

    2017-02-17

    Ewing's Family Tumors; Renal Tumors; Hepatoblastoma; Rhabdomyosarcoma; Soft Tissue Sarcoma; Primary Malignant Brain Neoplasms; Retinoblastoma; Medulloblastoma; Supra-tentorial Primative Neuro-Ectodermal Tumor (PNET); Atypical Teratoid/Rhabdoid Tumor (AT/RT); CNS Tumors; Germ Cell Tumors

  7. Pembrolizumab Combined With Itacitinib (INCB039110) and/or Pembrolizumab Combined With INCB050465 in Advanced Solid Tumors

    ClinicalTrials.gov

    2017-02-02

    Advanced Solid Tumors; Endometrial Cancer; Melanoma; Microsatellite Unstable (MSI) Colorectal Cancer; MMR-deficient Tumors; Non-small Cell Lung Cancer; Renal Cell Carcinoma; Head and Neck Squamous Cell Carcinoma; Triple Negative Breast Cancer; Transitional Cell Carcinoma of the Genitourinary Tract; Pancreatic Ductal Adenocarcinoma; Small Cell Lung Cancer

  8. Hemolymphangioma: a rare differential diagnosis of cystic-solid or cystic tumors of the pancreas.

    PubMed

    Dong, Fei; Zheng, Yi; Wu, Jian-Jun; Fu, Yan-Biao; Jin, Kai; Chao, Ming

    2013-06-14

    We report a case of pancreatic hemolymphangioma. Hemolymphangioma is a malformation of both lymphatic vessels and blood vessels. The incidence of this disease in the pancreas is extremely rare. To the best of our knowledge, only seven cases have been reported worldwide (PubMed). A 39-year-old woman with a one-day history of abdominal pain was admitted to our hospital. There was no obvious precipitating factor. The preoperative examination, including ultrasonography and computed tomography, showed a cystic-solid tumor in the pancreas, and it was considered to be a mucinous cystadenoma or cystadenocarcinoma. Pancreatic body-tail resection combined with splenectomy was performed. After the operation, the tumor was pathologically demonstrated to be a pancreatic hemolymphangioma. Although pancreatic hemolymphangioma is rare, we believe that it should be considered in the differential diagnosis of cystic-solid tumors of the pancreas, particularly when there is no sufficient evidence for diagnosing cystadenoma, cystadenocarcinoma or some other relatively common disease of the pancreas.

  9. [Bolande tumor in adults: apropos of a case].

    PubMed

    el Mrini, M; Debbagh, A; Hafiani, M; Aboutaieb, R; Bennani, S; Benjelloun, S

    1998-02-01

    Bolande's tumour or congenital mesoblastic nephroma is essentially a tumour of infants under the age of one year and is rare in adults, in whom only 10 cases have been described. The authors report the 11th case in a 30-year-old woman, in whom a right renal tumour was discovered during ultrasonography at 34 weeks of pregnancy. Radical nephrectomy was performed after delivery, with a favourable course at 3 years, with no recurrence or metastasis. The aetiopathogenic and diagnostic aspects are discussed, with emphasis on the possibility of a hormonal inducing factor in the histogenesis of this tumour.

  10. Adding chemo after radiation treatment improves survival for adults with a type of brain tumor

    Cancer.gov

    Adults with low-grade gliomas, a form of brain tumor, who received chemotherapy following completion of radiation therapy lived longer than patients who received radiation therapy alone, according to long-term follow-up results from a NIH-supported random

  11. Novel and Expanded Oncology Drug Approvals of 2016-PART 1: New Options in Solid Tumor Management.

    PubMed

    Knepper, Todd C; Saller, James; Walko, Christine M

    2017-02-15

    The nonradiologic medical management of solid tumors has evolved from the use of traditional cytotoxic agents to modern targeted therapies, monoclonal antibodies, and immunotherapies. Advances in the understanding of cancer biology and therapeutic strategies have resulted in increasing numbers of new drug applications and approvals. Consequently, practicing oncologists need to learn how the newly available agents function and what toxicities to watch for, as well as ways to optimize the use of both new drugs and previously approved drugs with new indications. In 2016, the US Food and Drug Administration approved three novel drugs for the treatment of solid malignancies-olaratumab in selected patients with soft-tissue sarcoma, atezolizumab for the treatment of bladder cancer, and rucaparib for the treatment of ovarian cancer; also in 2016, the use of previously approved anticancer agents (including atezolizumab) was expanded into 11 new patient populations. The diversity of options for patients is evident in the broad range of the 2016 approvals, which include immune checkpoint inhibitors, targeted therapies, monoclonal antibodies, and traditional cytotoxic agents. This article focuses on the new agents and indications that emerged in 2016 for solid tumor treatment. We review the drug indications, mechanisms of action, pivotal trial data, pertinent toxicities, use in special populations, and the appropriate clinical contexts for treatment planning.

  12. Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas

    ClinicalTrials.gov

    2017-04-04

    Childhood Solid Neoplasm; Metastatic Melanoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Hodgkin Lymphoma; Recurrent Malignant Solid Neoplasm; Recurrent Melanoma; Recurrent Neuroblastoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Osteosarcoma; Recurrent Rhabdomyosarcoma; Refractory Hodgkin Lymphoma; Refractory Non-Hodgkin Lymphoma; Stage III Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma

  13. Solid-organ transplantation in childhood: transitioning to adult health care.

    PubMed

    LaRosa, Christopher; Glah, Caryle; Baluarte, H Jorge; Meyers, Kevin E C

    2011-04-01

    Pediatric solid-organ transplantation is an increasingly successful treatment for solid-organ failure. With dramatic improvements in patient survival rates over the last several decades, there has been a corresponding emergence of complications attributable to pretransplant factors, transplantation itself, and the management of transplantation with effective immunosuppression. The predominant solid-organ transplantation sequelae are medical and psychosocial. These sequelae have a substantial effect on transition to adult care; as such, hurdles to successful transition of care arise from the patients, their families, and pediatric and adult health care providers. Crucial to successful transitioning is the ongoing development of a sense of autonomy and responsibility for one's own care. In this article we address the barriers to transitioning that occur with long-term survival in pediatric solid-organ transplantation. Although a particular transitioning model is not promoted, practical tools and strategies that contribute to successful transitioning of pediatric patients who have received a transplant are suggested.

  14. Imaging diagnosis and fundamental knowledge of common brain tumors in adults.

    PubMed

    Tanaka, Akio

    2006-07-01

    The most common primary brain tumors in Japanese adults are meningiomas, gliomas, pituitary adenomas, and schwannomas, which together account for 84.0% of all primary brain tumors. The typical imaging findings of these tumors are well known by radiologists; therefore, the clinical and pathological issues, including terminology, genetics, and relation to hormones are discussed in this article. Other diseases important for the differential diagnoses are also mentioned. The molecular genetic analysis of brain tumors has recently become important. For instance, genetic analysis is important for differentiating oligodendroglial tumors from astrocytic tumors, and the gene mutation predicts response to chemotherapy for anaplastic oligodendrogliomas. Background factors such as hormones, history of cranial irradiation, and medications influence oncogenesis, tumor growth, and tumor appearances as seen by imaging modalities. A differential diagnosis with knowledge of the above may have some advantages over diagnoses based on imaging findings alone. Nonneoplastic diseases such as abscesses and demyelinating diseases may mimic gliomas. Pituitary adenomas may be confused with nonneoplastic conditions such as physiological hypertrophy and Rathke's cleft cyst. Such misdiagnoses would result in a treatment protocol very different from what would be suitable. Such conditions should be carefully distinguished from neoplasms.

  15. Radiation Treatment for Ewing Family of Tumors in Adults: University of Florida Experience

    SciTech Connect

    Shi Wenyin; Indelicato, Daniel J.; Keole, Sameer R.; Morris, Christopher G.; Scarborough, Mark T.; Gibbs, Parker C.; Zlotecki, Robert A.

    2008-11-15

    Purpose: To review the clinical characteristics and outcomes of adult patients with Ewing family of tumors treated with radiation at University of Florida. Methods and Materials: Clinical features, treatment, and outcomes of 47 patients older than 18 years with Ewing family of tumors treated with combined radiation therapy and chemotherapy from 1970 to 2005 were retrospectively reviewed. Analysis was stratified by age older or younger than 30 years. Patients with metastatic disease at the time of diagnosis were excluded from the study. Results: The 29 men and 18 women had a median age of 24 years. Thirty-three patients were 18-30 years old and 14 patients were older than 30 years. Median follow-up of living patients was 8.2 years. The 5-year overall survival rate for all patients was 43% (p = 0.8523). The 5-year local control rate for all patients was 75% (p = 0.9326). The 5-year rate of freedom from distant metastasis for all patients was 45% (p = 0.5471). There were no significant differences in 5-year overall survival, local control, and freedom from distant metastasis rates; patterns of distant failure; or toxicity profiles between older adult patients and younger adult patients. Conclusions: We found that the natural history and treatment outcomes of the Ewing family of tumors were consistently similar in adults (young and old) and children. Thus, aggressive combined modality approaches should be considered for adult patients.

  16. [Adolescent and Young Adults (AYAS) brain tumor national Web conference. On behalf of ANOCEF, GO-AJA and SFCE societies].

    PubMed

    Frappaz, Didier; Sunyach, Marie-Pierre; Le Rhun, Emilie; Blonski, Marie; Laurence, Valérie; Bonneville Levard, Alice; Loiseau, Hugues; Meyronnet, David; Callies, Arnaud; Laigle-Donadey, F; Faure Conter, Cecile

    2016-12-01

    The skills of adult versus pediatric neuro-oncologists are not completely similar though additive. Because the tumors and their protocols are different and the tolerance and expected sequelae are specific. Multidisciplinary meetings including adult and pediatric neuro-oncologists are warranted to share expertise. Since 2008, a weekly national web based conference was held in France. Any patient with the following criteria could be discussed: Adolescent and Young Adults aged between 15 and 25 years, and any adult with a pediatric type pathology, including medulloblastoma, germ cell tumors, embryonic tumors, ependymoma, pilocytic astrocytoma.

  17. Adoptive therapy with CAR redirected T cells: the challenges in targeting solid tumors.

    PubMed

    Abken, Hinrich

    2015-01-01

    Recent spectacular success in the adoptive cell therapy of leukemia and lymphoma with chimeric antigen receptor (CAR)-modified T cells raised the expectations that this therapy may be efficacious in a wide range of cancer entities. The expectations are based on the predefined specificity of CAR T cells by an antibody-derived binding domain that acts independently of the natural T-cell receptor, recognizes targets independently of presentation by the major histocompatibility complex and allows targeting toward virtually any cell surface antigen. We here discuss that targeting CAR T cells toward solid tumors faces certain circumstances critical for the therapeutic success. Targeting tumor stroma and taking advantage of TRUCK cells, in other words, CAR T cells with inducible release of a transgenic payload, are some strategies envisaged to overcome current limitations in the near future.

  18. Denosumab for the management of bone disease in patients with solid tumors.

    PubMed

    Body, Jean-Jacques

    2012-03-01

    Many patients with advanced cancer develop bone metastases, which reduces their quality of life. Bone metastases are associated with an increased risk of skeletal-related events, which can lead to increased morbidity and mortality. In patients with bone metastases, tumor cells disrupt the normal process of bone remodeling, leading to increased bone destruction. Denosumab is a fully human monoclonal antibody against receptor activator of NF-κB ligand (RANKL), a key regulatory factor in bone remodeling. By binding to RANKL, denosumab disrupts the cycle of bone destruction. In clinical studies in patients with prostate or breast cancer and bone metastases, denosumab was superior to the current standard of care, zoledronic acid, for delaying skeletal-related events, while in patients with other solid tumors or multiple myeloma, denosumab was noninferior to zoledronic acid. This article examines the pharmacokinetics, efficacy, and safety and tolerability of denosumab for the management of bone events in patients with cancer.

  19. The value of new high-throughput technologies for diagnosis and prognosis in solid tumors.

    PubMed

    Pinto, Rosamaria; De Summa, Simona; Petriella, Daniela; Tudoran, Oana; Danza, Katia; Tommasi, Stefania

    2014-01-01

    Advances in our understanding of the molecular basis of tumors, as well as in the technology of DNA analysis, are rapidly changing the landscape of these diseases. Traditional approaches such as sequencing methods and arrays have too many limits. These have been overcome by the advent of next generation sequencing (NGS) methods which facilitate and accelerate the analysis of multiple genes and samples. These technologies allow new applications in molecular biology and medicine, for example precise analysis of RNA transcripts for gene expression; profiling of small RNAs, DNA methylation patterns and histone modification analysis; identification of splicing isoforms and of DNA regions that interact with regulatory proteins; pharmacogenomics studies and so on. In this review we describe recent applications of NGS in genomics, transcriptomics and epigenomics for a better comprehension of solid tumor metabolisms.

  20. Epigenetic therapy for solid tumors: from bench science to clinical trials.

    PubMed

    Juo, Yen-Yi; Gong, Xue-Jun; Mishra, Ankita; Cui, Xiao; Baylin, Stephen B; Azad, Nilofer S; Ahuja, Nita

    2015-01-01

    The cancer epigenome is characterized by global DNA methylation and chromatin changes, such as the hypermethylation of specific CpG island promoters. Epigenetic agents like DNA methyltransferase or histone deacetylase inhibitors induce phenotype changes by reactivation of epigenetically silenced tumor suppressor genes. Despite initial promise in hematologic malignancies, epigenetic agents have not shown significant efficacy as monotherapy against solid tumors. Recent trials showed that epigenetic agents exert favorable modifier effects when combined with chemotherapy, hormonal therapy, or other epigenetic agents. Due to the novel nature of their mechanism, it is important to reconsider the optimal patient selection, drug regimen, study design, and outcome measures when pursuing future trials in order to discover the full potential of this new therapeutic modality.

  1. Role of NK cells in immunotherapy and virotherapy of solid tumors.

    PubMed

    Cantoni, Claudia; Grauwet, Korneel; Pietra, Gabriella; Parodi, Monica; Mingari, Maria Cristina; Maria, Andrea De; Favoreel, Herman; Vitale, Massimo

    2015-01-01

    Although natural killer (NK) cells are endowed with powerful cytolytic activity against cancer cells, their role in different therapies against solid tumors has not yet been fully elucidated. Their interactions with various elements of the tumor microenvironment as well as their possible effects in contributing to and/or limiting oncolytic virotherapy render this potential immunotherapeutic tool still difficult to exploit at the bedside. Here, we will review the current literature with the aim of providing new hints to manage this powerful cell type in future innovative therapies, such as the use of NK cells in combination with new cytokines, specific mAbs (inducing ADCC), Tyr-Kinase inhibitors, immunomodulatory drugs and/or the design of oncolytic viruses aimed at optimizing the effect of NK cells in virotherapy.

  2. Magna-field irradiation and autologous marrow rescue in the treatment of pediatric solid tumors

    SciTech Connect

    Munoz, L.L.; Wharam, M.D.; Kaizer, H.; Leventhal, B.G.; Ruymann, R.

    1983-12-01

    Marrow ablative therapy has been given to pediatric patients with a variety of disseminated tumors. Eight patients with advanced neuroblastoma received autologous marrow reinfusion after intensive therapy. Three of eight are in continuous complete remission from 7 to 60 months. An additional four patients received allogeneic marrow transplantation and two remain in continuous complete response at 21 and 39 months. Intensive therapy and autologous marrow reinfusion have been applied to Ewing's sarcoma, but only preliminary results are available. Six patients with disseminated rhabdomyosarcoma and extra-osseous Ewing's sarcoma received conventional chemotherapy followed by sequential hemi-body irradiation. Four of six patients received autologous marrow rescue. Their median disease-free survival is 17 months. This preliminary experience demonstrates the feasibility of using marrow ablative therapy with autologous marrow transplantation in the treatment of pediatric solid tumors. Continuing Phase II studies are required to substantiate its efficacy.

  3. Preparation, characterization, and anti-tumor property of podophyllotoxin-loaded solid lipid nanoparticles

    NASA Astrophysics Data System (ADS)

    Zhu, R. R.; Qin, L. L.; Wang, M.; Wu, S. M.; Wang, S. L.; Zhang, R.; Liu, Z. X.; Sun, X. Y.; Yao, S. D.

    2009-02-01

    In an effort to develop an alternative formulation of podophyllotoxin suitable for drug release and delivery, podophyllotoxin-loaded solid lipid nanoparticles (PPT-SLNs) were constructed, characterized and examined for in vitro cytotoxicity and tumor inhibition. The SLNs were prepared by using a solvent emulsification-evaporation method, and their size was around 50 nm. TEM detection showed that the SLNs were homogeneous and spherical in shape, and differential scanning calorimetry (DSC) measurement revealed a new conformation of PPT-SLNs. An in vitro drug release study showed that PPT was released from the SLNs in a slow but time-dependent manner. Furthermore, the treatment of 293T and HeLa cells with PPT-SLNs demonstrated that PPT-SLNs were less toxic to normal cells and more effective in anti-tumor potency compared with unconjugated PPT. A colony forming efficiency assay showed an effective long-term cancer growth suppression of PPT-SLNs; in addition, they can also enhance the apoptotic and cellular uptake processes on tumor cells compared with PPT. These results collectively demonstrated that this SLN formulation has a potential application as an alternative delivery system for anti-tumor drugs.

  4. Solid-Pseudopapillary Tumor of the Pancreas: A Single Center Experience

    PubMed Central

    Beltrame, Valentina; Pozza, Gioia; Fantin, Alberto; Valmasoni, Michele

    2016-01-01

    Aim of this study was to review the institutional experience of solid-pseudopapillary tumors of the pancreas with particular attention to the problems of preoperative diagnosis and treatment. From 1997 to 2013, SPT was diagnosed in 18 patients among 451 pancreatic cystic neoplasms (3.7%). All patients underwent preoperative abdominal ultrasound, computed assisted tomography, and tumor markers (CEA and CA 19-9) determinations. In some instances, magnetic resonance, positron emission tomography, and endoscopic ultrasound with aspiration cytology were performed. There were two males and 16 females. Serum CA 19-9 was slightly elevated in one case. Preoperative diagnosis was neuroendocrine tumor (n = 2), mucinous tumor (n = 2), and SPT (n = 14). Two patients underwent previous operation before referral to our department: one explorative laparotomy and one enucleation of SPT resulting in surgical margins involvement. All patients underwent pancreatic resection associated with portal vein resection (n = 1) or liver metastases (n = 1). One patient died of metastatic disease, 77 months after operation, and 17 are alive and free with a median survival time of 81.5 months (range 36–228 months). Most of SPT can be diagnosed by CT or MRI, and the role of other diagnostic tools is very limited. We lack sufficient information regarding clinicopathologic features predicting prognosis. Caution is needed when performing limited resection, and long and careful follow-up is required for all patients after surgery. PMID:28119738

  5. Therapeutic Potential and Challenges of Natural Killer Cells in Treatment of Solid Tumors

    PubMed Central

    Gras Navarro, Andrea; Björklund, Andreas T.; Chekenya, Martha

    2015-01-01

    Natural killer (NK) cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing, requiring one-to-one target engagement and site-directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells, and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME) and augment adaptive immune responses by promoting differentiation, activation, and/or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes, and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach. PMID:25972872

  6. A rare case report of Solid Pseudopapillary Tumor of the pancreas with portal hypertension

    PubMed Central

    Reddy, Asha; Sanniyasi, Saravanan; George, Dilip Joseph; Narayanan, Cunnigaiper Dhanasekaran

    2016-01-01

    Introduction Solid Pseudopapillary Tumor of the pancreas (SPT) is a rare pancreatic tumor and represents 1–3% of all pancreatic tumors. It usually presents in young females with abdominal pain, nausea, vomiting and abdominal fullness. The first case report was documented in 1959 and since then multiple case reports have been documented on the various surgical approaches for SPT. However, there are not many reported cases where surgery has been performed on SPT with portal hypertension. Presentation of case In our case report, a 19 year old girl presented with a mass in the left side of the abdomen with associated dragging pain. Ultrasound Abdomen and CT (computed tomography) confirmed an SPT with portal hypertension, with the lesion involving the body and tail of pancreas. Discussion Although few reports are available on SPT with portal hypertension, ours is the first report on a benign SPT with sinistral portal hypertension treated with a distal pancreatectomy. The presence of portal hypertension made the excision of the tumor and delineation of the vessels very difficult. However, when great care is taken while handling the dilated vessels, dissection can be completed with minimal blood loss. Conclusion Meticulous surgical technique along with accurate identification of vasculature will aid in the resection. Although some SPTs behave aggressively, most of them are benign and patients with SPT have an excellent prognosis. PMID:27046101

  7. Mitochondrially targeted wild-type p53 induces apoptosis in a solid human tumor xenograft model

    PubMed Central

    Palacios, Gustavo; Crawford, Howard C.; Vaseva, Angelina; Moll, Ute M.

    2013-01-01

    Classic but also novel roles of p53 are becoming increasingly well characterized. We previously showed that ex vivo retroviral transfer of mitochondrially targeted wild type p53 (mitop53) in the Eμ-myc mouse lymphoma model efficiently induces tumor cell killing in vivo. In an effort to further explore the therapeutic potential of mitop53 for its pro-apoptotic effect in solid tumors, we generated replication-deficient recombinant human Adenovirus type 5 vectors. We show here that adenoviral delivery of mitop53 by intratumoral injection into HCT116 human colon carcinoma xenograft tumors in nude mice is surprisingly effective, resulting in tumor cell death of comparable potency to conventional p53. These apoptotic effects in vivo were confirmed by Ad5-mitop53 mediated cell death of HCT116 cells in culture. Together, these data provide encouragement to further explore the potential for novel mitop53 proteins in cancer therapy to execute the shortest known circuitry of p53 death signaling. PMID:18719383

  8. Solid tumor second primary neoplasms: who is at risk, what can we do?

    PubMed

    Oeffinger, Kevin C; Baxi, Shrujal S; Novetsky Friedman, Danielle; Moskowitz, Chaya S

    2013-12-01

    Eighteen percent of incident malignancies in the United States are a second (or subsequent) cancer. Second primary neoplasms (SPNs), particularly solid tumors, are a major cause of mortality and serious morbidity among cancer survivors successfully cured of their first cancer. Multiple etiologies may lead to a cancer survivor subsequently being diagnosed with an SPN, including radiotherapy for the first cancer, unhealthy lifestyle behaviors, genetic factors, aging, or an interaction between any of these factors. In this article, we discuss these factors and synthesize this information for use in clinical practice, including preventive strategies and screening recommendations for SPNs.

  9. Targeting apoptosis in solid tumors: the role of bortezomib from preclinical to clinical evidence.

    PubMed

    Russo, Antonio; Fratto, Maria E; Bazan, Viviana; Schiró, Valentina; Agnese, Valentina; Cicero, Giuseppe; Vincenzi, Bruno; Tonini, Giuseppe; Santini, Daniele

    2007-12-01

    The ubiquitin-proteasome pathway is the main proteolytic system present in the nucleus and cytoplasm of all eukaryotic cells. Apoptosis activation induced by ubiquitin-proteasome pathway inhibition makes the proteasome a new target of anticancer therapy. Bortezomib is the first proteasome inhibitor to be approved by the US FDA; in 2003 as a third line and in 2005 as a second line therapy for the treatment of multiple myeloma only. This review focuses on the use of bortezomib, not only in its therapeutic role but also, more specifically, in its biologic role and discusses the most recent applications of the drug in solid tumors, both at a preclinical and clinical level.

  10. Solid Tumor Second Primary Neoplasms: Who is at Risk, What Can We Do?

    PubMed Central

    Oeffinger, Kevin C.; Baxi, Shrujal S.; Friedman, Danielle Novetsky; Moskowitz, Chaya S.

    2014-01-01

    Eighteen percent of incident malignancies in the U.S. are a second (or subsequent) cancer. Second primary neoplasms (SPN), particularly solid tumors, are a major cause of mortality and serious morbidity among cancer survivors successfully cured of their first cancer. Multiple etiologies may lead to a cancer survivor subsequently being diagnosed with an SPN, including radiotherapy for the first cancer, unhealthy lifestyle behaviors, germline and somatic mutations, aging, or an interaction between any of these factors. In this article, we discuss these factors and synthesize this information for use in clinical practice, including preventive strategies and screening recommendations for SPNs. PMID:24331190

  11. Expression of intercellular adhesion molecule-3 (ICAM-3/CD50) in malignant lymphoproliferative disorders and solid tumors.

    PubMed

    Terol, M J; Cid, M C; López-Guillermo, A; Juan, M; Yagüe, J; Miralles, A; Vilella, R; Vives, J; Cardesa, A; Montserrat, E; Campo, E

    1996-10-01

    ICAM-3/CD50 is a recently described LFA-1 counter receptor that seems to play an important role in the initiation of immune responses. In this study we have examined the expression of ICAM-3/CD50 in a large series of human neoplasms including 101 Non-Hodgkin's lymphomas (NHL), 26 Hodgkin's disease, and 38 solid tumors to define the distribution patterns of this molecule in malignant neoplasms and their possible correlation with clinical and pathological characteristics of the patients. In NHL, ICAM-3/CD50 was expressed in almost all the tumors with a tendency to be lost in high grade lymphomas. Reed-Sternberg cells and their variants in Hodgkin's disease were always negative independently of the histological subtype of the disease. No expression was observed in tumor epithelial cells of the 38 solid tumors examined. Strong endothelial cell staining was observed in 31% of the NHL and 31% of Hodgkin's disease. ICAM-3 expression in these cases was restricted to small tumor vessels. ICAM-3 expression in endothelial cells of NHL was significantly more frequent in high grade (40%) than in low grade lymphomas (14%) (p = 0.012). In addition, tumor vessels were also positive in 29% of solid tumors independently of the histological type. No correlation was observed between ICAM-3 expression in tumor or endothelial cells and other clinical and pathological characteristics of the patients. These findings indicate that ICAM-3 expression in human tumors is restricted to hematological neoplasms with a tendency to be lost in high grade lymphomas and Hodgkin's disease. ICAM-3 is also expressed by endothelial cells from tumor-associated neovascularization in both lymphoid and solid tumors.

  12. Weekly Doses of Cilengitide and Paclitaxel in Treating Patients With Advanced Solid Tumors That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2016-03-14

    Adult Solid Neoplasm; Estrogen Receptor Negative; HER2/Neu Negative; Male Breast Carcinoma; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  13. Veliparib in Combination With Carboplatin and Paclitaxel in Treating Patients With Locally Advanced or Metastatic Solid Tumors

    ClinicalTrials.gov

    2015-05-22

    Adult Solid Neoplasm; Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; Male Breast Carcinoma; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  14. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors

    PubMed Central

    Willingham, Stephen B.; Volkmer, Jens-Peter; Gentles, Andrew J.; Sahoo, Debashis; Dalerba, Piero; Mitra, Siddhartha S.; Wang, Jian; Contreras-Trujillo, Humberto; Martin, Robin; Cohen, Justin D.; Lovelace, Patricia; Scheeren, Ferenc A.; Chao, Mark P.; Weiskopf, Kipp; Tang, Chad; Volkmer, Anne Kathrin; Naik, Tejaswitha J.; Storm, Theresa A.; Mosley, Adriane R.; Edris, Badreddin; Schmid, Seraina M.; Sun, Chris K.; Chua, Mei-Sze; Murillo, Oihana; Rajendran, Pradeep; Cha, Adriel C.; Chin, Robert K.; Kim, Dongkyoon; Adorno, Maddalena; Raveh, Tal; Tseng, Diane; Jaiswal, Siddhartha; Enger, Per Øyvind; Steinberg, Gary K.; Li, Gordon; So, Samuel K.; Majeti, Ravindra; Harsh, Griffith R.; van de Rijn, Matt; Teng, Nelson N. H.; Sunwoo, John B.; Alizadeh, Ash A.; Clarke, Michael F.; Weissman, Irving L.

    2012-01-01

    CD47, a “don't eat me” signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies. PMID:22451913

  15. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors.

    PubMed

    Willingham, Stephen B; Volkmer, Jens-Peter; Gentles, Andrew J; Sahoo, Debashis; Dalerba, Piero; Mitra, Siddhartha S; Wang, Jian; Contreras-Trujillo, Humberto; Martin, Robin; Cohen, Justin D; Lovelace, Patricia; Scheeren, Ferenc A; Chao, Mark P; Weiskopf, Kipp; Tang, Chad; Volkmer, Anne Kathrin; Naik, Tejaswitha J; Storm, Theresa A; Mosley, Adriane R; Edris, Badreddin; Schmid, Seraina M; Sun, Chris K; Chua, Mei-Sze; Murillo, Oihana; Rajendran, Pradeep; Cha, Adriel C; Chin, Robert K; Kim, Dongkyoon; Adorno, Maddalena; Raveh, Tal; Tseng, Diane; Jaiswal, Siddhartha; Enger, Per Øyvind; Steinberg, Gary K; Li, Gordon; So, Samuel K; Majeti, Ravindra; Harsh, Griffith R; van de Rijn, Matt; Teng, Nelson N H; Sunwoo, John B; Alizadeh, Ash A; Clarke, Michael F; Weissman, Irving L

    2012-04-24

    CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.

  16. Clinical outcomes of children and adults with central nervous system primitive neuroectodermal tumor.

    PubMed

    Lester, Rachael A; Brown, Lindsay C; Eckel, Laurence J; Foote, Robert T; NageswaraRao, Amulya A; Buckner, Jan C; Parney, Ian F; Wetjen, Nicholas M; Laack, Nadia N

    2014-11-01

    Central nervous system primitive neuroectodermal tumors (CNS PNETs) predominantly occur in children and rarely in adults. Because of the rarity of this tumor, its outcomes and prognostic variables are not well characterized. The purpose of this study was to evaluate clinical outcomes and prognostic factors for children and adults with CNS PNET. The records of 26 patients (11 children and 15 adults) with CNS PNET from 1991 to 2011 were reviewed retrospectively. Disease-free survival (DFS) and overall survival (OS) were estimated with the Kaplan-Meier method, and relevant prognostic factors were analyzed. For the cohort, both the 5-year DFS and the OS were 46 %. For pediatric patients, the 5-year DFS was 78 %; for adult patients, it was 22 % (P = 0.004). Five-year OS for the pediatric and adult patients was 67 and 33 %, respectively (P = 0.07). With bivariate analysis including chemotherapy regimen (high dose vs. standard vs. nonstandard) or risk stratification (standard vs. high) and age, the increased risk of disease recurrence in adults persisted. A nonsignificant tendency toward poorer OS in adult patients relative to pediatric patients also persisted. High-dose chemotherapy with stem cell rescue was associated with a statistically significant improvement in OS and a tendency toward improved DFS, although the findings were mitigated when the effect of age was considered. Local recurrence was the primary pattern of treatment failure in both adults and children. Our results suggest that adult patients with CNS PNETs have inferior outcomes relative to the pediatric cohort. Further research is needed to improve outcomes for CNS PNET in populations of all ages.

  17. Phase I and Pharmacokinetic Study of Cetuximab and Irinotecan in Children With Refractory Solid Tumors: A Study of the Pediatric Oncology Experimental Therapeutic Investigators' Consortium

    PubMed Central

    Trippett, Tanya M.; Herzog, Cynthia; Whitlock, James A.; Wolff, Johannes; Kuttesch, John; Bagatell, Rochelle; Hunger, Stephen P.; Boklan, Jessica; Smith, Amy A.; Arceci, Robert J.; Katzenstein, Howard M.; Harbison, Christopher; Zhou, Xiaofei; Lu, Haolan; Langer, Christiane; Weber, Martin; Gore, Lia

    2009-01-01

    Purpose To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors. Patients and Methods This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m2) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m2/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected. Results Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m2 weekly plus irinotecan 16 mg/m2/d (pediatric) or 20 mg/m2/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%). Conclusion The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen. PMID:19770383

  18. Neural Underpinnings of Working Memory in Adult Survivors of Childhood Brain Tumors.

    PubMed

    King, Tricia Z; Na, Sabrina; Mao, Hui

    2015-08-01

    Adult survivors of childhood brain tumors are at risk for cognitive performance deficits that require the core cognitive skill of working memory. Our goal was to examine the neural mechanisms underlying working memory performance in survivors. We studied the working memory of adult survivors of pediatric posterior fossa brain tumors using a letter n-back paradigm with varying cognitive workload (0-, 1-, 2-, and 3-back) and functional magnetic resonance imaging as well as neuropsychological measures. Survivors of childhood brain tumors evidenced lower working memory performance than demographically matched healthy controls. Whole-brain analyses revealed significantly greater blood-oxygen level dependent (BOLD) activation in the left superior / middle frontal gyri and left parietal lobe during working memory (2-back versus 0-back contrast) in survivors. Left frontal BOLD response negatively correlated with 2- and 3-back working memory performance, Auditory Consonant Trigrams (ACT), and Digit Span Backwards. In contrast, parietal lobe BOLD response negatively correlated with 0-back (vigilance task) and ACT. The results revealed that adult survivors of childhood posterior fossa brain tumors recruited additional cognitive control resources in the prefrontal lobe during increased working memory demands. This increased prefrontal activation is associated with lower working memory performance and is consistent with the allocation of latent resources theory.

  19. Magnetite Nanoparticles Inhibit Tumor Growth and Upregulate the Expression of P53/P16 in Ehrlich Solid Carcinoma Bearing Mice

    PubMed Central

    Bassiony, Heba; Sabet, Salwa; Salah El-Din, Taher A.; Mohamed, Mona M.; El-Ghor, Akmal A.

    2014-01-01

    Background Magnetite nanoparticles (MNPs) have been widely used as contrast agents and have promising approaches in cancer treatment. In the present study we used Ehrlich solid carcinoma (ESC) bearing mice as a model to investigate MNPs antitumor activity, their effect on expression of p53 and p16 genes as an indicator for apoptotic induction in tumor tissues. Method MNPs coated with ascorbic acid (size: 25.0±5.0 nm) were synthesized by co-precipitation method and characterized. Ehrlich mice model were treated with MNPs using 60 mg/Kg day by day for 14 injections; intratumorally (IT) or intraperitoneally (IP). Tumor size, pathological changes and iron content in tumor and normal muscle tissues were assessed. We also assessed changes in expression levels of p53 and p16 genes in addition to p53 protein level by immunohistochemistry. Results Our results revealed that tumor growth was significantly reduced by IT and IP MNPs injection compared to untreated tumor. A significant increase in p53 and p16 mRNA expression was detected in Ehrlich solid tumors of IT and IP treated groups compared to untreated Ehrlich solid tumor. This increase was accompanied with increase in p53 protein expression. It is worth mentioning that no significant difference in expression of p53 and p16 could be detected between IT ESC and control group. Conclusion MNPs might be more effective in breast cancer treatment if injected intratumorally to be directed to the tumor tissues. PMID:25375144

  20. Histone deacetylase inhibitors: an overview of the clinical studies in solid tumors.

    PubMed

    Slingerland, Marije; Guchelaar, Henk-Jan; Gelderblom, Hans

    2014-02-01

    The histone deacetylase inhibitors (HDACi) are a group of small molecules that target histone deacetylases (HDACs) by inhibiting their activity. HDACi have a long history of use in neurology and psychiatry as antiepileptics and mood stabilizers. More recently, they have been investigated as possible treatments for cancer. HDACi have undergone rapid clinical development in recent years, on the basis of their preclinical in-vitro and in-vivo antitumor activity in hematological malignancies and solid tumors. Many HDACi have entered phase I-III clinical trials. Among the HDACi, vorinostat and romidepsin are currently the most extensively studied. In 2006 and 2009, respectively, they received approval by the United States Food and Drug Administration for treatment of cutaneous T-cell lymphoma and romidepsin for the treatment of peripheral T-cell lymphoma. Other HDACi, such as panobinostat and valproic acid, also demonstrated activity as therapeutic anticancer agents. In this article we give an overview of the clinical studies of HDACi in solid tumors. We start with a short description of the working mechanism of HDACi in general.

  1. Impact of multimodality approach for patients with leptomeningeal metastases from solid tumors.

    PubMed

    Kwon, Jeanny; Chie, Eui Kyu; Kim, Kyubo; Kim, Hak Jae; Wu, Hong-Gyun; Kim, Il Han; Oh, Do-Youn; Lee, Se-Hoon; Kim, Dong-Wan; Im, Seock-Ah; Kim, Tae-You; Heo, Dae-Seog; Bang, Yung-Jue; Ha, Sung W

    2014-08-01

    The purpose of this study was to evaluate treatment patterns, outcome and prognosticators for patients with leptomeningeal metastases from solid tumor. Medical records of 80 patients from January 1, 2004 to May 31, 2011 were retrospectively reviewed. Most frequent site of origin was the lung (59%) followed by the breast (25%). Most patients were treated with intrathecal chemotherapy (90%) and/or whole brain radiotherapy (67.5%). Systemic therapy was offered to 27 patients (33.8%). Percentage of patients treated with single, dual, and triple modality were 32.5%, 43.8%, and 23.8%, respectively. Median survival was 2.7 months and 1 yr survival rate was 11.3%. Multivariate analysis showed that negative cerebrospinal fluid cytology, fewer chemotherapy regimen prior to leptomeningeal metastases, whole brain radiotherapy, systemic therapy, and combined modality treatment (median survival; single 1.4 vs. dual 2.8 vs. triple 8.3 months, P<0.001) had statistical significance on survival. Subgroup analysis of non-small cell lung cancer (NSCLC) patients showed that targeted therapy had significant independent impact on survival (median survival; 10.5 vs. 3.0 months, P=0.008). Unlike previous reports, survival of patients with NSCLC primary was comparable to breast primary. Furthermore, combined modality treatment for all patients and additionally targeted therapy for NSCLC patients should be considered in the treatment of leptomeningeal metastases from solid tumor.

  2. It’s About Time: Lessons For Solid Tumors From Chronic Myelogenous Leukemia Therapy

    PubMed Central

    Westin, Jason R.; Kurzrock, Razelle

    2014-01-01

    The use of imatinib in chronic myelogenous leukemia (CML) transformed the disease, rapidly changing the median survival from 4 years to at least 20 years. In this review, we outline the causes of this revolution, including the identification of a critical driving molecular aberration--BCR-ABL--and the development of a potent and specific inhibitor--imatinib. Equally important was the timing of the targeted therapy, specifically its administration to patients with newly diagnosed disease. In solid tumors, targeted therapies are often both developed and used in metastatic malignancies after conventional approaches have failed. We postulate that this strategy is similar to using imatinib in blast crisis CML, where response rates are <15%, all patients relapse, and median survival remains only about one year. We hypothesize that the imatinib-led revolution in CML, including the critically important factor of timing, may be applicable to other cancers as well. Therefore, it will be important to utilize promising targeted therapies in the earliest phases of biomarker-defined solid tumors, prior to metastatic progression, to determine if outcomes can be significantly improved, and hence establish if the success of imatinib in CML is an anomaly or a paradigm. PMID:23204432

  3. Prognostic significance of microRNA-100 in solid tumors: an updated meta-analysis

    PubMed Central

    Wang, Jiangfeng; Yu, Miao; Guan, Shanghui; Zhang, Guangyu; Wang, Jianbo; Cheng, Yufeng

    2017-01-01

    Objective The aim of this study was to identify prognostic significance of microRNA-100 (miR-100) in solid tumor. Methods Literature search was conducted in databases such as PubMed, Embase, and Web of Science, using the following words “(microRNA-100 OR miR-100 OR mir100) AND (tumor OR neoplasm OR cancer OR carcinoma OR malignancy).” The search was updated up until July 10, 2016. Newcastle–Ottawa scale was used to evaluate the quality of studies. Pooled hazard ratio (HR) with 95% confidence interval (CI) for patients’ survival was calculated by using a fixed-effects or a random-effects model on the basis of heterogeneity. Subgroup analysis, sensitive analysis, and meta-regression were used to investigate the sources of heterogeneity. Publication bias was evaluated by using Begg’s and Egger’s tests. Results A total of 16 articles with 1,501 patients were included in the present meta-analysis. It was demonstrated that a lower expression of miR-100 plays a negative role in the overall survival (OS) of patients with solid tumor (HR =1.92; 95% CI =1.25–2.94). In addition, the association between miR-100 and prognosis was also revealed in the following subgroups: non-small-cell lung cancer (NSCLC; HR =2.46; 95% CI =1.98–3.06), epithelial ovarian cancer (EOC; HR =2.29, 95% CI =1.72–3.04), and bladder cancer (BC; HR =4.14, 95% CI =1.85–9.27). Conclusion This meta-analysis indicates that lower expression of miR-100 is related to poorer OS in patients with solid tumor, especially in those with NSCLC, EOC, and BC. MiR-100 is a promising prognosis predictor and may be a potential target for therapy in the future. PMID:28176958

  4. Increased nitric oxide levels in cerebellum of cachectic rats with Walker 256 solid tumor.

    PubMed

    Fenner, Fabio Leandro; Guarnier, Flavia Alessandra; Bernardes, Sara Santos; Ramalho, Leandra Naira Zambelli; Cecchini, Rubens; Cecchini, Alessandra Lourenço

    2015-01-01

    In cancer cachexia, the role of nitric oxide (NO) in the central nervous system remains unclear. Cerebellar degeneration has been reported in cancer patients, but the participation of NO has not been studied. Thus, this study investigated the mechanism of oxidative cerebellar injury in a time-course cancer cachexia experimental model. The cachexia index is progressive and evident during the evolution of the tumor. Nitric oxide and lipid hydroperoxidation quantification was performed using a very sensitive and precise chemiluminescence method, which showed that both analyzed parameters were increased after tumor implantation. In the day 5 group, NO was significantly increased, and this experimental time was chosen to treat the rats with the NO inhibitors N-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG). When treated with NO inhibitors, a significant decrease in both NO and lipid hydroperoxide levels occurred in the cerebellum. 3-nitrotyrosine was also analyzed in cerebellar tissue by immunohistochemistry; it was increased at the three experimental time points studied, and decreased when treated with L-NAME and AG. Besides demonstrating that lipid hydroperoxidation in the cerebellum of rats with cachexia increases in a time-dependent manner, this study is the first to describe the participation of NO and its oxidized product 3-NT in the cerebellum of cachectic rats bearing the Walker 256 solid tumor.

  5. Evaluation of Immunogenicity of Nivolumab Monotherapy and Its Clinical Relevance in Patients With Metastatic Solid Tumors.

    PubMed

    Agrawal, Shruti; Statkevich, Paul; Bajaj, Gaurav; Feng, Yan; Saeger, Sally; Desai, Dharmesh D; Park, Jong-Soon; Waxman, Ian M; Roy, Amit; Gupta, Manish

    2017-03-01

    Nivolumab is a fully human IgG4 monoclonal antibody targeting the programmed death-1 (PD-1) receptor that blocks interactions between PD-1 and its ligands on tumor cells to prevent T-cell exhaustion in patients with cancer. It has demonstrated efficacy in multiple tumor types, including melanoma, non-small-cell lung cancer, and renal cell carcinoma. This analysis assessed the immunogenicity of nivolumab and its impact on pharmacokinetics, safety, and efficacy in patients with solid tumors enrolled in 6 clinical studies. The incidence and prevalence of antidrug antibodies (ADAs) were determined by validated electrochemiluminescence assays in samples collected during nivolumab treatment and up to 100 days after the last dose. Confirmed positive samples from the 6 studies were also tested for presence of neutralizing antibodies (NAbs). Among 1086 nivolumab-treated patients, 138 patients (12.7%) were ADA positive (relative to baseline), only 3 (0.3%) of whom were persistently positive for ADA, and 9 (0.8%) were NAb positive at 1 time point. The presence of ADAs was not associated with hypersensitivity, infusion reactions, or loss of efficacy and had minimal impact on nivolumab clearance. Additionally, the presence of NAbs was not associated with loss of efficacy. In conclusion, immunogenicity of nivolumab is not clinically meaningful.

  6. HER2 in solid tumors: more than 10 years under the microscope; where are we now?

    PubMed

    Martin, Vittoria; Cappuzzo, Federico; Mazzucchelli, Luca; Frattini, Milo

    2014-06-01

    HER2 is a well-recognized mediator of the cancerogenic process. It is dysregulated in a wide range of solid tumors, mainly via protein overexpression and/or gene amplification, thus making HER2 an attractive target for tailored treatment. The anti-HER2 therapy trastuzumab was approved for the treatment of HER2-positive metastatic breast cancer patients more than 10 years ago. Since then, trastuzumab and other HER2-inhibitors have been entered into clinical practice for the treatment of breast cancer and, more recently, have been approved to treat HER2-positive metastatic gastric cancers. Currently, HER2-targeted therapies are under evaluation in other tumor types. Due to the relevance of proper patient selection, the accurate assessment of HER2 status is fundamental. This review will discuss the established knowledge and novel insights into the HER2 story, mainly focusing on breast, gastric and colorectal cancers, as well as providing a brief overview of salivary gland, bladder, ovarian and lung tumors.

  7. Alvespimycin Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors

    ClinicalTrials.gov

    2013-04-09

    and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Gastric Cancer; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Melanoma; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Ovarian Epithelial Cancer; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Unspecified Adult Solid Tumor, Protocol Specific; Untreated Metastatic Squamous Neck Cancer With Occult Primary

  8. Approaching Solid Tumor Heterogeneity on a Cellular Basis by Tissue Proteomics Using Laser Capture Microdissection and Biological Mass Spectrometry

    PubMed Central

    Johann, Donald J.; Rodriguez-Canales, Jaime; Mukherjee, Sumana; Prieto, DaRue A.; Hanson, Jeffrey C.; Emmert-Buck, Michael; Blonder, Josip

    2010-01-01

    The purpose of this study was to examine solid tumor heterogeneity on a cellular basis using tissue proteomics that relies on a functional relationship between Laser Capture Microdissection (LCM) and biological mass spectrometry (MS). With the use of LCM, homogeneous regions of cells exhibiting uniform histology were isolated and captured from fresh frozen tissue specimens, which were obtained from a human lymph node containing breast carcinoma metastasis. Six specimens ∼50 000 cell each (three from tumor proper and three from tumor stroma) were collected by LCM. Specimens were processed directly on LCM caps, using sonication in buffered methanol to lyse captured cells, solubilize, and digest extracted proteins. Prepared samples were analyzed by LC/MS/MS resulting in more than 500 unique protein identifications. Decoy database searching revealed a false-positive rate between 5 and 10%. Subcellular localization analysis for stromal cells revealed plasma membrane 14%, cytoplasm 39%, nucleus 11%, extracellular space 27%, and unknown 9%; and tumor cell results were 5%, 58%, 26%, 4%, and 7%, respectively. Western blot analysis confirmed specific linkage of validated proteins to underlying pathology and their potential role in solid tumor heterogeneity. With continued research and optimization of this method including analysis of additional clinical specimens, this approach may lead to an improved understanding of tumor heterogeneity, and serve as a platform for solid tumor biomarker discovery. PMID:19284784

  9. Multicenter study on adult growth hormone level in postoperative pituitary tumor patients.

    PubMed

    Cheng, Jing-min; Gu, Jian-wen; Kuang, Yong-qin; Ma, Yuan; Xia, Xun; Yang, Tao; Lu, Min; He, Wei-qi; Sun, Zhi-yong; Zhang, Yan-chao

    2015-03-01

    The objective of this study is to observe the adult growth hormone level in postoperative pituitary tumor patients of multi-centers, and explore the change of hypophyseal hormones in postoperative pituitary tumor patients. Sixty patients with pituitary tumor admitted during March, 2011-March, 2012 were selected. Postoperative hypophyseal hormone deficiency and the change of preoperative, intraoperative, and postoperative growth hormone levels were recorded. Growth hormone hypofunction was the most common hormonal hypofunction, which took up to 85.0 %. Adrenocortical hormone hypofunction was next to it and accounted for 58.33 %. GH + ACTH + TSH + Gn deficiency was the most common in postoperative hormone deficiency, which took up to 40.00 %, and GH + ACTH + TSH + Gn + AVP and GH deficiencies were next to it and accounted for 23.33 and 16.67 %, respectively. The hormone levels in patients after total pituitary tumor resection were significantly lower than those after partial pituitary tumor resection, and the difference was statistically significant; growth hormone and serum prolactin levels after surgery in two groups were decreased, and the difference was statistically significant. The incidence rate of growth hormone deficiency in postoperative pituitary tumor patients is high, which is usually complicated with deficiency of various hypophyseal hormones. In clinical, we should pay attention to the levels of the hypopnyseal hormones, and take timely measures to avoid postoperative complications.

  10. Liquid and solid meal replacement products differentially affect postprandial appetite and food intake in older adults.

    PubMed

    Stull, April J; Apolzan, John W; Thalacker-Mercer, Anna E; Iglay, Heidi B; Campbell, Wayne W

    2008-07-01

    Liquid and solid foods are documented to elicit differential appetitive and food intake responses. This study was designed to assess the influences of liquid vs solid meal replacement products on postprandial appetite ratings and subsequent food intake in healthy older adults. This study used a randomized and crossover design with two 1-day trials (1 week between trials), and 24 adults (12 men and 12 women) aged 50 to 80 years with body mass index (calculated as kg/m2) between 22 and 30 participated. After an overnight fast, the subjects consumed meal replacement products as either a beverage (liquid) or a bar (solid). The meal replacement products provided 25% of each subject's daily estimated energy needs with comparable macronutrient compositions. Subjects rated their appetite on a 100 mm quasilogarithmic visual analog scale before and 15, 30, 45, 60, 90, 120, and 150 minutes after consuming the meal replacement product. At minute 120, each subject consumed cooked oatmeal ad libitum to a "comfortable level of fullness." Postprandial composite (area under the curve from minute 15 to minute 120) hunger was higher (P=0.04) for the liquid vs solid meal replacement products and desire to eat (P=0.15), preoccupation with thoughts of food (P=0.07), and fullness (P=0.25) did not differ for the liquid vs solid meal replacement products. On average, the subjects consumed 13.4% more oatmeal after the liquid vs solid (P=0.006) meal replacement product. These results indicate that meal replacement products in liquid and solid form do not elicit comparable appetitive and ingestive behavior responses and that meal replacement products in liquid form blunt the postprandial decline in hunger and increase subsequent food intake in older adults.

  11. Liquid and Solid Meal Replacement Products Differentially Affect Postprandial Appetite and Food Intake in Older Adults

    PubMed Central

    Stull, April J.; Apolzan, John W.; Thalacker-Mercer, Anna E.; Iglay, Heidi B.; Campbell, Wayne W.

    2008-01-01

    Liquid and solid foods are documented to elicit differential appetitive and food intake responses. This study was designed to assess the influences of liquid vs solid meal replacement products on postprandial appetite ratings and subsequent food intake in healthy older adults. This study used a randomized and crossover design with two 1-day trials (1 week between trials), and 24 adults (12 men and 12 women) aged 50 to 80 years with body mass index (calculated as kg/m2) between 22 and 30 participated. After an overnight fast, the subjects consumed meal replacement products as either a beverage (liquid) or a bar (solid). The meal replacement products provided 25% of each subject's daily estimated energy needs with comparable macro-nutrient compositions. Subjects rated their appetite on a 100 mm quasilogarithmic visual analog scale before and 15, 30, 45, 60, 90, 120, and 150 minutes after consuming the meal replacement product. At minute 120, each subject consumed cooked oatmeal ad libitum to a “comfortable level of fullness.” Postprandial composite (area under the curve from minute 15 to minute 120) hunger was higher (P=0.04) for the liquid vs solid meal replacement products and desire to eat (P=0.15), preoccupation with thoughts of food (P=0.07), and fullness (P=0.25) did not differ for the liquid vs solid meal replacement products. On average, the subjects consumed 13.4% more oatmeal after the liquid vs solid (P=0.006) meal replacement product. These results indicate that meal replacement products in liquid and solid form do not elicit comparable appetitive and ingestive behavior responses and that meal replacement products in liquid form blunt the postprandial decline in hunger and increase subsequent food intake in older adults. PMID:18589034

  12. Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors

    ClinicalTrials.gov

    2016-10-13

    Retinoblastoma; Clear Cell Sarcoma; Renal Cell Carcinoma; Rhabdoid Tumor; Wilms Tumor; Hepatoblastoma; Neuroblastoma; Germ Cell Tumors; Ewings Sarcoma; Non-rhabdomyosarcoma Soft Tissue Sarcoma; Osteosarcoma; Rhabdomyosarcoma

  13. Lymphoid tumors of Xenopus laevis with different capacities for growth in larvae and adults.

    PubMed

    Robert, J; Guiet, C; Du Pasquier, L

    1994-01-01

    Three new lymphoid tumors offering an assortment of variants in terms of MHC class I expressions, MHC class II expression, and Ig gene transcription have been discovered in the amphibian Xenopus. One was developed in an individual of the isogenic LG15 clone (LG15/0), one in a frog of the LG15/40 clone (derived from a small egg recombinant of LG15), and one (ff-2) in a male ff sib of the individual in which MAR1, the first lymphoid tumor in Xenopus was found 2 years ago. These tumors developed primarily as thymus outgrowths and were transplantable in histocompatible tadpoles but not in nonhistocompatible hosts. Whereas LG15/0 and LG15/40 tumor cells also grow in adult LG15 frogs, the ff-2 tumor, like the MAR1 cell line, is rejected by adult ff animals. Using flow cytometry with fluorescence-labeled antibodies and immunoprecipitation analysis, we could demonstrate that, like MAR1, these three new tumors express on their cell surface lymphopoietic markers recognized by mAbs F1F6 and RC47, as well as T-cell lineage markers recognized by mAbs AM22 (CD8-like) and X21.2, but not by immunologobulin (Ig) nor MHC class II molecules. Another lymphocyte-specific marker AM15 is expressed by 15/0 and 15/40 but not ff-2 tumor cells. The ff-2 tumor cell expresses MHC class I molecule in association with beta 2-microglobulin on the surface, 15/40 cells contain cytoplasmic class I alpha chain that is barely detected at the cell surface by fluocytometry, and 15/0 cells do not synthesize class I alpha chain at all. The three new tumors all produce large amounts of IgM mRNA of two different sizes but no Ig protein on the membrane nor in the cytoplasm. All tumor cell types synthesize large amount of Myc mRNA and MHC class I-like transcripts considered to be non classical.

  14. A Study of Epacadostat in Combination With a PD-1 Inhibitor and Chemotherapy in Subjects With Advanced or Metastatic Solid Tumors (ECHO-207)

    ClinicalTrials.gov

    2017-03-20

    Advanced or Metastatic Solid Tumors; Advanced or Metastatic Colorectal Cancer (CRC); Pancreatic Ductal Adenocarcinoma (PDAC); Non-Small Cell Lung Cancer (NSCLC; Squamous or Nonsquamous); Advanced or Metastatic Solid Tumor That Progressed on Previous Therapy With a Programmed Cell Death Protein 1 (PD-1) Inhibitor; Advanced or Metastatic Solid Tumor That Progressed on Previous Therapy With a Programmed Cell Death Ligand 1 (PD-L1) Inhibitor

  15. Vorinostat in Combination With Paclitaxel and Carboplatin in Treating Patients With Metastatic or Recurrent Solid Tumors and HIV Infection

    ClinicalTrials.gov

    2016-10-11

    HIV Infection; Recurrent Anal Cancer; Recurrent Breast Cancer; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Stage IV Anal Cancer; Stage IV Breast Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Unspecified Adult Solid Tumor, Protocol Specific

  16. Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors.

    PubMed

    Beg, Muhammad S; Brenner, Andrew J; Sachdev, Jasgit; Borad, Mitesh; Kang, Yoon-Koo; Stoudemire, Jay; Smith, Susan; Bader, Andreas G; Kim, Sinil; Hong, David S

    2017-04-01

    Purpose Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-in-human, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Patients and Methods Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3 + 3 dose escalation trial. MRX34 was given intravenously twice weekly (BIW) for three weeks in 4-week cycles. Results Forty-seven patients with various solid tumors, including hepatocellular carcinoma (HCC; n = 14), were enrolled. Median age was 60 years, median prior therapies was 4 (range, 1-12), and most were Caucasian (68%) and male (57%). Most common adverse events (AEs) included fever (all grade %/G3%: 64/2), fatigue (57/13), back pain (57/11), nausea (49/2), diarrhea (40/11), anorexia (36/4), and vomiting (34/4). Laboratory abnormalities included lymphopenia (G3%/G4%: 23/9), neutropenia (13/11), thrombocytopenia (17/0), increased AST (19/4), hyperglycemia (13/2), and hyponatremia (19/2). Dexamethasone premedication was required to manage infusion-related AEs. The MTD for non-HCC patients was 110 mg/m(2), with two patients experiencing dose-limiting toxicities of G3 hypoxia and enteritis at 124 mg/m(2). The half-life was >24 h, and Cmax and AUC increased with increasing dose. One patient with HCC achieved a prolonged confirmed PR lasting 48 weeks, and four patients experienced SD lasting ≥4 cycles. Conclusion MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors. The MTD for the BIW schedule was 110 mg/m(2) for non-HCC and 93 mg/m2 for HCC

  17. Adult Embryonal Sarcoma of the Liver: Management of a Massive Liver Tumor

    PubMed Central

    Roudenko, Alexandra; El Hussein, Siba; Rizer, Magda

    2016-01-01

    Undifferentiated embryonal sarcomas of the liver are extremely rare cases in adults. We report the case of a 30-year-old male who presented with early satiety and abdominal pain due to a massive tumor originating from the left liver and occupying the entire epigastrium. The patient underwent bland embolization in an attempt to decrease the size of the tumor. He then underwent a formal left hepatectomy with resection of liver segments 2, 3, and 4. Extrahepatic inflow control of the portal vein and hepatic artery was performed prior to parenchymal transection. No Pringle maneuver was required. Pathology analysis showed a 45 cm tumor consistent with an undifferentiated embryonal sarcoma and negative microscopic margins. The epidemiology, treatment, and prognosis of this unusual cancer presentation are reviewed. PMID:27895954

  18. Neurocognitive and Family Functioning and Quality of Life Among Young Adult Survivors of Childhood Brain Tumors

    PubMed Central

    Hocking, Matthew C.; Hobbie, Wendy L.; Deatrick, Janet A.; Lucas, Matthew S.; Szabo, Margo M.; Volpe, Ellen M.; Barakat, Lamia P.

    2012-01-01

    Many childhood brain tumor survivors experience significant neurocognitive late effects across multiple domains that negatively affect quality of life. A theoretical model of survivorship suggests that family functioning and survivor neurocognitive functioning interact to affect survivor and family outcomes. This paper reviews the types of neurocognitive late effects experienced by survivors of pediatric brain tumors. Quantitative and qualitative data from three case reports of young adult survivors and their mothers are analyzed according to the theoretical model and presented in this paper to illustrate the importance of key factors presented in the model. The influence of age at brain tumor diagnosis, family functioning, and family adaptation to illness on survivor quality of life and family outcomes are highlighted. Future directions for research and clinical care for this vulnerable group of survivors are discussed. PMID:21722062

  19. Gamma-Secretase Inhibitor RO4929097 in Treating Young Patients With Relapsed or Refractory Solid Tumors, CNS Tumors, Lymphoma, or T-Cell Leukemia

    ClinicalTrials.gov

    2014-11-04

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood Infratentorial Ependymoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Gonadotroph Adenoma; Pituitary Basophilic Adenoma; Pituitary Chromophobe Adenoma; Pituitary Eosinophilic Adenoma; Prolactin Secreting Adenoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Spinal Cord Neoplasm; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent Pituitary Tumor; Recurrent/Refractory Childhood Hodgkin Lymphoma; T-cell Childhood Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; TSH Secreting Adenoma; Unspecified Childhood Solid Tumor, Protocol Specific

  20. Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors

    PubMed Central

    Do, Khanh; Wilsker, Deborah; Ji, Jiuping; Zlott, Jennifer; Freshwater, Tomoko; Kinders, Robert J.; Collins, Jerry; Chen, Alice P.; Doroshow, James H.; Kummar, Shivaani

    2015-01-01

    Purpose Wee1 tyrosine kinase phosphorylates and inactivates cyclin-dependent kinase (Cdk) 1/2 in response to DNA damage. AZD1775 is a first-in-class inhibitor of Wee1 kinase with single-agent antitumor activity in preclinical models. We conducted a phase I study of single-agent AZD1775 in adult patients with refractory solid tumors to determine its maximum-tolerated dose (MTD), pharmacokinetics, and modulation of phosphorylated Tyr15-Cdk (pY15-Cdk) and phosphorylated histone H2AX (γH2AX) levels in paired tumor biopsies. Patients and Methods AZD1775 was administered orally twice per day over 2.5 days per week for up to 2 weeks per 21-day cycle (3 + 3 design). At the MTD, paired tumor biopsies were obtained at baseline and after the fifth dose to determine pY15-Cdk and γH2AX levels. Six patients with BRCA-mutant solid tumors were also enrolled at the MTD. Results Twenty-five patients were enrolled. The MTD was established as 225 mg twice per day orally over 2.5 days per week for 2 weeks per 21-day cycle. Confirmed partial responses were observed in two patients carrying BRCA mutations: one with head and neck cancer and one with ovarian cancer. Common toxicities were myelosuppression and diarrhea. Dose-limiting toxicities were supraventricular tachyarrhythmia and myelosuppression. Accumulation of drug (t1/2 approximately 11 hours) was observed. Reduction in pY15-Cdk levels (two of five paired biopsies) and increases in γH2AX levels (three of five paired biopsies) were demonstrated. Conclusion This is the first report of AZD1775 single-agent activity in patients carrying BRCA mutations. Proof-of-mechanism was demonstrated by target modulation and DNA damage response in paired tumor biopsies. PMID:25964244

  1. Sulfatinib, a novel kinase inhibitor, in patients with advanced solid tumors: Results from a phase I study.

    PubMed

    Xu, Jian Ming; Wang, Yan; Chen, Yu Ling; Jia, Ru; Li, Jie; Gong, Ji Fang; Li, Jing; Qi, Chuan; Hua, Ye; Tan, Cui Rong; Wang, Jian; Li, Ke; Sai, Yang; Zhou, Feng; Ren, Yong Xin; Qing, Wei Guo; Jia, Hong; Su, Wei Guo; Shen, Lin

    2017-02-01

    Sulfatinib is a small molecule kinase inhibitor that targets tumor angiogenesis and immune modulation. This phase I study (NCT02133157) investigated the safety, pharmacokinetic characteristics, and preliminary anti-tumor activity of sulfatinib in patients with advanced solid tumors. The study included a dose-escalation phase (50-350 mg/day, 28-day cycle) with a Fibonacci (3+3) design, and a tumor-specific expansion phase investigating the tumor response to treatment. Two sulfatinib formulations were assessed: formulation 1 (5, 25, and 50 mg capsules) and formulation 2 (50 and 200 mg capsules). Seventy-seven Chinese patients received oral sulfatinib; the maximum tolerated dose was not reached. Dose-limiting toxicities included abnormal hepatic function and coagulation tests, and upper gastrointestinal hemorrhage. The most common treatment-related adverse events were proteinuria, hypertension and diarrhea. Among 34 patients receiving sulfatinib formulation 2, one patient with hepatocellular carcinoma and eight with neuroendocrine tumors exhibited a partial response; 15 had stable disease. The objective response rate was 26.5% (9/34) and the disease control rate was 70.6% (24/34). Pharmacokinetic, safety, and efficacy data supported continuous oral administration of sulfatinib at 300 mg as the recommended phase II dose. Sulfatinib exhibited an acceptable safety profile and encouraging antitumor activity in patients with advanced solid tumors, particularly neuroendocrine tumors.

  2. The Role of Myeloid-Derived Suppressor Cells in Patients with Solid Tumors: A Meta-Analysis

    PubMed Central

    Liu, Li; Wang, Guoping; Yuan, Xia

    2016-01-01

    Targeting immune cells or factors are effective for patients with solid tumors. Myeloid-derived suppressor cells (MDSCs) are known to have immunosuppressive functions, and the levels of MDSCs in patients with solid tumor are assumed to have prognostic values. This meta-analysis aimed at evaluating the relationship between MDSCs and the prognosis of patients with solid tumors. We searched articles in PUBMED and EMBASE comprehensively, updated to March 2016. Eight studies with 442 patients were included in the meta-analysis. We analyzed pooled hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS). The results showed that MDSCs were associated with poor OS (HR, 1.94; 95% confidence interval [CI], 1.42–2.66; P < 0.0001) in patients with solid tumors. PFS/RFS (HR, 1.85; 95% CI, 1.16–2.97; P = 0.01) also indicated the association between MDSCs and prognosis. The HRs and 95% CIs for OS in Asian and non-Asian patients were 2.53 (95% CI 1.61–3.42, p < 0.00001) and 1.67 (95% CI 1.14–2.46, p < 0.0001), respectively. We further analyzed the data according to tumor types. The combined HRs and 95% CIs for OS were 1.26 (95% CI 1.10–1.44, p = 0.0003) for gastrointestinal (GI) cancer, 2.59 (95% CI 1.69–3.98, p < 0.0001) for hepatocellular carcinoma (HCC) and 1.86 (95% CI 1.26–2.75, p = 0.002) for other tumor types. In conclusion, MDSCs had a fine prognostic value for OS and PFS/RFS in patients with solid tumors. MDSCs could be used as biomarkers to evaluate prognosis in clinical practice. PMID:27780254

  3. Romidepsin in Treating Patients With Lymphoma, Chronic Lymphocytic Leukemia, or Solid Tumors With Liver Dysfunction

    ClinicalTrials.gov

    2017-03-23

    Glioma; Lymphoma; Metastatic Malignant Solid Neoplasm; Neuroendocrine Neoplasm; Recurrent Adult Soft Tissue Sarcoma; Recurrent Bladder Carcinoma; Recurrent Breast Carcinoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Colorectal Carcinoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Malignant Solid Neoplasm; Recurrent Melanoma; Recurrent Pancreatic Carcinoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Thyroid Gland Carcinoma; Refractory Chronic Lymphocytic Leukemia; Refractory Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Stage III Lung Cancer; Stage III Pancreatic Cancer; Stage III Prostate Cancer; Stage III Renal Cell Cancer; Stage III Soft Tissue Sarcoma; Stage IIIA Breast Cancer; Stage IIIA Colorectal Cancer; Stage IIIA Skin Melanoma; Stage IIIB Breast Cancer; Stage IIIB Colorectal Cancer; Stage IIIB Skin Melanoma; Stage IIIC Breast Cancer; Stage IIIC Colorectal Cancer; Stage IIIC Skin Melanoma; Stage IV Breast Cancer; Stage IV Lung Cancer; Stage IV Pancreatic Cancer; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IV Skin Melanoma; Stage IV Soft Tissue Sarcoma; Stage IVA Colorectal Cancer; Stage IVB Colorectal Cancer; Unresectable Solid Neoplasm

  4. Risk of solid tumors and hematological malignancy in persons with Turner and Klinefelter syndromes: A national cohort study.

    PubMed

    Ji, Jianguang; Zöller, Bengt; Sundquist, Jan; Sundquist, Kristina

    2016-08-15

    The risk of solid and hematological malignancy in patients with Turner syndrome, characterized by X chromosome monosomy in women, and Klinefelter syndrome, characterized with two and more X chromosomes in men, is not well established, but such evidence may have etiological implications on cancer development. We identified a total of 1,409 women with Turner syndrome and 1,085 men with Klinefelter syndrome from the Swedish Hospital Discharge and Outpatient Register. These individuals were further linked to the Swedish Cancer Register to examine the standardized incidence ratios (SIRs) of cancer using the general population without Turner and Klinefelter syndromes as reference. The overall risk of cancer was 1.34 for women with Turner syndrome; it was increased only for solid tumors. For a specific type of tumor, the risk of melanoma and central nervous system tumor was significantly increased. For persons with Klinefelter syndrome, the risk of solid tumors was decreased (SIR = 0.66), whereas the risk of hematological malignancy was increased (SIR = 2.72). Non-Hodgkin lymphoma and leukemia showed an increased SIR of 3.02 and 3.62, respectively. Our study supported the hypothesis that X chromosome plays an important role in the etiology of solid tumors. The underlying mechanisms for the increased incidence of non-Hodgkin lymphoma and leukemia in persons with Klinefelter syndrome need to be investigated further.

  5. Consolidation treatment for high risk solid tumors in children with myeloablative chemotherapy and autologous hematopoietic progenitor stem cell transplantation

    PubMed Central

    Vargas, Alberto Olaya; Luna, Roberto Rivera; Garcia, Martin Perez; Cardos, Rocio Cárdenas; Hidalgo, Liliana Velasco; Jácome, Doris LordMéndez; Gutiérrez, Mariana Campos

    2013-01-01

    Background In childhood cancer, consolidation treatment with chemotherapy followed by autologous hematopoietic progenitor stem cell transplantation is currently an accepted treatment modality in patients with high-risk solid tumors or in patients who have relapsed after conventional treatment. Objectives The objective of this study was to describe the results of transplantation of a group of children who had high-risk solid tumors or relapsed after conventional chemotherapy regimens. Methods A retrospective analysis was conducted from January 1998 to October 2004 of all children with pathologic diagnoses of high-risk solid tumors or children that had previously relapsed after conventional chemotherapy and that were subsequently submitted to autologous hematopoietic progenitor stem cell transplantation. The analysis included overall survival rates, event-free survival rates, mortality rates and chemotherapy complications. Results Nineteen patients were submitted to this approach. The age range was from 27 to 196 months with a median age of 52 months. The overall survival rate at 100 days was observed in 79%, the three-year event-free survival rate was 63%. The mortality rate secondary to the myeloablative chemotherapy regimen was 21% (n = 4). Only three patients (15.8%) relapsed with tumor progression after transplant. Conclusion Autologous hematopoietic progenitor stem cell transplantation is still a successful procedure in patients with solid tumors refractory to conventional chemotherapy. PMID:24255618

  6. Treatment of solid tumors with chimeric antigen receptor-engineered T cells: current status and future prospects.

    PubMed

    Di, Shengmeng; Li, Zonghai

    2016-04-01

    Chimeric antigen receptors (CARs) are artificial recombinant receptors that generally combine the antigen-recognition domain of a monoclonal antibody with T cell activation domains. Recent years have seen great success in clinical trials employing CD19-specific CAR-T cell therapy for B cell leukemia. Nevertheless, solid tumors remain a major challenge for CAR-T cell therapy. This review summarizes the preclinical and clinical studies on the treatment of solid tumors with CAR-T cells. The major hurdles for the success of CAR-T and the novel strategies to address these hurdles have also been described and discussed.

  7. Veliparib, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed or Refractory Lymphoma, Multiple Myeloma, or Solid Tumors

    ClinicalTrials.gov

    2015-10-14

    Adult B Acute Lymphoblastic Leukemia; Adult Nasal Type Extranodal NK/T-Cell Lymphoma; Adult Solid Neoplasm; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Hepatosplenic T-Cell Lymphoma; Intraocular Lymphoma; Lymphomatous Involvement of Non-Cutaneous Extranodal Site; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Nodal Marginal Zone Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Plasma Cell Myeloma; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  8. Glucose transporter GLUT1 expression and clinical outcome in solid tumors: a systematic review and meta-analysis.

    PubMed

    Wang, Ji; Ye, Chenyang; Chen, Cong; Xiong, Hanchu; Xie, Binbin; Zhou, Jichun; Chen, Yongxia; Zheng, Shu; Wang, Linbo

    2017-02-07

    Glucose transporter 1 (GLUT1), the uniporter protein encoded by the SLC2A1 gene, is a key rate-limiting factor in the transport of glucose in cancer cells, and frequently expressed in a significant proportion of human cancers. Numerous studies have reported paradoxical evidence of the relationship between GLUT1 expression and prognosis in solid human tumors. To address this discrepancy, we conducted a thorough search of Pubmed and Web of Science for studies evaluating the expression of GLUT1 and overall survival (OS) and disease-free survival (DFS) in patients with solid cancer from 1993 to April 2016. Data from published researches were extracted and computed into odds ratio (OR). A total of 26 studies including 2948 patients met our search criteria and were evaluated. Overexpression of GLUT1 was found to significantly correlate with poor 3-year OS (OR: 2.86; 95% CI, 1.90-4.32, P < 0.00001) and 5-year OS (OR: 2.52; 95% CI, 1.75-3.61, P < 0.00001) of solid tumors. Similar results were observed when analysis of DFS was performed. Subgroup analysis revealed that elevated GLUT1 expression was associated with worse prognosis of oral squamous cell carcinoma and breast cancer. Taken together, overexpression of GLUT1 is correlated with poor survival in most solid tumors, suggesting that the expression status of GLUT1 is a vital prognostic indicator and promising therapeutic target in solid tumors.

  9. Interleukin-2 Plus Interferon Alfa in Treating Adults With Metastatic Cancer

    ClinicalTrials.gov

    2011-05-10

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Precancerous/Nonmalignant Condition; Unspecified Adult Solid Tumor, Protocol Specific

  10. Pediatric and adult malignant peripheral nerve sheath tumors: an analysis of data from the surveillance, epidemiology, and end results program.

    PubMed

    Amirian, E Susan; Goodman, J Clay; New, Pamela; Scheurer, Michael E

    2014-02-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft tissue sarcomas that arise predominantly from Schwann cells. Despite the fact that MPNSTs have high local recurrence rates and are generally associated with poor prognosis, little is known about prognostic factors or effective clinical management for this tumor type. The purpose of this study was to describe the distributions of patient and tumor characteristics and to identify predictors of cause-specific survival among MPNST cases reported to SEER between 1973 and 2008. Patient and tumor characteristics were compared between pediatric and adult MPNST cases. Cox regression and tree-based survival analysis were used to examine factors associated with MPNST-related mortality separately among adults and children. A total of 1,315 MPNST cases were isolated from the 1973-2008 SEER dataset. Among pediatric cases, sex, race, and radiation therapy predicted MPNST survival, whereas among adults, tumor site, tumor grade, number of primary tumors, and tumor size were significant predictors. As tumor size at diagnosis/resection may be the only somewhat "modifiable" prognostic factor, future studies should aim to identify biological and social attributes associated with tumor size at diagnosis, separately among individuals with and without NF-1, in order to help identify earlier opportunities for clinical intervention.

  11. Oxaliplatin, Ifosfamide and Etoposide in Treating Young Patients With Recurrent or Refractory Solid Tumors or Lymphoma

    ClinicalTrials.gov

    2014-02-21

    Angioimmunoblastic T-cell Lymphoma; B-cell Childhood Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; T-cell Childhood Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

  12. Metabolism, Excretion, and Pharmacokinetics of Oral Brivanib in Patients with Advanced or Metastatic Solid Tumors

    PubMed Central

    Masson, Eric; Fischer, Bruce S.; Gong, Jiachang; Iyer, Ramaswamy; Gan, Jinping; Pursley, Janice; Patricia, Daniel; Williams, Daphne; Ganapathi, Ram

    2010-01-01

    The goal of this study was to evaluate the pharmacokinetics, mass balance, metabolism, routes and extent of elimination, and safety of a single oral dose of 14C-labeled brivanib alaninate and the safety and tolerability of brivanib after multiple doses in patients with advanced or metastatic solid tumors. This was a two-part, single-center, open-label, single oral-dose (part A) followed by multiple-dose (part B) study in patients with advanced or metastatic solid tumors. In part A, patients received a single dose of [14C]brivanib alaninate and in part B patients received 800 mg of nonradiolabeled brivanib alaninate every day. Four patients (two white, two black: two with non–small-cell lung cancer, one with ovarian cancer, and one with renal cell carcinoma) were treated in both parts. The median time to reach the maximal plasma concentration of brivanib was 1 h, geometric mean maximal plasma concentration was 6146 ng/ml, mean terminal half-life was 13.8 h, and geometric mean apparent oral clearance was 14.7 l/h. After a single oral dose of [14C]brivanib alaninate, 12.2 and 81.5% of administered radioactivity was recovered in urine and feces, respectively. Brivanib alaninate was completely converted to the active moiety, brivanib, and the predominant route of elimination was fecal. Renal excretion of unchanged brivanib was minimal. Brivanib was well tolerated; fatigue was the most frequent adverse event occurring in all patients and the most frequent treatment-related adverse event in three (75%). The best clinical response in one patient was stable disease; the other three had progressive disease. Brivanib alaninate was rapidly absorbed and extensively metabolized after a single 800-mg oral dose; the majority of drug-related radioactivity was excreted in feces. PMID:20671097

  13. Endoplasmic reticulum stress in the proapoptotic action of edelfosine in solid tumor cells.

    PubMed

    Nieto-Miguel, Teresa; Fonteriz, Rosalba I; Vay, Laura; Gajate, Consuelo; López-Hernández, Silvia; Mollinedo, Faustino

    2007-11-01

    The endoplasmic reticulum (ER) has been posited as a potential anticancer target. The synthetic antitumor alkyl-lysophospholipid analogue edelfosine accumulates in the ER of solid tumor cells. This ER accumulation of the drug leads to the inhibition of phosphatidylcholine and protein synthesis, G(2)-M arrest, depletion of ER-stored Ca(2+), Bax up-regulation and activation, transcriptional factor growth arrest and DNA damage-inducible gene 153 up-regulation, caspase-4 and caspase-8 activation, and eventually to apoptosis. Edelfosine prompted ER stress apoptotic signaling, but not the survival unfolded protein response. Edelfosine also induced persistent c-Jun NH(2)-terminal kinase (JNK) activation. Gene transfer-mediated overexpression of apoptosis signal-regulating kinase 1, which plays a crucial role in ER stress, enhanced edelfosine-induced JNK activation and apoptosis. Inhibition of JNK, caspase-4, or caspase-8 activation diminished edelfosine-induced apoptosis. Edelfosine treatment led to the generation of the p20 caspase-8 cleavage fragment of BAP31, directing proapoptotic signals between the ER and the mitochondria. bax(-/-)bak(-/-) double-knockout cells fail to undergo edelfosine-induced ER-stored Ca(2+) release and apoptosis. Wild-type and bax(-/-)bak(-/-) cells showed similar patterns of phosphatidylcholine and protein synthesis inhibition, despite their differences in drug sensitivity. Thus, edelfosine-induced apoptosis is dependent on Bax/Bak-mediated ER-stored Ca(2+) release, but phosphatidylcholine and protein synthesis inhibition is not critical. Transfection-enforced expression of Bcl-X(L), which localizes specifically in mitochondria, prevented apoptosis without inhibiting ER-stored Ca(2+) release. These data reveal that edelfosine induces an ER stress response in solid tumor cells, providing novel insights into the edelfosine-mediated antitumor activity. Our data also indicate that mitochondria are indispensable for this edelfosine-induced cell

  14. Vorinostat With or Without Isotretinoin in Treating Young Patients With Recurrent or Refractory Solid Tumors, Lymphoma, or Leukemia

    ClinicalTrials.gov

    2014-06-16

    Childhood Acute Promyelocytic Leukemia (M3); Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Juvenile Myelomonocytic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Relapsing Chronic Myelogenous Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

  15. Safe and Immunocompatible Nanocarriers Cloaked in RBC Membranes for Drug Delivery to Treat Solid Tumors

    PubMed Central

    Luk, Brian T.; Fang, Ronnie H.; Hu, Che-Ming J.; Copp, Jonathan A.; Thamphiwatana, Soracha; Dehaini, Diana; Gao, Weiwei; Zhang, Kang; Li, Shulin; Zhang, Liangfang

    2016-01-01

    The therapeutic potential of nanoparticle-based drug carriers depends largely on their ability to evade the host immune system while delivering their cargo safely to the site of action. Of particular interest are simple strategies for the functionalization of nanoparticle surfaces that are both inherently safe and can also bestow immunoevasive properties, allowing for extended blood circulation times. Here, we evaluated a recently reported cell membrane-coated nanoparticle platform as a drug delivery vehicle for the treatment of a murine model of lymphoma. These biomimetic nanoparticles, consisting of a biodegradable polymeric material cloaked with natural red blood cell membrane, were shown to efficiently deliver a model chemotherapeutic, doxorubicin, to solid tumor sites for significantly increased tumor growth inhibition compared with conventional free drug treatment. Importantly, the nanoparticles also showed excellent immunocompatibility as well as an advantageous safety profile compared with the free drug, making them attractive for potential translation. This study demonstrates the promise of using a biomembrane-coating approach as the basis for the design of functional, safe, and immunocompatible nanocarriers for cancer drug delivery. PMID:27217833

  16. Phase I Study of Capecitabine, Oxaliplatin, Bevacizumab, and Everolimus in Advanced Solid Tumors

    PubMed Central

    Rangwala, F.; Bendell, J.; Kozloff, M.; Arrowood, C.; Dellinger, A.; Meadows, J.; Tourt-Uhlig, S.; Murphy, J.; Meadows, K.L.; Starr, A.; Broderick, S.; Brady, J.C.; Cushman, S. M.; Morse, M.; Uronis, H.; Hsu, S.D.; Zafar, S.Y.; Wallace, J.; Starodub, A.; Strickler, J.; Pang, H.; Nixon, A.B.; Hurwitz, H.

    2014-01-01

    Purpose To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients. Design This was a standard “3+3” dose-escalation trial. All subjects received bevacizumab 7.5mg/kg on day one of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. Results Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; eight of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival. Conclusions Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5mg daily; capecitabine 680mg/m2 BID days 1-14; oxaliplatin 100mg/m2 and bevacizumab 7.5mg/kg, day one. Activity was noted in mCRC. PMID:24711126

  17. Pancreatic neuroendocrine tumor and solid-pseudopapillary neoplasm: Key immunohistochemical profiles for differential diagnosis

    PubMed Central

    Ohara, Yusuke; Oda, Tatsuya; Hashimoto, Shinji; Akashi, Yoshimasa; Miyamoto, Ryoichi; Enomoto, Tsuyoshi; Satomi, Kaishi; Morishita, Yukio; Ohkohchi, Nobuhiro

    2016-01-01

    AIM To reveal better diagnostic markers for differentiating neuroendocrine tumor (NET) from solid-pseudopapillary neoplasm (SPN), focusing primarily on immunohistochemical analysis. METHODS We reviewed 30 pancreatic surgical specimens of NET (24 cases) and SPN (6 cases). We carried out comprehensive immunohistochemical profiling using 9 markers: Synaptophysin, chromogranin A, pan-cytokeratin, E-cadherin, progesterone receptor, vimentin, α-1-antitrypsin, CD10, and β-catenin. RESULTS E-cadherin staining in NETs, and nuclear labeling of β-catenin in SPNs were the most sensitive and specific markers. Dot-like staining of chromogranin A might indicate the possibility of SPNs rather than NETs. The other six markers were not useful because their expression overlapped widely between NETs and SPNs. Moreover, two cases that had been initially diagnosed as NETs on the basis of their morphological features, demonstrated SPN-like immunohistochemical profiles. Careful diagnosis is crucial as we actually found two confusing cases showing disagreement between the tumor morphology and immunohistochemical profiles. CONCLUSION E-cadherin, chromogranin A, and β-catenin were the most useful markers which should be employed for differentiating between NET and SPN. PMID:27784972

  18. Profile of farletuzumab and its potential in the treatment of solid tumors

    PubMed Central

    Sato, Seiya; Itamochi, Hiroaki

    2016-01-01

    Folate receptor (FR) α expression in normal tissues is restricted to a subpopulation of epithelial cells. In contrast, FRα is overexpressed in epithelial ovarian cancer (EOC) and non-small-cell lung carcinoma. Therefore, FRα is considered a promising therapeutic target for EOC and non-small-cell lung carcinoma. Farletuzumab (MORAb-003) is a humanized monoclonal antibody of immunoglobulin G subtype 1 kappa, targeting human FRα. To date, Phase I/II clinical trials have clearly demonstrated the feasibility and safety of farletuzumab as a treatment option against solid tumors. However, in Phase III clinical trial that was conducted to verify the combined effect of paclitaxel–carboplatin combination therapy and farletuzumab for patients with recurrent EOC, improvement in progression-free survival was not statistically significant. This result might be owing to the fact that the eligibility criteria for these studies did not include FRα expression. The significance of FRα as a predictive/prognostic biomarker remains unclear. In addition, there is currently no established biomarker to predict the response and toxicities among patients receiving farletuzumab therapy. Furthermore, the primary mechanism of action of farletuzumab has not yet been identified. Therefore, further research to identify the mechanism of farletuzumab in tumor suppression is necessary to clarify the full potential of this chemotherapeutic agent. PMID:27022278

  19. Doxorubicin-transferrin conjugate triggers pro-oxidative disorders in solid tumor cells.

    PubMed

    Szwed, Marzena; Wrona, Dominika; Kania, Katarzyna D; Koceva-Chyla, Aneta; Marczak, Agnieszka

    2016-03-01

    The formation of reactive oxygen species (ROS) is a widely accepted mechanism of doxorubicin (DOX) toxicity toward cancer cells. However, little is known about the potential of new systems, designed for more efficient and targeted doxorubicin delivery (i.e. protein conjugates, polymeric micelles, liposomes, monoclonal antibodies), to induce oxidative stress (OS) in tumors and hematological malignancies. Therefore, the objective of our study was to determine the relation between the toxicity of doxorubicin-transferring (DOX-TRF) conjugate and its capability to generate oxidative/nitrosative stress in solid tumor cells. Our research proves that DOX-TRF conjugate displays higher cytotoxicity towards lung adenocarcinoma epithelial (A549) and hepatocellular carcinoma (HepG2) cell lines than the reference free drug (DOX) and induces more extensive OS, characterized by a significant decrease in the total cellular antioxidant capacity, glutathione level and amount of -SH groups and an increase in hydroperoxide content. The intracellular redox imbalance was accompanied by changes in the transcription of genes encoding key antioxidant enzymes engaged in the sustaining of cellular redox homeostasis: superoxide dismutase (SOD), catalase (CAT), glutathione transferase (GST) and glutathione peroxidase (GP).

  20. Gold-nanoparticle-based theranostic agents for radiotherapy of malignant solid tumors

    NASA Astrophysics Data System (ADS)

    Moeendarbari, Sina

    Radiation therapy is one of the three major methods of cancer treatment. The fundamental goal of radiotherapy is to deliver high radiation doses to targets while simultaneously minimizing doses to critical structures and healthy normal tissues. The aim of this study is to develop a general, practical, and facile method to prepare nanoscale theranostic agents for more efficacious radiation therapy with less adverse side effects. First, a novel type of gold nanoparticle, hollow Au nanoparticles (HAuNPs) which was synthesized using the unique bubble template synthesis method developed in our lab, are studied in vitro and in vivo to investigate their effect as radiosensitizing agents to enhance the radiation dose during external radiotherapy. The results showed the promising potential of using HAuNPs as radiosensitization agents for efficacious treatment of breast cancer. Second, a novel radiolabeling method is developed to incorporate medical radioisotopes to gold nanoparticles. We incorporate palladium-103 (103Pd), a radioisotope currently in clinical brachytherapy, into a hollow gold nanoparticle. The resulting 103Pd Au nanoparticles in the form of a colloidal suspension can be administered by direct injection into tumors, serving as internal radiation sources (nanoseeds) for radiation therapy. The size of the nanoseed, 150nm in diameter, is large enough to prevent nanoseeds from diffusing into other areas while still small enough to allow them to homogeneously distribute inside the tumor. The therapeutic efficacy of 103Pd Au nanoseeds have been tested when intratumorally injected into a prostate cancer xenograft model. The findings showed that this nanoseed-based brachytherapy has the potential to provide a theranostic solution to unresectable solid tumors. Finally, to make real clinical application more plausible, multi-functional magnetic nanoseeds nanoparticles for imaging-guided radiotherapy are synthesized and characterized.

  1. Systemic irradiation for selected stage IV and recurrent pediatric solid tumors: method, toxicity, and preliminary results

    SciTech Connect

    Wharam, M.D.; Kaizer, H.; Leventhal, B.G.; Munoz, L.; Tutschka, P.J.; Santos, G.W.; Elfenbein, G.J.; Order, S.E.

    1980-02-01

    Eight patients with advanced pediatric solid tumors received either sequential upper and lower half-body irradiation (HBI) (7.5 rad/min to 500 rad total) or total body irradiation (TBI) (7.5 rad/min to 800 rad total) as part of two multimodality treatment regimens. All patients received combination chemotherapy; drugs were determined by the tumor type. The TBI regimen was selected for two patients who had progression of disease with conventional chemotherapy and for two patients with stage IV neuroblastoma. This intensive regimen consisted of bone marrow harvesting, followed by local radiation to gross disease, marrow-ablative chemotherapy, TBI, and re-infusion of the cryopreserved autologous marrow. Significant acute toxicity was followed by hematologic reconstitution in each patient within seven weeks. At this writing, two patients survived, one of whom is disease free two and one half years without maintenance chemotherapy. A less intensive, outpatient regimen was selected for four patients; three had a complete or good partial response to chemotherapy. The fourth patient had tumor-involved bone marrow not responsive to chemotherapy and was therefore ineligible for marrow cryopreservation and TBI. Each of these four patients received HBI after chemotherapy and local radiation to the primary and/or metastatic sites. Acute toxicity was limited to nausea and vomiting. Significant leukopenia and thrombocytopenia occurred in three patients. All four patients were alive 10 to 26 months post HBI. This pilot study demonstrates that chemotherapy can be integrated with local fractionated radiation, and systemic radiation given as HBI or TBI with acceptable toxicity; sufficient bone marrow stem cells can be harvested after conventional chemotherapy and then cryopreserved to permit hematologic reconstitution of the patient who receives marrow ablative therapy.

  2. Stress-mediated progression of solid tumors: effect of mechanical stress on tissue oxygenation, cancer cell proliferation and drug delivery

    PubMed Central

    Mpekris, Fotios; Angeli, Stelios; Pirentis, Athanassios P.; Stylianopoulos, Triantafyllos

    2015-01-01

    Oxygen supply plays a central role in cancer cell proliferation. While vascular density increases at the early stages of carcinogenesis, mechanical solid stresses developed during growth compress tumor blood vessels and, thus, drastically reduce the supply of oxygen, but also the delivery of drugs at inner tumor regions. Among other effects, hypoxia and reduced drug delivery compromise the efficacy of radiation and chemo/nano therapy, respectively. In the present study, we developed a mathematical model of tumor growth to investigate the interconnections among tumor oxygenation that supports cancer cell proliferation, the heterogeneous accumulation of mechanical stresses owing to tumor growth, the non-uniform compression of intratumoral blood vessels due to the mechanical stresses, and the insufficient delivery of oxygen and therapeutic agents because of vessel compression. We found that the high vascular density and increased cancer cell proliferation often observed in the periphery compared to the interior of a tumor can be attributed to heterogeneous solid stress accumulation. Highly vascularized peripheral regions are also associated with greater oxygenation compared with the compressed, less vascularized inner regions. We also modeled the delivery of drugs of two distinct sizes, namely chemotherapy and nanomedicine. Model predictions suggest that drug delivery is affected negatively by vessel compression independently of the size of the therapeutic agent. Finally, we demonstrated the applicability of our model to actual geometries, employing a breast tumor model derived from MR images. PMID:25968141

  3. A multi-functional role of interferon regulatory factor-8 in solid tumor and myeloid cell biology.

    PubMed

    Abrams, Scott I

    2010-03-01

    Understanding mechanisms of tumor escape are critically important not only to improving our knowledge of cancer biology, but also for the overall development of more effective anti-neoplastic therapies. Our laboratory focuses on mechanisms of apoptotic resistance, with emphasis on Fas loss of function as an important determinant of tumor progression. Our work in solid tumor systems has led to the identification of interferon regulatory factor-8 (IRF-8) as a differentially expressed gene important for tumor cell response to cytotoxicity, including Fas-mediated apoptosis and host-anti-tumor immunosurveillance mechanisms. Although IRF-8 was originally identified in the regulation of normal and neoplastic myeloid cell development, these findings revealed a new functional role for IRF-8 in non-hematopoietic malignancies and establish a molecular basis for its potential manipulation during cancer therapy.

  4. Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors and increase nanoparticle delivery.

    PubMed

    Fu, Xinping; Rivera, Armando; Tao, Lihua; Zhang, Xiaoliu

    2013-11-15

    Converting T cells into tumor cell killers by grafting them with a chimeric antigen receptor (CAR) has shown promise as a cancer immunotherapeutic. However, the inability of these cells to actively migrate and extravasate into tumor parenchyma has limited their effectiveness in vivo. Here we report the construction of a CAR containing an echistatin as its targeting moiety (eCAR). As echistatin has high binding affinity to αvβ3 integrin that is highly expressed on the surface of endothelial cells of tumor neovasculature, T cells engrafted with eCAR (T-eCAR) can efficiently lyse human umbilical vein endothelial cells and tumor cells that express αvβ3 integrin when tested in vitro. Systemic administration of T-eCAR led to extensive bleeding in tumor tissues with no evidence of damage to blood vessels in normal tissues. Destruction of tumor blood vessels by T-eCAR significantly inhibited the growth of established bulky tumors. Moreover, when T-eCAR was codelivered with nanoparticles in a strategically designed temporal order, it dramatically increased nanoparticle deposition in tumor tissues, pointing to the possibility that it may be used together with nanocarriers to increase their capability to selectively deliver antineoplastic drugs to tumor tissues.

  5. Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors, and increase nanoparticle delivery

    PubMed Central

    Fu, Xinping; Rivera, Armando; Tao, Lihua; Zhang, Xiaoliu

    2013-01-01

    Converting T cells into tumor cell killers by grafting them with a chimeric antigen receptor (CAR) has shown promise as a cancer immunotherapeutic. However, the inability of these cells to actively migrate and extravasate into tumor parenchyma has limited their effectiveness in vivo. Here we report the construction of a chimeric antigen receptor containing an echistatin as its targeting moiety (eCAR). As echistatin has high binding affinity to αvβ3 integrin that is highly expressed on the surface of endothelial cells of tumor neovasculature, T cells engrafted with eCAR (T-eCAR) can efficiently lyse human umbilical vein endothelial cells and tumor cells that express αvβ3 integrin when tested in vitro. Systemic administration of T-eCAR led to extensive bleeding in tumor tissues with no evidence of damage to blood vessels in normal tissues. Destruction of tumor blood vessels by T-eCAR significantly inhibited the growth of established bulky tumors. Moreover, when T-eCAR was co-delivered with nanoparticles in a strategically designed temporal order, it dramatically increased nanoparticle deposition in tumor tissues, pointing to the possibility that it may be used together with nanocarriers to increase their capability to selectively deliver antineoplastic drugs to tumor tissues. PMID:23661285

  6. Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2016-02-18

    Dose Escalation; Safety; Preliminary Efficacy; Advanced Solid Tumors; Metastatic Breast Cancer; Advanced Pancreatic Adenocarcinoma; Metastatic Colorectal Cancer; Recurrent Glioblastoma Multiforme; Gastric Cancer; Gastroesophageal Junction Cancer; Triple Negative Metastatic Breast Cancer; Hormone Receptor Positive (ER+/PR+, and Her2-) Metastatic Breast Cancer

  7. TMPRSS4 as an emerging potential poor prognostic factor for solid tumors: A systematic review and meta-analysis

    PubMed Central

    Zeng, Ping; Zhang, Peng; Zhou, Li-Na; Tang, Min; Shen, Yi-Xin; Jin, Jun; Zhu, Ya-Qun; Chen, Min-Bin

    2016-01-01

    Recent studies have investigated the potential prognostic value of the transmembrane protease serine 4 (TMPRSS4) in various solid tumors. Yet, the results are inconclusive. Here, we performed this meta-analysis to clarify this issue. Relevant articles were identified by searching PubMed, Web of Science and Embase databases. The primary outcome endpoints were patients' overall survival (OS) and time to tumor progression (TTP). Twelve studies involving 1,955 participants were included. We showed that high TMPRSS4 expression in tumor tissues was significantly associated with patients' poor OS (pooled HR = 2.981, 95% CI = 2.296-3.869, P < 0.001) and short TTP (pooled HR = 2.456, 95% CI = 1.744-3.458, P < 0.001). A subgroup analysis revealed that the association between TMPRSS4 and the outcome endpoints (OS or TTP) was also significant within China region. We conclude that TMPRSS4 overexpression in solid tumors is associated with patients' poor prognosis. TMPRSS4 could be a valuable prognosis biomarker or a promising therapeutic target of solid tumor. PMID:27344186

  8. Immunogenicity of murine solid tumor models as a defining feature of in vivo behavior and response to immunotherapy.

    PubMed

    Lechner, Melissa G; Karimi, Saman S; Barry-Holson, Keegan; Angell, Trevor E; Murphy, Katherine A; Church, Connor H; Ohlfest, John R; Hu, Peisheng; Epstein, Alan L

    2013-01-01

    Immune profiling has been widely used to probe mechanisms of immune escape in cancer and identify novel targets for therapy. Two emerging uses of immune signatures are to identify likely responders to immunotherapy regimens among individuals with cancer and to understand the variable responses seen among subjects with cancer in immunotherapy trials. Here, the immune profiles of 6 murine solid tumor models (CT26, 4T1, MAD109, RENCA, LLC, and B16) were correlated to tumor regression and survival in response to 2 immunotherapy regimens. Comprehensive profiles for each model were generated using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and flow cytometry techniques, as well as functional studies of suppressor cell populations (regulatory T cells and myeloid-derived suppressor cells), to analyze intratumoral and draining lymphoid tissues. Tumors were stratified as highly or poorly immunogenic, with highly immunogenic tumors showing a significantly greater presence of T-cell costimulatory molecules and immune suppression in the tumor microenvironment. An absence of tumor-infiltrating cytotoxic T lymphocytes and mature dendritic cells was seen across all models. Delayed tumor growth and increased survival with suppressor cell inhibition and tumor-targeted chemokine+/-dendritic cells vaccine immunotherapy were associated with high tumor immunogenicity in these models. Tumor MHC class I expression correlated with the overall tumor immunogenicity level and was a singular marker to predict immunotherapy response with these regimens. By using experimental tumor models as surrogates for human cancers, these studies demonstrate how select features of an immune profile may be utilized to identify patients most likely to respond to immunotherapy regimens.

  9. A facile route to core-shell nanoparticulate formation of arsenic trioxide for effective solid tumor treatment

    NASA Astrophysics Data System (ADS)

    Zhang, Zongjun; Liu, Hanyu; Zhou, Hualu; Zhu, Xianglong; Zhao, Zhenghuan; Chi, Xiaoqin; Shan, Hong; Gao, Jinhao

    2016-02-01

    Arsenic trioxide has achieved great clinical success in the treatment of acute promyelocytic leukemia (APL). However, it is difficult to replicate the success in other cancers, such as solid tumors, in part because of the rapid renal clearance and dose-limiting toxicity. Nanotechnology is expected to overcome these disadvantages through altering its pharmacokinetics and concentrating the drug at the desired sites. Herein, we report a ``one-pot'' method to develop arsenic-based nanodrugs by in situ coating the as-prepared arsenic nanocomplexes with porous silica shells. This process can be easily reproduced and scaled up because no complicated synthesis and purification steps are involved. This core-shell embedding method endows nanodrugs with high loading capacity (57.9 wt%) and a prolonged pH-responsive releasing profile, which is crucial to increase the drug concentration at tumor sites and improve the drug efficacy. Based on these unique features, the nanodrugs significantly inhibit the growth of solid tumors without adverse side effects. Therefore, we anticipate that the arsenic-based nanodrugs generated by this facile synthetic route may be a powerful and alternative strategy for solid tumor therapy.Arsenic trioxide has achieved great clinical success in the treatment of acute promyelocytic leukemia (APL). However, it is difficult to replicate the success in other cancers, such as solid tumors, in part because of the rapid renal clearance and dose-limiting toxicity. Nanotechnology is expected to overcome these disadvantages through altering its pharmacokinetics and concentrating the drug at the desired sites. Herein, we report a ``one-pot'' method to develop arsenic-based nanodrugs by in situ coating the as-prepared arsenic nanocomplexes with porous silica shells. This process can be easily reproduced and scaled up because no complicated synthesis and purification steps are involved. This core-shell embedding method endows nanodrugs with high loading capacity

  10. Adolescent and young adult survivors of childhood brain tumors: Life after treatment in their own words

    PubMed Central

    Hobbie, Wendy L.; Ogle, Sue; Reilly, Maureen; Barakat, Lamia; Lucas, Matthew S.; Ginsberg, Jill P.; Fisher, Michael J.; Volpe, Ellen M.; Deatrick, Janet A.

    2015-01-01

    Background To date there are few studies that examine the perspectives of older survivors of childhood brain tumors who are living with their families in terms of their sense of self and their role in their families. Objective To describe how adolescent and young adult survivors (AYA) of childhood brain tumors describe their HRQOL, that is their physical, emotional, and social functioning. Methods This qualitative descriptive study included a purposive sample of 41 AYA survivors of a childhood brain tumor who live with their families. Home interviews were conducted using a semi-structured interview guide. Directed content analytic techniques were used to analyze data using HRQOL as a framework. Results This group of brain tumor survivors described their everyday lives in terms of their physical health, neurocognitive functioning, emotional health, social functioning, and self-care abilities. Overall, survivors struggle for normalcy in the face of changed functioning due to their cancer and the (late) effects of their treatment. Conclusions Neurocognitive issues seemed most compelling in the narratives. The importance of families went beyond the resources, structure, and support for functioning. Their families provided the recognition that they were important beings and their existence mattered to someone. Implications for Practice The value and complexity of care coordination was highlighted by the multifaceted needs of the survivors. Advocacy for appropriate and timely educational, vocational, and social support is critical as part of comprehensive cancer survivorship care. PMID:25950583

  11. A Pediatric Tumor Found Frequently in the Adult Population: A Case of Anaplastic Astroblastoma in an Elderly Patient and Review of the Literature

    PubMed Central

    Batouli, Ali; Stabingas, Kristen; Alcindor, Dunbar; Abdel Aziz, Khaled; Pu, Cunfeng; Williams, Robert; Yu, Alexander

    2017-01-01

    Astroblastomas are rare, potentially curable primary brain tumors which can be difficult to diagnose. We present the case of astroblastoma in a 73-year-old male, an atypical age for this tumor, more classically found in pediatric and young adult populations. Through our case and review of the literature, we note that this tumor is frequently reported in adult populations and the presentation of this tumor in the elderly is well described. This tumor is an important consideration in the differential diagnosis when managing both pediatric and adult patients of any age who present with the imaging findings characteristic of this rare tumor. PMID:28239500

  12. BRAFV600 mutations in solid tumors, other than metastatic melanoma and papillary thyroid cancer, or multiple myeloma: a screening study

    PubMed Central

    Cohn, Allen L; Day, Bann-Mo; Abhyankar, Sarang; McKenna, Edward; Riehl, Todd; Puzanov, Igor

    2017-01-01

    Background Mutations in the BRAF gene have been implicated in several human cancers. The objective of this screening study was to identify patients with solid tumors (other than metastatic melanoma or papillary thyroid cancer) or multiple myeloma harboring activating BRAFV600 mutations for enrollment in a vemurafenib clinical study. Methods Formalin-fixed, paraffin-embedded tumor samples were collected and sent to a central laboratory to identify activating BRAFV600 mutations by bidirectional direct Sanger sequencing. Results Overall incidence of BRAFV600E mutation in evaluable patients (n=548) was 3% (95% confidence interval [CI], 1.7–4.7): 11% in colorectal tumors (n=75), 6% in biliary tract tumors (n=16), 3% in non-small cell lung cancers (n=71), 2% in other types of solid tumors (n=180), and 3% in multiple myeloma (n=31). There were no BRAFV600 mutations in this cohort of patients with ovarian tumors (n=68), breast cancer (n=86), or prostate cancer (n=21). Conclusion This multicenter, national screening study confirms previously reported incidences of BRAFV600 mutations from single-center studies. Patients identified with BRAFV600 mutations were potentially eligible for enrollment in the VE-BASKET study. PMID:28255242

  13. Dextran-functionalized magnetic fluid mediating magnetohyperthermia for treatment of Ehrlich-solid-tumor-bearing mice: toxicological and histopathological evaluations.

    PubMed

    Miranda-Vilela, Ana Luisa; Yamamoto, Kelly Reis; Miranda, Kely Lopes Caiado; Matos, Breno Noronha; de Almeida, Marcos Célio; Longo, João Paulo Figueiró; de Souza Filho, José; Fernandes, Juliana Menezes Soares; Sartoratto, Patrícia Pommé Confessori; Lacava, Zulmira Guerrero Marques

    2014-04-01

    Dextran-functionalized maghemite fluid (DexMF) has been tested to treat Ehrlich-solid-tumor-bearing mice, evidencing its potential use in mediating magnetohyperthermia in breast cancer treatment. However, although magnetic nanoparticles tend to accumulate in tumor tissues, part of the nanomaterial can reach the blood stream, and then the organism. The aim of this study was to investigate the acute systemic effects of the intratumoral injection of DexMF mediating magnetohyperthermia in the treatment of an advanced clinical Ehrlich-solid-tumor, assessed through histopathological analyses of liver, kidneys, heart and spleen, comet assay, micronucleus test, hemogram, and serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, creatinine, and urea. The tumor's histopathology and morphometry were used to assess its aggressiveness and regression. DexMF mediating hyperthermia was effective in containing tumor aggressiveness and in inducing tumor regression, besides showing no toxic effects. Its physical characteristics also suggest that it is safe to use in other biomedical applications.

  14. Distinct expression profiles of Notch-1 protein in human solid tumors: Implications for development of targeted therapeutic monoclonal antibodies

    PubMed Central

    Li, Yuan; Burns, Janine A; Cheney, Carol A; Zhang, Ningyan; Vitelli, Salvatore; Wang, Fubao; Bett, Andrew; Chastain, Michael; Audoly, Laurent P; Zhang, Zhi-Qiang

    2010-01-01

    Biological therapies, such as monoclonal antibodies (mAbs) that target tumor-associated antigens have been considered an effective therapeutic approach in oncology. In considering Notch-1 receptor as a potential target, we performed immunohistochemistry on tissue microarrays to determine 1) whether the receptor is overexpressed in tumor cells as compared to their corresponding normal tissues and 2) the clinical significance of its expression levels in human breast, colorectal, lung and prostate cancers. We found that the expression of Notch-1 protein was overexpressed in primary colorectal adenocarcinoma and nonsmall cell lung carcinoma (NSCLC), but not in primary ductal breast carcinoma or prostate adenocarcinoma. Further analysis revealed that higher levels of Notch-1 protein expression were significantly associated with poorer differentiation of breast and prostate tumors. Strikingly, for NSCLC, the expression levels of Notch-1 protein were found to be inversely correlated with tumor differentiation and progression. For colorectal tumors, however, no correlation of Notch-1 protein expression was found with any tumor clinicopathological parameters, in spite of its overexpression in tumor cells. Our data demonstrated the complexity of Notch-1 protein expression in human solid tumors and further supported the notion that the roles of Notch-1 expression in tumorigenesis are highly context-dependent. The findings could provide the basis for development of distinct therapeutic strategies of Notch-1 mAbs for its applications in the treatment of suitable types of human cancers. PMID:20631820

  15. Interleukin-12 in Treating Patients With Hematologic Cancers or Solid Tumors

    ClinicalTrials.gov

    2014-09-09

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Kidney Cancer; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  16. A Nation-Wide Epidemiological Study of Newly Diagnosed Primary Spine Tumor in the Adult Korean Population, 2009–2011

    PubMed Central

    Sohn, Seil; Kim, Jinhee; Chung, Chun Kee; Lee, Na Rae; Sohn, Moon Jun; Kim, Sung Hwan

    2017-01-01

    Objective This 2009–2011 nation-wide study of adult Koreans was aimed to provide characteristics, medical utilization states, and survival rates for newly diagnosed patients with primary nonmalignant and malignant spine tumors. Methods Data for patients with primary spine tumors were selected from the Korean Health Insurance Review and Assessment Service database. The data included their age, sex, health insurance type, co-morbidities, medical cost, and hospital stay duration. Hospital stay duration and medical costs per person occurring in one calendar year were used. In addition, survival rates of patients with primary malignant spine tumors were evaluated. Results The incidence rate of a primary spine tumor increased with age, and the year of diagnosis (p≤0.0001). Average annual medical costs ranged from 1627 USD (pelvis & sacrum & coccyx tumors) to 6601 USD (spinal cord tumor) for primary nonmalignant spine tumor and from 12137 USD (spinal meningomas) to 20825 USD (pelvis & sacrum & coccyx tumors) for a primary malignant spine tumor. Overall survival rates for those with a primary malignant spine tumor were 87.0%, 75.3%, and 70.6% at 3, 12, and 24 months, respectively. The Cox regression model results showed that male sex, medicare insurance were significantly positive factors affecting survival after a diagnosis of primary malignant spine tumor. Conclusion Our study provides a detailed view of the characteristics, medical utilization states, and survival rates of patients newly diagnosed with primary spine tumors in Korea. PMID:28264240

  17. The multi-epitope approach for immunotherapy for cancer: identification of several CTL epitopes from various tumor-associated antigens expressed on solid epithelial tumors.

    PubMed

    Kawashima, I; Hudson, S J; Tsai, V; Southwood, S; Takesako, K; Appella, E; Sette, A; Celis, E

    1998-01-01

    One approach to development of specific cancer immunotherapy relies on the induction of cytotoxic T lymphocytes (CTL) specific for tumor-associated antigens (TAA). Induction of TAA-specific CTL could be used towards the eradication of established tumors, or to prevent their dissemination or recurrence after primary treatment. The present study identifies a set of CTL epitopes from TAA frequently found on solid epithelial tumors such as breast, lung and gastro-intestinal tumors. Specifically, HLA-A2.1 binding peptides from the MAGE2, MAGE3, HER-2/neu and CEA antigens were tested for their capacity to elicit in vitro anti-tumor CTL using lymphocytes from normal volunteers and autologous dendritic cells as antigen-presenting cells. A total of 6 new epitopes (MAGE2[10(157)], MAGE3[9(112)], CEA[9(691)], CEA[9(24)], HER2[9(435)] and HER2[9(5)]) were identified which were capable of specifically recognizing tumor cell lines lines expressing HLA-A2.1 and the corresponding TAA. In one case (CEA[9(24)]), induction of vigorous anti-tumor CTL responses required epitope engineering to increase HLA-A2.1 binding affinity. Finally, most of the newly identified epitopes (5 out of 6) were found to be highly crossreactive with other common HLA alleles of the A2 supertype (A2.2, A2.3, A2.6 and A6802), thus demonstrating their potential in providing broad and non-ethnically biased population coverage. The results are discussed in the context of the development of multi-epitope-based therapies with broad applicability for patients suffering from commonly found tumors.

  18. Cisplatin Nephrotoxicity and Longitudinal Growth in Children With Solid Tumors: A Retrospective Cohort Study.

    PubMed

    Jiménez-Triana, Clímaco Andres; Castelán-Martínez, Osvaldo D; Rivas-Ruiz, Rodolfo; Jiménez-Méndez, Ricardo; Medina, Aurora; Clark, Patricia; Rassekh, Rod; Castañeda-Hernández, Gilberto; Carleton, Bruce; Medeiros, Mara

    2015-08-01

    Cisplatin, a major antineoplastic drug used in the treatment of solid tumors, is a known nephrotoxin. This retrospective cohort study evaluated the prevalence and severity of cisplatin nephrotoxicity in 54 children and its impact on height and weight.We recorded the weight, height, serum creatinine, and electrolytes in each cisplatin cycle and after 12 months of treatment. Nephrotoxicity was graded as follows: normal renal function (Grade 0); asymptomatic electrolyte disorders, including an increase in serum creatinine, up to 1.5 times baseline value (Grade 1); need for electrolyte supplementation <3 months and/or increase in serum creatinine 1.5 to 1.9 times from baseline (Grade 2); increase in serum creatinine 2 to 2.9 times from baseline or need for electrolyte supplementation for more than 3 months after treatment completion (Grade 3); and increase in serum creatinine ≥3 times from baseline or renal replacement therapy (Grade 4).Nephrotoxicity was observed in 41 subjects (75.9%). Grade 1 nephrotoxicity was observed in 18 patients (33.3%), Grade 2 in 5 patients (9.2%), and Grade 3 in 18 patients (33.3%). None had Grade 4 nephrotoxicity. Nephrotoxicity patients were younger and received higher cisplatin dose, they also had impairment in longitudinal growth manifested as statistically significant worsening on the height Z Score at 12 months after treatment. We used a multiple logistic regression model using the delta of height Z Score (baseline-12 months) as dependent variable in order to adjust for the main confounder variables such as: germ cell tumor, cisplatin total dose, serum magnesium levels at 12 months, gender, and nephrotoxicity grade. Patients with nephrotoxicity Grade 1 where at higher risk of not growing (OR 5.1, 95% CI 1.07-24.3, P=0.04). The cisplatin total dose had a significant negative relationship with magnesium levels at 12 months (Spearman r=-0.527, P=<0.001).

  19. Aberrant expression of the hematopoietic-restricted minor histocompatibility antigen LRH-1 on solid tumors results in efficient cytotoxic T cell-mediated lysis.

    PubMed

    Overes, Ingrid M; Levenga, T Henriëtte; Vos, Johanna C M; van Horssen-Zoetbrood, Agnes; van der Voort, Robbert; De Mulder, Pieter H; de Witte, Theo M; Dolstra, Harry

    2009-03-01

    CD8(+) T cells recognizing minor histocompatibility antigens (MiHA) on solid tumor cells may mediate effective graft-versus-tumor (GVT) reactivity after allogeneic stem cell transplantation (SCT). Previously, we identified LRH-1 as a hematopoietic-restricted MiHA encoded by the P2X5 gene. Here, we report that LRH-1 is aberrantly expressed on solid tumor cells. P2X5 mRNA expression is demonstrated in a significant portion of solid tumor cell lines, including renal cell carcinoma (RCC), melanoma, colorectal carcinoma, brain cancer and breast cancer. Importantly, P2X5 gene expression was also detected in a subset of primary solid tumor specimens derived from RCC, brain cancer and breast cancer patients. Furthermore, P2X5 expressing solid tumor cells can be effectively targeted by LRH-1-specific cytotoxic T lymphocytes under inflammatory conditions. The expression of HLA-B7 and CD54 on tumor cells increases upon cytokine stimulation resulting in improved T cell activation as observed by higher levels of degranulation and enhanced tumor cell lysis. Overall, hematopoietic-restricted MiHA LRH-1 is aberrantly expressed on solid tumor cells and may be used as target in GVT-specific immunotherapy after SCT.

  20. Liquid biopsies for solid tumors: Understanding tumor heterogeneity and real time monitoring of early resistance to targeted therapies.

    PubMed

    Esposito, Angela; Criscitiello, Carmen; Locatelli, Marzia; Milano, Monica; Curigliano, Giuseppe

    2016-01-01

    In the era of personalized medicine detection of the molecular drivers of tumors and of specific DNA mutations predicting response or resistance to targeted agents has become routine practice in clinical oncology. The tumor biopsy depicts only a single timeframe from a single site, and might be inadequate to characterize a tumor because of intratumoral and intermetastatic heterogeneity. Circulating tumor DNA offers a "real time" tool for serially monitoring tumor genomes in a non-invasive manner providing accessible genetic biomarkers for cancer diagnosis, prognosis, and response to therapy. The liquid biopsy can be used for a variety of clinical and investigational applications. Future development will have to provide a cost effective analysis mainly identifying the genes known to be recurrently mutated in each tumor. Therefore, developing standardized methodologies for DNA analyses and validation in large prospective clinical studies is mandatory to implement the 'liquid biopsy' approach in the clinical management of cancer patients. In our review, we will focus on the clinical applications of liquid biopsies and on the recent findings in this field.

  1. Akt Inhibitor MK2206 and Hydroxychloroquine in Treating Patients With Advanced Solid Tumors, Melanoma, Prostate or Kidney Cancer

    ClinicalTrials.gov

    2017-02-06

    Adult Solid Neoplasm; Hormone-Resistant Prostate Cancer; Recurrent Melanoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IV Skin Melanoma

  2. Cabozantinib S-Malate in Treating Younger Patients With Recurrent or Refractory Solid Tumors

    ClinicalTrials.gov

    2017-03-20

    Childhood Solid Neoplasm; Childhood Thyroid Gland Medullary Carcinoma; Recurrent Childhood Central Nervous System Neoplasm; Recurrent Malignant Solid Neoplasm; Recurrent Melanoma; Recurrent Thyroid Gland Carcinoma

  3. Prognostic value of increased KPNA2 expression in some solid tumors: A systematic review and meta-analysis

    PubMed Central

    Zhou, Li-Na; Tan, Yue; Li, Ping; Zeng, Ping; Chen, Min-Bin; Tian, Ye; Zhu, Ya-Qun

    2017-01-01

    Background Karyopherin α2 (KPNA2), a member of the Karyopherin α family, has recently been reported to play an important role in tumor progression. However, the association between KPNA2 expression and prognosis in cancer remains controversial. So we performed this meta-analysis to evaluate whether expression of KPNA2 was associated with prognosis in patients with solid tumor. Methods/Findings 24 published eligible studies, including 6164 cases, were identified and included in this meta-analysis through searching of PubMed, EMBASE and Web of Science. We found that KPNA2 expression was an independent predictor for the prognosis of solid tumor with primary outcome (overall survival [OS]: pooled HR=1.767, 95% CI=1.503-2.077, P<0.001) and secondary outcomes (time to recurrence [TTR], recurrence free survival [RFS] and progression free survival [PFS]). However, the association between KPNA2 overexpression and disease free survival [DFS] in solid tumors was not significant (pooled HR=1.653, 95% CI=0.903-3.029, P=0.104). Furthermore, the subgroup analysis revealed that KPNA2 overexpression was associated with poor OS in East-Asian patients and European patients, as well as patients with gastric and colorectal cancer. Conclusion KPNA2 expression may be a useful prognostic biomarker to monitor cancer prognosis. Further prospective studies with larger sample sizes are required to confirm our findings. PMID:27974678

  4. Replication Study: The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors

    PubMed Central

    Horrigan, Stephen K

    2017-01-01

    In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Chroscinski et al., 2015) that described how we intended to replicate selected experiments from the paper “The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors “(Willingham et al., 2012). Here we report the results of those experiments. We found that treatment of immune competent mice bearing orthotopic breast tumors with anti-mouse CD47 antibodies resulted in short-term anemia compared to controls, consistent with the previously described function of CD47 in normal phagocytosis of aging red blood cells and results reported in the original study (Table S4; Willingham et al., 2012). The weight of tumors after 30 days administration of anti-CD47 antibodies or IgG isotype control were not found to be statistically different, whereas the original study reported inhibition of tumor growth with anti-CD47 treatment (Figure 6A,B; Willingham et al., 2012). However, our efforts to replicate this experiment were confounded because spontaneous regression of tumors occurred in several of the mice. Additionally, the excised tumors were scored for inflammatory cell infiltrates. We found IgG and anti-CD47 treated tumors resulted in minimal to moderate lymphocytic infiltrate, while the original study observed sparse lymphocytic infiltrate in IgG-treated tumors and increased inflammatory cell infiltrates in anti-CD47 treated tumors (Figure 6C; Willingham et al., 2012). Furthermore, we observed neutrophilic infiltration was slightly increased in anti-CD47 treated tumors compared to IgG control. Finally, we report a meta-analysis of the result. DOI: http://dx.doi.org/10.7554/eLife.18173.001 PMID:28100392

  5. Tissue Distribution and Efficacy of Gold Nanorods Coupled with Laser Induced Photoplasmonic Therapy in Ehrlich Carcinoma Solid Tumor Model

    PubMed Central

    El-Sayed, Mostafa A.; Shabaka, Ali A.; El-Shabrawy, Osama A.; Yassin, Nemat A.; Mahmoud, Sawsan S.; El-Shenawy, Siham M.; Al-Ashqar, Emad; Eisa, Wael H.; Farag, Niveen M.; El-Shaer, Marwa A.; Salah, Nabila; Al-Abd, Ahmed M.

    2013-01-01

    Gold nanorods (GNR) within tumor microregions are characterized by their ability to absorb near IR light and emit heat in what is called photoplasmonic effect. Yet, the efficacy of nanoparticles is limited due to intratumoral tissue distribution reasons. In addition, distribution of GNRs to normal tissue might result in non specific toxicity. In the current study, we are assessing the intratumoral and tissue distribution of PEGylated GNRs on the top of its antitumor characteristics when given intravenously or intratumoral to solid tumor bearing mice and coupled with laser photoplasmonic sessions. PEGylated GNRs with a longitudinal size of less than 100 nm were prepared with aspect ratio of 4.6 showing strong surface plasmon absorption at wavelength 800 nm. Pharmacokinetics of GNR after single I.V. administration (0.1 mg/kg) showed very short systemic circulating time (less than 3 h). On the other hand, tissue distribution of I.V. GNR (0.1 mg/kg) to normal animals showed preferential deposition in spleen tissue. Repeated administration of I.V. GNR resulted in preferential accumulation in both liver and spleen tissues. In addition, I.V. administration of GNR to Ehrlich carcinoma tumor bearing mice resulted in similar tissue distribution; tumor accumulation and anti-tumor effect compared to intratumoral administration. In conclusion, the concentration of GNR achieved within tumors microregions after I.V. administration was comparable to I.T. administration and sufficient to elicit tumoral growth arrest when coupled with laser-aided photoplasmonic treatment. PMID:24098446

  6. The treatment of solid tumors by alpha emitters released from 224Ra-loaded sources—internal dosimetry analysis

    NASA Astrophysics Data System (ADS)

    Arazi, L.; Cooks, T.; Schmidt, M.; Keisari, Y.; Kelson, I.

    2010-02-01

    Diffusing alpha-emitters radiation therapy (DART) is a proposed new form of brachytherapy, allowing the treatment of solid tumors by alpha particles. DART utilizes implantable sources carrying small activities of radium-224, which continually release into the tumor radon-220, polonium-216 and lead-212 atoms, while radium-224 itself remains fixed to the source. The released atoms disperse inside the tumor by diffusive and convective processes, creating, through their alpha emissions, a high-dose region measuring several mm in diameter about each source. The efficacy of DART has been demonstrated in preclinical studies on mice-borne squamous cell carcinoma and lung tumors and the method is now being developed toward clinical trials. This work studies DART safety with respect to the dose delivered to distant organs as a result of lead-212 leakage from the tumor through the blood, relying on a biokinetic calculation coupled to internal dose assessments. It is found that the dose-limiting organs are the kidneys and red bone marrow. Assuming a typical source spacing of ~5 mm and a typical radium-224 activity density of 0.4-0.8 MBq g-1 of tumor tissue, it is predicted that tumors weighing up to several hundred grams may be treated without reaching the tolerance dose in any organ.

  7. Prevalence of Café-au-Lait Spots in children with solid tumors

    PubMed Central

    dos Santos, Anna Claudia Evangelista; Heck, Benjamin; Camargo, Beatriz De; Vargas, Fernando Regla

    2016-01-01

    Abstract Cafe-au-lait maculae (CALM) are frequently observed in humans, and usually are present as a solitary spot. Multiple CALMs are present in a smaller fraction of the population and are usually associated with other congenital anomalies as part of many syndromes. Most of these syndromes carry an increased risk of cancer development. Previous studies have indicated that minor congenital anomalies may be more prevalent in children with cancer. We investigated the prevalence of CALMs in two samples of Brazilian patients with childhood solid tumors, totaling 307 individuals. Additionally, 176 school children without diagnosis of cancer, or of a cancer predisposing syndrome, were investigated for the presence of CALMs. The prevalence of solitary CALM was similar in both study groups (18% and 19%) and also in the group of children without cancer. Multiple CALMs were more frequently observed in one of the study groups (Z = 2.1). However, when both groups were analyzed together, the significance disappeared (Z = 1.5). The additional morphological abnormalities in children with multiple CALMs were analyzed and compared to the findings observed in the literature. The nosologic entities associated with CALMs are reviewed. PMID:27223488

  8. Prevalence of Café-au-Lait Spots in children with solid tumors.

    PubMed

    Santos, Anna Claudia Evangelista Dos; Heck, Benjamin; Camargo, Beatriz De; Vargas, Fernando Regla

    2016-05-24

    Cafe-au-lait maculae (CALM) are frequently observed in humans, and usually are present as a solitary spot. Multiple CALMs are present in a smaller fraction of the population and are usually associated with other congenital anomalies as part of many syndromes. Most of these syndromes carry an increased risk of cancer development. Previous studies have indicated that minor congenital anomalies may be more prevalent in children with cancer. We investigated the prevalence of CALMs in two samples of Brazilian patients with childhood solid tumors, totaling 307 individuals. Additionally, 176 school children without diagnosis of cancer, or of a cancer predisposing syndrome, were investigated for the presence of CALMs. The prevalence of solitary CALM was similar in both study groups (18% and 19%) and also in the group of children without cancer. Multiple CALMs were more frequently observed in one of the study groups (Z = 2.1). However, when both groups were analyzed together, the significance disappeared (Z = 1.5). The additional morphological abnormalities in children with multiple CALMs were analyzed and compared to the findings observed in the literature. The nosologic entities associated with CALMs are reviewed.

  9. MK2206 in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Leukemia

    ClinicalTrials.gov

    2014-04-28

    Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  10. Numerical Modeling of Interstitial Fluid Flow Coupled with Blood Flow through a Remodeled Solid Tumor Microvascular Network.

    PubMed

    Soltani, M; Chen, P

    2013-01-01

    Modeling of interstitial fluid flow involves processes such as fluid diffusion, convective transport in extracellular matrix, and extravasation from blood vessels. To date, majority of microvascular flow modeling has been done at different levels and scales mostly on simple tumor shapes with their capillaries. However, with our proposed numerical model, more complex and realistic tumor shapes and capillary networks can be studied. Both blood flow through a capillary network, which is induced by a solid tumor, and fluid flow in tumor's surrounding tissue are formulated. First, governing equations of angiogenesis are implemented to specify the different domains for the network and interstitium. Then, governing equations for flow modeling are introduced for different domains. The conservation laws for mass and momentum (including continuity equation, Darcy's law for tissue, and simplified Navier-Stokes equation for blood flow through capillaries) are used for simulating interstitial and intravascular flows and Starling's law is used for closing this system of equations and coupling the intravascular and extravascular flows. This is the first study of flow modeling in solid tumors to naturalistically couple intravascular and extravascular flow through a network. This network is generated by sprouting angiogenesis and consisting of one parent vessel connected to the network while taking into account the non-continuous behavior of blood, adaptability of capillary diameter to hemodynamics and metabolic stimuli, non-Newtonian blood flow, and phase separation of blood flow in capillary bifurcation. The incorporation of the outlined components beyond the previous models provides a more realistic prediction of interstitial fluid flow pattern in solid tumors and surrounding tissues. Results predict higher interstitial pressure, almost two times, for realistic model compared to the simplified model.

  11. Validation of a Hypoxia-Inducible Factor-1α Specimen Collection Procedure and Quantitative ELISA in Solid Tumor Tissues

    PubMed Central

    Park, Sook Ryun; Kinders, Robert J.; Khin, Sonny; Hollingshead, Melinda; Antony, Smitha; Parchment, Ralph E.; Tomaszewski, Joseph E.; Kummar, Shivaani; Doroshow, James H.

    2016-01-01

    Hypoxia-inducible factor-1 alpha (HIF-1α) is an important marker of hypoxia in human tumors and has been implicated in tumor progression. Drugs targeting HIF-1α are being developed, but the ability to measure drug-induced changes in HIF-1α is limited by the lability of the protein in normoxia. Our goal was to devise methods for specimen collection and processing that preserve HIF-1α in solid tumor tissues and to develop and validate a two-site chemiluminescent quantitative ELISA for HIF-1α. We tested various strategies for HIF-1α stabilization in solid tumors including nitrogen gas-purged lysis buffer, addition of proteasome inhibitors, or the prolyl hydroxylase inhibitor 2-hydroxyglutarate, and bead homogenization. Degassing and addition of 2-hydroxyglutarate to the collection buffer significantly increased HIF-1α recovery, while bead-homogenization in sealed tubes improved HIF-1α recovery and reduced sample variability. Validation of the ELISA demonstrated intra- and inter-assay variability of less than 15% and accuracy of 99.8% ± 8.3% as assessed by spike recovery. Inter-laboratory reproducibility was also demonstrated (R2 = 0.999). Careful sample handling techniques allow us to quantitatively detect HIF-1α in samples as small as 2.5 µg of total protein extract, and this method is currently being applied to analyze tumor biopsy specimens in early-phase clinical trials. PMID:24799347

  12. StrandAdvantage test for early-line and advanced-stage treatment decisions in solid tumors.

    PubMed

    Sen, Manimala; Katragadda, Shanmukh; Ravichandran, Aarthi; Deshpande, Gouri; Parulekar, Minothi; Nayanala, Swetha; Vittal, Vikram; Shen, Weiming; Phooi Nee Yong, Melanie; Jacob, Jemima; Parchuru, Sravanthi; Dhanuskodi, Kalpana; Eyring, Kenneth; Agrawal, Pooja; Agarwal, Smita; Shanmugam, Ashwini; Gupta, Satish; Vishwanath, Divya; Kumari, Kiran; Hariharan, Arun K; Balaji, Sai A; Liang, Qiaoling; Robolledo, Belen; Gauribidanur Raghavendrachar, Vijayashree; Oomer Farooque, Mohammed; Buresh, Cary J; Ramamoorthy, Preveen; Bahadur, Urvashi; Subramanian, Kalyanasundaram; Hariharan, Ramesh; Veeramachaneni, Vamsi; Sankaran, Satish; Gupta, Vaijayanti

    2017-04-03

    Comprehensive genetic profiling of tumors using next-generation sequencing (NGS) is gaining acceptance for guiding treatment decisions in cancer care. We designed a cancer profiling test combining both deep sequencing and immunohistochemistry (IHC) of relevant cancer targets to aid therapy choices in both standard-of-care (SOC) and advanced-stage treatments for solid tumors. The SOC report is provided in a short turnaround time for four tumors, namely lung, breast, colon, and melanoma, followed by an investigational report. For other tumor types, an investigational report is provided. The NGS assay reports single-nucleotide variants (SNVs), copy number variations (CNVs), and translocations in 152 cancer-related genes. The tissue-specific IHC tests include routine and less common markers associated with drugs used in SOC settings. We describe the standardization, validation, and clinical utility of the StrandAdvantage test (SA test) using more than 250 solid tumor formalin-fixed paraffin-embedded (FFPE) samples and control cell line samples. The NGS test showed high reproducibility and accuracy of >99%. The test provided relevant clinical information for SOC treatment as well as more information related to investigational options and clinical trials for >95% of advanced-stage patients. In conclusion, the SA test comprising a robust and accurate NGS assay combined with clinically relevant IHC tests can detect somatic changes of clinical significance for strategic cancer management in all the stages.

  13. Mammary gland tumors in captive African hedgehogs.

    PubMed

    Raymond, J T; Gerner, M

    2000-04-01

    From December 1995 to July 1999, eight mammary gland tumors were diagnosed in eight adult captive female African hedgehogs (Atelerix albiventris). The tumors presented as single or multiple subcutaneous masses along the cranial or caudal abdomen that varied in size for each hedgehog. Histologically, seven of eight (88%) mammary gland tumors were malignant. Tumors were classified as solid (4 cases), tubular (2 cases), and papillary (2 cases). Seven tumors had infiltrated into the surrounding stroma and three tumors had histologic evidence of neoplastic vascular invasion. Three hedgehogs had concurrent neoplasms. These are believed to be the first reported cases of mammary gland tumors in African hedgehogs.

  14. Dimers of melampomagnolide B exhibit potent anticancer activity against hematological and solid tumor cells

    PubMed Central

    Janganati, Venumadhav; Ponder, Jessica; Jordan, Craig T.; Borrelli, Michael J.; Penthala, Narsimha Reddy; Crooks, Peter A.

    2016-01-01

    A series of novel carbamate and carbonate dimers of melampomagnolide B (MMB) have been synthesized by reaction of the MMB-triazole carbamate synthon 6 with various terminal diamino and dihydroxy alkanes. The resulting dimeric products 7b, 7c and 7f were selected and evaluated for anticancer activity against a panel of 60 human hematological and solid tumor cell lines. The most active compounds, 7b, 7c and 7f, exhibited GI50 values in the range 250-780 nM against the majority of leukemia cell lines in the tumor cell panel. Specifically, compounds 7b and 7f exhibited potent growth inhibition against non-small cell lung cancer cell lines NCI-H522 (GI50 = 160 nM) and HOP-92 (GI50 = 170 nM), respectively. Also, compound 7f also potently inhibited the growth of melanoma cell lines LOX IMVI, MALME-3M, and UACC-62 (GI50 values = 170, 190 and 190 nM, respectively); breast cancer cell line MDA-MB-468 (GI50 = 190 nM); colon cancer cell line HCT-116 (GI50 = 190 nM); and renal cancer cell line RXF 393 (GI50 = 160 nM). Compound 7f and the simple dicarbonate dimer of MMB (8) showed anticancer activity 300-fold and 1 × 106-fold, respectively, more cytotoxic than 7f and DMAPT at a concentration of 10 μM against rat 9L-SF gliosarcoma cells. The dimeric compounds 7a-7j & 8 were also screened for antileukemic activity against M9-ENL1 acute myelogenous leukemia (AML) cells and primary AML cell specimens. These compounds exhibited two to twelve-fold more potent antileukemic activity (EC50 = 0.5-2.9 μM) against the M9-ENL1 cell line when compared to parthenolide (EC50 = 6.0 μM). The dimeric analogues were also active against the primary AML cell specimens in the nanomolar to lower micromolar range and exhibited two to ten-fold more potent antileukemic activity (EC50 = 0.86-4.2 μM) when compared to parthenolide (EC50 = 2.5-16 μM). Thus, dimer 7f exhibited promising anticancer activity against a variety of both hematological and solid human tumor cell lines, while dimer 8 was

  15. Self-reported electrical appliance use and risk of adult brain tumors.

    PubMed

    Kleinerman, Ruth A; Linet, Martha S; Hatch, Elizabeth E; Tarone, Robert E; Black, Peter M; Selker, Robert G; Shapiro, William R; Fine, Howard A; Inskip, Peter D

    2005-01-15

    Electrical appliances produce the highest intensity exposures to residential extremely low frequency electromagnetic fields. The authors investigated whether appliances may be associated with adult brain tumors in a hospital-based case-control study at three centers in the United States from 1994 to 1998. A total of 410 glioma, 178 meningioma, and 90 acoustic neuroma cases and 686 controls responded to a self-administered questionnaire about 14 electrical appliances. There was little evidence of association between brain tumors and curling iron, heating pad, vibrating massager, electric blanket, heated water bed, sound system, computer, television, humidifier, microwave oven, and electric stove. Ever use of hair dryers was associated with glioma (odds ratio = 1.7, 95% confidence interval: 1.1, 2.5), but there was no evidence of increasing risk with increasing amount of use. In men, meningioma was associated with electric shaver use (odds ratio = 10.9, 95% confidence interval: 2.3, 50), and odds ratios increased with cumulative minutes of use, although they were based on only two nonexposed cases. Recall bias for appliances used regularly near the head or chance may provide an alternative explanation for the observed associations. Overall, results indicate that extremely low frequency electromagnetic fields from commonly used household appliances are unlikely to increase the risk of brain tumors.

  16. Evaluation of SCCVII tumor cell survival in clamped and non-clamped solid tumors exposed to carbon-ion beams in comparison to X-rays.

    PubMed

    Hirayama, Ryoichi; Uzawa, Akiko; Takase, Nobuhiro; Matsumoto, Yoshitaka; Noguchi, Miho; Koda, Kana; Ozaki, Masakuni; Yamashita, Kei; Li, Huizi; Kase, Yuki; Matsufuji, Naruhiro; Koike, Sachiko; Masunaga, Shin-ichiro; Ando, Koichi; Okayasu, Ryuichi; Furusawa, Yoshiya

    2013-08-30

    The aim of this study was to measure the RBE (relative biological effectiveness) and OER (oxygen enhancement ratio) for survival of cells within implanted solid tumors following exposure to 290MeV/nucleon carbon-ion beams or X-rays. Squamous cell carcinoma cells (SCCVII) were transplanted into the right hind legs of syngeneic C3H male mice. Irradiation with either carbon-ion beams with a 6-cm spread-out Bragg peak (SOBP, at 46 and 80keV/μm) or X-rays was delivered to 5-mm or less diameter tumors. We defined three different oxygen statuses of the irradiated cells. Hypoxic and normoxic conditions in tumors were produced by clamping or not clamping the leg to avoid blood flow. Furthermore, single-cell suspensions were prepared from non-irradiated tumors and directly used to determine the radiation response of aerobic cells. Single-cell suspensions (aerobic condition) were fully air-saturated. Single-cell suspensions were prepared from excised and trypsinized tumors, and were used for in vivo-in vitro colony formation assays to obtain cell survival curves. The RBE values increased with increasing LET in SOBP beams. The maximum RBE values in three different oxygen conditions; hypoxic tumor, normoxic tumor and aerobic cells, were 2.16, 1.76 and 1.66 at an LET of 80keV/μm, respectively. After X-ray irradiation the OERh/n values (hypoxic tumor/normoxic tumor) were lower than the OERh/a (hypoxic tumor/aerobic cells), and were 1.87±0.13 and 2.52±0.11, respectively. The OER values of carbon-ion irradiated samples were small in comparison to those of X-ray irradiated samples. However, no significant changes of the OER at proximal and distal positions within the SOBP carbon-ion beams were observed. To conclude, we found that the RBE values for cell survival increased with increasing LET and that the OER values changed little with increasing LET within the SOBP carbon-ion beams.

  17. Oxaliplatin in Treating Young Patients With Recurrent Solid Tumors That Have Not Responded to Previous Treatment

    ClinicalTrials.gov

    2013-06-04

    Childhood Central Nervous System Germ Cell Tumor; Childhood Extragonadal Germ Cell Tumor; Childhood Hepatoblastoma; Childhood Hepatocellular Carcinoma; Childhood High-grade Cerebral Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Malignant Ovarian Germ Cell Tumor; Childhood Malignant Testicular Germ Cell Tumor; Childhood Teratoma; Recurrent Adrenocortical Carcinoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Colon Cancer; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Nasopharyngeal Cancer; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Rectal Cancer; Recurrent Renal Cell Cancer

  18. A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors.

    PubMed

    Liu, Xiaojun; Ranganathan, Raghuveer; Jiang, Shuguang; Fang, Chongyun; Sun, Jing; Kim, Soyeon; Newick, Kheng; Lo, Albert; June, Carl H; Zhao, Yangbing; Moon, Edmund K

    2016-03-15

    Chimeric antigen receptor (CAR)-modified adoptive T-cell therapy has been successfully applied to the treatment of hematologic malignancies, but faces many challenges in solid tumors. One major obstacle is the immune-suppressive effects induced in both naturally occurring and genetically modified tumor-infiltrating lymphocytes (TIL) by inhibitory receptors (IR), namely PD1. We hypothesized that interfering with PD1 signaling would augment CAR T-cell activity against solid tumors. To address this possibility, we introduced a genetically engineered switch receptor construct, comprising the truncated extracellular domain of PD1 and the transmembrane and cytoplasmic signaling domains of CD28, into CAR T cells. We tested the effect of this supplement, "PD1CD28," on human CAR T cells targeting aggressive models of human solid tumors expressing relevant tumor antigens. Treatment of mice bearing large, established solid tumors with PD1CD28 CAR T cells led to significant regression in tumor volume due to enhanced CAR TIL infiltrate, decreased susceptibility to tumor-induced hypofunction, and attenuation of IR expression compared with treatments with CAR T cells alone or PD1 antibodies. Taken together, our findings suggest that the application of PD1CD28 to boost CAR T-cell activity is efficacious against solid tumors via a variety of mechanisms, prompting clinical investigation of this potentially promising treatment modality.

  19. Adult metastatic yolk sac tumor descending from an intra-abdominal testis: A case report and review of the literature.

    PubMed

    Wang, Zhao; Yan, Bin; Wei, Yong-Bao; Yin, Zhuo; Zhou, Ke-Qin; Yang, Jin-Rui

    2015-12-01

    Pure yolk sac tumors are extremely rare in adults; to the best of our knowledge, <20 cases have been reported. Multiple metastases originating from a pure yolk sac testicular tumor, descending from an intra-abdominal testis, are additionally extremely rare. In the present case, a man exhibiting a 30-year history of cryptorchidism and indirect inguinal hernia, was admitted to the Department of Urology (The Second Xiangya Hospital, Changsha, China) due to a mass that had descended from the abdominal cavity 7 months previously. Elevated levels of specific serum marker (α-fetoprotein, lactate dehydrogenase and human chorionic gonadotropin) did not indicate potential testicular germ cell types prior to surgery and pathological examination. Pathological results and immunohistochemistry revealed a testicular pure yolk sac tumor subsequent to surgery. The present case report and literature review describes the typical characteristics of an adult testicular yolk sac tumor, as well as the diagnosis and management of the disease.

  20. Adult metastatic yolk sac tumor descending from an intra-abdominal testis: A case report and review of the literature

    PubMed Central

    WANG, ZHAO; YAN, BIN; WEI, YONG-BAO; YIN, ZHUO; ZHOU, KE-QIN; YANG, JIN-RUI

    2015-01-01

    Pure yolk sac tumors are extremely rare in adults; to the best of our knowledge, <20 cases have been reported. Multiple metastases originating from a pure yolk sac testicular tumor, descending from an intra-abdominal testis, are additionally extremely rare. In the present case, a man exhibiting a 30-year history of cryptorchidism and indirect inguinal hernia, was admitted to the Department of Urology (The Second Xiangya Hospital, Changsha, China) due to a mass that had descended from the abdominal cavity 7 months previously. Elevated levels of specific serum marker (α-fetoprotein, lactate dehydrogenase and human chorionic gonadotropin) did not indicate potential testicular germ cell types prior to surgery and pathological examination. Pathological results and immunohistochemistry revealed a testicular pure yolk sac tumor subsequent to surgery. The present case report and literature review describes the typical characteristics of an adult testicular yolk sac tumor, as well as the diagnosis and management of the disease. PMID:26788184

  1. Malignant rhabdoid tumor of the floor of mouth: first reported case in the oral cavity of an adult.

    PubMed

    Wetzel, Stephanie L; Kerpel, Stanley; Reich, Renee F; Freedman, Paul D

    2015-06-01

    Malignant rhabdoid tumors (MRTs) are exceedingly rare lesions. To our knowledge, only 2 cases have been reported in the oral cavity, with both examples occurring in infants. The current case is the third reported case of MRT of the oral cavity and the first reported case to occur in an adult at this location. The following report describes the clinical, histologic and immunohistochemical features of this tumor.

  2. Concurrent anti-vascular therapy and chemotherapy in solid tumors using drug-loaded acoustic nanodroplet vaporization.

    PubMed

    Ho, Yi-Ju; Yeh, Chih-Kuang

    2017-02-01

    Drug-loaded nanodroplets (NDs) can be converted into gas bubbles through ultrasound (US) stimulation, termed acoustic droplet vaporization (ADV), which provides a potential strategy to simultaneously induce vascular disruption and release drugs for combined physical anti-vascular therapy and chemotherapy. Doxorubicin-loaded NDs (DOX-NDs) with a mean size of 214nm containing 2.48mg DOX/mL were used in this study. High-speed images displayed bubble formation and cell debris, demonstrating the reduction in cell viability after ADV. Intravital imaging provided direct visualization of disrupted tumor vessels (vessel size <30μm), the extravasation distance was 12μm in the DOX-NDs group and increased over 100μm in the DOX-NDs+US group. Solid tumor perfusion on US imaging was significantly reduced to 23% after DOX-NDs vaporization, but gradually recovered to 41%, especially at the tumor periphery after 24h. Histological images of the DOX-NDs+US group revealed tissue necrosis, a large amount of drug extravasation, vascular disruption, and immune cell infiltration at the tumor center. Tumor sizes decreased 22%, 36%, and 68% for NDs+US, DOX-NDs, and DOX-NDs+US, respectively, to prolong the survival of tumor-bearing mice. Therefore, this study demonstrates that the combination of physical anti-vascular therapy and chemotherapy with DOX-NDs vaporization promotes uniform treatment to improve therapeutic efficacy.

  3. Numerical Modeling of Interstitial Fluid Flow Coupled with Blood Flow through a Remodeled Solid Tumor Microvascular Network

    PubMed Central

    Soltani, M.; Chen, P.

    2013-01-01

    Modeling of interstitial fluid flow involves processes such as fluid diffusion, convective transport in extracellular matrix, and extravasation from blood vessels. To date, majority of microvascular flow modeling has been done at different levels and scales mostly on simple tumor shapes with their capillaries. However, with our proposed numerical model, more complex and realistic tumor shapes and capillary networks can be studied. Both blood flow through a capillary network, which is induced by a solid tumor, and fluid flow in tumor’s surrounding tissue are formulated. First, governing equations of angiogenesis are implemented to specify the different domains for the network and interstitium. Then, governing equations for flow modeling are introduced for different domains. The conservation laws for mass and momentum (including continuity equation, Darcy’s law for tissue, and simplified Navier–Stokes equation for blood flow through capillaries) are used for simulating interstitial and intravascular flows and Starling’s law is used for closing this system of equations and coupling the intravascular and extravascular flows. This is the first study of flow modeling in solid tumors to naturalistically couple intravascular and extravascular flow through a network. This network is generated by sprouting angiogenesis and consisting of one parent vessel connected to the network while taking into account the non-continuous behavior of blood, adaptability of capillary diameter to hemodynamics and metabolic stimuli, non-Newtonian blood flow, and phase separation of blood flow in capillary bifurcation. The incorporation of the outlined components beyond the previous models provides a more realistic prediction of interstitial fluid flow pattern in solid tumors and surrounding tissues. Results predict higher interstitial pressure, almost two times, for realistic model compared to the simplified model. PMID:23840579

  4. Erlotinib and Temozolomide in Treating Young Patients With Recurrent or Refractory Solid Tumors

    ClinicalTrials.gov

    2013-06-04

    Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma

  5. Tanespimycin in Treating Young Patients With Recurrent or Refractory Leukemia or Solid Tumors

    ClinicalTrials.gov

    2013-06-03

    Childhood Chronic Myelogenous Leukemia; Childhood Desmoplastic Small Round Cell Tumor; Disseminated Neuroblastoma; Metastatic Childhood Soft Tissue Sarcoma; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Osteosarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma

  6. Risk of fatigue in patients with solid tumors treated with everolimus, temsirolimus or ridaforolimus: a comparative meta-analysis.

    PubMed

    Abdel-Rahman, Omar; Fouad, Mona

    2015-04-01

    We performed a meta-analysis of fatigue associated with the use of everolimus, temsirolimus or ridaforolimus in patients with solid tumors. Eligible studies included randomized trials of patients with solid tumors on everolimus, temsirolimus or ridaforolimus describing events of fatigue. A total of 18 clinical trials including 8143 patients were considered eligible for the meta-analysis. On the basis of random-effects model, we found that the relative risk of all-grade and high-grade fatigue were 1.26 [95% CI: 1.09-1.46; p < 0.0001], 1.49 [95% CI: 0.99, 2.24; p = 0.05], respectively. On subgroup analysis, we cannot identify any difference between everolimus and temsirolimus in the risk of fatigue. Thus, our meta-analysis has demonstrated that regimens containing everolimus, temsirolimus or ridaforolimus for the treatment of solid tumors are associated with an increased risk of all-grade fatigue, whereas the risk of high-grade fatigue did not reach the threshold of statistical significance. Close clinical monitoring and pre-emptive treatment for fatigue are recommended.

  7. Different Efficiency of Liposomal Forms with Hydrophilic and Hydrophobic Antitumor Agents in Relation to Solid Transplants of Mouse Tumor and Its Metastases in the Liver.

    PubMed

    Popova, N A; Kaledin, V I; Nikolin, V P; Bogdanova, L A; Morozkova, T S; Tornuev, Yu V

    2016-10-01

    Experiments were performed on the model of transplanted mouse tumor with high incidence of liver metastases. Hydrophilic drug cycloplatam (injected intravenously in liposomes) was more potent than "free cycloplatam" (injected intravenously or intraperitoneally in physiological saline) in inhibiting the growth of natural and experimental metastases in the liver. By contrast, liposomal cycloplatam had lower efficiency than free cycloplatam in suppressing the growth of solid tumor. Liposomal and free cortifen (hydrophobic hormonal cytostatic) produced nearly the same effects on solid tumor growth. Our results suggest that liposomal forms of hydrophobic compounds producing nonselective effect on tumor cells (e.g., actinomycin D or Cosmegen), should not have advantages over free forms.

  8. Hemorheological changes in solid tumor patients after treatment with recombinant erythropoetin.

    PubMed

    Muravyov, A V; Cheporov, S V; Kislov, N V; Volkova, E L

    2009-01-01

    The subject of this study was the effect of erythropoetin (Epoetin) treatment of anemic patients (n=30) with solid tumors on parameters of hemorheological profile. Both prior to and following Epoetin treatment (10,000 units subcutaneously thrice weekly) for four weeks hemorheological measurements included plasma and red blood cell (RBC) suspension viscosity; high and low shear whole blood viscosity; hematocrit (Hct), hemoglobin, RBC aggregation (RBCA) and deformation. It was found that the patients had reduced Hb up to 92.96+/-2.99 g/l, and the Hct - 28.2%. These parameters were significant increased after four weeks of Epoetin treatment: Hb by 28% (p<0.01) and Hct by 31% (p<0.01). In macrorheological part of the profile, both the high shear blood viscosity, and the low one were increased by 23 and 27% (p<0.05), respectively. These changes were mainly associated with the Hct rise. As for microrheological part of profile after Epoetin treatment, RBCA was decreased by 25% (p<0.05). While the red cell rigidity index (Tk) was lowered only slightly (by 8%). RBC incubation with Epoetin (10.0 I.E./ml) was accompanied by 10% decrease of Tk. It is important to note that before Epoetin treatment incubation with it led to decrease of RBCA by 30% (p<0.05), whereas after four week of the treatment period a 27% (p<0.05) rise of aggregation was found in majority of patients. Thus these results suggest that Epoetin is an effective, safe and convenient therapy for the management of anaemia in patients with cancer. And this drug has a moderate positive hemorheological effect on RBC and on the microrheological properties in particular. These data suggested that Epoetin has an effect on the membrane properties regulating RBC aggregation and deformation and affects by the signal transduction system, including Ca2+-dependant signaling pathway and tyrosine kinase and phosphotase activity change.

  9. Phase I study of oral CP-4126, a gemcitabine derivative, in patients with advanced solid tumors.

    PubMed

    Stuurman, F E; Voest, E E; Awada, A; Witteveen, P O; Bergeland, T; Hals, P-A; Rasch, W; Schellens, J H M; Hendlisz, A

    2013-08-01

    CP-4126 is a gemcitabine (2',2'-difluorodeoxycytidine; dFdC) 5' elaidic acid ester. The purpose of this dose-escalating study was to assess safety, pharmacokinetics (PK) and preliminary antitumor activity of the oral formulation and to determine the recommended dose (RD) for phase II studies. The study had a two-step design: a non-randomized dose-escalating step I with oral CP-4126 alone, followed by a randomized, cross-over step II that compared oral CP-4126 with dFdC i.v.. CP-4126 was given on days 1,8,15 in a 4-week schedule with increasing doses until the RD was established. 26 patients with different solid tumours were enrolled in step I at seven dose levels (100-3,000 mg/day). The most frequent drug-related AEs were fatigue and dysgeusia, the majority being grade 1-2. One patient experienced a dose limiting toxicity after one dose of CP-4126 at 1,300 mg/day (ASAT grade 3). PK of CP-4126 could not be determined. The metabolites dFdC and dFdU obeyed dose-dependent pharmacokinetics. Exposures to dFdC were about ten-fold lower compared to exposures after comparable doses of dFdC i.v.. Nine patients reached stable disease as best response, whereby in one patient with vaginal carcinoma a 25 % reduction of tumor volume was reached. This study demonstrates that CP-4126 can be safely administered orally to patients up to 3,000 mg/day in a d1,8,15 q4w schedule with a tolerable safety profile. CP-4126 acts as a prodrug for dFdC when given orally, but because of the poor absorption and the rapid pre-systemic metabolism the study was terminated early and no RD could be determined.

  10. Capturing Treatment Decision Making Among Patients With Solid Tumors and Their Caregivers

    PubMed Central

    Jones, Randy A.; Steeves, Richard; Ropka, Mary E.; Hollen, Patricia

    2013-01-01

    Purpose/Objectives To examine the feasibility and acceptability of using a decision aid with an interactive decision-making process in patients with solid tumors and their caregivers during cancer-related treatment. Research Approach A phenomenologic approach was used to analyze qualitative data, with a focus on the meaning of participants’ lived experiences. Interviews were conducted by telephone or in person. Setting Outpatient clinics at two regional cancer centers. Participants 160 total individuals; 80 patients with newly diagnosed breast (n = 22), advanced-stage prostate (n = 19), or advanced-stage lung (n = 39) cancer, and their caregivers (n = 80). Methodologic Approach Twenty-seven of the 80 pairs engaged in audio recorded interviews that were conducted using a semistructured interview guide. Continuous text immersion revealed themes. Validity of qualitative analysis was achieved by member checking. Findings Significant findings included three themes: (a) the decision aid helped patients and caregivers understand treatment decisions better, (b) the decision aid helped patients and caregivers to be more involved in treatment decisions, and (c) frequent contact with the study nurse was valuable. Conclusions Decision making was more complex than participants expected. The decision aid helped patients and caregivers make satisfying treatment decisions and become integral in a shared treatment decision-making process. Interpretation Decision aids can help patients and their caregivers make difficult treatment decisions affecting quantity and quality of life during cancer treatment. The findings provide valuable information for healthcare providers helping patients and their caregivers make treatment decisions through a shared, informed, decision-making process. Knowledge Translation Decision aids can be helpful with treatment choices. Caregivers’ understanding about treatment is just as important in the decision-making process as the patients

  11. Pharmacokinetics and excretion of (14)C-lenvatinib in patients with advanced solid tumors or lymphomas.

    PubMed

    Dubbelman, Anne-Charlotte; Rosing, Hilde; Nijenhuis, Cynthia; Huitema, Alwin D R; Mergui-Roelvink, Marja; Gupta, Anubha; Verbel, David; Thompson, Gary; Shumaker, Robert; Schellens, Jan H M; Beijnen, Jos H

    2015-02-01

    Lenvatinib is an orally available multi-targeted tyrosine kinase inhibitor with anti-angiogenic and antitumor activity. To get more insight into the disposition of lenvatinib, a mass balance study was performed in patients with advanced solid tumors. A single oral 24 mg (100 μCi) dose of (14)C-lenvatinib was administered to six patients, followed by collection of blood, plasma, urine and feces for 7 to 10 days. The collected material was analyzed for total radioactivity, unchanged lenvatinib and selected metabolites. The safety and antitumor effect of a daily oral dose of 24 mg non-labeled lenvatinib were assessed in the extension phase of the study. Peak plasma concentrations of lenvatinib and total radioactivity were reached 1.6 and 1.4 h after administration, respectively, and their terminal phase half-lifes were 34.5 and 17.8 h, respectively. Unchanged lenvatinib systemic exposure accounted for 60 % of the total radioactivity in plasma. Peak concentrations of the analyzed metabolite were over 700-fold lower than the peak plasma concentration of lenvatinib. Ten days after the initial dose, the geometric mean (± CV) recovery of administered dose was 89 % ±10 %, with 64 % ±11 % recovered in feces and 25 % ±18 % in urine. Unchanged lenvatinib in urine and feces accounted for 2.5 % ±68 % of the administered dose, indicating a major role of metabolism in the elimination of lenvatinib. In conclusion, lenvatinib is rapidly absorbed and extensively metabolized, with subsequent excretion in urine and, more predominantly, in feces. Additionally, lenvatinib showed acceptable safety and preliminary antitumor activity.

  12. Mesothelin-specific Chimeric Antigen Receptor mRNA-Engineered T cells Induce Anti-Tumor Activity in Solid Malignancies

    PubMed Central

    Beatty, Gregory L.; Haas, Andrew R.; Maus, Marcela V.; Torigian, Drew A.; Soulen, Michael C.; Plesa, Gabriela; Chew, Anne; Zhao, Yangbing; Levine, Bruce L.; Albelda, Steven M.; Kalos, Michael; June, Carl H.

    2014-01-01

    Off-target toxicity due to the expression of target antigens in normal tissue represents a major obstacle to the use of chimeric antigen receptor (CAR)-engineered T cells for treatment of solid malignancies. To circumvent this issue, we established a clinical platform for engineering T cells with transient CAR expression by using in vitro transcribed mRNA encoding a CAR that includes both the CD3-ζ and 4-1BB co-stimulatory domains. We present two case reports from ongoing trials indicating that adoptive transfer of mRNA CAR T cells that target mesothelin (CARTmeso cells) is feasible and safe without overt evidence of off-tumor on-target toxicity against normal tissues. CARTmeso cells persisted transiently within the peripheral blood after intravenous administration and migrated to primary and metastatic tumor sites. Clinical and laboratory evidence of antitumor activity was demonstrated in both patients and the CARTmeso cells elicited an antitumor immune response revealed by the development of novel anti-self antibodies. These data demonstrate the potential of utilizing mRNA engineered T cells to evaluate, in a controlled manner, potential off-tumor on-target toxicities and show that short-lived CAR T cells can induce epitope-spreading and mediate antitumor activity in patients with advanced cancer. Thus, these findings support the development of mRNA CAR-based strategies for carcinoma and other solid tumors. PMID:24579088

  13. Glycoengineered mesenchymal stem cells as an enabling platform for two-step targeting of solid tumors.

    PubMed

    Layek, Buddhadev; Sadhukha, Tanmoy; Prabha, Swayam

    2016-05-01

    Current tumor targeted drug and diagnostic delivery systems suffer from a lack of selectivity for tumor cells. Here, we propose a two-step tumor targeting strategy based on mesenchymal stem cells (MSCs), which actively traffic to tumors. We developed glycoengineering protocols to induce expression of non-natural azide groups on the surface of MSCs without affecting their viability or tumor homing properties. Glycoengineered MSCs demonstrated active tumor homing in subcutaneous and orthotopic lung and ovarian tumor models. Subsequent systemic administration of dibenzyl cyclooctyne (DBCO)-labeled fluorophores or nanoparticles to MSC pretreated mice resulted in enhanced tumor accumulation of these agents through bio-orthogonal copper-free click chemistry. Further, administration of glycoengineered MSCs along with paclitaxel-loaded DBCO-functionalized nanoparticles resulted in significant (p < 0.05) inhibition of tumor growth and improved survival (p < 0.0001) in an orthotopic metastatic ovarian tumor model. These results provide evidence for the potential of MSC-based two-step targeting strategy to improve the tumor specificity of diagnostic agents and drugs, and thus potentially improve the treatment outcomes for patients diagnosed with cancer.

  14. Solid tumors provide niche-specific conditions that lead to preferential growth of Salmonella

    PubMed Central

    Silva-Valenzuela, Cecilia A.; Desai, Prerak T.; Molina-Quiroz, Roberto C.; Pezoa, David; Zhang, Yong; Porwollik, Steffen; Zhao, Ming; Hoffman, Robert M.; Contreras, Inés; Santiviago, Carlos A.; McClelland, Michael

    2016-01-01

    Therapeutic attenuated strains of Salmonella Typhimurium target and eradicate tumors in mouse models. However, the mechanism of S. Typhimurium for tumor targeting is still poorly understood. We performed a high-throughput screening of single-gene deletion mutants of S. Typhimurium in an orthotopic, syngeneic murine mammary model of breast cancer. The mutants under selection in this system were classified into functional categories to identify bacterial processes involved in Salmonella accumulation within tumors. Niche-specific genes involved in preferential tumor colonization were identified and exemplars were confirmed by competitive infection assays. Our results show that the chemotaxis gene cheY and the motility genes motAB confer an advantage for colonization of Salmonella within orthotopic syngeneic breast tumors. In addition, eutC, a gene belonging to the ethanolamine metabolic pathway, also confers an advantage for Salmonella within tumors, perhaps by exploiting either ethanolamine or an alternative nutrient in the inflamed tumor environment. PMID:27145267

  15. Occasional detection of thymic epithelial tumor 4 years after diagnosis of adult onset Still disease

    PubMed Central

    Lococo, Filippo; Bajocchi, Gianluigi; Caruso, Andrea; Valli, Riccardo; Ricchetti, Tommaso; Sgarbi, Giorgio; Salvarani, Carlo

    2016-01-01

    Abstract Background: Thymoma is a T cell neoplasm arising from the thymic epithelium that due to its immunological role, frequently undercover derangements of immunity such a tumors and autoimmune diseases. Methods: Herein, we report, to the best of our knowledge, the first description of an association between thymoma and adult onset Still disease (AOSD) in a 47-year-old man. The first one was occasionally detected 4 years later the diagnosis of AOSD, and surgically removed via right lateral thoracotomy. Histology confirmed an encapsulated thymic tumor (type AB sec. WHO-classification). Results: The AOSD was particularly resistant to the therapy, requiring a combination of immunosuppressant followed by anti-IL1R, that was the only steroids-sparing treatment capable to induce and maintain the remission. The differential diagnosis was particularly challenging because of the severe myasthenic-like symptoms that, with normal laboratory tests, were initially misinterpreted as fibromyalgia. The pathogenic link of this association could be a thymus escape of autoreactive T lymphocytes causing autoimmunity. Conclusion: Clinicians should be always include the possibility of a thymoma in the differential diagnosis of an unusual new onset of weakness and normal laboratories data, in particular once autoimmune disease is present in the medical history. PMID:27603335

  16. Increased risk of solid renal tumors in lithium-treated patients.

    PubMed

    Zaidan, Mohamad; Stucker, Fabien; Stengel, Bénédicte; Vasiliu, Viorel; Hummel, Aurélie; Landais, Paul; Boffa, Jean-Jacques; Ronco, Pierre; Grünfeld, Jean-Pierre; Servais, Aude

    2014-07-01

    Cystic kidney diseases and toxic interstitial nephritis may be complicated by renal tumors. Long-term lithium intake is associated with tubulointerstitial nephritis and renal cysts but to date such an association with tumors has not been determined. We evaluated this in a retrospective study to determine whether lithium-treated patients were at higher risk of renal tumors compared with lithium-free patients with chronic kidney disease (CKD), and to the general population. Over a 16-year period, 14 of 170 lithium-treated patients had renal tumors, including seven malignant and seven benign tumors. The mean duration of lithium exposure at diagnosis was 21.4 years. The renal cancers included three clear-cell and two papillary renal cell carcinomas, one hybrid tumor with chromophobe and oncocytoma characteristics, and one clear-cell carcinoma with leiomyomatous stroma. The benign tumors included four oncocytomas, one mixed epithelial and stromal tumor, and two angiomyolipomas. The percentage of renal tumors, particularly cancers and oncocytomas, was significantly higher in lithium-treated patients compared with 340 gender-, age-, and estimated glomerular filtration rate (eGFR)-matched lithium-free patients. Additionally, the Standardized Incidence Ratio of renal cancer was significantly higher in lithium-treated patients compared with the general population: 7.51 (95% confidence interval (CI) (1.51-21.95)) and 13.69 (95% CI (3.68-35.06)) in men and women, respectively. Thus, there is an increased risk of renal tumors in lithium-treated patients.

  17. Preferential action of arsenic trioxide in solid-tumor microenvironment enhances radiation therapy

    SciTech Connect

    Griffin, Robert J. . E-mail: griff007@umn.edu; Williams, Brent W.; Park, Heon Joo; Song, Chang W.

    2005-04-01

    Purpose: To investigate the effect of arsenic trioxide, Trisenox (TNX), on primary cultures of endothelial cells and tumor tissue under varying pH and pO{sub 2} environments and the effects of combined TNX and radiation therapy on experimental tumors. Methods and Materials: Human dermal microvascular endothelial cells were cultured in vitro and exposed to TNX under various combinations of aerobic, hypoxic, neutral, or acidic conditions, and levels of activated JNK MAP kinase were assessed by Western blotting. FSaII fibrosarcoma cells grown in the hind limb of female C3H mice were used to study the effect of TNX on tumor blood perfusion and oxygenation. The tumor-growth delay after a single or fractionated irradiation with or without TNX treatment was assessed. Results: A single intraperitoneal injection of 8 mg/kg TNX reduced the blood perfusion in FSaII tumors by 53% at 2 hours after injection. To increase the oxygenation of the tumor vasculature during TNX treatment, some animals were allowed to breathe carbogen (95% O{sub 2}/5% CO{sub 2}). Carbogen breathing alone for 2 hours reduced tumor perfusion by 33%. When carbogen breathing was begun immediately after TNX injection, no further reduction occurred in tumor blood perfusion at 2 hours after injection. In vitro, TNX exposure increased activity JNK MAP kinase preferentially in endothelial cells cultured in an acidic or hypoxic environment. In vivo, the median oxygenation in FSaII tumors measured at 3 or 5 days after TNX injection was found to be significantly elevated compared with control tumors. Subsequently, radiation-induced tumor-growth delay was synergistically increased when radiation and TNX injection were fractionated at 3-day or 5-day intervals. Conclusions: Trisenox has novel vascular-damaging properties, preferentially against endothelium in regions of low pH or pO{sub 2}, which leads to tumor cell death and enhancement of the response of tumors to radiotherapy.

  18. A comparative immunohistochemical study of Ki-67 and Bcl-2 expression in solid ameloblastoma and adenomatoid odontogenic tumor

    PubMed Central

    Razavi, Sayed Mohammad; Tabatabaie, Sayed Hosein; Hoseini, Ali Tavakoli; Hoseini, Ehsan Tavakoli; Khabazian, Arezu

    2012-01-01

    Background: Solid ameloblastoma (SAB) is an invasive tumor which infiltrates adjacent normal tissues. Adenomatoid odontogenic tumor is a noninvasive tumor and never infiltrates surrounding normal tissues. The purpose of this study was to determine the biological behavior of these two epithelial odontogenic neoplasm by detecting Ki-67 and Bcl-2, which are mitotic and anti apoptotic markers respectively. Materials and Methods: In this analytical retrospective study, 16 samples of SAB and 16 samples of adenomatoid odontogenic tumor were selected. The samples were deparafinized and antigens were retrieved. Immunohistochemistry technique was applied for evaluation of these two markers. Monoclonal antibodies MIB1 and Bcl-2 were used to detect Ki-67 and Bcl-2 protein respectively, then the labeling index (LI) was calculated for both markers according to cellular staining. Data were analyzed by “t” test, (P<0.05). Results: The mean values of LI for Ki-67 in SAB and Adenomatiod odontogenic tumor (AOT) were 4 and 1% respectively and for Bcl-2 in SAB and AOT were 63 and 26% respectively. The indices of both markers were higher in SAB compared to AOT (P <0.05). Conclusions: Higher percentage of these two markers in SAB compared to AOT confirms the aggressive behavior of SAB and the hamartomatosis behavior of AOT. PMID:22623937

  19. Imetelstat Sodium in Treating Younger Patients With Relapsed or Refractory Solid Tumors

    ClinicalTrials.gov

    2017-02-08

    Childhood Hepatoblastoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Rhabdomyosarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma

  20. Tumors and Proliferative Lesions in Adult Offspring After Maternal Exposure to Methylarsonous Acid During Gestation in CD1 Mice

    EPA Science Inventory

    Developmental exposure to inorganic arsenic is carcinogenic in humans and mice, and adult offspring of mice exposed to inorganic arsenic can develop tumors of the lung, liver, adrenal, uterus, and ovary. It has been suggested that methylarsonous acid (MMA3+), a product of the bi...

  1. Tumors and Proliferative Lesions in Adult Offspring After Maternal Exposure to Methylarsonous Acid During Gestation in CDl Mice.

    EPA Science Inventory

    Inorganic arsenic exposure is carcinogenic in humans and rodents. When pregnant mice are exposed to inorganic arsenic in the drinking water their offspring, when adults, develop tumors and proliferative lesions at several sites, such as lung, liver, adrenal, uterus, ovary and ovi...

  2. The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition

    PubMed Central

    2012-01-01

    Background It has been shown in many solid tumors that the overexpression of the pro-survival Bcl-2 family members Bcl-xL and Mcl-1 confers resistance to a variety of chemotherapeutic agents. Mcl-1 is a critical survival protein in a variety of cell lineages and is critically regulated via ubiquitination. Methods The Mcl-1, Bcl-xL and USP9X expression patterns in human lung and colon adenocarcinomas were evaluated via immunohistochemistry. Interaction between USP9X and Mcl-1 was demonstrated by immunoprecipitation-western blotting. The protein expression profiles of Mcl-1, Bcl-xL and USP9X in multiple cancer cell lines were determined by western blotting. Annexin-V staining and cleaved PARP western blotting were used to assay for apoptosis. The cellular toxicities after various treatments were measured via the XTT assay. Results In our current analysis of colon and lung cancer samples, we demonstrate that Mcl-1 and Bcl-xL are overexpressed and also co-exist in many tumors and that the expression levels of both genes correlate with the clinical staging. The downregulation of Mcl-1 or Bcl-xL via RNAi was found to increase the sensitivity of the tumor cells to chemotherapy. Furthermore, our analyses revealed that USP9X expression correlates with that of Mcl-1 in human cancer tissue samples. We additionally found that the USP9X inhibitor WP1130 promotes Mcl-1 degradation and increases tumor cell sensitivity to chemotherapies. Moreover, the combination of WP1130 and ABT-737, a well-documented Bcl-xL inhibitor, demonstrated a chemotherapeutic synergy and promoted apoptosis in different tumor cells. Conclusion Mcl-1, Bcl-xL and USP9X overexpression are tumor survival mechanisms protective against chemotherapy. USP9X inhibition increases tumor cell sensitivity to various chemotherapeutic agents including Bcl-2/Bcl-xL inhibitors. PMID:23171055

  3. Association between serum levels of C-reactive protein and response to treatment of chemotherapy-induced anemia in patients with solid tumors: a multicenter, prospective, observational study.

    PubMed

    Esquerdo Galiana, Gaspar; Cervera, Jose Manuel; Barrajón, Enrique; Juárez, Asunción; Llorca, Cristina; Díaz, Nieves; López, Antonio; Peiró, Rafael

    2013-03-01

    Our objective was to determine the association between C-reactive protein (CRP) levels at initiation of anemia treatment and response in solid tumor patients with chemotherapy (CT)-induced anemia. This was a multicenter, prospective, observational study which included adult patients with solid tumor initiating treatment for CT-induced anemia. Data were collected up to 16 weeks, or until premature discontinuation. We included 98 patients (median age 62.5 years, 64 % males, 57 % with ECOG 0-1, 85.7 % at stages III-IV and 54.1 % undergoing palliative CT). Mean (SD) Hb levels at baseline were 10.3 (0.9) g/dL (85.7 % < 11 g/dL) and median (Q1; Q3) CRP was 16.4 mg/L (3.9; 77.8) (68 % ≥ 5 mg/L). A total of 96 % of patients initiated erythropoiesis-stimulating agents (ESA) and iron supplementation; 4 % initiated iron monotherapy. After a median of 85 days, 65 % of patients had Hb ≥ 11 g/dL (in absence of transfusion) (mean change: +0.86 g/dL, 95 % confidence interval (CI) 0.53-1.19). A total of 8 patients required transfusion. A significant correlation (r = -0.39, p = 0.003) was observed between baseline CRP and final Hb levels. In the multivariate linear regression analysis, the independent predictors of higher final Hb levels were a high baseline Hb (adjusted ß = +0.69 g/dL for each g/dL of baseline Hb, 95 % CI 0.17-1.21) and a low log baseline CRP (-0.62 for each log mg/L, 95 %CI -1.22 to -0.02). Our results suggest that, in patients with solid tumors and CT-induced anemia, high CRP levels at treatment initiation predict a poor response to treatment with ESA and iron, independently from anemia severity at therapy initiation and from other patient and disease characteristics.

  4. The impact of ranitidine on monocyte responses in the context of solid tumors

    PubMed Central

    Vila-Leahey, Ava; Rogers, Dakota; Marshall, Jean S.

    2016-01-01

    Monocytes and myeloid derived suppressor cells (MDSC) have been implicated on the regulation of tumor growth. Histamine is also important for regulating MDSC responses. Oral administration of the H2 receptor antagonist ranitidine can inhibit breast tumor growth and metastasis. In the current study, we examined the impact of oral ranitidine treatment, at a clinically relevant dose, on multiple murine tumor models. The impact of ranitidine on monocyte responses and the role of CCR2 in ranitidine-induced tumor growth inhibition were also investigated. Oral ranitidine treatment did not reduce tumor growth in the B16-F10 melanoma, LLC1 lung cancer and EL4 thymoma models. However, it consistently reduced E0771 primary tumor growth and metastasis in the 4T1 model. Ranitidine had no impact on E0771 tumor growth in mice deficient in CCR2, where monocyte recruitment to tumors was limited. Analysis of splenic monocytes also revealed an elevated ratio of H2 versus H1 expression from tumor-bearing compared with naïve mice. More detailed examination of the role of ranitidine on monocyte development demonstrated a decrease in monocyte progenitor cells following ranitidine treatment. Taken together, these results reveal that H2 signaling may be a novel target to alter the monocyte population in breast tumor models, and that targeting H2 on monocytes via oral ranitidine treatment impacts effective tumor immunity. Ranitidine is widely used for control of gastrointestinal disorders. The potential role of ranitidine as an adjunct to immunotherapies for breast cancer and the potential impact of H2 antagonists on breast cancer outcomes should be considered. PMID:26863636

  5. Efficacy of combined antiangiogenic and vascular disrupting agents in treatment of solid tumors

    SciTech Connect

    Siemann, Dietmar W. . E-mail: siemadw@ufl.edu; Shi Wenyin

    2004-11-15

    Purpose: To evaluate the antitumor efficacy of a vascular targeting strategy that combines an agent that disrupts established tumor blood vessels (ZD6126) with one that interferes with new vessel formation (ZD6474) in models of human renal cell carcinoma (Caki-1) and Kaposi's sarcoma (KSY-1). Methods and materials: Caki-1 and KSY-1 xenograft-bearing nude mice were treated with ZD6126 and ZD6474 either as single agents or in combination when the tumors reached a size of {approx}200 mm{sup 3}. ZD6126 therapy consisted of three doses of 100 mg/kg administered 1, 3, and 5 days after the tumor reached the starting size. ZD6474 was administered daily (25 mg/kg) on Days 1-5. In the combination studies, ZD6474 treatment began immediately after the first dose of ZD6126. The tumor response to treatment was evaluated using a regrowth delay endpoint. Results: Significant tumor growth delays were observed in both tumor models with either agent with the treatment regimen used. In the Caki-1 and KSY-1 models, respectively, ZD6126 treatment resulted in a tumor growth delay of 23 and 26 days and ZD6474 produced a tumor growth delay of 24.5 and 14.5 days. When ZD6126 and ZD6474 were combined, the tumor growth delays increased to 55 (Caki-1) and 86 (KSY-1) days. In the KSY-1 model, the combination therapy also resulted in 3 of 8 long-term tumor-free survivors. Conclusion: These results indicate that statistically significant antitumor efficacy can be achieved using a treatment strategy that combines a therapy that targets the established tumor blood vessels with one that interferes with the process of angiogenesis.

  6. Yoga Therapy in Treating Patients With Malignant Brain Tumors

    ClinicalTrials.gov

    2017-01-17

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Tumor; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Recurrent Adult Brain Tumor

  7. Tumor

    MedlinePlus

    ... plants (aflatoxins) Excessive sunlight exposure Genetic problems Obesity Radiation exposure Viruses Types of tumors known to be caused by or linked with viruses are: Cervical cancer (human papillomavirus) Most anal cancers (human papillomavirus) Some throat ...

  8. Evaluation of uptake and distribution of gold nanoparticles in solid tumors*

    PubMed Central

    England, Christopher G.; Gobin, André M.; Frieboes, Hermann B.

    2015-01-01

    Although nanotherapeutics offer a targeted and potentially less toxic alternative to systemic chemotherapy in cancer treatment, nanotherapeutic transport is typically hindered by abnormal characteristics of tumor tissue. Once nanoparticles targeted to tumor cells arrive in the circulation of tumor vasculature, they must extravasate from irregular vessels and diffuse through the tissue to ideally reach all malignant cells in cytotoxic concentrations. The enhanced permeability and retention effect can be leveraged to promote extravasation of appropriately sized particles from tumor vasculature; however, therapeutic success remains elusive partly due to inadequate intra-tumoral transport promoting heterogeneous nanoparticle uptake and distribution. Irregular tumor vasculature not only hinders particle transport but also sustains hypoxic tissue kregions with quiescent cells, which may be unaffected by cycle-dependent chemotherapeutics released from nanoparticles and thus regrow tumor tissue following nanotherapy. Furthermore, a large proportion of systemically injected nanoparticles may become sequestered by the reticuloendothelial system, resulting in overall diminished efficacy. We review recent work evaluating the uptake and distribution of gold nanoparticles in pre-clinical tumor models, with the goal to help improve nanotherapy outcomes. We also examine the potential role of novel layered gold nanoparticles designed to address some of these critical issues, assessing their uptake and transport in cancerous tissue. PMID:27014559

  9. Evaluation of uptake and distribution of gold nanoparticles in solid tumors

    NASA Astrophysics Data System (ADS)

    England, Christopheri G.; Gobin, André M.; Frieboes, Hermann B.

    2015-11-01

    Although nanotherapeutics offer a targeted and potentially less toxic alternative to systemic chemotherapy in cancer treatment, nanotherapeutic transport is typically hindered by abnormal characteristics of tumor tissue. Once nanoparticles targeted to tumor cells arrive in the circulation of tumor vasculature, they must extravasate from irregular vessels and diffuse through the tissue to ideally reach all malignant cells in cytotoxic concentrations. The enhanced permeability and retention effect can be leveraged to promote extravasation of appropriately sized particles from tumor vasculature; however, therapeutic success remains elusive partly due to inadequate intra-tumoral transport promoting heterogeneous nanoparticle uptake and distribution. Irregular tumor vasculature not only hinders particle transport but also sustains hypoxic tissue kregions with quiescent cells, which may be unaffected by cycle-dependent chemotherapeutics released from nanoparticles and thus regrow tumor tissue following nanotherapy. Furthermore, a large proportion of systemically injected nanoparticles may become sequestered by the reticulo-endothelial system, resulting in overall diminished efficacy. We review recent work evaluating the uptake and distribution of gold nanoparticles in pre-clinical tumor models, with the goal to help improve nanotherapy outcomes. We also examine the potential role of novel layered gold nanoparticles designed to address some of these critical issues, assessing their uptake and transport in cancerous tissue.

  10. Alisertib in Treating Young Patients With Recurrent or Refractory Solid Tumors or Leukemia

    ClinicalTrials.gov

    2016-07-20

    Hepatoblastoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Kidney Neoplasm; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma

  11. Entinostat in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors

    ClinicalTrials.gov

    2017-04-04

    Childhood Brain Stem Neoplasm; Childhood Lymphoma; Childhood Solid Neoplasm; Pineal Region Neoplasm; Recurrent Childhood Central Nervous System Neoplasm; Recurrent Childhood Visual Pathway Glioma; Refractory Central Nervous System Neoplasm

  12. Inhibition of solid tumor growth by gene transfer of VEGF receptor-1 mutants.

    PubMed

    Heidenreich, Regina; Machein, Marcia; Nicolaus, Anke; Hilbig, Andreas; Wild, Carola; Clauss, Matthias; Plate, Karl H; Breier, Georg

    2004-09-01

    Vascular endothelial growth factor (VEGF) and the high-affinity VEGF receptor Flk-1/KDR (VEGFR-2) are key regulators of tumor angiogenesis. Strategies to block VEGF/VEGFR-2 signaling were successfully used to inhibit experimental tumor growth and indicated that VEGFR-2 is the main signaling VEGF receptor in proliferating tumor endothelium. Here, we investigated the role of the VEGF receptor-1 (VEGFR-1/Flt-1) in the vascularization of 2 different experimental tumors in vivo. VEGFR-1 mutants were generated that lack the intracellular tyrosine kinase domain. Retrovirus-mediated gene transfer of the VEGFR-1 mutants led to a strong reduction of tumor growth and angiogenesis in xenografted C6 glioma and in syngeneic BFS-1 fibrosarcoma. Histological analysis of the inhibited fibrosarcoma revealed reduced vascular density, decreased tumor cell proliferation as well as increased tumor cell apoptosis and the formation of necrosis. The retroviral gene transfer of the full length VEGFR-1 also caused a significant reduction of tumor growth in both models. The inhibitory effects of the VEGFR-1 mutants and the full length VEGFR-1 in BFS-1 fibrosarcoma were mediated through host tumor endothelial cells because the BFS-1 fibrosarcoma cells were not infected by the retrovirus. The formation of heterodimers between VEGFR-2 and full length or truncated VEGFR-1 was observed in vitro and might contribute to the growth inhibitory effect by modulating distinct signal transduction pathways. The results of our study underline the central role of the VEGF/VEGFR-1 signaling system in tumor angiogenesis and demonstrate that VEGFR-1 can serve as a target for anti-angiogenic gene therapy.

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

    SciTech Connect

    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 prevention 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.

  14. Temsirolimus and Vinorelbine Ditartrate in Treating Patients With Unresectable or Metastatic Solid Tumors

    ClinicalTrials.gov

    2016-06-09

    Extensive Stage Small Cell Lung Cancer; Hereditary Paraganglioma; Male Breast Cancer; Malignant Paraganglioma; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Pheochromocytoma; Pancreatic Polypeptide Tumor; Recurrent Breast Cancer; Recurrent Cervical Cancer; Recurrent Endometrial Carcinoma; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Recurrent Neuroendocrine Carcinoma of the Skin; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pheochromocytoma; Recurrent Prostate Cancer; Recurrent Renal Cell Cancer; Recurrent Small Cell Lung Cancer; Recurrent Uterine Sarcoma; Regional Gastrointestinal Carcinoid Tumor; Regional Pheochromocytoma; Stage III Cervical Cancer; Stage III Endometrial Carcinoma; Stage III Neuroendocrine Carcinoma of the Skin; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage III Prostate Cancer; Stage III Renal Cell Cancer; Stage III Uterine Sarcoma; Stage IIIA Breast Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Breast Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Endometrial Carcinoma; Stage IV Neuroendocrine Carcinoma of the Skin; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IV Uterine Sarcoma; Stage IVA Cervical Cancer; Stage IVB Cervical Cancer; Thyroid Gland Medullary Carcinoma

  15. Combining radiation and immunotherapy: a new systemic therapy for solid tumors?

    PubMed

    Tang, Chad; Wang, Xiaohong; Soh, Hendrick; Seyedin, Steven; Cortez, Maria Angelica; Krishnan, Sunil; Massarelli, Erminia; Hong, David; Naing, Aung; Diab, Adi; Gomez, Daniel; Ye, Huiping; Heymach, John; Komaki, Ristuko; Allison, James P; Sharma, Padmanee; Welsh, James W

    2014-09-01

    With the recent success of checkpoint inhibitors and other immunomodulating agents, there has been renewed interest in the combination of such agents with radiation. The biologic premise behind such a strategy is that the tumor-antigen release achieved by localized radiation will promote specific tumor targeting by the adaptive immune system, which can be augmented further by systemic immune-stimulating agents. In this manner, clinicians hope to induce a phenomenon known as the abscopal effect, whereby localized radiation results in immune-mediated tumor regression in disease sites well outside of the radiation field. Herein, we present a comprehensive overview of the early clinical and preclinical evidence behind this approach.

  16. A facile preparation method of a PFC-containing nano-sized emulsion for theranostics of solid tumors.

    PubMed

    Shiraishi, Kouichi; Endoh, Reiko; Furuhata, Hiroshi; Nishihara, Masamichi; Suzuki, Ryo; Maruyama, Kazuo; Oda, Yusuke; Jo, Jun-ichiro; Tabata, Yasuhiko; Yamamoto, Jun; Yokoyama, Masayuki

    2011-12-15

    Theranostics means a therapy conducted in a diagnosis-guided manner. For theranostics of solid tumors by means of ultrasound, we designed a nano-sized emulsion containing perfluoropentane (PFC5). This emulsion can be delivered into tumor tissues through the tumor vasculatures owing to its nano-size, and the emulsion is transformed into a micron-sized bubble upon sonication through phase transition of PFC5. The micron-sized bubbles can more efficiently absorb ultrasonic energy for better diagnostic images and can exhibit more efficient ultrasound-driven therapeutic effects than nano-sized bubbles. For more efficient tumor delivery, smaller size is preferable, yet the preparation of a smaller emulsion is technically more difficult. In this paper, we used a bath-type sonicator to successfully obtain small PFC5-containing emulsions in a diameter of ca. 200nm. Additionally, we prepared these small emulsions at 40°C, which is above the boiling temperature of PFC5. Accordingly, we succeeded in obtaining very small nano-emulsions for theranostics through a very facile method.

  17. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors

    PubMed Central

    Dunbar, E. M.; Coats, B. S.; Shroads, A. L.; Langaee, T.; Lew, A.; Forder, J. R.; Shuster, J. J.; Wagner, D. A.

    2015-01-01

    Summary Background Recurrent malignant brain tumors (RMBTs) carry a poor prognosis. Dichloroacetate (DCA) activates mitochondrial oxidative metabolism and has shown activity against several human cancers. Design We conducted an open-label study of oral DCA in 15 adults with recurrent WHO grade III – IV gliomas or metastases from a primary cancer outside the central nervous system. The primary objective was detection of a dose limiting toxicity for RMBTs at 4 weeks of treatment, defined as any grade 4 or 5 toxicity, or grade 3 toxicity directly attributable to DCA, based on the National Cancer Institute’s Common Toxicity Criteria for Adverse Events, version 4.0. Secondary objectives involved safety, tolerability and hypothesis-generating data on disease status. Dosing was based on haplotype variation in glutathione transferase zeta 1/maleylacetoacetate isomerase (GSTZ1/MAAI), which participates in DCA and tyrosine catabolism. Results Eight patients completed at least 1 four week cycle. During this time, no dose-limiting toxicities occurred. No patient withdrew because of lack of tolerance to DCA, although 2 subjects experienced grade 0–1 distal parasthesias that led to elective withdrawal and/or dose-adjustment. All subjects completing at least 1 four week cycle remained clinically stable during this time and remained on DCA for an average of 75.5 days (range 26–312). Conclusions Chronic, oral DCA is feasible and well-tolerated in patients with recurrent malignant gliomas and other tumors metastatic to the brain using the dose range established for metabolic diseases. The importance of genetic-based dosing is confirmed and should be incorporated into future trials of chronic DCA administration. PMID:24297161

  18. Variant call concordance between two laboratory-developed, solid tumor targeted genomic profiling assays using distinct workflows and sequencing instruments.

    PubMed

    Hampel, Ken J; de Abreu, Francine B; Sidiropoulos, Nikoletta; Peterson, Jason D; Tsongalis, Gregory J

    2017-02-10

    Targeted genomic profiling (TGP) using massively parallel DNA sequencing is becoming the standard methodology in clinical laboratories for detecting somatic variants in solid tumors. The variety of methodologies and sequencing platforms in the marketplace for TGP has resulted in a variety of clinical TGP laboratory developed tests (LDT). The variability of LDTs is a challenge for test-to-test and laboratory-to-laboratory reliability. At the University of Vermont Medical Center (UVMMC), we validated a TGP assay for solid tumors which utilizes DNA hybridization capture and complete exon and selected intron sequencing of 29 clinically actionable genes. The validation samples were run on the Illumina MiSeq platform. Clinical specificity and sensitivity were evaluated by testing samples harboring genomic variants previously identified in CLIA-approved, CAP accredited laboratories with clinically validated molecular assays. The Molecular Laboratory at Dartmouth Hitchcock Medical Center (DHMC) provided 11 FFPE specimens that had been analyzed on AmpliSeq Cancer Hotspot Panel version 2 (CHPv2) and run on the Ion Torrent PGM. A Venn diagram of the gene lists from the two institutions is shown. This provided an excellent opportunity to compare the inter-laboratory reliability using two different target sequencing methods and sequencing platforms. Our data demonstrated an exceptionally high level of concordance with respect to the sensitivity and specificity of the analyses. All clinically-actionable SNV and InDel variant calls in genes covered by both panels (n=17) were identified by both laboratories. This data supports the proposal that distinct gene panel designs and sequencing workflows are capable of making consistent variant calls in solid tumor FFPE-derived samples.

  19. Healthcare resource use and costs associated with renal impairment in US patients with bone metastases from solid tumors.

    PubMed

    Qian, Yi; Arellano, Jorge; Bhowmik, Debajyoti; Thomson, Erin; Smith, David M; Hechmati, Guy; Song, Xue

    2017-04-01

    Introduction During cancer progression, more than half of patients develop renal insufficiency, including chronic kidney disease. The primary and secondary objectives of this study were to estimate healthcare resource use and costs, respectively, associated with renal impairment in patients with bone metastases from solid tumors in the United States. Methods and materials This was a retrospective, observational cohort study conducted using administrative claims data for individuals with solid tumors and bone metastases. Control patients were matched to renal impairment patients using propensity scores (ratio up to 3:1) based on demographics, clinical characteristics, and baseline costs. Average per-patient per-year healthcare resource utilization and costs (total costs and cost components; 2013 dollars) were reported. Results In total, 2616 renal impairment patients were matched to 7211 control patients. Renal impairment patients had greater healthcare resource use compared with controls, including a greater mean number of hospital admissions (4.4 versus 2.1), longer average stay per hospital admission (7.4 versus 6.5 days), as well as greater mean number of physician office visits (22.9 versus 18.8), emergency department visits (3.1 versus 2.0), and hospital-based outpatient visits (18.8 versus 16.0) compared with control patients. Total costs were > $50,000 higher among renal impairment patients ($142,267 versus $88,839; P < 0.001), with hospital costs accounting for $72,557 for renal impairment patients, and $27,858 for control patients ( P < 0.001). Conclusion The healthcare resource use and costs associated with renal impairment in patients with bone metastases from solid tumors is high; efforts to reduce renal impairment in this population, including the potential avoidance of nephrotoxic agents, are warranted.

  20. Positron Emission Tomography Using Fluorine F 18 EF5 to Find Oxygen in Tumor Cells of Patients Who Are Undergoing Surgery or Biopsy for Newly Diagnosed Brain Tumors

    ClinicalTrials.gov

    2013-01-15

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Central Nervous System Germ Cell Tumor; Adult Choroid Plexus Tumor; Adult Craniopharyngioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade I Meningioma; Adult Grade II Meningioma; Adult Grade III Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Pilocytic Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Subependymoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Meningeal Melanocytoma

  1. A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy

    PubMed Central

    Han, Leiqiang; Wang, Tianqi; Wu, Jingliang; Yin, Xiaolan; Fang, Hao; Zhang, Na

    2016-01-01

    Small molecule-based nanodrugs with nanoparticles (NPs) that are mainly composed of small molecules, have been considered as a promising candidate for a next-generation nanodrug, owing to their unique properties. Vorinostat (SAHA) is a canonical US Food and Drug Administration-approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma. However, the lack of efficacy against solid tumors hinders its progress in clinical use. Herein, a novel nanodrug of SAHA was developed based on disulfide-linked prodrug SAHA-S-S-VE. SAHA-S-S-VE could self-assemble into 148 nm NPs by disulfide-induced mechanisms, which were validated by molecular dynamics simulations. Under reduced conditions, the redox-responsive behavior of SAHA-S-S-VE was investigated, and the HDAC inhibition results verified the efficient release of free SAHA. With a biocompatible d-a-tocopheryl polyethylene glycol succinate (TPGS) functionalization, the SAHA-S-S-VE/TPGS NPs exhibited low critical aggregation concentration of 4.5 μM and outstanding stability in vitro with drug-loading capacity of 24%. In vitro biological assessment indicated that SAHA-S-S-VE/TPGS NPs had significant anticancer activity against HepG2. Further in vivo evaluation demonstrated that the resulting NPs could be accumulated in the tumor region and inhibit the tumor growth effectively. This approach, which turned SAHA into a self-assembled redox-responsive nanodrug, provided a new channel for the use of HDAC inhibitor in solid tumor therapy. PMID:27956831

  2. Diagnosis and treatment of solid pseudopapillary tumor of the pancreas: experience of one single institution from Turkey

    PubMed Central

    2013-01-01

    Background Solid pseudopapillary neoplasia (SPN) of the pancreas is an extremely rare epithelial tumor of low malignant potential. SPN accounts for less than 1% to 2% of exocrine pancreatic tumors. The aim of this study is to report our experience with SPN of the pancreas. It includes a summary of the current literature to provide a reference for the management of this rare clinical entity. Methods A retrospective analysis was performed of all patients diagnosed and treated for SPN in our hospital over the past 15 years (1998 to 2013). A database of the characteristics of these patients was developed, including age, gender, tumor location and size, treatment, and histopathological and immunohistochemical features. Results During this time period, 255 patients with pancreatic malignancy (which does not include ampulla vateri, distal choledocal and duodenal tumor) were admitted to our department, only 10 of whom were diagnosed as having SPN (2.5%). Nine patients were women (90%) and one patient was a man (10%). Their median age was 38.8 years (range 18 to 71). The most common symptoms were abdominal pain and dullness. Seven patients (70%) presented with abdominal pain or abdominal dullness and three patient (30%) were asymptomatic with the diagnosis made by an incidental finding on routine examination. Abdominal computed tomography and/or magnetic resonance imaging showed the typical features of solid pseudopapillary neoplasm in six (60%) of the patients. Four patients underwent distal pancreatectomy with splenectomy, one patient underwent a total mass excision, and one patient underwent total pancreatic resection. Two required extended distal pancreatectomy with splenectomy. Two underwent spleen-preserving distal pancreatectomy. Conclusions SPN is a rare neoplasm that primarily affects young women. The prognosis is favorable even in the presence of distant metastasis. Although surgical resection is generally curative, a close follow-up is advised in order to

  3. Extent of resection and postoperative functional declination of Klekamp's type A intramedullary tumors in adult patients

    PubMed Central

    Rabadán, Alejandra T.; Hernandez, Diego; Paz, Leonardo

    2016-01-01

    Background: The most commonly primary intramedullary spinal cord tumors (ISCT) in adults are the noninfiltrative lesions, corresponding to Klekamp's type A classification. There are few reports exclusively considering this type of lesions, their resectability and postoperative functional declination risk, and to our knowledge, none from Latin America. This led us to evaluate our results to provide information that might contribute to the decision making process in our region. Methods: A retrospective observational study was conducted comprising a cohort of 21 adults having primary Klekamp's type A ISCT. Diagnosis was made by magnetic resonance imaging (MRI), along with diffusion tensor/tractography in the last 7 cases. Preoperative functional status was assessed using the McCormick's modified scale (mMs), which was also used for the postoperative assessment within postoperative 90 days period. MRI was used to confirm the extent of resection. Results: Radical resection was obtained in 20/21 cases. The postoperative functional status was stable in 42.8% of the cases, and in 57.4% was even better than in the preoperative period. Temporary declination was observed in 2 cases in the early postoperative period. There were 2 cases with complications; one patient had cerebrospinal fluid fistula with meningitis, which was conservatively resolved, and another patient died from pulmonary embolism. Conclusion: Although the number of patients in this series does not allow to conclude from a statistical point of view, the outcomes showed that the modern surgery of Klekamp's type A ISCT permits a complete resection with low functional declination risk. PMID:28144469

  4. Flow cytometric monitoring of hormone receptor expression in human solid tumors

    NASA Astrophysics Data System (ADS)

    Krishan, Awtar

    2002-05-01

    Hormone receptor expression in human breast and prostate tumors is of diagnostic and therapeutic importance. With the availability of anti-estrogen, androgen and progesterone antibodies, immunohistochemistry has become a standard tool for determination of receptor expression in human tumor biopsies. However, this method is dependent on examination of a small number of cells under a microscope and the data obtained in most cases is not quantitative. As most of the commercially used anti-hormone antibodies have nuclear specificity, we have developed methods for isolation and antigen unmasking of nuclei from formalin fixed/paraffin embedded archival human tumors. After immunostaining with the antibodies and propidium iodide (for DNA content and cell cycle analysis), nuclei are analyzed by multiparametric laser flow cytometry for hormone receptor expression, DNA content, aneuploidy and cell cycle determination. These multiparametric methods are especially important for retrospective studies seeking to correlate hormone receptor expression with clinical response to anti-hormonal therapy of human breast and prostate tumors.

  5. An Adaptive Multigrid Algorithm for Simulating Solid Tumor Growth Using Mixture Models

    PubMed Central

    Wise, S.M.; Lowengrub, J.S.; Cristini, V.

    2010-01-01

    In this paper we give the details of the numerical solution of a three-dimensional multispecies diffuse interface model of tumor growth, which was derived in (Wise et al., J. Theor. Biol. 253 (2008)) and used to study the development of glioma in (Frieboes et al., NeuroImage 37 (2007) and tumor invasion in (Bearer et al., Cancer Research, 69 (2009)) and (Frieboes et al., J. Theor. Biol. 264 (2010)). The model has a thermodynamic basis, is related to recently developed mixture models, and is capable of providing a detailed description of tumor progression. It utilizes a diffuse interface approach, whereby sharp tumor boundaries are replaced by narrow transition layers that arise due to differential adhesive forces among the cell-species. The model consists of fourth-order nonlinear advection-reaction-diffusion equations (of Cahn-Hilliard-type) for the cell-species coupled with reaction-diffusion equations for the substrate components. Numerical solution of the model is challenging because the equations are coupled, highly nonlinear, and numerically stiff. In this paper we describe a fully adaptive, nonlinear multigrid/finite difference method for efficiently solving the equations. We demonstrate the convergence of the algorithm and we present simulations of tumor growth in 2D and 3D that demonstrate the capabilities of the algorithm in accurately and efficiently simulating the progression of tumors with complex morphologies. PMID:21076663

  6. Ultrasonic rf-based imaging for the purposes of characterizing the microstructure of solid tumors

    NASA Astrophysics Data System (ADS)

    Oelze, Michael; Zachary, James F.; O'Brien, William D., Jr.

    2002-04-01

    Eight retired breeder rats were acquired that had developed spontaneous mammary tumors. Tumors were diagnosed microscopically as mammary gland fibroadenomas. Two-dimensional gray-scale B-mode images of the tumors in the rats were constructed from backscattered echoes using an 8 MHz (90% bandwidth) single element ultrasonic transducer. From the gray-scale B-mode images, regions-of-interest (ROIs) were selected in the tumors and surrounding tissues. The power spectra of backscattered RF echoes gated from the ROIs were used to estimate the average scatterer diameters and concentrations. A unique estimation scheme was used to obtain the average scatterer diameters and concentrations. The average scatterer diameter was related to the slope of the best-fit line to the reduced measured power spectrum versus the frequency squared. The scatterer concentration was determined from the intercept of the best-fit line. The reduced measured power spectrum is the measured power spectrum minus 40 log of the frequency. Parametric B-mode images were constructed by converting ROI boxes into colored pixels. The color of the pixels was related to the estimated scatterer properties. The images showed a distinct difference between the tumor and surrounding healthy tissues. Scatterer sizes inside the tumor were on average 30% larger than scatterer sizes in surrounding normal tissues.

  7. Nutritional and supranutritional levels of selenate differentially suppress prostate tumor growth in adult but not young nude mice.

    PubMed

    Holmstrom, Alexandra; Wu, Ryan T Y; Zeng, Huawei; Lei, K Y; Cheng, Wen-Hsing

    2012-09-01

    The inhibitory effect of oral methylseleninic acid or methylselenocysteine administration on cancer cell xenograft development in nude mice is well characterized; however, less is known about the efficacy of selenate and age on selenium chemoprevention. In this study, we tested whether selenate and duration on diets would regulate prostate cancer xenograft in nude mice. Thirty-nine homozygous NU/J nude mice were fed a selenium-deficient, Torula yeast basal diet alone (Se-) or supplemented with 0.15 (Se) or 1.0 (Se+) mg selenium/kg (as Na₂SeO₄) for 6 months in Experiment 1 and for 4 weeks in Experiment 2, followed by a 47-day PC-3 prostate cancer cell xenograft on the designated diet. In Experiment 1, the Se- diet enhanced the initial tumor development on days 11-17, whereas the Se+ diet suppressed tumor growth on days 35-47 in adult nude mice. Tumors grown in Se- mice were loosely packed and showed increased necrosis and inflammation as compared to those in Se and Se+ mice. In Experiment 2, dietary selenium did not affect tumor development or histopathology throughout the time course. In both experiments, postmortem plasma selenium concentrations in Se and Se+ mice were comparable and were twofold greater than those in Se- mice. Taken together, dietary selenate at nutritional and supranutritional levels differentially inhibit tumor development in adult, but not young, nude mice engrafted with PC-3 prostate cancer cells.

  8. Use of the levonorgestrel 52-mg intrauterine system in adolescent and young adult solid organ transplant recipients: a case series.

    PubMed

    Huguelet, P S; Sheehan, C; Spitzer, R F; Scott, S

    2017-04-01

    This case series reports on the safety and efficacy of the levonorgestrel 52-mg intrauterine system in adolescent and young adult solid organ transplant recipients. All patients used the device for contraception, with no documented cases of disseminated pelvic infection or unplanned pregnancy.

  9. Identification of immunoglobulin V(D)J recombinations in solid tumor specimen exome files: Evidence for high level B-cell infiltrates in breast cancer.

    PubMed

    Tong, Wei Lue; Tu, Yaping N; Samy, Mohammad D; Sexton, Wade J; Blanck, George

    2017-01-13

    It has recently become apparent that it is possible to characterize productively recombined, T-cell receptor (TcR) gene segments in tumor exome files, which presumably include representations of the DNA of other cells in the microenvironment. Similar characterizations have been done for TcR recombinations in tumor specimen RNASeq files. While exome files have been used to characterize immunoglobulin gene segment recombinations for tumors closely related to B-cells, immunoglobulin recombinations have yet to be characterized for putative microenvironment cells for solid tumors. Here we report a novel scripted algorithm that detects productive and unproductive immunoglobulin recombinations in both B-cell related tumor exome files and in solid tumor exome files, with the most important result being the relatively high level B-cell infiltrate in breast cancer. This analysis has the potential of streamlining and dramatically augmenting the knowledge base regarding B-cell infiltrates into solid tumors; and leading to antibody reagents directed against tumor antigens and tissue resident, infectious pathogens.

  10. Hyaluronic acid based self-assembling nanosystems for CD44 target mediated siRNA delivery to solid tumors.

    PubMed

    Ganesh, Shanthi; Iyer, Arun K; Morrissey, David V; Amiji, Mansoor M

    2013-04-01

    Anticancer therapeutics employing RNA interference mechanism holds promising potentials for sequence-specific silencing of target genes. However targeted delivery of siRNAs to tumor tissues and cells and more importantly, their intracellular release at sites of interest still remains a major challenge that needs to be addressed before this technique could become a clinically viable option. In the current study, we have engineered and screened a series of CD44 targeting hyaluronic acid (HA) based self-assembling nanosystems for targeted siRNA delivery. The HA polymer was functionalized with lipids of varying carbon chain lengths/nitrogen content, as well as polyamines for assessing siRNA encapsulation. From the screens, several HA-derivatives were identified that could stably encapsulate/complex siRNAs and form self-assembled nanosystems, as determined by gel retardation assays and dynamic light scattering. Many HA derivatives could transfect siRNAs into cancer cells overexpressing CD44 receptors. Interestingly, blocking the CD44 receptors on the cells using free excess soluble HA prior to incubation of cy3-labeled-siRNA loaded HA nano-assemblies resulted in >90% inhibition of the receptor mediated uptake, confirming target specificity. In addition, SSB/PLK1 siRNA encapsulated in HA-PEI/PEG nanosystems demonstrated dose dependent and target specific gene knockdown in both sensitive and resistant A549 lung cancer cells overexpressing CD44 receptors. More importantly, these siRNA encapsulated nanosystems demonstrated tumor selective uptake and target specific gene knock down in vivo in solid tumors as well as in metastatic tumors. The HA based nanosystems thus portend to be promising siRNA delivery vectors for systemic targeting of CD44 overexpressing cancers including tumor initiating (stem-) cells and metastatic lesions.

  11. New Strategies in Personalized Medicine for Solid Tumors: Molecular Markers and Clinical Trial Designs

    PubMed Central

    Jürgensmeier, Juliane M.; Eder, Joseph P.; Herbst, Roy S.

    2017-01-01

    The delineation of signaling pathways to understand tumor biology combined with the rapid development of technologies that allow broad molecular profiling and data analysis, has led to a new era of personalized medicine in oncology. Many academic institutions now routinely profile patients and discuss them in personalized medicine tumor boards before making treatment recommendations. Clinical trials initiated by pharmaceutical companies often require specific markers for enrollment or at least explore multiple options for future markers. In addition to the still small number of targeted agents that are approved for the therapy of patients with histological and molecularly defined tumors, there is a broad range of novel targeted agents in development that are undergoing clinical studies with companion profiling to determine the best responding patient population. While the present focus of profiling are genetic analyses, additional testing of RNA, protein and immune parameters are being developed and incorporated in clinical research and are likely to contribute significantly to future patient selection and treatment approaches. As the advances in tumor biology and human genetics have identified promising tumor targets, the ongoing clinical evaluation of novel agents will now need to show if the promise can be translated into benefit for patients. PMID:25183480

  12. Solid-tumor mortality in the vicinity of uranium cycle facilities and nuclear power plants in Spain.

    PubMed Central

    López-Abente, G; Aragonés, N; Pollán, M

    2001-01-01

    To ascertain solid tumor mortality in towns near Spain's four nuclear power plants and four nuclear fuel facilities from 1975 to 1993, we conducted a mortality study based on 12,245 cancer deaths in 283 towns situated within a 30-km radius of the above installations. As nonexposed areas, we used 275 towns lying within a 50- to 100-km radius of each installation, matched by population size and sociodemographic characteristics (income level, proportion of active population engaged in farming, proportion of unemployed, percentage of illiteracy, and province). Using log-linear models, we examined relative risk for each area and trends in risk with increasing proximity to an installation. The results reveal a pattern of solid-tumor mortality in the vicinity of uranium cycle facilities, basically characterized by excess lung [relative risk (RR) 1.12, 95% confidence interval (CI), 1.02-1.25] and renal cancer mortality (RR 1.37, 95% CI, 1.07-1.76). Besides the effects of natural radiation, these results could well be evincing the influence on public health exerted by the environmental impact of mining. No such well-defined pattern appeared in the vicinity of nuclear power plants. Monitoring of cancer incidence and mortality is recommended in areas surrounding nuclear fuel facilities and nuclear power plants, and more specific studies are called for in areas adjacent to installations that have been fully operational for longer periods. In this regard, it is important to use dosimetric information in all future studies. PMID:11485872

  13. Detection of circulating solid tumor cells by reverse transcriptase polymerase chain reaction.

    PubMed

    Burchill, S A

    1998-01-01

    Despite advances in cancer treatment, disseminating disease continues to pose a major problem in clinical management. The dissemination of cancer cells around the body, or metastasis, involves multiple tumor-host interactions. The relatronship between circulating tumor cells and development of secondary disease is not fully understood, though for cells to metastasize they must be capable of entering and surviving in peripheral blood or bone marrow. Although it is thought less than 0.01% of cnculating tumor cells will successfully establish metastatic colonies (1) detect small numbers of such cells will allow evaluation of their role in the disease process. This may provide the clinician with a powerful tool to predict recurrence and relapse. In the longterm this may lead to improved clinical outcome by additional treament of persistent disease following conventional therapy or early intervention in patients with micrometastatic disease and preclinical relapse.

  14. Scanning with iodine-131 MIBG in children with solid tumors: an initial appraisal

    SciTech Connect

    Hadley, G.P.; Rabe, E.

    1986-05-01

    Twelve children with malignant disease in whom there was either a clinical, radiologic, or histologic differential diagnosis including neuroblastoma were investigated using iodine-131 metaiodobenzylguanidine (MIBG) scanning. In six children in whom a final diagnosis of neuroblastoma was substantiated, scans were positive; in five children with other malignancies, scans were negative. In one child, clinically and radiologically tumor free following excision on an abdominal neuroblastoma, scans were also negative. MIBG scanning proved of value as a discriminant of malignant undifferentiated tumors in children, and in the diagnosis and staging of neuroblastoma. During treatment, MIBG scans in two patients correlated with contemporaneous computed tomographic scans and may allow noninvasive monitoring of therapeutic response and completeness of surgical excision. Primary and recurrent abdominal tumors, and visceral, osseous, and marrow deposits were demonstrated using this technique.

  15. Evaluation of the effects of thalidomide-loaded biodegradable devices in solid Ehrlich tumor.

    PubMed

    Pereira, Bruno Gonçalves; Ligorio Fialho, Silvia; Maria de Souza, Cristina; Dantas Cassali, Geovanni; Silva-Cunha, Armando

    2013-03-01

    Regarding thalidomide's effects in cancer and the problems related to its physicochemical characteristics and toxic effects, we proposed a new biodegradable polymeric implant to this drug. In this paper, we evaluate the antiangiogenic activity and antitumor effect of thalidomide when incorporated in poly-lactide-co-glycolide (PLGA) implants in an animal model for Ehrlich tumor. This dosage form permits the prolonged drug release. The biodegradable implants could reduce the blood vessel in a chorioallantoic membrane (CAM) model. When applied to the Ehrlich tumor model, implant also showed to reduce the number of vessels. It was also observed to reduce areas of inflammation and increases the area of necrosis in the group of thalidomide implant. A 47% reduction in tumor volume was observed in the thalidomide implant group, which is discussed in relation to literature reported results of thalidomide conventional administration ways.

  16. Combining Radiation and Immunotherapy: A New Systemic Therapy for Solid tumors?

    PubMed Central

    Tang, Chad; Wang, Xiaohong; Soh, Hendrick; Seyedin, Steven; Cortez, Maria Angelica; Krishnan, Sunil; Massarelli, Erminia; Hong, David; Naing, Aung; Diab, Adi; Gomez, Daniel; Ye, Huiping; Heymach, John; Komaki, Ristuko; Allison, James; Sharma, Padmanee; Welsh, James W.

    2017-01-01

    With the recent success of checkpoint inhibitors and other immune-modulating agents, there has been renewed interest in the combination of such agents with radiation. The biological premise behind such a strategy is that the tumor-antigen release achieved by localized radiation will promote specific tumor-targeting by the adaptive immune system, which can be augmented further by systemic immune-stimulating agents. In this manner, clinicians hope to induce a phenomenon known as the abscopal effect, whereby localized radiation results in immune-mediated tumor regression in disease sites well outside of the radiation field. In this Crossroads in Cancer Immunology article, we will present a comprehensive overview of the early clinical and pre-clinical evidence behind this approach. PMID:25187273

  17. Interstitial laser coagulation for localized destruction of solid tumors: overview of strategies

    NASA Astrophysics Data System (ADS)

    van Hillegersberg, Richard

    1997-06-01

    Interstitial laser coagulation (ILC) is a new method of producing localized tissue destruction, that may be used to eliminate soli tumors, such as liver metastases, pancreatic carcinomas, brain glioma and benign prostate hyperplasia. In ILC, Nd:YAG laser light is guided through flexible quartz fibers implanted directly into the tumor. Several experimental studies have shown the effectiveness of this therapy. Clinical application is feasible, however success in malignant tumors is limited by: (1) the restricted lesion size produced by a single optical fiber and (2) the lack of reliable on-line monitoring of the laser-induced effects. Research is therefore directed towards the development of multiple fiber application, guided by real time feedback of the laser-tissue interaction.

  18. TORC1/2 Inhibitor MLN0128 and Bevacizumab in Treating Patients With Recurrent Glioblastoma or Advanced Solid Tumors

    ClinicalTrials.gov

    2017-01-31

    Adult Glioblastoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Serous Adenocarcinoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Solid Neoplasm; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  19. Polyplex-Microbubble Hybrids for Ultrasound-Guided Plasmid DNA Delivery to Solid Tumors

    PubMed Central

    Sirsi, Shashank; Hernandez, Sonia; Zielinski, Lukasz; Blomback, Henning; Koubaa, Adel; Synder, Milo; Homma, Shunichi; Kandel, Jessica J.; Yamashiro, Darrell J.; Borden, Mark A.

    2013-01-01

    Microbubble ultrasound contrast agents are being developed as image-guided gene carriers for targeted delivery in vivo. In this study, novel polyplex-microbubbles were synthesized, characterized and evaluated for systemic circulation and tumor transfection. Branched polyethylenimine (PEI; 25 kDa) was modified with polyethylene glycol (PEG; 5 kDa), thiolated and covalently attached to maleimide groups on lipid-coated microbubbles. The PEI-microbubbles demonstrated increasingly positive surface charge and DNA loading capacity with increasing maleimide content. The in vivo ultrasound contrast persistence of PEI-microbubbles was measured in the healthy mouse kidney, and a two-compartment pharmacokinetic model accounting for free and adherent microbubbles was developed to describe the anomalous time-intensity curves. The model suggested that PEI loading dramatically reduced free circulation and increased nonspecific adhesion to the vasculature. However, DNA loading to form polyplex-microbubbles increased circulation in the bloodstream and decreased nonspecific adhesion. PEI-microbubbles coupled to a luciferase bioluminescence reporter plasmid DNA were shown to transfect tumors implanted in the mouse kidney. Site-specific delivery was achieved using ultrasound applied over the tumor area following bolus injection of the DNA/PEI-microbubbles. In vivo imaging showed over 10-fold higher bioluminescence from the tumor region compared to untreated tissue. Ex vivo analysis of excised tumors showed greater than 40-fold higher expression in tumor tissue than non-sonicated control (heart) tissue. These results suggest that the polyplex-microbubble platform offers improved control of DNA loading and packaging suitable for ultrasound-guided tissue transfection. PMID:21945680

  20. Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy.

    PubMed

    Siemann, Dietmar W; Mercer, Emma; Lepler, Sharon; Rojiani, Amyn M

    2002-05-01

    The utility of combining the vascular targeting agents 5,6-dimethyl-xanthenone-4 acetic acid (DMXAA) and combretastatin A-4 disodium phosphate (CA4DP) with the anticancer drugs cisplatin and cyclophosphamide (CP) was evaluated in experimental rodent (KHT sarcoma), human breast (SKBR3) and ovarian (OW-1) tumor models. Doses of the vascular targeting agents that led to rapid vascular shutdown and subsequent extensive central tumor necrosis were identified. Histologic evaluation showed morphologic damage of tumor cells within a few hours after treatment, followed by extensive hemorrhagic necrosis and dose-dependent neoplastic cell death as a result of prolonged ischemia. Whereas these effects were induced by a range of CA4DP doses (10-150 mg/kg), the dose response to DMXAA was extremely steep; doses < or = 15 mg/kg were ineffective and doses > or = 20 mg/kg were toxic. DMXAA also enhanced the tumor cell killing of cisplatin, but doses > 15 mg/kg were required. In contrast, CA4DP increased cisplatin-induced tumor cell killing at all doses studied. This enhancement of cisplatin efficacy was dependent on the sequence and interval between the agents. The greatest effects were achieved when the vascular targeting agents were administered 1-3 hr after cisplatin. When CA4DP (100 mg/kg) or DMXAA (17.5 mg/kg) were administered 1 hr after a range of doses of cisplatin or CP, the tumor cell kill was 10-500-fold greater than that seen with chemotherapy alone. In addition, the inclusion of the antivascular agents did not increase bone marrow stem cell toxicity associated with these anticancer drugs, thus giving rise to a therapeutic gain.

  1. Screening for somatic mutations of the neurofibromatosis genes in nervous system and other solid tumors

    SciTech Connect

    Rangaratnam, S.; Narod, S.; Ruttledge, M.

    1994-09-01

    Von Recklinghausen neurofibromatosis (NF1) and neurofibromatosis type 2 (NF2) are autosomal dominant inherited disorders which predispose carriers to various benign and malignant tumors. Both genes are thought to act as tumor suppressors with inactivation of both alleles resulting in abnormal cell growth. By inference from other hereditary cancer syndromes, it has been hypothesized that somatic mutation at the NF1 and NF2 loci is involved in the development of sporadic tumors of the types found with increased prevalence in these disorders. In addition to other malignancies, individuals with NF1 are at increased risk to develop astrocytomas and rhabdomyosarcomas. We have therefore screened 40 astrocytomas for LOH using three NF1-derived cDNA probes, and have found no abnormalities. Single-strand conformation polymorphism (SSCP) analysis of exons of the NF1 GAP-related domain has also failed to show any variants in a total of 70 astrocytomas and 14 rhabdomyosarcomas (7 each of embryonal and alveolar types). LOH of chromosome 22 markers is known to occur in meningioma, malignant melanoma, breast cancer, and ependymoma. SSCP of all 17 exons of the NF2 gene in 27 melanoma cell lines, 42 breast cancers, and 27 pendymomas revealed no alterations. In a screen of 151 menigiomas, 26 new variants have been found, bringing our total to 50 variants in this sample. These represent inactivating mutations (frameshift, splice-site, and nonsense), determined by direct sequencing. Since the majority of these changes occur in tumors previously shown to have LOH at chromosome 22 markers flanking NF2, our results support a tumor sequence role for this gene in meningiomas. In addition, given that 40% of our tumors do not show LOH over this region, we propose that other genes are involved in the development of this latter subset of meningiomas.

  2. Spatiotemporally Photoradiation-Controlled Intratumoral Depot for Combination of Brachytherapy and Photodynamic Therapy for Solid Tumor

    PubMed Central

    Mukerji, Ratul; Schaal, Jeffrey; Li, Xinghai; Bhattacharyya, Jayanta; Asai, Daisuke; Zalutsky, Michael R.; Chilkoti, Ashutosh; Liu, Wenge

    2015-01-01

    In an attempt to spatiotemporally control both tumor retention and the coverage of anticancer agents, we developed a photoradiation-controlled intratumoral depot (PRCITD) driven by convention enhanced delivery (CED). This intratumoral depot consists of recombinant elastin-like polypeptide (ELP) containing periodic cysteine residues and is conjugated with a photosensitizer, chlorin-e6 (Ce6) at the N-terminus of the ELP. We hypothesized that this cysteine-containing ELP (cELP) can be readily crosslinked through disulfide bonds upon exposure to oxidative agents, specifically the singlet oxygen produced during photodynamic stimulation. Upon intratumoral injection, CED drives the distribution of the soluble polypeptide freely throughout the tumor interstitium. Formation and retention of the depot was monitored using fluorescence molecular tomography imaging. When imaging shows that the polypeptide has distributed throughout the entire tumor, 660-nm light is applied externally at the tumor site. This photo-radiation wavelength excites Ce6 and generates reactive oxygen species (ROS) in the presence of oxygen. The ROS induce in situ disulfide crosslinking of the cysteine thiols, stabilizing the ELP biopolymer into a stable therapeutic depot. Our results demonstrate that this ELP design effectively forms a hydrogel both in vitro and in vivo. These depots exhibit high stability in subcutaneous tumor xenografts in nude mice and significantly improved intratumoral retention compared to controls without crosslinking, as seen by fluorescent imaging and iodine-125 radiotracer studies. The photodynamic therapy provided by the PRCITD was found to cause significant tumor inhibition in a Ce6 dose dependent manner. Additionally, the combination of PDT and intratumoral radionuclide therapy co-delivered by PRCITD provided a greater antitumor effect than either monotherapy alone. These results suggest that the PRCITD could provide a stable platform for delivering synergistic, anti

  3. Optimizing the Delivery of Short-Lived Alpha Particle-Emitting Isotopes to Solid Tumors

    SciTech Connect

    Adams, Gregory P.

    2004-11-24

    The underlying hypothesis of this project was that optimal alpha emitter-based radioimmunotherapy (RAIT) could be achieved by pairing the physical half-life of the radioisotope to the biological half-life of the targeting vehicle. The project had two specific aims. The first aim was to create and optimize the therapeutic efficacy of 211At-SAPS-C6.5 diabody conjugates. The second aim was to develop bispecific-targeting strategies that increase the specificity and efficacy of alpha-emitter-based RAIT. In the performance of the first aim, we created 211At-SAPS-C6.5 diabody conjugates that specifically targeted the HER2 tumor associated antigen. In evaluating these immunoconjugates we determined that they were capable of efficient tumor targeting and therapeutic efficacy of established human tumor xenografts growing in immunodeficient mice. We also determined that therapeutic doses were associated with late renal toxicity, likely due to the role of the kidneys in the systemic elimination o f these agents. We are currently performing more studies focused on better understanding the observed toxicity. In the second aim, we successfully generated bispecific single-chain Fv (bs-scFv) molecules that co-targeted HER2 and HER3 or HER2 and HER4. The in vitro kinetics and in vivo tumor-targeting properties of these molecules were evaluated. These studies revealed that the bs-scFv molecules selectively localized in vitro on tumor cells that expressed both antigens and were capable of effective tumor localization in in vivo studies.

  4. Quantitative PCR for HTLV-1 provirus in adult T-cell leukemia/lymphoma using paraffin tumor sections.

    PubMed

    Kato, Junki; Masaki, Ayako; Fujii, Keiichiro; Takino, Hisashi; Murase, Takayuki; Yonekura, Kentaro; Utsunomiya, Atae; Ishida, Takashi; Iida, Shinsuke; Inagaki, Hiroshi

    2016-11-01

    Detection of HTLV-1 provirus using paraffin tumor sections may assist the diagnosis of adult T-cell leukemia/lymphoma (ATLL). For the detection, non-quantitative PCR assay has been reported, but its usefulness and limitations remain unclear. To our knowledge, quantitative PCR assay using paraffin tumor sections has not been reported. Using paraffin sections from ATLLs and non-ATLL T-cell lymphomas, we first performed non-quantitative PCR for HTLV-1 provirus. Next, we determined tumor ratios and carried out quantitative PCR to obtain provirus copy numbers. The results were analyzed with a simple regression model and a novel criterion, cut-off using 95 % rejection limits. Our quantitative PCR assay showed an excellent association between tumor ratios and the copy numbers (r = 0.89, P < 0.0001). The 95 % rejection limits provided a statistical basis for the range for the determination of HTLV-1 involvement. Its application suggested that results of non-quantitative PCR assay should be interpreted very carefully and that our quantitative PCR assay is useful to estimate the status of HTLV-1 involvement in the tumor cases. In conclusion, our quantitative PCR assay using paraffin tumor sections may be useful for the screening of ATLL cases, especially in HTLV-1 non-endemic areas where easy access to serological testing for HTLV-1 infection is limited.

  5. Agent-Based Modeling of Cancer Stem Cell Driven Solid Tumor Growth.

    PubMed

    Poleszczuk, Jan; Macklin, Paul; Enderling, Heiko

    2016-01-01

    Computational modeling of tumor growth has become an invaluable tool to simulate complex cell-cell interactions and emerging population-level dynamics. Agent-based models are commonly used to describe the behavior and interaction of individual cells in different environments. Behavioral rules can be informed and calibrated by in vitro assays, and emerging population-level dynamics may be validated with both in vitro and in vivo experiments. Here, we describe the design and implementation of a lattice-based agent-based model of cancer stem cell driven tumor growth.

  6. STAT3 as a target for inducing apoptosis in solid and hematological tumors

    PubMed Central

    Siddiquee, Khandaker Al Zaid; Turkson, James

    2008-01-01

    Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 (STAT3) in malignant transformation and tumorigenesis. Thus, it is now generally accepted that STAT3 is one of the critical players in human cancer formation and represents a valid target for novel anticancer drug design. This review focuses on aberrant STAT3 and its role in promoting tumor cell survival and supporting the malignant phenotype. A brief evaluation of the current strategies targeting STAT3 for the development of novel anticancer agents against human tumors harboring constitutively active STAT3 will also be presented. PMID:18227858

  7. Monoclonal Antibodies in the Lymphatics: Selective Delivery to Lymph Node Metastases of a Solid Tumor

    NASA Astrophysics Data System (ADS)

    Weinstein, John N.; Steller, Michael A.; Keenan, Andrew M.; Covell, David G.; Key, Marc E.; Sieber, Susan M.; Oldham, Robert K.; Hwang, Kou M.; Parker, Robert J.

    1983-10-01

    After subcutaneous injection, monoclonal antibodies directed against a tumor can enter local lymphatic vessels, pass to the draining lymph nodes, and bind to metastases there. Lymphatic delivery of antibody to early metastases is more efficient than intravenous administration, and the lymphatic route can be used to image smaller metastatic deposits. Perhaps more important, the lymphatic route minimizes binding of antibodies to circulating tumor antigens and to cross-reactive antigens present on normal tissues. Antibodies inappropriate for intravenous use because of binding to normal tissues may therefore be useful against lymph node metastases when injected subcutaneously or directly into lymphatic vessels.

  8. Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis).

    PubMed

    Kummar, Shivaani; O'Sullivan Coyne, Geraldine; Do, Khanh T; Turkbey, Baris; Meltzer, Paul S; Polley, Eric; Choyke, Peter L; Meehan, Robert; Vilimas, Rasa; Horneffer, Yvonne; Juwara, Lamin; Lih, Ann; Choudhary, Amul; Mitchell, Sandra A; Helman, Lee J; Doroshow, James H; Chen, Alice P

    2017-03-28

    Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the γ-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.

  9. Phase I dose-escalation and pharmacokinetic study of oral gefitinib and irinotecan in children with refractory solid tumors

    PubMed Central

    Brennan, R. C.; Furman, W.; Mao, S.; Wu, J.; Turner, D. C.; Stewart, C. F.; Santana, V.; McGregor, L. M.

    2015-01-01

    Purpose This phase I study endeavored to estimate the maximum tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) of oral irinotecan with gefitinib in children with refractory solid tumors. Methods Oral irinotecan was administered on days 1-5 and 8-12 with oral gefitinib (fixed dose, 150mg/m2/day) on days 1-12 of a 21-day course. The Escalation with Overdose Control (EWOC) method guided irinotecan dose escalation (7 dose levels, range 5mg/m2/day to 40mg/m2/day). Results Sixteen of 19 patients were evaluable, with serial pharmacokinetic studies in 10 patients. Diagnoses included osteosarcoma (N=5), neuroblastoma (N=3), sarcoma (N=3), and others (N=5). Patients received a median of two courses (range 1-20), with at least two patients treated on dose levels 2-7. Three patients had five DLTs; the most common being metabolic (hypokalemia, N=2 and hypophosphatemia, N=1) at dose levels two (10mg/m2) and four (20mg/m2). One patient experienced grade 3 diarrhea (40mg/m2). Irinotecan bioavailability was 2.5-fold higher when co-administered with gefitinib while the conversion rate of irinotecan to SN-38 lactone was unaffected. The study closed due to poor accrual before evaluation of the next recommended irinotecan dose level (35mg/m2). Of eleven patients receiving at least two courses of therapy, three had stable disease (SD) lasting two to four courses and one patient maintained a complete response through 18 courses. Conclusions The combination of oral gefitinib and irinotecan has acceptable toxicity and anti-tumor activity in pediatric patients with refractory solid tumors. Pharmacokinetic analysis confirms that co-administration of gefitinib increases irinotecan bioavailability leading to an increased SN-38 lactone systemic exposure. PMID:25257509

  10. Prognostic role of high B7-H4 expression in patients with solid tumors: a meta-analysis

    PubMed Central

    Gu, Wendong; Xu, Chao; Mao, Huihui; Pei, Honglei; Jiang, Jingting

    2016-01-01

    Background Recently, many studies have shown that B7-H4 exhibits altered expression in various cancers. We performed a meta-analysis to evaluate the prognostic role of B7-H4 expression in solid tumors. Results Data from 18 observational studies and 2467 patients were summarized. An elevated baseline B7-H4 was significantly associated with worse OS (pooled HR = 1.79; 95% CI = 1.56–2.06). Differences across subgroups of tumor type, patients' ethnicity, analysis type, HR obtain method and cut-off value were not significant (PD = 0.313, PD = 0.716, PD = 0.896, PD = 0.290 and PD = 0.153, respectively). Furthermore, patients with high B7-H4 had a significantly shorter DFS (pooled HR = 2.12; 95%CI = 1.45–3.09). Materials and Methods We searched PubMed, Embase and the Cochrane Library (last update by November 26, 2015) to identify studies assessing the effect of B7-H4 on survival of cancer patients. Pooled hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) were estimated using fixed-effects models and random-effects models respectively. Conclusions This meta-analysis clarified that high B7-H4 expression in tissue was significantly associated with poor survival in patients with solid tumors. Future clinical studies are warranted to determine whether B7-H4 blockade has a favorable effect on disease recurrence and mortality. PMID:27058425

  11. Survival in Patients With Severe Lymphopenia Following Treatment With Radiation and Chemotherapy for Newly Diagnosed Solid Tumors

    PubMed Central

    Grossman, Stuart A.; Ellsworth, Susannah; Campian, Jian; Wild, Aaron T.; Herman, Joseph M.; Laheru, Dan; Brock, Malcolm; Balmanoukian, Ani; Ye, Xiaobu

    2016-01-01

    Background The immune system plays an important role in cancer surveillance and therapy. Chemoradiation can cause severe treatment-related lymphopenia (TRL) (<500 cells/mm3) that is associated with reduced survival. Materials and Methods Data from 4 independent solid tumor studies on serial lymphocyte counts, prognostic factors, treatment, and survival were collected and analyzed. The data set included 297 patients with newly diagnosed malignant glioma (N=96), resected pancreatic cancer (N=53), unresectable pancreatic cancer (N=101), and non–small cell lung cancer (N=47). Results Pretreatment lymphocyte counts were normal in 83% of the patient population, and no patient had severe baseline lymphopenia. Two months after initiating chemoradiation, 43% developed severe and persistent lymphopenia (P=.001). An increased risk for death was attributable to TRL in each cancer cohort (gliomas: hazard rate [HR], 1.8; 95% CI, 1.13–2.87; resected pancreas: HR, 2.2; 95% CI, 1.17–4.12; unresected pancreas: HR, 2.9; 95% CI, 1.53–5.42; and lung: HR, 1.7; 95% CI, 0.8–3.61) and in the entire study population regardless of pathologic findings (HR, 2.1; 95% CI, 1.54–2.78; P<.0001). Severe TRL was observed in more than 40% of patients 2 months after initiating chemoradiation, regardless of histology or chemotherapy regimen, and was independently associated with shorter survival from tumor progression. Conclusions Increased attention and research should be focused on the cause, prevention, and reversal of this unintended consequence of cancer treatment that seems to be related to survival in patients with solid tumors. PMID:26483062

  12. From adult stem cells to cancer stem cells: Oct-4 Gene, cell-cell communication, and hormones during tumor promotion.

    PubMed

    Trosko, James E

    2006-11-01

    Carcinogenesis is characterized by "initiation," "promotion," and "progression" phases. The "stem cell theory" and "de-differentiation" theories are used to explain the origin of cancer. Growth control for stem cells, which lack functional gap junctional intercellular communication (GJIC), involves negative soluble or niche factors, while for progenitor cells, it involves GJIC. Tumor promoters, hormones, and growth factors inhibit GJIC reversibly. Oncogenes stably inhibit GJIC. Cancer cells, which lack growth control and the ability to terminally differentiate and to apoptose, lack GJIC. The Oct3/4 gene, a POU (Pit-Oct-Unc) family of transcription factors was thought to be expressed only in embryonic stem cells and in tumor cells. With the availability of normal adult human stem cells, tests for the expression of Oct3/4 gene and the stem cell theory in human carcinogenesis became possible. Human breast, liver, pancreas, kidney, mesenchyme, and gastric stem cells, HeLa and MCF-7 cells, and canine tumors were tested with antibodies and polymerase chain reaction (PCR) primers for Oct3/4. Adult human breast stem cells, immortalized nontumorigenic and tumor cell lines, but not the normal differentiated cells, expressed Oct3/4. Adult human differentiated cells lose their Oct-4 expression. Oct3/4 is expressed in a few cells found in the basal layer of human skin epidermis. The data demonstrate that normal adult stem cells and cancer stem cells maintain expression of Oct3/4, consistent with the stem cell hypothesis of carcinogenesis. These Oct-4 positive cells might represent the "cancer stem cells." A strategy to target "cancer stem cells" is to suppress the Oct-4 gene in order to cause the cells to differentiate.

  13. Augmented lymphocyte expansion from solid tumors with engineered cells for costimulatory enhancement

    PubMed Central

    Friedman, Kevin M; DeVillier, Laura E; Feldman, Steven A; Rosenberg, Steven A; Dudley, Mark E

    2011-01-01

    Treatment of patients with adoptive T cell therapy requires expansion of unique tumor-infiltrating lymphocyte (TIL) cultures from single cell suspensions processed from melanoma biopsies. Strategies which increase the expansion and reliability of TIL generation from tumor digests are necessary to improve access to TIL therapy. Prior work evaluated artificial antigen presenting cells (aAPCs) for their antigen-specific and costimulatory properties. We investigated engineered cells for co-stimulatory enhancement (ECCE) consisting of K562 cells which express 4-1BBL in the absence of artificial antigen stimulation. ECCE accelerated TIL expansion and significantly improved TIL numbers (p=0.001) from single cell melanoma suspensions. TIL generated with ECCE contain significantly more CD8+CD62L+ and CD8+CD27+ T cells then comparable IL-2-expanded TIL and maintained anti-tumor reactivity. Moreover, ECCE improved TIL expansion from non-melanoma cell suspensions similar to that seen with melanoma tumors. These data demonstrate that ECCE addition to TIL production will enable treatment of patients ineligible using current methods. PMID:21989413

  14. Effects of black tea extract on transplantable and solid tumors in Swiss albino mice.

    PubMed

    Javed, S; Shukla, Y

    2000-09-01

    The chemopreventive effects of green tea and its polyphenols are well documented in the literature. Epidemiological studies have suggested that green tea consumption might be effective in the prevention of certain human cancers. About 80% of the tea is consumed as black tea. Limited studies have been carried out to assess the usefulness of black tea as anti-carcinogen. The present set of investigations were initiated to study the anti-tumorigenic potential of aqueous black tea extract (ATE) in Swiss albino mice in in vivo animal bioassay, using 7, 12 dimethyl-benzanthracene (DMBA) as carcinogen. In the experimental group, 2% ATE was given orally as sole source of drinking water, while the control were allowed to drink normal water, ad lib. The results revealed that drinking of 2% ATE could effectively inhibit the onset of tumorigenesis, cumulative number of tumors and average number of tumors per mouse. In ATE drinking group 44% animals remained tumor free till the termination of experiment, i.e. 26 weeks. In the second set of experiment the preventive efficacy of 2% ATE of different cultivars of black tea, viz orthodox, CTC and dust were tested in Ehrlich Ascites (EA) tumor bearing mice. The preventive effects of ATE were observed in terms of increased life span (ILS). All the cultivars of tea showed more than 25% increase in life span of the animals. Cytotoxic effect of various doses of all three cultivars of black tea was also observed in vitro on EA cells.

  15. Effects of target antigen competition on distribution of monoclonal antibody to solid tumors.

    PubMed

    Kennel, S J

    1992-03-01

    Monoclonal antibody (MoAb) 11A and MoAb 13A recognize normal murine cell surface glycoproteins, which are also expressed in high concentrations on Line 1 lung carcinoma. Studies were initiated to examine the competition in vivo for radiolabeled MoAb between sites on the tumor versus sites on normal tissue. Quantitative 2-site assay of the alpha 6 beta 4 integrin recognized by MoAb 11A showed that major sites of expression are tumor, intestine, and skin. Microdistribution studies show that at doses of 125I-labeled MoAb 11A less than the total body antigen load, the MoAb bound to beta 4 endothelial cells with little extravasation to epithelial sites. As the MoAb dose was increased, and endothelial sites became saturated, deposition at epithelial sites including skin and tumor became apparent. Quantitative radioimmunoassay with MoAb 13A, recognizing CD44 (P100), demonstrated major sites of expression as tumor, intestine, liver and, to a lesser extent, spleen and skin. Microdistribution studies at low doses of 125I-labeled MoAb showed deposition mainly in the liver and spleen sinusoids, whereas higher doses were necessary to maximize MoAb accumulation in tumor. The rapid access of MoAb to target antigen is the most important parameter in efficient localization of MoAb. Access of antigen outside the vascular space is regulated at least in part by the permeability of the endothelial barrier. Of the organs studied, antigen accessibility increases in the following order: lung epithelium less than skin epithelium less than intestine and uterus epithelium less than epithelial tumors less than liver and spleen sinusoids less than intervascular sites. Antigens in easily accessible sites interact with MoAb first and must be saturated before MoAb will penetrate to less accessible areas. Thus, the extent of competition of antigen for available MoAb depends not only on the amount of antigen, but also on the site at which it is expressed. Doses that achieve maximum binding to tumor

  16. Differential expression of mitotic regulators and tumor microenvironment influences the regional growth pattern of solid sarcoma along the cranio-caudal axis.

    PubMed

    Chattopadhyay, Sukalpa; Chaklader, Malay; Chatterjee, Ritam; Law, Aditya; Law, Sujata

    2016-01-01

    Soft tissue sarcomas are relatively rare, unusual, anatomically diverse group of malignancies. According to the recent literature and medical bulletins, tumor growth and aggressiveness immensely relies on its anatomical locations. However, it is unclear whether the cranio-caudal anatomical axis of the mammalian body can influence sarcoma development and the underlying molecular mechanisms are not yet deciphered. Here, we investigated the growth pattern of solid sarcoma implanted into the murine cranial and caudal anatomical locations and tried to explore the location specific expression pattern of crucial mammalian mitotic regulators such as Aurora kinase A, Histone H3 and c-Myc in the cranio-caudally originated solid tumors. In addition, the influence of local tumor microenvironment on regional sarcoma growth was also taken into consideration. We found that solid sarcoma developed differentially when implanted into two different anatomical locations and most notably, enhanced tumor growth was observed in case of cranially implanted sarcoma than the caudal sarcoma. Interestingly, Aurora kinase A and c-Myc expression and histone H3 phosphorylation level were comparatively higher in the cranial tumor than the caudal. In addition, variation of tumor stroma in a location specific manner also facilitated tumor growth. Cranial sarcoma microenvironment was well vascularized than the caudal one and consequently, a significantly higher microvessel density count was observed which was parallel with low hypoxic response with sign of local tumor inflammation in this region. Taken together, our findings suggest that differential gradient of mitotic regulators together with varied angiogenic response and local tumor microenvironment largely controls solid sarcoma growth along the cranio-caudal anatomical axis.

  17. Injury signals cooperate with Nf1 loss to relieve the tumor-suppressive environment of adult peripheral nerve.

    PubMed

    Ribeiro, Sara; Napoli, Ilaria; White, Ian J; Parrinello, Simona; Flanagan, Adrienne M; Suter, Ueli; Parada, Luis F; Lloyd, Alison C

    2013-10-17

    Schwann cells are highly plastic cells that dedifferentiate to a progenitor-like state following injury. However, deregulation of this plasticity, may be involved in the formation of neurofibromas, mixed-cell tumors of Schwann cell (SC) origin that arise upon loss of NF1. Here, we show that adult myelinating SCs (mSCs) are refractory to Nf1 loss. However, in the context of injury, Nf1-deficient cells display opposing behaviors along the wounded nerve; distal to the injury, Nf1(-/-) mSCs redifferentiate normally, whereas at the wound site Nf1(-/-) mSCs give rise to neurofibromas in both Nf1(+/+) and Nf1(+/-) backgrounds. Tracing experiments showed that distinct cell types within the tumor derive from Nf1-deficient SCs. This model of neurofibroma formation demonstrates that neurofibromas can originate from adult SCs and that the nerve environment can switch from tumor suppressive to tumor promoting at a site of injury. These findings have implications for both the characterization and treatment of neurofibromas.

  18. Engineering of double recombinant vaccinia virus with enhanced oncolytic potential for solid tumor virotherapy

    PubMed Central

    Kochneva, Galina; Sivolobova, Galina; Tkacheva, Anastasiya; Grazhdantseva, Antonina; Troitskaya, Olga; Nushtaeva, Anna; Tkachenko, Anastasiya; Kuligina, Elena; Richter, Vladimir; Koval, Olga

    2016-01-01

    Vaccinia virus (VACV) oncolytic therapy has been successful in a number of tumor models. In this study our goal was to generate a double recombinant vaccinia virus (VV-GMCSF-Lact) with enhanced antitumor activity that expresses exogenous proteins: the antitumor protein lactaptin and human granulocyte-macrophage colony-stimulating factor (GM-CSF). Lactaptin has previously been demonstrated to act as a tumor suppressor in mouse hepatoma as well as MDA-MB-231 human adenocarcinoma cells grafted into SCID mice. VV-GMCSF-Lact was engineered from Lister strain (L-IVP) vaccinia virus and has deletions of the viral thymidine kinase and vaccinia growth factor genes. Cell culture experiments revealed that engineered VV-GMCSF-Lact induced the death of cultured cancer cells more efficiently than recombinant VACV coding only GM-CSF (VV-GMCSF-dGF). Normal human MCF-10A cells were resistant to both recombinants up to 10 PFU/cell. The selectivity index for breast cancer cells measured in pair cultures MCF-7/MCF-10A was 200 for recombinant VV-GMCSF-Lact coding lactaptin and 100 for VV-GMCSF-dGF. Using flow cytometry we demonstrated that both recombinants induced apoptosis in treated cells but that the rate in the cells with active caspase −3 and −7 was higher after treatment with VV-GMCSF-Lact than with VV-GMCSF-dGF. Tumor growth inhibition and survival outcomes after VV-GMCSF-Lact treatment were estimated using immunodeficient and immunocompetent mice models. We observed that VV-GMCSF-Lact efficiently delays the growth of sensitive and chemoresistant tumors. These results demonstrate that recombinant VACVs coding an apoptosis-inducing protein have good therapeutic potential against chemoresistant tumors. Our data will also stimulate further investigation of coding lactaptin double recombinant VACV in clinical settings. PMID:27708236

  19. Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy

    ClinicalTrials.gov

    2016-06-30

    Basal-Like Breast Carcinoma; BRCA1 Mutation Carrier; BRCA2 Mutation Carrier; Breast Carcinoma; Estrogen Receptor Negative; HER2/Neu Negative; Hereditary Breast and Ovarian Cancer Syndrome; Ovarian Carcinoma; Pancreatic Carcinoma; Progesterone Receptor Negative; Prostate Carcinoma; Recurrent Breast Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Solid Neoplasm; Triple-Negative Breast Carcinoma

  20. Adult T-cell leukemia/lymphoma: a case report of primary cutaneous tumoral type

    PubMed Central

    Lyra-da-Silva, Julia Ocampo; de Mello Gonzaga, Yung Bruno; de Melo Espíndola, Otávio; de Andrada-Serpa, Maria José; Dib, Cassio; Jeunon, Thiago

    2012-01-01

    Background: Adult T-cell leukemia/lymphoma (ATLL) is a distinctive peripheral T- lymphocytic malignancy associated with human T-cell lymphotropic virus type 1 (HTLV-1). It may closely resemble other skin lymphomas, particularly mycosis fungoides (MF). Case report: A 38-year-old woman presented some ellipsoid scaling patches lasting 18 months and developed a large tumoral lesion in the abdomen, which were previously diagnosed as MF. Although histopathologic and immunohistochemistry findings were in consonance with this diagnosis, the fast progression of the disease raised the suspicion that it could represent another type of T-cell lymphoma. The work-up revealed a positive anti-HTLV-1 serology and molecular studies confirmed the monoclonal integration of HTLV-1 provirus into neoplastic cells of the skin, but not into circulating lymphocytes. Extensive investigations were unable to demonstrate any systemic involvement. The final diagnosis was of primary cutaneous type of ATLL. The patient was submitted to a chemotherapy regimen with cyclophosphamide, doxorubicin, vincristine and prednisone, later to conjugated dexamethasone and surgical cytoreduction and then to a second line treatment with gemcitabine, resulting in partial response. A bone marrow heterologous transplantation was performed, but failed to achieve a sustained remission. Discussion: ATLL is a rare lymphoid malignancy in non-endemic HTLV-1 areas, the diagnosis of which could be missed if not highly suspected. In addition to the four subtypes of Shimoyama classification (acute, lymphomatous, chronic and smoldering), a fifth one denominated primary cutaneous and characterized by presence of lesions only in the skin had been proposed and is herein exemplified. PMID:23785591

  1. International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors.

    PubMed

    Lassman, Andrew B; Iwamoto, Fabio M; Cloughesy, Timothy F; Aldape, Kenneth D; Rivera, Andreana L; Eichler, April F; Louis, David N; Paleologos, Nina A; Fisher, Barbara J; Ashby, Lynn S; Cairncross, J Gregory; Roldán, Gloria B; Wen, Patrick Y; Ligon, Keith L; Schiff, David; Robins, H Ian; Rocque, Brandon G; Chamberlain, Marc C; Mason, Warren P; Weaver, Susan A; Green, Richard M; Kamar, Francois G; Abrey, Lauren E; DeAngelis, Lisa M; Jhanwar, Suresh C; Rosenblum, Marc K; Panageas, Katherine S

    2011-06-01

    Treatment for newly diagnosed anaplastic oligodendroglial tumors is controversial. Radiotherapy (RT) alone and in combination with chemotherapy (CT) are the most well studied strategies. However, CT alone is often advocated, especially in cases with 1p19q codeletion. We retrospectively identified 1013 adults diagnosed from 1981-2007 treated initially with RT alone (n = 200), CT + RT (n = 528), CT alone (n = 201), or other strategies (n = 84). Median overall survival (OS) was 6.3 years and time to progression (TTP) was 3.1 years. 1p19q codeletion correlated with longer OS and TTP than no 1p or 19q deletion. In codeleted cases, median TTP was longer following CT + RT (7.2 y) than following CT (3.9 y, P = .003) or RT (2.5 y, P < .001) alone but without improved OS; median TTP was longer following treatment with PCV alone than temozolomide alone (7.6 vs. 3.3 y, P = .019). In cases with no deletion, median TTP was longer following CT + RT (3.1 y) than CT (0.9 y, P = .0124) or RT (1.1 y, P < .0001) alone; OS also favored CT + RT (median 5.0 y) over CT (2.2 y, P = .02) or RT (1.9 y, P < .0001) alone. In codeleted cases, CT alone did not appear to shorten OS in comparison with CT + RT, and PCV appeared to offer longer disease control than temozolomide but without a clear survival advantage. Combined CT + RT led to longer disease control and survival than did CT or RT alone in cases with no 1p19q deletion. Ongoing trials will address these issues prospectively.

  2. Restricted access to the environment and quality of life in adult survivors of childhood brain tumors.

    PubMed

    Brinkman, Tara M; Li, Zhenghong; Neglia, Joseph P; Gajjar, Amar; Klosky, James L; Allgood, Rachel; Stovall, Marilyn; Krull, Kevin R; Armstrong, Gregory T; Ness, Kirsten K

    2013-01-01

    Survivors of pediatric brain tumors (BTs) are at-risk for late effects which may affect mobility within and access to the physical environment. This study examined the prevalence of and risk factors for restricted environmental access in survivors of childhood BTs and investigated the associations between reduced environmental access, health-related quality of life (HRQOL), and survivors' social functioning. In-home evaluations were completed for 78 BT survivors and 78 population-based controls matched on age, sex, and zip-code. Chi-square tests and multivariable logistic regression models were used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for poor environmental access and reduced HRQOL. The median age of survivors was 22 years at the time of study. Compared to controls, survivors were more likely to report avoiding most dimensions of their physical environment, including a single flight of stairs (p < 0.001), uneven surfaces (p < 0.001), traveling alone (p = 0.01), and traveling to unfamiliar places (p = 0.001). Overall, survivors were 4.8 times more likely to report poor environmental access (95 % CI 2.0-11.5, p < 0.001). In survivors, poor environmental access was associated with reduced physical function (OR = 3.6, 95 % CI 1.0-12.8, p = 0.04), general health (OR = 6.0, 95 % CI 1.8-20.6, p = 0.002), and social functioning (OR = 4.3, 95 % CI 1.1-17.3, p = 0.03). Adult survivors of pediatric BTs were more likely to avoid their physical environment than matched controls. Restricted environmental access was associated with reduced HRQOL and diminished social functioning. Interventions directed at improving physical mobility may have significant impact on survivor quality of life.

  3. A Simple Mathematical Model Based on the Cancer Stem Cell Hypothesis Suggests Kinetic Commonalities in Solid Tumor Growth

    PubMed Central

    Molina-Peña, Rodolfo; Álvarez, Mario Moisés

    2012-01-01

    Background The Cancer Stem Cell (CSC) hypothesis has gained credibility within the cancer research community. According to this hypothesis, a small subpopulation of cells within cancerous tissues exhibits stem-cell-like characteristics and is responsible for the maintenance and proliferation of cancer. Methodologies/Principal Findings We present a simple compartmental pseudo-chemical mathematical model for tumor growth, based on the CSC hypothesis, and derived using a “chemical reaction” approach. We defined three cell subpopulations: CSCs, transit progenitor cells, and differentiated cells. Each event related to cell division, differentiation, or death is then modeled as a chemical reaction. The resulting set of ordinary differential equations was numerically integrated to describe the time evolution of each cell subpopulation and the overall tumor growth. The parameter space was explored to identify combinations of parameter values that produce biologically feasible and consistent scenarios. Conclusions/Significance Certain kinetic relationships apparently must be satisfied to sustain solid tumor growth and to maintain an approximate constant fraction of CSCs in the tumor lower than 0.01 (as experimentally observed): (a) the rate of symmetrical and asymmetrical CSC renewal must be in the same order of magnitude; (b) the intrinsic rate of renewal and differentiation of progenitor cells must be half an order of magnitude higher than the corresponding intrinsic rates for cancer stem cells; (c) the rates of apoptosis of the CSC, transit amplifying progenitor (P) cells, and terminally differentiated (D) cells must be progressively higher by approximately one order of magnitude. Simulation results were consistent with reports that have suggested that encouraging CSC differentiation could be an effective therapeutic strategy for fighting cancer in addition to selective killing or inhibition of symmetric division of CSCs. PMID:22363395

  4. Phase I Combination of Sorafenib and Erlotinib Therapy in Solid Tumors: Safety, Pharmacokinetic and Pharmacodynamic Evaluation from an Expansion Cohort

    PubMed Central

    Quintela-Fandino, Miguel; Le Tourneau, Christophe; Duran, Ignacio; Chen, Eric X.; Wang, Lisa; Tsao, Ming; Bandarchi-Chamkhaleh, Bizhan; Pham, Nhu-Ann; Do, Trevor; MacLean, Martha; Nayyar, Rakesh; Tusche, Michael W.; Metser, Ur; Wright, John J.; Mak, Tak W.; Siu, Lillian L.

    2010-01-01

    The aims of this study were to further define the safety of sorafenib and erlotinib, given at their full approved monotherapy doses, and to correlate pharmacokinetic (PK) and pharmacodynamic (PD) markers with clinical outcome. In addition, a novel PD marker based on the real-time measurement of RAF signal transduction capacity (STC) is described. Sorafenib was administered alone for a one-week run-in period, and then both drugs were given together continuously. RAF STC was assessed in peripheral blood monocytes prior to erlotinib initiation. EGFR expression and K-RAS mutations were measured in archival tumor samples. Changes in pERK and CD31 were determined in fresh tumor biopsies obtained pre-treatment, prior to erlotinib dosing and during the administration of both drugs. In addition, PET-CT scans and PK assessments were performed. Eleven patients received a total of 57 cycles (median: 5, range: 1–10). Only 4 patients received full doses of both drugs for the entire study course, with elevation of liver enzymes being the main reason for dose reductions and delays. Among 10 patients evaluable for response, 8 experienced tumor stabilization of 4 or more cycles. PK analysis revealed no significant interaction of erlotinib with sorafenib. Sorafenib-induced decrease in RAF-STC showed statistically significant correlation with time-to-progression in 7 patients. Other PD markers did not correlate with clinical outcome. This drug combination resulted in promising clinical activity in solid tumor patients although significant toxicity warrants close monitoring. RAF-STC deserves further study as a predictive marker for sorafenib. PMID:20197396

  5. Phase I Study of CKD-516, a Novel Vascular Disrupting Agent, in Patients with Advanced Solid Tumors

    PubMed Central

    Oh, Do-Youn; Kim, Tae-Min; Han, Sae-Won; Shin, Dong-Yeop; Lee, Yun Gyoo; Lee, Keun-Wook; Kim, Jee Hyun; Kim, Tae-You; Jang, In-Jin; Lee, Jong-Seok; Bang, Yung-Jue

    2016-01-01

    Purpose CKD-516 is a newly developed vascular disrupting agent. This phase I dose-escalation study of CKD-516 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. Materials and Methods Patients received CKD-516 intravenously on D1 and D8 every 3 weeks, in a standard 3+3 design. Safety was evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.02 and response was assessed by Response Evaluation Criteria in Solid Tumor ver. 1.1. Results Twenty-three patients were treated with CKD-516 at seven dosing levels: 1 mg/m2/day (n=3), 2 mg/m2/day (n=3), 3.3 mg/m2/day (n=3), 5 mg/m2/day (n=3), 7 mg/m2/day (n=3), 9 mg/m2/day (n=6), and 12 mg/m2/day (n=2). Mean age was 54 and 56.5% of patients were male. Two dose-limiting toxicities, which were both grade 3 hypertension, were observed in two patients at 12 mg/m2/day. The MTD was determined as 12 mg/m2/day. Most common adverse events were gastrointestinal adverse events (diarrhea, 34.8% [30.4% grade 1/2, 13.0% grade 3]; nausea, 21.7% [all grade 1/2]; vomiting, 21.7% [all grade 1/2]), myalgia (17.4%, all grade 1/2), and abdominal pain (21.7% [21.7% grade 1/2, 4.3% grade 3]). The pharmacokinetic study showed the dose-linearity of all dosing levels. Among 23 patients, six patients (26.1%) showed stable disease. Median progression-free survival was 39 days (95% confidence interval, 37 to 41 days). Conclusion This study demonstrates feasibility of CKD-516, novel vascular disrupting agent, in patients with advanced solid tumor. MTD of CKD-516 was defined as 12 mg/m2/day on D1 and D8 every 3 weeks. PMID:25715767

  6. Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors.

    PubMed

    Dienstmann, R; Rodon, J; Prat, A; Perez-Garcia, J; Adamo, B; Felip, E; Cortes, J; Iafrate, A J; Nuciforo, P; Tabernero, J

    2014-03-01

    The fibroblast growth factor receptor (FGFR) cascade plays crucial roles in tumor cell proliferation, angiogenesis, migration and survival. Accumulating evidence suggests that in some tumor types, FGFRs are bona fide oncogenes to which cancer cells are addicted. Because FGFR inhibition can reduce proliferation and induce cell death in a variety of in vitro and in vivo tumor models harboring FGFR aberrations, a growing number of research groups have selected FGFRs as targets for anticancer drug development. Multikinase FGFR/vascular endothelial growth factor receptor (VEGFR) inhibitors have shown promising activity in breast cancer patients with FGFR1 and/or FGF3 amplification. Early clinical trials with selective FGFR inhibitors, which may overcome the toxicity constraints raised by multitarget kinase inhibition, are recruiting patients with known FGFR(1-4) status based on genomic screens. Preliminary signs of antitumor activity have been demonstrated in some tumor types, including squamous cell lung carcinomas. Rational combination of targeted therapies is expected to further increase the efficacy of selective FGFR inhibitors. Herein, we discuss unsolved questions in the clinical development of these agents and suggest guidelines for management of hyperphosphatemia, a class-specific mechanism-based toxicity. In addition, we propose standardized definitions for FGFR1 and FGFR2 gene amplification based on in situ hybridization methods. Extended access to next-generation sequencing platforms will facilitate the identification of diseases in which somatic FGFR(1-4) mutations, amplifications and fusions are potentially driving cancer cell viability, further strengthening the role of FGFR signaling in cancer biology and providing more possibilities for the therapeutic application of FGFR inhibitors.

  7. Augmented lymphocyte expansion from solid tumors with engineered cells for costimulatory enhancement.

    PubMed

    Friedman, Kevin M; Devillier, Laura E; Feldman, Steven A; Rosenberg, Steven A; Dudley, Mark E

    2011-01-01

    Treatment of patients with adoptive T-cell therapy requires expansion of unique tumor-infiltrating lymphocyte (TIL) cultures from single-cell suspensions processed from melanoma biopsies. Strategies which increase the expansion and reliability of TIL generation from tumor digests are necessary to improve access to TIL therapy. Previous studies have evaluated artificial antigen presenting cells for their antigen-specific and costimulatory properties. We investigated engineered cells for costimulatory enhancement (ECCE) consisting of K562 cells that express 4-1BBL in the absence of artificial antigen stimulation. ECCE accelerated TIL expansion and significantly improved TIL numbers (P=0.001) from single-cell melanoma suspensions. TIL generated with ECCE contain significantly more CD8CD62L and CD8CD27 T cells then comparable interleukin-2-expanded TIL and maintained antitumor reactivity. Moreover, ECCE improved TIL expansion from nonmelanoma-cell suspensions similar to that seen with melanoma tumors. These data demonstrate that the addition of ECCE to TIL production will enable the treatment of patients that are ineligible using current methods.

  8. A Nanostructured Matrices Assessment to Study Drug Distribution in Solid Tumor Tissues by Mass Spectrometry Imaging

    PubMed Central

    Giordano, Silvia; Pifferi, Valentina; Morosi, Lavinia; Morelli, Melinda; Falciola, Luigi; Cappelletti, Giuseppe; Visentin, Sonja; Licandro, Simonetta A.; Frapolli, Roberta; Zucchetti, Massimo; Pastorelli, Roberta; Brunelli, Laura; D’Incalci, Maurizio; Davoli, Enrico

    2017-01-01

    The imaging of drugs inside tissues is pivotal in oncology to assess whether a drug reaches all cells in an adequate enough concentration to eradicate the tumor. Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging (MALDI-MSI) is one of the most promising imaging techniques that enables the simultaneous visualization of multiple compounds inside tissues. The choice of a suitable matrix constitutes a critical aspect during the development of a MALDI-MSI protocol since the matrix ionization efficiency changes depending on the analyte structure and its physico-chemical properties. The objective of this study is the improvement of the MALDI-MSI technique in the field of pharmacology; developing specifically designed nanostructured surfaces that allow the imaging of different drugs with high sensitivity and reproducibility. Among several nanomaterials, we tested the behavior of gold and titanium nanoparticles, and halloysites and carbon nanotubes as possible matrices. All nanomaterials were firstly screened by co-spotting them with drugs on a MALDI plate, evaluating the drug signal intensity and the signal-to-noise ratio. The best performing matrices were tested on control tumor slices, and were spotted with drugs to check the ion suppression effect of the biological matrix. Finally; the best nanomaterials were employed in a preliminary drug distribution study inside tumors from treated mice. PMID:28336905

  9. The distribution of BRAF gene fusions in solid tumors and response to targeted therapy.

    PubMed

    Ross, Jeffrey S; Wang, Kai; Chmielecki, Juliann; Gay, Laurie; Johnson, Adrienne; Chudnovsky, Jacob; Yelensky, Roman; Lipson, Doron; Ali, Siraj M; Elvin, Julia A; Vergilio, Jo-Anne; Roels, Steven; Miller, Vincent A; Nakamura, Brooke N; Gray, Adam; Wong, Michael K; Stephens, Philip J

    2016-02-15

    Although the BRAF V600E base substitution is an approved target for the BRAF inhibitors in melanoma, BRAF gene fusions have not been investigated as anticancer drug targets. In our study, a wide variety of tumors underwent comprehensive genomic profiling for hundreds of known cancer genes using the FoundationOne™ or FoundationOne Heme™ comprehensive genomic profiling assays. BRAF fusions involving the intact in-frame BRAF kinase domain were observed in 55 (0.3%) of 20,573 tumors, across 12 distinct tumor types, including 20 novel BRAF fusions. These comprised 29 unique 5' fusion partners, of which 31% (9) were known and 69% (20) were novel. BRAF fusions included 3% (14/531) of melanomas; 2% (15/701) of gliomas; 1.0% (3/294) of thyroid cancers; 0.3% (3/1,062) pancreatic carcinomas; 0.2% (8/4,013) nonsmall-cell lung cancers and 0.2% (4/2,154) of colorectal cancers, and were enriched in pilocytic (30%) vs. nonpilocytic gliomas (1%; p < 0.0001), Spitzoid (75%) vs. nonSpitzoid melanomas (1%; p = 0.0001), acinar (67%) vs. nonacinar pancreatic cancers (<1%; p < 0.0001) and papillary (3%) vs. nonpapillary thyroid cancers (0%; p < 0.03). Clinical responses to trametinib and sorafenib are presented. In conclusion, BRAF fusions are rare driver alterations in a wide variety of malignant neoplasms, but enriched in Spitzoid melanoma, pilocytic astrocytomas, pancreatic acinar and papillary thyroid cancers.

  10. CD8+ T-cell responses against hemoglobin-beta prevent solid tumor growth.

    PubMed

    Komita, Hideo; Zhao, Xi; Taylor, Jennifer L; Sparvero, Louis J; Amoscato, Andrew A; Alber, Sean; Watkins, Simon C; Pardee, Angela D; Wesa, Amy K; Storkus, Walter J

    2008-10-01

    Bone marrow-derived dendritic cells engineered using recombinant adenovirus to secrete high levels of IL-12p70 dramatically inhibited the growth of established CMS4 sarcomas in BALB/c mice after intratumoral administration. An analysis of splenic CD8(+) T cells in regressor mice revealed a strong, complex reactivity pattern against high-performance liquid chromatography (HPLC)-resolved peptides isolated by acid elution from single-cell suspensions of surgically resected CMS4 lesions. Mass spectrometry analyses defined two major overlapping peptide species that derive from the murine hemoglobin-beta (HBB) protein within the most stimulatory HPLC fractions. Although cultured CMS4 tumor cells failed to express HBB mRNA based on reverse transcription-PCR analyses, prophylactic vaccination of BALB/c mice with vaccines containing HBB peptides promoted specific CD8(+) T-cell responses that protected mice against a subsequent challenge with CMS4 or unrelated syngeneic (HBB(neg)) tumors of divergent histology (sarcoma, carcinomas of the breast or colon). In situ imaging suggested that vaccines limit or destabilize tumor-associated vascular structures, potentially by promoting immunity against HBB+ vascular pericytes. Importantly, there were no untoward effects of vaccination with the HBB peptide on peripheral RBC numbers, RBC hemoglobin content, or vascular structures in the brain or eye.

  11. CD8+ T Cell Responses Against Hemoglobin-β Prevent Solid Tumor Growth

    PubMed Central

    Komita, Hideo; Zhao, Xi; Taylor, Jennifer L.; Sparvero, Louis J.; Amoscato, Andrew A.; Alber, Sean; Watkins, Simon C.; Pardee, Angela D.; Wesa, Amy K.; Storkus, Walter J.

    2008-01-01

    Bone marrow-derived dendritic cells (DCs) engineered using recombinant adenovirus to secrete high levels of IL-12p70 dramatically inhibited the growth of established CMS4 sarcomas in BALB/c mice after intratumoral administration. An analysis of splenic CD8+ T cells in regressor mice revealed a strong, complex reactivity pattern against HPLC-resolved peptides isolated by acid elution from single-cell suspensions of surgically-resected CMS4 lesions. Mass spectrometry analyses defined 2 major overlapping peptide species that derive from the murine hemoglobin-β (HBB) protein within the most stimulatory HPLC fractions. Although cultured CMS4 tumor cells failed to express HBB mRNA based on RT-PCR analyses, prophylactic vaccination of BALB/c mice with vaccines containing HBB peptides promoted specific CD8+ T cell responses that protected mice against a subsequent challenge with CMS4, or unrelated syngenic (HBBneg) tumors of divergent histology (sarcoma, carcinomas of the breast or colon). In situ imaging suggested that vaccines limit or destabilize tumor-associated vascular structures, potentially by promoting immunity against HBB+ vascular pericytes. Importantly, there were no untoward effects of vaccination with the HBB peptide on peripheral red blood cell (RBC) numbers, RBC hemoglobin content or vascular structures in the brain or eye. PMID:18829566

  12. MEK and PI3K inhibition in solid tumors: rationale and evidence to date

    PubMed Central

    Koivunen, J.P.

    2015-01-01

    PI3K-AKT-mTOR and Ras-Raf-MEK-ERK are the most commonly altered oncogenic pathways in solid malignancies. There has been a lot of enthusiasm to develop inhibitors to these pathways for cancer therapy. Unfortunately, the antitumor activities of single-agent therapies have generally been disappointing, excluding B-Raf mutant melanoma and renal cell cancer. Preclinical studies have suggested that concurrent targeting of the PI3K-AKT-mTOR and Ras-Raf-MEK-ERK pathways is an active combination in various solid malignancies. In the current work, we review the preclinical data of the PI3K and MEK dual targeting as a cancer therapy and the results of early-phase clinical trials, and propose future directions. PMID:26673580

  13. Some implications of Scale Relativity theory in avascular stages of growth of solid tumors in the presence of an immune system response.

    PubMed

    Buzea, C Gh; Agop, M; Moraru, Evelina; Stana, Bogdan A; Gîrţu, Manuela; Iancu, D

    2011-08-07

    We present a traveling-wave analysis of a reduced mathematical model describing the growth of a solid tumor in the presence of an immune system response in the framework of Scale Relativity theory. Attention is focused upon the attack of tumor cells by tumor-infiltrating cytotoxic lymphocytes (TICLs), in a small multicellular tumor, without necrosis and at some stage prior to (tumor-induced) angiogenesis. For a particular choice of parameters, the underlying system of partial differential equations is able to simulate the well-documented phenomenon of cancer dormancy and propagation of a perturbation in the tumor cell concentration by cnoidal modes, by depicting spatially heterogeneous tumor cell distributions that are characterized by a relatively small total number of tumor cells. This behavior is consistent with several immunomorphological investigations. Moreover, the alteration of certain parameters of the model is enough to induce soliton like modes and soliton packets into the system, which in turn result in tumor invasion in the form of a standard traveling wave. In the same framework of Scale Relativity theory, a very important feature of malignant tumors also results, that even in avascular stages they might propagate and invade healthy tissues, by means of a diffusion on a Newtonian fluid.

  14. Panobinostat (LBH589): a potent pan-deacetylase inhibitor with promising activity against hematologic and solid tumors.

    PubMed

    Prince, H Miles; Bishton, Mark J; Johnstone, Ricky W

    2009-06-01

    The deacetylase inhibitors are a structurally diverse class of targeted antineoplastic agents that have demonstrated in vitro and in vivo preclinical activity in a wide range of malignancies. Based on this preclinical activity, several deacetylase inhibitors have undergone rapid clinical development in recent years. Among these, the deacetylase inhibitor panobinostat is one of the most widely studied, with extensive pharmacokinetic, pharmacodynamic and dose-finding data available across a wide variety of hematologic and solid tumors. Furthermore, panobinostat has demonstrated favorable clinical activity against various hematologic malignancies, most notably lymphomas and myeloid malignancies in Phase I and II studies. In this article, we discuss the preclinical data on panobinostat and emerging data from Phase I and II studies in cancer patients.

  15. Polymeric micelles for the solubilization and delivery of STAT3 inhibitor cucurbitacins in solid tumors

    PubMed Central

    Molavi, Ommoleila; Ma, Zengshuan; Mahmud, Abdullah; Alshamsan, Aws; Samuel, John; Lai, Raymond; Kwon, Glen S.; Lavasanifar, Afsaneh

    2009-01-01

    Poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) and newly developed poly(ethylene oxide)-block-poly(α-benzyl carboxylate ε-caprolactone) (PEO-b-PBCL) micelles were evaluated for the solubilization and delivery of cucurbitacin I and B, poorly water soluble inhibitors of signal transducer and activator of transcription 3 (STAT3). Encapsulation of cucurbitacins in PEO-b-PCL and PEO-b-PBCL by co-solvent evaporation technique resulted in polymeric micelles <90 nm in diameter. The aqueous solubility of both derivatives increased from less than 0.05 mg/mL in the absence of the copolymer to around 0.30–0.44 and 0.65–0.68 mg/mL in the presence of 5000–5000 and 5000–24,000 PEO-b-PCL micelles, respectively. Maximum cucurbitacin solubilization was achieved with PEO-b-PBCL micelles for both derivatives. PEO-b-PCL micelles having longer PCL block were found to be more efficient in sustaining the rate of release for cucurbitacins. The anti-cancer and STAT3 inhibitory activity of polymeric micellar cucurbitacins were comparable with free drugs in B16.F10 melanoma cell line in vitro. Intratumoral injection of 1 mg/kg/day cucurbitacin I resulted in the regression of established B16.F10 mouse melanoma tumors in vivo. In comparison to free cucurbitacin I, PEO-b-PBCL micellar cucurbitacin I was found to provide comparable anti-cancer effects against B16.F10 tumors and limit drug levels in animal serum while maintaining high drug levels in tumor following intratumoral administration. The results indicate the potential of polymeric micelles as suitable vehicles for the delivery of cucurbitacin- I and B. PMID:17681440

  16. The Impact of Cell Density and Mutations in a Model of Multidrug Resistance in Solid Tumors

    PubMed Central

    Greene, James; Lavi, Orit; Gottesman, Michael M.; Levy, Doron

    2016-01-01

    In this paper we develop a mathematical framework for describing multidrug resistance in cancer. To reflect the complexity of the underlying interplay between cancer cells and the therapeutic agent, we assume that the resistance level is a continuous parameter. Our model is written as a system of integro-differential equations that are parametrized by the resistance level. This model incorporates the cell-density and mutation dependence. Analysis and simulations of the model demonstrate how the dynamics evolves to a selection of one or more traits corresponding to different levels of resistance. The emerging limit distribution with nonzero variance is the desirable modeling outcome as it represents tumor heterogeneity. PMID:24553772

  17. Barriers to the Access of Bevacizumab in Patients with Solid Tumors and the Potential Impact of Biosimilars: A Physician Survey.

    PubMed

    Monk, Bradley J; Lammers, Philip E; Cartwright, Thomas; Jacobs, Ira

    2017-01-28

    Access to bevacizumab, an important component of oncology treatment regimens, may be limited. This survey of oncologists in the US (n = 150), Europe (n = 230), and emerging markets (EM: Brazil, Mexico, and Turkey; n = 130) examined use of and barriers to accessing bevacizumab as treatment of advanced solid tumors. We also assessed the likelihood that physicians would prescribe a bevacizumab biosimilar, if available. Bevacizumab was frequently used as early-line therapy in metastatic colorectal cancer, metastatic non-squamous non-small-cell lung cancer, and metastatic ovarian cancer (all markets), and as a second-line therapy in glioblastoma multiforme (US, EM). A greater percentage of EM-based physicians cited access-related issues as a barrier to prescribing bevacizumab versus US and EU physicians. Lack of reimbursement and high out-of-pocket costs were cited as predominant barriers to prescribing and common reasons for reducing the number of planned cycles. Overall, ~50% of physicians reported they "definitely" or "probably" would prescribe a bevacizumab biosimilar, if available. Efficacy and safety data in specific tumor types and lower cost were factors cited that would increase likelihood to prescribe a bevacizumab biosimilar. A lower cost bevacizumab biosimilar could address the unmet needs of patients and physicians worldwide, and may have the greatest impact on patient outcomes in EM.

  18. Barriers to the Access of Bevacizumab in Patients with Solid Tumors and the Potential Impact of Biosimilars: A Physician Survey

    PubMed Central

    Monk, Bradley J.; Lammers, Philip E.; Cartwright, Thomas; Jacobs, Ira

    2017-01-01

    Access to bevacizumab, an important component of oncology treatment regimens, may be limited. This survey of oncologists in the US (n = 150), Europe (n = 230), and emerging markets (EM: Brazil, Mexico, and Turkey; n = 130) examined use of and barriers to accessing bevacizumab as treatment of advanced solid tumors. We also assessed the likelihood that physicians would prescribe a bevacizumab biosimilar, if available. Bevacizumab was frequently used as early-line therapy in metastatic colorectal cancer, metastatic non-squamous non–small-cell lung cancer, and metastatic ovarian cancer (all markets), and as a second-line therapy in glioblastoma multiforme (US, EM). A greater percentage of EM-based physicians cited access-related issues as a barrier to prescribing bevacizumab versus US and EU physicians. Lack of reimbursement and high out-of-pocket costs were cited as predominant barriers to prescribing and common reasons for reducing the number of planned cycles. Overall, ~50% of physicians reported they “definitely” or “probably” would prescribe a bevacizumab biosimilar, if available. Efficacy and safety data in specific tumor types and lower cost were factors cited that would increase likelihood to prescribe a bevacizumab biosimilar. A lower cost bevacizumab biosimilar could address the unmet needs of patients and physicians worldwide, and may have the greatest impact on patient outcomes in EM. PMID:28134851

  19. Evaluation of anterior mediastinal solid tumors by CT perfusion: a preliminary study

    PubMed Central

    Bakan, Selim; Kandemirli, Sedat Giray; Dikici, Atilla Süleyman; Erşen, Ezel; Yıldırım, Onur; Samancı, Cesur; Batur, Şebnem; Olgun, Deniz Çebi; Kantarcı, Fatih; Akman, Canan

    2017-01-01