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Sample records for pancreatic tumor motion

  1. Characterization of Pancreatic Tumor Motion Using Cine MRI: Surrogates for Tumor Position Should Be Used With Caution

    SciTech Connect

    Feng, Mary Balter, James M.; Normolle, Daniel; Adusumilli, Saroja; Cao Yue; Chenevert, Thomas L.; Ben-Josef, Edgar

    2009-07-01

    Purpose: Our current understanding of intrafraction pancreatic tumor motion due to respiration is limited. In this study, we characterized pancreatic tumor motion and evaluated the application of several radiotherapy motion management strategies. Methods and Materials: Seventeen patients with unresectable pancreatic cancer were enrolled in a prospective internal review board-approved study and imaged during shallow free-breathing using cine MRI on a 3T scanner. Tumor borders were agreed on by a radiation oncologist and an abdominal MRI radiologist. Tumor motion and correlation with the potential surrogates of the diaphragm and abdominal wall were assessed. These data were also used to evaluate planning target volume margin construction, respiratory gating, and four-dimensional treatment planning for pancreatic tumors. Results: Tumor borders moved much more than expected. To provide 99% geometric coverage, margins of 20 mm inferiorly, 10 mm anteriorly, 7 mm superiorly, and 4 mm posteriorly are required. Tumor position correlated poorly with diaphragm and abdominal wall position, with patient-level Pearson correlation coefficients of -0.18-0.43. Sensitivity and specificity of gating with these surrogates was also poor, at 53%-68%, with overall error of 35%-38%, suggesting that the tumor may be underdosed and normal tissues overdosed. Conclusions: Motion of pancreatic tumor borders is highly variable between patients and larger than expected. There is substantial deformation with breathing, and tumor border position does not correlate well with abdominal wall or diaphragmatic position. Current motion management strategies may not account fully for tumor motion and should be used with caution.

  2. Pancreatic Tumor Growth Prediction with Multiplicative Growth and Image-Derived Motion.

    PubMed

    Wong, Ken C L; Summers, Ronald M; Kebebew, Electron; Yao, Jianhua

    2015-01-01

    Pancreatic neuroendocrine tumors are abnormal growths of hormone-producing cells in the pancreas. Different from the brain in the skull, the pancreas in the abdomen can be largely deformed by the body posture and the surrounding organs. In consequence, both tumor growth and pancreatic motion attribute to the tumor shape difference observable from images. As images at different time points are used to personalize the tumor growth model, the prediction accuracy may be reduced if such motion is ignored. Therefore, we incorporate the image-derived pancreatic motion to tumor growth personalization. For realistic mechanical interactions, the multiplicative growth decomposition is used with a hyperelastic constitutive law to model tumor mass effect, which allows growth modeling without compromising the mechanical accuracy. With also the FDG-PET and contrast-enhanced CT images, the functional, structural, and motion data are combined for a more patient-specific model. Experiments on synthetic and clinical data show the importance of image-derived motion on estimating physiologically plausible mechanical properties and the promising performance of our framework. From six patient data sets, the recall, precision, Dice coefficient, relative volume difference, and average surface distance were 89.8 ± 3.5%, 85.6 ± 7.5%, 87.4 ± 3.6%, 9.7 ± 7.2%, and 0.6 ± 0.2 mm, respectively. PMID:26221698

  3. Optimizing 4-Dimensional Magnetic Resonance Imaging Data Sampling for Respiratory Motion Analysis of Pancreatic Tumors

    SciTech Connect

    Stemkens, Bjorn; Tijssen, Rob H.N.; Senneville, Baudouin D. de

    2015-03-01

    Purpose: To determine the optimum sampling strategy for retrospective reconstruction of 4-dimensional (4D) MR data for nonrigid motion characterization of tumor and organs at risk for radiation therapy purposes. Methods and Materials: For optimization, we compared 2 surrogate signals (external respiratory bellows and internal MRI navigators) and 2 MR sampling strategies (Cartesian and radial) in terms of image quality and robustness. Using the optimized protocol, 6 pancreatic cancer patients were scanned to calculate the 4D motion. Region of interest analysis was performed to characterize the respiratory-induced motion of the tumor and organs at risk simultaneously. Results: The MRI navigator was found to be a more reliable surrogate for pancreatic motion than the respiratory bellows signal. Radial sampling is most benign for undersampling artifacts and intraview motion. Motion characterization revealed interorgan and interpatient variation, as well as heterogeneity within the tumor. Conclusions: A robust 4D-MRI method, based on clinically available protocols, is presented and successfully applied to characterize the abdominal motion in a small number of pancreatic cancer patients.

  4. Modeling Pancreatic Tumor Motion Using 4-Dimensional Computed Tomography and Surrogate Markers

    SciTech Connect

    Huguet, Florence; Yorke, Ellen D.; Davidson, Margaret; Zhang, Zhigang; Jackson, Andrew; Mageras, Gig S.; Wu, Abraham J.; Goodman, Karyn A.

    2015-03-01

    Purpose: To assess intrafractional positional variations of pancreatic tumors using 4-dimensional computed tomography (4D-CT), their impact on gross tumor volume (GTV) coverage, the reliability of biliary stent, fiducial seeds, and the real-time position management (RPM) external marker as tumor surrogates for setup of respiratory gated treatment, and to build a correlative model of tumor motion. Methods and Materials: We analyzed the respiration-correlated 4D-CT images acquired during simulation of 36 patients with either a biliary stent (n=16) or implanted fiducials (n=20) who were treated with RPM respiratory gated intensity modulated radiation therapy for locally advanced pancreatic cancer. Respiratory displacement relative to end-exhalation was measured for the GTV, the biliary stent, or fiducial seeds, and the RPM marker. The results were compared between the full respiratory cycle and the gating interval. Linear mixed model was used to assess the correlation of GTV motion with the potential surrogate markers. Results: The average ± SD GTV excursions were 0.3 ± 0.2 cm in the left-right direction, 0.6 ± 0.3 cm in the anterior-posterior direction, and 1.3 ± 0.7 cm in the superior-inferior direction. Gating around end-exhalation reduced GTV motion by 46% to 60%. D95% was at least the prescribed 56 Gy in 76% of patients. GTV displacement was associated with the RPM marker, the biliary stent, and the fiducial seeds. The correlation was better with fiducial seeds and with biliary stent. Conclusions: Respiratory gating reduced the margin necessary for radiation therapy for pancreatic tumors. GTV motion was well correlated with biliary stent or fiducial seed displacements, validating their use as surrogates for daily assessment of GTV position during treatment. A patient-specific internal target volume based on 4D-CT is recommended both for gated and not-gated treatment; otherwise, our model can be used to predict the degree of GTV motion.

  5. Harmonic Motion Imaging for Abdominal Tumor Detection and High-intensity Focused Ultrasound Ablation Monitoring: A Feasibility Study in a Transgenic Mouse Model of Pancreatic Cancer

    PubMed Central

    Chen, Hong; Hou, Gary Y.; Han, Yang; Payen, Thomas; Palermo, Carmine F.; Olive, Kenneth P.; Konofagou, Elisa E.

    2015-01-01

    Harmonic motion imaging (HMI) is a radiation force-based elasticity imaging technique that tracks oscillatory tissue displacements induced by sinusoidal ultrasonic radiation force to assess relative tissue stiffness. The objective of this study was to evaluate the feasibility of HMI in pancreatic tumor detection and high-intensity focused ultrasound (HIFU) treatment monitoring. The HMI system consisted of a focused ultrasound transducer, which generated sinusoidal radiation force to induce oscillatory tissue motion at 50 Hz, and a diagnostic ultrasound transducer, which detected the axial tissue displacements based on acquired radiofrequency signals using a 1D cross-correlation algorithm. For pancreatic tumor detection, HMI images were generated for pancreatic tumors in transgenic mice and normal pancreases in wild-type mice. The obtained HMI images showed a high contrast between normal and malignant pancreases with an average peak-to-peak HMI displacement ratio of 3.2. Histological analysis showed that no tissue damage was associated with HMI when it was used for the sole purpose of elasticity imaging. For pancreatic tumor ablation monitoring, the focused ultrasound transducer was operated with a higher acoustic power and longer pulse length than that used in tumor detection to simultaneously induce HIFU thermal ablation and oscillatory tissue displacements, allowing HMI monitoring without interrupting tumor ablation. HMI monitoring of HIFU ablation found significant decreases in the peak-to-peak HMI displacements before and after HIFU ablation with a reduction rate ranging from 15.8% to 57.0%. The formation of thermal lesions after HIFU exposure was confirmed by histological analysis. This study demonstrated the feasibility of HMI in abdominal tumor detection and HIFU ablation monitoring. PMID:26415128

  6. Harmonic motion imaging for abdominal tumor detection and high-intensity focused ultrasound ablation monitoring: an in vivo feasibility study in a transgenic mouse model of pancreatic cancer.

    PubMed

    Chen, Hong; Hou, Gary Y; Han, Yang; Payen, Thomas; Palermo, Carmine F; Olive, Kenneth P; Konofagou, Elisa E

    2015-09-01

    Harmonic motion imaging (HMI) is a radiationforce- based elasticity imaging technique that tracks oscillatory tissue displacements induced by sinusoidal ultrasonic radiation force to assess the resulting oscillatory displacement denoting the underlying tissue stiffness. The objective of this study was to evaluate the feasibility of HMI in pancreatic tumor detection and high-intensity focused ultrasound (HIFU) treatment monitoring. The HMI system consisted of a focused ultrasound transducer, which generated sinusoidal radiation force to induce oscillatory tissue motion at 50 Hz, and a diagnostic ultrasound transducer, which detected the axial tissue displacements based on acquired radio-frequency signals using a 1-D cross-correlation algorithm. For pancreatic tumor detection, HMI images were generated for pancreatic tumors in transgenic mice and normal pancreases in wild-type mice. The obtained HMI images showed a high contrast between normal and malignant pancreases with an average peak-to-peak HMI displacement ratio of 3.2. Histological analysis showed that no tissue damage was associated with HMI when it was used for the sole purpose of elasticity imaging. For pancreatic tumor ablation monitoring, the focused ultrasound transducer was operated at a higher acoustic power and longer pulse length than that used in tumor detection to simultaneously induce HIFU thermal ablation and oscillatory tissue displacements, allowing HMI monitoring without interrupting tumor ablation. HMI monitoring of HIFU ablation found significant decreases in the peak-to-peak HMI displacements before and after HIFU ablation with a reduction rate ranging from 15.8% to 57.0%. The formation of thermal lesions after HIFU exposure was confirmed by histological analysis. This study demonstrated the feasibility of HMI in abdominal tumor detection and HIFU ablation monitoring. PMID:26415128

  7. SU-C-210-04: Considerable Pancreatic Tumor Motion During Breath-Hold Measured Using Intratumoral Fiducials On Fluoroscopic Movies

    SciTech Connect

    Lens, E; Horst, A van der; Versteijne, E; Tienhoven, G van; Bel, A

    2015-06-15

    Purpose: Using a breath hold (BH) technique during radiotherapy of pancreatic tumors is expected to reduce intra-fractional motion. The aim of this study was to evaluate the tumor motion during BH. Methods: In this pilot study, we included 8 consecutive pancreatic cancer patients. All had 2– 4 intratumoral gold fiducials. Patients were asked to perform 3 consecutive 30-second end-inhale BHs on day 5, 10 and 15 of their three-week treatment. During BH, airflow through a mouthpiece was measured using a spirometer. Any inadvertent flow of air during BH was monitored for all patients. We measured tumor motion on lateral fluoroscopic movies (57 in total) made during BH. In each movie the fiducials as a group were tracked over time in superior-inferior (SI) and anterior-posterior (AP) direction using 2-D image correlation between consecutive frames. We determined for each patient the range of intra-BH motion over all movies; we also determined the absolute means and standard deviations (SDs) for the entire patient group. Additionally, we investigated the relation between inadvertent airflow during BH and the intra-BH motion. Results: We found intra-BH tumor motion of up to 12.5 mm (range, 1.0–12.5 mm) in SI direction and up to 8.0 mm (range, 1.0–8.0 mm) in AP direction. The absolute mean motion over the patient population was 4.7 (SD: 3.0) mm and 2.8 (SD: 1.2) mm in the SI and AP direction, respectively. Patients were able to perform stable consecutive BHs; during only 20% of the movies we found very small airflows (≤ 65 ml). These were mostly stepwise in nature and could not explain the continuous tumor motions we observed. Conclusion: We found substantial (up to 12.5 mm) pancreatic tumor motion during BHs. We found minimal inadvertent airflow, seen only during a minority of BHs, and this did not explain the obtained results. This work was supported by the foundation Bergh in het Zadel through the Dutch Cancer Society (KWF Kankerbestrijding) project No. UVA 2011-5271.

  8. Pancreatic islet cell tumor

    MedlinePlus

    Islet cell tumors; Islet of Langerhans tumor; Neuroendocrine tumors ... In the healthy pancreas, cells called islet cells produce hormones that regulate a several bodily functions. These include blood sugar level and the production of ...

  9. Update on pancreatic neuroendocrine tumors

    PubMed Central

    McKenna, Logan R.

    2014-01-01

    Pancreatic neuroendocrine tumors (pNETs) are relatively rare tumors comprising 1-2% of all pancreas neoplasms. In the last 10 years our understanding of this disease has increased dramatically allowing for advancements in the treatment of pNETs. Surgical excision remains the primary therapy for localized tumors and only potential for cure. New surgical techniques using laparoscopic approaches to complex pancreatic resections are a major advancement in surgical therapy and increasingly possible. With early detection being less common, most patients present with metastatic disease. Management of these patients requires multidisciplinary care combining the best of surgery, chemotherapy and other targeted therapies. In addition to surgical advances, recently, there have been significant advances in systemic therapy and targeted molecular therapy. PMID:25493258

  10. Adaptive motion mapping in pancreatic SBRT patients using Fourier transforms

    PubMed Central

    Jones, Bernard L.; Schefter, Tracey; Miften, Moyed

    2015-01-01

    Background and Purpose Recent studies suggest that 4DCT is unable to accurately measure respiratory-induced pancreatic tumor motion. In this work, we assessed the daily motion of pancreatic tumors treated with SBRT, and developed adaptive strategies to predict and account for this motion. Materials and Methods The daily motion trajectory of pancreatic tumors during CBCT acquisition was calculated using a model which reconstructs the instantaneous 3D position in each 2D CBCT projection image. We developed a metric (termed “Spectral Coherence,” SC) based on the Fourier frequency spectrum of motion in the SI direction, and analyzed the ability of SC to predict motion-based errors and classify patients according to motion characteristics. Results The amplitude of daily motion exceeded the predictions of pre-treatment 4DCT imaging by an average of 3.0 mm, 2.3 mm, and 3.5 mm in the AP/LR/SI directions. SC was correlated with daily motion differences and tumor dose coverage. In a simulated adaptive protocol, target margins were adjusted based on SC, resulting in significant increases in mean target D95, D99, and minimum dose. Conclusions Our Fourier-based approach differentiates between consistent and inconsistent motion characteristics of respiration and correlates with daily motion deviations from pre-treatment 4DCT. The feasibility of an SC-based adaptive protocol was demonstrated, and this patient-specific respiratory information was used to improve target dosimetry by expanding coverage in inconsistent breathers while shrinking treatment volumes in consistent breathers. PMID:25890573

  11. General Information about Pancreatic Neuroendocrine Tumors (Islet Cell Tumors)

    MedlinePlus

    ... Islet Cell Tumors) Treatment (PDQ®)–Patient Version General Information About Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Go ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  12. Radiotherapy for Pancreatic Neuroendocrine Tumors

    SciTech Connect

    Contessa, Joseph N.; Griffith, Kent A.; Wolff, Elizabeth; Ensminger, William; Zalupski, Mark; Ben-Josef, Edgar

    2009-11-15

    Purpose: Pancreatic neuroendocrine tumors (PNTs) are rare malignant neoplasms considered to be resistant to radiotherapy (RT), although data on efficacy are scarce. We reviewed our institutional experience to further delineate the role of RT for patients with PNTs. Methods and Materials: Between 1986 and 2006, 36 patients with PNTs were treated with RT to 49 sites. Of these 36 patients, 23 had radiographic follow-up data, which were used to determine the tumor response rate and freedom from local progression. Long-term toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Results: The overall response rate to RT was 39% (13% complete response, 26% partial response, 56% stable disease, and 4% progressive disease). A significant difference in the freedom from local progression between the groups receiving either greater than or less than the median 2 Gy/fraction biologically equivalent dose of 49.6 Gy was found, with all radiographic progression occurring in patients who had received <=32 Gy. The actuarial 3-year local freedom from progression rate was 49%. Palliation was achieved in 90% of patients, with either improvement or resolution of symptoms after RT. Of 35 patients, 33 had metastatic disease at their referral for RT, and the median overall survival for this patient population was 2 years. Three long-term Grade 3 or greater toxicities were recorded. Conclusion: RT is an effective modality for achieving local control in patients with PNTs. RT produces high rates of symptomatic palliation and freedom from local progression. Prospective trials of radiotherapy for PNTs are warranted.

  13. Capecitabine, Temozolomide and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2016-07-19

    Gastrinoma; Glucagonoma; Insulinoma; Pancreatic Polypeptide Tumor; Recurrent Islet Cell Carcinoma; Recurrent Pancreatic Cancer; Somatostatinoma; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer

  14. Everolimus and Octreotide Acetate With or Without Bevacizumab in Treating Patients With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2016-06-20

    Gastrin-Producing Neuroendocrine Tumor; Malignant Pancreatic Gastrinoma; Malignant Pancreatic Glucagonoma; Malignant Pancreatic Insulinoma; Malignant Pancreatic Somatostatinoma; Pancreatic Alpha Cell Adenoma; Pancreatic Beta Cell Adenoma; Pancreatic Delta Cell Adenoma; Pancreatic G-Cell Adenoma; Pancreatic Glucagonoma; Pancreatic Insulinoma; Pancreatic Polypeptide Tumor; Recurrent Pancreatic Carcinoma; Recurrent Pancreatic Neuroendocrine Carcinoma; Somatostatin-Producing Neuroendocrine Tumor; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer

  15. Pancreatic neuroendocrine tumors: biology, diagnosis, and treatment

    PubMed Central

    Ro, Cynthia; Chai, Wanxing; Yu, Victoria E.; Yu, Run

    2013-01-01

    Pancreatic neuroendocrine tumors (PNETs), a group of endocrine tumors arising in the pancreas, are among the most common neuroendocrine tumors. The genetic causes of familial and sporadic PNETs are somewhat understood, but their molecular pathogenesis remains unknown. Most PNETs are indolent but have malignant potential. The biological behavior of an individual PNET is unpredictable; higher tumor grade, lymph node and liver metastasis, and larger tumor size generally indicate a less favorable prognosis. Endocrine testing, imaging, and histological evidence are necessary to accurately diagnose PNETs. A 4-pronged aggressive treatment approach consisting of surgery, locoregional therapy, systemic therapy, and complication control has become popular in academic centers around the world. The optimal application of the multiple systemic therapeutic modalities is under development; efficacy, safety, availability, and cost should be considered when treating a specific patient. The clinical presentation, diagnosis, and treatment of specific types of PNETs and familial PNET syndromes, including the novel Mahvash disease, are summarized. PMID:23237225

  16. Surgical management of pancreatic neuroendocrine tumors.

    PubMed

    Kimura, Wataru; Tezuka, Koji; Hirai, Ichiro

    2011-10-01

    This study outlines the surgical management and clinicopathological findings of pancreatic neuroendocrine tumors (P-NETs). There are various surgical options, such as enucleation of the tumor, spleen-preserving distal pancreatectomy, distal pancreatectomy with splenectomy, pancreatoduodenectomy, and duodenum-preserving pancreas head resection. Lymph node dissection is performed for malignant cases. New guidelines and classifications have been proposed and are now being used in clinical practice. However, there are still no clear indications for organ-preserving pancreatic resection or lymph node dissection. Hepatectomy is the first choice for liver metastases of well-differentiated neuroendocrine carcinoma without extrahepatic metastases. On the other hand, cisplatin-based combination therapy is performed as first-line chemotherapy for metastatic poorly differentiated neuroendocrine carcinoma. Other treatment options are radiofrequency ablation, transarterial chemoembolization/embolization, and liver transplantation. Systematic chemotherapy and biotherapy, such as that with somatostatin analogue and interferon-α, are used for recurrence after surgery. The precise surgical techniques for enucleation of the tumor and spleen-preserving distal pancreatectomy are described. PMID:21922354

  17. Irreversible electroporation for the treatment of pancreatic neuroendocrine tumors

    PubMed Central

    Papamichail, Michail; Ali, Amir; Pizanias, Michail; Peddu, Praveen; Karani, John

    2016-01-01

    Backgrounds/Aims Resection or enucleation is currently the treatment of choice for small pancreatic neuroendocrine tumors (NETs). Irreversible electroporation is a novel ablative method that is used for locally advanced pancreatic adenocarcinoma, but little data exists for its use for pancreatic NETs. We report an early experience of IRE for early pancreatic NETs. Methods Between April 2014 and March 2015, 3 patients with small (<2 cm) pancreatic NETs were treated with percutaneous IRE. Results There were no adverse effects during the procedure. Mean hospital stay was 2.6 days. All patients remained disease free on 12-19 months follow up. One patient developed recurrent pancreatitis with pseudocyst formation. Conclusions IRE for small tumors of the pancreas is practical and may offer advantages over other thermal ablative techniques, since it preserves vital structures such as blood vessels, bile and pancreatic ducts. Further data regarding the long term disease free interval is required to establish efficacy. PMID:27621748

  18. Genomic landscape of pancreatic neuroendocrine tumors

    PubMed Central

    Gebauer, Niklas; Schmidt-Werthern, Christian; Bernard, Veronica; Feller, Alfred C; Keck, Tobias; Begum, Nehara; Rades, Dirk; Lehnert, Hendrik; Brabant, Georg; Thorns, Christoph

    2014-01-01

    AIM: To investigate the prognostic role of genomic stability and copy number alterations (CNAs) pancreatic neuroendocrine tumors (PanNETs). METHODS: A high-resolution array-based comparative genomic hybridization approach was utilized in order to investigate and quantify chromosomal aberrations in a panel of 37 primary PanNET and 11 metastatic samples. DNA samples were extracted from formalin-fixed and paraffin-embedded tumor specimen. Genomic findings were correlated with histopathological and immunohistochemical data. Moreover, the dataset was subjected to employing an unsupervised hierarchical clustering analysis approach utilizing Euclidean distance and average linkage and associations between genomically defined tumor groups and recurrent CNAs or clinicopathological features of the study group were assessed. RESULTS: Numerous chromosomal aberrations were recurrently detected in both, primary tumor samples and metastases. Copy number gains were most frequently observed at 06p22.2-p22.1 (27.1%), 17p13.1 (20.8%), 07p21.3-p21.2 (18.8%), 09q34.11 (18.8%). Genomic losses were significantly less frequent and the only recurrent aberration affected 08q24.3 (6.3%). Moreover, we detected a high degree of genomic heterogeneity between primary tumors and metastatic lesions. Unsupervised hierarchical clustering of loci affected by CNAs in more than 3 primary tumor samples revealed two genetically distinct tumor groups as well as two chromosomal clusters of genomic imbalances indicating a small subset of tumors with common molecular features (13.5%). Aberrations affecting 6p22.2-22.1, 8q24.3, 9q34.11 and 17p13.1 (P = 0.011; 0.003; 0.003; 0.001), were significantly associated with a poorer survival prognosis. CONCLUSION: This study suggests that several frequent CNAs in numerous candidate regions are involved in the pathogenesis and metastatic progression of PanNET. PMID:25516664

  19. Therapy for metastatic pancreatic neuroendocrine tumors

    PubMed Central

    Massironi, Sara; Conte, Dario; Peracchi, Maddalena

    2014-01-01

    Background Pancreatic neuroendocrine tumors (pNETs) are frequently malignant (50-80%, except for insulinoma) and may show an aggressive course with metastases to the liver as well as more distant sites. These heterogeneous neoplasms include functioning tumors, which secrete a variety of peptide hormones, and non-functioning tumors (up to 90% of pNETs), which often show metastases at the time of diagnosis. Methods A PubMed search was performed for English-language publications from 1995 through December 2012. Reference lists from studies selected were manually searched to identify further relevant reports. Manuscripts comparing different therapeutic options and advances for metastatic pNETs were selected. Results The therapeutic options for metastatic pNETs are expanding and include surgery, which remains the only curative approach, liver-directed therapies, and medical therapy. In selected cases also liver transplantation (OLT) may be considered. The option of OLT for metastatic disease is unique to neuroendocrine tumors. Recently, novel promising targeted therapies have been proposed for progressive well-differentiated pNETs. Conclusions The best therapeutic approach for pNETs is still matter of debating. However, since pNETs often show a more indolent behavior compared to other malignancies, the preservation of the quality of life of the patient and the personalization of the therapy according to tumor’s and patient’s features are mandatory. PMID:25332984

  20. TNM Staging of Pancreatic Neuroendocrine Tumors

    PubMed Central

    Yang, Min; Zeng, Lin; Zhang, Yi; Wang, Wei-guo; Wang, Li; Ke, Neng-wen; Liu, Xu-bao; Tian, Bo-le

    2015-01-01

    Abstract We aimed to analyze the clinical characteristics and compare the surgical outcome of pancreatic neuroendocrine tumors (p-NETs) using the 2 tumor-node-metastasis (TNM) systems by both the American Joint Committee on Cancer (AJCC) Staging Manual (seventh edition) and the European Neuroendocrine Tumor Society (ENETS). Moreover, we sought to validate the prognostic value of the new AJCC criterion. Data of 145 consecutive patients who were all surgically treated and histologically diagnosed as p-NETs from January 2002 to June 2013 in our single institution were retrospectively collected and analyzed. The 5-year overall survival (OS) rates for AJCC classifications of stages I, II, III, and IV were 79.5%, 63.1%, 15.0%, and NA, respectively, (P < 0.005). As for the ENETS system, the OS rates at 5 years for stages I, II, III, and IV were 75.5%, 72.7%, 29.0%, and NA, respectively, (P < 0.005). Both criteria present no statistically notable difference between stage I and stage II (P > 0.05) but between stage I and stages III and IV (P < 0.05), as well as those between stage II and stages III and IV (P < 0.05). Difference between stage III and IV by ENETS was significant (P = 0.031), whereas that by the AJCC was not (P = 0.144). What's more, the AJCC Staging Manual (seventh edition) was statistically significant in both uni- and multivariate analyses by Cox regression (P < 0.005 and P = 0.025, respectively). Our study indicated that the ENETS TNM staging system might be superior to the AJCC Staging Manual (seventh edition) for the clinical practice of p-NETs. Together with tumor grade and radical resection, the new AJCC system was also validated to be an independent predictor for p-NETs. PMID:25816036

  1. Pancreatic tumor margin detection by oblique incidence diffuse reflectance spectroscopy

    NASA Astrophysics Data System (ADS)

    Garcia-Uribe, Alejandro; Chang, Cheng-Chung; Zou, Jun; Banerjee, Bhaskar; Kuczynski, John; Wang, Lihong V.

    2011-03-01

    In surgical treatment of pancreatic cancers, the effectiveness of the procedures largely depends on the ability to completely and precisely remove the malignant tumors. We present the ex-vivo use of oblique incidence diffuse reflectance spectroscopy (OIRDS) to detect and differentiate normal from neoplastic tissue. An OIRDS probe has been constructed to provide scattering and absorption information of the pancreatic tissue. To reveal the physiological origin of the difference in these optical signatures, the optical scattering coefficients were extracted along the pancreatic duct with 1-cm spacing. Experimental results show that OIDRS was able to successfully determinate the tumor margins based on the higher optical scattering on malignant tissue.

  2. Penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis

    PubMed Central

    Ranjan, Alok; Srivastava, Sanjay K.

    2016-01-01

    Pancreatic tumors exhibit enhanced autophagy as compared to any other cancer, making it resistant to chemotherapy. We evaluated the effect of penfluridol against pancreatic cancer. Penfluridol treatment induced apoptosis and inhibited the growth of Panc-1, BxPC-3 and AsPC-1, pancreatic cancer cells with IC50 ranging between 6–7 μM after 24 h of treatment. Significant autophagy was induced by penfluridol treatment in pancreatic cancer cells. Punctate LC3B and autophagosomes staining confirmed autophagy. Inhibiting autophagy by chloroquine, bafilomycin, 3-methyladenine or LC3BsiRNA, significantly blocked penfluridol-induced apoptosis, suggesting that autophagy lead to apoptosis in our model. Penfluridol treatment suppressed the growth of BxPC-3 tumor xenografts by 48% as compared to 17% when treated in combination with chloroquine. Similarly, penfluridol suppressed the growth of AsPC-1 tumors by 40% versus 16% when given in combination with chloroquine. TUNEL staining and caspase-3 cleavage revealed less apoptosis in the tumors from mice treated with penfluridol and chloroquine as compared to penfluridol alone. Penfluridol treatment also suppressed the growth of orthotopically implanted Panc-1 tumors by 80% by inducing autophagy-mediated apoptosis in the tumors. These studies established that penfluridol inhibits pancreatic tumor growth by autophagy-mediated apoptosis. Since penfluridol is already in clinic, positive findings from our study will accelerate its clinical development. PMID:27189859

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

    ClinicalTrials.gov

    2016-08-09

    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

  4. Is Diaphragm Motion a Good Surrogate for Liver Tumor Motion?

    SciTech Connect

    Yang, Juan; Cai, Jing; Wang, Hongjun; Chang, Zheng; Czito, Brian G.; Bashir, Mustafa R.; Palta, Manisha; Yin, Fang-Fang

    2014-11-15

    Purpose: To evaluate the relationship between liver tumor motion and diaphragm motion. Methods and Materials: Fourteen patients with hepatocellular carcinoma (10 of 14) or liver metastases (4 of 14) undergoing radiation therapy were included in this study. All patients underwent single-slice cine–magnetic resonance imaging simulations across the center of the tumor in 3 orthogonal planes. Tumor and diaphragm motion trajectories in the superior–inferior (SI), anterior–posterior (AP), and medial–lateral (ML) directions were obtained using an in-house-developed normalized cross-correlation–based tracking technique. Agreement between the tumor and diaphragm motion was assessed by calculating phase difference percentage, intraclass correlation coefficient, and Bland-Altman analysis (Diff). The distance between the tumor and tracked diaphragm area was analyzed to understand its impact on the correlation between the 2 motions. Results: Of all patients, the mean (±standard deviation) phase difference percentage values were 7.1% ± 1.1%, 4.5% ± 0.5%, and 17.5% ± 4.5% in the SI, AP, and ML directions, respectively. The mean intraclass correlation coefficient values were 0.98 ± 0.02, 0.97 ± 0.02, and 0.08 ± 0.06 in the SI, AP, and ML directions, respectively. The mean Diff values were 2.8 ± 1.4 mm, 2.4 ± 1.1 mm, and 2.2 ± 0.5 mm in the SI, AP, and ML directions, respectively. Tumor and diaphragm motions had high concordance when the distance between the tumor and tracked diaphragm area was small. Conclusions: This study showed that liver tumor motion had good correlation with diaphragm motion in the SI and AP directions, indicating diaphragm motion in the SI and AP directions could potentially be used as a reliable surrogate for liver tumor motion.

  5. Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression.

    PubMed

    Mohammed, Altaf; Janakiram, Naveena B; Madka, Venkateshwar; Brewer, Misty; Ritchie, Rebekah L; Lightfoot, Stan; Kumar, Gaurav; Sadeghi, Michael; Patlolla, Jagan Mohan R; Yamada, Hiroshi Y; Cruz-Monserrate, Zobeida; May, Randal; Houchen, Courtney W; Steele, Vernon E; Rao, Chinthalapally V

    2015-06-20

    Recent development of genetically engineered mouse models (GEMs) for pancreatic cancer (PC) that recapitulates human disease progression has helped to identify new strategies to delay/inhibit PC development. We first found that expression of the pancreatic tumor-initiating/cancer stem cells (CSC) marker DclK1 occurs in early stage PC and in both early and late pancreatic intraepithelial neoplasia (PanIN) and that it increases as disease progresses in GEM and also in human PC. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEM mice revealed significantly increased DclK1 along with inflammatory genes. Genetic ablation of cyclo-oxygenase-2 (COX-2) decreased DclK1 in GEM. Induction of inflammation/pancreatitis with cerulein in GEM mice increased DclK1, and the novel dual COX/5-lipoxygenase (5-LOX) inhibitor licofelone reduced it. Dietary licofelone significantly inhibited the incidence of PDAC and carcinoma in situ with significant inhibition of pancreatic CSCs. Licofelone suppressed pancreatic tumor COX-2 and 5-LOX activities and modulated miRNAs characteristic of CSC and inflammation in correlation with PDAC inhibition. These results offer a preclinical proof of concept to target the inflammation initiation to inhibit cancer stem cells early for improving the treatment of pancreatic cancers, with immediate clinical implications for repositioning dual COX/5-LOX inhibitors in human trials for high risk patients. PMID:25906749

  6. Practical management and treatment of pancreatic neuroendocrine tumors

    PubMed Central

    Ikeda, Yasuharu

    2014-01-01

    Pancreatic neuroendocrine tumors (NETs) are uncommon disease, about which little is known. Pancreatic NETs are usually slow growing and their malignant potential are often underestimated. The management of this disease poses a challenge because of the heterogeneous clinical presentation and varying degrees of aggressiveness. Recently, several guidelines for the management of pancreatic NETs have been established and help to devise clinical strategy. In the treatment algorithms, however, a lot of uncertain points are included. Practical treatment decisions of pancreatic NETs are still sometimes made in a patient- and/or physicians-oriented manner. The tumor grading system proposed by the European Neuroendocrine Tumor Society (ENETS) gives important prognostic information, however, the implication of grading regarding medical treatment strategies to choose has not yet been clarified. Moreover, the place of surgical treatment is unclear in the overall management course of advanced pancreatic NETs. In some cases, practical management and treatment have to be individualized depending on predominant symptoms, tumor spread, and general health of the patients. Current issues and a few points to make a strategy in the management of pancreatic NETs would be reviewed. PMID:25493259

  7. [Neuroendocrine pancreatic tumors and helpfulness of targeted therapies].

    PubMed

    Vaysse, Thibaut; Coriat, Romain; Perkins, Géraldine; Dhooge, Marion; Brezault, Catherine; Chaussade, Stanislas

    2013-06-01

    The neuroendocrine pancreatic tumors are rare tumors, but their incidence is constantly rising. Even if the management of these tumors has to be surgical as soon as possible, the disease is most often metastatic at the stage of the diagnostic. The prognostic and the therapeutic options differ from pancreatic adenocarcinoma. Available treatments have evolved over the last years with recent publications of studies that bring to light the benefits of targeted therapies in this pathology. This has resulted in modifications of both practices and either French and international guidelines. Therefore, we focus on the management of the grade 1 and grade 2 well-differentiated neuroendocrine pancreatic tumors as classified in new WHO classification of neuroendocrine neoplasms published in 2010. PMID:23009947

  8. Role of the tumor microenvironment in pancreatic adenocarcinoma.

    PubMed

    Sun, Xian-Jun; Jiang, Ting-Hui; Zhang, Xiao-Ping; Mao, Ai-Wu

    2016-01-01

    Pancreatic cancer is a devastating disease with proclivity for early metastasis, which accounts for its poor prognosis. The clinical problem of pancreatic cancer is its resistance to conventional therapies, such as chemotherapy or radiation. Based upon these challenges, the focus of research on pancreatic cancer has shifted gradually towards the tumor microenvironment. The cancer microenvironment consists of various components, including fibroblasts, endothelial cells, immune cells, and endocrine cells, that interact with each other, and with the cancer cells in a complex fashion. Evidence is accumulating that the cancer microenvironment plays an active role in disease progression, and efforts are being made to target this interplay between cancer cells and host cells, to improve the prognosis of the disease. In the present review, we describe the cellular microenvironment of pancreatic ductal adenocarcinoma (PDA), the major type of pancreatic cancer. Our hope is that a better understanding of the cellular microenvironment of PDA will eventually lead to better treatments for this disease. PMID:26709759

  9. Pancreatic body adenocarcinoma with neuroendocrine tumor characteristics: A case report

    PubMed Central

    TAJIMA, HIDEHIRO; KITAGAWA, HIROHISA; SHOJI, MASATOSHI; WATANABE, TOSHIFUMI; NAKANUMA, SHINICHI; OKAMOTO, KOICHI; SAKAI, SEISHO; KINOSHITA, JUN; MAKINO, ISAMU; FURUKAWA, HIROYUKI; NAKAMURA, KEISHI; HAYASHI, HIRONORI; OYAMA, KATSUNOBU; INOKUCHI, MASAFUMI; NAKAGAWARA, HISATOSHI; MIYASHITA, TOMOHARU; ITOH, HIROSHI; TAKAMURA, HIROYUKI; NINOMIYA, ITASU; FUSHIDA, SACHIO; FUJIMURA, TAKASHI; OHTA, TETSUO; SATOH, HIROHIDE; IKEDA, HIROKO; HARADA, KENICHI; NAKANUMA, YASUNI

    2014-01-01

    A 61-year-old female with pancreatic body cancer underwent a distal pancreatectomy. The tumor was a moderately- to poorly-differentiated adenocarcinoma. Tumor growth filled the dilated main pancreatic duct (MPD) and infiltrated the surrounding area. Six months later, metastases to the left diaphragm and MPD of the remnant pancreatic head were detected. Chemoradiotherapy was administered, but the patient succumbed 22 months after surgery. An autopsy demonstrated that a moderately- to poorly-differentiated adenocarcinoma had arisen from the pancreatic head and infiltrated the duodenum and bile duct. Huge liver metastases and multiple peritoneal disseminations were also present. Microscopically, a portion of the tumor had a pseudo-rosette appearance in the adenocarcinoma component, while another section showed characteristics of a neuroendocrine tumor (NET) immunohistochemically. The original surgically-resected tumor also showed NET characteristics immunohistochemically. It is therefore necessary to search for NET components in pancreatic cancer with atypical growth and metastases, even when adenocarcinoma has been diagnosed histologically. PMID:24944667

  10. Magnetic resonance imaging of less common pancreatic malignancies and pancreatic tumors with malignant potential

    PubMed Central

    Franz, D.; Esposito, I.; Kapp, A.-C.; Gaa, J.; Rummeny, E.J.

    2014-01-01

    Pancreatic tumors are an increasingly common finding in abdominal imaging. Various kinds of pathologies of the pancreas are well known, but it often remains difficult to classify the lesions radiologically in respect of type and grade of malignancy. Magnetic resonance imaging (MRI) is the method of choice for the evaluation of pancreatic pathologies due to its superior soft tissue contrast. In this article we present a selection of less common malignant and potentially malignant pancreatic neoplasms with their characteristic appearance on established MRI sequences with and without contrast enhancement. PMID:26937427

  11. [Endoscopic Ultrasound-guided Local Therapy of Pancreatic Tumors].

    PubMed

    Yoon, Won Jae; Seo, Dong Wan

    2015-09-01

    The development of curvilinear EUS has enabled EUS-guided fine-needle aspiration of intra-abdominal mass lesions. With the introduction of interventional EUS, this technology has undergone several modifications in order to be applied to clinical medicine. One of the potential uses of interventional EUS is the EUS-guided local therapy of pancreatic tumors. Various treatment modalities such as fine-needle injection, radiofrequency ablation, photodynamic therapy, laser ablation, and brachytherapy have been tried under EUS guidance. Some of these modalities are being applied clinically. These methods for EUS-guided local therapy of pancreatic tumors will be reviewed in this article. PMID:26387698

  12. Endoscopic approach to the diagnosis of pancreatic cystic tumor.

    PubMed

    Kawaguchi, Yoshiaki; Mine, Tetsuya

    2016-02-15

    Because of the aging of the population, prevalence of medical checkups, and advances in imaging studies, the number of pancreatic cystic lesions detected has increased. Once these lesions are detected, neoplastic cysts should be differentiated from non-neoplastic cysts. Furthermore, because of the malignant potential of some neoplastic pancreatic cysts, further differentiation between benign and malignant cysts should be made regardless of their size. Although endoscopic ultrasound (EUS) has a very high diagnostic performance for pancreatic cystic lesions among the various imaging modalities, EUS findings alone are insufficient for the differentiation of pancreatic cysts and diagnosis of malignancy. In addition, cytology by EUS-guided fine-needle aspiration (FNA) has a high specificity but a low sensitivity for diagnosing malignancy in pancreatic cystic tumors. The levels of amylase, lipase, and tumor markers in pancreatic cystic fluid are considered auxiliary parameters for diagnosis of benign and malignant cysts, and a definitive diagnosis of malignancy using these parameters is difficult. Thus, in addition to EUS, cytology by EUS-FNA, and cystic fluid analysis, new techniques based on EUS-guided through-the-needle imaging, such as confocal laser endomicroscopy and cystoscopy, have been explored in recent years. PMID:26909130

  13. Endoscopic approach to the diagnosis of pancreatic cystic tumor

    PubMed Central

    Kawaguchi, Yoshiaki; Mine, Tetsuya

    2016-01-01

    Because of the aging of the population, prevalence of medical checkups, and advances in imaging studies, the number of pancreatic cystic lesions detected has increased. Once these lesions are detected, neoplastic cysts should be differentiated from non-neoplastic cysts. Furthermore, because of the malignant potential of some neoplastic pancreatic cysts, further differentiation between benign and malignant cysts should be made regardless of their size. Although endoscopic ultrasound (EUS) has a very high diagnostic performance for pancreatic cystic lesions among the various imaging modalities, EUS findings alone are insufficient for the differentiation of pancreatic cysts and diagnosis of malignancy. In addition, cytology by EUS-guided fine-needle aspiration (FNA) has a high specificity but a low sensitivity for diagnosing malignancy in pancreatic cystic tumors. The levels of amylase, lipase, and tumor markers in pancreatic cystic fluid are considered auxiliary parameters for diagnosis of benign and malignant cysts, and a definitive diagnosis of malignancy using these parameters is difficult. Thus, in addition to EUS, cytology by EUS-FNA, and cystic fluid analysis, new techniques based on EUS-guided through-the-needle imaging, such as confocal laser endomicroscopy and cystoscopy, have been explored in recent years. PMID:26909130

  14. APC promoter is frequently methylated in pancreatic juice of patients with pancreatic carcinomas or periampullary tumors

    PubMed Central

    Ginesta, Mireia M.; Diaz-Riascos, Zamira Vanessa; Busquets, Juli; Pelaez, Núria; Serrano, Teresa; Peinado, Miquel Àngel; Jorba, Rosa; García-Borobia, Francisco Javier; Capella, Gabriel; Fabregat, Joan

    2016-01-01

    Early detection of pancreatic and periampullary neoplasms is critical to improve their clinical outcome. The present authors previously demonstrated that DNA hypermethylation of adenomatous polyposis coli (APC), histamine receptor H2 (HRH2), cadherin 13 (CDH13), secreted protein acidic and cysteine rich (SPARC) and engrailed-1 (EN-1) promoters is frequently detected in pancreatic tumor cells. The aim of the present study was to assess their prevalence in pancreatic juice of carcinomas of the pancreas and periampullary area. A total of 135 pancreatic juices obtained from 85 pancreatic cancer (PC), 26 ampullary carcinoma (AC), 10 intraductal papillary mucinous neoplasm (IPMN) and 14 chronic pancreatitis (CP) patients were analyzed. The methylation status of the APC, HRH2, CDH13, SPARC and EN-1 promoters was analyzed using methylation specific-melting curve analysis (MS-MCA). Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were also tested with allele-specific quantitative polymerase chain reaction amplification. Out of the 5 promoters analyzed, APC (71%) and HRH2 (65%) were the most frequently methylated in PC juice. APC methylation was also detected at a high frequency in AC (76%) and IPMN (80%), but only occasionally observed in CP (7%). APC methylation had a high sensitivity (71–80%) for all types of cancer analyzed. The panel (where a sample scored as positive when ≥2 markers were methylated) did not outperform APC as a single marker. Finally, KRAS detection in pancreatic juice offered a lower sensitivity (50%) and specificity (71%) for detection of any cancer. APC hypermethylation in pancreatic juice, as assessed by MS-MCA, is a frequent event of potential clinical usefulness in the diagnosis of pancreatic and periampullary neoplasms. PMID:27602165

  15. Meso-pancreatectomy for pancreatic neuroendocrine tumor.

    PubMed

    Ferrarese, Alessia; Borello, Alessandro; Gentile, Valentina; Bindi, Marco; Ferrara, Yuri; Solej, Mario; Martino, Valter; Nano, Mario

    2014-01-01

    We report a case of a meso-pancreatectomy performed on a pancreatic glucagonoma in a 58 years-old woman. MP is a conservative surgical treatment consisting in a resection of the body of the pancreas with the aim of reducing postoperative hormone insufficiency. This approach is curative in benign or low-malignant neoplasm of the central part of the pancreas. PMID:24859404

  16. Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer.

    PubMed

    Sunamura, Makoto; Duda, Dan G; Ghattas, Maivel H; Lozonschi, Lucian; Motoi, Fuyuhiko; Yamauchi, Jun-Ichiro; Matsuno, Seiki; Shibahara, Shigeki; Abraham, Nader G

    2003-01-01

    Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease. PMID:14517400

  17. Recent developments in imaging of pancreatic neuroendocrine tumors

    PubMed Central

    Kartalis, Nikolaos; Mucelli, Raffaella Maria Pozzi; Sundin, Anders

    2015-01-01

    Pancreatic neuroendocrine tumors (PNETs) are very rare, accounting for 1-2% of all pancreatic neoplasms. They are classified into functioning and non-functioning and their behavior varies widely from benign to highly malignant. For their investigation, a variety of anatomical and functional imaging methods are available. Anatomical methods include computed tomography (CT), magnetic resonance imaging, and ultrasonography. Functional methods include scintigraphy and positron emission tomography (PET). A combination of anatomical and morphological methods results in the so-called hybrid imaging, such as PET/CT. We herein discuss the currently available imaging modalities for the investigation of PNETs and, more specifically, their applications in tumor detection and staging as well as in choice of therapy, imaging follow up and prediction of response, with emphasis on the recent developments. PMID:25830417

  18. Opportunities and Challenges for Pancreatic Circulating Tumor Cells.

    PubMed

    Nagrath, Sunitha; Jack, Rhonda M; Sahai, Vaibhav; Simeone, Diane M

    2016-09-01

    Sensitive and reproducible platforms have been developed for detection, isolation, and enrichment of circulating tumor cells (CTCs)-rare cells that enter the blood from solid tumors, including those of the breast, prostate gland, lung, pancreas, and colon. These might be used as biomarkers in diagnosis or determination of prognosis. CTCs are no longer simply detected and quantified; they are now used in ex vivo studies of anticancer agents and early detection. We review what we have recently learned about CTCs from pancreatic tumors, describing advances in their isolation and analysis and challenges to their clinical utility. We summarize technologies used to isolate CTCs from blood samples of patients with pancreatic cancer, including immunoaffinity and label-free physical attribute-based capture. We explain methods of CTC analysis and how findings from these studies might be used to detect cancer at earlier stages, monitor disease progression, and determine prognosis. We review studies that have expanded CTCs for testing of anticancer agents and how these approaches might be used to personalize treatment. Advances in the detection, isolation, and analysis of CTCs have increased our understanding of the dissemination and progression of pancreatic cancer. However, standardization of methodologies and prospective studies are needed for this emerging technology to have a significant effect on clinical care. PMID:27339829

  19. Quantification of Murine Pancreatic Tumors by High Resolution Ultrasound

    PubMed Central

    Sastra, Stephen A.; Olive, Kenneth P.

    2013-01-01

    Summary Ultrasonography is a powerful imaging modality that enables non-invasive, real time visualization of abdominal organs and tissues. This technology may be adapted for use in mice through the utilization of higher frequency transducers, allowing for extremely high resolution imaging of the mouse pancreas. This technique is particularly well-suited to pancreas imaging due to the ultrasonographic properties of the normal mouse pancreas, easily accessible imaging planes for the head and tail of the mouse pancreas, and the comparative difficulty in imaging the mouse pancreas with other technologies. A suite of measurements tools is available to characterize the normal and diseased states of tissues. Of particular utility for cancer applications is the ability to use tomography to construct a 3D tumor volume, enabling longitudinal imaging studies to track tumor development, or response to therapies. Here, we describe a detailed method for performing high resolution ultrasound to detect and measure pancreatic lesions in a genetically engineered mouse model of pancreatic ductal using the VisualSonics Vevo2100 High Resolution Ultrasound System. The method includes preparation of the animal for imaging, 2D and 3D image acquisition, and post-acquisition analysis of tumors volumes. The combined procedure has been utilized extensively by our group and others for the preclinical evaluation of novel therapeutic agents in the treatment of pancreatic ductal adenocarcinoma (1–4). PMID:23359158

  20. Latexin exhibits tumor-suppressor potential in pancreatic ductal adenocarcinoma

    PubMed Central

    XUE, ZHANXIONG; ZHOU, YUHUI; WANG, CHENG; ZHENG, JIHANG; ZHANG, PU; ZHOU, LINGLING; WU, LIANG; SHAN, YUNFENG; YE, MENGSI; HE, YUN; CAI, ZHENZHAI

    2016-01-01

    Recent studies suggest that latexin (Lxn) expression is involved in stem cell regulation and that it plays significant roles in tumor cell migration and invasion. The clinicopathological significance of Lxn expression and its possible correlation with CD133 expression in pancreatic ductal adenocarcinoma (PDAC) is currently unknown. In the present study, immunohistochemical analysis was performed to determine Lxn and CD133 expression in 43 PDAC patient samples and in 32 corresponding adjacent non-cancerous samples. The results were analyzed and compared with patient age, gender, tumor site and size, histological grade, clinical stage and overall mean survival time. Lxn expression was clearly decreased in the PDAC tissues compared with that in the adjacent non-cancerous tissues, while CD133 expression was increased. Low Lxn expression in the PDAC tissues was significantly correlated with tumor size (P=0.002), histological grade (P=0.000), metastasis (P=0.007) and clinical stage (P=0.018), but not with age (P=0.451), gender (P=0.395) or tumor site (P=0.697). Kaplan-Meier survival analysis revealed that low Lxn expression was significantly correlated with reduced overall survival time (P=0.000). Furthermore, Lxn expression was found to be inversely correlated with CD133 expression (r=−0.485, P=0.001). Furthermore, CD133-positive MIA PaCa-2 pancreatic tumor cells were sorted by magnetic-activated cell sorting (MACS), and those that overexpressed Lxn exhibited a significantly higher rate of apoptosis and lower proliferative activity. Our findings suggest that Lxn may function as a tumor suppressor that targets CD133-positive pancreatic cancer cells. PMID:26530530

  1. Identification of peptides that bind to irradiated pancreatic tumor cells

    SciTech Connect

    Huang Canhui; Liu, Xiang Y.; Rehemtulla, Alnawaz; Lawrence, Theodore S. . E-mail: tsl@med.umich.edu

    2005-08-01

    Purpose: Peptides targeting tumor vascular cells or tumor cells themselves have the potential to be used as vectors for delivering either DNA in gene therapy or antitumor agents in chemotherapy. We wished to determine if peptides identified by phage display could be used to target irradiated pancreatic cancer cells. Methods and Materials: Irradiated Capan-2 cells were incubated with 5 x 10{sup 12} plaque-forming units of a phage display library. Internalized phage were recovered and absorbed against unirradiated cells. After five such cycles of enrichment, the recovered phage were subjected to DNA sequencing analysis and synthetic peptides made. The binding of both phage and synthetic peptides was evaluated by fluorescence staining and flow cytometry in vitro and in vivo. Results: We identified one 12-mer peptide (PA1) that binds to irradiated Capan-2 pancreatic adenocarcinoma cells but not to unirradiated cells. The binding of peptide was significant after 48 h incubation with cells. In vivo experiments with Capan-2 xenografts in nude mice demonstrated that these small peptides are able to penetrate tumor tissue after intravenous injections and bind specifically to irradiated tumor cells. Conclusion: These data suggest that peptides can be identified that target tumors with radiation-induced cell markers and may be clinically useful.

  2. Origin of induced pancreatic islet tumors: a radioautographic study

    SciTech Connect

    Michels, J.E.; Bauer, G.E.; Dixit, P.K.

    1987-02-01

    Endocrine tumors of the pancreas are induced in a high percentage of young rats by injections of streptozotocin and nicotinamide (SZ/NA). Benign tumors first appear 20 to 36 weeks after drug injections. To determine the possible site of their origin, the incorporation of (/sup 3/H)thymidine into islets, ducts, acini, microtumors, and gross tumors was examined by radioautography of histologic sections at 1 to 36 weeks after drug injection. Drug treatment led to early (1- to 6-week) increases in nuclear /sup 3/H labeling of exocrine pancreatic structures (ductal and acinar cells), which may involve DNA repair processes. A secondary increase in labeling of duct cells during the period of tumor emergence supports the assumption that SZ/NA-induced tumors are of ductal origin. Microtumors and gross tumors also exhibited markedly elevated rates of (/sup 3/H)thymidine incorporation compared to control islets. Nontumorous islet tissue, which exhibited a gradual decrease in volume due to B-cell destruction by the drug injection, showed about 10-fold higher /sup 3/H labeling than islets of controls at all time points. The results suggest that in addition to ductal precursors, islets that survive SZ/NA-induced injury may also provide sites of focal endocrine cell differentiation to tumor tissue. Once established, both microtumors and gross tumors continue to grow by accelerated cell division.

  3. Variation of tumoral marker after radiofrequency ablation of pancreatic adenocarcinoma

    PubMed Central

    Barbi, Emilio; Girelli, Roberto; Tinazzi Martini, Paolo; De Robertis, Riccardo; Ciaravino, Valentina; Salvia, Roberto; Butturini, Giovanni; Frigerio, Isabella; Milazzo, Teresa; Crosara, Stefano; Paiella, Salvatore; Pederzoli, Paolo; Bassi, Claudio

    2016-01-01

    Background To evaluate the correlation between variations of CA 19.9 blood levels and the entity of necrosis at CT after radiofrequency ablation (RFA) of unresectable pancreatic adenocarcinoma. Methods In this study, from June 2010 to February 2014, patients with diagnosis of unresectable and not metastatic pancreatic ductal adenocarcinoma, expressing tumor marker CA 19.9, treated with RFA procedure were included. All these patients underwent RFA. CT study was performed 1 week after RFA. The dosage of CA 19.9 levels was performed 1 month after RFA. Features of necrosis at CT, as mean entity, density and necrosis percentages compared to the original lesion, were evaluated and compared by using t-test with CA 19.9 blood levels variations after RFA procedure. Results In this study were included 51 patients with diagnosis of unresectable and not metastatic pancreatic ductal adenocarcinoma, expressing tumor marker CA 19.9, treated with RFA procedure and with CT study and CA 19.9 available for analysis. After the procedure, CA 19.9 blood levels reduced in 24/51 (47%), remained stable in 10/51 (20%) and increased in 17/51 (33%). In patients with CA 19.9 levels reduced, the tumor marker were reduced less than 20% in 4/24 (17%) and more than 20% in 20/24 (83%); instead the tumor marker were reduced less than 30% in 8/24 (33%) and more than 30% in 16/24 (67%). At CT scan necrotic area density difference was not statistically significant. Also there was no statistically significant difference among the mean area, the mean volume and the mean ablation volume in percentage related to the treated tumor among the three different groups of patients divided depending on the CA 19.9 blood levels. But a tendency to a statistically significant difference was found in comparing the mean percentage of ablation volume between two subgroups of patients with a decrease of CA 19.9 levels with less or more than 20% reduction of tumor markers and between two subgroups with less or more than

  4. Multi-detector row CT of pancreatic islet cell tumors.

    PubMed

    Horton, Karen M; Hruban, Ralph H; Yeo, Charles; Fishman, Elliot K

    2006-01-01

    Pancreatic islet cell tumors (ICTs) are neuroendocrine neoplasms that produce and secrete hormones to a variable degree. These neoplasms can present a diagnostic challenge, both clinically and radiologically. ICTs can be classified as either syndromic or nonsyndromic on the basis of their clinical manifestations. Multi-detector row computed tomography (CT) plays an important role in the diagnosis and staging of both syndromic and nonsyndromic ICTs. In general, syndromic ICTs are less than 3 cm in size. They are typically hyperenhancing and are usually best seen on CT scans obtained during the arterial phase. Nonsyndromic ICTs tend to be larger than syndromic ICTs at presentation and are more likely to be cystic or necrotic. It is important for the radiologist to be familiar with appropriate CT protocol for the evaluation of patients with suspected pancreatic ICT and to understand the variable CT appearances of these neoplasms. PMID:16549609

  5. On using an adaptive neural network to predict lung tumor motion during respiration for radiotherapy applications

    SciTech Connect

    Isaksson, Marcus; Jalden, Joakim; Murphy, Martin J.

    2005-12-15

    In this study we address the problem of predicting the position of a moving lung tumor during respiration on the basis of external breathing signals--a technique used for beam gating, tracking, and other dynamic motion management techniques in radiation therapy. We demonstrate the use of neural network filters to correlate tumor position with external surrogate markers while simultaneously predicting the motion ahead in time, for situations in which neither the breathing pattern nor the correlation between moving anatomical elements is constant in time. One pancreatic cancer patient and two lung cancer patients with mid/upper lobe tumors were fluoroscopically imaged to observe tumor motion synchronously with the movement of external chest markers during free breathing. The external marker position was provided as input to a feed-forward neural network that correlated the marker and tumor movement to predict the tumor position up to 800 ms in advance. The predicted tumor position was compared to its observed position to establish the accuracy with which the filter could dynamically track tumor motion under nonstationary conditions. These results were compared to simplified linear versions of the filter. The two lung cancer patients exhibited complex respiratory behavior in which the correlation between surrogate marker and tumor position changed with each cycle of breathing. By automatically and continuously adjusting its parameters to the observations, the neural network achieved better tracking accuracy than the fixed and adaptive linear filters. Variability and instability in human respiration complicate the task of predicting tumor position from surrogate breathing signals. Our results show that adaptive signal-processing filters can provide more accurate tumor position estimates than simpler stationary filters when presented with nonstationary breathing motion.

  6. Cyclopamine disrupts tumor extracellular matrix and improves the distribution and efficacy of nanotherapeutics in pancreatic cancer.

    PubMed

    Zhang, Bo; Jiang, Ting; Shen, Shun; She, Xiaojian; Tuo, Yanyan; Hu, Yu; Pang, Zhiqing; Jiang, Xinguo

    2016-10-01

    The dense extracellular matrix in pancreatic ductal adenocarcinoma dramatically reduces the penetration and efficacy of nanotherapeutics. Disruption of the tumor extracellular matrix may help improve the distribution and efficacy of nanotherapeutics in pancreatic cancer. In this study, we tested whether cyclopamine, a special inhibitor of the hedgehog signaling pathway with powerful anti-fibrotic activity, could promote the penetration and efficacy of nanotherapeutics in pancreatic cancer. It was shown that cyclopamine disrupted tumor extracellular fibronectins, decompressed tumor blood vessels, and improved tumor perfusion. Furthermore, cyclopamine improved the accumulation and intratumoral distribution of i.v.-administered fluorescence indicator-labeled nanoparticles. Finally, cyclopamine also significantly improved the tumor growth inhibition effect of i.v.-injected nanotherapeutics in pancreatic tumor xenograft mouse models. Thus, cyclopamine may have great potential to improve the therapeutic effects of nanomedicine in patients with pancreatic cancer. PMID:27376555

  7. Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report.

    PubMed

    Duffy, M J; Sturgeon, C; Lamerz, R; Haglund, C; Holubec, V L; Klapdor, R; Nicolini, A; Topolcan, O; Heinemann, V

    2010-03-01

    Pancreatic ductal adenocarcinoma is one of the most difficult malignancies to diagnose and treat. The aim of this article is to review how tumor markers can aid the diagnosis and management of patients with this malignancy. The most widely used and best validated marker for pancreatic cancer is CA 19-9. Inadequate sensitivity and specificity limit the use of CA 19-9 in the early diagnosis of pancreatic cancer. In non-jaundiced patients, however, CA 19-9 may complement other diagnostic procedures. In patients with resectable pancreatic cancer, presurgical and postresection CA 19-9 levels correlate with overall survival. In advanced disease, elevated pretreatment levels of CA 19-9 are associated with adverse patient outcome and thus may be combined with other factors for risk stratification. Most, but not all, reports indicate that serial levels of CA 19-9 correlate with response to systemic therapy. Use of CA 19-9 kinetics in conjunction with imaging is therefore recommended in monitoring therapy. Although several potential serum and tissue markers for pancreatic cancer are currently undergoing evaluation, none are sufficiently validated for routine clinical use. CA 19-9 thus remains the serum pancreatic cancer marker against which new markers for this malignancy should be judged. PMID:19690057

  8. Epigenetic silencing of EYA2 in pancreatic adenocarcinomas promotes tumor growth

    PubMed Central

    Vincent, Audrey; Hong, Seung-Mo; Hu, Chaoxin; Omura, Noriyuki; Young, Angela; Kim, Haeryoung; Yu, Jun; Knight, Spencer; Ayars, Michael; Griffith, Margaret; Van Seuningen, Isabelle; Maitra, Anirban; Goggins, Michael

    2014-01-01

    To identify potentially important genes dysregulated in pancreatic cancer, we analyzed genome-wide transcriptional analysis of pancreatic cancers and normal pancreatic duct samples and identified the transcriptional coactivator, EYA2 (Drosophila Eyes Absent Homologue-2) as silenced in the majority of pancreatic cancers. We investigated the role of epigenetic mechanisms of EYA2 gene silencing in pancreatic cancers, performed in vitro and in vivo proliferation and migration assays to assess the effect of EYA2 silencing on tumor cell growth and metastasis formation, and expression analysis to identify genes transcriptionally regulated by EYA2. We found loss of tumoral Eya2 expression in 63% of pancreatic cancers (120/189 cases). Silencing of EYA2 expression in pancreatic cancer cell lines correlated with promoter methylation and histone deacetylation and was reversible with DNA methyltransferase and HDAC inhibitors. EYA2 knockdown in pancreatic cancer cell lines increased cell proliferation. Compared to parental pancreatic cancer cells, pancreatic cancers stably-expressing EYA2 grew more slowly and had fewer metastases in orthotopic models. The transcriptional changes after stable expression of EYA2 in pancreatic cancer cells included induction of genes in the TGFbeta pathway. Epigenetic silencing of EYA2 is a common event in pancreatic cancers and stable expression EYA2 limits the growth and metastases of pancreatic adenocarcinoma. PMID:24810906

  9. Surgical Treatment and Clinical Outcome of Nonfunctional Pancreatic Neuroendocrine Tumors

    PubMed Central

    Yang, Min; Zeng, Lin; Zhang, Yi; Su, An-ping; Yue, Peng-ju; Tian, Bo-le

    2014-01-01

    Abstract Our primary aim of the present study was to analyze the clinical characteristics and surgical outcome of nonfunctional pancreatic neuroendocrine tumors (non-F-P-NETs), with an emphasis on evaluating the prognostic value of the newly updated 2010 grading classification of the World Health Organization (WHO). Data of 55 consecutive patients who were surgically treated and pathologically diagnosed as non-F-P-NETs in our single institution from January 2000 to December 2013 were retrospectively collected. This entirety comprised of 55 patients (31 males and 24 females), with a mean age of 51.24 ± 12.95 years. Manifestations of non-F-P-NETs were nonspecific. Distal pancreatectomy, pancreaticoduodenectomy, and local resection of pancreatic tumor were the most frequent surgical procedures, while pancreatic fistula was the most common but acceptable complication (30.3%). The overall 5-year survival rate of this entire cohort was 41.0%, with a median survival time of 60.4 months. Patients who underwent R0 resections obtained a better survival than those who did not (P < 0.005). As for the prognostic analysis, tumor size and lymph invasion were only statistically significant in univariate analysis (P = 0.046 and P < 0.05, respectively), whereas the newly updated 2010 grading classification of WHO (G1 and G2 vs G3), distant metastasis, and surgical margin were all meaningful in both univariate and multivariate analysis (P = 0.045, 0.001, and 0.042, respectively). Non-F-P-NETs are a kind of rare neoplasm, with mostly indolent malignancy. Patients with non-F-P-NETs could benefit from the radical resections. The new WHO criteria, distant metastasis and surgical margin, might be independent predictors for the prognosis of non-F-P-NETs. PMID:25396335

  10. Suppression of CD51 in pancreatic stellate cells inhibits tumor growth by reducing stroma and altering tumor-stromal interaction in pancreatic cancer.

    PubMed

    Horioka, Kohei; Ohuchida, Kenoki; Sada, Masafumi; Zheng, Biao; Moriyama, Taiki; Fujita, Hayato; Manabe, Tatsuya; Ohtsuka, Takao; Shimamoto, Masaya; Miyazaki, Tetsuyuki; Mizumoto, Kazuhiro; Oda, Yoshinao; Nakamura, Masafumi

    2016-04-01

    Pancreatic stellate cells (PSCs) enhance the malignant behavior of pancreatic cancer by interacting with cancer cells and producing extracellular matrix (ECM). To date, several stroma-targeted therapies for pancreatic cancer have been attempted, but these therapies are still not in practical use. Integrins expressed in stromal cells are involved in fibrosis of several organs, as well as promoting tumor malignancy. We investigated whether CD51, also known as integrin αV, expressed in PSCs was associated with stromal formation of pancreatic cancer and enhancement of tumor malignancy. We also assessed the effects of suppression of CD51 in PSCs on pancreatic cancer. Immunohistochemistry for CD51 in resected pancreatic cancer tissues showed that high expression of CD51 in the tumor stroma was associated with lymph node metastasis (P=0.025), positive pathologic margin (P=0.025), and shorter patient survival times (P=0.043). Lentivirus-mediated short hairpin RNA knockdown of CD51 decreased the proliferation and migration of PSCs. Quantitative real-time polymerase chain reaction showed that expression levels of genes related with ECM and tumor-stromal interactions were decreased by CD51 knockdown in PSCs. In a co-implantation model of pancreatic cancer cells and PSCs, tumor growth in vivo was inhibited by CD51 knockdown in PSCs (P<0.05). We also found reduced tumor stroma and decreased proliferation of cancer cells in implanted cancer tissues with CD51-silenced PSCs (P<0.05). Our results showed that CD51 expression in pancreatic cancer stroma is associated with enhanced tumor malignancy and that CD51 may be a potential therapeutic target for pancreatic cancer. PMID:26846197

  11. Clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors

    PubMed Central

    Furukori, Mariko; Imai, Koji; Karasaki, Hidenori; Watanabe, Kenji; Oikawa, Kensuke; Miyokawa, Naoyuki; Taniguchi, Masahiko; Furukawa, Hiroyuki

    2014-01-01

    AIM: To present our experiences in studying the clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs). METHODS: The subjects included 9 patients with NF-pNETs who underwent pancreatectomy between April 1996 and September 2012. The surgical procedure, histopathological findings, and prognosis were assessed. RESULTS: All tumors were incidentally detected by computed tomography. The median diameter was 10 mm (5-32 mm). One patient was diagnosed with von Hippel-Lindau disease, and the others were sporadic cases. For the histopathological findings, 7 patients were G1; 1 patient was G2; and 1 patient, whose tumor was 22 mm, had neuroendocrine carcinoma (NEC). One patient who had a tumor that was 32 mm had direct invasion to a regional lymph node and 1 patient with NEC, had regional lymph node metastases. Six of the 7 patients with sporadic NF-pNETs, excluding the patient with NEC, had tumors that were smaller than 10 mm. Tumors smaller than 10 mm showed no malignancy and lacked lymph node metastasis. CONCLUSION: Sporadic NF-pNETs smaller than 10 mm tend to have less malignant potential. These findings suggest that lymphadenectomy may be omitted for small NF-pNETs after further investigation. PMID:25548493

  12. Statistical analysis and correlation discovery of tumor respiratory motion.

    PubMed

    Wu, Huanmei; Sharp, Gregory C; Zhao, Qingya; Shirato, Hiroki; Jiang, Steve B

    2007-08-21

    Tumors, especially in the thorax and abdomen, are subject to respiratory motion, and understanding the structure of respiratory motion is a key component to the management and control of disease in these sites. We have applied statistical analysis and correlation discovery methods to analyze and mine tumor respiratory motion based on a finite state model of tumor motion. Aggregates (such as minimum, maximum, average and mean), histograms, percentages, linear regression and multi-round statistical analysis have been explored. The results have been represented in various formats, including tables, graphs and text description. Different graphs, for example scatter plots, clustered column figures, 100% stacked column figures and box-whisker plots, have been applied to highlight different aspects of the results. The internal tumor motion from 42 lung tumors, 30 of which have motion larger than 5 mm, has been analyzed. Results for both inter-patient and intra-patient motion characteristics, such as duration and travel distance patterns, are reported. New knowledge of patient-specific tumor motion characteristics have been discovered, such as expected correlations between properties. The discovered tumor motion characteristics will be utilized in different aspects of image-guided radiation treatment, including treatment planning, online tumor motion prediction and real-time radiation dose delivery. PMID:17671334

  13. Statistical analysis and correlation discovery of tumor respiratory motion

    NASA Astrophysics Data System (ADS)

    Wu, Huanmei; Sharp, Gregory C.; Zhao, Qingya; Shirato, Hiroki; Jiang, Steve B.

    2007-08-01

    Tumors, especially in the thorax and abdomen, are subject to respiratory motion, and understanding the structure of respiratory motion is a key component to the management and control of disease in these sites. We have applied statistical analysis and correlation discovery methods to analyze and mine tumor respiratory motion based on a finite state model of tumor motion. Aggregates (such as minimum, maximum, average and mean), histograms, percentages, linear regression and multi-round statistical analysis have been explored. The results have been represented in various formats, including tables, graphs and text description. Different graphs, for example scatter plots, clustered column figures, 100% stacked column figures and box-whisker plots, have been applied to highlight different aspects of the results. The internal tumor motion from 42 lung tumors, 30 of which have motion larger than 5 mm, has been analyzed. Results for both inter-patient and intra-patient motion characteristics, such as duration and travel distance patterns, are reported. New knowledge of patient-specific tumor motion characteristics have been discovered, such as expected correlations between properties. The discovered tumor motion characteristics will be utilized in different aspects of image-guided radiation treatment, including treatment planning, online tumor motion prediction and real-time radiation dose delivery.

  14. The diaphragm as an anatomic surrogate for lung tumor motion

    NASA Astrophysics Data System (ADS)

    Cerviño, Laura I.; Chao, Alvin K. Y.; Sandhu, Ajay; Jiang, Steve B.

    2009-06-01

    Lung tumor motion due to respiration poses a challenge in the application of modern three-dimensional conformal radiotherapy. Direct tracking of the lung tumor during radiation therapy is very difficult without implanted fiducial markers. Indirect tracking relies on the correlation of the tumor's motion and the surrogate's motion. The present paper presents an analysis of the correlation between tumor motion and diaphragm motion in order to evaluate the potential use of diaphragm as a surrogate for tumor motion. We have analyzed the correlation between diaphragm motion and superior-inferior lung tumor motion in 32 fluoroscopic image sequences from ten lung cancer patients. A simple linear model and a more complex linear model that accounts for phase delays between the two motions have been used. Results show that the diaphragm is a good surrogate for tumor motion prediction for most patients, resulting in an average correlation factor of 0.94 and 0.98 with each model respectively. The model that accounts for delays leads to an average localization prediction error of 0.8 mm and an error at the 95% confidence level of 2.1 mm. However, for one patient studied, the correlation is much weaker compared to other patients. This indicates that, before using diaphragm for lung tumor prediction, the correlation should be examined on a patient-by-patient basis.

  15. Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors.

    PubMed

    Bonnavion, Rémy; Teinturier, Romain; Jaafar, Rami; Ripoche, Doriane; Leteurtre, Emmanuelle; Chen, Yuan-Jia; Rehfeld, Jens F; Lepinasse, Florian; Hervieu, Valérie; Pattou, François; Vantyghem, Marie-Christine; Scoazec, Jean-Yves; Bertolino, Philippe; Zhang, Chang Xian

    2015-10-01

    The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from embryonic day 12.5 until postnatal day 7, are derived from pancreatic Ptf1a(+) and neurogenin 3-expressing (Ngn3(+)) progenitors. Importantly, the majority of them coexpress glucagon, with 4% coexpressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic endocrine tumors (pNETs) that have not been diagnosed as gastrinomas (in 9/34 pNETs from 6/14 patients with multiple endocrine neoplasia type 1, in 5/35 sporadic nonfunctioning pNETs, and in 2/20 sporadic insulinomas), consistent with observations made in mouse models. Our work provides insight into the histogenesis of pancreatic gastrin-expressing tumors. PMID:26169832

  16. Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors

    PubMed Central

    Bonnavion, Rémy; Teinturier, Romain; Jaafar, Rami; Ripoche, Doriane; Leteurtre, Emmanuelle; Chen, Yuan-Jia; Rehfeld, Jens F.; Lepinasse, Florian; Hervieu, Valérie; Pattou, François; Vantyghem, Marie-Christine; Scoazec, Jean-Yves; Bertolino, Philippe

    2015-01-01

    The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from embryonic day 12.5 until postnatal day 7, are derived from pancreatic Ptf1a+ and neurogenin 3-expressing (Ngn3+) progenitors. Importantly, the majority of them coexpress glucagon, with 4% coexpressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic endocrine tumors (pNETs) that have not been diagnosed as gastrinomas (in 9/34 pNETs from 6/14 patients with multiple endocrine neoplasia type 1, in 5/35 sporadic nonfunctioning pNETs, and in 2/20 sporadic insulinomas), consistent with observations made in mouse models. Our work provides insight into the histogenesis of pancreatic gastrin-expressing tumors. PMID:26169832

  17. Pancreatic neuroendocrine tumor accompanied with multiple liver metastases

    PubMed Central

    Hori, Tomohide; Takaori, Kyoichi; Uemoto, Shinji

    2014-01-01

    Pancreatic neuroendocrine tumor (P-NET) is rare and slow-growing. Current classifications predict its prognosis and postoperative recurrence. Curative resection is ideal, although often difficult, because over 80% of patients have unresectable multiple liver metastases and extrahepatic metastasis. Aggressive surgery for liver metastases is important to improve survival. Aggressive or cytoreductive surgery for liver metastases is indicated to reduce hormone levels and improve symptoms and prognosis. Liver transplantation was originally conceived as an ideal therapy for unresectable liver metastases. Unfortunately, there is no clear consensus on the role and timing of surgery for primary tumor and liver metastases. Surgeons still face questions in deciding the best surgical scenario in patients with P-NET with unresectable liver metastases. PMID:25232452

  18. Biotherapy of pancreatic neuroendocrine tumors using somatostatin analogs.

    PubMed

    Igarashi, Hisato; Hijioka, Masayuki; Lee, Lingaku; Ito, Tetsuhide

    2015-08-01

    Basically, pancreatic neuroendocrine tumor (PNET) should be treated surgically; however, in unresectable cases, a treatment that aims to improve the prognosis by inhibiting the growth of the tumor and control the clinical symptoms becomes necessary. In the case of functional tumors, the quality of life of patients is decreased by not only the symptoms with tumor invasion and/or metastasis but also by the symptoms of hormone excess. The efficacy of somatostatin analogs against the latter has been previously reported, and their sustained release formulations have been developed. Somatostatin analogs are recommended to treat the endocrine symptoms of functional PNET; however, in case they can cause hypoglycemia in patients with insulinoma. On the other hand, results from the PROMID study demonstrated a tumor-stabilizing effect when octreotide LAR (long acting repeatable) was used to treat patients with advanced midgut NET; however, there has been no consensus regarding its antitumor effect for PNET. Additionally, a recent result from the CLARINET study suggests that lanreotide autogel has an antitumor effect against nonfunctional NET including PNET. Further clinical study results are awaited. PMID:25689143

  19. Diabetic ketoacidosis with concurrent pancreatitis, pancreatic β islet cell tumor, and adrenal disease in an obese ferret (Mustela putorius furo).

    PubMed

    Phair, Kristen A; Carpenter, James W; Schermerhorn, Thomas; Ganta, Chanran K; DeBey, Brad M

    2011-07-01

    A 5.5-y-old spayed female ferret (Mustela putorius furo) with a history of adrenal disease, respiratory disease, and chronic obesity was evaluated for progressive lethargy and ataxia, diminished appetite, and possible polyuria and polydipsia. Physical examination revealed obesity, lethargy, tachypnea, dyspnea, a pendulous abdomen, significant weakness and ataxia of the hindlimbs, prolonged skin tenting, and mild tail-tip alopecia. Clinicopathologic analysis revealed severe hyperglycemia, azotemia, an increased anion gap, glucosuria, ketonuria, proteinuria, and hematuria. Abdominal ultrasonography showed hyperechoic hepatomegaly, bilateral adrenomegaly, splenic nodules, mild peritoneal effusion, and thickened and mildly hypoechoic limbs of the pancreas with surrounding hyperechoic mesentery. Fine-needle aspirates of the liver were highly suggestive of hepatic lipidosis. In light of a diagnosis of concurrent diabetic ketoacidosis and pancreatitis, the ferret was treated with fluid therapy, regular and long-acting insulin administration, and pain medication. However, electrolyte derangements, metabolic acidosis, dyspnea, and the clinical appearance of the ferret progressively worsened despite treatment, and euthanasia was elected. Necropsy revealed severe hepatic lipidosis, severe suppurative pancreatitis and vacuolar degeneration of pancreatic islet cells, a pancreatic β islet cell tumor, bilateral adrenal cortical adenomas, and myocardial fibrosis. To our knowledge, this case represents the first report of concurrent diabetes mellitus, pancreatitis, pancreatic β islet cell tumor (insulinoma), and adrenal disease in a domestic ferret. The simultaneous existence of 3 endocrine diseases, pancreatitis, and their associated complications is a unique and clinically challenging situation. PMID:21838985

  20. Diabetic Ketoacidosis with Concurrent Pancreatitis, Pancreatic β Islet Cell Tumor, and Adrenal Disease in an Obese Ferret (Mustela putorius furo)

    PubMed Central

    Phair, Kristen A; Carpenter, James W; Schermerhorn, Thomas; Ganta, Chanran K; DeBey, Brad M

    2011-01-01

    A 5.5-y-old spayed female ferret (Mustela putorius furo) with a history of adrenal disease, respiratory disease, and chronic obesity was evaluated for progressive lethargy and ataxia, diminished appetite, and possible polyuria and polydipsia. Physical examination revealed obesity, lethargy, tachypnea, dyspnea, a pendulous abdomen, significant weakness and ataxia of the hindlimbs, prolonged skin tenting, and mild tail-tip alopecia. Clinicopathologic analysis revealed severe hyperglycemia, azotemia, an increased anion gap, glucosuria, ketonuria, proteinuria, and hematuria. Abdominal ultrasonography showed hyperechoic hepatomegaly, bilateral adrenomegaly, splenic nodules, mild peritoneal effusion, and thickened and mildly hypoechoic limbs of the pancreas with surrounding hyperechoic mesentery. Fine-needle aspirates of the liver were highly suggestive of hepatic lipidosis. In light of a diagnosis of concurrent diabetic ketoacidosis and pancreatitis, the ferret was treated with fluid therapy, regular and long-acting insulin administration, and pain medication. However, electrolyte derangements, metabolic acidosis, dyspnea, and the clinical appearance of the ferret progressively worsened despite treatment, and euthanasia was elected. Necropsy revealed severe hepatic lipidosis, severe suppurative pancreatitis and vacuolar degeneration of pancreatic islet cells, a pancreatic β islet cell tumor, bilateral adrenal cortical adenomas, and myocardial fibrosis. To our knowledge, this case represents the first report of concurrent diabetes mellitus, pancreatitis, pancreatic β islet cell tumor (insulinoma), and adrenal disease in a domestic ferret. The simultaneous existence of 3 endocrine diseases, pancreatitis, and their associated complications is a unique and clinically challenging situation. PMID:21838985

  1. Management of pancreatic neuroendocrine tumors in patients with MEN 1

    PubMed Central

    Sadowski, Samira M.

    2015-01-01

    Pancreatic neuroendocrine tumors (PNETs) are frequent and can be non-functional (NF) in patients with multiple endocrine neoplasia type 1 (MEN1). Their identification is of clinical importance because malignant PNETs are reported to be the most common cause of death in patients with MEN1. Once the diagnosis of MEN1 is established in an individual based on clinical manifestations and/or genetic testing results, an active surveillance program is instituted for early detection and treatment of MEN1-associated disease. Ultrasonography, endoscopic ultrasonography (EUS), CT, MRI, selective arterial angiography and somatostatin receptor scintigraphy are all used for localization of tumors. Managing PNETs can be challenging and includes diagnosis, surveillance, adequate staging, and interdisciplinary, multimodal treatments to optimize patient outcome. Treatment includes surgical resection for loco-regional disease, as well as liver directed and targeted chemotherapies for advanced progressive disease. To date, the recommendation for surgical resection in NF-PNETs is based on tumor size, as a higher rate of metastases was found in patients with larger tumors. This review summarizes key concepts in managing PNETs in patients with MEN1. PMID:25713781

  2. Antibody against CD44s Inhibits Pancreatic Tumor Initiation and Post-Radiation Recurrence in Mice

    PubMed Central

    Li, Ling; Hao, Xinbao; Qin, Jun; Tang, Wenhua; He, Fengtian; Smith, Amber; Zhang, Min; Simeone, Diane M.; Qiao, Xiaotan T.; Chen, Zhi-Nan; Lawrence, Theodore S.; Xu, Liang

    2014-01-01

    Background & Aims CD44s is a surface marker of tumor-initiating cells (TICs); high tumor levels correlate with metastasis and recurrence, as well as poor outcomes of patients. Monoclonal antibodies against CD44s might eliminate TICs with minimal toxicity. This strategy is unclear for treatment of pancreatic cancer, and little is known about how anti-CD44s affect pancreatic cancer initiation or recurrence after radiotherapy. Methods 192 pairs of human pancreatic adenocarcinoma and adjacent non-tumor pancreatic tissues were collected from patients undergoing surgery. We measured CD44s levels in tissue samples and pancreatic cancer cell lines by immunohistochemistry, real-time PCR and immunoblot; levels were correlated with patient survival times. We studied the effects of anti-CD44s in mice with human pancreatic tumor xenografts, and used flow cytometry to determine effects on TICs. Changes in CD44s signaling were examined by real-time PCR, immunoblot, reporter assay, and in vitro tumorsphere formation assays. Results Levels of CD44s were significantly higher in pancreatic cancer than adjacent non-tumor tissues. Patients whose tumors expressed high levels of CD44s had a median survival of 10 months, compared to 43 months for those with low levels. Anti-CD44s reduced growth, metastasis, and post-radiation recurrence of pancreatic xenograft tumors in mice. The antibody reduced the number of TICs in cultured pancreatic cancer cells and in xenograft tumors, as well as their tumorigenicity. In cultured pancreatic cancer cell lines, anti-CD44s downregulated the stem cell self-renewal genes Nanog, Sox-2, and Rex-1 and inhibited STAT3-mediated cell proliferation and survival signaling. Conclusions The TIC marker CD44s is upregulated in human pancreatic tumors and associated with patient survival time. CD44s is required for initiation, growth, metastasis, and post-radiation recurrence of xenograft tumors in mice. Anti-CD44s eliminated bulk tumor cells as well as TICs from the

  3. Modulation of the Leptin Receptor Mediates Tumor Growth and Migration of Pancreatic Cancer Cells

    PubMed Central

    Chalfant, Madeleine C.; Gorden, Lee D.

    2015-01-01

    Obesity has been implicated as a significant risk factor for development of pancreatic cancer. In the setting of obesity, a systemic chronic inflammatory response is characterized by alterations in the production and secretion of a wide variety of growth factors. Leptin is a hormone whose level increases drastically in the serum of obese patients. High fat diet induced obesity in mice leads to an overall increased body weight, pancreatic weight, serum leptin, and pancreatic tissue leptin levels. Here we report the contribution of obesity and leptin to pancreatic cancer growth utilizing an in vivo orthotopic murine pancreatic cancer model, which resulted in increased tumor proliferation with concomitant increased tumor burden in the diet induced obese mice compared to lean mice. Human and murine pancreatic cancer cell lines were found to express the short as well as the long form of the leptin receptor and functionally responded to leptin induced activation through an increased phosphorylation of AKT473. In vitro, leptin stimulation increased cellular migration which was blocked by addition of a PI3K inhibitor. In vivo, depletion of the leptin receptor through shRNA knockdown partially abrogated increased orthotopic tumor growth in obese mice. These findings suggest that leptin contributes to pancreatic tumor growth through activation of the PI3K/AKT pathway, which promotes pancreatic tumor cell migration. PMID:25919692

  4. MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors.

    PubMed

    Cros, J; Hentic, O; Rebours, V; Zappa, M; Gille, N; Theou-Anton, N; Vernerey, D; Maire, F; Lévy, P; Bedossa, P; Paradis, V; Hammel, P; Ruszniewski, P; Couvelard, A

    2016-08-01

    Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27-84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15-0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29-1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease. PMID:27353036

  5. Transcriptional dissection of pancreatic tumors engrafted in mice

    PubMed Central

    2014-01-01

    Background Engraftment of primary pancreas ductal adenocarcinomas (PDAC) in mice to generate patient-derived xenograft (PDX) models is a promising platform for biological and therapeutic studies in this disease. However, these models are still incompletely characterized. Here, we measured the impact of the murine tumor environment on the gene expression of the engrafted human tumoral cells. Methods We have analyzed gene expression profiles from 35 new PDX models and compared them with previously published microarray data of 18 PDX models, 53 primary tumors and 41 cell lines from PDAC. The results obtained in the PDAC system were further compared with public available microarray data from 42 PDX models, 108 primary tumors and 32 cell lines from hepatocellular carcinoma (HCC). We developed a robust analysis protocol to explore the gene expression space. In addition, we completed the analysis with a functional characterization of PDX models, including if changes were caused by murine environment or by serial passing. Results Our results showed that PDX models derived from PDAC, or HCC, were clearly different to the cell lines derived from the same cancer tissues. Indeed, PDAC- and HCC-derived cell lines are indistinguishable from each other based on their gene expression profiles. In contrast, the transcriptomes of PDAC and HCC PDX models can be separated into two different groups that share some partial similarity with their corresponding original primary tumors. Our results point to the lack of human stromal involvement in PDXs as a major factor contributing to their differences from the original primary tumors. The main functional differences between pancreatic PDX models and human PDAC are the lower expression of genes involved in pathways related to extracellular matrix and hemostasis and the up- regulation of cell cycle genes. Importantly, most of these differences are detected in the first passages after the tumor engraftment. Conclusions Our results suggest

  6. Abdominal and pancreatic motion correlation using 4D CT, 4D transponders, and a gating belt.

    PubMed

    Betancourt, Ricardo; Zou, Wei; Plastaras, John P; Metz, James M; Teo, Boon-Keng; Kassaee, Alireza

    2013-01-01

    The correlation between the pancreatic and external abdominal motion due to respiration was investigated on two patients. These studies utilized four dimensional computer tomography (4D CT), a four dimensional (4D) electromagnetic transponder system, and a gating belt system. One 4D CT study was performed during simulation to quantify the pancreatic motion using computer tomography images at eight breathing phases. The motion under free breathing and breath-hold were analyzed for the 4D electromagnetic transponder system and the gating belt system during treatment. A linear curve was fitted for all data sets and correlation factors were evaluated between the 4D electromagnetic transponder system and the gating belt system data. The 4D CT study demonstrated a modest correlation between the external marker and the pancreatic motion with R-square values larger than 0.8 for the inferior-superior (inf-sup). Then, the relative pressure from the belt gating system correlated well with the 4D electromagnetic transponder system's motion in the anterior-posterior (ant-post) and the inf-post directions. These directions have a correlation value of -0.93 and 0.76, while the lateral only had a 0.03 correlation coefficient. Based on our limited study, external surrogates can be used as predictors of the pancreatic motion in the inf-sup and the ant-post directions. Although there is a low correlation on the lateral direction, its motion is significantly shorter. In conclusion, an appropriate treatment delivery can be used for pancreatic cancer when an internal tracking system, such as the 4D electromagnetic transponder system, is unavailable. PMID:23652242

  7. Feasibility of Electromagnetic Transponder Use to Monitor Inter- and Intrafractional Motion in Locally Advanced Pancreatic Cancer Patients

    SciTech Connect

    Shinohara, Eric T.; Kassaee, Alireza; Mitra, Nandita; Vapiwala, Neha; Plastaras, John P.; Drebin, Jeff; Wan, Fei; Metz, James M.

    2012-06-01

    Purpose: The primary objective of this study was to determine the feasibility of electromagnetic transponder implantation in patients with locally advanced unresectable pancreatic cancer. Secondarily, the use of transponders to monitor inter- and intrafractional motion, and the efficacy of breath holding for limiting target motion, were examined. Methods and Materials: During routine screening laparoscopy, 5 patients without metastatic disease were implanted with transponders peri-tumorally. The Calypso System's localization and tracking modes were used to monitor inter- and intrafractional motion, respectively. Intrafractional motion, with and without breath holding, was also examined using Calypso tracking mode. Results: Transponder implantation was well tolerated in all patients, with minimal migration, aside from 1 patient who expulsed a single transponder. Interfractional motion based on mean shifts from setup using tattoos/orthogonal imaging to transponder based localization from 164 treatments was significant in all dimensions. Mean shift (in millimeters), followed by the standard deviation and p value, were as follows: X-axis: 4.5 mm (1.0, p = 0.01); Y axis: 6.4 mm (1.9, p = 0.03); and Z-axis 3.9 mm (0.6, p = 0.002). Mean intrafractional motion was also found to be significant in all directions: superior, 7.2 mm (0.9, p = 0.01); inferior, 11.9 mm (0.9, p < 0.01); anterior: 4.9 mm (0.5, p = 0.01); posterior, 2.9 mm (0.5, p = 0.02); left, 2.2 mm (0.4, p = 0.02); and right, 3.1 mm (0.6, p = 0.04). Breath holding during treatment significantly decreased tumor motion in all directions. Conclusions: Electromagnetic transponder implantation appears to be safe and effective for monitoring inter- and intrafractional motion. Based on these results a larger clinical trial is underway.

  8. PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors.

    PubMed

    Ohki, Rieko; Saito, Kozue; Chen, Yu; Kawase, Tatsuya; Hiraoka, Nobuyoshi; Saigawa, Raira; Minegishi, Maiko; Aita, Yukie; Yanai, Goichi; Shimizu, Hiroko; Yachida, Shinichi; Sakata, Naoaki; Doi, Ryuichiro; Kosuge, Tomoo; Shimada, Kazuaki; Tycko, Benjamin; Tsukada, Toshihiko; Kanai, Yae; Sumi, Shoichiro; Namiki, Hideo; Taya, Yoichi; Shibata, Tatsuhiro; Nakagama, Hitoshi

    2014-06-10

    The molecular mechanisms underlying the development of pancreatic neuroendocrine tumors (PanNETs) have not been well defined. We report here that the genomic region of the PHLDA3 gene undergoes loss of heterozygosity (LOH) at a remarkably high frequency in human PanNETs, and this genetic change is correlated with disease progression and poor prognosis. We also show that the PHLDA3 locus undergoes methylation in addition to LOH, suggesting that a two-hit inactivation of the PHLDA3 gene is required for PanNET development. We demonstrate that PHLDA3 represses Akt activity and Akt-regulated biological processes in pancreatic endocrine tissues, and that PHLDA3-deficient mice develop islet hyperplasia. In addition, we show that the tumor-suppressing pathway mediated by MEN1, a well-known tumor suppressor of PanNETs, is dependent on the pathway mediated by PHLDA3, and inactivation of PHLDA3 and MEN1 cooperatively contribute to PanNET development. Collectively, these results indicate the existence of a novel PHLDA3-mediated pathway of tumor suppression that is important in the development of PanNETs. PMID:24912192

  9. TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis.

    PubMed

    Principe, Daniel R; DeCant, Brian; Mascariñas, Emman; Wayne, Elizabeth A; Diaz, Andrew M; Akagi, Naomi; Hwang, Rosa; Pasche, Boris; Dawson, David W; Fang, Deyu; Bentrem, David J; Munshi, Hidayatullah G; Jung, Barbara; Grippo, Paul J

    2016-05-01

    In early pancreatic carcinogenesis, TGFβ acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGFβ appears to promote tumor progression. Therefore, to better understand the contributions of TGFβ signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency. We found that epithelial suppression of TGFβ signals facilitated pancreatic tumorigenesis, whereas global loss of TGFβ signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGFβ1 production, and the resultant restoration of antitumor immune function. Similarly, TGFBR-deficient T cells resisted TGFβ-induced inactivation ex vivo, and adoptive transfer of TGFBR-deficient CD8(+) T cells led to enhanced infiltration and granzyme B-mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGFβ expression correlated with increased fibrosis and associated negatively with expression of granzyme B. Collectively, our findings suggest that, despite opposing the proliferation of some epithelial cells, TGFβ may promote pancreatic cancer development by affecting stromal and hematopoietic cell function. Therefore, the use of TGFBR inhibition to target components of the tumor microenvironment warrants consideration as a potential therapy for pancreatic cancer, particularly in patients who have already lost tumor-suppressive TGFβ signals in the epithelium. Cancer Res; 76(9); 2525-39. ©2016 AACR. PMID:26980767

  10. Acute Pancreatitis and Gastroduodenal Intussusception Induced by an Underlying Gastric Gastrointestinal Stromal Tumor: A Case Report

    PubMed Central

    Doğan, Ahmet; Koparan, Ibrahim Halil; Adin, Mehmet Emin

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal system and comprise only 1% to 3% of all gastrointestinal tract tumors, with the majority of them arising in the stomach. In this report, we present the unique findings of a case of gastroduodenal intussusception caused by an underlying gastric GIST and complicated with severe acute pancreatitis. PMID:27104028

  11. Diaphragm motion characterization using chest motion data for biomechanics-based lung tumor tracking during EBRT

    NASA Astrophysics Data System (ADS)

    Karami, Elham; Gaede, Stewart; Lee, Ting-Yim; Samani, Abbas

    2016-03-01

    Despite recent advances in image-guided interventions, lung cancer External Beam Radiation Therapy (EBRT) is still very challenging due to respiration induced tumor motion. Among various proposed methods of tumor motion compensation, real-time tumor tracking is known to be one of the most effective solutions as it allows for maximum normal tissue sparing, less overall radiation exposure and a shorter treatment session. As such, we propose a biomechanics-based real-time tumor tracking method for effective lung cancer radiotherapy. In the proposed algorithm, the required boundary conditions for the lung Finite Element model, including diaphragm motion, are obtained using the chest surface motion as a surrogate signal. The primary objective of this paper is to demonstrate the feasibility of developing a function which is capable of inputting the chest surface motion data and outputting the diaphragm motion in real-time. For this purpose, after quantifying the diaphragm motion with a Principal Component Analysis (PCA) model, correlation coefficient between the model parameters of diaphragm motion and chest motion data was obtained through Partial Least Squares Regression (PLSR). Preliminary results obtained in this study indicate that the PCA coefficients representing the diaphragm motion can be obtained through chest surface motion tracking with high accuracy.

  12. MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor

    PubMed Central

    Kuninty, Praneeth R.; Bojmar, Linda; Tjomsland, Vegard; Larsson, Marie; Storm, Gert; Östman, Arne; Sandström, Per; Prakash, Jai

    2016-01-01

    Pancreatic stellate cells (PSCs) are the key precursor cells for cancer-associated fibroblasts (CAFs) in pancreatic tumor stroma. In this study, we explored miRNA as therapeutic targets in tumor stroma and found miR-199a-3p and miR-214-3p induced in patient-derived pancreatic CAFs and TGF-β-activated human PSCs (hPSCs). Inhibition of miR-199a/-214 using hairpin inhibitors significantly inhibited TGFβ-induced differentiation markers (e.g. α-SMA, collagen, PDGFβR), migration and proliferation. Furthermore, heterospheroids of Panc-1 and hPSCs attained smaller size with hPSCs transfected with anti-miR-199a/-214 compared to control anti-miR. The conditioned medium obtained from TGFβ-activated hPSCs induced tumor cell growth and endothelial cell tube formation. Interestingly, these inductions were abrogated in hPSCs transfected with anti-miR-199a or miR-214. Moreover, IPA analyses revealed signaling pathways related to miR-199a (TP53, mTOR, Smad1) and miR-214 (PTEN, Bax, ING4). Taken together, this study reveals miR-199a-3p and miR-214-3p as major regulators of PSC activation and PSC-induced pro-tumoral effects, representing them as key therapeutic targets in pancreatic cancer. PMID:26918939

  13. Paclitaxel tumor priming promotes delivery and transfection of intravenous lipid-siRNA in pancreatic tumors.

    PubMed

    Wang, Jie; Lu, Ze; Wang, Junfeng; Cui, Minjian; Yeung, Bertrand Z; Cole, David J; Wientjes, M Guillaume; Au, Jessie L-S

    2015-10-28

    The major barrier for using small interfering RNA (siRNA) as cancer therapeutics is the inadequate delivery and transfection in solid tumors. We have previously shown that paclitaxel tumor priming, by inducing apoptosis, expands the tumor interstitial space, improves the penetration and dispersion of nanoparticles and siRNA-lipoplexes in 3-dimensional tumor histocultures, and promotes the delivery and transfection efficiency of siRNA-lipoplexes under the locoregional setting in vivo (i.e., intraperitoneal treatment of intraperitoneal tumors). The current study evaluated whether tumor priming is functional for systemically delivered siRNA via intravenous injection, which would subject siRNA to several additional delivery barriers and elimination processes. We used the same pegylated cationic (PCat)-siRNA lipoplexes as in the intraperitoneal study to treat mice bearing subcutaneous human pancreatic Hs766T xenograft tumors. The target gene was survivin, an inducible chemoresistance gene. The results show single agent paclitaxel delayed tumor growth but also significantly induced the survivin protein level in residual tumors, whereas addition of PCat-siSurvivin completely reversed the paclitaxel-induced survivin and enhanced the paclitaxel activity (p<0.05). In comparison, PCat-siSurvivin alone did not yield survivin knockdown or antitumor activity, indicating the in vivo effectiveness of intravenous siRNA-mediated gene silencing requires paclitaxel cotreatment. Additional in vitro studies showed that paclitaxel promoted the cytoplasmic release of siGLO, a 22 nucleotide double-stranded RNA that has no mRNA targets, from its PCat lipoplex and/or endosomes/lysosomes. Taken together, our earlier and current data show paclitaxel tumor priming, by promoting the interstitial transport and cytoplasmic release, is critical to promote the delivery and transfection of siRNA in vivo. In addition, because paclitaxel has broad spectrum activity and is used to treat multiple types

  14. Somatostatin receptor-1 induces cell cycle arrest and inhibits tumor growth in pancreatic cancer.

    PubMed

    Li, Min; Wang, Xiaochi; Li, Wei; Li, Fei; Yang, Hui; Wang, Hao; Brunicardi, F Charles; Chen, Changyi; Yao, Qizhi; Fisher, William E

    2008-11-01

    Functional somatostatin receptors (SSTR) are lost in human pancreatic cancer. Transfection of SSTR-1 inhibited pancreatic cancer cell proliferation in vitro. We hypothesize that stable transfection of SSTR-1 may inhibit pancreatic cancer growth in vivo possibly through cell cycle arrest. In this study, we examined the expression of SSTR-1 mRNA in human pancreatic cancer tissue specimens, and investigated the effect of SSTR-1 overexpression on cell proliferation, cell cycle, and tumor growth in a subcutaneous nude mouse model. We found that SSTR-1 mRNA was downregulated in the majority of pancreatic cancer tissue specimens. Transfection of SSTR-1 caused cell cycle arrest at the G(0)/G(1) growth phase, with a corresponding decline of cells in the S (mitotic) phase. The overexpression of SSTR-1 significantly inhibited subcutaneous tumor size by 71% and 43% (n = 5, P < 0.05, Student's t-test), and inhibited tumor weight by 69% and 47% (n = 5, P < 0.05, Student's t-test), in Panc-SSTR-1 and MIA-SSTR-1 groups, respectively, indicating the potent inhibitory effect of SSTR-1 on pancreatic cancer growth. Our data demonstrate that overexpression of SSTR-1 significantly inhibits pancreatic cancer growth possibly through cell cycle arrest. This study suggests that gene therapy with SSTR-1 may be a potential adjuvant treatment for pancreatic cancer. PMID:18823376

  15. Somatostatin Receptor-1 Induces Cell Cycle Arrest and Inhibits Tumor Growth in Pancreatic Cancer

    PubMed Central

    Li, Min; Wang, Xiaochi; Li, Wei; Li, Fei; Yang, Hui; Wang, Hao; Brunicardi, F. Charles; Chen, Changyi; Yao, Qizhi; Fisher, William E.

    2010-01-01

    Functional somatostatin receptors (SSTRs) are lost in human pancreatic cancer. Transfection of SSTR-1 inhibited pancreatic cancer cell proliferation in vitro. We hypothesize that stable transfection of SSTR-1 may inhibit pancreatic cancer growth in vivo possibly through cell cycle arrest. In this study, we examined the expression of SSTR-1 mRNA in human pancreatic cancer tissue specimens, and investigated the effect of SSTR-1 overexpression on cell proliferation, cell cycle, and tumor growth in in a subcutaneous nude mouse model. We found that SSTR-1 mRNA was downregulated in the majority of pancreatic cancer tissue specimens. Transfection of SSTR-1 caused cell cycle arrest at the G0/G1 growth phase, with a corresponding decline of cells in the S (mitotic) phase. The overexpression of SSTR-1 significantly inhibited subcutaneous tumor size by 71% and 43% (n=5, p<0.05, t-test), and inhibited tumor weight by 69% and 47%, (n=5, p<0.05, t-test), in Panc-SSTR-1 and MIA-SSTR-1 groups, respectively, indicating the potent inhibitory effect of SSTR-1 on pancreatic cancer growth. Our data demonstrate that overexpression of SSTR-1 significantly inhibits pancreatic cancer growth possibly through cell cycle arrest. This study suggests that gene therapy with SSTR-1 may be a potential adjuvant treatment for pancreatic cancer. PMID:18823376

  16. 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

  17. WE-G-18C-06: Is Diaphragm Motion a Good Surrogate for Liver Tumor Motion?

    SciTech Connect

    Yang, J; Cai, J; Zheng, C; Czito, B; Palta, M; Yin, F; Wang, H; Bashir, M

    2014-06-15

    Purpose: To investigate whether diaphragm motion is a good surrogate for liver tumor motion by comparing their motion trajectories obtained from cine-MRI. Methods: Fourteen patients with hepatocellular carcinoma (10/14) or liver metastases (4/14) undergoing radiation therapy were included in this study. All patients underwent single-slice 2D cine-MRI simulations across the center of the tumor in three orthogonal planes. Tumor and diaphragm motion trajectories in the superior-inferior (SI), anteriorposterior (AP), and medial-lateral (ML) directions were obtained using the normalized cross-correlation based tracking technique. Agreement between tumor and diaphragm motions was assessed by calculating the phase difference percentage (PDP), intra-class correlation coefficient (ICC), Bland-Altman analysis (Diffs) and paired t-test. The distance (D) between tumor and tracked diaphragm area was analyzed to understand its impact on the correlation between tumor and diaphragm motions. Results: Of all patients, the means (±standard deviations) of PDP were 7.1 (±1.1)%, 4.5 (±0.5)% and 17.5 (±4.5)% in the SI, AP and ML directions, respectively. The means of ICC were 0.98 (±0.02), 0.97 (±0.02), and 0.08 (±0.06) in the SI, AP and ML directions, respectively. The Diffs were 2.8 (±1.4) mm, 2.4 (±1.1) mm, and 2.2 (±0.5) mm in the SI, AP and ML directions, respectively. The p-values derived from the paired t-test were < 0.02 in SI and AP directions, whereas were > 0.58 in ML direction primarily due to the small motion in ML direction. Tumor and diaphragmatic motion had high concordance when the distance between the tumor and tracked diaphragm areas was small. Conclusion: Preliminary results showed that liver tumor motion had good correlations with diaphragm motion in the SI and AP directions, indicating diaphragm motion in the SI and AP directions could potentially be a reliable surrogate for liver tumor motion. NIH (1R21CA165384-01A1), Golfers Against Cancer (GAC

  18. Dominant Expression of DCLK1 in Human Pancreatic Cancer Stem Cells Accelerates Tumor Invasion and Metastasis

    PubMed Central

    Ito, Hiromitsu; Tanaka, Shinji; Akiyama, Yoshimitsu; Shimada, Shu; Adikrisna, Rama; Matsumura, Satoshi; Aihara, Arihiro; Mitsunori, Yusuke; Ban, Daisuke; Ochiai, Takanori; Kudo, Atsushi; Arii, Shigeki; Yamaoka, Shoji; Tanabe, Minoru

    2016-01-01

    Patients with pancreatic cancer typically develop tumor invasion and metastasis in the early stage. These malignant behaviors might be originated from cancer stem cells (CSCs), but the responsible target is less known about invisible CSCs especially for invasion and metastasis. We previously examined the proteasome activity of CSCs and constructed a real-time visualization system for human pancreatic CSCs. In the present study, we found that CSCs were highly metastatic and dominantly localized at the invading tumor margins in a liver metastasis model. Microarray and siRNA screening assays showed that doublecortin-like kinase 1 (DCLK1) was predominantly expressed with histone modification in pancreatic CSCs with invasive and metastatic potential. Overexpression of DCLK1 led to amoeboid morphology, which promotes the migration of pancreatic cancer cells. Knockdown of DCLK1 profoundly suppressed in vivo liver metastasis of pancreatic CSCs. Clinically, DCLK1 was overexpressed in the metastatic tumors in patients with pancreatic cancer. Our studies revealed that DCLK1 is essential for the invasive and metastatic properties of CSCs and may be a promising epigenetic and therapeutic target in human pancreatic cancer. PMID:26764906

  19. Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth

    PubMed Central

    Shukla, Surendra K.; Dasgupta, Aneesha; Mehla, Kamiya; Gunda, Venugopal; Vernucci, Enza; Souchek, Joshua; Goode, Gennifer; King, Ryan; Mishra, Anusha; Rai, Ibha; Nagarajan, Sangeetha; Chaika, Nina V.; Yu, Fang; Singh, Pankaj K.

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models. PMID:26510913

  20. Neutrophil-Derived Proteases in the Microenvironment of Pancreatic Cancer -Active Players in Tumor Progression

    PubMed Central

    Felix, Klaus; Gaida, Matthias M.

    2016-01-01

    A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the fibro-inflammatory microenvironment, consisting of activated pancreatic stellate cells, extracellular matrix proteins, and a variety of inflammatory cells, such as T cells, macrophages, or neutrophils. Tumor-infiltrating immune cells, which are found in nearly all cancers, including PDAC, often fail to eliminate the tumor, but conversely can promote its progression by altering the tumor microenvironment. Pancreatic cancer cells are able to attract polymorphonuclear neutrophils (PMN) via tumor secreted chemokines and in human PDAC, PMN infiltrates can be observed in the vicinity of tumor cells and in the desmoplastic tumor stroma, which correlate with undifferentiated tumor growth and poor prognosis. The behavior of tumor-infiltrating neutrophils in the tumor micromilieu is not yet understood at a mechanistic level. It has been shown that PMN have the potential to kill tumor cells, either directly or by antibody-dependent cell-mediated cytotoxicity, but on the other side various adverse effects of PMN, such as promotion of aggressive tumor growth with epithelial-to-mesenchymal transition and increased metastatic potential, have been described. Recent therapeutic approaches for PDAC focus not only the tumor cell itself, but also elements of the tumor microenvironment. Therefore, the role of PMN and their derived products (e.g. cytokines, proteases) as a new vein for a therapeutic target should be critically evaluated in this context. This review summarizes the current understanding of the interplay between proteases of tumor-infiltrating neutrophils and pancreatic tumor cells and elements of the desmoplastic stroma. PMID:26929737

  1. SU-E-J-07: A Functional MR Protocol for the Pancreatic Tumor Delineation

    SciTech Connect

    Andreychenko, A; Heerkens, H; Meijer, G; Vulpen, M van; Lagendijk, J; Berg, C van den

    2014-06-01

    Purpose: Pancreatic cancer is one of the cancers with the poorest survival prognosis. At the time of diagnosis most of pancreatic cancers are unresectable and those patients can be treated by radiotherapy. Radiotherapy for pancreatic cancer is limited due to uncertainties in CT-based delineations. MRI provides an excellent soft tissue contrast. Here, an MR protocol is developed to improve delineations for radiotherapy treatment of pancreatic cancer. In a later stage this protocol can also be used for on-line visualization of the pancreas during MRI guided treatments. Methods: Nine pancreatic cancer patients were included. The MR protocol included T2 weighted(T2w), T1 weighted(T1w), diffusion weighted(DWI) and dynamic contrast enhanced(DCE) techniques. The tumor was delineated on T2w and T1w MRI by an experienced radiation oncologist. Healthy pancreas or pancreatitis (assigned by the oncologist based on T2w) areas were also delineated. Apparent diffusion coefficient(ADC), and area under the curve(AUC)/time to peak(TTP) maps were obtained from DWI and DCE scans, respectively. Results: A clear demarcation of tumor area was visible on b800 DWI images in 5 patients. ADC maps of those patients characterized tumor as an area with restricted water diffusion. Tumor delineations based on solely DCE were possible in 7 patients. In 6 of those patients AUC maps demonstrated tumor heterogeneity: a hypointense area with a hyperintense ring. TTP values clearly discriminated the tumor and the healthy pancreas but could not distinguish tumor and the pancreatitis accurately. Conclusion: MR imaging results in a more pronounced tumor contrast than contrast enhanced CT. The addition of quantitative, functional MRI provides valuable, additional information to the radiation oncologist on the spatial tumor extent by discriminating tumor from the healthy pancreas(TTP, DWI) and characterizing the tumor(ADC). Our findings indicate that tumor delineation in pancreatic cancer can greatly

  2. Acute pancreatitis following granulosa cell tumor removal in a mare

    PubMed Central

    Gomez, Diego E.; Radtke, Catherine L.; Russell, Lauren A.; Lopez, Alfonso; Wichtel, Maureen W.

    2015-01-01

    Acute pancreatitis is a rare disease in horses and is often associated with gastrointestinal disorders. Accurate diagnosis is challenging due to the presence of nonspecific clinical signs. This case represents the first documentation of acute pancreatitis in a horse following surgery of the reproductive tract. PMID:26483579

  3. Pancreatic tumor detection using hypericin-based fluorescence spectroscopy and cytology

    NASA Astrophysics Data System (ADS)

    Lavu, Harish; Geary, Kevin; Fetterman, Harold R.; Saxton, Romaine E.

    2005-04-01

    Hypericin is a novel, highly fluorescent photosensitizer that exhibits selective tumor cell uptake properties and is particularly resistant to photobleaching. In this study, we have characterized hypericin uptake in human pancreatic tumor cells with relation to incubation time, cell number, and drug concentration. Ex vivo hypericin based fluorescence spectroscopy was performed to detect the presence of MIA PaCa-2 pancreatic tumor cells in the peritoneal cavity of BALB/c nude mice, as well as to quantify gross tumor burden. Hypericin based cytology of peritoneal lavage samples, using both one and two photon laser confocal microscopy, demonstrated more than a two-fold increase in fluorescence emission of pancreatic tumor cells as compared to control samples. In vitro treatment of pancreatic cancer cells with hypericin based photodynamic therapy showed tumor cell cytotoxicity in a drug dose, incident laser power, and time dependent manner. For these experiments, a continuous wavelength solid-state laser source (532 nm) was operated at power levels in the range of 100-400 mW. Potential applications of hypericin in tumor diagnosis, staging, and therapy will be presented.

  4. UFT plus leucovorin in advanced hepatobiliary tumors and pancreatic adenocarcinomas.

    PubMed

    Mani, S

    1997-09-01

    UFT (tegafur and uracil) has been studied extensively in Japan, with documented efficacy in hepatobiliary and pancreatic cancer. In the United States, UFT with or without leucovorin has not undergone phase II testing in these malignancies. Our current trial is designed primarily to assess the efficacy in terms of response rates to UFT with leucovorin in patients with advanced hepatobiliary and pancreatic cancer. Secondary objectives include determining response duration, time to disease progression, overall survival, quality of life, and toxicity. PMID:9348584

  5. The Tumor Suppressor rpl36 Restrains KRASG12V-Induced Pancreatic Cancer

    PubMed Central

    Provost, Elayne; Bailey, Jennifer M.; Aldrugh, Sumar; Liu, Shu; Iacobuzio-Donahue, Christine

    2014-01-01

    Abstract Ribosomal proteins are known to be required for proper assembly of mature ribosomes. Recent studies indicate an additional role for ribosomal proteins as candidate tumor suppressor genes. Pancreatic acinar cells, recently identified as effective cells of origin for pancreatic adenocarcinoma, display especially high-level expression of multiple ribosomal proteins. We, therefore, functionally interrogated the ability of two ribosomal proteins, rpl36 and rpl23a, to alter the response to oncogenic Kras in pancreatic acinar cells using a newly established model of zebrafish pancreatic cancer. These studies reveal that rpl36, but not rpl23a, acts as a haploinsufficient tumor suppressor, as manifested by more rapid tumor progression and decreased survival in rpl36hi1807/+;ptf1a:gal4VP16Tg;UAS:GFP-KRASG12V fish compared with their rpl36+/+;ptf1a:gal4VP16;UAS:GFP-KRASG12V siblings. These results suggest that rpl36 may function as an effective tumor suppressor during pancreatic tumorigenesis. PMID:25380065

  6. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer

    PubMed Central

    Koay, Eugene J.; Baio, Flavio E.; Ondari, Alexander; Truty, Mark J.; Cristini, Vittorio; Thomas, Ryan M.; Chen, Rong; Chatterjee, Deyali; Kang, Ya’an; Zhang, Joy; Court, Laurence; Bhosale, Priya R.; Tamm, Eric P.; Qayyum, Aliya; Crane, Christopher H.; Javle, Milind; Katz, Matthew H.; Gottumukkala, Vijaya N.; Rozner, Marc A.; Shen, Haifa; Lee, Jeffrey E.; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L.; Wolff, Robert A.; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R.; Fleming, Jason B.

    2014-01-01

    There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of

  7. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer

    NASA Astrophysics Data System (ADS)

    Koay, Eugene J.; Baio, Flavio E.; Ondari, Alexander; Truty, Mark J.; Cristini, Vittorio; Thomas, Ryan M.; Chen, Rong; Chatterjee, Deyali; Kang, Ya'an; Zhang, Joy; Court, Laurence; Bhosale, Priya R.; Tamm, Eric P.; Qayyum, Aliya; Crane, Christopher H.; Javle, Milind; Katz, Matthew H.; Gottumukkala, Vijaya N.; Rozner, Marc A.; Shen, Haifa; Lee, Jeffrey E.; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L.; Wolff, Robert A.; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R.; Fleming, Jason B.

    2014-12-01

    There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of

  8. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer.

    PubMed

    Koay, Eugene J; Baio, Flavio E; Ondari, Alexander; Truty, Mark J; Cristini, Vittorio; Thomas, Ryan M; Chen, Rong; Chatterjee, Deyali; Kang, Ya'an; Zhang, Joy; Court, Laurence; Bhosale, Priya R; Tamm, Eric P; Qayyum, Aliya; Crane, Christopher H; Javle, Milind; Katz, Matthew H; Gottumukkala, Vijaya N; Rozner, Marc A; Shen, Haifa; Lee, Jeffrey E; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L; Wolff, Robert A; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R; Fleming, Jason B

    2014-01-01

    There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of

  9. EFFECTS OF TUMORS ON INHALED PHARMACOLOGIC DRUGS: II. PARTICLE MOTION

    EPA Science Inventory

    ABSTRACT

    Computer simulations were conducted to describe drug particle motion in human lung bifurcations with tumors. The computations used FIDAP with a Cray T90 supercomputer. The objective was to better understand particle behavior as affected by particle characteristics...

  10. Reduction of setup uncertainties and tumor motion in the radiation therapy of lung tumors

    NASA Astrophysics Data System (ADS)

    Nelson, Christopher Lee

    Because the goal of radiation therapy is to deliver a lethal dose to the tumor, accurate information on the location of the tumor needs to be known. Margins are placed around the tumor to account for variations in the daily position of the tumor. If tumor motion and patient setup uncertainties can be reduced, margins that account for such uncertainties in tumor location in can be reduced allowing dose escalation, which in turn could potentially improve survival rates. In the first part of this study, we monitor the location of fiducials implanted in the periphery of lung tumors to determine the extent of non-gated and gated fiducial motion, and to quantify patient setup uncertainties. In the second part we determine where the tumor is when different methods of image-guided patient setup and respiratory gating are employed. In the final part we develop, validate, and implement a technique in which patient setup uncertainties are reduced by aligning patients based upon fiducial locations in projection images. Results from the first part indicate that respiratory gating reduces fiducial motion relative to motion during normal respiration and setup uncertainties when the patients were aligned each day using externally placed skin marks are large. The results from the second part indicate that current margins that account for setup uncertainty and tumor motion result in less than 2% of the tumor outside of the planning target volume (PTV) when the patient is aligned using skin marks. In addition, we found that if respiratory gating is going to be used, it is most effective if used in conjunction with image-guided patient setup. From the third part, we successfully developed, validated, and implemented on a patient a technique for aligning a moving target prior to treatment to reduce the uncertainties in tumor location. In conclusion, setup uncertainties and tumor motion are a significant problem when treating tumors located within the thoracic region. Image

  11. Incidental detection of pancreatic hemangioma mimicking a metastatic tumor of renal cell carcinoma

    PubMed Central

    Kim, Sung Hyun; Kim, Ji-Ye; Choi, Jin Young; Choi, Young Deuk

    2016-01-01

    Adult pancreatic hemangioma is a rare disease. We presented a case of a woman with pancreatic tail mass mimicking a distant metastasis from the kidney. A 68-year-old woman was found with a left kidney mass on medical checkup. Computed tomography scan showed a 4.3 cm-sized mass in the left kidney, suggesting renal cell carcinoma (RCC), and a strongly enhancing tiny nodule in the pancreatic tail. We could not rule the possibility of RCC metastasis, hence, surgical resection of the pancreatic mass simultaneously with radical nephrectomy for RCC was conducted. Gross pathologic examination revealed hemangioma. Immunohistochemistry revealed that the tumor was positive for CD34, CD31 and factor VIII-related antigen. There were no significant postoperative events, and the patient was discharged on postoperative day 7 without any complications. Treatment strategies for pancreatic hemangioma have not been established. To our knowledge, this was the first case report of asymptomatic pancreatic hemangioma. In previous literature, treatment differed on a case-by-case basis, ranging from observation to surgical resection. The most important factor in deciding whether to perform surgery is possibly risk-benefit effectiveness; however, tumor location, patient symptoms, and other factors are also important.

  12. Incidental detection of pancreatic hemangioma mimicking a metastatic tumor of renal cell carcinoma.

    PubMed

    Kim, Sung Hyun; Kim, Ji-Ye; Choi, Jin Young; Choi, Young Deuk; Kim, Kyung Sik

    2016-05-01

    Adult pancreatic hemangioma is a rare disease. We presented a case of a woman with pancreatic tail mass mimicking a distant metastasis from the kidney. A 68-year-old woman was found with a left kidney mass on medical checkup. Computed tomography scan showed a 4.3 cm-sized mass in the left kidney, suggesting renal cell carcinoma (RCC), and a strongly enhancing tiny nodule in the pancreatic tail. We could not rule the possibility of RCC metastasis, hence, surgical resection of the pancreatic mass simultaneously with radical nephrectomy for RCC was conducted. Gross pathologic examination revealed hemangioma. Immunohistochemistry revealed that the tumor was positive for CD34, CD31 and factor VIII-related antigen. There were no significant postoperative events, and the patient was discharged on postoperative day 7 without any complications. Treatment strategies for pancreatic hemangioma have not been established. To our knowledge, this was the first case report of asymptomatic pancreatic hemangioma. In previous literature, treatment differed on a case-by-case basis, ranging from observation to surgical resection. The most important factor in deciding whether to perform surgery is possibly risk-benefit effectiveness; however, tumor location, patient symptoms, and other factors are also important. PMID:27212999

  13. [Two cases of pancreatic tumor with von Hippel-Lindau disease].

    PubMed

    Karasaki, Hidenori; Ishizaki, Akira; Yanagawa, Nobuyuki; Nakano, Yasuhiro; Sasajima, Jyunpei; Mizukami, Yusuke; Tanno, Satoshi; Tokusashi, Yoshihiko; Miyokawa, Naoyuki; Obara, Mitsuhiro; Goto, Junichi; Kino, Shuichi; Kono, Toru; Kasai, Shinichi

    2008-05-01

    Von Hippel-Lindau disease (VHL disease) is an inherited neoplasia syndrome. VHL disease which frequently complicates pancreatic lesions is rarely diagnosed by existence of pancreatic involvements. We report two cases of VHL disease with pancreatic lesions. The first patient was a 40-year-old woman. Adrenal pheochromocytoma, spinal hemangioblastoma and pancreatic endocrine tumor were resected. The second case was a 68-year-old woman with past surgical histories included cerebellar and spinal hemangioblastoma. Subtotal pancreatectomy was performed for multiple serous cystadenoma. IPMN which has been never reported as pancreatic involvement of VHL disease were documented by imaging diagnosis in the first case, and by histological examination in the second case. We considered VHL disease from coexistent multiple tumors include pancreatic involvements and finally diagnosed by genetic examination in both cases. Care should be taken regarding the patient's right for treatment against for the genetic disease. We hold a genetic conference composed of multidisciplinary team. Consequently we detected another VHL disease patient from patient's family. PMID:18460863

  14. Targeting Inhibitors of the Tumor Suppressor PP2A for the Treatment of Pancreatic Cancer

    PubMed Central

    Farrell, Amy S.; Allen-Petersen, Brittany; Daniel, Colin J.; Wang, Xiaoyan; Wang, Zhiping; Rodriguez, Sarah; Impey, Soren; Oddo, Jessica; Vitek, Michael P.; Lopez, Charles; Christensen, Dale J.; Sheppard, Brett; Sears, Rosalie C.

    2014-01-01

    Pancreatic cancer is a deadly disease that is usually diagnosed in the advanced stages when few effective therapies are available. Given the aggressive clinical course of this disease and lack of good treatment options, the development of new therapeutic agents for the treatment of pancreatic cancer is of the upmost importance. Several pathways shown to contribute to pancreatic cancer progression are negatively regulated by the tumor suppressor, protein phosphatase 2A (PP2A). Here, the endogenous inhibitors of PP2A, SET (also known as I2PP2A) and Cancerous Inhibitor of PP2A (CIP2A), were shown to be overexpressed in human pancreatic cancer, contributing to decreased PP2A activity, and overexpression and stabilization of the oncoprotein c-Myc, a key PP2A target. Knockdown of SET or CIP2A increases PP2A activity, increases c-Myc degradation, and decreases the tumorigenic potential of pancreatic cancer cell lines both in vitro and in vivo. Moreover, treatment with a novel SET inhibitor, OP449, pharmacologically recapitulates the phenotypes and significantly reduces proliferation and tumorigenic potential of several pancreatic cancer cell lines, with an accompanying attenuation of cell growth and survival signaling. Furthermore, primary cells from pancreatic cancer patients were sensitive to OP449 treatment, indicating that PP2A regulated pathways are highly relevant to this deadly disease. PMID:24667985

  15. mir-329 restricts tumor growth by targeting grb2 in pancreatic cancer

    PubMed Central

    Wen, Chenlei; Shi, Minmin; Tang, Xiaomei; Chen, Hao; Peng, Chenghong; Li, Hongwei; Fang, Yuan; Deng, Xiaxing; Shen, Baiyong

    2016-01-01

    Pancreatic cancer is one of the most lethal malignancies worldwide. To illustrate the pathogenic mechanism(s), we looked into the expression and function of miR-329 associated with pancreatic cancer development. It was found that miR-329 expression was downregulated in the pancreatic cancer patients who demonstrated significantly shorter overall survival than the patients having upregulated expression. Also, more advanced pT stage cases were observed in the low miR-329 expression group of patients. Interestingly, our studies uncovered that miR-329 overexpression inhibited proliferation and induced apoptosis of pancreatic cancer cells, in contrast the miR-329 inhibitor reversed this phenomenon dramatically. Additionally, overexpression of miR-329 significantly limited tumor growth in the xenograft model. In the mechanistic study, we identified GRB2 as a direct target of miR-329 in pancreatic cancer cells, and expression of GRB2 was inversely correlated with miR-329 expression in pancreatic cancer patients. Furthermore, GRB2 overexpression in cell line and xenograft model dramatically diminished miR-329 mediated anti-proliferation and apoptosis induction, indicating that GRB2/pERK pathway was mainly downregulated by miR-329 expression. In general, our study has shed light on miR-329 regulated mechanism and, miR-329/GRB2/pERK is potential to be targeted for pancreatic cancer management. PMID:26885689

  16. Positional Reproducibility of Pancreatic Tumors Under End-Exhalation Breath-Hold Conditions Using a Visual Feedback Technique

    SciTech Connect

    Nakamura, Mitsuhiro; Shibuya, Keiko; Shiinoki, Takehiro; Matsuo, Yukinori; Nakamura, Akira; Nakata, Manabu; Sawada, Akira; Mizowaki, Takashi; Hiraoka, Masahiro

    2011-04-01

    Purpose: To assess positional reproducibility of pancreatic tumors under end-exhalation (EE) breath-hold (BH) conditions with a visual feedback technique based on computed tomography (CT) images. Methods and Materials: Ten patients with pancreatic cancer were enrolled in an institutional review board-approved trial. All patients were placed in a supine position on an individualized vacuum pillow with both arms raised. At the time of CT scan, they held their breath at EE with the aid of video goggles displaying their abdominal displacement. Each three-consecutive helical CT data set was acquired four times (sessions 1-4; session 1 corresponded to the time of CT simulation). The point of interest within or in proximity to a gross tumor volume was defined based on certain structural features. The positional variations in point of interest and margin size required to cover positional variations were assessed. Results: The means {+-} standard deviations (SDs) of intrafraction positional variations were 0.0 {+-} 1.1, 0.1 {+-} 1.2, and 0.1 {+-} 1.0 mm in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions, respectively (p = 0.726). The means {+-} SDs of interfraction positional variations were 0.3 {+-} 2.0, 0.8 {+-} 1.8, and 0.3 {+-} 1.8 mm in the LR, AP, and SI directions, respectively (p = 0.533). Population-based margin sizes required to cover 95th percentiles of the overall positional variations were 4.7, 5.3, and 4.9 mm in the LR, AP, and SI directions, respectively. Conclusions: A margin size of 5 mm was needed to cover the 95th percentiles of the overall positional variations under EE-BH conditions, using this noninvasive approach to motion management for pancreatic tumors.

  17. Pancreatitis

    MedlinePlus

    ... the hormones insulin and glucagon into the bloodstream. Pancreatitis is inflammation of the pancreas. It happens when digestive enzymes start digesting the pancreas itself. Pancreatitis can be acute or chronic. Either form is ...

  18. Intraductal Delivery of Adenoviruses Targets Pancreatic Tumors in Transgenic Ela-myc Mice and Orthotopic Xenografts

    PubMed Central

    José, Anabel; Sobrevals, Luciano; Camacho-Sánchez, Juan Miguel; Huch, Meritxell; Andreu, Núria; Ayuso, Eduard; Navarro, Pilar; Alemany, Ramon; Fillat, Cristina

    2013-01-01

    Gene-based anticancer therapies delivered by adenoviruses are limited by the poor viral distribution into the tumor. In the current work we have explored the feasibility of targeting pancreatic tumors through a loco-regional route. We have taken advantage of the ductal network in the pancreas to retrogradelly inject adenoviruses through the common bile duct in two different mouse models of pancreatic carcinogenesis: The transgenic Ela-myc mice that develop mixed neoplasms displaying both acinar-like and duct-like neoplastic cells affecting the whole pancreas; and mice bearing PANC-1 and BxPC-3 orthotopic xenografts that constitute a model of localized human neoplastic tumors. We studied tumor targeting and the anticancer effects of newly thymidine kinase-engineered adenoviruses both in vitro and in vivo, and conducted comparative studies between intraductal or intravenous administration. Our data indicate that the intraductal delivery of adenovirus efficiently targets pancreatic tumors in the two mouse models. The in vivo application of AduPARTKT plus ganciclovir (GCV) treatment induced tumor regression in Ela-myc mice. Moreover, the intraductal injection of ICOVIR15-TKT oncolytic adenoviruses significantly improved mean survival of mice bearing PANC-1 and BxPC-3 pancreatic xenografts from 30 to 52 days and from 20 to 68 days respectively (p<0.0001) when combined with GCV. Of notice, both AduPARTKT and ICOVIR15-TKT antitumoral responses were stronger by ductal viral application than intravenously, in line with the 38-fold increase in pancreas transduction observed upon ductal administration. In summary our data show that cytotoxic adenoviruses retrogradelly injected to the pancreas can be a feasible approach to treat localized pancreatic tumors. PMID:23328228

  19. Efficient targeting and tumor retardation effect of pancreatic adenocarcinoma up-regulated factor (PAUF)-specific RNA replacement in pancreatic cancer mouse model.

    PubMed

    Kim, Yun-Hee; Moon, Ju Young; Kim, Eun-Ok; Lee, Sang-Jin; Kang, Se Hun; Kim, Seok Ki; Heo, Kyun; Lee, Yusun; Kim, Hana; Kim, Kyung-Tae; Kim, Daehong; Song, Min Sun; Lee, Seoung-Wook; Lee, Yangsoon; Koh, Sang Seok; Kim, In-Hoo

    2014-03-28

    The soluble protein pancreatic adenocarcinoma up-regulated factor (PAUF) plays an important role in pancreatic tumor progression and has begun to attract attention as a therapeutic target for pancreatic cancer. We herein present PAUF RNA-targeting gene therapy strategies with both targeting and therapeutic function using trans-splicing ribozyme (TSR) in pancreatic cancer. We developed adenoviral PAUF-targeting TSR (Rz) containing a PAUF-specific internal guide sequence (IGS) determined by library screening. This Rz harbors suicide gene, herpes simplex virus thymidine kinase (HSV-tk) or firefly luciferase (Luc) as a transgene for 3' exon replacement of PAUF RNAs. Ad-Rz-TK, Rz harboring the HSV-tk, showed significant inhibition of tumor growth in vivo as well as PAUF-dependent cell death in vitro via a successful trans-splicing reaction. Selective induction of Rz-controlled transgene in PAUF-expressing pancreatic cancer was confirmed through noninvasive in vivo imaging; a luminescence signal from Rz harboring Luc (Ad-Rz-Luc) was detectable only in pancreatic tumor sites, not in normal mice. In addition, a [(125)I] FIAU signal reflecting thymidine kinase expression through SPECT and ex vivo biodistribution was co-localized with the tumor sites when we treated with Ad-Rz-TK in orthotopic xenograft model. Taken together, these results imply that PAUF-targeting TSR can contribute to successful targeted gene therapy for pancreatic cancer. PMID:24189457

  20. Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors.

    PubMed

    Krampitz, Geoffrey Wayne; George, Benson M; Willingham, Stephen B; Volkmer, Jens-Peter; Weiskopf, Kipp; Jahchan, Nadine; Newman, Aaron M; Sahoo, Debashis; Zemek, Allison J; Yanovsky, Rebecca L; Nguyen, Julia K; Schnorr, Peter J; Mazur, Pawel K; Sage, Julien; Longacre, Teri A; Visser, Brendan C; Poultsides, George A; Norton, Jeffrey A; Weissman, Irving L

    2016-04-19

    Pancreatic neuroendocrine tumors (PanNETs) are a type of pancreatic cancer with limited therapeutic options. Consequently, most patients with advanced disease die from tumor progression. Current evidence indicates that a subset of cancer cells is responsible for tumor development, metastasis, and recurrence, and targeting these tumor-initiating cells is necessary to eradicate tumors. However, tumor-initiating cells and the biological processes that promote pathogenesis remain largely uncharacterized in PanNETs. Here we profile primary and metastatic tumors from an index patient and demonstrate that MET proto-oncogene activation is important for tumor growth in PanNET xenograft models. We identify a highly tumorigenic cell population within several independent surgically acquired PanNETs characterized by increased cell-surface protein CD90 expression and aldehyde dehydrogenase A1 (ALDHA1) activity, and provide in vitro and in vivo evidence for their stem-like properties. We performed proteomic profiling of 332 antigens in two cell lines and four primary tumors, and showed that CD47, a cell-surface protein that acts as a "don't eat me" signal co-opted by cancers to evade innate immune surveillance, is ubiquitously expressed. Moreover, CD47 coexpresses with MET and is enriched in CD90(hi)cells. Furthermore, blocking CD47 signaling promotes engulfment of tumor cells by macrophages in vitro and inhibits xenograft tumor growth, prevents metastases, and prolongs survival in vivo. PMID:27035983

  1. Pancreatic neuroendocrine tumor with ectopic adrenocorticotropin production: a case report and review of literature.

    PubMed

    Patel, Forum B; Khagi, Simon; Daly, Kevin P; Lechan, Ronald M; Ummaritchot, Vorawan; Saif, Muhammad W

    2013-09-01

    Pancreatic neuroendocrine tumors (p-NETs) entail a vast array of tumors, which can vary from benign neoplastic growths to rapidly aggressive malignancies. Such is the case with ectopic adrenocorticotropic hormone (ACTH)-producing p-NETs. These tumors have been found to be quite aggressive and a challenge to treat, especially due to the occurrence of metastatic disease even after resection of the primary tumor. We discuss the case of a 44-year-old female who initially presented with vague, non-specific symptoms, in which a malignant p-NET was found to be the cause of her clinical presentation. Although resection of the pancreatic mass was performed, the patient presented again with metastatic disease to the liver. PMID:24023341

  2. LDL Receptor: An open route to feed pancreatic tumor cells

    PubMed Central

    Vasseur, Sophie; Guillaumond, Fabienne

    2016-01-01

    ABSTRACT The role of altered lipid metabolism in pancreatic ductal adenocarcinoma (PDAC) is poorly appreciated. We recently identified the lipid signature of PDAC and revealed low-density lipoprotein receptor (Ldlr) as a metabolic driver of this disease. Here, we comment our findings that disruption of Ldlr leads to intratumoral cholesterol imbalance and improves chemotherapy efficiency. PMID:27308549

  3. Pharmacokinetically Guided Everolimus in Patients With Breast Cancer, Pancreatic Neuroendocrine Tumors, or Kidney Cancer

    ClinicalTrials.gov

    2016-01-12

    Estrogen Receptor-positive Breast Cancer; Gastrinoma; Glucagonoma; HER2-negative Breast Cancer; Insulinoma; Mucositis; Oral Complications; Pancreatic Polypeptide Tumor; Progesterone Receptor-positive Breast Cancer; Recurrent Breast Cancer; Recurrent Islet Cell Carcinoma; Recurrent Renal Cell Cancer; Somatostatinoma; Stage III Renal Cell Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Renal Cell Cancer

  4. Harmonic Motion Imaging (HMI) for Tumor Imaging and Treatment Monitoring

    PubMed Central

    Maleke, Caroline; Vappou, Jonathan

    2014-01-01

    Palpation is an established screening procedure for the detection of several superficial cancers including breast, thyroid, prostate, and liver tumors through both self and clinical examinations. This is because solid masses typically have distinct stiffnesses compared to the surrounding normal tissue. In this paper, the application of Harmonic Motion Imaging (HMI) for tumor detection based on its stiffness as well as its relevance in thermal treatment is reviewed. HMI uses a focused ultrasound (FUS) beam to generate an oscillatory acoustic radiation force for an internal, non-contact palpation to internally estimate relative tissue hardness. HMI studies have dealt with the measurement of the tissue dynamic motion in response to an oscillatory acoustic force at the same frequency, and have been shown feasible in simulations, phantoms, ex vivo human and bovine tissues as well as animals in vivo. Using an FUS beam, HMI can also be used in an ideal integration setting with thermal ablation using high-intensity focused ultrasound (HIFU), which also leads to an alteration in the tumor stiffness. In this paper, a short review of HMI is provided that encompasses the findings in all the aforementioned areas. The findings presented herein demonstrate that the HMI displacement can accurately depict the underlying tissue stiffness, and the HMI image of the relative stiffness could accurately detect and characterize the tumor or thermal lesion based on its distinct properties. HMI may thus constitute a non-ionizing, cost-efficient and reliable complementary method for noninvasive tumor detection, localization, diagnosis and treatment monitoring. PMID:25364321

  5. Endoscopic Ultrasonography-Guided Ethanol Ablation for Small Pancreatic Neuroendocrine Tumors: Results of a Pilot Study

    PubMed Central

    Choi, Jun-Ho; Oh, Dongwook; Lee, Sang Soo; Seo, Dong-Wan; Lee, Sung Koo; Kim, Myung-Hwan

    2015-01-01

    Background/Aims Endoscopic ultrasonography (EUS)-guided ethanol ablation is gaining popularity for the treatment of focal pancreatic lesions. The aim of this study was to evaluate the safety, feasibility, and treatment response after EUS-guided ethanol injection for small pancreatic neuroendocrine tumors (p-NETs). Methods This was a retrospective analysis of a prospectively collected database including 11 consecutive patients with p-NETs who underwent EUS-guided ethanol injection. Results EUS-guided ethanol injection was successfully performed in 11 patients with 14 tumors. The final diagnosis was based on histology and clinical signs as follows: 10 non-functioning neuroendocrine tumors and four insulinomas. During follow-up (median, 370 days; range, 152 to 730 days), 10 patients underwent clinical follow-up after treatment, and one patient was excluded because of loss to follow-up. A single treatment session with an injection of 0.5 to 3.8 mL of ethanol resulted in complete responses (CRs) at the 3-month radiologic imaging for seven of 13 tumors (response rate, 53.8%). Multiple treatment sessions performed in three tumors with residual viable enhancing tissue increased the number of tumors with CRs to eight of 13 (response rate, 61.5%). Mild pancreatitis occurred in three of 11 patients. Conclusions EUS-guided ethanol injection appears to be a safe, feasible, and potentially effective method for treating small p-NETs in patients who are poor surgical candidates. PMID:25844345

  6. Harmonic Motion Microwave Doppler Imaging method for breast tumor detection.

    PubMed

    Top, Can Barıs; Tafreshi, Azadeh Kamali; Gençer, Nevzat G

    2014-01-01

    Harmonic Motion Microwave Doppler Imaging (HMMDI) method is recently proposed as a non-invasive hybrid breast imaging technique for tumor detection. The acquired data depend on acoustic, elastic and electromagnetic properties of the tissue. The potential of the method is analyzed with simulation studies and phantom experiments. In this paper, the results of these studies are summarized. It is shown that HMMDI method has a potential to detect malignancies inside fibro-glandular tissue. PMID:25571382

  7. Endoscopic Ultrasound-Guided Radiofrequency Ablation of the Pancreatic Tumors: A Promising Tool in Management of Pancreatic Tumors

    PubMed Central

    2016-01-01

    Objective. Radiofrequency ablation is a well-established antitumor treatment and is recognized as one of the least invasive therapeutic modalities for pancreatic neoplasm. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) delivery can be used to treat both pancreatic cancer and asymptomatic premalignant pancreatic neoplasms and may serve as a less invasive alternative to surgical resection. This is an appealing option that may result in less morbidity and mortality. The aim of this review was to summarize and evaluate the clinical and technical effectiveness of EUS-guided RFA of pancreatic neoplasms. Methods. A through literature review was performed to identify the studies describing this novel technique. In this review article, we have summarized human case series. The indications, techniques, limitations, and complications reported are discussed. Results. A total of six studies were included. Overall, a 100% technical success rate was reported in human studies. Complications related to endoscopic ultrasound-guided radiofrequency ablation delivery have been described; however, few cases have presented life-threatening outcomes. Conclusion. We believe that this novel technique can be a safe and effective alternative approach in the management of selected patients. PMID:27478820

  8. SU-D-201-04: Study On the Impact of Tumor Shape and Size On Drug Delivery to Pancreatic Tumors

    SciTech Connect

    Soltani, M; Bazmara, H; Sefidgar, M; Subramaniam, R; Rahmim, A

    2015-06-15

    Purpose: Drug delivery to solid tumors can be expressed physically using transport phenomena such as convection and diffusion for the drug of interest within extracellular matrices. We aimed to carefully model these phenomena, and to investigate the effect of tumor shape and size on drug delivery to solid tumors in the pancreas. Methods: In this study, multiple tumor geometries as obtained from clinical PET/CT images were considered. An advanced numerical method was used to simultaneously solve fluid flow and solute transport equations. Data from n=45 pancreatic cancer patients with non-resectable locoregional disease were analyzed, and geometrical information from the tumors including size, shape, and aspect ratios were classified. To investigate effect of tumor shape, tumors with similar size but different shapes were selected and analyzed. Moreover, to investigate effect of tumor size, tumors with similar shapes but different sizes, ranging from 1 to 77 cm{sup 3}, were selected and analyzed. A hypothetical tumor similar to one of the analyzed tumors, but scaled to reduce its size below 0.2 cm{sup 3}, was also analyzed. Results: The results showed relatively similar average drug concentration profiles in tumors with different sizes. Generally, smaller tumors had higher absolute drug concentration. In the hypothetical tumor, with volume less than 0.2 cm{sup 3}, the average drug concentration was 20% higher in comparison to its counterparts. For the various real tumor geometries, however, the maximum difference between average drug concentrations was 10% for the smallest and largest tumors. Moreover, the results demonstrated that for pancreatic tumors the shape is not significant. The negligible difference of drug concentration in different tumor shapes was due to the minimum effect of convection in pancreatic tumors. Conclusion: In tumors with different sizes, smaller tumors have higher drug delivery; however, the impact of tumor shape in the case of pancreatic

  9. [Von Hippel-Lindau disease type 2-related pancreatic neuroendocrine tumor and adrenal myelolipoma].

    PubMed

    Dolzhansky, O V; Morozova, M M; Korostelev, S A; Kanivets, I V; Chardarov, N K; Shatveryan, G A; Pal'tseva, E M; Fedorov, D N

    2016-01-01

    The paper describes a case of von Hippel--Lindau-related pancreatic neuroendocrine tumor and adrenal myelolipoma in a 44-year-old woman. The pancreatic tumor and a left retroperitoneal mass were removed in the women in July 2014 and May 2015. Histological examination of the pancreatic tumor revealed that the latter consisted of clear cells forming tubular and tubercular structures showing the expression of chromogranin A, synaptophysin, and cytokeratins 18 and 19 and a negative response to CD10 and RCC. The adrenal medullary mass presented as clear-cell alveolar structures with inclusions of adipose tissue mixed with erythroid, myeloid, and lymphoid cells. The clear-cell component of the adrenal gland expressed neuroendocrine markers with a negative response to cytokeratins, CD10, and RCC. Molecular genetic examination yielded a signal corresponding to two copies of the VHL gene. No deletions or amplifications of the gene were detected. Cases of von Hippel--Lindau disease concurrent with adrenal pheochromocytoma and myelolipoma and simultaneous pancreatic involvement were not found in the literature. PMID:26978235

  10. Pancreatic polypeptide-rich islets in the posterior portion of the pancreatic head--a tumor mimic in somatostatin receptor scintigraphy.

    PubMed

    Albers, Max Benjamin; Maurer, Elisabeth; Klöppel, Günter; Bartsch, Detlef Klaus

    2014-05-01

    A 74-year-old man with recurrent duodenal ulcers underwent somatostatin receptor scintigraphy (SRS) in suspicion of gastrinoma. A 2-cm area of focal uptake was visualized within the pancreatic head. Serum chromogranin A levels were elevated, but serum gastrin levels and the secretin test were normal. Computed tomography and endoscopic ultrasonography were not conclusive. After partial duodenopancreatectomy, pathological examination failed to reveal any neuroendocrine tumor. Instead, the dorsal portion of the pancreatic head was found to be densely populated by pancreatic polypeptide cell-rich islets. This area correlated with the site of tracer uptake seen on SRS. Thus, pancreatic polypeptide cell-rich islets in elderly patients should be kept in mind when interpreting SRS results to avoid unnecessary major pancreatic resections. PMID:24713672

  11. Dual role of Ski in pancreatic cancer cells: tumor-promoting versus metastasis-suppressive function.

    PubMed

    Wang, Peng; Chen, Zhen; Meng, Zhi-Qiang; Fan, Jie; Luo, Jian-Min; Liang, Wang; Lin, Jun-Hua; Zhou, Zhen-Hua; Chen, Hao; Wang, Kun; Shen, Ye-Hua; Xu, Zu-De; Liu, Lu-Ming

    2009-09-01

    Ski used to be defined as an oncogene that contributes to the resistance of tumor cells to transforming growth factor-beta (TGF-beta)-induced growth arrest. As TGF-beta has a dual effect on tumor growth with both tumor-suppressing and -promoting activity depending on the stage of carcinogenesis and the cell type, the precise role of Ski in carcinogenesis remains unclear. In this study, we show that downregulation of Ski through lentivirus-mediated RNA interference decreases tumor growth both in vitro and in vivo, yet promotes cell invasiveness in vitro, and lung metastasis in vivo in the pancreatic cancer cell line SW1990, which contain wild-type Smad4 expression, and the BxPC3 cell line, which is Smad4 deficient. We also show that the downregulation of Ski increases TGF-beta-induced transcriptional activity, which is associated with increased TGF-beta-dependent Smad2/3 phosphorylation, and results in an altered expression profile of TGF-beta-inducible genes involved in metastasis, angiogenesis and cell proliferation and epithelial-mesenchymal transition. Immunohistochemical analysis of specimens from 71 patients with pancreatic adenocarcinoma showed a significant association between overexpression of Ski and decreased patient survival time (P = 0.0024). Our results suggest that Ski may act as a tumor proliferation-promoting factor or as a metastatic suppressor in human pancreatic cancer. PMID:19546161

  12. A Sporadic Desmoid Tumor: an Exceptional Pancreatic Cystic-Solid Mass.

    PubMed

    Ardakani, Jalal Vahedian; Mehrjardi, Ali Zare; Wadji, Massoud Baghai; Saraee, Amir

    2016-08-01

    Desmoid tumors are locally aggressive and non-metastatic neoplasms with a high rate of recurrence. Desmoid tumors of the pancreas are, however, very rare, and only a few cases have been reported in the literature. This paper reports an anecdotal case of a diffuse pancreatic desmoid tumor with the involvement of the pancreatic head, body, and-partially-tail. The patient underwent the Whipple procedure and subtotal pancreatectomy. Histopathological assessment showed that the tissues were partly positive for smooth muscle actin, but not for S100 or PanCK. The Ki67 index of the cells was only 1 %. Unfortunately, the patient died on the 10th postoperative day due to massive upper gastrointestinal bleeding. PMID:27574352

  13. Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma.

    PubMed

    Penny, Hweixian Leong; Sieow, Je Lin; Adriani, Giulia; Yeap, Wei Hseun; See Chi Ee, Peter; San Luis, Boris; Lee, Bernett; Lee, Terence; Mak, Shi Ya; Ho, Ying Swan; Lam, Kong Peng; Ong, Choon Kiat; Huang, Ruby Y J; Ginhoux, Florent; Rotzschke, Olaf; Kamm, Roger D; Wong, Siew Cheng

    2016-08-01

    Patients with pancreatic ductal adenocarcinoma (PDAC) face a clinically intractable disease with poor survival rates, attributed to exceptionally high levels of metastasis. Epithelial-to-mesenchymal transition (EMT) is pronounced at inflammatory foci within the tumor; however, the immunological mechanisms promoting tumor dissemination remain unclear. It is well established that tumors exhibit the Warburg effect, a preferential use of glycolysis for energy production, even in the presence of oxygen, to support rapid growth. We hypothesized that the metabolic pathways utilized by tumor-infiltrating macrophages are altered in PDAC, conferring a pro-metastatic phenotype. We generated tumor-conditioned macrophages in vitro, in which human peripheral blood monocytes were cultured with conditioned media generated from normal pancreatic or PDAC cell lines to obtain steady-state and tumor-associated macrophages (TAMs), respectively. Compared with steady-state macrophages, TAMs promoted vascular network formation, augmented extravasation of tumor cells out of blood vessels, and induced higher levels of EMT. TAMs exhibited a pronounced glycolytic signature in a metabolic flux assay, corresponding with elevated glycolytic gene transcript levels. Inhibiting glycolysis in TAMs with a competitive inhibitor to Hexokinase II (HK2), 2-deoxyglucose (2DG), was sufficient to disrupt this pro-metastatic phenotype, reversing the observed increases in TAM-supported angiogenesis, extravasation, and EMT. Our results indicate a key role for metabolic reprogramming of tumor-infiltrating macrophages in PDAC metastasis, and highlight the therapeutic potential of using pharmacologics to modulate these metabolic pathways. PMID:27622062

  14. Pancreatic Cancer Tumor Size on CT Scan Versus Pathologic Specimen: Implications for Radiation Treatment Planning

    SciTech Connect

    Arvold, Nils D.; Niemierko, Andrzej; Mamon, Harvey J.; Hong, Theodore S.

    2011-08-01

    Purpose: Pancreatic cancer primary tumor size measurements are often discordant between computed tomography (CT) and pathologic specimen after resection. Dimensions of the primary tumor are increasingly relevant in an era of highly conformal radiotherapy. Methods and Materials: We retrospectively evaluated 97 consecutive patients with resected pancreatic cancer at two Boston hospitals. All patients had CT scans before surgical resection. Primary endpoints were maximum dimension (in millimeters) of the primary tumor in any direction as reported by the radiologist on CT and by the pathologist for the resected gross fresh specimen. Endoscopic ultrasound (EUS) findings were analyzed if available. Results: Of the patients, 87 (90%) had preoperative CT scans available for review and 46 (47%) had EUS. Among proximal tumors (n = 69), 40 (58%) had pathologic duodenal invasion, which was seen on CT in only 3 cases. The pathologic tumor size was a median of 7 mm larger compared with CT size for the same patient (range, -15 to 43 mm; p < 0.0001), with 73 patients (84%) having a primary tumor larger on pathology than CT. Endoscopic ultrasound was somewhat more accurate, with pathologic tumor size being a median of only 5 mm larger compared with EUS size (range, -15 to 35 mm; p = 0.0003). Conclusions: Computed tomography scans significantly under-represent pancreatic cancer tumor size compared with pathologic specimens in resectable cases. We propose a clinical target volume expansion formula for the primary tumor based on our data. The high rate of pathologic duodenal invasion suggests a risk of duodenal undercoverage with highly conformal radiotherapy.

  15. Applications of a novel tumor-grading-metastasis staging system for pancreatic neuroendocrine tumors

    PubMed Central

    Yang, Min; Tan, Chun-Lu; Zhang, Yi; Ke, Neng-Wen; Zeng, Lin; Li, Ang; Zhang, Hao; Xiong, Jun-Jie; Guo, Zi-Heng; Tian, Bo-Le; Liu, Xu-Bao

    2016-01-01

    Abstract The ability to stratify patients with pancreatic neuroendocrine tumors (p-NETs) into prognostic groups has been hindered by the absence of a commonly accepted staging system. Both the 7th tumor-node-metastasis (TNM) staging guidelines by the American Joint Committee on Cancer (AJCC) and the 2010 grading classifications by the World Health Organization (WHO) were validated to be unsatisfactory. We aim to evaluate the feasibility of combining the latest AJCC and WHO criteria to devise a novel tumor-grading-metastasis (TGM) staging system. We also sought to examine the stage-specific survival rates and the prognostic value of this new TGM system for p-NETs. Data of 120 patients with surgical resection and histopathological diagnosis of p-NETs from January 2004 to February 2014 in our institution were retrospectively collected and analyzed. Based on the AJCC and WHO criteria, we replaced the stage N0 and N1 with stage Ga (NET G1 and NET G2) and Gb (NET G3 and MANEC) respectively, without changes of the definition of T or M stage. The present novel TGM staging system was grouped as follows: stage I was defined as T1–2, Ga, M0; stage II as T3, Ga, M0 or as T1–3, Gb, M0; stage III as T4, Ga–b, M0 and stage IV as any T, M1. The new TGM staging system successfully distributed 55, 42, 12, and 11 eligible patients in stage I to IV, respectively. Differences of survival compared stage I with III and IV for patients with p-NETs were both statistically significant (P < 0.001), as well as those of stage II with III and IV (P < 0.001). Patients in stage I showed better a survival than those in stage II, whereas difference between stages III and IV was not notable (P = 0.001, P = 0.286, respectively). In multivariate models, when the TGM staging system was evaluated in place of the individual T, G, and M variables, this new criteria were proven to be an independent predictor of survival for surgically resected p-NETs (P < 0.05). Stratifying patients well

  16. Von Hippel Lindau disease with metastatic pancreatic neuroendocrine tumor causing ectopic Cushing's syndrome.

    PubMed

    Hatipoglu, Esra; Kepicoglu, Hasan; Rusen, Elif; Kabasakal, Levent; Gundogdu, Sadi; Kadioglu, Pinar

    2013-01-01

    We present a 39-year-old woman who was previously diagnosed with Von Hippel Lindau Disease (VHLD). She had surgery and radiotherapy for cranial hemangioblastoma (HA) 11 years ago and had unilateral adrenalectomy for pheochromocytoma in another hospital 6 month prior to her admission to our center. Moon face, buffalo hump, central obesity, progressive weight gain and menstrual irregularities persisted after adrenalectomy. Her laboratory results were consistent with ectopic Cushing's syndrome (ECS). A pancreatic solid mass with a nodule on the left lung were revealed upon computed tomography. In addition, Gallium-68 Somatostatin Receptor PET confirmed the pancreatic involvement and demonstrated additional lesions on the left lung and in the aortocaval lymphatic system on the right side, suggesting metastatic pancreatic neuroendocrine tumor (PNET). Peptide receptor radionuclide therapy (PRRT) with [177Lutetium-DOTA0,Tyr3] octreotate was performed on the patient, with no side effects observed. She was discharged from the hospital 10 days after the first cycle. PMID:23524618

  17. Chondroitin Sulfate Proteoglycan CSPG4 as a Novel Hypoxia-Sensitive Marker in Pancreatic Tumors

    PubMed Central

    Keleg, Shereen; Titov, Alexandr; Heller, Anette; Giese, Thomas; Tjaden, Christine; Ahmad, Sufian S.; Gaida, Matthias M.; Bauer, Andrea S.; Werner, Jens; Giese, Nathalia A.

    2014-01-01

    CSPG4 marks pericytes, undifferentiated precursors and tumor cells. We assessed whether the shed ectodomain of CSPG4 (sCSPG4) might circulate and reflect potential changes in CSPG4 tissue expression (pCSPG4) due to desmoplastic and malignant aberrations occurring in pancreatic tumors. Serum sCSPG4 was measured using ELISA in test (n = 83) and validation (n = 221) cohorts comprising donors (n = 11+26) and patients with chronic pancreatitis (n = 11+20) or neoplasms: benign (serous cystadenoma SCA, n = 13+20), premalignant (intraductal dysplastic IPMNs, n = 9+55), and malignant (IPMN-associated invasive carcinomas, n = 4+14; ductal adenocarcinomas, n = 35+86). Pancreatic pCSPG4 expression was evaluated using qRT-PCR (n = 139), western blot analysis and immunohistochemistry. sCSPG4 was found in circulation, but its level was significantly lower in pancreatic patients than in donors. Selective maintenance was observed in advanced IPMNs and PDACs and showed a nodal association while lacking prognostic relevance. Pancreatic pCSPG4 expression was preserved or elevated, whereby neoplastic cells lacked pCSPG4 or tended to overexpress without shedding. Extreme pancreatic overexpression, membranous exposure and tissuehigh/seralow-discordance highlighted stroma-poor benign cystic neoplasm. SCA is known to display hypoxic markers and coincide with von-Hippel-Lindau and Peutz-Jeghers syndromes, in which pVHL and LBK1 mutations affect hypoxic signaling pathways. In vitro testing confined pCSPG4 overexpression to normal mesenchymal but not epithelial cells, and a third of tested carcinoma cell lines; however, only the latter showed pCSPG4-responsiveness to chronic hypoxia. siRNA-based knockdowns failed to reduce the malignant potential of either normoxic or hypoxic cells. Thus, overexpression of the newly established conditional hypoxic indicator, CSPG4, is apparently non-pathogenic in pancreatic malignancies but might mark distinct epithelial

  18. Expression of dynamin immunoreactivity in experimental pancreatic tumors induced in rat by mancozeb-nitrosomethylurea.

    PubMed

    Valentich, M A; Cook, T; Urrutia, R

    1996-04-19

    Dynamins are GTPases which support receptor-mediated endocytosis and bind to several tyrosine kinase receptor-associated proteins known to mediate cell proliferation and differentiation. We have recently established that dynamin expression correlates with normal neuronal (Torre et al., J. Biol. Chem., 269 (1994) 32411-32417) and acinar pancreatic cell differentiation (Cook et al., Mol. Biol. Cell, 6 (1995) 405a). To begin to understand the role of dynamin in neoplastic pancreatic cell differentiation, we have followed the expression of this protein by immunohistochemistry during the development of pancreatic tumors in a mancozeb-nitrosomethylurea (NMU)-based carcinogenesis model recently developed in our laboratory (Monis and Valentich, Carcinogenesis, 14 (1993) 929-933). After a single intraperitoneal injection (50 mg/g body wt) of this carcinogen, rats fed with mancozeb develop pancreatic focal acinar hyperplasia (FACH), dysplastic foci (DYF) displaying acinar-like and ductular-like structures, and ductular-like carcinoma in situ (CIS). After histochemical staining using a monoclonal anti-dynamin antibody, high levels of this protein are consistently observed in well-differentiated acinar tumors (FACH). In contrast, dynamin immunoreactivity is almost undetectable in more advanced lesions showing a ductular-like phenotype (ductular-like DYF and CIS). This change in the expression pattern of dynamin during the progression of acinar into ductular-like DYF and CIS lesions correlates with recent findings from our laboratory showing a differential expression pattern for dynamin in pancreatic cells during embryonic development, with ductular-like precursor cells expressing low levels of this protein. Based upon these results, we conclude that more advanced ductular-like neoplastic cells induced by the carcinogen NMU in rat pancreas behave phenotypically like pancreatic precursor cells in their pattern of expression for dynamin. PMID:8603375

  19. MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma.

    PubMed

    Tinder, Teresa L; Subramani, Durai B; Basu, Gargi D; Bradley, Judy M; Schettini, Jorge; Million, Arefayene; Skaar, Todd; Mukherjee, Pinku

    2008-09-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

  20. MUC1 enhances tumor progression and contributes towards immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma

    PubMed Central

    Tinder, Teresa L.; Subramani, Durai B.; Basu, Gargi D.; Bradley, Judy M.; Schettini, Jorge; Million, Arefayene; Skaar, Todd

    2008-01-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune competent host. Significant enhancement in the development of pancreatic intraepithelial pre-neoplastic lesions (PanINs) and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and indoleamine 2,3, dioxygenase compared to PDA mice lacking MUC1, especially during early stages of tumor development. The increased pro-inflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease which in turn regulate the immune responses. Thus, the mouse model is ideally-suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

  1. Prognostication and response assessment in liver and pancreatic tumors: The new imaging.

    PubMed

    De Robertis, Riccardo; Tinazzi Martini, Paolo; Demozzi, Emanuele; Puntel, Gino; Ortolani, Silvia; Cingarlini, Sara; Ruzzenente, Andrea; Guglielmi, Alfredo; Tortora, Giampaolo; Bassi, Claudio; Pederzoli, Paolo; D'Onofrio, Mirko

    2015-06-14

    Diffusion-weighted imaging (DWI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and perfusion computed tomography (CT) are technical improvements of morphologic imaging that can evaluate functional properties of hepato-bilio-pancreatic tumors during conventional MRI or CT examinations. Nevertheless, the term "functional imaging" is commonly used to describe molecular imaging techniques, as positron emission tomography (PET) CT/MRI, which still represent the most widely used methods for the evaluation of functional properties of solid neoplasms; unlike PET or single photon emission computed tomography, functional imaging techniques applied to conventional MRI/CT examinations do not require the administration of radiolabeled drugs or specific equipments. Moreover, DWI and DCE-MRI can be performed during the same session, thus providing a comprehensive "one-step" morphological and functional evaluation of hepato-bilio-pancreatic tumors. Literature data reveal that functional imaging techniques could be proposed for the evaluation of these tumors before treatment, given that they may improve staging and predict prognosis or clinical outcome. Microscopic changes within neoplastic tissues induced by treatments can be detected and quantified with functional imaging, therefore these techniques could be used also for post-treatment assessment, even at an early stage. The aim of this editorial is to describe possible applications of new functional imaging techniques apart from molecular imaging to hepatic and pancreatic tumors through a review of up-to-date literature data, with a particular emphasis on pathological correlations, prognostic stratification and post-treatment monitoring. PMID:26078555

  2. Prognostication and response assessment in liver and pancreatic tumors: The new imaging

    PubMed Central

    De Robertis, Riccardo; Tinazzi Martini, Paolo; Demozzi, Emanuele; Puntel, Gino; Ortolani, Silvia; Cingarlini, Sara; Ruzzenente, Andrea; Guglielmi, Alfredo; Tortora, Giampaolo; Bassi, Claudio; Pederzoli, Paolo; D’Onofrio, Mirko

    2015-01-01

    Diffusion-weighted imaging (DWI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and perfusion computed tomography (CT) are technical improvements of morphologic imaging that can evaluate functional properties of hepato-bilio-pancreatic tumors during conventional MRI or CT examinations. Nevertheless, the term “functional imaging” is commonly used to describe molecular imaging techniques, as positron emission tomography (PET) CT/MRI, which still represent the most widely used methods for the evaluation of functional properties of solid neoplasms; unlike PET or single photon emission computed tomography, functional imaging techniques applied to conventional MRI/CT examinations do not require the administration of radiolabeled drugs or specific equipments. Moreover, DWI and DCE-MRI can be performed during the same session, thus providing a comprehensive “one-step” morphological and functional evaluation of hepato-bilio-pancreatic tumors. Literature data reveal that functional imaging techniques could be proposed for the evaluation of these tumors before treatment, given that they may improve staging and predict prognosis or clinical outcome. Microscopic changes within neoplastic tissues induced by treatments can be detected and quantified with functional imaging, therefore these techniques could be used also for post-treatment assessment, even at an early stage. The aim of this editorial is to describe possible applications of new functional imaging techniques apart from molecular imaging to hepatic and pancreatic tumors through a review of up-to-date literature data, with a particular emphasis on pathological correlations, prognostic stratification and post-treatment monitoring. PMID:26078555

  3. Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages

    PubMed Central

    Chin, Shan M.; Vardam-Kaur, Trupti; Liu, Hao; Hato, Tai; Babykutty, Suboj; Chen, Ivy; Deshpande, Vikram; Jain, Rakesh K.; Fukumura, Dai

    2015-01-01

    Background Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with a dismal prognosis for most patients. Fibrosis and inflammation are hallmarks of tumor desmoplasia. We have previously demonstrated that preventing the activation of pancreatic stellate cells (PSCs) and alleviating desmoplasia are beneficial strategies in treating PDAC. Metformin is a widely used glucose-lowering drug. It is also frequently prescribed to diabetic pancreatic cancer patients and has been shown to associate with a better outcome. However, the underlying mechanisms of this benefit remain unclear. Metformin has been found to modulate the activity of stellate cells in other disease settings. In this study, we examine the effect of metformin on PSC activity, fibrosis and inflammation in PDACs. Methods/Results In overweight, diabetic PDAC patients and pre-clinical mouse models, treatment with metformin reduced levels of tumor extracellular matrix (ECM) components, in particular hyaluronan (HA). In vitro, we found that metformin reduced TGF-ß signaling and the production of HA and collagen-I in cultured PSCs. Furthermore, we found that metformin alleviates tumor inflammation by reducing the expression of inflammatory cytokines including IL-1β as well as infiltration and M2 polarization of tumor-associated macrophages (TAMs) in vitro and in vivo. These effects on macrophages in vitro appear to be associated with a modulation of the AMPK/STAT3 pathway by metformin. Finally, we found in our preclinical models that the alleviation of desmoplasia by metformin was associated with a reduction in ECM remodeling, epithelial-to-mesenchymal transition (EMT) and ultimately systemic metastasis. Conclusion Metformin alleviates the fibro-inflammatory microenvironment in obese/diabetic individuals with pancreatic cancer by reprogramming PSCs and TAMs, which correlates with reduced disease progression. Metformin should be tested/explored as part of the treatment strategy in overweight

  4. Hypothyroidism in Pancreatic Cancer: Role of Exogenous Thyroid Hormone in Tumor Invasion—Preliminary Observations

    PubMed Central

    Sarosiek, Konrad; Gandhi, Ankit V.; Saxena, Shivam; Kang, Christopher Y.; Chipitsyna, Galina I.; Yeo, Charles J.; Arafat, Hwyda A.

    2016-01-01

    According to the epidemiological studies, about 4.4% of American general elderly population has a pronounced hypothyroidism and relies on thyroid hormone supplements daily. The prevalence of hypothyroidism in our patients with pancreatic cancer was much higher, 14.1%. A retrospective analysis was performed on patients who underwent pancreaticoduodenectomy (Whipple procedure) or distal pancreatectomy and splenectomy (DPS) at Thomas Jefferson University Hospital, Philadelphia, from 2005 to 2012. The diagnosis of hypothyroidism was correlated with clinicopathologic parameters including tumor stage, grade, and survival. To further understand how thyroid hormone affects pancreatic cancer behavior, functional studies including wound-induced cell migration, proliferation, and invasion were performed on pancreatic cancer cell lines, MiaPaCa-2 and AsPC-1. We found that hypothyroid patients taking exogenous thyroid hormone were more than three times likely to have perineural invasion, and about twice as likely to have higher T stage, nodal spread, and overall poorer prognostic stage (P < 0.05). Pancreatic cancer cell line studies demonstrated that exogenous thyroid hormone treatment increased cell proliferation, migration, and invasion (P < 0.05). We conclude that exogenous thyroid hormone may contribute to the progression of pancreatic cancer. PMID:27123358

  5. Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors.

    PubMed

    Nair, Vijayalekshmi; Pathi, Satya; Jutooru, Indira; Sreevalsan, Sandeep; Basha, Riyaz; Abdelrahim, Maen; Samudio, Ismael; Safe, Stephen

    2013-12-01

    Metformin is a widely used antidiabetic drug, and epidemiology studies for pancreatic and other cancers indicate that metformin exhibits both chemopreventive and chemotherapeutic activities. Several metformin-induced responses and genes are similar to those observed after knockdown of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 by RNA interference, and we hypothesized that the mechanism of action of metformin in pancreatic cancer cells was due, in part, to downregulation of Sp transcription factors. Treatment of Panc1, L3.6pL and Panc28 pancreatic cancer cells with metformin downregulated Sp1, Sp3 and Sp4 proteins and several pro-oncogenic Sp-regulated genes including bcl-2, survivin, cyclin D1, vascular endothelial growth factor and its receptor, and fatty acid synthase. Metformin induced proteasome-dependent degradation of Sps in L3.6pL and Panc28 cells, whereas in Panc1 cells metformin decreased microRNA-27a and induced the Sp repressor, ZBTB10, and disruption of miR-27a:ZBTB10 by metformin was phosphatase dependent. Metformin also inhibited pancreatic tumor growth and downregulated Sp1, Sp3 and Sp4 in tumors in an orthotopic model where L3.6pL cells were injected directly into the pancreas. The results demonstrate for the first time that the anticancer activities of metformin are also due, in part, to downregulation of Sp transcription factors and Sp-regulated genes. PMID:23803693

  6. Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors

    PubMed Central

    Safe, Stephen

    2013-01-01

    Metformin is a widely used antidiabetic drug, and epidemiology studies for pancreatic and other cancers indicate that metformin exhibits both chemopreventive and chemotherapeutic activities. Several metformin-induced responses and genes are similar to those observed after knockdown of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 by RNA interference, and we hypothesized that the mechanism of action of metformin in pancreatic cancer cells was due, in part, to downregulation of Sp transcription factors. Treatment of Panc1, L3.6pL and Panc28 pancreatic cancer cells with metformin downregulated Sp1, Sp3 and Sp4 proteins and several pro-oncogenic Sp-regulated genes including bcl-2, survivin, cyclin D1, vascular endothelial growth factor and its receptor, and fatty acid synthase. Metformin induced proteasome-dependent degradation of Sps in L3.6pL and Panc28 cells, whereas in Panc1 cells metformin decreased microRNA-27a and induced the Sp repressor, ZBTB10, and disruption of miR-27a:ZBTB10 by metformin was phosphatase dependent. Metformin also inhibited pancreatic tumor growth and downregulated Sp1, Sp3 and Sp4 in tumors in an orthotopic model where L3.6pL cells were injected directly into the pancreas. The results demonstrate for the first time that the anticancer activities of metformin are also due, in part, to downregulation of Sp transcription factors and Sp-regulated genes. PMID:23803693

  7. CD14/TLR4 priming potentially recalibrates and exerts anti-tumor efficacy in tumor associated macrophages in a mouse model of pancreatic carcinoma.

    PubMed

    Prakash, Hridayesh; Nadella, Vinod; Singh, Sandhya; Schmitz-Winnenthal, Hubertus

    2016-01-01

    Pancreatic cancer is the fourth major cause of cancer related deaths in the world and 5 year survival is below 5%. Among various tumor directed therapies, stimulation of Toll-like receptors (TLR) has shown promising effects in various tumor models. However, pancreatic cancer cells frequently express these receptors themselves and their stimulation (TLR 2 and/or 4 particularly) within tumor microenvironment is known to potentially enhance tumor cell proliferation and cancer progression. Consistent stimulation of tumor associated macrophages (TAMs), in particular with tumor derived TLR ligand within the tumor microenvironment promotes cancer related inflammation, which is sterile, non-immunogenic and carcinogenic in nature. In view of this, recalibrating of TAM has the potential to induce immunogenic inflammation. Consistent with this, we provide experimental evidence for the first time in this study that priming of TAMs with TLR4 ligend (LPS) alone or in combination with IFN-γ not only recalibrates pancreatic tumor cells induced M2 polarization, but also confers anti-tumor potential in TAMs. Most interestingly, reduced tumor growth in macrophage depleted animals suggests that macrophage directed approaches are important for the management of pancreatic tumors. PMID:27511884

  8. CD14/TLR4 priming potentially recalibrates and exerts anti-tumor efficacy in tumor associated macrophages in a mouse model of pancreatic carcinoma

    PubMed Central

    Prakash, Hridayesh; Nadella, Vinod; Singh, Sandhya; Schmitz-Winnenthal, Hubertus

    2016-01-01

    Pancreatic cancer is the fourth major cause of cancer related deaths in the world and 5 year survival is below 5%. Among various tumor directed therapies, stimulation of Toll-like receptors (TLR) has shown promising effects in various tumor models. However, pancreatic cancer cells frequently express these receptors themselves and their stimulation (TLR 2 and/or 4 particularly) within tumor microenvironment is known to potentially enhance tumor cell proliferation and cancer progression. Consistent stimulation of tumor associated macrophages (TAMs), in particular with tumor derived TLR ligand within the tumor microenvironment promotes cancer related inflammation, which is sterile, non-immunogenic and carcinogenic in nature. In view of this, recalibrating of TAM has the potential to induce immunogenic inflammation. Consistent with this, we provide experimental evidence for the first time in this study that priming of TAMs with TLR4 ligend (LPS) alone or in combination with IFN-γ not only recalibrates pancreatic tumor cells induced M2 polarization, but also confers anti-tumor potential in TAMs. Most interestingly, reduced tumor growth in macrophage depleted animals suggests that macrophage directed approaches are important for the management of pancreatic tumors. PMID:27511884

  9. Procathepsin E is highly abundant but minimally active in pancreatic ductal adenocarcinoma tumors.

    PubMed

    O'Donoghue, Anthony J; Ivry, Sam L; Chaudhury, Chaity; Hostetter, Daniel R; Hanahan, Douglas; Craik, Charles S

    2016-09-01

    The cathepsin family of lysosomal proteases is increasingly being recognized for their altered expression in cancer and role in facilitating tumor progression. The aspartyl protease cathepsin E is overexpressed in several cancers and has been investigated as a biomarker for pancreatic ductal adenocarcinoma (PDAC). Here we show that cathepsin E expression in mouse PDAC tumors is increased by more than 400-fold when compared to healthy pancreatic tissue. Cathepsin E accumulates over the course of disease progression and accounts for more than 3% of the tumor protein in mice with end-stage disease. Through immunoblot analysis we determined that only procathepsin E exists in mouse PDAC tumors and cell lines derived from these tumors. By decreasing the pH, this procathepsion E is converted to the mature form, resulting in an increase in proteolytic activity. Although active site inhibitors can bind procathepsin E, treatment of PDAC mice with the aspartyl protease inhibitor ritonavir did not decrease tumor burden. Lastly, we used multiplex substrate profiling by mass spectrometry to identify two synthetic peptides that are hydrolyzed by procathepsin E near neutral pH. This work represents a comprehensive analysis of procathepsin E in PDAC and could facilitate the development of improved biomarkers for disease detection. PMID:27149201

  10. Hypoxia Responsive, Tumor Penetrating Lipid Nanoparticles for Delivery of Chemotherapeutics to Pancreatic Cancer Cell Spheroids.

    PubMed

    Kulkarni, Prajakta; Haldar, Manas K; Katti, Preeya; Dawes, Courtney; You, Seungyong; Choi, Yongki; Mallik, Sanku

    2016-08-17

    Solid tumors are often poorly irrigated due to structurally compromised microcirculation. Uncontrolled multiplication of cancer cells, insufficient blood flow, and the lack of enough oxygen and nutrients lead to the development of hypoxic regions in the tumor tissues. As the partial pressure of oxygen drops below the necessary level (10 psi), the cancer cells modulate their genetic makeup to survive. Hypoxia triggers tumor progression by enhancing angiogenesis, cancer stem cell production, remodeling of the extracellular matrix, and epigenetic changes in the cancer cells. However, the hypoxic regions are usually located deep in the tumors and are usually inaccessible to the intravenously injected drug carrier or the drug. Considering the designs of the reported nanoparticles, it is likely that the drug is delivered to the peripheral tumor tissues, close to the blood vessels. In this study, we prepared lipid nanoparticles (LNs) comprising the synthesized hypoxia-responsive lipid and a peptide-lipid conjugate. We observed that the resultant LNs penetrated to the hypoxic regions of the tumors. Under low oxygen partial pressure, the hypoxia-responsive lipid undergoes reduction, destabilizing the lipid membrane, and releasing encapsulated drugs from the nanoparticles. We demonstrated the results employing spheroidal cultures of the pancreatic cancer cells BxPC-3. We observed that the peptide-decorated, drug encapsulated LNs reduced the viability of pancreatic cancer cells of the spheroids to 35% under hypoxic conditions. PMID:27391789

  11. Imaging Tumor Variation in Response to Photodynamic Therapy in Pancreatic Cancer Xenograft Models

    SciTech Connect

    Samkoe, Kimberley S.; Chen, Alina; Rizvi, Imran; O'Hara, Julia A.; Hoopes, P. Jack; Pereira, Stephen P.; Hasan, Tayyaba; Pogue, Brian W.

    2010-01-15

    Purpose: A treatment monitoring study investigated the differential effects of orthotopic pancreatic cancer models in response to interstitial photodynamic therapy (PDT), and the validity of using magnetic resonance imaging as a surrogate measure of response was assessed. Methods and Materials: Different orthotopic pancreatic cancer xenograft models (AsPC-1 and Panc-1) were used to represent the range of pathophysiology observed in human beings. Identical dose escalation studies (10, 20, and 40J/cm) using interstitial verteporfin PDT were performed, and magnetic resonance imaging with T2-weighted and T1-weighted contrast were used to monitor the total tumor volume and the vascular perfusion volume, respectively. Results: There was a significant amount of necrosis in the slower-growing Panc-1 tumor using high light dose, although complete necrosis was not observed. Lower doses were required for the same level of tumor kill in the faster-growing AsPC-1 cell line. Conclusions: The tumor growth rate and vascular pattern of the tumor affect the optimal PDT treatment regimen, with faster-growing tumors being relatively easier to treat. This highlights the fact that therapy in human beings shows a heterogeneous range of outcomes, and suggests a need for careful individualized treatment outcomes assessment in clinical work.

  12. Pancreatic neuroendocrine tumors: Challenges in an underestimated disease.

    PubMed

    Viúdez, A; De Jesus-Acosta, A; Carvalho, F L; Vera, R; Martín-Algarra, S; Ramírez, N

    2016-05-01

    Pancreatic neuroendocrine tumours (PanNETs) are considered a relatively unusual oncologic entity. Due to its relative good prognosis, surgery remains the goal standard therapy not only in localized disease but also in the setting of locally or metastatic disease. Most of the patients are diagnosed in metastatic scenario, where multidisciplinary approach based on surgery, chemotherapies, liver-directed and/or molecular targeted therapies are commonly used. Owing to a deeper molecular knowledge of this disease, these targeted therapies are nowadays widely implemented, being the likely discovery of predictive biomarkers that would allow its use in other settings. This review is focused on describing the different classifications, etiology, prognostic biomarkers and multidisciplinary approaches that are typically used in PanNET. PMID:27021395

  13. MUC1-specific CTLs are non-functional within a pancreatic tumor microenvironment.

    PubMed

    Mukherjee, P; Ginardi, A R; Madsen, C S; Tinder, T L; Jacobs, F; Parker, J; Agrawal, B; Longenecker, B M; Gendler, S J

    2001-01-01

    Pancreatic cancer is a highly aggressive, treatment refractory disease and is the fourth leading cause of death in the United States. In humans, 90% of pancreatic adenocarcinomas over-express altered forms of a tumor-associated antigen, MUC1 (an epithelial mucin glycoprotein), which is a target for immunotherapy. Using a clinically relevant mouse model of pancreas cancer that demonstrates peripheral and central tolerance to human MUC1 and develops spontaneous tumors of the pancreas, we have previously reported the presence of functionally active, low affinity, MUC1-specific precursor cytotoxic T cells (pCTLs). Hypothesis for this study is that MUC1-based immunization may enhance the low level MUC1-specific immunity that may lead to an effective anti-tumor response. Data demonstrate that MUC1 peptide-based immunization elicits mature MUC1-specific CTLs in the peripheral lymphoid organs. The mature CTLs secrete IFN-gamma and are cytolytic against MUC1-expressing tumor cells in vitro. However, active CTLs that infiltrate the pancreas tumor microenvironment become cytolytically anergic and are tolerized to MUC1 antigen, allowing the tumor to grow. We demonstrate that the CTL tolerance could be reversed at least in vitro with the use of anti-CD40 co-stimulation. The pancreas tumor cells secrete immunosuppressive cytokines, including IL-10 and TGF-beta that are partly responsible for the down-regulation of CTL activity. In addition, they down-regulate their MHC class I molecules to avoid immune recognition. CD4+ CD25+ T regulatory cells, which secrete IL-10, were also found in the tumor environment. Together these data indicate the use of several immune evasion mechanisms by tumor cells to evade CTL killing. Thus altering the tumor microenvironment to make it more conducive to CTL killing may be key in developing a successful anti-cancer immunotherapy. PMID:12820727

  14. Pancreatitis

    MedlinePlus

    ... open. Balloon dilatation. Some endoscopes have a small balloon that the doctor uses to dilate, or stretch, a narrowed pancreatic or bile duct. A temporary stent may be placed for a few months to ...

  15. Characterization of a pancreatic islet cell tumor in a polar bear (Ursus maritimus).

    PubMed

    Fortin, Jessica S; Benoit-Biancamano, Marie-Odile

    2014-01-01

    Herein, we report a 25-year-old male polar bear suffering from a pancreatic islet cell tumor. The aim of this report is to present a case of this rare tumor in a captive polar bear. The implication of potential risk factors such as high carbohydrate diet or the presence of amyloid fibril deposits was assessed. Necropsy examination revealed several other changes, including nodules observed in the liver, spleen, pancreas, intestine, and thyroid glands that were submitted for histopathologic analysis. Interestingly, the multiple neoplastic nodules were unrelated and included a pancreatic islet cell tumor. Immunohistochemistry of the pancreas confirmed the presence of insulin and islet amyloid polypeptide (IAPP) within the pancreatic islet cells. The IAPP gene was extracted from the paraffin-embedded liver tissue and sequenced. IAPP cDNA from the polar bear exhibits some differences as compared to the sequence published for several other species. Different factors responsible for neoplasms in bears such as diet, infectious agents, and industrial chemical exposure are reviewed. This case report raised several issues that further studies may address by evaluating the prevalence of cancers in captive or wild animals. PMID:25273481

  16. Correlation between internal fiducial tumor motion and external marker motion for liver tumors imaged with 4D-CT

    SciTech Connect

    Beddar, A. Sam . E-mail: abeddar@mdanderson.org; Kainz, Kristofer; Briere, Tina Marie; Tsunashima, Yoshikazu; Pan Tinsu; Prado, Karl; Mohan, Radhe; Gillin, Michael; Krishnan, Sunil

    2007-02-01

    Purpose: We investigated the correlation between the motions of an external marker and internal fiducials implanted in the liver for 8 patients undergoing respiratory-based computed tomography (four-dimensional CT [4D-CT]) procedures. Methods and Materials: The internal fiducials were gold seeds, 3 mm in length and 1.2 mm in diameter. Four patients each had one implanted fiducial, and the other four had three implanted fiducials. The external marker was a plastic box, which is part of the Real-Time Position Management System (RPM) used to track the patient's respiration. Each patient received a standard helical CT scan followed by a time-correlated CT-image acquisition (4D-CT). The 4D-CT images were reconstructed in 10 separate phases covering the entire respiratory cycle. Results: The internal fiducial motion is predominant in the superior-inferior direction, with a range of 7.5-17.5 mm. The correlation between external respiration and internal fiducial motion is best during expiration. For 2 patients with their three fiducials separated by a maximum of 3.2 cm, the motions of the fiducials were well correlated, whereas for 2 patients with more widely spaced fiducials, there was less correlation. Conclusions: In general, there is a good correlation between internal fiducial motion imaged by 4D-CT and external marker motion. We have demonstrated that gating may be best performed at the end of the respiratory cycle. Special attention should be paid to gating for patients whose fiducials do not move in synchrony, because targeting on the correct respiratory amplitude alone would not guarantee that the entire tumor volume is within the treatment field.

  17. Schwann Cells Increase Prostate and Pancreatic Tumor Cell Invasion Using Laminin Binding A6 Integrin

    PubMed Central

    Sroka, Isis C.; Chopra, Harsharon; Das, Lipsa; Gard, Jaime M.C.; Nagle, Raymond B.; Cress, Anne E.

    2016-01-01

    Human pancreatic and prostate cancers metastasize along nerve axons during perineural invasion. The extracellular matrix laminin class of proteins is an abundant component of both myelinated and non-myelinated nerves. Analysis of human pancreatic and prostate tissue revealed both perineural and endoneural invasion with Schwann cells surrounded or disrupted by tumor, respectively. Tumor and nerve cell co-culture conditions were used to determine if myelinating or non-myelinating Schwann cell (S16 and S16Y, respectively) phenotype was equally likely to promote integrin-dependent cancer cell invasion and migration on laminin. Conditioned medium from S16 cells increased tumor cell (DU145, PC3, and CFPAC1) invasion into laminin approximately 1.3–2.0 fold compared to fetal bovine serum (FBS) treated cells. Integrin function (e.g., ITGA6p formation) increased up to 1.5 fold in prostate (DU145, PC3, RWPE-1) and pancreatic (CFPAC1) cells, and invasion was dependent on ITGA6p formation and ITGB1 as determined by function-blocking antibodies. In contrast, conditioned medium isolated from S16Y cells (non-myelinating phenotype) decreased constitutive levels of ITGA6p in the tumor cells by 50% compared to untreated cells and decreased ITGA6p formation 3.0 fold compared to S16 treated cells. Flow cytometry and western blot analysis revealed loss of ITGA6p formation as reversible and independent of overall loss of ITGA6 expression. These results suggest that the myelinating phenotype of Schwann cells within the tumor microenvironment increased integrin-dependent tumor invasion on laminin. PMID:26239765

  18. Efficacy and Safety of Endoscopic Ultrasound-guided Ethanol Ablation Therapy for Pancreatic Neuroendocrine Tumors.

    PubMed

    Matsumoto, Kazuyuki; Kato, Hironari; Tsutsumi, Koichiro; Mizukawa, Sho; Yabe, Syuntaro; Seki, Hiroyuki; Akimoto, Yutaka; Uchida, Daisuke; Tomoda, Takeshi; Yamamoto, Naoki; Horiguchi, Shigeru; Okada, Hiroyuki

    2016-08-01

    Recently, endoscopic ultrasonography (EUS)-guided ethanol ablation for small pancreatic neuroendocrine tumors (p-NETs) has been reported. However, the efficacy and safety of the technique remain unclear. We have launched a prospective pilot study of EUS-guided ethanol ablation for p-NETs. The major eligibility criteria are the presence of a pathologically diagnosed grade (G) 1 or G2 p-NET, a tumor size of 2cm, and being a poor candidate for surgery. A total of 5 patients will be treated. The primary endpoint will be the complete ablation rate at 1 month after treatment. PMID:27549680

  19. New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies.

    PubMed

    Schmitt, Anja M; Marinoni, Ilaria; Blank, Annika; Perren, Aurel

    2016-09-01

    The recent findings on the roles of death-associated protein 6/α-thalassemia/mental retardation X-linked (DAXX/ATRX) in the development of pancreatic neuroendocrine tumors (PanNETs) have led to major advances in the molecular understanding of these rare tumors and open up completely new therapeutic windows. This overview aims at giving a simplified view on these findings and their possible therapeutic implications. The importance of epigenetic changes in PanNET is also underlined by recent findings of a cross-species study on microRNA (miRNA) and messenger RNA (mRNA) profiles in PanNETs. PMID:27456058

  20. Polyethylenimine-coated SPION exhibits potential intrinsic anti-metastatic properties inhibiting migration and invasion of pancreatic tumor cells.

    PubMed

    Mulens-Arias, Vladimir; Rojas, José Manuel; Pérez-Yagüe, Sonia; Morales, María del Puerto; Barber, Domingo F

    2015-10-28

    Due to its aggressive behavior, pancreatic cancer is one of the principal causes of cancer-related deaths. The highly metastatic potential of pancreatic tumor cells demands the development of more effective anti-metastatic approaches for this disease. Although polyethylenimine-coated superparamagnetic iron oxide nanoparticles (PEI-coated SPIONs) have been studied for their utility as transfection agents, little is known of their effect on tumor cell biology. Here we demonstrated that PEI-coated SPIONs have potent inhibitory effects on pancreatic tumor cell migration/invasion, through inhibition of Src kinase and decreased expression of MT1-MMP and MMP2 metalloproteinases. When treated with PEI-coated SPIONs, the pancreatic tumor cell line Pan02 showed reduced invadosome density and thus, a decrease in their ability to invade through basement membrane. These nanoparticles temporarily downmodulated microRNA-21, thereby upregulating the cell migration inhibitors PTEN, PDCD4 and Sprouty-1. PEI-coated SPIONs thus show intrinsic, possibly anti-metastatic properties for modulating pancreatic tumor cell migration machinery, which indicates their potential as anti-metastatic agents for treatment of pancreatic cancer. PMID:26264831

  1. Accumulation of Extracellular Hyaluronan by Hyaluronan Synthase 3 Promotes Tumor Growth and Modulates the Pancreatic Cancer Microenvironment

    PubMed Central

    Zhao, Chunmei; Singha, Netai C.; Osgood, Ryan J.; Symons, Rebecca; Jiang, Ping; Li, Xiaoming; Thompson, Curtis B.; Infante, Jeffrey R.; Jacobetz, Michael A.; Tuveson, David A.; Frost, Gregory I.; Shepard, H. Michael; Huang, Zhongdong

    2014-01-01

    Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmic β-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin and β-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth. PMID:25147816

  2. Accumulation of extracellular hyaluronan by hyaluronan synthase 3 promotes tumor growth and modulates the pancreatic cancer microenvironment.

    PubMed

    Kultti, Anne; Zhao, Chunmei; Singha, Netai C; Zimmerman, Susan; Osgood, Ryan J; Symons, Rebecca; Jiang, Ping; Li, Xiaoming; Thompson, Curtis B; Infante, Jeffrey R; Jacobetz, Michael A; Tuveson, David A; Frost, Gregory I; Shepard, H Michael; Huang, Zhongdong

    2014-01-01

    Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmic β-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin and β-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth. PMID:25147816

  3. Metastatic pancreatic neuroendocrine tumor to the central nervous system in a patient with von Hippel-Lindau disease: A case report and literature review.

    PubMed

    Reynolds, Matthew R; Crilly, Shane M; Sweeney, Kieron J; Farrell, Michael; Rawluk, Daniel

    2015-04-01

    Pancreatic neuroendocrine tumor (NET) is frequently encountered in patients with von Hippel-Lindau disease (VHL) and uncommonly metastasizes to the central nervous system. Here, we present the case of a VHL patient with symptomatic pancreatic NET metastases to both the cervical spinal cord and a preexisting brainstem hemangioblastoma (e.g., tumor- to-tumor metastasis). PMID:25232806

  4. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma

    PubMed Central

    Moffitt, Richard A.; Marayati, Raoud; Flate, Elizabeth L.; Volmar, Keith E.; Loeza, S. Gabriela Herrera; Hoadley, Katherine A.; Rashid, Naim U.; Williams, Lindsay A.; Eaton, Samuel C.; Chung, Alexander H.; Smyla, Jadwiga K.; Anderson, Judy M.; Kim, Hong Jin; Bentrem, David J.; Talamonti, Mark S.; Iacobuzio-Donahue, Christine A.; Hollingsworth, Michael A.; Yeh, Jen Jen

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here, we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, which includes primary, metastatic, and normal samples. By digitally separating tumor, stroma, and normal gene expression, we have identified and validated two tumor-specific subtypes including a “basal-like” subtype which has worse outcome, and is molecularly similar to basal tumors in bladder and breast cancer. Furthermore, we define “normal” and “activated” stromal subtypes which are independently prognostic. Our results provide new insight into the molecular composition of PDAC which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies is critical. PMID:26343385

  5. Pancreatic perivascular epithelioid cell tumor: A case report with clinicopathological features and a literature review

    PubMed Central

    Jiang, Hui; Ta, Na; Huang, Xiao-Yi; Zhang, Ming-Hua; Xu, Jing-Jing; Zheng, Kai-Lian; Jin, Gang; Zheng, Jian-Ming

    2016-01-01

    Perivascular epithelioid cell tumor (PEComa) of the pancreas is an unusual tumor deriving from mesenchyma. This paper described a case of pancreatic PEComa, which was initially suspected as neuroendocrine carcinoma by biopsy, and therefore surgical treatment was recommended due to undetermined diagnosis. Examination of the surgical specimen under a microscope showed that the tumor cell’s morphology was epithelioid or spindle-shaped, and ranged in a nested pattern. Additionally, these cells had a large extent of acidophilic cytoplasm, no mitotic figures, and expressed HMB-45, melan-p, and smooth muscle actin immunohistochemically. Pathological examination indicated that PEComa originated from the pancreas, but symptoms related to tuberous sclerosis were absent. Since PEComa is extremely rare in the pancreas, it is likely to be ignored in differential diagnosis. In conclusion, our article highlighted the clinicopathological features of PEComa, and we conducted a literature review focusing on PEComa so as to deepen the understanding of this tumor type. PMID:27053862

  6. Pancreatic ductal adenocarcinoma mice lacking mucin 1 have a profound defect in tumor growth and metastasis.

    PubMed

    Besmer, Dahlia M; Curry, Jennifer M; Roy, Lopamudra D; Tinder, Teresa L; Sahraei, Mahnaz; Schettini, Jorge; Hwang, Sun-Il; Lee, Yong Y; Gendler, Sandra J; Mukherjee, Pinku

    2011-07-01

    MUC1 is overexpressed and aberrantly glycosylated in more than 60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In this study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared with both KC and KCM. Cell lines derived from KCKO tumors have significantly less tumorigenic capacity compared with cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared with mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor, platelet-derived growth factor, or matrix metalloproteinase 9. Further, significantly less KCKO cells entered the G(2)-M phase of the cell cycle compared with the KCM cells. Proteomics and Western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of mitogen-activated protein kinase (MAPK), as well as a significant decrease in nestin and tubulin-α2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. PMID:21558393

  7. Zyflamend Suppresses Growth and Sensitizes Human Pancreatic Tumors to Gemcitabine in an Orthotopic Mouse Model Through Modulation of Multiple Targets

    PubMed Central

    Kunnumakkara, Ajaikumar B.; Sung, Bokyung; Ravindran, Jayaraj; Diagaradjane, Parmeswaran; Deorukhkar, Amit; Dey, Sanjit; Koca, Cemile; Tong, Zhimin; Gelovani, Juri G.; Guha, Sushovan; Krishnan, Sunil; Aggarwal, Bharat B.

    2011-01-01

    Agents that can potentiate the efficacy of standard chemotherapy against pancreatic cancer are of great interest. Because of their low cost and safety, patients commonly use a variety of dietary supplements, although evidence of their efficacy is often lacking. One such commonly used food supplement, Zyflamend, is a polyherbal preparation with potent anti-inflammatory activities, and preclinical efficacy against prostate and oral cancer. Whether Zyflamend has any efficacy against human pancreatic cancer alone or in combination with gemcitibine, a commonly used agent, was examined in cell cultures and in an orthotopic mouse model. In vitro, Zyflamend inhibited the proliferation of pancreatic cancer cell lines regardless of p53 status and also enhanced gemcitabine-induced apoptosis. This finding correlated with inhibition of NF-κB activation by Zyflamend and suppression of cyclin D1, c-myc, COX-2, Bcl-2, IAP, survivin, VEGF, ICAM-1, and CXCR4. In nude mice, oral administration of Zyflamend alone significantly inhibited the growth of orthotopically transplanted human pancreatic tumors, and when combined with gemcitabine, further enhanced the antitumor effects. Immunohistochemical and Western blot analyses of tumor tissue showed that the suppression of pancreatic cancer growth correlated with inhibition of proliferation index marker (Ki-67), COX-2, MMP-9, NF-κB, and VEGF. Overall, these results suggest that the concentrated multiherb product Zyflamend alone can inhibit the growth of human pancreatic tumors and, in addition, can sensitize pancreatic cancers to gemcitabine through the suppression of multiple targets linked to tumorigenesis. PMID:21935918

  8. Assessment of biophysical tumor response to PDT in pancreatic cancer using localized reflectance spectroscopy

    NASA Astrophysics Data System (ADS)

    Isabelle, Martin; Klubben, William; He, Ting; Laughney, Ashley M.; Glaser, Adam; Krishnaswamy, Venkataramanan; Hoopes, P. Jack; Hasan, Tayyaba; Pogue, Brian W.

    2011-02-01

    Biophysical changes such as inflammation and necrosis occur immediately following PDT and may be used to assess the treatment response to PDT treatment in-vivo. This study uses localized reflectance measurements to quantify the scatter changes in tumor tissue occurring in response to verteporfin-based PDT treatment in xenograft pancreas tumors. Nude mice were implanted with subcutaneous AsPC-1 pancreatic tumors cells in matrigel, and allowed to establish solid tumors near 100mm3 volume. The mice were sensitized with 1mg/kg of the active component of verteporfin (benzoporphryin derivative, BPD), one hour before light delivery. The optical irradiation was performed using a 1 cm cylindrical interstitial diffusing tip fiber with 20J of red light (690nm). Tumor tissue was excised progressively and imaged, from 1 day to 4 weeks, after PDT treatment. The tissue sections were stained and analyzed by an expert veterinary pathologist, who provided information on tissue regions of interest. This information was correlated with variations in scattering and absorption parameters elucidated from the spectral images and the degree of necrosis and inflammation involvement was identified. Areas of necrosis and dead cells exhibited the lowest average scatter irradiance signature (3.78 and 4.07 respectively) compared to areas of viable pancreatic tumor cells and areas of inflammation (5.81 and 7.19 respectively). Bilirubin absorbance parameters also showed a lower absorbance value in necrotic tissue and areas of dead cells (0.05 and 0.1 respectively) compared to tissue areas for viable pancreatic tumor cells and areas of inflammation (0.28 and 0.35). These results demonstrate that localized reflectance spectroscopy is an imaging modality that can be used to identify tissue features associated with PDT treatment (e.g. necrosis and inflammation) that can be correlated with histopathologically-reviewed H&E stained slides. Further study of this technique may provide means for automated

  9. Orchestrating the Tumor Microenvironment to Improve Survival for Patients With Pancreatic Cancer Normalization, Not Destruction

    PubMed Central

    Whatcott, Clifford J.; Hanl, Haiyong; Von Hoff, Daniel D.

    2016-01-01

    Pancreatic cancer is the fourth leading cause of cancer death in the United States. The microenvironment of pancreatic cancer could be one of the “perfect storms” that support the growth of a cancer. Indeed, pancreatic cancer may be the poster child of a problem with the microenvironment. In this article, we review the rationale and attempts to date on modifying or targeting structural proteins in the microenvironment including hyaluronan (HA) (in primary and metastases), collagen, and SPARC (secreted protein, acidic, and rich in cysteine). Indeed, working in this area has produced a regimen that improves survival for patients with advanced pancreatic cancer (nab-paclitaxel + gemcitabine). In addition, in initial clinical trials, PEGylated hyaluronidase appears promising. We also review a new approach that is different than targeting/destroying the microenvironment and that is orchestrating, reengineering, reprogramming, or normalizing the microenvironment (including normalizing structural proteins, normalizing an immunologically tumor-friendly environment to a less friendly environment, reversing epithelial-to-mesenchymal transition, and so on). We believe this will be most effectively done by agents that have global effects on transcription. There is initial evidence that this can be done by agents such as vitamin D derivatives and other new agents. There is no doubt these opportunities can now be tried in the clinic with hopefully beneficial effects. PMID:26222082

  10. A Rationally Optimized Nanoparticle System for the Delivery of RNA Interference Therapeutics into Pancreatic Tumors in Vivo.

    PubMed

    Teo, Joann; McCarroll, Joshua A; Boyer, Cyrille; Youkhana, Janet; Sagnella, Sharon M; Duong, Hien T T; Liu, Jie; Sharbeen, George; Goldstein, David; Davis, Thomas P; Kavallaris, Maria; Phillips, Phoebe A

    2016-07-11

    Pancreatic cancer is a devastating disease with a dismal prognosis. Short-interfering RNA (siRNA)-based therapeutics hold promise for the treatment of cancer. However, development of efficient and safe delivery vehicles for siRNA remains a challenge. Here, we describe the synthesis and physicochemical characterization of star polymers (star 1, star 2, star 3) using reversible addition-fragmentation chain transfer polymerization (RAFT) for the delivery of siRNA to pancreatic cancer cells. These star polymers were designed to contain different lengths of cationic poly(dimethylaminoethyl methacrylate) (PDMAEMA) side-arms and varied amounts of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA). We showed that star-POEGMA polymers could readily self-assemble with siRNA to form nanoparticles. The star-POEGMA polymers were nontoxic to normal cells and delivered siRNA with high efficiency to pancreatic cancer cells to silence a gene (TUBB3/βIII-tubulin) which is currently undruggable using chemical agents, and is involved in regulating tumor growth and metastases. Notably, systemic administration of star-POEGMA-siRNA resulted in high accumulation of siRNA to orthotopic pancreatic tumors in mice and silenced βIII-tubulin expression by 80% at the gene and protein levels in pancreatic tumors. Together, these novel findings provide strong rationale for the use of star-POEGMA polymers as delivery vehicles for siRNA to pancreatic tumors. PMID:27305597

  11. 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

    2016-06-07

    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

  12. Pancreatic neuroendocrine tumors with transformation to insulinoma: an unusual presentation of a rare disease

    PubMed Central

    Grozinsky-Glasberg, Simona; Salmon, Asher; Gross, David J

    2015-01-01

    Summary Approximately 35% of the pancreatic neuroendocrine tumors (pNETs) are functional, the most common of which is an insulinoma. Rarely can initially nonfunctioning tumor undergo biological transformation to a hormone-secreting tumor with subsequent changes in the clinical picture. We present here three unique patients with long-standing pNETs who developed life-threatening hyperinsulinemic hypoglycemia along with tumor progression. In two of the patients, everolimus (Afinitor) was administered in an attempt to control both tumor growth and hypoglycemia. In two cases everolimus therapy resulted in the abolishment of hypoglycemia and induced significant tumor regression; however these beneficial responses were transient. These cases highlight the exceptional ability of pNETs to change biological behavior in parallel with disease progression. Our experience concurs with recently published studies demonstrating the utility of everolimus for the control of both hypoglycemia and tumor progression. Learning points Nonfunctional pNET can gain new features such as insulin secretion with related morbidity.Gain of function in a previously nonfunctional pNET signifies tumor progression and is usually associated with poor prognosis.Everolimus proved to be a viable treatment for hypoglycemia in insulinoma patients and was also proven highly effective in the patients presented here.As disease progresses, the effect of everolimus on hypoglycemia wanes. We report for the first time the development of hypoglycemia during everolimus treatment. PMID:26113980

  13. Thermal therapy of pancreatic tumors using endoluminal ultrasound: parametric and patient-specific modeling

    PubMed Central

    Adams, Matthew S.; Scott, Serena J.; Salgaonkar, Vasant A.; Sommer, Graham; Diederich, Chris J.

    2016-01-01

    Purpose To investigate endoluminal ultrasound applicator configurations for volumetric thermal ablation and hyperthermia of pancreatic tumors using 3D acoustic and biothermal finite element models. Materials and Methods Parametric studies compared endoluminal heating performance for varying applicator transducer configurations (planar, curvilinear-focused, or radial-diverging), frequencies (1–5 MHz), and anatomical conditions. Patient-specific pancreatic head and body tumor models were used to evaluate feasibility of generating hyperthermia and thermal ablation using an applicator positioned in the duodenal or stomach lumen. Temperature and thermal dose were calculated to define ablation (>240 EM43°C) and moderate hyperthermia (40–45 °C) boundaries, and to assess sparing of sensitive tissues. Proportional-integral control was incorporated to regulate maximum temperature to 70–80 °C for ablation and 45 °C for hyperthermia in target regions. Results Parametric studies indicated that 1–3 MHz planar transducers are most suitable for volumetric ablation, producing 5–8 cm3 lesion volumes for a stationary 5 minute sonication. Curvilinear-focused geometries produce more localized ablation to 20–45 mm depth from the GI tract and enhance thermal sparing (Tmax<42 °C) of the luminal wall. Patient anatomy simulations show feasibility in ablating 60.1–92.9% of head/body tumor volumes (4.3–37.2 cm3) with dose <15 EM43°C in the luminal wall for 18–48 min treatment durations, using 1–3 applicator placements in GI lumen. For hyperthermia, planar and radial-diverging transducers could maintain up to 8 cm3 and 15 cm3 of tissue, respectively, between 40–45 °C for a single applicator placement. Conclusions Modeling studies indicate the feasibility of endoluminal ultrasound for volumetric thermal ablation or hyperthermia treatment of pancreatic tumor tissue. PMID:27097663

  14. CD133 initiates tumors, induces epithelial-mesenchymal transition and increases metastasis in pancreatic cancer

    PubMed Central

    Nomura, Alice; Banerjee, Sulagna; Chugh, Rohit; Dudeja, Vikas; Yamamoto, Masato; Vickers, Selwyn M.; Saluja, Ashok K.

    2015-01-01

    CD133 has been implicated as a cancer stem cell (CSC) surface marker in several malignancies including pancreatic cancer. However, the functional role of this surface glycoprotein in the cancer stem cell remains elusive. In this study, we determined that CD133 overexpression induced “stemness” properties in MIA-PaCa2 cells along with increased tumorigenicity, tumor progression, and metastasis in vivo. Additionally, CD133 expression induced epithelial-mesenchymal transition (EMT) and increased in vitro invasion. EMT induction and increased invasiveness were mediated by NF-κB activation, as inhibition of NF-κB mitigated these effects. This study showed that CD133 expression contributes to pancreatic cancer “stemness,” tumorigenicity, EMT induction, invasion, and metastasis. PMID:25829252

  15. Beyond pancreatic cancer: irinotecan and gemcitabine in solid tumors and hematologic malignancies.

    PubMed

    Rocha Lima, C M; Urbanic, J J; Lal, A; Kneuper-Hall, R; Brunson, C Y; Green, M R

    2001-06-01

    Non-platinum combinations including gemcitabine and irinotecan (Gemzar; Eli Lilly and Company, Indianapolis, IN) for the management of a variety of malignancies have started to emerge. Gemcitabine and irinotecan are well-tolerated single agents, each with a broad spectrum of antitumor activity. Preclinical data suggests synergy for the two drugs when used in combination. A phase I trial has defined a well-tolerated combination regimen using both drugs on a day-1, -8 schedule every 3 weeks. Phase II data suggest activity for the combination in pancreatic cancer, and a phase III trial of the two-drug combination versus gemcitabine alone is underway in previously untreated pancreatic cancer patients. Other phase II trials evaluating the impact of this combination on a variety of other tumors, such as non-small cell lung, small cell lung, breast, colorectal, and non-Hodgkin's lymphoma, are either forthcoming or in progress. Semin Oncol 28 (suppl 10):34-43. PMID:11510032

  16. Pancreatitis

    MedlinePlus

    ... to the abdomen. In 1 out of 4 childhood cases, a cause is never found. What are the symptoms of pancreatitis? Inflammation of the pancreas is often associated with pain in the upper abdomen and/or the back which may develop slowly, ...

  17. Multiorgan chronic inflammatory hepatobiliary pancreatic murine model deficient in tumor necrosis factor receptors 1 and 2

    PubMed Central

    Oz, Helieh S

    2016-01-01

    AIM: To provoke persistent/chronic multiorgan inflammatory response and to contribute to stones formation followed by fibrosis in hepatobiliary and pancreatic tissues. METHODS: Tumor necrosis factor receptors 1 and 2 (TNFR1/R2) deficient mice reared in-house were given dibutyltin dichloride (DBTC) twice within 10 d by oral gavage delivery. Sham control animals received vehicle treatment and naïve animals remained untreated throughout the study. Animals were monitored daily for symptoms of pain and discomfort. The abdominal and hindpaw hypersensitivity were assessed with von Frey microfilaments. Exploratory behaviors were recorded at the baseline, after initiation of treatment, and before study termination. Histopathological changes were examined postmortem in tissues. Collagen accumulation and fibrosis were confirmed with Sirius Red staining. RESULTS: Animals lost weight after oral administration of DBTC and developed persistent inflammatory abdominal and hindpaw hypersensitivity compared to sham-treated controls (P < 0.0001). These pain related secondary mechanical hypersensitivity responses increased more than 2-fold in DBTC-treated animals. The drastically diminished rearing and grooming rates persisted after DBTC administration throughout the study. Gross as well as micropathology at one month confirmed that animals treated with DBTC developed chronic hepatobiliary injuries evidenced with activation of stellate cells, multifocal necrosis, fatty degeneration of hepatocytes, periportal infiltration of inflammatory cells, and prominent biliary ductal dilation. The severity of hepatitis was scored 3.7 ± 0.2 (severe) in DBTC-treated animals vs score 0 (normal) in sham-treated animals. Fibrotic thickening was extensive around portal ducts, in hepatic parenchyma as well as in lobular pancreatic structures and confirmed with Sirius Red histopathology. In addition, pancreatic microarchitecture was presented with distortion of islets, and parenchyma, infiltration of

  18. Targeted tumor delivery and controlled release of neuronal drugs with ferritin nanoparticles to regulate pancreatic cancer progression.

    PubMed

    Lei, Yifeng; Hamada, Yoh; Li, Jun; Cong, Liman; Wang, Nuoxin; Li, Ying; Zheng, Wenfu; Jiang, Xingyu

    2016-06-28

    Pancreatic cancer is a lethal malignancy whose progression is highly dependent on the nervous microenvironment. This study develops neural drug-loaded ferritin nanoparticles (Ft NPs) to regulate the nervous microenvironment, in order to control the pancreatic cancer progression. The drug-loaded Ft NPs can target pancreatic tumors via passive targeting of EPR effects of tumors and active targeting via transferrin receptor 1 (TfR1) binding on cancer cells, with a triggered drug release in acidic tumor environment. Two drugs, one activates neural activity (carbachol), the other impairs neural activity (atropine), are encapsulated into the Ft NPs to form two kinds of nano drugs, Nano-Cab NPs and Nano-Ato NPs, respectively. The activation of the nervous microenvironment by Nano-Cab NPs significantly promotes the pancreatic tumor progression, whereas the blockage of neural niche by Nano-Ato NPs remarkably impairs the neurogenesis in tumors and the progression of pancreatic cancer. The Ft-based nanoparticles thus comprise an effective and safe route of delivery of neural drugs for novel anti-cancer therapy. PMID:27046157

  19. Hypercalcemia from metastatic pancreatic neuroendocrine tumor secreting 1,25-dihydroxyvitamin D

    PubMed Central

    Zhu, Viola; de las Morenas, Antonio; Janicek, Milos

    2014-01-01

    Malignant hypercalcemia occurs in about 20-30% of patients with cancer, both solid tumors and hematologic malignancies. The secretion of parathyroid hormone-related protein (PTH-rP) is the most common cause and has been shown to be the etiology of hypercalcemia associated with neuroendocrine tumors. Here we report the case of a patient with metastatic pancreatic neuroendocrine tumor who developed hypercalcemia more than 4 years after the initial diagnosis as a result of secretion of 1,25-dihydroxyvitamin D, a mechanism only commonly seen in lymphomas. The successful control of the patient’s disease with capecitabine and temozolomide led to the alleviation of this paraneoplastic syndrome. PMID:25083313

  20. Transcriptomic and CRISPR/Cas9 technologies reveal FOXA2 as a tumor suppressor gene in pancreatic cancer.

    PubMed

    Vorvis, Christina; Hatziapostolou, Maria; Mahurkar-Joshi, Swapna; Koutsioumpa, Marina; Williams, Jennifer; Donahue, Timothy R; Poultsides, George A; Eibl, Guido; Iliopoulos, Dimitrios

    2016-06-01

    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with low survival rates and limited therapeutic options. Thus elucidation of signaling pathways involved in PDAC pathogenesis is essential for identifying novel potential therapeutic gene targets. Here, we used a systems approach to elucidate those pathways by integrating gene and microRNA profiling analyses together with CRISPR/Cas9 technology to identify novel transcription factors involved in PDAC pathogenesis. FOXA2 transcription factor was found to be significantly downregulated in PDAC relative to control pancreatic tissues. Functional experiments revealed that FOXA2 has a tumor suppressor function through inhibition of pancreatic cancer cell growth, migration, invasion, and colony formation. In situ hybridization analysis revealed miR-199a to be significantly upregulated in pancreatic cancer. Bioinformatics and luciferase analyses showed that miR-199a negatively but directly regulates FOXA2 expression through binding in its 3'-untranslated region (UTR). Evaluation of the functional importance of miR-199a on pancreatic cancer revealed that miR-199a acts as an inhibitor of FOXA2 expression, inducing an increase in pancreatic cancer cell proliferation, migration, and invasion. Additionally, gene ontology and network analyses in PANC-1 cells treated with a small interfering RNA (siRNA) against FOXA2 revealed an enrichment for cell invasion mechanisms through PLAUR and ERK activation. FOXA2 deletion (FOXA2Δ) by using two CRISPR/Cas9 vectors in PANC-1 cells induced tumor growth in vivo resulting in upregulation of PLAUR and ERK pathways in FOXA2Δ xenograft tumors. We have identified FOXA2 as a novel tumor suppressor in pancreatic cancer and it is regulated directly by miR-199a, thereby enhancing our understanding of how microRNAs interplay with the transcription factors to affect pancreatic oncogenesis. PMID:27151939

  1. Identification of a Novel Subpopulation of Tumor-Initiating Cells from Gemcitabine-Resistant Pancreatic Ductal Adenocarcinoma Patients

    PubMed Central

    Shimizu, Kazuya; Chiba, Sachie; Hori, Yuichi

    2013-01-01

    Pancreatic ductal adenocarcinoma is highly resistant to systemic chemotherapy. Although there are many reports using pancreatic cancer cells derived from patients who did not receive chemotherapy, characteristics of pancreatic cancer cells from chemotherapy-resistant patients remain unclear. In this study, we set out to establish a cancer cell line in disseminated cancer cells derived from gemcitabine-resistant pancreatic ductal adenocarcinoma patients. By use of in vitro co-culture system with stromal cells, we established a novel pancreatic tumor-initiating cell line. The cell line required its direct interaction with stromal cells for its in vitro clonogenic growth and passaging. Their direct interaction induced basal lamina-like extracellular matrix formation that maintained colony formation. The cell line expressed CD133 protein, which expression level changed autonomously and by culture conditions. These results demonstrated that there were novel pancreatic tumor-initiating cells that required direct interactions with stromal cells for their in vitro cultivation in gemcitabine-resistant pancreatic ductal adenocarcinoma. This cell line would help to develop novel therapies that enhance effects of gemcitabine or novel anti-cancer drugs. PMID:24278411

  2. Targeted Disruption of Orchestration between Stroma and Tumor Cells in Pancreatic Cancer: Molecular Basis and Therapeutic Implications

    PubMed Central

    Kong, Xiangyu; Li, Lei; Li, Zhaoshen; Xie, Keping

    2012-01-01

    Pancreatic cancer is one of the most lethal malignancies, with a prominent desmoplastic reaction as the defining hallmark of the disease. The past several decades have seen dramatic progress in understanding of pancreatic cancer pathogenesis, including the identification of precursor lesions, sequential transformation from normal pancreas to invasive pancreatic cancer and corresponding signature genetic events, and the biological impact of those alterations on malignant behaviors. However, the current therapeutic strategies for epithelial tumor cells, which have exhibited potent antitumor activity in cell culture and animal models, have failed to have significant effects in the clinic. The desmoplastic stroma surrounding pancreatic cancer cells, which accounts for about 90% of a tumor’s mass, clearly is not a passive scaffold for cancer cells but an active contributor to carcinogenesis. Improved understanding of the dynamic interaction between cancer cells and their stroma will be important to designing new, effective therapeutic strategies for pancreatic cancer. This review focuses on the origination of stromal molecular and cellular components in pancreatic tumors, their biological effects on pancreatic cancer cells, and the orchestration between these two components. PMID:22749856

  3. Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer.

    PubMed

    Zhang, S; Chung, W-C; Xu, K

    2016-05-12

    Notch controls pancreatic differentiation during development and is reactivated in pancreatic cancer. In recent years, the importance of Notch signaling in pancreatic tumorigenesis has become increasingly evident; however, it remains unclear how Notch activities are regulated in this context. Here we report differential regulation of Notch receptors by Lunatic Fringe (Lfng), which encodes an O-fucosylpeptide 3-β-N-acetylglucosaminyltransferase known to modify epidermal growth factor repeats in the Notch extracellular domain, during pathogenesis of Kras-induced pancreatic ductal adenocarcinoma (PDAC). We show that Lfng is uniquely expressed in a subset of acinar cells in the adult pancreas. Deletion of Lfng in the Kras(LSL-G12D/+);Pdx1-Cre mouse model caused increased activation of Notch3 throughout PDAC initiation and progression, and Notch1 after the onset of disease, associated with marked upregulation of Notch target gene Hes1. Deletion of Lfng also resulted in accumulation of Aldh1-positive cell population. We found that loss of Lfng significantly accelerated Kras-initiated PDAC development and shortened survival of the PDAC mice. Interestingly, Lfng-deficient tumors showed a propensity for a poorly differentiated state with features of epithelial-to-mesenchymal transition. Likewise, knockdown of LFNG in human PDAC cell lines caused elevated Notch activation, associated with either accelerated cell proliferation or expanded Aldh1-positive cell population. Deletion of Lfng resulted in downregulation of Tgfb1, Tgfb2 and Tgfbr2 expression in the wild-type pancreas at all ages examined, and in the Kras(LSL-G12D/+);Pdx1-Cre pancreas after PDAC onset, as well as reduced phospho-Smad2 levels in pancreatic tumors. We provide evidence that Lfng regulates transforming growth factor (TGF)-β signaling through Notch-mediated transcriptional repression of TGF-β pathway genes. Taken together, our results reveal a potent tumor-suppressive function for Lfng and crosstalk

  4. [Treatment Strategy for Non-Functional Pancreatic Neuroendocrine Tumors (P-NETs) at Kurume University Hospital].

    PubMed

    Kawashima, Yusuke; Ishikawa, Hiroto; Hisaka, Toru; Okuda, Kouji; Akagi, Yoshito

    2016-01-01

    Pancreatic neuroendocrine tumors (P-NETs) are relatively rare. Approximately 50-90% of non-functioning P-NETs are malignant, and the only curative treatment is surgical resection. Liver and lymph node metastases often occur. In Japan, the mTOR inhibitor everolimus is now covered by the national health insurance for treatment of P-NETs, including advanced and unresectable tumors. We present a case of P-NETs with liver metastases seen at our hospital and discuss our treatment strategy for this disease. Patients with tumors≤1 cm receive follow-up observation. For G1 and G2 (other than G3) tumors, if their size is >1 cm when first discovered, resection of the primary lesion along with lymph node dissection (as for pancreatic cancer) is performed. In G1 and G2 tumors with synchronous distant metastases, the primary lesion is first resected, and depending on the pathological findings, chemotherapy (LAR plus everolimus) may be administered. After 4 courses of chemotherapy, the response is assessed, and if further resection is possible, resection is performed. When there are synchronous liver metastases, if partial resection and local treatment (such as RFA) are possible, the primary lesion and synchronous lesions are resected. If a major hepatic resection procedure such as a segmentectomy or lobectomy is possible, the primary lesion is resected, followed by chemotherapy. After 4 courses of chemotherapy, the response is assessed, and if further resection is possible, hepatic resection is performed. G3 tumors are usually highly malignant, advanced, and often associated with metastases at the time of diagnosis. Chemotherapy may be an option for treating patients with G3 tumors. PMID:26809536

  5. 64-Slice spiral computed tomography and three-dimensional reconstruction in the diagnosis of cystic pancreatic tumors

    PubMed Central

    WEN, ZHAOXIA; YAO, FENGQING; WANG, YUXING

    2016-01-01

    The present study aimed to describe the characteristics of cystic pancreatic tumors using computed tomography (CT) and to evaluate the diagnostic accuracy (DA) of post-imaging three-dimensional (3D) reconstruction. Clinical and imaging data, including multi-slice spiral CT scans, enhanced scans and multi-faceted reconstruction, from 30 patients with pathologically confirmed cystic pancreatic tumors diagnosed at the Linyi People's Hospital between August 2008 and June 2014 were retrospectively analyzed. Following the injection of Ultravist® 300 contrast agent, arterial, portal venous and parenchymal phase scans were obtained at 28, 60 and 150 sec, respectively, and 3D reconstructions of the CT images were generated. The average age of the patients was 38.4 years (range, 16–77 years), and the cohort included 5 males and 25 females (ratio, 1:5). The patients included 8 cases of mucinous cystadenoma (DA), 80%]; 9 cases of cystadenocarcinoma (DA, 84%); 6 cases of serous cystadenoma (DA, 100%); 3 cases of solid pseudopapillary tumor (DA, 100%); and 4 cases of intraductal papillary mucinous neoplasm (DA, 100%). 3D reconstructions of CT images were generated and, in the 4 cases of intraductal papillary mucinous neoplasm, the tumor was connected to the main pancreatic duct and multiple mural nodules were detected in one of these cases. The DA of the 3D-reconstructed images of cystic pancreatic tumors was 89.3%. The 64-slice spiral CT and 3D-reconstructed CT images facilitated the visualization of cystic pancreatic tumor characteristics, in particular the connections between the tumor and the main pancreatic duct. In conclusion, the 3D reconstruction of multi-slice CT data may provide an important source of information for the surgical team, in combination with the available clinical data. PMID:27073473

  6. Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis

    PubMed Central

    Kim, Haeryoung; Saka, Burcu; Knight, Spencer; Borges, Michael; Childs, Erica; Klein, Alison; Wolfgang, Christopher; Herman, Joseph; Adsay, Volkan N.; Hruban, Ralph H.; Goggins, Michael

    2014-01-01

    Purpose To determine how often loss of ATM protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance. Experimental Design The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically-resected pancreatic ductal adenocarcinomas (Hopkins), a second set of 159 cases (Emory) and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival. Results Tumoral ATM loss was observed in one cancer known to have bi-allelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%) (p=0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (p=0.019) and was a significant independent predictor of decreased overall survival (p=0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (p=0.1). Multivariate analysis of the combined Hopkins/Emory cases found tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival (HR 2.61, CI1.27–5.37, p=0.009). Of 21 cancers examined after neoadjuvant chemoradiotherapy one had tumoral loss of ATM; it had no histological evidence of tumor response. Conclusions Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection. PMID:24486587

  7. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.

    PubMed

    Laklai, Hanane; Miroshnikova, Yekaterina A; Pickup, Michael W; Collisson, Eric A; Kim, Grace E; Barrett, Alex S; Hill, Ryan C; Lakins, Johnathon N; Schlaepfer, David D; Mouw, Janna K; LeBleu, Valerie S; Roy, Nilotpal; Novitskiy, Sergey V; Johansen, Julia S; Poli, Valeria; Kalluri, Raghu; Iacobuzio-Donahue, Christine A; Wood, Laura D; Hebrok, Matthias; Hansen, Kirk; Moses, Harold L; Weaver, Valerie M

    2016-05-01

    Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype. PMID:27089513

  8. A rare case of three different tumors in the same pancreatic specimen: a case report and brief review of the literature

    PubMed Central

    Paiella, Salvatore; Luchini, Claudio; Amodio, Antonio; Rusev, Borislav; Bassi, Claudio; Manfredi, Riccardo; Frulloni, Luca

    2016-01-01

    Solid pseudopapillary tumors (SPT) of the pancreas are rare neoplasms mainly affecting young women. Pancreatic serous cystadenomas (SCAs) and pancreatic neuroendocrine tumors (PanNETs) account for about 2% of all pancreatic neoplasms. The combination of these three lesions, to our knowledge, has never been described in literature. Here we report a case of combined SPT, SCA and PanNET affecting a 33-year-old woman. PMID:27284489

  9. SU-E-J-29: Audiovisual Biofeedback Improves Tumor Motion Consistency for Lung Cancer Patients

    SciTech Connect

    Lee, D; Pollock, S; Makhija, K; Keall, P; Greer, P; Arm, J; Hunter, P; Kim, T

    2014-06-01

    Purpose: To investigate whether the breathing-guidance system: audiovisual (AV) biofeedback improves tumor motion consistency for lung cancer patients. This will minimize respiratory-induced tumor motion variations across cancer imaging and radiotherapy procedues. This is the first study to investigate the impact of respiratory guidance on tumor motion. Methods: Tumor motion consistency was investigated with five lung cancer patients (age: 55 to 64), who underwent a training session to get familiarized with AV biofeedback, followed by two MRI sessions across different dates (pre and mid treatment). During the training session in a CT room, two patient specific breathing patterns were obtained before (Breathing-Pattern-1) and after (Breathing-Pattern-2) training with AV biofeedback. In each MRI session, four MRI scans were performed to obtain 2D coronal and sagittal image datasets in free breathing (FB), and with AV biofeedback utilizing Breathing-Pattern-2. Image pixel values of 2D images after the normalization of 2D images per dataset and Gaussian filter per image were used to extract tumor motion using image pixel values. The tumor motion consistency of the superior-inferior (SI) direction was evaluated in terms of an average tumor motion range and period. Results: Audiovisual biofeedback improved tumor motion consistency by 60% (p value = 0.019) from 1.0±0.6 mm (FB) to 0.4±0.4 mm (AV) in SI motion range, and by 86% (p value < 0.001) from 0.7±0.6 s (FB) to 0.1±0.2 s (AV) in period. Conclusion: This study demonstrated that audiovisual biofeedback improves both breathing pattern and tumor motion consistency for lung cancer patients. These results suggest that AV biofeedback has the potential for facilitating reproducible tumor motion towards achieving more accurate medical imaging and radiation therapy procedures.

  10. Polymorphic genetic control of tumor invasion in a mouse model of pancreatic neuroendocrine carcinogenesis.

    PubMed

    Chun, Matthew G H; Mao, Jian-Hua; Chiu, Christopher W; Balmain, Allan; Hanahan, Douglas

    2010-10-01

    Cancer is a disease subject to both genetic and environmental influences. In this study, we used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to identify a genetic locus that influences tumor progression to an invasive growth state. RT2 mice inbred into the C57BL/6 (B6) background develop both noninvasive pancreatic neuroendocrine tumors (PNET) and invasive carcinomas with varying degrees of aggressiveness. In contrast, RT2 mice inbred into the C3HeB/Fe (C3H) background are comparatively resistant to the development of invasive tumors, as are RT2 C3HB6(F1) hybrid mice. Using linkage analysis, we identified a 13-Mb locus on mouse chromosome 17 with significant linkage to the development of highly invasive PNETs. A gene residing in this locus, the anaplastic lymphoma kinase (Alk), was expressed at significantly lower levels in PNETs from invasion-resistant C3H mice compared with invasion-susceptible B6 mice, and pharmacological inhibition of Alk led to reduced tumor invasiveness in RT2 B6 mice. Collectively, our results demonstrate that tumor invasion is subject to polymorphic genetic control and identify Alk as a genetic modifier of invasive tumor growth. PMID:20855625

  11. An Integrated Framework for Automatic Ki-67 Scoring in Pancreatic Neuroendocrine Tumor

    PubMed Central

    Xing, Fuyong; Su, Hai; Yang, Lin

    2015-01-01

    The Ki-67 labeling index is a valid and important biomarker to gauge neuroendocrine tumor cell progression. Automatic Ki-67 assessment is very challenging due to complex variations of cell characteristics. In this paper, we propose an integrated learning-based framework for accurate Ki-67 scoring in pancreatic neuroendocrine tumor. The main contributions of our method are: a novel and robust cell detection algorithm is designed to localize both tumor and non-tumor cells; a repulsive deformable model is applied to correct touching cell segmentation; a two stage learning-based scheme combining cellular features and regional structure information is proposed to differentiate tumor from non-tumor cells (such as lymphocytes); an integrated automatic framework is developed to accurately assess the Ki-67 labeling index. The proposed method has been extensively evaluated on 101 tissue microarray (TMA) whole discs, and the cell detection performance is comparable to manual annotations. The automatic Ki-67 score is very accurate compared with pathologists’ estimation. PMID:24505696

  12. eIF4E-phosphorylation-mediated Sox2 upregulation promotes pancreatic tumor cell repopulation after irradiation.

    PubMed

    Yu, Yang; Tian, Ling; Feng, Xiao; Cheng, Jin; Gong, Yanping; Liu, Xinjian; Zhang, Zhengxiang; Yang, Xuguang; He, Sijia; Li, Chuan-Yuan; Huang, Qian

    2016-05-28

    Pancreatic cancer is a devastating disease characterized by treatment resistance and high recurrence rate. Repopulation of surviving tumor cells undergoing radiotherapy is one of the most common reasons for recurrence. Our previous studies have discovered a novel mechanism for repopulation after irradiation that activation of caspase-3 in irradiated tumor cells activates PKCδ/p38 axis to transmit proliferation signals promoting repopulation of surviving tumor cells. Here we found Sox2 expression is up-regulated in irradiated pancreatic cancer cells, which played a major role in tumor cell repopulation after irradiation. Over-expression of Sox2 strongly enhanced the growth-stimulating effect of irradiated dying tumor cells on living tumor cells through a paracrine modality. Furthermore, we identified activated eIF4E, which is phosphorylated by MNK1, as a regulator of Sox2 expression after irradiation, and pharmacologic inhibition of eIF4E with CGP57380 and Ribavirin significantly weakened Sox2-mediated tumor cell repopulation. Finally, we showed the activation of caspase 3/PKCδ/p38/MNK1 signal pathway in irradiated pancreatic tumor cells. Together, we showed a novel pathway regulating Sox2 expression and Sox2 may be a promising target to reduce recurrence due to repopulation of surviving tumor cells after radiotherapy. PMID:26945967

  13. Genetic polymorphisms of interleukin 1β gene and sporadic pancreatic neuroendocrine tumors susceptibility

    PubMed Central

    Karakaxas, Dimitrios; Sioziou, Anna; Aravantinos, Gerasimos; Coker, Ahmet; Papanikolaou, Ioannis S; Liakakos, Theodoros; Dervenis, Christos; Gazouli, Maria

    2016-01-01

    AIM: To evaluate the association between the interleukin 1β (IL-1β) polymorphisms and the pancreatic neuroendocrine tumor (pNET) development. METHODS: A case-control study was conducted analyzing IL-1β polymorphisms using germline DNA collected in a population-based case-control study of pancreatic cancer (51 pNET cases, 85 pancreatic ductal adenocarcinoma cases, 19 intraductal papillary mucinous neoplasm and 98 healthy controls). RESULTS: The distribution of genotypes for the -511 C/T polymorphism in the pNET patient groups showed significant difference compared to the control group. It is known that the carriers of the IL-1β -511T allele have increased concentrations of IL-1β. The -511 CT and TT high-expression genotypes were over-represented in pNET patients. CONCLUSION: The findings of this study suggested a possible role of IL-1β -511 C/T genotypes in the pathogenesis of pNETs since the presence of the IL-1β -511 CT and TT genotypes and the T allele was associated with an increased risk of pNET only. PMID:27326321

  14. Capsaicin induces cytotoxicity in pancreatic neuroendocrine tumor cells via mitochondrial action.

    PubMed

    Skrzypski, M; Sassek, M; Abdelmessih, S; Mergler, S; Grötzinger, C; Metzke, D; Wojciechowicz, T; Nowak, K W; Strowski, M Z

    2014-01-01

    Capsaicin (CAP), the pungent ingredient of chili peppers, inhibits growth of various solid cancers via TRPV1 as well as TRPV1-independent mechanisms. Recently, we showed that TRPV1 regulates intracellular calcium level and chromogranin A secretion in pancreatic neuroendocrine tumor (NET) cells. In the present study, we characterize the role of the TRPV1 agonist - CAP - in controlling proliferation and apoptosis of pancreatic BON and QGP-1 NET cells. We demonstrate that CAP reduces viability and proliferation, and stimulates apoptotic death of NET cells. CAP causes mitochondrial membrane potential loss, inhibits ATP synthesis and reduces mitochondrial Bcl-2 protein production. In addition, CAP increases cytochrome c and cleaved caspase 3 levels in cytoplasm. CAP reduces reactive oxygen species (ROS) generation. The antioxidant N-acetyl-l-cysteine (NAC) acts synergistically with CAP to reduce ROS generation, without affecting CAP-induced toxicity. TRPV1 protein reduction by 75% reduction fails to attenuate CAP-induced cytotoxicity. In summary, these results suggest that CAP induces cytotoxicity by disturbing mitochondrial potential, and inhibits ATP synthesis in NET cells. Stimulation of ROS generation by CAP appears to be a secondary effect, not related to CAP-induced cytotoxicity. These results justify further evaluation of CAP in modulating pancreatic NETs in vivo. PMID:24075930

  15. Novel agents and new combination treatments on phase I studies on solid tumors and pancreatic cancer.

    PubMed

    Strimpakos, Alexios S; Syrigos, Kostas N; Saif, Muhammad W

    2012-07-01

    Pancreatic cancer is a relatively rare malignancy with a very aggressive natural course, not restrained by the existing current treatments. At the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, the results of few phase I clinical studies on solid tumors and pancreatic cancer were presented. In particular, in the field of immunotherapy, a pilot phase I study tested for first time a carcinoembryonic antigen (CEA)-based vaccine (Abstract #2561) on patients with pancreatic adenocarcinoma and another one the optimal dose and efficacy of trabedersen, an inhibitor of tissue growth factor-beta 2 (TGF-β2) aiming to enhance antitumor immune responses (Abstract #4034). Other phase I studies explored the pharmacokinetic and pharmacodynamic properties of an oral gemcitabine pro-drug (LY2334737; Abstract #2554), or of the combination of gemcitabine with sirolimus (Abstract #3096) or the combination of gemcitabine with an inhibitor of mitogen-activated protein kinase (MAPK), extracellular signal-regulated protein kinase (ERK) (MEK 1/2; Abstract #4034). PMID:22797386

  16. Resected Pancreatic Neuroendocrine Tumors: Patterns of Failure and Disease-Related Outcomes With or Without Radiotherapy

    SciTech Connect

    Zagar, Timothy M.; White, Rebekah R.; Willett, Christopher G.; Tyler, Douglas S.; Papavassiliou, Paulie; Papalezova, Katia T.; Guy, Cynthia D.; Broadwater, Gloria; Clough, Robert W.; Czito, Brian G.

    2012-07-15

    Purpose: Pancreatic neuroendocrine tumors (NET) are rare and have better disease-related outcomes compared with pancreatic adenocarcinoma. Surgical resection remains the standard of care, although many patients present with locally advanced or metastatic disease. Little is known regarding the use of radiotherapy in the prevention of local recurrence after resection. To better define the role of radiotherapy, we performed an analysis of resected patients at our institution. Methods: Between 1994 and 2009, 33 patients with NET of the pancreatic head and neck underwent treatment with curative intent at Duke University Medical Center. Sixteen patients were treated with surgical resection alone while an additional 17 underwent resection with adjuvant or neoadjuvant radiation therapy, usually with concurrent fluoropyrimidine-based chemotherapy (CMT). Median radiation dose was 50.4 Gy and median follow-up 28 months. Results: Thirteen patients (39%) experienced treatment failure. Eleven of the initial failures were distant, one was local only and one was local and distant. Two-year overall survival was 77% for all patients. Two-year local control for all patients was 87%: 85% for the CMT group and 90% for the surgery alone group (p = 0.38). Two-year distant metastasis-free survival was 56% for all patients: 46% and 69% for the CMT and surgery patients, respectively (p = 0.10). Conclusions: The primary mode of failure is distant which often results in mortality, with local failure occurring much less commonly. The role of radiotherapy in the adjuvant management of NET remains unclear.

  17. Risk Factors for Pancreatic Neuroendocrine Tumors (PNETs): A Clinic-Based Case-Control study

    PubMed Central

    Halfdanarson, Thorvardur R.; Bamlet, William R.; McWilliams, Robert R; Hobday, Timothy J.; Burch, Patrick A.; Rabe, Kari G.; Petersen, Gloria M.

    2014-01-01

    Objectives Pancreatic neuroendocrine tumors (PNETs) are uncommon, and little is known about their risk factors and association with other cancers. We evaluated whether risk factors known to be associated with pancreatic adenocarcinoma are also associated with PNETs: smoking, alcohol use, family history of PNET and other cancers, and personal history of diabetes as potential risk factors. Methods Patients with PNETs seen at Mayo Clinic Rochester between 2000 and 2011 were compared to controls seen for a general medical evaluation. Patients and controls completed the same questionnaires. After excluding insulinoma and high-grade PNETs, 355 cases were evaluated, and 309 were matched to 602 controls (2:1) on age, sex, and region of residence. Results Personal smoking history was not associated with PNETs. Alcohol use was less common among cases (54% vs. 67%, p<0.001). Cases were more likely to report a family member with sarcoma (p=0.02), PNET (p=0.02), gall bladder cancer (p=0.02), ovarian cancer (p=0.04) and gastric cancer (p=0.01). There was no association with other cancers in family members. Diabetes was more commonly reported by cases than controls (19% vs. 11%, p<0.001). Conclusions With the exception of diabetes, risk factors that are associated with pancreatic adenocarcinoma are not risk factors for PNETs. PMID:25291526

  18. En Masse Resection of Pancreas, Spleen, Celiac Axis, Stomach, Kidney, Adrenal, and Colon for Invasive Pancreatic Corpus and Tail Tumor

    PubMed Central

    Kutluturk, Koray; Alam, Abdul Hamid; Kayaalp, Cuneyt; Otan, Emrah; Aydin, Cemalettin

    2013-01-01

    Providing a more comfortable life and a longer survival for pancreatic corpus/tail tumors without metastasis depends on the complete resection. Recently, distal pancreatectomy with celiac axis resection was reported as a feasible and favorable method in selected pancreatic corpus/tail tumors which had invaded the celiac axis. Additional organ resections to the celiac axis were rarely required, and when necessary it was included only a single extra organ resection such as adrenal or intestine. Here, we described a distal pancreatic tumor invading most of the neighboring organs—stomach, celiac axis, left renal vein, left adrenal gland, and splenic flexure were treated by en bloc resection of all these organs. The patient was a 60-year-old man without any severe medical comorbidities. Postoperative course of the patient was uneventful, and he was discharged on postoperative day eight without any complication. Histopathology and stage of the tumor were adenocarcinoma and T4 N1 M0, respectively. Preoperative back pain of the patient was completely relieved in the postoperative period. As a result, celiac axis resection for pancreatic cancer is an extensive surgery, and a combined en masse resection of the invaded neighboring organs is a more extensive surgery than the celiac axis resection alone. This more extensive surgery is safe and feasible for selected patients with pancreatic cancer. PMID:24159408

  19. En masse resection of pancreas, spleen, celiac axis, stomach, kidney, adrenal, and colon for invasive pancreatic corpus and tail tumor.

    PubMed

    Kutluturk, Koray; Alam, Abdul Hamid; Kayaalp, Cuneyt; Otan, Emrah; Aydin, Cemalettin

    2013-01-01

    Providing a more comfortable life and a longer survival for pancreatic corpus/tail tumors without metastasis depends on the complete resection. Recently, distal pancreatectomy with celiac axis resection was reported as a feasible and favorable method in selected pancreatic corpus/tail tumors which had invaded the celiac axis. Additional organ resections to the celiac axis were rarely required, and when necessary it was included only a single extra organ resection such as adrenal or intestine. Here, we described a distal pancreatic tumor invading most of the neighboring organs-stomach, celiac axis, left renal vein, left adrenal gland, and splenic flexure were treated by en bloc resection of all these organs. The patient was a 60-year-old man without any severe medical comorbidities. Postoperative course of the patient was uneventful, and he was discharged on postoperative day eight without any complication. Histopathology and stage of the tumor were adenocarcinoma and T4 N1 M0, respectively. Preoperative back pain of the patient was completely relieved in the postoperative period. As a result, celiac axis resection for pancreatic cancer is an extensive surgery, and a combined en masse resection of the invaded neighboring organs is a more extensive surgery than the celiac axis resection alone. This more extensive surgery is safe and feasible for selected patients with pancreatic cancer. PMID:24159408

  20. MED29, a component of the Mediator complex, possesses both oncogenic and tumor suppressive characteristics in pancreatic cancer

    PubMed Central

    Kuuselo, Riina; Savinainen, Kimmo; Sandström, Saana; Autio, Reija; Kallioniemi, Anne

    2011-01-01

    Mediator complex subunit 29 (MED29) is part of a large multiprotein coactivator complex that mediates regulatory signals from gene-specific activators to general transcription machinery in RNA polymerase II mediated transcription. We previously found that MED29 is amplified and overexpressed in pancreatic cancer and that MED29 silencing leads to decreased cell survival in PANC-1 pancreatic cancer cells with high MED29 expression. Here we further demonstrate decreased migration, invasion and colony formation in PANC-1 cells after MED29 silencing. Unexpectedly, lentiviral-based overexpression of MED29 led to decreased proliferation of NIH/3T3 cells as well as MIAPaCa-2 pancreatic cancer cells with low endogenous expression. More importantly, subcutaneous inoculation of the MED29-transduced pancreatic cancer cells into immuno-compromised mice resulted in dramatic tumor suppression. The mock-control mice developed large tumors, whereas the animals with MED29-xenografts showed both decreased tumor incidence and a major reduction in tumor size. Gene expression analysis in the MED29-transduced pancreatic cancer cells revealed differential expression of genes involved in control of cell cycle and cell division. The observed gene expression changes are expected to modulate the cell cycle in a way that leads to reduced cell growth, explaining the in vivo tumor suppressive phenotype. Taken together, these data implicate MED29 as an important regulator of key cellular functions in pancreatic cancer with both oncogenic and tumor suppressive characteristics. Such a dualistic role appears to be more common than previously thought and is likely to depend on the genetic background of the cancer cells and their surrounding environment. PMID:21225629

  1. Massive renal urothelial carcinoma with renal vein tumor thrombus, pancreatic infiltration and adrenal metastasis: A case report

    PubMed Central

    Li, Tao; Gao, Liang; Wu, Weilu; Chen, Peng; Bu, Siyuan; Wei, Qiang; Yang, Lu

    2016-01-01

    A 49-year-old female patient presented with a massive left renal tumor, recurrent left flank pain and gross hematuria. The tumor was accompanied by a renal vein tumor thrombus, pancreatic infiltration and a solitary adrenal metastasis. Radical nephrectomy, distal pancreatectomy, ipsilateral adrenalectomy and splenectomy were performed. Histopathological examination suggested high-grade urothelial carcinoma (UC); however, tumor recurrence and multiple metastases were detected only 3 months after the surgery, and the patient succumbed during follow-up 1 month later. To the best of our knowledge, this is the first case of renal UC of such advanced stage with renal vein tumor thrombus, pancreatic infiltration and a solitary adrenal metastasis. PMID:27446406

  2. Pancreatic extragastrointestinal stromal tumor: A case report and comprehensive literature review

    PubMed Central

    Akbulut, Sami; Yavuz, Rıdvan; Otan, Emrah; Hatipoglu, Sinan

    2014-01-01

    AIM: To provide an overview of the literature on pancreatic extragastrointestinal stromal tumors (EGISTs). METHODS: We report a case of pancreatic EGIST and review published studies on pancreatic EGIST accessed via the PubMed, MEDLINE, Google Scholar, and Google databases. The keywords used were “pancreas and GIST”, “pancreas and extra GIST”, “pancreas and gastrointestinal stromal tumor”, and “pancreas and extragastrointestinal stromal tumor”. Literature reviews and/or duplicate studies were excluded. The search included articles published in the English language between January 1, 2000 and May 15, 2014. RESULTS: From our literature survey, 30 manuscripts on pancreatic EGISTs were considered, of which 27 met the search criteria and three were excluded. The studies involved 30 patients (15 men, 15 women) with a mean age of 55.3 ± 14.3 years (range 30-84 years). The mean age of the male patients was 50.8 ± 13.7 years (range 30-84 years); that of the female patients was 59.9 ± 13.3 years (range 38-81 years). Tumor dimensions were obtained for 28 cases (mean 114.4 ± 78.6 mm; range 20-350 mm). Tumors were diagnosed incidentally in 23.3% of patients; abdominal discomfort and weight loss were the major complaints in symptomatic patients. Risk of aggressive behavior according to Fletcher criteria was determined in 25 of 30 patients (68%: high risk, 28%: intermediate risk, 4%: low risk). Histopathological examination revealed the presence of spindle cells in 96.1% of cases; CD117 and CD34 were present immunohistochemically in 96.6% and 84% of patients, respectively. The most common surgical procedures were distal pancreatectomy with splenectomy (n = 9) and pancreaticoduodenectomy (n = 7). The total follow-up period for the 28 patients ranged from 3-66 mo, during which locoregional or distant metastases were diagnosed in six patients and two patients died. CONCLUSION: Studies on EGISTs have only been published in the last decade. The lack of studies with

  3. Gastro-entero-pancreatic neuroendocrine tumors: Is now time for a new approach?

    PubMed Central

    Berardi, Rossana; Torniai, Mariangela; Savini, Agnese; Rinaldi, Silvia; Cascinu, Stefano

    2016-01-01

    Gastro-entero-pancreatic tumors (GEP-NETs) are rare neoplasms often characterized by an overexpression of somatostatin receptors. Thus, radiolabeled somatostatin analogues have showed an increasing relevance both in diagnosis and treatment, especially in low- and intermediate-differentiated GEP-NETs. These evidences have led to a growing development of new functional imaging techniques as 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) proved useful in the management of these neoplasms. However these tumors have a heterogeneous behavior also modifying their aggressiveness through time. Therefore sometimes 18F-fluorodeoxyglucose PET/CT appears to be more appropriate to obtain a better assessment of the disease. According to these considerations, the combination of different functional imaging techniques should be considered in the management of GEP-NETs patients allowing clinicians to choose the tailored therapeutic approach among available options. PMID:27081635

  4. Improving pancreatic cancer diagnosis using circulating tumor cells: prospects for staging and single-cell analysis

    PubMed Central

    Court, Colin M; Ankeny, Jacob S; Hou, Shuang; Tseng, Hsian-Rong; Tomlinson, James S

    2016-01-01

    Pancreatic cancer (PC) is the fourth most common cause of cancer-related death in the USA, primarily due to late presentation coupled with an aggressive biology. The lack of adequate biomarkers for diagnosis and staging confound clinical decision-making and delay potentially effective therapies. Circulating tumor cells (CTCs) are a promising new biomarker in PC. Preliminary studies have demonstrated their potential clinical utility, and newer CTC isolation platforms have the potential to provide clinicians access to tumor tissue in a reliable, real-time manner. Such a ‘liquid biopsy’ has been demonstrated in several cancers, and small studies have demonstrated its potential applications in PC. This article reviews the available literature on CTCs as a biomarker in PC and presents the latest innovations in CTC research as well as their potential applications in PC. PMID:26390158

  5. Future Directions in the Treatment of Gastrointestinal and Pancreatic Neuroendocrine Tumors.

    PubMed

    Asmis, Timothy

    2016-07-01

    Recently, the landscape of the diagnosis and treatment of patients with well-differentiated gastrointestinal/pancreatic neuroendocrine tumors (previously referred to as carcinoid tumors) has changed dramatically. We will need to work with all of the stakeholders including clinicians, patients, regulatory agencies, and industry to best navigate future treatment and research. Future protocols will require us to define clinically relevant end points. In designing future clinical trials, we will need to determine which patients will be included in these studies. Future research will need to address the best way to image and follow patient's disease both in the clinic and on research studies. Timely access to new therapies will be the utmost importance to both current and future patients. We must work together to establish relevant clinical questions and to pursue collaborative research that promotes the health of our patients. PMID:27295530

  6. Importance of NAB2-STAT6 Fusion in the Diagnosis of Pancreatic Solitary Fibrous Tumor with Hamartoma-Like Features: A Case Report and Review of the Literature

    PubMed Central

    Tanaka, Kei; Kishimoto, Takashi; Ohtsuka, Masayuki; Nakatani, Yukio; Miyazaki, Masaru

    2015-01-01

    We report a case of pancreatic hamartoma-like solitary fibrous tumor which was differentiated from pancreatic hamartoma with the detection of NAB2-STAT6 fusion, a specific mutation for solitary fibrous tumors. A pancreatic well-demarcated solid nodule, 21 × 17 mm, of 82-year-old man was surgically enucleated. Microscopic findings were close to a pancreatic hamartoma that consisted of sparsely distributed pancreatic ducts and acini in heavily collagenized fibrous stroma. Neither islet nor peripheral nerve existed in the tumor. The fibroblastic cells in the stroma were immune-positive for CD34, CD99, and bcl-2. But these expressions were not decisive in the differentiation between solitary fibrous tumor and pancreatic hamartoma, because CD34 was positive for both tumors, and CD99 and bcl-2 expressions were not elucidated in the previous cases of pancreatic hamartomas. Thus, we evaluated NAB2-STAT6 fusion. The fibroblastic cells were positive for STAT6 and sequencing analysis revealed the gene fusion between NAB2 exon 4 and STAT6 exon 2, with which the final diagnos is of solitary fibrous tumor was achieved. In conclusion, detection of NAB2-STAT6 fusion has a great diagnostic value for pancreatic solitary fibrous tumors with hamartoma-like features. PMID:26425382

  7. Low expression of ARHI is associated with shorter progression-free survival in pancreatic endocrine tumors.

    PubMed

    Dalai, Irene; Missiaglia, Edoardo; Barbi, Stefano; Butturini, Giovanni; Doglioni, Claudio; Falconi, Massimo; Scarpa, Aldo

    2007-03-01

    Little is known about the molecular anomalies involved in the development and progression of malignancy of pancreatic endocrine tumors (PETs). A recently identified member of the Ras family, Ras homologue member I (ARHI), has been shown to be involved in breast, ovary, and thyroid carcinogenesis. Unlike other members, it acts as a tumor suppressor gene that inhibits cell growth. Here we analyzed the mRNA expression of ARHI in 52 primary PETs and 16 normal pancreata using quantitative reverse transcription-polymerase chain reaction. ARHI expression showed a statistically significant difference between either normal pancreas or well-differentiated endocrine tumors (WDET) and poorly differentiated endocrine carcinomas (PDECs) (P < .001 and P < .001, respectively). Moreover, ARHI expression among WDEC samples was more heterogeneous than in WDET, with several tumors showing level of expression analogous to that observed in PDECs. A significant correlation between lower ARHI expression and shorter survival (P = .020) was identified, and a low ARHI expression was associated to a shorter time to progression (P < .001), even considering the proliferation index Ki67 in the multivariate analysis. ARHI is involved in PET progression. Its mRNA expression seemed to be a prognostic factor for disease outcome and, in association with the proliferative index Ki67, a predictor for a rapid tumor relapse. PMID:17401457

  8. Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

    PubMed Central

    Cortez, Eliane; Gladh, Hanna; Braun, Sebastian; Bocci, Matteo; Cordero, Eugenia; Björkström, Niklas K.; Miyazaki, Hideki; Michael, Iacovos P.; Eriksson, Ulf; Folestad, Erika; Pietras, Kristian

    2016-01-01

    Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis. PMID:26831065

  9. Correlation of monoclonal and polyclonal somatostatin receptor 5 antibodies in pancreatic neuroendocrine tumors

    PubMed Central

    Kaemmerer, Daniel; Lupp, Amelie; Peter, Luisa; Fischer, Elke; Schulz, Stefan; Klöppel, Günter; Hommann, Merten

    2013-01-01

    Aims: To evaluate the frequency of somatostatin-receptor 5 (SSTR 5) in pancreatic neuroendocrine tumors by using monoclonal and polyclonal antibodies. Material and Method: we analyzed 66 proven pancreatic neuroendocrine tumors immunohistochemically with monoclonal (clone UMB-4) and polyclonal SSTR 5-antibodies. Immunoreactive score (IRS) and DAKO-score Her2/neu were evaluated. Results: Immunohistochemistry analysis demonstrated for the IRS a significant higher staining of all specimen using the monoclonal antibodies ( IRS SSTR5 poly vs IRS SSTR 5 mono; 20.0% vs 30.3% p < 0.001) by a correlation of 0.21; p = 0.04. For the HER2 score there was also a significant higher staining in the monoclonal group (Her2 SSTR 5 poly vs Her2 SSTR 5 mono; 21.5% vs 28.8% p < 0.001) by a correlation of 0.20; p = 0.08. Conclusion: Both antibodies are useful in staining of SSTR, although UMB-4 demonstrated a 10% higher SSTR 5 staining. Due to the previous underestimated expression rate of SSTR 5, current standards in diagnostics and therapy should be reconsidered. The increasing usage of long-acting pansomatostatin receptor analogues will rise the adverse effects connected to SSTR5 binding. PMID:23236542

  10. Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures.

    PubMed

    Mohamed, Amira; Blanchard, Marie-Pierre; Albertelli, Manuela; Barbieri, Federica; Brue, Thierry; Niccoli, Patricia; Delpero, Jean-Robert; Monges, Genevieve; Garcia, Stephane; Ferone, Diego; Florio, Tullio; Enjalbert, Alain; Moutardier, Vincent; Schonbrunn, Agnes; Gerard, Corinne; Barlier, Anne; Saveanu, Alexandru

    2014-10-01

    Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability. PMID:25012983

  11. CDDO-Me inhibits tumor growth and prevents recurrence of pancreatic ductal adenocarcinoma

    PubMed Central

    GAO, XIAOHUA; DEEB, DORRAH; LIU, YONGBO; LIU, PATRICIA; ZHANG, YIGUAN; SHAW, JIAJIU; GAUTAM, SUBHASH C.

    2015-01-01

    Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) has shown potent antitumorigenic activity against a wide range of cancer cell lines in vitro and inhibited the growth of liver, lung and prostate cancer in vivo. In the present study, we examined the antitumor activity of CDDO-Me for pancreatic ductal adenocarcinoma (PDAC) cells with and without activating K-ras mutations. Treatment of K-ras mutant MiaPaCa-2 and K-ras normal BxPC-3 cells with CDDO-Me elicited strong antiproliferative and proapop-topic responses in both cell lines in culture. The inhibition of cell proliferation and induction of apoptosis was accompanied by the inhibition of antiapoptotic/prosurvival p-Akt, NF-κB and p-mTOR signaling proteins. For testing efficacy of CDDO-Me in vivo heterotopic and orthotopic xenografts were generated by implanting BxPC-3 and MiaPaCa-2 cells subcutaneously and in the pancreatic tail, respectively. Treatment with CDDO-Me significantly inhibited the growth of BxPC-3 xenografts and reduced the levels of p-Akt and p-mTOR in tumor tissue. In mice with orthotopic MiaPaCa-2 xenografts, treatment with CDDO-Me prolonged the survival of mice when administered following the surgical resection of tumors. The latter was attributed to the eradication of residual PDAC remaining after resection of tumors. These preclinical data demonstrate the potential of CDDO-Me for treating primary PDAC tumors and for preventing relapse/recurrence through the destruction of residual disease. PMID:26497549

  12. Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells

    PubMed Central

    ZHAO, LU; ZHAO, YUE; SCHWARZ, BETTINA; MYSLIWIETZ, JOSEF; HARTIG, ROLAND; CAMAJ, PETER; BAO, QI; JAUCH, KARL-WALTER; GUBA, MAKUS; ELLWART, JOACHIM WALTER; NELSON, PETER JON; BRUNS, CHRISTIANE JOSEPHINE

    2016-01-01

    Tumor side population (SP) cells display stem-like properties that can be modulated by treatment with the calcium channel blocker verapamil. Verapamil can enhance the cytotoxic effects of chemotherapeutic drugs and multi-drug resistance by targeting the transport function of the P-glycoprotein (P-gp). This study focused on the therapeutic potential of verapamil on stem-like SP tumor cells, and further investigated its chemosensitizing effects using L3.6pl and AsPC-1 pancreatic carcinoma models. As compared to parental L3.6pl cells (0.9±0.22%), L3.6pl gemcitabine-resistant cells (L3.6plGres) showed a significantly higher percentage of SP cells (5.38±0.99%) as detected by Hoechst 33342/FACS assays. The L3.6plGres SP cells showed stable gemcitabine resistance, enhanced colony formation ability and increased tumorigenicity. Verapamil effectively inhibited L3.6plGres and AsPC-1 SP cell proliferation in vitro. A pro-apoptotic effect of verapamil was observed in L3.6pl cells, but not in L3.6plGres cells, which was linked to their differential expression of P-gp and equilibrative nucleoside transporter-1 (ENT-1). In an orthotopic pancreatic cancer mouse model, both low and high dose verapamil was shown to substantially reduce L3.6plGres-SP cell tumor growth and metastasis, enhance tumor apoptosis, and reduce microvascular density. PMID:27177126

  13. Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells.

    PubMed

    Zhao, Lu; Zhao, Yue; Schwarz, Bettina; Mysliwietz, Josef; Hartig, Roland; Camaj, Peter; Bao, Qi; Jauch, Karl-Walter; Guba, Makus; Ellwart, Joachim Walter; Nelson, Peter Jon; Bruns, Christiane Josephine

    2016-07-01

    Tumor side population (SP) cells display stem-like properties that can be modulated by treatment with the calcium channel blocker verapamil. Verapamil can enhance the cytotoxic effects of chemotherapeutic drugs and multidrug resistance by targeting the transport function of the P-glycoprotein (P-gp). This study focused on the therapeutic potential of verapamil on stem-like SP tumor cells, and further investigated its chemosensitizing effects using L3.6pl and AsPC-1 pancreatic carcinoma models. As compared to parental L3.6pl cells (0.9±0.22%), L3.6pl gemcitabine-resistant cells (L3.6plGres) showed a significantly higher percentage of SP cells (5.38±0.99%) as detected by Hoechst 33342/FACS assays. The L3.6plGres SP cells showed stable gemcitabine resistance, enhanced colony formation ability and increased tumorigenicity. Verapamil effectively inhibited L3.6plGres and AsPC-1 SP cell proliferation in vitro. A pro-apoptotic effect of verapamil was observed in L3.6pl cells, but not in L3.6plGres cells, which was linked to their differential expression of P-gp and equilibrative nucleoside transporter-1 (ENT-1). In an orthotopic pancreatic cancer mouse model, both low and high dose verapamil was shown to substantially reduce L3.6plGres-SP cell tumor growth and metastasis, enhance tumor apoptosis, and reduce microvascular density. PMID:27177126

  14. Role of magnetic resonance imaging in the detection and characterization of solid pancreatic nodules: An update

    PubMed Central

    Ansari, Najwa Al; Ramalho, Miguel; Semelka, Richard C; Buonocore, Valeria; Gigli, Silvia; Maccioni, Francesca

    2015-01-01

    Pancreatic ductal adenocarcinoma is the most common malignant tumor of the pancreas. The remaining pancreatic tumors are a diverse group of pancreatic neoplasms that comprises cystic pancreatic neoplasms, endocrine tumors and other uncommon pancreatic tumors. Due to the excellent soft tissue contrast resolution, magnetic resonance imaging (MRI) is frequently able to readily separate cystic from noncystic tumors. Cystic tumors are often easy to diagnose with MRI; however, noncystic non-adenocarcinoma tumors may show a wide spectrum of imaging features, which can potentially mimic ductal adenocarcinoma. MRI is a reliable technique for the characterization of pancreatic lesions. The implementation of novel motion-resistant pulse sequences and respiratory gating techniques, as well as the recognized benefits of MR cholangiopancreatography, make MRI a very accurate examination for the evaluation of pancreatic masses. MRI has the distinctive ability of non-invasive assessment of the pancreatic ducts, pancreatic parenchyma, neighbouring soft tissues, and vascular network in one examination. MRI can identify different characteristics of various solid pancreatic lesions, potentially allowing the differentiation of adenocarcinoma from other benign and malignant entities. In this review we describe the MRI protocols and MRI characteristics of various solid pancreatic lesions. Recognition of these characteristics may establish the right diagnosis or at least narrow the differential diagnosis, thus avoiding unnecessary tests or procedures and permitting better management. PMID:26644822

  15. Model-based risk assessment for motion effects in 3D radiotherapy of lung tumors

    NASA Astrophysics Data System (ADS)

    Werner, René; Ehrhardt, Jan; Schmidt-Richberg, Alexander; Handels, Heinz

    2012-02-01

    Although 4D CT imaging becomes available in an increasing number of radiotherapy facilities, 3D imaging and planning is still standard in current clinical practice. In particular for lung tumors, respiratory motion is a known source of uncertainty and should be accounted for during radiotherapy planning - which is difficult by using only a 3D planning CT. In this contribution, we propose applying a statistical lung motion model to predict patients' motion patterns and to estimate dosimetric motion effects in lung tumor radiotherapy if only 3D images are available. Being generated based on 4D CT images of patients with unimpaired lung motion, the model tends to overestimate lung tumor motion. It therefore promises conservative risk assessment regarding tumor dose coverage. This is exemplarily evaluated using treatment plans of lung tumor patients with different tumor motion patterns and for two treatment modalities (conventional 3D conformal radiotherapy and step-&- shoot intensity modulated radiotherapy). For the test cases, 4D CT images are available. Thus, also a standard registration-based 4D dose calculation is performed, which serves as reference to judge plausibility of the modelbased 4D dose calculation. It will be shown that, if combined with an additional simple patient-specific breathing surrogate measurement (here: spirometry), the model-based dose calculation provides reasonable risk assessment of respiratory motion effects.

  16. Consensus Recommendations for the Diagnosis and Management of Pancreatic Neuroendocrine Tumors: Guidelines from a Canadian National Expert Group.

    PubMed

    Singh, Simron; Dey, Chris; Kennecke, Hagen; Kocha, Walter; Maroun, Jean; Metrakos, Peter; Mukhtar, Tariq; Pasieka, Janice; Rayson, Daniel; Rowsell, Corwyn; Sideris, Lucas; Wong, Ralph; Law, Calvin

    2015-08-01

    Pancreatic neuroendocrine tumors (pNETs) are rare heterogeneous tumors that have been steadily increasing in both incidence and prevalence during the past few decades. Pancreatic NETs are categorized as functional (F) or nonfunctional (NF) based on their ability to secrete hormones that elicit clinically relevant symptoms. Specialized diagnostic tests are required for diagnosis. Treatment options are diverse and include surgical resection, intraarterial hepatic therapy, and peptide receptor radionuclide therapy (PRRT). Systemic therapy options include targeted agents as well as chemotherapy when indicated. Diagnosis and management should occur through a collaborative team of health care practitioners well-experienced in managing pNETs. Recent advances in pNET treatment options have led to the development of the Canadian consensus document described in this report. The discussion includes the epidemiology, classification, pathology, clinical presentation and prognosis, imaging and laboratory testing, medical and surgical management, and recommended treatment algorithms for pancreatic neuroendocrine cancers. PMID:25366583

  17. Doublecortin-Like Kinase 1 Is Elevated Serologically in Pancreatic Ductal Adenocarcinoma and Widely Expressed on Circulating Tumor Cells

    PubMed Central

    Weygant, Nathaniel; May, Randal; Aiello, Nicole; Rhim, Andrew; Zhao, Lichao; Zheng, Wei; Lightfoot, Stanley; Pant, Shubham; Irvan, Jeremy; Postier, Russell; Hocker, James; Hanas, Jay S.; Ali, Naushad; Sureban, Sripathi M.; An, Guangyu; Schlosser, Michael J.; Stanger, Ben; Houchen, Courtney W.

    2015-01-01

    Doublecortin-like kinase 1 (DCLK1) is a putative pancreatic stem cell marker and is upregulated in pancreatic cancer, colorectal cancer, and many other solid tumors. It marks tumor stem cells in mouse models of intestinal neoplasia. Here we sought to determine whether DCLK1 protein can be detected in the bloodstream and if its levels in archived serum samples could be quantitatively assessed in pancreatic cancer patients. DCLK1 specific ELISA, western blotting, and immunohistochemical analyses were used to determine expression levels in the serum and staining intensity in archived tumor tissues of pancreatic ductal adenocarcinoma (PDAC) patients and in pancreatic cancer mouse models. DCLK1 levels in the serum were elevated in early stages of PDAC (stages I and II) compared to healthy volunteers (normal controls). No differences were observed between stages III/IV and normal controls. In resected surgical tissues, DCLK1 expression intensity in the stromal cells was significantly higher than that observed in tumor epithelial cells. Circulating tumor cells were isolated from KPCY mice and approximately 52% of these cells were positive for Dclk1 staining. Dclk1 levels in the serum of KPC mice were also elevated. We have previously demonstrated that DCLK1 plays a potential role in regulating epithelial mesenchymal transition (EMT). Given the increasingly recognized role of EMT derived stem cells in cancer progression and metastasis, we hypothesize that DCLK1 may contribute to the metastatic process. Taken together, our results suggest that DCLK1 serum levels and DCLK1 positive circulating tumor cells should be further assessed for their potential diagnostic and prognostic significance. PMID:25723399

  18. Loss of Stromal Caveolin-1 Expression: A Novel Tumor Microenvironment Biomarker That Can Predict Poor Clinical Outcomes for Pancreatic Cancer

    PubMed Central

    Shan, Tao; Lu, Hongwei; Ji, Hong; Li, Yiming; Guo, Jian; Chen, Xi; Wu, Tao

    2014-01-01

    Aims Cancer development and progression is not only associated with the tumor cell proliferation but also depends on the interaction between tumor cells and the stromal microenvironment. A new understanding of the role of the tumor microenvironment suggests that the loss of stromal caveolin-1 (Cav-1) as a key regulator may become a potential therapy target. This study aims to elucidate whether stromal Cav-1 expression in pancreatic cancer can be a strong prognosis biomarker. Methods Tissue samples from 45 pancreatic cancer patients were studied. Parenchyma and stroma were separated and purified using laser capture microdissection. Stromal Cav-1 expression was measured from pancreatic cancer, paraneoplastic, and normal tissue using immunohistochemistry. We analyzed the correlation of stromal Cav-1 expression with clinicopathologic features and prognostic indicators, such as tumor marker HER-2/neu gene. Results Specimens from six patients (13.3%) showed high levels of stromal Cav-1 staining, those from eight patients (17.8%) showed a lower, intermediate level of staining, whereas those from 31 patients (68.9%) showed an absence of staining. Cav-1 expression in cancer-associated fibroblasts was lower than that in paracancer-associated and in normal fibroblasts. Stromal Cav-1 loss was associated with TNM stage (P = 0.018), lymph node metastasis (P = 0.014), distant metastasis (P = 0.027), and HER-2/neu amplification (P = 0.007). The relationships of age, sex, histological grade, and tumor size with stromal Cav-1 expression were not significant (P>0.05). A negative correlation was found between circulating tumor cells and stromal Cav-1 expression (P<0.05). Conclusion The loss of stromal Cav-1 in pancreatic cancer was an independent prognostic indicator, thus suggesting that stromal Cav-1 may be an effective therapeutic target for patients with pancreatic cancer. PMID:24949874

  19. Broncho-biliary fistula secondary to biliary obstruction and lung abscess in a patient with pancreatic neuro-endocrine tumor.

    PubMed

    Panda, Dipanjan; Aggarwal, Mayank; Yadav, Vikas; Kumar, Sachin; Mukund, Amar; Baghmar, Saphalta

    2016-06-01

    We present a case report of broncho-biliary fistula that developed due to the blockage of biliary stent placed during the management of pancreatic neuroendocrine tumor (pNET); diagnosed on high clinical suspicion, percutaneous cholangiogram and contrast enhanced computed tomography (CECT); and successfully treated with percutaneous transhepatic biliary drainage (PTBD). PMID:26994644

  20. CD133+ tumor initiating cells (TIC) in a syngenic murine model of pancreatic cancer respond to Minnelide

    PubMed Central

    Banerjee, Sulagna; Nomura, Alice; Sangwan, Veena; Chugh, Rohit; Dudeja, Vikas; Vickers, Selwyn M; Saluja, Ashok

    2014-01-01

    Purpose Pancreatic adenocarcinoma is the fourth leading cause for cancer-related mortality with a survival rate of less than 5%. Late diagnosis and lack of effective chemotherapeutic regimen contribute to these grim survival statistics. Relapse of any tumor is largely attributed to the presence of tumor-initiating cells (TIC) or cancer stem cells (CSC). These cells are considered as hurdles to cancer therapy as no known chemotherapeutic compound is reported to target them. Thus, there is an urgent need to develop a TIC-targeted therapy for pancreatic cancer. Experimental design We isolated CD133+ cells from a spontaneous PDAC mouse model and studied both surface expression, molecular markers of pancreatic TICs. We also studied tumor initiation properties by implanting low numbers of CD133+ cells in immune competent mice. Effect of Minnelide, a drug currently under Phase I clinical trial, was studied on the tumors derived from the CD133+ cells. Results Our study showed for the first time that CD133+ population demonstrated all the molecular markers for pancreatic TIC. These cells initiated tumors in immunocompetent mouse models and showed increased expression of pro-survival and pro-invasive proteins compared to the CD133− non-TIC population. Our study further showed that Minnelide, was very efficient in downregulating both CD133− and CD133+ population in the tumors, resulting in a 60% decrease in tumor volume compared to the untreated ones. Conclusion As Minnelide is currently under Phase I clinical trial, its evaluation in reducing tumor burden by decreasing TIC as well as non-TIC population suggests its potential as an effective therapy. PMID:24634377

  1. Preclinical evaluation of a novel CEA-targeting near-infrared fluorescent tracer delineating colorectal and pancreatic tumors.

    PubMed

    Boonstra, Martin C; Tolner, Berend; Schaafsma, Boudewijn E; Boogerd, Leonora S F; Prevoo, Hendrica A J M; Bhavsar, Guarav; Kuppen, Peter J K; Sier, Cornelis F M; Bonsing, Bert A; Frangioni, John V; van de Velde, Cornelis J H; Chester, Kerry A; Vahrmeijer, Alexander L

    2015-10-15

    Surgery is the cornerstone of oncologic therapy with curative intent. However, identification of tumor cells in the resection margins is difficult, resulting in nonradical resections, increased cancer recurrence and subsequent decreased patient survival. Novel imaging techniques that aid in demarcating tumor margins during surgery are needed. Overexpression of carcinoembryonic antigen (CEA) is found in the majority of gastrointestinal carcinomas, including colorectal and pancreas. We developed ssSM3E/800CW, a novel CEA-targeted near-infrared fluorescent (NIRF) tracer, based on a disulfide-stabilized single-chain antibody fragment (ssScFv), to visualize colorectal and pancreatic tumors in a clinically translatable setting. The applicability of the tracer was tested for cell and tissue binding characteristics and dosing using immunohistochemistry, flow cytometry, cell-based plate assays and orthotopic colorectal (HT-29, well differentiated) and pancreatic (BXPC-3, poorly differentiated) xenogeneic human-mouse models. NIRF signals were visualized using the clinically compatible FLARE™ imaging system. Calculated clinically relevant doses of ssSM3E/800CW selectively accumulated in colorectal and pancreatic tumors/cells, with highest tumor-to-background ratios of 5.1 ± 0.6 at 72 hr postinjection, which proved suitable for intraoperative detection and delineation of tumor boarders and small (residual) tumor nodules in mice, between 8 and 96 hr postinjection. Ex vivo fluorescence imaging and pathologic examination confirmed tumor specificity and the distribution of the tracer. Our results indicate that ssSM3E/800CW shows promise as a diagnostic tool to recognize colorectal and pancreatic cancers for fluorescent-guided surgery applications. If successfully translated clinically, this tracer could help improve the completeness of surgery and thus survival. PMID:25895046

  2. Image-Guided Radiofrequency Ablation of a Pancreatic Tumor with a New Triple Spiral-Shaped Electrode

    SciTech Connect

    Thanos, Loukas; Poulou, Loukia S.; Mailli, Lito; Pomoni, Maria; Kelekis, Dimitrios A.

    2010-02-15

    Image-guided, minimally invasive treatment modalities have become an area of considerable interest and research during the last few years for the treatment of primary and secondary liver tumors. We report our experience with an unresectable pancreatic tumor, treated with application of radiofrequency ablation under CT guidance that even though a complication occurred during the procedure, had excellent results on follow-up CT scans.

  3. Impact and Clinical Predictors of Lymph Node Metastases in Nonfunctional Pancreatic Neuroendocrine Tumors

    PubMed Central

    Jiang, Yu; Jin, Jia-Bin; Zhan, Qian; Deng, Xia-Xing; Shen, Bai-Yong

    2015-01-01

    Background: The optimal surgical management of nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) is still controversial. Here, we evaluated the impact of lymph node status on postoperative recurrence in patients with NF-PNET and the potential of preoperative variables for predicting lymph node metastasis (LNM). Methods: In this mono-institutional retrospective cohort study conducted in 100 consecutive patients who underwent NF-PNET resection between January 2004 and December 2014, we evaluated risk factors for survival using the Kaplan–Meier method and the Cox regression model. Predictors of LNM were evaluated using the logistic regression model, and the power of predictive models was evaluated using receiver operating characteristic curve analysis. Results: Five-year disease-free survival of resected NF-PNET was 64.1%. LNM was independently associated with postoperative recurrence (hazard ratio = 3.995, P = 0.003). Multivariate analysis revealed tumor grade as an independent factor associated with LNM (G2 vs. G1: odds ratio [OR] =6.287, P = 0.008; G3 vs. G1: OR = 12.407, P = 0.001). When tumor grade was excluded, radiological tumor diameter >2.5 cm (OR = 5.430, P = 0.013) and presence of symptoms (OR = 3.366, P = 0.039) were significantly associated with LNM. Compared to neoplasms with radiological diameter >2.5 cm (32.1%), tumors ≤2.5 cm had an obviously lower risk of LNM (7.7%), indicating the reliability of this parameter in predicting LNM (area under the curve, 0.693). Incidentally discovered NF-PNETs ≤2.5 cm were associated with a low-risk of LNM and excellent survival. Conclusions: LNM is significantly associated with postoperative recurrence. Radiological tumor diameter is a reliable predictor of LNM in NF-PNETs. Our results indicate that lymphadenectomy in small (≤2.5 cm) NF-PNETs is not routinely necessary. PMID:26668149

  4. Pancreatic Gastrointestinal Stromal Tumor after Upper Gastrointestinal Hemorrhage and Performance of Whipple Procedure: A Case Report and Literature Review

    PubMed Central

    Aziret, Mehmet; Çetinkünar, Süleyman; Aktaş, Elife; İrkörücü, Oktay; Bali, İlhan; Erdem, Hasan

    2015-01-01

    Patient: Male, 56 Final Diagnosis: Pancreatic GIST Symptoms: Abdominal pain Medication: None Clinical Procedure: Whipple procedure Specialty: Surgery Objective: Rare disease Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal system. These types of tumors originate from any part of the tract as well as from the intestine, colon, omentum, mesentery or retroperitoneum. GIST is a rare tumor compared to other types of tumors, accounting for less than 1% of all gastrointestinal tumors. Case Report: A 56-year-old male patient was hospitalized due to an upper gastrointestinal hemorrhage and the start of abdominal pain on the same day. In the upper gastrointestinal endoscopy that was performed, a solitary mass was found in the second section of the duodenum and a blood vessel (Forrest type 2a) was seen. The extent and location of the mass was detected by abdominal tomography. After hemodynamic recovery, a Whipple procedure was performed without any complications. A subsequent histopathological examination detected a c-kit-positive (CD117) pancreatic GIST with high mitotic index. Conclusions: The most effective treatment method for GISTs is surgical resection. In patients with a head of pancreatic GIST, the Whipple procedure can be used more safely and effectively. PMID:26237079

  5. Inhibitory effects of somatostatin on tumor necrosis factor-alpha-induced interleukin-6 secretion in human pancreatic periacinar myofibroblasts.

    PubMed

    Andoh, Akira; Hata, Kazunori; Shimada, Mitsue; Fujino, Sanae; Tasaki, Kazuhito; Bamba, Shigeki; Araki, Yoshio; Fujiyama, Yoshihide; Bamba, Tadao

    2002-07-01

    Pancreatic periacinar myofibroblasts are considered to be therapeutic targets for the suppression of acute pancreatitis. To elucidate the mechanisms mediating the therapeutic actions of somatostatin on acute pancreatitis, we investigated how somatostatin affects the tumor necrosis factor (TNF)-alpha-induced interleukin (IL)-6 and IL-8 secretion from pancreatic myofibroblasts. Cytokine secretion was determined by enzyme-linked immunosorbent assay (ELISA) and Northern blotting. Nuclear factor (NF)-kappaB DNA-binding activity was evaluated by electrophoretic mobility shift assay (EMSAs). The expression of somatostatin receptor (SSTR) mRNA was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Somatostatin dose-dependently inhibited the TNF-alpha-induced IL-6 secretion. In comparison, the effects on IL-8 secretion were modest. Northern blot analysis demonstrated that somatostatin decreased the TNF-alpha-induced IL-6 mRNA expression, and that this effect was completely blocked by the somatostatin antagonist cyclo-somatostatin. Furthermore, somatostatin suppressed TNF-alpha-induced NF-kappaB activation. These cells bear SSTR subtypes 1 and 2. Somatostatin down-regulated the TNF-alpha-induced IL-6 secretion in human pancreatic periacinar myofibroblasts. These findings suggest that some of the therapeutic actions of somatostatin on acute pancreatitis might be mediated by reducing local IL-6 secretion in the pancreas. PMID:12060857

  6. Lysates of S. pyogenes serotype M49 induce pancreatic tumor growth delay by specific and unspecific antitumor immune responses.

    PubMed

    Linnebacher, Michael; Maletzki, Claudia; Emmrich, Jörg; Kreikemeyer, Bernd

    2008-10-01

    Treatment of pancreatic cancer by active unspecific bacterial immunotherapy is a promising new strategy. Recently, we showed that a single intratumoral injection of wildtype Streptococcus pyogenes M49 results in complete regression of pancreatic carcinoma in mice mediated both by unspecific cytotoxicity and by specific immune reactions against tumor cells. As for potential clinical use, conditioning and especially inactivation of bacteria would abolish the risk of systemic bacterial infections; we here explored the potential of a streptococcal lysate prepared by bacteriophage lysine to affect pancreatic carcinoma growth in vivo. Application of the lysate into established Panc02 tumors resulted in pronounced growth cessation accompanied by raises in levels of circulating monocytes, granulocytes, and natural killer cells. Detailed analysis of splenocyte subsets revealed lysate-induced transient increases in pre-B cells followed by raised levels of activated T cells. Moreover, blood levels of proinflammatory, T helper-1-type cytokines were significantly elevated. These systemic immunologic effects were accompanied by massive infiltrations of cytotoxic T cells into the tumors. Concomitantly, lymphocytes obtained from treated mice specifically recognized Panc02 tumor cells in IFN-gamma-enzyme-linked immunosorbent spot and in cellular cytotoxicity assays. In rechallenge experiments, these immunologic effector cells were found to delay, but not completely prevent growth of secondary tumors. However, when considering the notoriously depressed immune status of individuals suffering from pancreatic carcinoma, the orchestrated antitumoral immune responses we analyzed here in detail significantly strengthen the potential usefulness of microbial compounds as active unspecific immunotherapeutic agent for treatment of pancreatic carcinoma. PMID:18779749

  7. Potential systematic uncertainties in IGRT when FBCT reference images are used for pancreatic tumors.

    PubMed

    Amoush, Ahmad; Abdel-Wahab, May; Abazeed, Mohamed; Xia, Ping

    2015-01-01

    The purpose of this study was to quantify the systematic uncertainties resulting from using free breathing computed tomography (FBCT) as a reference image for image-guided radiation therapy (IGRT) for patients with pancreatic tumors, and to quantify the associated dosimetric impact that resulted from using FBCT as reference for IGRT. Fifteen patients with implanted fiducial markers were selected for this study. For each patient, a FBCT and an average intensity projection computed tomography (AIP) created from four-dimensional computed tomography (4D CT) were acquired at the simulation. The treatment plan was created based on the FBCT. Seventy-five weekly kilovoltage (kV) cone-beam computed tomography (CBCT) images (five for each patient) were selected for this study. Bony alignment without rotation correction was performed 1) between the FBCT and CBCT, 2) between the AIP and CBCT, and 3) between the AIP and FBCT. The contours of the fiducials from the FBCT and AIP were transferred to the corresponding CBCT and were compared. Among the 75 CBCTs, 20 that had > 3 mm differences in centers of mass (COMs) in any directions between the FBCT and AIP were chosen for further dosimetric analysis. These COM discrepancies were converted into isocenter shifts in the corresponding planning FBCT, and dose was recalculated and compared to the initial FBCT plans. For the 75 CBCTs studied, the mean absolute differences in the COMs of the fiducial markers between the FBCT and CBCTs were 3.3 mm ± 2.5 mm, 3.5 mm ± 2.4 mm, and 5.8 mm ± 4.4 mm in the right-left (RL), anterior-posterior (AP), and superior-inferior (SI) directions, respectively. Between the AIP and CBCTs, the mean absolute differences were 3.2 mm ± 2.2mm, 3.3 mm ± 2.3 mm, and 6.3 mm ± 5.4 mm. The absolute mean discrepancies in these COMs shifts between FBCT/CBCT and AIP/CBCT were 1.1 mm ± 0.8 mm, 1.3 mm ± 0.9 mm, and 3.3 mm ± 2.6 mm in RL, AP, and SI, respectively. This represented a potential systematic error

  8. A PAUF-neutralizing antibody targets both carcinoma and endothelial cells to impede pancreatic tumor progression and metastasis

    SciTech Connect

    Kim, Su Jin; Chang, Suhwan; Lee, Yangsoon; Kim, Na Young; Hwang, Yeonsil; Min, Hye Jin; Yoo, Kyung-Sook; Park, Eun Hye; Kim, Seokho; Chung, Young-Hwa; Park, Young Woo; Koh, Sang Seok

    2014-11-07

    Highlights: • PMAb83, a human monoclonal antibody against PAUF, impaired tumor progression in vivo. • PMAb83 attenuated aggressiveness of tumor cells and suppressed angiogenesis. • PMAb83 in combination with gemcitabine conferred improved survival of mouse model. - Abstract: Pancreatic adenocarcinoma up-regulated factor (PAUF) is expressed in pancreatic ductal adenocarcinoma (PDAC) and plays an important role in tumor progression and metastasis. Here we evaluate the anti-tumor efficacy of a human monoclonal antibody against PAUF, PMAb83, to provide a therapeutic intervention to treat the disease. PMAb83 reduced tumor growth and distant metastasis in orthotopically xenografted mice of human PDAC cells. PMAb83 treatment retarded proliferation along with weakened aggressiveness traits of the carcinoma cells. AKT/β-catenin signaling played a role in the carcinoma cell proliferation and the treated xenograft tumors exhibited reduced levels of β-catenin and cyclin D1. Moreover PMAb83 abrogated the PAUF-induced angiogenic responses of endothelial cells, reducing the density of CD31{sup +} vessels in the treated tumors. In combination with gemcitabine, PMAb83 conferred enhanced survival of xenografted mice by about twofold compared to gemcitabine alone. Taken together, our findings show that PMAb83 treatment decreases the aggressiveness of carcinoma cells and suppresses tumor vascularization, which culminates in mitigated tumor growth and metastasis with improved survival in PDAC mouse models.

  9. Retinoblastoma tumor suppressor protein in pancreatic progenitors controls α- and β-cell fate.

    PubMed

    Cai, Erica P; Wu, Xiaohong; Schroer, Stephanie A; Elia, Andrew J; Nostro, M Cristina; Zacksenhaus, Eldad; Woo, Minna

    2013-09-01

    Pancreatic endocrine cells expand rapidly during embryogenesis by neogenesis and proliferation, but during adulthood, islet cells have a very slow turnover. Disruption of murine retinoblastoma tumor suppressor protein (Rb) in mature pancreatic β-cells has a limited effect on cell proliferation. Here we show that deletion of Rb during embryogenesis in islet progenitors leads to an increase in the neurogenin 3-expressing precursor cell population, which persists in the postnatal period and is associated with increased β-cell mass in adults. In contrast, Rb-deficient islet precursors, through repression of the cell fate factor aristaless related homeobox, result in decreased α-cell mass. The opposing effect on survival of Rb-deficient α- and β-cells was a result of opposing effects on p53 in these cell types. As a consequence, loss of Rb in islet precursors led to a reduced α- to β-cell ratio, leading to improved glucose homeostasis and protection against diabetes. PMID:23946427

  10. A biomechanical approach for in vivo lung tumor motion prediction during external beam radiation therapy

    NASA Astrophysics Data System (ADS)

    Karami, Elham; Gaede, Stewart; Lee, Ting-Yim; Samani, Abbas

    2015-03-01

    Lung Cancer is the leading cause of cancer death in both men and women. Among various treatment methods currently being used in the clinic, External Beam Radiation Therapy (EBRT) is used widely not only as the primary treatment method, but also in combination with chemotherapy and surgery. However, this method may lack desirable dosimetric accuracy because of respiration induced tumor motion. Recently, biomechanical modeling of the respiratory system has become a popular approach for tumor motion prediction and compensation. This approach requires reasonably accurate data pertaining to thoracic pressure variation, diaphragm position and biomechanical properties of the lung tissue in order to predict the lung tissue deformation and tumor motion. In this paper, we present preliminary results of an in vivo study obtained from a Finite Element Model (FEM) of the lung developed to predict tumor motion during respiration.

  11. Pituitary tumor transforming gene-null male mice exhibit impaired pancreatic beta cell proliferation and diabetes

    PubMed Central

    Wang, Zhiyong; Moro, Enrico; Kovacs, Kalman; Yu, Run; Melmed, Shlomo

    2003-01-01

    The mammalian securin, pituitary tumor transforming gene (PTTG), regulates sister chromatid separation during mitosis. Mice or cell lines deficient in PTTG expression, however, are surprisingly viable. Here we show that PTTG disruption in mice (PTTG−/−) severely impairs glucose homeostasis leading to diabetes during late adulthood, especially in males associated with nonautoimmune insulinopenia and reversed alpha/beta cell ratio. Islet beta cell mass in PTTG−/− mice was already diminished before development of frank diabetes and only increased minimally during growth. BrdUrd incorporation of islet cells in PTTG-null mice was ≈65% lower (P < 0.005) than in the WT pancreas, whereas apoptosis rates were similar. PTTG−/− beta cells had pleiotropic nuclei, suggesting defects in cell division. The results indicated that securin is indispensable for normal pancreatic beta cell proliferation. PMID:12626748

  12. Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): recent insights and advances

    PubMed Central

    Ito, Tetsuhide; Igarashi, Hisato

    2013-01-01

    Neuroendocrine tumors (NETs) [carcinoids, pancreatic neuroendocrine tumors (pNETs)] are becoming an increasing clinical problem because not only are they increasing in frequency, but they can frequently present with advanced disease that requires diagnostic and treatment approaches different from those used in the neoplasms that most physicians are used to seeing and treating. In the past few years there have been numerous advances in all aspects of NETs including: an understanding of their unique pathogenesis; specific classification systems developed which have prognostic value; novel methods of tumor localization developed; and novel treatment approaches described. In patients with advanced metastatic disease these include the use of newer chemotherapeutic approaches, an increased understanding of the role of surgery and cytoreductive methods, the development of methods for targeted delivery of cytotoxic agents, and the development of targeted medical therapies (everolimus, sunitinib) based on an increased understanding of the disease biology. Although pNETs and gastrointestinal NETs share many features, recent studies show they differ in pathogenesis and in many aspects of diagnosis and treatment, including their responsiveness to different therapies. Because of limited space, this review will be limited to the advances made in the management and treatment of patients with advanced metastatic pNETs over the past 5 years. PMID:22886480

  13. Comparison of Liver Tumor Motion With and Without Abdominal Compression Using Cine-Magnetic Resonance Imaging

    SciTech Connect

    Eccles, Cynthia L.; Patel, Ritesh; Simeonov, Anna K.; Lockwood, Gina; Haider, Masoom; Dawson, Laura A.

    2011-02-01

    Purpose: Abdominal compression (AC) can be used to reduce respiratory liver motion in patients undergoing liver stereotactic body radiotherapy. The purpose of the present study was to measure the changes in three-dimensional liver tumor motion with and without compression using cine-magnetic resonance imaging. Patients and Methods: A total of 60 patients treated as a part of an institutional research ethics board-approved liver stereotactic body radiotherapy protocol underwent cine T2-weighted magnetic resonance imaging through the tumor centroid in the coronal and sagittal planes. A total of 240 cine-magnetic resonance imaging sequences acquired at one to three images each second for 30-60 s were evaluated using an in-house-developed template matching tool (based on the coefficient correlation) to measure the magnitude of the tumor motion. The average tumor edge displacements were used to determine the magnitude of changes in the caudal-cranial (CC) and anteroposterior (AP) directions, with and without AC. Results: The mean tumor motion without AC of 11.7 mm (range, 4.8-23.3) in the CC direction was reduced to 9.4 mm (range, 1.6-23.4) with AC. The tumor motion was reduced in both directions (CC and AP) in 52% of the patients and in a single direction (CC or AP) in 90% of the patients. The mean decrease in tumor motion with AC was 2.3 and 0.6 mm in the CC and AP direction, respectively. Increased motion occurred in one or more directions in 28% of patients. Clinically significant (>3 mm) decreases were observed in 40% and increases in <2% of patients in the CC direction. Conclusion: AC can significantly reduce three-dimensional liver tumor motion in most patients, although the magnitude of the reduction was smaller than previously reported.

  14. Allelic deletion and mutation of the von Hippel-Lindau (VHL) tumor suppressor gene in pancreatic microcystic adenomas.

    PubMed Central

    Vortmeyer, A. O.; Lubensky, I. A.; Fogt, F.; Linehan, W. M.; Khettry, U.; Zhuang, Z.

    1997-01-01

    An association between pancreatic microcystic (serous) adenomas (MCAs) and von Hippel-Lindau (VHL) disease has been suggested. However, genetic alterations of the VHL gene in MCAs of the pancreas have never been reported. In this study, we performed genetic analysis of 12 pancreatic MCAs. In 2 cases, VHL disease was documented clinically, and 10 cases were sporadic. For LOH analysis, tumor and normal pancreatic cells were procured from formalin-fixed, paraffin-embedded material using tissue microdissection. After DNA extraction, the samples were amplified by polymerase chain reaction using the polymorphic markers D3S2452, D3S1110, D3S192, and D3S656. In addition, the sporadic tumors were analyzed for VHL gene mutations using probes 3b/10b and K55/K56. Both MCAs associated with VHL disease showed LOH with at least one of the microsatellite markers tested. Among the 10 sporadic cases, 7 tumors showed LOH at the VHL gene locus. A somatic VHL gene mutation on exon 2 was documented in one sporadic case. The study provides the first direct genetic evidence for the role of the VHL gene in MCA tumorigenesis. Furthermore, VHL gene alterations may be detected in both VHL-associated and sporadic pancreatic MCAs. Images Figure 1 Figure 2 PMID:9327728

  15. Dying tumor cells stimulate proliferation of living tumor cells via caspase-dependent protein kinase Cδ activation in pancreatic ductal adenocarcinoma.

    PubMed

    Cheng, Jin; Tian, Ling; Ma, Jingjing; Gong, Yanping; Zhang, Zhengxiang; Chen, Zhiwei; Xu, Bing; Xiong, Hui; Li, Chuanyuan; Huang, Qian

    2015-01-01

    Pancreatic cancer is one of the most lethal human cancers, and radiotherapy is often implemented for locally advanced pancreatic ductal adenocarcinoma. Tumor cell repopulation is a major challenge in treating cancers after radiotherapy. In order to address the problem of tumor repopulation, our previous studies have demonstrated that dying cells stimulate the proliferation of living tumor cells after radiotherapy. In particular, dying cells undergoing apoptosis also activate survival or proliferation signals and release growth factors to surrounding living cells. In the present study, we used an in vitro model to examine the possible mechanisms for dying cell stimulated tumor repopulation in pancreatic cancer. In this model, a small number of living, luciferase-labeled pancreatic cancer cells (reporter) were seeded onto a layer of a much larger number of irradiated, unlabeled pancreatic cancer cells and the growth of the living cells was measured over time as a gage of tumor repopulation. Our results indicate that irradiated, dying Panc1 feeder cells significantly stimulated the proliferation of living Panc1 reporter cells. Importantly, we identified that the percentage of apoptotic cells and the cleavage of caspases 3 and 7 and protein kinase Cδ (PKCδ) were increased in irradiated Panc1 cells. We presumed that caspases 3 and 7 and PKCδ as integral mediators in the process of dying pancreatic cancer cell stimulation of living tumor cell growth. In order to demonstrate the importance of caspases 3, 7 and PKCδ, we introduced dominant-negative mutants of caspase 3 (DN_C3), caspase 7 (DN_C7), or PKCδ (DN_PKCδ) into Panc1 cells using lentiviral vectors. The stably transduced Panc1 cells were irradiated and used as feeders and we found a significant decrease in the growth of living Panc1 reporter cells when compared with irradiated wild-type Panc1 cells as feeders. Moreover, the role of PKCδ in the growth stimulation of living tumor cells was further confirmed

  16. Transformation of nonfunctioning pancreatic tumor into malignant insulinoma after 3 years: an uncommon clinical course of insulinoma.

    PubMed

    Arslan, Muyesser Sayki; Ozbek, Mustafa; Karakose, Melia; Tutal, Esra; Ucan, Bekir; Yilmazer, Demet; Dilli, Alper; Gultekin, Salih Sinan; Cakal, Erman; Delibasi, Tuncay

    2015-06-01

    A 62-year-old man admitted to our outpatient clinic with two months of recurrent life threatening hypoglycemia episodes. He was diagnosed as malignant insulinoma with multiple metastases of liver and peripancreatic lymph nodes. Liver biopsy specimen was demonstrated grade 2 neuroendocrine tumor compatible with clinical and radiological results. He was followed under the treatment of continuous intravenous glucose infusion during the diagnostic procedures. He had a pancreatic lesion history measured 20 x 12 mm in diameter via the abdominal tomography examination approximately two years before the diagnosis. Unusual course of this case suggests the transformation of nonfunctioning pancreatic neuroendocrine tumor into functional insulin secreting tumor with metastases. The patient was found inoperable and started on chemotherapy. PMID:26154097

  17. Endoscopic ultrasound guided radiofrequency ablation, for pancreatic cystic neoplasms and neuroendocrine tumors

    PubMed Central

    Pai, Madhava; Habib, Nagy; Senturk, Hakan; Lakhtakia, Sundeep; Reddy, Nageshwar; Cicinnati, Vito R; Kaba, Iyad; Beckebaum, Susanne; Drymousis, Panagiotis; Kahaleh, Michel; Brugge, William

    2015-01-01

    AIM: To outline the feasibility, safety, adverse events and early results of endoscopic ultrasound (EUS)-radiofrequency ablation (RFA) in pancreatic neoplasms using a novel probe. METHODS: This is a multi-center, pilot safety feasibility study. The intervention described was radiofrequency ablation (RF) which was applied with an innovative monopolar RF probe (1.2 mm Habib EUS-RFA catheter) placed through a 19 or 22 gauge fine needle aspiration (FNA) needle once FNA was performed in patients with a tumor in the head of the pancreas. The Habib™ EUS-RFA is a 1 Fr wire (0.33 mm, 0.013”) with a working length of 190 cm, which can be inserted through the biopsy channel of an echoendoscope. RF power is applied to the electrode at the end of the wire to coagulate tissue in the liver and pancreas. RESULTS: Eight patients [median age of 65 (range 27-82) years; 7 female and 1 male] were recruited in a prospective multicenter trial. Six had a pancreatic cystic neoplasm (four a mucinous cyst, one had intraductal papillary mucinous neoplasm and one a microcystic adenoma) and two had a neuroendocrine tumors (NET) in the head of pancreas. The mean size of the cystic neoplasm and NET were 36.5 mm (SD ± 17.9 mm) and 27.5 mm (SD ± 17.7 mm) respectively. The EUS-RFA was successfully completed in all cases. Among the 6 patients with a cystic neoplasm, post procedure imaging in 3-6 mo showed complete resolution of the cysts in 2 cases, whilst in three more there was a 48.4% reduction [mean pre RF 38.8 mm (SD ± 21.7 mm) vs mean post RF 20 mm (SD ± 17.1 mm)] in size. In regards to the NET patients, there was a change in vascularity and central necrosis after EUS-RFA. No major complications were observed within 48 h of the procedure. Two patients had mild abdominal pain that resolved within 3 d. CONCLUSION: EUS-RFA of pancreatic neoplasms with a novel monopolar RF probe was well tolerated in all cases. Our preliminary data suggest that the procedure is straightforward and safe. The

  18. Effect of Audio Coaching on Correlation of Abdominal Displacement With Lung Tumor Motion

    SciTech Connect

    Nakamura, Mitsuhiro Narita, Yuichiro; Matsuo, Yukinori; Narabayashi, Masaru; Nakata, Manabu; Sawada, Akira; Mizowaki, Takashi; Nagata, Yasushi; Hiraoka, Masahiro

    2009-10-01

    Purpose: To assess the effect of audio coaching on the time-dependent behavior of the correlation between abdominal motion and lung tumor motion and the corresponding lung tumor position mismatches. Methods and Materials: Six patients who had a lung tumor with a motion range >8 mm were enrolled in the present study. Breathing-synchronized fluoroscopy was performed initially without audio coaching, followed by fluoroscopy with recorded audio coaching for multiple days. Two different measurements, anteroposterior abdominal displacement using the real-time positioning management system and superoinferior (SI) lung tumor motion by X-ray fluoroscopy, were performed simultaneously. Their sequential images were recorded using one display system. The lung tumor position was automatically detected with a template matching technique. The relationship between the abdominal and lung tumor motion was analyzed with and without audio coaching. Results: The mean SI tumor displacement was 10.4 mm without audio coaching and increased to 23.0 mm with audio coaching (p < .01). The correlation coefficients ranged from 0.89 to 0.97 with free breathing. Applying audio coaching, the correlation coefficients improved significantly (range, 0.93-0.99; p < .01), and the SI lung tumor position mismatches became larger in 75% of all sessions. Conclusion: Audio coaching served to increase the degree of correlation and make it more reproducible. In addition, the phase shifts between tumor motion and abdominal displacement were improved; however, all patients breathed more deeply, and the SI lung tumor position mismatches became slightly larger with audio coaching than without audio coaching.

  19. Development of an endoluminal high-intensity ultrasound applicator for image-guided thermal therapy of pancreatic tumors

    PubMed Central

    Scott, Serena J.; Salgaonkar, Vasant A.; Jones, Peter D.; Plata-Camargo, Juan C.; Sommer, Graham; Diederich, Chris J.

    2015-01-01

    An ultrasound applicator for endoluminal thermal therapy of pancreatic tumors has been introduced and evaluated through acoustic/biothermal simulations and ex vivo experimental investigations. Endoluminal therapeutic ultrasound constitutes a minimally invinvasive conformal therapy and is compatible with ultrasound or MR-based image guidance. The applicator would be placed in the stomach or duodenal lumen, and sonication would be performed through the luminal wall into the tumor, with concurrent water cooling of the wall tissue to prevent its thermal injury. A finite-element (FEM) 3D acoustic and biothermal model was implemented for theoretical analysis of the approach. Parametric studies over transducer geometries and frequencies revealed that operating frequencies within 1-3 MHz maximize penetration depth and lesion volume while sparing damage to the luminal wall. Patient-specific FEM models of pancreatic head tumors were generated and used to assess the feasibility of performing endoluminal ultrasound thermal ablation and hyperthermia of pancreatic tumors. Results indicated over 80% of the volume of small tumors (~2 cm diameter) within 35 mm of the duodenum could be safely ablated in under 30 minutes or elevated to hyperthermic temperatures at steady-state. Approximately 60% of a large tumor (~5 cm diameter) model could be safely ablated by considering multiple positions of the applicator along the length of the duodenum to increase coverage. Prototype applicators containing two 3.2 MHz planar transducers were fabricated and evaluated in ex vivo porcine carcass heating experiments under MR temperature imaging (MRTI) guidance. The applicator was positioned in the stomach adjacent to the pancreas, and sonications were performed for 10 min at 5 W/cm2 applied intensity. MRTI indicated over 40°C temperature rise in pancreatic tissue with heating penetration extending 3 cm from the luminal wall. PMID:26677314

  20. Development of an endoluminal high-intensity ultrasound applicator for image-guided thermal therapy of pancreatic tumors

    NASA Astrophysics Data System (ADS)

    Adams, Matthew S.; Scott, Serena J.; Salgaonkar, Vasant A.; Jones, Peter D.; Plata-Camargo, Juan C.; Sommer, Graham; Diederich, Chris J.

    2015-03-01

    An ultrasound applicator for endoluminal thermal therapy of pancreatic tumors has been introduced and evaluated through acoustic/biothermal simulations and ex vivo experimental investigations. Endoluminal therapeutic ultrasound constitutes a minimally invasive conformal therapy and is compatible with ultrasound or MR-based image guidance. The applicator would be placed in the stomach or duodenal lumen, and sonication would be performed through the luminal wall into the tumor, with concurrent water cooling of the wall tissue to prevent its thermal injury. A finite-element (FEM) 3D acoustic and biothermal model was implemented for theoretical analysis of the approach. Parametric studies over transducer geometries and frequencies revealed that operating frequencies within 1-3 MHz maximize penetration depth and lesion volume while sparing damage to the luminal wall. Patient-specific FEM models of pancreatic head tumors were generated and used to assess the feasibility of performing endoluminal ultrasound thermal ablation and hyperthermia of pancreatic tumors. Results indicated over 80% of the volume of small tumors (~2 cm diameter) within 35 mm of the duodenum could be safely ablated in under 30 minutes or elevated to hyperthermic temperatures at steady-state. Approximately 60% of a large tumor (~5 cm diameter) model could be safely ablated by considering multiple positions of the applicator along the length of the duodenum to increase coverage. Prototype applicators containing two 3.2 MHz planar transducers were fabricated and evaluated in ex vivo porcine carcass heating experiments under MR temperature imaging (MRTI) guidance. The applicator was positioned in the stomach adjacent to the pancreas, and sonications were performed for 10 min at 5 W/cm2 applied intensity. MRTI indicated over 400C temperature rise in pancreatic tissue with heating penetration extending 3 cm from the luminal wall.

  1. Appropriateness of systemic treatments in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

    PubMed Central

    Strosberg, Jonathan R; Fisher, George A; Benson, Al B; Anthony, Lowell B; Arslan, Bulent; Gibbs, John F; Greeno, Edward; Iyer, Renuka V; Kim, Michelle K; Maples, William J; Philip, Philip A; Wolin, Edward M; Cherepanov, Dasha; Broder, Michael S

    2015-01-01

    AIM: To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors (PNETs) and provide consensus treatment recommendations. METHODS: Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs, angiogenesis inhibitors, inhibitors of mammalian target of rapamycin and cytotoxic agents. At this time, there is little data to guide treatment selection and sequence. We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations. Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process. After studying the literature, a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale. Ratings were done both before and after an extended discussion of the evidence. Quantitative measurements of agreement were made and consensus statements developed from the second round ratings. RESULTS: Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean of 15.5 years (range: 6-33). Among 202 rated scenarios, disagreement decreased from 13.2% (26 scenarios) before the face-to-face discussion of evidence to 1% (2) after. In the final ratings, 46.5% (94 scenarios) were rated inappropriate, 21.8% (44) were uncertain, and 30.7% (62) were appropriate. Consensus statements from the scenarios included: (1) it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic; (2) it is appropriate to use everolimus, sunitinib, or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors; and (3) beyond first line, these same agents can be used. In patients with uncontrolled

  2. Diagnostic imaging of pancreatic neuroendocrine neoplasms (pNEN): tumor detection, staging, prognosis, and response to treatment.

    PubMed

    Baur, Alexander D J; Pavel, Marianne; Prasad, Vikas; Denecke, Timm

    2016-03-01

    Pancreatic neuroendocrine neoplasms (pNEN) are rare malignancies arising from neuroendocrine cells of the pancreas. Functional tumors can present with specific clinical syndromes due to hormonal secretion. These tumors can present as incidental findings on imaging performed for unrelated purposes or they are diagnosed when workup is initiated in patients with specific syndromes or metastases. This article presents an overview of available imaging techniques focusing on computed tomography and magnetic resonance imaging. Recommendations regarding examination protocols are given. Typical imaging features of pNEN and metastases are described. Their potential value for the evaluation of prognosis as well as tumor response under treatment is discussed. PMID:25855665

  3. Lung tumor motion prediction during lung brachytherapy using finite element model

    NASA Astrophysics Data System (ADS)

    Shirzadi, Zahra; Sadeghi Naini, Ali; Samani, Abbas

    2012-02-01

    A biomechanical model is proposed to predict deflated lung tumor motion caused by diaphragm respiratory motion. This model can be very useful for targeting the tumor in tumor ablative procedures such as lung brachytherapy. To minimize motion within the target lung, these procedures are performed while the lung is deflated. However, significant amount of tissue deformation still occurs during respiration due to the diaphragm contact forces. In the absence of effective realtime image guidance, biomechanical models can be used to estimate tumor motion as a function of diaphragm's position. To develop this model, Finite Element Method (FEM) was employed. To demonstrate the concept, we conducted an animal study of an ex-vivo porcine deflated lung with a tumor phantom. The lung was deformed by compressing a diaphragm mimicking cylinder against it. Before compression, 3D-CT image of this lung was acquired, which was segmented and turned into FE mesh. The lung tissue was modeled as hyperelastic material with a contact loading to calculate the lung deformation and tumor motion during respiration. To validate the results from FE model, the motion of a small area on the surface close to the tumor was tracked while the lung was being loaded by the cylinder. Good agreement was demonstrated between the experiment results and simulation results. Furthermore, the impact of tissue hyperelastic parameters uncertainties in the FE model was investigated. For this purpose, we performed in-silico simulations with different hyperelastic parameters. This study demonstrated that the FEM was accurate and robust for tumor motion prediction.

  4. Everolimus in the treatment of patients with advanced pancreatic neuroendocrine tumors: latest findings and interpretations

    PubMed Central

    Liu, Eric; Marincola, Paula

    2013-01-01

    Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms with various clinical presentations. More than half of patients present with so-called nonfunctioning tumors with no hormone-related symptoms, whereas other tumors produce symptoms like gastric problems, ulcers, hypoglycemia, skin rash and diarrhea related to hormone production. The traditional treatment for pNETs over the last three decades has been cytotoxic agents, mainly streptozotocin plus 5-fluorouracil or doxorubicin. Most recently two new compounds have been registered worldwide for the treatment of pNETs, the mammalian target of rapamycin (mTOR) inhibitor everolimus and the tyrosine kinase inhibitor sunitinib. This paper concentrates on the use of mTOR inhibitors and the mechanisms of action. The mTOR pathway is altered in a number of pNETs. Everolimus (RAD001) is an orally active rapamycin analog and mTOR inhibitor. It blocks activity of the mTOR pathway by binding with high affinity to the cytoplasmic protein FKBP-12. The efficacy of everolimus in pNETs has been demonstrated in two multicenter studies (RADIANT 1 and 3). The RADIANT 3 study was a randomized controlled study in pNETs of everolimus 10 mg/day versus placebo, showing an increased progression-free survival (11.7 months versus 4.6 months) and hazard ratio of 0.35 (p < 0.001). Current studies indicate that there is strong evidence to support the antitumor effect of rapalogs in pNETs. However, significant tumor reduction is very rarely obtained, usually in less than 10% of treated patients. Therefore, these drugs may be more effective in combination with other anticancer agents, including chemotherapy, targeted therapies as well as peptide receptor radiotherapy. PMID:24003341

  5. Four-Dimensional Computed Tomography-Based Interfractional Reproducibility Study of Lung Tumor Intrafractional Motion

    SciTech Connect

    Michalski, Darek Sontag, Marc; Li Fang; Andrade, Regiane S. de; Uslene, Irmute; Brandner, Edward D.; Heron, Dwight E.; Yue Ning; Huq, M. Saiful

    2008-07-01

    Purpose: To evaluate the interfractional reproducibility of respiration-induced lung tumors motion, defined by their centroids and the intrafractional target motion range. Methods and Materials: Twentythree pairs of four-dimensional/computed tomography scans were acquired for 22 patients. Gross tumor volumes were contoured, Clinical target volumes (CTVs) were generated. Geometric data for CTVs and lung volumes were extracted. The motion tracks of CTV centroids, and CTV edges along the cranio-caudal, anterior-posterior, and lateral directions were evaluated. The Pearson correlation coefficient for motion tracks along the cranio-caudal direction was determined for the entire respiratory cycle and for five phases about the end of expiration. Results: The largest motion extent was along the cranio-caudal direction. The intrafractional motion extent for five CTVs was <0.5 cm, the largest motion range was 3.59 cm. Three CTVs with respiration-induced displacement >0.5 cm did not exhibit the similarity of motion, and for 16 CTVs with motion >0.5 cm the correlation coefficient was >0.8. The lung volumes in corresponding phases for cases that demonstrated CTVs motion similarity were reproducible. No correlation between tumor size and mobility was found. Conclusion: Target motion reproducibility seems to be present in 87% of cases in our dataset. Three cases with dissimilar motion indicate that it is advisable to verify target motion during treatment. The adaptive adjustment to compensate the possible interfractional shifts in a target position should be incorporated as a routine policy for lung cancer radiotherapy.

  6. Pancreatic Cancer

    PubMed Central

    Maitra, Anirban; Hruban, Ralph H.

    2009-01-01

    The past two decades have witnessed an explosion in our understanding of pancreatic cancer, and it is now clear that pancreatic cancer is a disease of inherited (germ-line) and somatic gene mutations. The genes mutated in pancreatic cancer include KRAS2, p16/CDKN2A, TP53, and SMAD4/DPC4, and these are accompanied by a substantial compendium of genomic and transcriptomic alterations that facilitate cell cycle deregulation, cell survival, invasion, and metastases. Pancreatic cancers do not arise de novo, and three distinct precursor lesions have been identified. Experimental models of pancreatic cancer have been developed in genetically engineered mice, which recapitulate the multistep progression of the cognate human disease. Although the putative cell of origin for pancreatic cancer remains elusive, minor populations of cells with stem-like properties have been identified that appear responsible for tumor initiation, metastases, and resistance of pancreatic cancer to conventional therapies. PMID:18039136

  7. A simulation study of irregular respiratory motion and its dosimetric impact on lung tumors

    NASA Astrophysics Data System (ADS)

    Mutaf, Y. D.; Scicutella, C. J.; Michalski, D.; Fallon, K.; Brandner, E. D.; Bednarz, G.; Huq, M. S.

    2011-02-01

    This study is aimed at providing a dosimetric evaluation of the irregular motion of lung tumors due to variations in patients' respiration. Twenty-three lung cancer patients are retrospectively enrolled in this study. The motion of the patient clinical target volume is simulated and two types of irregularities are defined: characteristic and uncharacteristic motions. Characteristic irregularities are representative of random fluctuations in the observed target motion. Uncharacteristic irregular motion is classified as systematic errors in determination of the target motion during the planning session. Respiratory traces from measurement of patient abdominal motion are also used for the target motion simulations. Characteristic irregular motion was observed to cause minimal changes in target dosimetry with the largest effect of 2.5% ± 0.9% (1σ) reduction in the minimum target dose (Dmin) observed for targets that move 2 cm on average and exhibiting 50% amplitude variations within a session. However, uncharacteristic irregular motion introduced more drastic changes in the clinical target volume (CTV) dose; 4.1% ± 1.7% reduction for 1 cm motion and 9.6% ± 1.7% drop for 2 cm. In simulations with patients' abdominal motion, corresponding changes in target dosimetry were observed to be negligible (<0.1%). Only uncharacteristic irregular motion was identified as a clinically significant source of dosimetric uncertainty.

  8. The impact of tumor motion upon CT image integrity and target delineation

    SciTech Connect

    Gagne, Isabelle M.; Robinson, Don M.

    2004-12-01

    Accurate planning target volume delineation is vital to the success of conformal radiation techniques such as standard three-dimensional conformal radiotherapy and intensity modulated radiation therapy. With the exception of breath-hold schemes, all current approaches acquire images while the tumor is nonstationary and, as such, are subject to the presence of motion artifacts. In lung cancer sites where tumor mobility can be significant, the detrimental effect of these motion-induced distortions on image quality and subsequently target volume delineation cannot be ignored in the pursuit of improved treatment outcomes. To investigate the fundamental nature and functional dependence of computed tomography (CT) artifacts associated with lung tumor motion, and the implications for tumor delineation, a filtered backprojection algorithm was developed in MATLAB to generate transverse CT simulation images. In addition, a three-dimensional phantom capable of mimicking the essential motions of lung tumors was constructed for experimental verification. Results show that the spatial extent of a mobile object is distorted from its true shape and location and does not accurately reflect the volume occupied during the extent of motion captured. The presence of motion also negatively impacts image intensity (density) integrity rendering accurate volume delineation highly problematic and calling into question the use of such data in CT-based heterogeneity correction algorithms for dosimetric calculation.

  9. Leveraging respiratory organ motion for non-invasive tumor treatment devices: a feasibility study

    NASA Astrophysics Data System (ADS)

    Möri, Nadia; Jud, Christoph; Salomir, Rares; Cattin, Philippe C.

    2016-06-01

    In noninvasive abdominal tumor treatment, research has focused on minimizing organ motion either by gating, breath holding or tracking of the target. The paradigm shift proposed in this study takes advantage of the respiratory organ motion to passively scan the tumor. In the proposed self-scanning method, the focal point of the HIFU device is held fixed for a given time, while it passively scans the tumor due to breathing motion. The aim of this paper is to present a treatment planning method for such a system and show by simulation its feasibility. The presented planning method minimizes treatment time and ensures complete tumor ablation under free-breathing. We simulated our method on realistic motion patterns from a patient specific statistical respiratory model. With our method, we achieved a shorter treatment time than with the gold-standard motion-compensation approach. The main advantage of the proposed method is that electrically steering of the focal spot is no longer needed. As a consequence, it is much easier to find an optimal solution for both avoiding near field heating and covering the whole tumor. However, the reduced complexity on the beam forming comes at the price of an increased complexity on the planning side as well as a reduced efficiency in the energy distribution. Although we simulate the approach on HIFU, the idea of self-scanning passes over to other tumor treatment modalities such as proton therapy or classical radiation therapy.

  10. Leveraging respiratory organ motion for non-invasive tumor treatment devices: a feasibility study.

    PubMed

    Möri, Nadia; Jud, Christoph; Salomir, Rares; Cattin, Philippe C

    2016-06-01

    In noninvasive abdominal tumor treatment, research has focused on minimizing organ motion either by gating, breath holding or tracking of the target. The paradigm shift proposed in this study takes advantage of the respiratory organ motion to passively scan the tumor. In the proposed self-scanning method, the focal point of the HIFU device is held fixed for a given time, while it passively scans the tumor due to breathing motion. The aim of this paper is to present a treatment planning method for such a system and show by simulation its feasibility. The presented planning method minimizes treatment time and ensures complete tumor ablation under free-breathing. We simulated our method on realistic motion patterns from a patient specific statistical respiratory model. With our method, we achieved a shorter treatment time than with the gold-standard motion-compensation approach. The main advantage of the proposed method is that electrically steering of the focal spot is no longer needed. As a consequence, it is much easier to find an optimal solution for both avoiding near field heating and covering the whole tumor. However, the reduced complexity on the beam forming comes at the price of an increased complexity on the planning side as well as a reduced efficiency in the energy distribution. Although we simulate the approach on HIFU, the idea of self-scanning passes over to other tumor treatment modalities such as proton therapy or classical radiation therapy. PMID:27191374

  11. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors.

    PubMed

    Cives, M; Ghayouri, M; Morse, B; Brelsford, M; Black, M; Rizzo, A; Meeker, A; Strosberg, J

    2016-09-01

    The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O(6)-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n=52), grade (n=128) and ALT activation (n=46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time. PMID:27552969

  12. Assessment of lung tumor motion and setup uncertainties using implanted fiducials

    SciTech Connect

    Nelson, Christopher . E-mail: chnelson@mdanderson.org; Starkschall, George; Balter, Peter; Morice, Rodolfo C.; Stevens, Craig W.; Chang, Joe Y.

    2007-03-01

    Purpose: The purpose of this work was to assess the magnitude of setup uncertainties and respiratory-induced motion of lung tumors by monitoring the location of fiducials implanted in the vicinity of the tumors. Methods and Materials: Gold fiducials were implanted in the periphery of lung tumors in 5 patients who had Stage III non-small-cell lung cancer. Fiducial motion was measured using weekly repeated four-dimensional computed tomography (4DCT) imaging and during gated treatment each day using an electronic portal imaging device (EPID). Setup uncertainties were quantified using both the EPID images and the 4DCT data sets. Results: We observed a reduction in fiducial motion (left/right and superior/inferior directions) during gated treatment; however, large gated motion was present (>1 cm). Systematic and random uncertainties based on patient setup ranged from 4 to 6 mm in all three directions as measured using fiducials on gated EPID images and repeat 4DCTs, and using bony anatomy on repeat 4DCTs. Conclusions: Respiratory gating may be an effective method of reducing average motion during the course of treatment, but large motion is still possible when delivering gated treatment. Setup uncertainties were on the order of, if not larger than, residual gated motion. We recommend careful consideration of all sources of error before reducing margins on the basis of respiratory motion management alone without a strategy for accurate patient setup on a daily basis.

  13. Extracellular matrix composition and rigidity regulate invasive behavior and response to PDT in 3D pancreatic tumor models

    NASA Astrophysics Data System (ADS)

    Cramer, Gwendolyn; El-Hamidi, Hamid; Jafari, Seyedehrojin; Jones, Dustin P.; Celli, Jonathan P.

    2016-03-01

    The composition and mechanical compliance of the extracellular matrix (ECM) have been shown to serve as regulators of tumor growth and invasive behavior. These effects may be particularly relevant in tumors of the pancreas, noted for a profound desmoplastic reaction and an abundance of stroma rich in ECM. In view of recent progress in the clinical implementation of photodynamic therapy (PDT) for pancreatic tumors, in this report we examine how ECM composition and rheological properties impact upon invasive behavior and response to PDT in 3D multicellular pancreatic tumor spheroids in ECM environments with characterized rheological properties. Tumor spheroids were cultured initially in attachment-free conditions to form millimeter-sized spheroids that were transplanted into reconstituted ECM microenvironments (Matrigel and Type I Collagen) that were characterized using bulk oscillatory shear rheology. Analysis of growth behavior shows that the soft collagen ECM promoted growth and extensive invasion and this microenvironment was used in subsequent assessment of PDT and chemotherapy response. Evaluation of treatment response revealed that primary tumor nodule growth is inhibited more effectively with PDT, while verteporfin PDT response is significantly enhanced in the ECM-infiltrating populations that are non-responsive to oxaliplatin chemotherapy. This finding is potentially significant, suggesting the potential for PDT to target these clinically problematic invasive populations that are associated with aggressive metastatic progression and chemoresistance. Experiments to further validate and identify the mechanistic basis of this observation are ongoing.

  14. Sequential treatment in disseminated well- and intermediate-differentiated pancreatic neuroendocrine tumors: Common sense or low rationale?

    PubMed

    Grande, Enrique

    2016-04-10

    Fortunately, the landscape of the systemic treatment for grade 1 and 2 pancreatic neuroendocrine tumors has changed in the last decade with at least four different alternatives approved in the field. Chemotherapy, somatostatin analogues, sunitinib and everolimus remind valid options according to the most referenced international guidelines. However, and although this is something done in the routine practice, there is a lack of evidence for the use of any of these strategies after failure to the others. Moreover, further sequential alternatives in third or fourth line have never been tested prospectively. The need for a better understanding of the rationale to sequence different systemic options is even greater in non-pancreatic neuroendocrine tumors since available therapies are scarce. Sequential strategies in other solid tumors have led to a clear improvement in overall survival. This is also believed to occur in neuroendocrine tumors but no clear data on it has been delivered yet. We postulate that the different mode of action of the systemic options available for the treatment of neuroendocrine tumors may avoid the complete resistance of one option after the other and that sequential use of these agents will be translated into a longer overall survival of patients. Prospective and randomized trials that seek for the activity of drugs after failure to another systemic alternatives are highly needed in this field of neuroendocrine tumors. PMID:27081637

  15. Tumor cell expression of MMP3 as a prognostic factor for poor survival in pancreatic, pulmonary, and mammary carcinoma

    PubMed Central

    Mehner, Christine; Miller, Erin; Nassar, Aziza; Bamlet, William R.; Radisky, Evette S.; Radisky, Derek C.

    2015-01-01

    Breast, lung, and pancreatic cancers collectively represent one third of all diagnosed tumors and are responsible for almost 40% of overall cancer mortality. Despite improvements in current treatments, efforts to develop more specific therapeutic options are warranted. Here we identify matrix metalloproteinase 3 (MMP3) as a potential target within all three of these tumor types. MMP3 has previously been shown to induce expression of Rac1b, a tumorigenic splice isoform of Rac1. In this study we find that MMP3 and Rac1b proteins are both strongly expressed by the tumor cells of all three tumor types and that expression of MMP3 protein is prognostic of poor survival in pancreatic cancer patients. We also find that MMP3 gene expression can serve as a prognostic marker for patient survival in breast and lung cancer. These results suggest an oncogenic MMP3-Rac1b signaling axis as a driver of tumor progression in three common poor prognosis tumor types, further suggesting that new therapies to target these pathways could have substantial therapeutic benefit. PMID:26807201

  16. Sequential treatment in disseminated well- and intermediate-differentiated pancreatic neuroendocrine tumors: Common sense or low rationale?

    PubMed Central

    Grande, Enrique

    2016-01-01

    Fortunately, the landscape of the systemic treatment for grade 1 and 2 pancreatic neuroendocrine tumors has changed in the last decade with at least four different alternatives approved in the field. Chemotherapy, somatostatin analogues, sunitinib and everolimus remind valid options according to the most referenced international guidelines. However, and although this is something done in the routine practice, there is a lack of evidence for the use of any of these strategies after failure to the others. Moreover, further sequential alternatives in third or fourth line have never been tested prospectively. The need for a better understanding of the rationale to sequence different systemic options is even greater in non-pancreatic neuroendocrine tumors since available therapies are scarce. Sequential strategies in other solid tumors have led to a clear improvement in overall survival. This is also believed to occur in neuroendocrine tumors but no clear data on it has been delivered yet. We postulate that the different mode of action of the systemic options available for the treatment of neuroendocrine tumors may avoid the complete resistance of one option after the other and that sequential use of these agents will be translated into a longer overall survival of patients. Prospective and randomized trials that seek for the activity of drugs after failure to another systemic alternatives are highly needed in this field of neuroendocrine tumors. PMID:27081637

  17. Correlation of lung tumor motion with external surrogate indicators of respiration

    SciTech Connect

    Hoisak, Jeremy D.P.; Sixel, Katharina E. . E-mail: Katharina.Sixel@sw.ca; Tirona, Romeo; Cheung, Patrick; Pignol, Jean-Philippe

    2004-11-15

    Purpose: To assess the correlation of respiratory volume and abdominal displacement with tumor motion as seen with X-ray fluoroscopy. Measurements throughout the patient's treatment course allowed an assessment of the interfractional reproducibility of this correlation. Methods and materials: Data were acquired from 11 patients; 5 were studied over multiple days. Measurements of respiratory volume by spirometry and abdominal displacement by a real-time position tracking system were correlated to simultaneously acquired X-ray fluoroscopy measurements of superior-inferior tumor displacement. The linear correlation coefficient was computed for each data acquisition. The phase relationship between the surrogate and tumor signals was estimated through cross-correlation delay analysis. Results: Correlation coefficients ranged from very high to very low (0.99-0.39, p < 0.0001). The correlation between tumor displacement and respiratory volume was higher and more reproducible from day to day than between tumor displacement and abdominal displacement. A nonzero phase relationship was observed in nearly all patients (-0.65 to +0.50 s). This relationship was observed to vary over inter- and intrafractional time scales. Only 1 of 5 patients studied over multiple days had a consistent relationship between tumor motion and either surrogate. Conclusions: Respiratory volume has a more reproducible correlation with tumor motion than does abdominal displacement. If forming a tumor-surrogate prediction model from a limited series of observations, the use of surrogates to guide treatment might result in geographic miss.

  18. Optimal surface marker locations for tumor motion estimation in lung cancer radiotherapy

    NASA Astrophysics Data System (ADS)

    Dong, Bin; Jiang Graves, Yan; Jia, Xun; Jiang, Steve B.

    2012-12-01

    Using fiducial markers on the patient’s body surface to predict the tumor location is a widely used approach in lung cancer radiotherapy. The purpose of this work is to propose an algorithm that automatically identifies a sparse set of locations on the patient’s surface with the optimal prediction power for the tumor motion. In our algorithm, it is assumed that there is a linear relationship between the surface marker motion and the tumor motion. The sparse selection of markers on the external surface and the linear relationship between the marker motion and the internal tumor motion are represented by a prediction matrix. Such a matrix is determined by solving an optimization problem, where the objective function contains a sparsity term that penalizes the number of markers chosen on the patient’s surface. Bregman iteration is used to solve the proposed optimization problem. The performance of our algorithm has been tested on realistic clinical data of four lung cancer patients. Thoracic 4DCT scans with ten phases are used for the study. On a reference phase, a grid of points are casted on the patient’s surfaces (except for the patient’s back) and propagated to other phases via deformable image registration of the corresponding CT images. Tumor locations at each phase are also manually delineated. We use nine out of ten phases of the 4DCT images to identify a small group of surface markers that are mostly correlated with the motion of the tumor and find the prediction matrix at the same time. The tenth phase is then used to test the accuracy of the prediction. It is found that on average six to seven surface markers are necessary to predict tumor locations with a 3D error of about 1 mm. It is also found that the selected marker locations lie closely in those areas where surface point motion has a large amplitude and a high correlation with the tumor motion. Our method can automatically select sparse locations on the patient’s external surface and

  19. Endoscopic ultrasound (EUS)-guided fiducial placement allows localization of small neuroendocrine tumors during parenchymal-sparing pancreatic surgery

    PubMed Central

    Law, Joanna K.; Singh, Vikesh K.; Khashab, Mouen A.; Hruban, Ralph H.; Canto, Marcia Irene; Shin, Eun Ji; Saxena, Payal; Weiss, Matthew J.; Pawlik, Timothy M.; Wolfgang, Christopher L.

    2014-01-01

    Background Parenchymal-sparing pancreatic surgery is ideal for lesions such as small pancreatic neuroendocrine tumors (PanNET). However, precise localization of these small tumors at surgery can be difficult. The placement of fiducials under endoscopic ultrasound (EUS) guidance (EUS-F) has been used to direct stereotactic radiation therapy for pancreatic adenocarcinoma. This report describes two cases in which placement of fiducials was used to guide surgical resection. This study aimed to assess the feasibility, safety, and efficacy of using EUS-F for intraoperative localization of small PanNETs. Methods A retrospective study analyzed two consecutive patients with small PanNETs who underwent EUS-F followed by enucleation in a tertiary-care referral hospital. The following features were examined: technical success and complication rates of EUS-F, visibility of the fiducial at the time of surgery, and fiducial migration. Results In the study, EUS-F was performed for two female patients with a 7-mm and a 9-mm PanNET respectively in the uncinate process and neck of the pancreas. In both patients, EUS-F was feasible with two Visicoil fiducials (Core Oncology, Santa Barbara, CA, USA) placed either within or adjacent to the tumors using a 22-gauge Cook Echotip needle. At surgery, the fiducials were clearly visible on intraoperative ultrasound, and both the tumor and the fiducials were successfully enucleated in both cases. No complications were associated with EUS-F, and no evidence of pancreatitis was shown either clinically or on surgical pathology. This investigation had the limitations of a small single-center study. Conclusions For patients undergoing enucleation, EUS-F is technically feasible and safe and aids intraoperative localization of small PanNETs. PMID:23636530

  20. Triphala inhibits both in vitro and in vivo xenograft growth of pancreatic tumor cells by inducing apoptosis

    PubMed Central

    Shi, Yan; Sahu, Ravi P; Srivastava, Sanjay K

    2008-01-01

    Background Triphala is commonly used in Ayurvedic medicine to treat variety of diseases; however its mechanism of action remains unexplored. This study elucidates the molecular mechanism of Triphala against human pancreatic cancer in the cellular and in vivo model. Methods Growth-inhibitory effects of Triphala were evaluated in Capan-2, BxPC-3 and HPDE-6 cells by Sulphoradamine-B assay. Apoptosis was determined by cell death assay and western blotting. Triphala was administered orally to nude mice implanted with Capan-2 xenograft. Tumors were analyzed by immunohistochemistry and western blotting. Results Exposure of Capan-2 cells to the aqueous extract of Triphala for 24 h resulted in the significant decrease in the survival of cells in a dose-dependent manner with an IC50 of about 50 μg/ml. Triphala-mediated reduced cell survival correlated with induction of apoptosis, which was associated with reactive oxygen species (ROS) generation. Triphala-induced apoptosis was linked with phosphorylation of p53 at Ser-15 and ERK at Thr-202/Tyr-204 in Capan-2 cells. Above mentioned effects were significantly blocked when the cells were pretreated with an antioxidant N-acetylcysteine (NAC), suggesting the involvement of ROS generation. Pretreatment of cells with pifithrin-α or U0126, specific inhibitors of p53 or MEK-1/2, significantly attenuated Triphala-induced apoptosis. Moreover, NAC or U0126 pretreatment significantly attenuated Triphala-induced p53 transcriptional activity. Similarly, Triphala induced apoptosis in another pancreatic cancer cell line BxPC-3 by activating ERK. On the other hand, Triphala failed to induce apoptosis or activate ERK or p53 in normal human pancreatic ductal epithelial (HPDE-6) cells. Further, oral administration of 50 mg/kg or 100 mg/kg Triphala in PBS, 5 days/week significantly suppressed the growth of Capan-2 pancreatic tumor-xenograft. Reduced tumor-growth in Triphala fed mice was due to increased apoptosis in the tumors cells, which was

  1. Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Coupled with Enzymatic Depletion of Tumor Hyaluronan Induces Complete Regression of Aggressive Pancreatic Tumors.

    PubMed

    Manuel, Edwin R; Chen, Jeremy; D'Apuzzo, Massimo; Lampa, Melanie G; Kaltcheva, Teodora I; Thompson, Curtis B; Ludwig, Thomas; Chung, Vincent; Diamond, Don J

    2015-09-01

    Bacterial-based therapies are emerging as effective cancer treatments and hold promise for refractory neoplasms, such as pancreatic ductal adenocarcinoma (PDAC), which has not shown significant improvement in therapy for more than 25 years. Using a novel combination of shIDO-ST, a Salmonella-based therapy targeting the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO), with an enzyme, PEGPH20, which depletes extracellular matrix hyaluronan, we observed extended survival with frequent total regression of autochthonous and orthotopic PDAC tumors. This observation was associated with migration and accumulation of activated polymorphonuclear neutrophils (PMN) from spleens into tumors, which was not seen using a scrambled control (shScr-ST). Purified splenic PMNs from PEGPH20/shIDO-ST-treated mice exhibited significant IDO knockdown and were able to kill tumor targets ex vivo through mechanisms involving FasL and serine proteases. In addition, CD8(+) T cells were observed to contribute to late control of pancreatic tumors. Collectively, our data demonstrate that entry of shIDO-ST and PMNs into otherwise impermeable desmoplastic tumors is facilitated by PEGPH20-mediated HA removal, further highlighting an important component of effective treatment for PDAC. PMID:26134178

  2. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids

    PubMed Central

    Huang, Ling; Holtzinger, Audrey; Jagan, Ishaan; BeGora, Michael; Lohse, Ines; Ngai, Nicholas; Nostro, Cristina; Wang, Rennian; Muthuswamy, Lakshmi B.; Crawford, Howard C.; Arrowsmith, Cheryl; Kalloger, Steve E.; Renouf, Daniel J.; Connor, Ashton A; Cleary, Sean; Schaeffer, David F.; Roehrl, Michael; Tsao, Ming-Sound; Gallinger, Steven; Keller, Gordon; Muthuswamy, Senthil K.

    2016-01-01

    There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells (PSCs) into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53R175H induced cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. Culture conditions are also defined for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture, phenotypic heterogeneity of the primary tumor, and retain patient-specific physiologic changes including hypoxia, oxygen consumption, epigenetic marks, and differential sensitivity to EZH2 inhibition. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies. PMID:26501191

  3. Dosimetric evaluation of intrafractional tumor motion by means of a robot driven phantom

    SciTech Connect

    Richter, Anne; Wilbert, Juergen; Flentje, Michael

    2011-10-15

    Purpose: The aim of the work was to investigate the influence of intrafractional tumor motion to the accumulated (absorbed) dose. The accumulated dose was determined by means of calculations and measurements with a robot driven motion phantom. Methods: Different motion scenarios and compensation techniques were realized in a phantom study to investigate the influence of motion on image acquisition, dose calculation, and dose measurement. The influence of motion on the accumulated dose was calculated by employing two methods (a model based and a voxel based method). Results: Tumor motion resulted in a blurring of steep dose gradients and a reduction of dose at the periphery of the target. A systematic variation of motion parameters allowed the determination of the main influence parameters on the accumulated dose. The key parameters with the greatest influence on dose were the mean amplitude and the pattern of motion. Investigations on necessary safety margins to compensate for dose reduction have shown that smaller safety margins are sufficient, if the developed concept with optimized margins (OPT concept) was used instead of the standard internal target volume (ITV) concept. Both calculation methods were a reasonable approximation of the measured dose with the voxel based method being in better agreement with the measurements. Conclusions: Further evaluation of available systems and algorithms for dose accumulation are needed to create guidelines for the verification of the accumulated dose.

  4. Treatment Parameters Optimization to Compensate for Interfractional Anatomy Variability and Intrafractional Tumor Motion

    PubMed Central

    Brevet, Romain; Richter, Daniel; Graeff, Christian; Durante, Marco; Bert, Christoph

    2015-01-01

    Scanned ion beam therapy of lung tumors is severely limited in its clinical applicability by intrafractional organ motion, interference effects between beam and tumor motion (interplay), as well as interfractional anatomic changes. To compensate for dose deterioration caused by intrafractional motion, motion mitigation techniques, such as gating, have been developed. However, optimization of the treatment parameters is needed to further improve target dose coverage and normal tissue sparing. The aim of this study was to determine treatment-planning parameters that permit to recover good target coverage for each fraction of lung tumor treatments. For 9 lung tumor patients from MD Anderson Cancer Center (Houston, Texas), a total of 70 weekly time-resolved computed tomography (4DCT) datasets, which depict the evolution of the patient anatomy over the several fractions of the treatment, were available. Using the GSI in-house treatment planning system TRiP4D, 4D simulations were performed on each weekly 4DCT for each patient using gating and optimization of a single treatment plan based on a planning CT acquired prior to treatment. The impact on target dose coverage (V 95%,CTV) of variations in focus size and length of the gating window, as well as different additional margins and the number of fields was analyzed. It appeared that interfractional variability could potentially have a larger impact on V 95%,CTV than intrafractional motion. However, among the investigated parameters, the use of a large beam spot size, a short gating window, additional margins, and multiple fields permitted to obtain an average V 95%,CTV of 96.5%. In the presented study, it was shown that optimized treatment parameters have an important impact on target dose coverage in the treatment of moving tumors. Indeed, intrafractional motion occurring during the treatment of lung tumors and interfractional variability were best mitigated using a large focus, a short gating window, additional margins

  5. Treatment Parameters Optimization to Compensate for Interfractional Anatomy Variability and Intrafractional Tumor Motion.

    PubMed

    Brevet, Romain; Richter, Daniel; Graeff, Christian; Durante, Marco; Bert, Christoph

    2015-01-01

    Scanned ion beam therapy of lung tumors is severely limited in its clinical applicability by intrafractional organ motion, interference effects between beam and tumor motion (interplay), as well as interfractional anatomic changes. To compensate for dose deterioration caused by intrafractional motion, motion mitigation techniques, such as gating, have been developed. However, optimization of the treatment parameters is needed to further improve target dose coverage and normal tissue sparing. The aim of this study was to determine treatment-planning parameters that permit to recover good target coverage for each fraction of lung tumor treatments. For 9 lung tumor patients from MD Anderson Cancer Center (Houston, Texas), a total of 70 weekly time-resolved computed tomography (4DCT) datasets, which depict the evolution of the patient anatomy over the several fractions of the treatment, were available. Using the GSI in-house treatment planning system TRiP4D, 4D simulations were performed on each weekly 4DCT for each patient using gating and optimization of a single treatment plan based on a planning CT acquired prior to treatment. The impact on target dose coverage (V 95%,CTV) of variations in focus size and length of the gating window, as well as different additional margins and the number of fields was analyzed. It appeared that interfractional variability could potentially have a larger impact on V 95%,CTV than intrafractional motion. However, among the investigated parameters, the use of a large beam spot size, a short gating window, additional margins, and multiple fields permitted to obtain an average V 95%,CTV of 96.5%. In the presented study, it was shown that optimized treatment parameters have an important impact on target dose coverage in the treatment of moving tumors. Indeed, intrafractional motion occurring during the treatment of lung tumors and interfractional variability were best mitigated using a large focus, a short gating window, additional margins

  6. Sensitivity of tumor motion simulation accuracy to lung biomechanical modeling approaches and parameters

    NASA Astrophysics Data System (ADS)

    Nasehi Tehrani, Joubin; Yang, Yin; Werner, Rene; Lu, Wei; Low, Daniel; Guo, Xiaohu; Wang, Jing

    2015-11-01

    Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end-expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the neo-Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right, anterior-posterior, and superior-inferior directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation.

  7. Sensitivity of tumor motion simulation accuracy to lung biomechanical modeling approaches and parameters.

    PubMed

    Tehrani, Joubin Nasehi; Yang, Yin; Werner, Rene; Lu, Wei; Low, Daniel; Guo, Xiaohu; Wang, Jing

    2015-11-21

    Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end-expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the neo-Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right, anterior-posterior, and superior-inferior directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation. PMID:26531324

  8. Deciphering the cellular source of tumor relapse identifies CD44 as a major therapeutic target in pancreatic adenocarcinoma

    PubMed Central

    Molejon, Maria Inés; Tellechea, Juan Ignacio; Loncle, Celine; Gayet, Odile; Gilabert, Marine; Duconseil, Pauline; Lopez-Millan, Maria Belen; Moutardier, Vincent; Gasmi, Mohamed; Garcia, Stephane; Turrini, Olivier; Ouaissi, Mehdi; Poizat, Flora; Dusetti, Nelson; Iovanna, Juan

    2015-01-01

    It has been commonly found that in patients presenting Pancreatic Ductal Adenocarcinoma (PDAC), after a period of satisfactory response to standard treatments, the tumor becomes non-responsive and patient death quickly follows. This phenomenon is mainly due to the rapid and uncontrolled development of the residual tumor. The origin and biological characteristics of residual tumor cells in PDAC still remain unclear. In this work, using PDACs from patients, preserved as xenografts in nude mice, we demonstrated that a residual PDAC tumor originated from a small number of CD44+ cells present in the tumor. During PDAC relapse, proliferating CD44+ cells decrease expression of ZEB1, while overexpressing the MUC1 protein, and gain morphological and biological characteristics of differentiation. Also, we report that CD44+ cells, in primary and residual PDAC tumors, are part of a heterogeneous population, which includes variable numbers of CD133+ and EpCAM+ cells. We confirmed the propagation of CD44+ cells in samples from cases of human relapse, following standard PDAC treatment. Finally, using systemic administration of anti-CD44 antibodies in vivo, we demonstrated that CD44 is an efficient therapeutic target for treating tumor relapse, but not primary PDAC tumors. We conclude that CD44+ cells generate the relapsing tumor and, as such, are themselves promising therapeutic targets for treating patients with recurrent PDAC. PMID:25797268

  9. Pancreatic Neuroendocrine Tumors With Involved Surgical Margins: Prognostic Factors and the Role of Adjuvant Radiotherapy

    SciTech Connect

    Arvold, Nils D.; Willett, Christopher G.; Fernandez-del Castillo, Carlos; Ryan, David P.; Ferrone, Cristina R.; Clark, Jeffrey W.; Blaszkowsky, Lawrence S.; Deshpande, Vikram; Niemierko, Andrzej; Allen, Jill N.; Kwak, Eunice L.; Wadlow, Raymond C.; Zhu, Andrew X.; Warshaw, Andrew L.; Hong, Theodore S.

    2012-07-01

    Purpose: Pancreatic neuroendocrine tumors (pNET) are rare neoplasms associated with poor outcomes without resection, and involved surgical margins are associated with a worse prognosis. The role of adjuvant radiotherapy (RT) in these patients has not been characterized. Methods and Materials: We retrospectively evaluated 46 consecutive patients with positive or close (<1 mm) margins after pNET resection, treated from 1983 to 2010, 16 of whom received adjuvant RT. Median RT dose was 50.4 Gy in 1.8-Gy fractions; half the patients received concurrent chemotherapy with 5-fluorouracil or capecitabine. No patients received adjuvant chemotherapy. Cox multivariate analysis (MVA) was used to analyze factors associated with overall survival (OS). Results: Median age at diagnosis was 56 years, and 52% of patients were female. Median tumor size was 38 mm, 57% of patients were node-positive, and 11% had a resected solitary liver metastasis. Patients who received RT were more likely to have larger tumors (median, 54 mm vs. 30 mm, respectively, p = 0.002) and node positivity (81% vs. 33%, respectively, p = 0.002) than those not receiving RT. Median follow-up was 39 months. Actuarial 5-year OS was 62% (95% confidence interval [CI], 41%-77%). In the group that did not receive RT, 3 patients (10%) experienced local recurrence (LR) and 5 patients (18%) developed new distant metastases, while in the RT group, 1 patient (6%) experienced LR and 5 patients (38%) developed distant metastases. Of all recurrences, 29% were LR. On MVA, male gender (adjusted hazard ratio [AHR] = 3.81; 95% CI, 1.21-11.92; p = 0.02) and increasing tumor size (AHR = 1.02; 95% CI, 1.01-1.04; p = 0.007) were associated with decreased OS. Conclusions: Long-term survival is common among patients with involved-margin pNET. Despite significantly worse pathologic features among patients receiving adjuvant RT, rates of LR between groups were similar, suggesting that RT might aid local control, and merits further

  10. Histopathologic tumor response after induction chemotherapy and stereotactic body radiation therapy for borderline resectable pancreatic cancer

    PubMed Central

    Chuong, Michael D.; Frakes, Jessica M.; Figura, Nicholas; Hoffe, Sarah E.; Shridhar, Ravi; Mellon, Eric A.; Hodul, Pamela J.; Malafa, Mokenge P.; Springett, Gregory M.

    2016-01-01

    Background While clinical outcomes following induction chemotherapy and stereotactic body radiation therapy (SBRT) have been reported for borderline resectable pancreatic cancer (BRPC) patients, pathologic response has not previously been described. Methods This single-institution retrospective review evaluated BRPC patients who completed induction gemcitabine-based chemotherapy followed by SBRT and surgical resection. Each surgical specimen was assigned two tumor regression grades (TRG), one using the College of American Pathologists (CAP) criteria and one using the MD Anderson Cancer Center (MDACC) criteria. Overall survival (OS) and progression free survival (PFS) were correlated to TRG score. Results We evaluated 36 patients with a median follow-up of 13.8 months (range, 6.1-24.8 months). The most common induction chemotherapy regimen (82%) was GTX (gemcitabine, docetaxel, capecitabine). A median SBRT dose of 35 Gy (range, 30-40 Gy) in 5 fractions was delivered to the region of vascular involvement. The margin-negative resection rate was 97.2%. Improved response according to MDACC grade trended towards superior PFS (P=061), but not OS. Any neoadjuvant treatment effect according to MDACC scoring (IIa-IV vs. I) was associated with improved OS and PFS (both P=0.019). We found no relationship between CAP score and OS or PFS. Conclusions These data suggest that the increased pathologic response after induction chemotherapy and SBRT is correlated with improved survival for BRPC patients. PMID:27034789

  11. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management and controversies

    PubMed Central

    Jensen, Robert T.; Berna, Marc J.; Bingham, David B; Norton, Jeffrey A.

    2008-01-01

    Pancreatic endocrine tumors (PETs) can occur in as part of four inherited disorders including: Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1(NF-1) [von Recklinghausen’s disease] and the tuberous sclerosis complex (TSC). The relative frequency with which patients with these disorders develop PETs is MEN1>VHL>NF-1>TSC. Over the last few years there have been major advances in the understanding of the genetics and molecular pathogenesis of these disorders as well in the localization, medical and surgical treatment of the PETs in these patients. The study of the PETs in these disorders has not only provided insights into the possible pathogenesis of sporadic PETs, but have also presented a number of unique management and treatment issues, some of which are applicable to patients with sporadic PETs. Therefore the study of PETs in these uncommon disorders has provided valuable insights that in many cases are applicable to the general group of patients with sporadic PETs. In this article these areas are briefly reviewed as well as the current state of knowledge of the PETs in these disorders and the controversies that exist in their management are briefly summarized and discussed. PMID:18798544

  12. Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer

    PubMed Central

    Takai, Erina; Totoki, Yasushi; Nakamura, Hiromi; Morizane, Chigusa; Nara, Satoshi; Hama, Natsuko; Suzuki, Masami; Furukawa, Eisaku; Kato, Mamoru; Hayashi, Hideyuki; Kohno, Takashi; Ueno, Hideki; Shimada, Kazuaki; Okusaka, Takuji; Nakagama, Hitoshi; Shibata, Tatsuhiro; Yachida, Shinichi

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect and monitor molecular characteristics of tumors. In the present study, we determined the mutational status of KRAS in plasma cfDNA using multiplex picoliter-droplet digital PCR in 259 patients with PDAC. We constructed a novel modified SureSelect-KAPA-Illumina platform and an original panel of 60 genes. We then performed targeted deep sequencing of cfDNA and matched germline DNA samples in 48 patients who had ≥1% mutant allele frequencies of KRAS in plasma cfDNA. Importantly, potentially targetable somatic mutations were identified in 14 of 48 patients (29.2%) examined by targeted deep sequencing of cfDNA. We also analyzed somatic copy number alterations based on the targeted sequencing data using our in-house algorithm, and potentially targetable amplifications were detected. Assessment of mutations and copy number alterations in plasma cfDNA may provide a prognostic and diagnostic tool to assist decisions regarding optimal therapeutic strategies for PDAC patients. PMID:26669280

  13. Liquid biopsy in patients with pancreatic cancer: Circulating tumor cells and cell-free nucleic acids

    PubMed Central

    Imamura, Taisuke; Komatsu, Shuhei; Ichikawa, Daisuke; Kawaguchi, Tsutomu; Miyamae, Mahito; Okajima, Wataru; Ohashi, Takuma; Arita, Tomohiro; Konishi, Hirotaka; Shiozaki, Atsushi; Morimura, Ryo; Ikoma, Hisashi; Okamoto, Kazuma; Otsuji, Eigo

    2016-01-01

    Despite recent advances in surgical techniques and perioperative management, the prognosis of pancreatic cancer (PCa) remains extremely poor. To provide optimal treatment for each patient with Pca, superior biomarkers are urgently needed in all phases of management from early detection to staging, treatment monitoring, and prognosis. In the blood of patients with cancer, circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs), such as DNA, mRNA, and noncoding RNA have been recognized. In the recent years, their presence in the blood has encouraged researchers to investigate their potential use as novel blood biomarkers, and numerous studies have demonstrated their potential clinical utility as a biomarker for certain types of cancer. This concept, called “liquid biopsy” has been focused on as a less invasive, alternative approach to cancer tissue biopsy for obtaining genetic and epigenetic aberrations that contribute to oncogenesis and cancer progression. In this article, we review the available literature on CTCs and cfNAs in patients with cancer, particularly focusing on PCa, and discuss future perspectives in this field. PMID:27433079

  14. IGRT/ART phantom with programmable independent rib cage and tumor motion

    SciTech Connect

    Haas, Olivier C. L.; Mills, John A.; Land, Imke; Mulholl, Pete; Menary, Paul; Crichton, Robert; Wilson, Adrian; Sage, John; Anna, Morenc; Depuydt, Tom

    2014-02-15

    Purpose: This paper describes the design and experimental evaluation of the Methods and Advanced Equipment for Simulation and Treatment in Radiation Oncology (MAESTRO) thorax phantom, a new anthropomorphic moving ribcage combined with a 3D tumor positioning system to move target inserts within static lungs. Methods: The new rib cage design is described and its motion is evaluated using Vicon Nexus, a commercial 3D motion tracking system. CT studies at inhale and exhale position are used to study the effect of rib motion and tissue equivalence. Results: The 3D target positioning system and the rib cage have millimetre accuracy. Each axis of motion can reproduce given trajectories from files or individually programmed sinusoidal motion in terms of amplitude, period, and phase shift. The maximum rib motion ranges from 7 to 20 mm SI and from 0.3 to 3.7 mm AP with LR motion less than 1 mm. The repeatability between cycles is within 0.16 mm root mean square error. The agreement between CT electron and mass density for skin, ribcage, spine hard and inner bone as well as cartilage is within 3%. Conclusions: The MAESTRO phantom is a useful research tool that produces programmable 3D rib motions which can be synchronized with 3D internal target motion. The easily accessible static lungs enable the use of a wide range of inserts or can be filled with lung tissue equivalent and deformed using the target motion system.

  15. Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in pancreatic ductal adenocarcinoma

    PubMed Central

    Zhang, Lingfu; Guo, Limei; Tao, Ming; Fu, Wei; Xiu, Dianrong

    2016-01-01

    Objective: To investigate the frequency of parasympathetic neurogenesis and determine its association with tumor budding and prognosis in pancreatic ductal adenocarcinoma (PDAC). Methods: Parasympathetic neurogenesis was defined as the distribution of abnormal parasympathetic nerves in the stroma tissue. Staining of vesicular acetylcholine transporter (VAChT), as a marker for parasympathetic neurogenesis, was performed on a representative specimen of the tumor for 59 PDAC patients with available clinical, pathologic, and follow-up information. Three specimens containing normal pancreatic tissues were stained in parallel. The number of parasympathetic nerve fibers was counted in five high-power microscopic fields (5×0.785 mm2). Cut-off values were calculated by receiver operating characteristic curve analysis. Results: VAChT-positive parasympathetic nerve fibers were not seen in the stroma of 3 cases of normal pancreatic tissues. In 59 PDAC cases, the range of parasympathetic neurogenesis was 4-38 fibers/(5×0.785) mm2, with a median of 18 fibers/(5×0.785) mm2. Patients with parasympathetic neurogenesis >15 fibers/(5×0.785) mm2 were defined as the high-density group (39 patients, 66.1%), and those with parasympathetic neurogenesis 15 fibers/(5×0.785) mm2 as the low-density group (20 patients, 33.9%). The high-density group had a higher occurrence of tumor budding (P=0.001) and a higher rate of early recurrence (P=0.035). Parasympathetic neurogenesis appeared to be an independent adverse prognostic factor [hazard ratio (HR)=2.45, 95% confidence interval (95% CI): 1.25-4.81, P=0.009], in addition to American Joint Committee on Cancer (AJCC) stage (P=0.010) and tumor budding (P=0.009). Conclusions: Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in PDAC. PMID:27199515

  16. Pancreatic Ductal Adenocarcinoma (PDA) mice lacking Mucin 1 have a profound defect in tumor growth and metastasis

    PubMed Central

    Besmer, Dahlia M.; Curry, Jennifer M.; Roy, Lopamudra D.; Tinder, Teresa L.; Sahraei, Mahnaz; Schettini, Jorge; Hwang, Sun-Il; Lee, Yong Y.; Gendler, Sandra J.; Mukherjee, Pinku

    2011-01-01

    MUC1 is over expressed and aberrantly glycosolated in >60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In the present study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared to both KC and KCM. Cell lines derived from KCKO tumors have significantly lower tumorigenic capacity compared to cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared to mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor (EGF), platelet-derived growth factor (PDGF), or matrix metalloproteinase-9 (MMP9). Further, significantly fewer KCKO cells entered the G2M phase of the cell cycle compared to the KCM cells. Proteomics and western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of MAPK, as well as a significant decrease in Nestin and Tubulin α-2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse in order to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. PMID:21558393

  17. Planning 4-Dimensional Computed Tomography (4DCT) Cannot Adequately Represent Daily Intrafractional Motion of Abdominal Tumors

    SciTech Connect

    Ge, Jiajia; Santanam, Lakshmi; Noel, Camille; Parikh, Parag J.

    2013-03-15

    Purpose: To evaluate whether planning 4-dimensional computed tomography (4DCT) can adequately represent daily motion of abdominal tumors in regularly fractionated and stereotactic body radiation therapy (SBRT) patients. Methods and Materials: Intrafractional tumor motion of 10 patients with abdominal tumors (4 pancreas-fractionated and 6 liver-stereotactic patients) with implanted fiducials was measured based on daily orthogonal fluoroscopic movies over 38 treatment fractions. The needed internal margin for at least 90% of tumor coverage was calculated based on a 95th and fifth percentile of daily 3-dimensional tumor motion. The planning internal margin was generated by fusing 4DCT motion from all phase bins. The disagreement between needed and planning internal margin was analyzed fraction by fraction in 3 motion axes (superior-inferior [SI], anterior-posterior [AP], and left-right [LR]). The 4DCT margin was considered as an overestimation/underestimation of daily motion when disagreement exceeded at least 3 mm in the SI axis and/or 1.2 mm in the AP and LR axes (4DCT image resolution). The underlying reasons for this disagreement were evaluated based on interfractional and intrafractional breathing variation. Results: The 4DCT overestimated daily 3-dimensional motion in 39% of the fractions in 7 of 10 patients and underestimated it in 53% of the fractions in 8 of 10 patients. Median underestimation was 3.9 mm, 3.0 mm, and 1.7 mm in the SI axis, AP axis, and LR axis, respectively. The 4DCT was found to capture irregular deep breaths in 3 of 10 patients, with 4DCT motion larger than mean daily amplitude by 18 to 21 mm. The breathing pattern varied from breath to breath and day to day. The intrafractional variation of amplitude was significantly larger than intrafractional variation (2.7 mm vs 1.3 mm) in the primary motion axis (ie, SI axis). The SBRT patients showed significantly larger intrafractional amplitude variation than fractionated patients (3.0 mm vs 2

  18. Internal-external correlation investigations of respiratory induced motion of lung tumors

    SciTech Connect

    Ionascu, Dan; Jiang, Steve B.; Nishioka, Seiko; Shirato, Hiroki; Berbeco, Ross I.

    2007-10-15

    In gated radiation therapy procedures, the lung tumor position is used directly (by implanted radiopaque markers) or indirectly (by external surrogate methods) to decrease the volume of irradiated healthy tissue. Due to a risk of pneumothorax, many clinics do not implant fiducials, and the gated treatment is primarily based on a respiratory induced external signal. The external surrogate method relies upon the assumption that the internal tumor motion is well correlated with the external respiratory induced motion, and that this correlation is constant in time. Using a set of data that contains synchronous internal and external motion traces, we have developed a dynamic data analysis technique to study the internal-external correlation, and to quantitatively estimate its underlying time behavior. The work presented here quantifies the time dependent behavior of the correlation between external respiratory signals and lung implanted fiducial motion. The corresponding amplitude mismatch is also reported for the lung patients studied. The information obtained can be used to improve the accuracy of tumor tracking. For the ten patients in this study, the SI internal-external motion is well correlated, with small time shifts and corresponding amplitude mismatches. Although the AP internal-external motion reveals larger time shifts than along the SI direction, the corresponding amplitude mismatches are below 5 mm.

  19. SU-E-J-133: Evaluation of Inter- and Intra-Fractional Pancreas Tumor Residual Motions with Abdominal Compression

    SciTech Connect

    Li, Y; Shi, F; Tian, Z; Jia, X; Meyer, J; Jiang, S; Mao, W

    2014-06-01

    Purpose: Abdominal compression (AC) has been widely used to reduce pancreas motion due to respiration for pancreatic cancer patients undergoing stereotactic body radiotherapy (SBRT). However, the inter-fractional and intra-fractional patient motions may degrade the treatment. The purpose of this work is to study daily CBCT projections and 4DCT to evaluate the inter-fractional and intra-fractional pancreatic motions. Methods: As a standard of care at our institution, 4D CT scan was performed for treatment planning. At least two CBCT scans were performed for daily treatment. Retrospective studies were performed on patients with implanted internal fiducial markers or surgical clips. The initial motion pattern was obtained by extracting marker positions on every phase of 4D CT images. Daily motions were presented by marker positions on CBCT scan projection images. An adaptive threshold segmentation algorithm was used to extract maker positions. Both marker average positions and motion ranges were compared among three sets of scans, 4D CT, positioning CBCT, and conformal CBCT, for inter-fractional and intra-fractional motion variations. Results: Data from four pancreatic cancer patients were analyzed. These patients had three fiducial markers implanted. All patients were treated by an Elekta Synergy with single fraction SBRT. CBCT projections were acquired by XVI. Markers were successfully detected on most of the projection images. The inter-fractional changes were determined by 4D CT and the first CBCT while the intra-fractional changes were determined by multiple CBCT scans. It is found that the average motion range variations are within 2 mm, however, the average marker positions may drift by 6.5 mm. Conclusion: The patients respiratory motion variation for pancreas SBRT with AC was evaluated by detecting markers from CBCT projections and 4DCT, both the inter-fraction and intra-fraction motion range change is small but the drift of marker positions may be comparable

  20. Overexpressed EDIL3 predicts poor prognosis and promotes anchorage-independent tumor growth in human pancreatic cancer

    PubMed Central

    Feng, Ming-Xuan; Wang, Ya-Hui; Yang, Xiao-Mei; He, Ping; Tian, Guang-Ang; Zhang, Xiao-Xin; Li, Qing; Cao, Xiao-Yan; Huo, Yan-Miao; Yang, Min-Wei; Fu, Xue-Liang; Li, Jiao; Liu, De-Jun; Dai, Miao; Wen, Shan-Yun; Gu, Jian-Ren; Hong, Jie; Hua, Rong; Zhang, Zhi-Gang; Sun, Yong-Wei

    2016-01-01

    Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), an extracellular matrix (ECM) protein associated with vascular morphogenesis and remodeling, is commonly upregulated in multiple types of human cancers and correlates with tumor progression. However, its expression pattern and underlying cellular functions in pancreatic ductal adenocarcinoma (PDAC) remain largely unexplored. In current study, we observed that expression of EDIL3 was significantly up-regulated in PDAC compared with normal controls in both cell lines and clinical specimens. In addition, elevated EDIL3 expression was positively correlated with patients’ TNM stage and T classification. Kaplan-Meier analysis indicated that high EDIL3 expression was significantly associated with shorter overall survival times in PDAC patients. Multivariate Cox regression analysis confirmed EDIL3 expression, age, lymph node metastasis and histological differentiation as independent prognostic factors in PDAC. Knockdown of EDIL3 showed no significant influence on cell viability, migration, invasion and starvation-induced apoptosis, but compromised anoikis resistance and anchorage independent tumor growth of PDAC cells. Meanwhile, treatment with recombinant EDIL3 protein markedly promoted anoikis resistance and anchorage independent tumor growth. Mechanistically, we demonstrated that altered protein expression of Bcl-2 family might contribute to the oncogenic activities of EDIL3. In conclusion, this study provides evidences that EDIL3 is a potential predictor and plays an important role in anchorage independent tumor growth of PDAC and EDIL3-related pathways might represent a novel therapeutic strategy for treatment of pancreatic cancer. PMID:26735172

  1. Successful case of pancreaticoduodenectomy with resection of the hepatic arteries preserving a single aberrant hepatic artery for a pancreatic neuroendocrine tumor: report of a case.

    PubMed

    Ichida, Akihiko; Sakamoto, Yoshihiro; Akahane, Masaaki; Ishizawa, Takeaki; Kaneko, Junichi; Aoki, Taku; Hasegawa, Kiyoshi; Sugawara, Yasuhiko; Kokudo, Norihiro

    2015-03-01

    A 65-year-old male with a pancreatic neuroendocrine tumor presenting with a duodenal ulcer was referred to our department. The tumor involved the common hepatic artery, gastroduodenal artery, left hepatic artery and the right posterior hepatic artery, but not the right anterior hepatic artery originating from the superior mesenteric artery. The hepatic arteries, except the aberrant right anterior hepatic artery, were embolized using coils 18 days before the surgery. The patient underwent pancreaticoduodenectomy with resection of the tumor-encased hepatic arteries, while preserving the aberrant artery. The patient was discharged uneventfully on postoperative day 13 with no ischemic complications. A histopathological examination revealed a grade 2 pancreatic neuroendocrine tumor according to the classification of the World Health Organization, and the surgical margin was negative. The patient developed hepatic metastases 16 months after surgery; hence, hepatic resection was performed. The present surgical strategy is applicable in patients with relatively low-grade pancreatic malignancies involving major hepatic arteries. PMID:24477525

  2. SPARC-Independent Delivery of Nab-Paclitaxel without Depleting Tumor Stroma in Patient-Derived Pancreatic Cancer Xenografts.

    PubMed

    Kim, Harrison; Samuel, Sharon; Lopez-Casas, Pedro; Grizzle, William; Hidalgo, Manuel; Kovar, Joy; Oelschlager, Denise; Zinn, Kurt; Warram, Jason; Buchsbaum, Donald

    2016-04-01

    The study goal was to examine the relationship between nab-paclitaxel delivery and SPARC (secreted protein acidic and rich in cysteine) expression in pancreatic tumor xenografts and to determine the antistromal effect of nab-paclitaxel, which may affect tumor vascular perfusion. SPARC-positive and -negative mice bearing Panc02 tumor xenografts (n = 5-6/group) were injected with IRDye 800CW (IR800)-labeled nab-paclitaxel. After 24 hours, tumors were collected and stained with DL650-labeled anti-SPARC antibody, and the correlation between nab-paclitaxel and SPARC distributions was examined. Eight groups of mice bearing either Panc039 or Panc198 patient-derived xenografts (PDX; 4 groups/model, 5 animals/group) were untreated (served as control) or treated with gemcitabine (100 mg/kg body weight, i.p., twice per week), nab-paclitaxel (30 mg/kg body weight, i.v., for 5 consecutive days), and these agents in combination, respectively, for 3 weeks, and tumor volume and perfusion changes were assessed using T2-weighted MRI and dynamic contrast-enhanced (DCE) MRI, respectively. All tumors were collected and stained with Masson's Trichrome Stain, followed by a blinded comparative analysis of tumor stroma density. IR800-nab-paclitaxel was mainly distributed in tumor stromal tissue, but nab-paclitaxel and SPARC distributions were minimally correlated in either SPARC-positive or -negative animals. Nab-paclitaxel treatment neither decreased tumor stroma nor increased tumor vascular perfusion in either PDX model when compared with control groups. These data suggest that the specific tumor delivery of nab-paclitaxel is not directly related to SPARC expression, and nab-paclitaxel does not deplete tumor stroma in general. Mol Cancer Ther; 15(4); 680-8. ©2016 AACR. PMID:26832793

  3. Real-time tracking of respiratory-induced tumor motion by dose-rate regulation

    NASA Astrophysics Data System (ADS)

    Han-Oh, Yeonju Sarah

    We have developed a novel real-time tumor-tracking technology, called Dose-Rate-Regulated Tracking (DRRT), to compensate for tumor motion caused by breathing. Unlike other previously proposed tumor-tracking methods, this new method uses a preprogrammed dynamic multileaf collimator (MLC) sequence in combination with real-time dose-rate control. This new scheme circumvents the technical challenge in MLC-based tumor tracking, that is to control the MLC motion in real time, based on real-time detected tumor motion. The preprogrammed MLC sequence describes the movement of the tumor, as a function of breathing phase, amplitude, or tidal volume. The irregularity of tumor motion during treatment is handled by real-time regulation of the dose rate, which effectively speeds up or slows down the delivery of radiation as needed. This method is based on the fact that all of the parameters in dynamic radiation delivery, including MLC motion, are enslaved to the cumulative dose, which, in turn, can be accelerated or decelerated by varying the dose rate. Because commercially available MLC systems do not allow the MLC delivery sequence to be modified in real time based on the patient's breathing signal, previously proposed tumor-tracking techniques using a MLC cannot be readily implemented in the clinic today. By using a preprogrammed MLC sequence to handle the required motion, the task for real-time control is greatly simplified. We have developed and tested the pre- programmed MLC sequence and the dose-rate regulation algorithm using lung-cancer patients breathing signals. It has been shown that DRRT can track the tumor with an accuracy of less than 2 mm for a latency of the DRRT system of less than 0.35 s. We also have evaluated the usefulness of guided breathing for DRRT. Since DRRT by its very nature can compensate for breathing-period changes, guided breathing was shown to be unnecessary for real-time tracking when using DRRT. Finally, DRRT uses the existing dose-rate control

  4. Quantification of Esophageal Tumor Motion on Cine-Magnetic Resonance Imaging

    SciTech Connect

    Lever, Frederiek M.; Lips, Irene M.; Crijns, Sjoerd P.M.; Reerink, Onne; Lier, Astrid L.H.M.W. van; Moerland, Marinus A.; Vulpen, Marco van; Meijer, Gert J.

    2014-02-01

    Purpose: To quantify the movement of esophageal tumors noninvasively on cine-magnetic resonance imaging (MRI) by use of a semiautomatic method to visualize tumor movement directly throughout multiple breathing cycles. Methods and Materials: Thirty-six patients with esophageal tumors underwent MRI. Tumors were located in the upper (8), middle (7), and lower (21) esophagus. Cine-MR images were collected in the coronal and sagittal plane during 60 seconds at a rate of 2 Hz. An adaptive correlation filter was used to automatically track a previously marked reference point. Tumor movement was measured in the craniocaudal (CC), left–right (LR), and anteroposterior (AP) directions and its relationship along the longitudinal axis of the esophagus was investigated. Results: Tumor registration within the individual images was typically done at a millisecond time scale. The mean (SD) peak-to-peak displacements in the CC, AP, and LR directions were 13.3 (5.2) mm, 4.9 (2.5) mm, and 2.7 (1.2) mm, respectively. The bandwidth to cover 95% of excursions from the mean position (c95) was also calculated to exclude outliers caused by sporadic movements. The mean (SD) c95 values were 10.1 (3.8) mm, 3.7 (1.9) mm, and 2.0 (0.9) mm in the CC, AP, and LR dimensions. The end-exhale phase provided a stable position in the respiratory cycle, compared with more variety in the end-inhale phase. Furthermore, lower tumors showed more movement than did higher tumors in the CC and AP directions. Conclusions: Intrafraction tumor movement was highly variable between patients. Tumor position proved the most stable during the respiratory cycle in the end-exhale phase. A better understanding of tumor motion makes it possible to individualize radiation delivery strategies accordingly. Cine-MRI is a successful noninvasive modality to analyze motion for this purpose in the future.

  5. A High Circulating Tumor Cell Count in Portal Vein Predicts Liver Metastasis From Periampullary or Pancreatic Cancer

    PubMed Central

    Tien, Yu Wen; Kuo, Hsun-Chuan; Ho, Be-Ing; Chang, Ming-Chu; Chang, Yu-Ting; Cheng, Mei-Fang; Chen, Huai-Lu; Liang, Ting-Yung; Wang, Chien-Fang; Huang, Chia-Yi; Shew, Jin-Yuh; Chang, Ying Chih; Lee, Eva YHP; Lee, Wen-Hwa

    2016-01-01

    Abstract Circulating tumor cells (CTCs) released from a periampullary or pancreatic cancer can be more frequently detected in the portal than the systemic circulation and potentially can be used to identify patients with liver micrometastases. Aims of this study is to determine if CTCs count in portal venous blood of patients with nonmetastatic periampullary or pancreatic adenocarcinoma can be used as a predictor for subsequent liver metastases. CTCs were quantified in portal and peripheral venous blood samples collected simultaneously during pancreaticoduodenectomy in patients with presumed periampullary or pancreatic adenocarcinoma without image-discernible metastasis. Postoperatively patients were monitored for liver metastasis by abdominal magnetic resonance imaging or computed tomography every 3 months for 1 year. Sixty patients with a pathological diagnosis of periampullary or pancreatic adenocarcinoma were included in the study. Multivariate analysis indicated that portal CTC count was a significant predictor for liver metastases within 6 months after surgery. Eleven of 13 patients with a high portal CTCs count (defined as >112 CMx Platform estimated CTCs in 2 mL blood) developed liver metastases within 6 months after surgery. In contrast, only 6 of 47 patients with a low portal CTC count developed liver metastases (P < 0.0001). A value of 112 CMx Platform estimated CTCs had 64.7% sensitivity and 95.4% specificity to predict liver metastases within 6 months after surgery. We concluded that a high CTC count in portal venous blood collected during pancreaticoduodenectomy in patients with periampullary or pancreatic adenocarcinoma without metastases detected by currently available imaging tools is a significant predictor for liver metastases within 6 months after surgery. PMID:27100430

  6. Long-term disease control of a pancreatic neuroendocrine tumor with lanreotide autogel(®): a case report.

    PubMed

    Lybaert, Willem; Van Hul, Erik; Woestenborghs, Heidi

    2014-09-01

    The CLARINET study (ClinicalTrials.gov: NCT00353496) showed that somatostatin analogs are able to stabilize tumor growth in patients with intestinal and pancreatic neuroendocrine tumors (NETs). Here, we present a case of NET originating from the pancreatic tail that was treated with lanreotide Autogel(®). A 60-year-old patient underwent resection of a pancreatic NET with splenectomy and distal pancreatectomy. Four months after surgery, there was an increase in chromogranin A levels, along with a hypercaptating lesion of approximately 3.5 cm at the residual part of the pancreatic corpus. Treatment with 30 mg monthly-administered octreotide long-acting release (LAR) was initiated. After 3 months of treatment, a control CT scan revealed diffuse metastases in the liver, although the patient presented no symptoms and liver tests were normal. Due to difficulties with the administration of octreotide LAR, treatment was switched to lanreotide Autogel(®) 120 mg, administered as monthly deep-subcutaneous injections. Progression-free survival, as shown by 3-monthly CT scans, was obtained for 2 years without the need to increase the lanreotide Autogel(®) dose, and the patient reported no side effects. After these 2 years, deterioration of the patient's clinical status and weight loss were observed, along with increased size of the liver lesions and appearance of peritoneal metastases. Chemotherapy treatment with cisplatinum-etoposide was initiated, while the lanreotide Autogel(®) injections were continued. After three chemotherapy cycles, a rapid decline in the patient's quality of life was noted, and she requested discontinuation of the chemotherapy and lanreotide injections. One month later, the patient died due to clinical progressive disease. PMID:25408662

  7. Long-Term Disease Control of a Pancreatic Neuroendocrine Tumor with Lanreotide Autogel®: A Case Report

    PubMed Central

    Lybaert, Willem; Van Hul, Erik; Woestenborghs, Heidi

    2014-01-01

    The CLARINET study (ClinicalTrials.gov: NCT00353496) showed that somatostatin analogs are able to stabilize tumor growth in patients with intestinal and pancreatic neuroendocrine tumors (NETs). Here, we present a case of NET originating from the pancreatic tail that was treated with lanreotide Autogel®. A 60-year-old patient underwent resection of a pancreatic NET with splenectomy and distal pancreatectomy. Four months after surgery, there was an increase in chromogranin A levels, along with a hypercaptating lesion of approximately 3.5 cm at the residual part of the pancreatic corpus. Treatment with 30 mg monthly-administered octreotide long-acting release (LAR) was initiated. After 3 months of treatment, a control CT scan revealed diffuse metastases in the liver, although the patient presented no symptoms and liver tests were normal. Due to difficulties with the administration of octreotide LAR, treatment was switched to lanreotide Autogel® 120 mg, administered as monthly deep-subcutaneous injections. Progression-free survival, as shown by 3-monthly CT scans, was obtained for 2 years without the need to increase the lanreotide Autogel® dose, and the patient reported no side effects. After these 2 years, deterioration of the patient's clinical status and weight loss were observed, along with increased size of the liver lesions and appearance of peritoneal metastases. Chemotherapy treatment with cisplatinum-etoposide was initiated, while the lanreotide Autogel® injections were continued. After three chemotherapy cycles, a rapid decline in the patient's quality of life was noted, and she requested discontinuation of the chemotherapy and lanreotide injections. One month later, the patient died due to clinical progressive disease. PMID:25408662

  8. Focused ultrasound treatment of VX2 tumors controlled by local harmonic motion

    NASA Astrophysics Data System (ADS)

    Curiel, Laura; Huang, Yuexi; Vykhodtseva, Natalia; Hynynen, Kullervo

    2009-06-01

    The purpose of this study was to evaluate the feasibility of using localized harmonic motion (LHM) to monitor and control focused ultrasound surgery (FUS) in VX2 tumors in vivo. FUS exposures were performed on 13 VX2 tumors implanted in nine rabbits. The same transducer induced coagulation and generated a localized oscillatory motion by periodically varying the radiation force. A separate diagnostic ultrasound transducer tracked motion by cross-correlating echo signals at different instances. A threshold in motion amplitude was instituted to cease exposure. Coagulation was confirmed by T2-weighted MR images, thermal dose obtained through MR thermometry and histological examinations. For tumor locations achieving coagulation, the LHM amplitude was 9% (p = 0.04) to 57% (p < 0.0001) lower than that before exposure. Control was successful for 74 (69%) out of 108 cases, with 52 (48%) reaching the threshold and achieving coagulation and 22 (21%) never reaching threshold nor coagulating. For the 34 (31%) unsuccessful exposures, 16 (15%) never reached the threshold but coagulation occurred, and 18 (16%) reached threshold without coagulation confirmed. Noise or radio-frequency signal changes explained motion over- or underestimation in 24 (22%) cases; the remaining 10 (9%) had other causes of error. The control was generally successful, but sudden change or noise in the acquired echo signal caused failure. Coagulation after exposure could be validated by comparing amplitudes before and after exposure.

  9. Reproducibility of Tumor Motion Probability Distribution Function in Stereotactic Body Radiation Therapy of Lung Cancer

    SciTech Connect

    Zhang Fan; Hu Jing; Kelsey, Chris R.; Yoo, David; Yin Fangfang; Cai Jing

    2012-11-01

    Purpose: To evaluate the reproducibility of tumor motion probability distribution function (PDF) in stereotactic body radiation therapy (SBRT) of lung cancer using cine megavoltage (MV) images. Methods and Materials: Cine MV images of 20 patients acquired during three-dimensional conformal (6-11 beams) SBRT treatments were retrospectively analyzed to extract tumor motion trajectories. For each patient, tumor motion PDFs were generated per fraction (PDF{sub n}) using three selected 'usable' beams. Patients without at least three usable beams were excluded from the study. Fractional PDF reproducibility (R{sub n}) was calculated as the Dice similarity coefficient between PDF{sub n} to a 'ground-truth' PDF (PDF{sub g}), which was generated using the selected beams of all fractions. The mean of R{sub n}, labeled as R{sub m}, was calculated for each patient and correlated to the patient's mean tumor motion rang (A{sub m}). Change of R{sub m} during the course of SBRT treatments was also evaluated. Intra- and intersubject coefficient of variation (CV) of R{sub m} and A{sub m} were determined. Results: Thirteen patients had at least three usable beams and were analyzed. The mean of R{sub m} was 0.87 (range, 0.84-0.95). The mean of A{sub m} was 3.18 mm (range, 0.46-7.80 mm). R{sub m} was found to decrease as A{sub m} increases following an equation of R{sub m} = 0.17e{sup -0.9Am} + 0.84. R{sub m} also decreased slightly throughout the course of treatments. Intersubject CV of R{sub m} (0.05) was comparable to intrasubject CV of R{sub m} (range, 0.02-0.09); intersubject CV of A{sub m} (0.73) was significantly greater than intrasubject CV of A{sub m} (range, 0.09-0.24). Conclusions: Tumor motion PDF can be determined using cine MV images acquired during the treatments. The reproducibility of lung tumor motion PDF decreased exponentially as the tumor motion range increased and decreased slightly throughout the course of the treatments.

  10. Differential Motion Between Mediastinal Lymph Nodes and Primary Tumor in Radically Irradiated Lung Cancer Patients

    SciTech Connect

    Schaake, Eva E.; Rossi, Maddalena M.G.; Buikhuisen, Wieneke A.; Burgers, Jacobus A.; Smit, Adrianus A.J.; Belderbos, José S.A.; Sonke, Jan-Jakob

    2014-11-15

    Purpose/Objective: In patients with locally advanced lung cancer, planning target volume margins for mediastinal lymph nodes and tumor after a correction protocol based on bony anatomy registration typically range from 1 to 1.5 cm. Detailed information about lymph node motion variability and differential motion with the primary tumor, however, is lacking from large series. In this study, lymph node and tumor position variability were analyzed in detail and correlated to the main carina to evaluate possible margin reduction. Methods and Materials: Small gold fiducial markers (0.35 × 5 mm) were placed in the mediastinal lymph nodes of 51 patients with non-small cell lung cancer during routine diagnostic esophageal or bronchial endoscopic ultrasonography. Four-dimensional (4D) planning computed tomographic (CT) and daily 4D cone beam (CB) CT scans were acquired before and during radical radiation therapy (66 Gy in 24 fractions). Each CBCT was registered in 3-dimensions (bony anatomy) and 4D (tumor, marker, and carina) to the planning CT scan. Subsequently, systematic and random residual misalignments of the time-averaged lymph node and tumor position relative to the bony anatomy and carina were determined. Additionally, tumor and lymph node respiratory amplitude variability was quantified. Finally, required margins were quantified by use of a recipe for dual targets. Results: Relative to the bony anatomy, systematic and random errors ranged from 0.16 to 0.32 cm for the markers and from 0.15 to 0.33 cm for the tumor, but despite similar ranges there was limited correlation (0.17-0.71) owing to differential motion. A large variability in lymph node amplitude between patients was observed, with an average motion of 0.56 cm in the cranial-caudal direction. Margins could be reduced by 10% (left-right), 27% (cranial-caudal), and 10% (anteroposterior) for the lymph nodes and −2%, 15%, and 7% for the tumor if an online carina registration protocol replaced a

  11. Toward in vivo lung's tissue incompressibility characterization for tumor motion modeling in radiation therapy

    SciTech Connect

    Shirzadi, Zahra; Sadeghi-Naini, Ali; Samani, Abbas

    2013-05-15

    Purpose: A novel technique is proposed to characterize lung tissue incompressibility variation during respiration. Estimating lung tissue incompressibility parameter variations resulting from air content variation throughout respiration is critical for computer assisted tumor motion tracking. Continuous tumor motion is a major challenge in lung cancer radiotherapy, especially with external beam radiotherapy. If not accounted for, this motion may lead to areas of radiation overdosage for normal tissue. Given the unavailability of imaging modality that can be used effectively for real-time lung tumor tracking, computer assisted approach based on tissue deformation estimation can be a good alternative. This approach involves lung biomechanical model where its fidelity depends on input tissue properties. This investigation shows that considering variable tissue incompressibility parameter is very important for predicting tumor motion accurately, hence improving the lung radiotherapy outcome. Methods: First, an in silico lung phantom study was conducted to demonstrate the importance of employing variable Poisson's ratio for tumor motion predication. After it was established that modeling this variability is critical for accurate tumor motion prediction, an optimization based technique was developed to estimate lung tissue Poisson's ratio as a function of respiration cycle time. In this technique, the Poisson's ratio and lung pressure value were varied systematically until optimal values were obtained, leading to maximum similarity between acquired and simulated 4D CT lung images. This technique was applied in an ex vivo porcine lung study where simulated images were constructed using the end exhale CT image and deformation fields obtained from the lung's FE modeling of each respiration time increment. To model the tissue, linear elastic and Marlow hyperelastic material models in conjunction with variable Poisson's ratio were used. Results: The phantom study showed that

  12. Real-time soft tissue motion estimation for lung tumors during radiotherapy delivery

    SciTech Connect

    Rottmann, Joerg; Berbeco, Ross; Keall, Paul

    2013-09-15

    Purpose: To provide real-time lung tumor motion estimation during radiotherapy treatment delivery without the need for implanted fiducial markers or additional imaging dose to the patient.Methods: 2D radiographs from the therapy beam's-eye-view (BEV) perspective are captured at a frame rate of 12.8 Hz with a frame grabber allowing direct RAM access to the image buffer. An in-house developed real-time soft tissue localization algorithm is utilized to calculate soft tissue displacement from these images in real-time. The system is tested with a Varian TX linear accelerator and an AS-1000 amorphous silicon electronic portal imaging device operating at a resolution of 512 × 384 pixels. The accuracy of the motion estimation is verified with a dynamic motion phantom. Clinical accuracy was tested on lung SBRT images acquired at 2 fps.Results: Real-time lung tumor motion estimation from BEV images without fiducial markers is successfully demonstrated. For the phantom study, a mean tracking error <1.0 mm [root mean square (rms) error of 0.3 mm] was observed. The tracking rms accuracy on BEV images from a lung SBRT patient (≈20 mm tumor motion range) is 1.0 mm.Conclusions: The authors demonstrate for the first time real-time markerless lung tumor motion estimation from BEV images alone. The described system can operate at a frame rate of 12.8 Hz and does not require prior knowledge to establish traceable landmarks for tracking on the fly. The authors show that the geometric accuracy is similar to (or better than) previously published markerless algorithms not operating in real-time.

  13. Anti-tumor properties of the cGMP/protein kinase G inhibitor DT3 in pancreatic adenocarcinoma.

    PubMed

    Soltek, Sabine; Karakhanova, Svetlana; Golovastova, Marina; D'Haese, Jan G; Serba, Susanne; Nachtigall, Ines; Philippov, Pavel P; Werner, Jens; Bazhin, Alexandr V

    2015-11-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Therefore, new therapeutic options are urgently needed to improve the survival of PDAC patients. Protein kinase G (PKG) conducts the interlude of cGMP signaling which is important for healthy as well as for cancer cells. DT3 is a specific inhibitor of PKG, and it has been shown to possess an anti-tumor cytotoxic activity in vitro. The main aim of this work was to investigate anti-tumor effects of DT3 upon PDAC in vivo.Expression of PKG was assessed with real-time PCR analysis in the normal and tumor pancreatic cells. In vitro cell viability, proliferation, apoptosis, necrosis, migration, and invasion of the murine PDAC cell line Panc02 were assessed after DT3 treatment. In vivo anti-tumor effects of DT3 were investigated in the murine Panc02 orthotopic model of PDAC. Western blot analysis was used to determine the phosphorylation state of the proteins of interest.Functional PKGI is preferentially expressed in PDAC cells. DT3 was capable to reduce viability, proliferation, and migration of murine PDAC cells in vitro. At the same time, DT3 treatment did not change the viability of normal epithelial cells of murine liver. In vivo, DT3 treatment reduced the tumor volume and metastases in PDAC-bearing mice, but it was ineffective to prolong the survival of the tumor-bearing animals. In addition, DT3 treatment decreased phosphorylation of GSK-3, P38, and CREB in murine PDAC.Inhibition of PKG could be a potential therapeutic strategy for PDAC treatment which should be carefully validated in future pre-clinical studies. PMID:26105003

  14. Application of a spring-dashpot system to clinical lung tumor motion data

    SciTech Connect

    Ackerley, E. J.; Wilson, P. L.; Cavan, A. E.; Berbeco, R. I.; Meyer, J.

    2013-02-15

    Purpose: The treatment efficacy of radiation therapy for lung tumors can be increased by compensating for breath-induced tumor motion. In this study, we quantitatively examine a mathematical model of pseudomechanical linkages between an external surrogate signal and lung tumor motion. Methods: A spring-dashpot system based on the Voigt model was developed to model the correlation between abdominal respiratory motion and tumor motion during lung radiotherapy. The model was applied to clinical data obtained from 52 treatments ('beams') from 10 patients, treated on the Mitsubishi Real-Time Radiation Therapy system, Sapporo, Japan. In Stage 1, model parameters were optimized for individual patients and beams to determine reference values and to investigate how well the model can describe the data. In Stage 2, for each patient the optimal parameters determined for a single beam were applied to data from other beams to investigate whether a beam-specific set of model parameters is sufficient to model tumor motion over a course of treatment. Results: In Stage 1, the baseline root mean square (RMS) residual error for all individually optimized beam data was 0.90 {+-} 0.40 mm (mean {+-} 1 standard deviation). In Stage 2, patient-specific model parameters based on a single beam were found to model the tumor position closely, even for irregular beam data, with a mean increase with respect to Stage 1 values in RMS error of 0.37 mm. On average, the obtained model output for the tumor position was 95% of the time within an absolute bound of 2.0 and 2.6 mm in Stages 1 and 2, respectively. The model was capable of dealing with baseline, amplitude and frequency variations of the input data, as well as phase shifts between the input abdominal and output tumor signals. Conclusions: These results indicate that it may be feasible to collect patient-specific model parameters during or prior to the first treatment, and then retain these for the rest of the treatment period. The model has

  15. Merlin/NF2 Suppresses Pancreatic Tumor Growth and Metastasis by Attenuating the FOXM1-Mediated Wnt/β-Catenin Signaling.

    PubMed

    Quan, Ming; Cui, Jiujie; Xia, Tian; Jia, Zhiliang; Xie, Dacheng; Wei, Daoyan; Huang, Suyun; Huang, Qian; Zheng, Shaojiang; Xie, Keping

    2015-11-15

    Merlin, the protein encoded by the NF2 gene, is a member of the band 4.1 family of cytoskeleton-associated proteins and functions as a tumor suppressor for many types of cancer. However, the roles and mechanism of Merlin expression in pancreatic cancer have remained unclear. In this study, we sought to determine the impact of Merlin expression on pancreatic cancer development and progression using human tissue specimens, cell lines, and animal models. Decreased expression of Merlin was pronounced in human pancreatic tumors and cancer cell lines. Functional analysis revealed that restored expression of Merlin inhibited pancreatic tumor growth and metastasis in vitro and in vivo. Furthermore, Merlin suppressed the expression of Wnt/β-catenin signaling downstream genes and the nuclear expression of β-catenin protein, and overexpression of Forkhead box M1 (FOXM1) attenuated the suppressive effect of Merlin on Wnt/β-catenin signaling. Mechanistically, Merlin decreased the stability of FOXM1 protein, which plays critical roles in nuclear translocation of β-catenin. Collectively, these findings demonstrated that Merlin critically regulated pancreatic cancer pathogenesis by suppressing FOXM1/β-catenin signaling, suggesting that targeting novel Merlin/FOXM1/β-catenin signaling is an effective therapeutic strategy for pancreatic cancer. PMID:26483206

  16. Specific Targeting of Tumor Endothelial Cells by a Shiga-like Toxin-Vascular Endothelial Growth Factor Fusion Protein as a Novel Treatment Strategy for Pancreatic Cancer1

    PubMed Central

    Hotz, Birgit; Backer, Marina V; Backer, Joseph M; Buhr, Heinz-J; Hotz, Hubert G

    2010-01-01

    Purpose Tumor endothelial cells express vascular endothelial growth factor receptor 2 (VEGFR-2). VEGF can direct toxins to tumor vessels through VEGFR-2 for antiangiogenic therapy. This study aimed to selectively damage the VEGFR-2-overexpressing vasculature of pancreatic cancer by SLT-VEGF fusion protein comprising VEGF and the A subunit of Shiga-like toxin which inhibits protein synthesis of cells with high VEGFR-2 expression. Experimental Design Expression of VEGF and VEGF receptors was evaluated in human pancreatic cancer cells (AsPC-1, HPAF-2) and in normal human endothelial cells (HUVEC) by reverse transcription-polymerase chain reaction. Cells were treated with SLT-VEGF (0.1–10 nM), and cell viability, proliferation, and endothelial tube formation were assessed. Orthotopic pancreatic cancer (AsPC-1, HPAF-2) was induced in nude mice. Animals were treated with SLT-VEGF fusion protein alone or in combination with gemcitabine. Treatment began 3 days or 6 weeks after tumor induction. Primary tumor volume and dissemination were determined after 14 weeks. Microvessel density and expression of VEGF and VEGF receptors were analyzed by immunohistochemistry. Results SLT-VEGF did not influence proliferation of pancreatic cancer cells; HUVECs (low-level VEGFR-2) reduced their proliferation rate and tube formation but not their viability. SLT-VEGF fusion protein reduced tumor growth and dissemination, increasing 14-week survival (AsPC-1, up to 75%; HPAF-2, up to 83%). Results of gemcitabine were comparable with SLT-VEGF monotherapy. Combination partly increased the therapeutic effects in comparison to the respective monotherapies. Microvessel density was reduced in all groups. Intratumoral VEGFR-2 expression was found in endothelial but not in tumor cells. Conclusions SLT-VEGF is toxic for tumor vasculature rather than for normal endothelial or pancreatic cancer cells. SLT-VEGF treatment in combination with gemcitabine may provide a novel approach for pancreatic cancer

  17. Real-time tumor motion estimation using respiratory surrogate via memory-based learning

    NASA Astrophysics Data System (ADS)

    Li, Ruijiang; Lewis, John H.; Berbeco, Ross I.; Xing, Lei

    2012-08-01

    Respiratory tumor motion is a major challenge in radiation therapy for thoracic and abdominal cancers. Effective motion management requires an accurate knowledge of the real-time tumor motion. External respiration monitoring devices (optical, etc) provide a noninvasive, non-ionizing, low-cost and practical approach to obtain the respiratory signal. Due to the highly complex and nonlinear relations between tumor and surrogate motion, its ultimate success hinges on the ability to accurately infer the tumor motion from respiratory surrogates. Given their widespread use in the clinic, such a method is critically needed. We propose to use a powerful memory-based learning method to find the complex relations between tumor motion and respiratory surrogates. The method first stores the training data in memory and then finds relevant data to answer a particular query. Nearby data points are assigned high relevance (or weights) and conversely distant data are assigned low relevance. By fitting relatively simple models to local patches instead of fitting one single global model, it is able to capture highly nonlinear and complex relations between the internal tumor motion and external surrogates accurately. Due to the local nature of weighting functions, the method is inherently robust to outliers in the training data. Moreover, both training and adapting to new data are performed almost instantaneously with memory-based learning, making it suitable for dynamically following variable internal/external relations. We evaluated the method using respiratory motion data from 11 patients. The data set consists of simultaneous measurement of 3D tumor motion and 1D abdominal surface (used as the surrogate signal in this study). There are a total of 171 respiratory traces, with an average peak-to-peak amplitude of ∼15 mm and average duration of ∼115 s per trace. Given only 5 s (roughly one breath) pretreatment training data, the method achieved an average 3D error of 1.5 mm and 95

  18. SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth.

    PubMed

    Yang, Hui; Zhou, Lisha; Shi, Qian; Zhao, Yuzheng; Lin, Huaipeng; Zhang, Mengli; Zhao, Shimin; Yang, Yi; Ling, Zhi-Qiang; Guan, Kun-Liang; Xiong, Yue; Ye, Dan

    2015-04-15

    The malate-aspartate shuttle is indispensable for the net transfer of cytosolic NADH into mitochondria to maintain a high rate of glycolysis and to support rapid tumor cell growth. The malate-aspartate shuttle is operated by two pairs of enzymes that localize to the mitochondria and cytoplasm, glutamate oxaloacetate transaminases (GOT), and malate dehydrogenases (MDH). Here, we show that mitochondrial GOT2 is acetylated and that deacetylation depends on mitochondrial SIRT3. We have identified that acetylation occurs at three lysine residues, K159, K185, and K404 (3K), and enhances the association between GOT2 and MDH2. The GOT2 acetylation at these three residues promotes the net transfer of cytosolic NADH into mitochondria and changes the mitochondrial NADH/NAD(+) redox state to support ATP production. Additionally, GOT2 3K acetylation stimulates NADPH production to suppress ROS and to protect cells from oxidative damage. Moreover, GOT2 3K acetylation promotes pancreatic cell proliferation and tumor growth in vivo. Finally, we show that GOT2 K159 acetylation is increased in human pancreatic tumors, which correlates with reduced SIRT3 expression. Our study uncovers a previously unknown mechanism by which GOT2 acetylation stimulates the malate-aspartate NADH shuttle activity and oxidative protection. PMID:25755250

  19. SIRT3-dependent GOT2 acetylation status affects the malate–aspartate NADH shuttle activity and pancreatic tumor growth

    PubMed Central

    Yang, Hui; Zhou, Lisha; Shi, Qian; Zhao, Yuzheng; Lin, Huaipeng; Zhang, Mengli; Zhao, Shimin; Yang, Yi; Ling, Zhi-Qiang; Guan, Kun-Liang; Xiong, Yue; Ye, Dan

    2015-01-01

    The malate–aspartate shuttle is indispensable for the net transfer of cytosolic NADH into mitochondria to maintain a high rate of glycolysis and to support rapid tumor cell growth. The malate–aspartate shuttle is operated by two pairs of enzymes that localize to the mitochondria and cytoplasm, glutamate oxaloacetate transaminases (GOT), and malate dehydrogenases (MDH). Here, we show that mitochondrial GOT2 is acetylated and that deacetylation depends on mitochondrial SIRT3. We have identified that acetylation occurs at three lysine residues, K159, K185, and K404 (3K), and enhances the association between GOT2 and MDH2. The GOT2 acetylation at these three residues promotes the net transfer of cytosolic NADH into mitochondria and changes the mitochondrial NADH/NAD+ redox state to support ATP production. Additionally, GOT2 3K acetylation stimulates NADPH production to suppress ROS and to protect cells from oxidative damage. Moreover, GOT2 3K acetylation promotes pancreatic cell proliferation and tumor growth in vivo. Finally, we show that GOT2 K159 acetylation is increased in human pancreatic tumors, which correlates with reduced SIRT3 expression. Our study uncovers a previously unknown mechanism by which GOT2 acetylation stimulates the malate–aspartate NADH shuttle activity and oxidative protection. PMID:25755250

  20. Systemic siRNA delivery to a spontaneous pancreatic tumor model in transgenic mice by PEGylated calcium phosphate hybrid micelles.

    PubMed

    Pittella, Frederico; Cabral, Horacio; Maeda, Yoshinori; Mi, Peng; Watanabe, Sumiyo; Takemoto, Hiroyasu; Kim, Hyun Jin; Nishiyama, Nobuhiro; Miyata, Kanjiro; Kataoka, Kazunori

    2014-03-28

    Efficient systems for delivery of small interfering RNA (siRNA) are required for clinical application of RNA interference (RNAi) in cancer therapy. Herein, we developed a safe and efficient nanocarrier comprising poly(ethylene glycol)-block-charge-conversional polymer (PEG-CCP)/calcium phosphate (CaP) hybrid micelles for systemic delivery of siRNA and studied their efficacy in spontaneous bioluminescent pancreatic tumors from transgenic mice. PEG-CCP was engineered to provide the siRNA-loaded hybrid micelles with enhanced colloidal stability and biocompatibility due to the PEG capsule and with endosome-disrupting functionality due to the acidic pH-responsive CCP segment where the polyanionic structure could be converted to polycationic structure at acidic pH through cis-aconitic amide cleavage. The resulting hybrid micelles were confirmed to have a diameter of <50nm, with a narrow size distribution. Intravenously injected hybrid micelles significantly reduced the luciferase-based luminescent signal from the spontaneous pancreatic tumors in an siRNA sequence-specific manner. The gene silencing activity of the hybrid micelles correlated with their preferential tumor accumulation, as indicated by fluorescence imaging and histological analysis. Moreover, there were no significant changes in hematological parameters in mice treated with the hybrid micelles. These results demonstrate the great potential of the hybrid micelles as siRNA carriers for RNAi-based cancer therapy. PMID:24440662

  1. Simulation of dosimetric consequences of 4D-CT-based motion margin estimation for proton radiotherapy using patient tumor motion data

    NASA Astrophysics Data System (ADS)

    Koybasi, Ozhan; Mishra, Pankaj; St. James, Sara; Lewis, John H.; Seco, Joao

    2014-02-01

    For the radiation treatment of lung cancer patients, four-dimensional computed tomography (4D-CT) is a common practice used clinically to image tumor motion and subsequently determine the internal target volume (ITV) from the maximum intensity projection (MIP) images. ITV, which is derived from short pre-treatment 4D-CT scan (<6 s per couch position), may not adequately cover the extent of tumor motion during the treatment, particularly for patients that exhibit a large respiratory variability. Inaccurate tumor localization may result in under-dosage of the tumor or over-dosage of the surrounding tissues. The purpose of this study is therefore to assess the degree of tumor under-dosage in case of regular and irregular breathing for proton radiotherapy using ITV-based treatment planning. We place a spherical lesion into a modified XCAT phantom that is also capable of producing 4D images based on irregular breathing, and move the tumor according to real tumor motion data, which is acquired over multiple days by tracking gold fiducial markers implanted into the lung tumors of patients. We derive ITVs by taking the union of all tumor positions during 6 s of tumor motion in the phantom using the first day patient tumor tracking data. This is equivalent to ITVs generated clinically from cine-mode 4D-CT MIP images. The treatment plans created for different ITVs are then implemented on dynamic phantoms with tumor motion governed by real tumor tracking data from consecutive days. By comparing gross tumor volume dose distribution on days of ‘treatment’ with the ITV dose distribution, we evaluate the deviation of the actually delivered dose from the predicted dose. Our results have shown that the proton treatment planning on ITV derived from pre-treatment cine-mode 4D-CT can result in under-dosage (dose covering 95% of volume) of the tumor by up to 25.7% over 3 min of treatment for the patient with irregular respiratory motion. Tumor under-dosage is less significant for

  2. Surgical treatment and clinical outcome of nonfunctional pancreatic neuroendocrine tumors: a 14-year experience from one single center.

    PubMed

    Yang, Min; Zeng, Lin; Zhang, Yi; Su, An-Ping; Yue, Peng-Ju; Tian, Bo-le

    2014-11-01

    Our primary aim of the present study was to analyze the clinical characteristics and surgical outcome of nonfunctional pancreatic neuroendocrine tumors (non-F-P-NETs), with an emphasis on evaluating the prognostic value of the newly updated 2010 grading classification of the World Health Organization (WHO).Data of 55 consecutive patients who were surgically treated and pathologically diagnosed as non-F-P-NETs in our single institution from January 2000 to December 2013 were retrospectively collected.This entirety comprised of 55 patients (31 males and 24 females), with a mean age of 51.24 ± 12.95 years. Manifestations of non-F-P-NETs were nonspecific. Distal pancreatectomy, pancreaticoduodenectomy, and local resection of pancreatic tumor were the most frequent surgical procedures, while pancreatic fistula was the most common but acceptable complication (30.3%). The overall 5-year survival rate of this entire cohort was 41.0%, with a median survival time of 60.4 months. Patients who underwent R0 resections obtained a better survival than those who did not (P < 0.005). As for the prognostic analysis, tumor size and lymph invasion were only statistically significant in univariate analysis (P = 0.046 and P < 0.05, respectively), whereas the newly updated 2010 grading classification of WHO (G1 and G2 vs G3), distant metastasis, and surgical margin were all meaningful in both univariate and multivariate analysis (P = 0.045, 0.001, and 0.042, respectively).Non-F-P-NETs are a kind of rare neoplasm, with mostly indolent malignancy. Patients with non-F-P-NETs could benefit from the radical resections. The new WHO criteria, distant metastasis and surgical margin, might be independent predictors for the prognosis of non-F-P-NETs. PMID:25396335

  3. Treatment of nitrosamine-induced pancreatic tumors in hamsters with analogs of somatostatin and luteinizing hormone-releasing hormone

    SciTech Connect

    Paz-Bouza, J.I.; Redding, T.W.; Schally, A.V.

    1987-02-01

    Pancreatic ductal adenocarcinoma was induced in female Syrian golden hamsters by injecting N-nitrosobis(2-oxopropyl)amine (BOP) once a week at a dose of 10 mg per kg of body weight for 18 weeks. Hamsters were then treated with somatostatin analog (RC-160) or with (6-D-tryptophan)luteinizing hormone-releasing hormone ((D-Trp/sup 6/)LH-RH) delayed delivery systems. After 18 weeks of BOP administration, the hamsters were divided into three groups of 10-20 animals each. Group I consisted of untreated controls, group II was injected with RC-160, and group III was injected with (D-Trp/sub 2/)LH-RH. A striking decrease in tumor weight and volume was obtained in animals treated with (D-Trp/sup 6/)LH-RH or with the somatostatin analog RC-160. After 45 days of treatment with either analog, the survival rate was significantly higher in groups II and III (70%), as compared with the control group (35%). The studies, done by light microscopy, high-resolution microscopy, and electron microscopy, showed a decrease in the total number of cancer cells and changes in the epithelium, connective tissue, and cellular organelles in groups II and III treated with the hypothalamic analogs as compared to controls. These results in female hamsters with induced ductal pancreatic tumors confirm and extend the authors findings, obtained in male animals with transplanted tumors, that (D-Trp/sub 6/)LH-RH and somatostatin analogs inhibit the growth of pancreatic cancers.

  4. Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma.

    PubMed

    Kokkinakis, Demetrius M; Liu, Xiaoyan; Neuner, Russell D

    2005-09-01

    The effect of methionine deprivation (methionine stress) on the proliferation, survival, resistance to chemotherapy, and regulation of gene and protein expression in pancreatic tumor lines is examined. Methionine stress prevents successful mitosis and promotes cell cycle arrest and accumulation of cells with multiple micronuclei with decondensed chromatin. Inhibition of mitosis correlates with CDK1 down-regulation and/or inhibition of its function by Tyr(15) phosphorylation or Thr(161) dephosphorylation. Inhibition of cell cycle progression correlates with loss of hyperphosphorylated Rb and up-regulation of p21 via p53 and/or transforming growth factor-beta (TGF-beta) activation depending on p53 status. Although methionine stress-induced toxicity is not solely dependent on p53, the gain in p21 and loss in CDK1 transcription are more enhanced in wild-type p53 tumors. Up-regulation of SMAD7, a TGF-beta signaling inhibitor, suggests that SMAD7 does not restrict the TGF-beta-mediated induction of p21, although it may prevent up-regulation of p27. cDNA oligoarray analysis indicated a pleiotropic response to methionine stress. Cell cycle and mitotic arrest is in agreement with up-regulation of NF2, ETS2, CLU, GADD45alpha, GADD45beta, and GADD45gamma and down-regulation of AURKB, TOP2A, CCNA, CCNB, PRC1, BUB1, NuSAP, IFI16, and BRCA1. Down-regulation of AREG, AGTR1, M-CSF, and EGF, IGF, and VEGF receptors and up-regulation of GNA11 and IGFBP4 signify loss of growth factor support. PIN1, FEN1, and cABL up-regulation and LMNB1, AREG, RhoB, CCNG, TYMS, F3, and MGMT down-regulation suggest that methionine stress sensitizes the tumor cells to DNA-alkylating drugs, 5-fluorouracil, and radiation. Increased sensitivity of pancreatic tumor cell lines to temozolomide is shown under methionine stress conditions and is attributed in part to diminished O(6)-methylguanine-DNA methyltransferase and possibly to inhibition of the cell cycle progression. PMID:16170025

  5. Nuclear medicine imaging of gastro-entero-pancreatic neuroendocrine tumors. The key role of cellular differentiation and tumor grade: from theory to clinical practice

    PubMed Central

    Rust, Edmond; Hubele, Fabrice; Marzano, Ettore; Goichot, Bernard; Pessaux, Patrick; Kurtz, Jean-Emmanuel

    2012-01-01

    Abstract Nuclear medicine imaging is a powerful diagnostic tool for the management of patients with gastro-entero-pancreatic neuroendocrine tumors, mainly developed considering some cellular characteristics that are specific to the neuroendocrine phenotype. Hence, overexpression of specific trans membrane receptors as well as the cellular ability to take up, accumulate, and decarboxylate amine precursors have been considered for diagnostic radiotracer development. Moreover, the glycolytic metabolism, which is not a specific energetic pathway of neuroendocrine tumors, has been proposed for radionuclide imaging of neuroendocrine tumors. The results of scintigraphic examinations reflect the pathologic features and tumor metabolic properties, allowing the in vivo characterization of the disease. In this article, the influence of both cellular differentiation and tumor grade in the scintigraphic pattern is reviewed according to the literature data. The relationship between nuclear imaging results and prognosis is also discussed. Despite the existence of a relationship between the results of scintigraphic imaging and cellular differentiation, tumor grade and patient outcome, the mechanism explaining the variability of the results needs further investigation. PMID:22743056

  6. RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

    PubMed Central

    Duewell, P; Steger, A; Lohr, H; Bourhis, H; Hoelz, H; Kirchleitner, S V; Stieg, M R; Grassmann, S; Kobold, S; Siveke, J T; Endres, S; Schnurr, M

    2014-01-01

    Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the production of type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction. Here, we investigated immunogenic consequences of RLH-induced tumor cell death. Treatment of murine pancreatic cancer cell lines with RLH ligands induced production of type I IFN and proinflammatory cytokines. In addition, tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of HMGB1 and translocation of calreticulin to the outer cell membrane. RLH-activated tumor cells led to activation of dendritic cells (DCs), which was mediated by tumor-derived type I IFN, whereas TLR, RAGE or inflammasome signaling was dispensable. Importantly, CD8α+ DCs effectively engulfed apoptotic tumor material and cross-presented tumor-associated antigen to naive CD8+ T cells. In comparison, tumor cell death mediated by oxaliplatin, staurosporine or mechanical disruption failed to induce DC activation and antigen presentation. Tumor cells treated with sublethal doses of RLH ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis. Vaccination of mice with RLH-activated tumor cells induced protective antitumor immunity in vivo. In addition, MDA5-based immunotherapy led to effective tumor control of established pancreatic tumors. In summary, RLH ligands induce a highly immunogenic form of tumor cell death linking innate and adaptive immunity. PMID:25012502

  7. Efforts to improve the diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration for pancreatic tumors

    PubMed Central

    Yamabe, Akane; Irisawa, Atsushi; Bhutani, Manoop S.; Shibukawa, Goro; Fujisawa, Mariko; Sato, Ai; Yoshida, Yoshitsugu; Arakawa, Noriyuki; Ikeda, Tsunehiko; Igarashi, Ryo; Maki, Takumi; Yamamoto, Shogo

    2016-01-01

    Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is widely used to obtain a definitive diagnosis of pancreatic tumors. Good results have been reported for its diagnostic accuracy, with high sensitivity and specificity of around 90%; however, technological developments and adaptations to improve it still further are currently underway. The endosonographic technique can be improved when several tips and tricks useful to overcome challenges of EUS-FNA are known. This review provides various techniques and equipment for improvement in the diagnostic accuracy in EUS-FNA. PMID:27503153

  8. Lung tumor tracking, trajectory reconstruction, and motion artifact removal using rotational cone-beam projections

    NASA Astrophysics Data System (ADS)

    Lewis, John Henry

    Management of lung tumor motion is a challenging and important problem for modern, highly conformal radiotherapy. Poorly managed tumor motion can lead to imaging artifacts, poor target coverage, and unnecessarily high dose to normal tissues. The goals of this dissertation are to develop a real-time localization algorithm that is applicable to rotational cone-beam projections acquired during regular (˜60 seconds) cone-beam computed tomography (CBCT) scans, and to use these tracking results to reconstruct a tumor's trajectory, shape and size immediately prior to treatment. Direct tumor tracking is performed via a multiple template matching algorithm where templates are derived from digitally reconstructed radiographs (DRRs) generated from four-dimensional computed tomography (4DCT). Three-dimensional (3D) tumor trajectories are reconstructed by binning twodimensional (2D) tracking results according to their corresponding respiratory phases. Within each phase bin a point is calculated approximating the 3D tumor position, resulting in a 3D phase-binned trajectory. These 3D trajectories are used to construct motion blurring functions which are in turn used to remove motion blurring artifacts from reconstructed CBCT volumes with a deconvolution algorithm. Finally, the initial direct tracking algorithm is combined with diaphragm-based tracking to develop a more robust "combined" tracking algorithm. Respiratory motion phantoms (digital and physical), and example patient cases were used to test each technique. Direct tumor tracking performed well for both phantom cases, with sub-millimeter root mean square error (e rms) in the axial and tangential imager dimensions. In patient studies the algorithm performed well for many angles, but exhibited large errors for some projections. Accurate 3D trajectories were successfully reconstructed for patients and phantoms. Errors in reconstructed trajectories were smaller than the errors in the direct tracking results in all cases. The

  9. Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation

    PubMed Central

    Roy, Nilotpal; Malik, Shivani; Villanueva, Karina E.; Urano, Atsushi; Lu, Xinyuan; Von Figura, Guido; Seeley, E. Scott; Dawson, David W.; Collisson, Eric A.

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a “ductal-like” state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo “ductal retrogression” to form IPMN-PDA. We further identify critical antagonistic roles for Brahma-related gene 1 (Brg1), a catalytic subunit of the SWI/SNF complexes, during IPMN-PDA development. In mature duct cells, Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We further show that JQ1, a drug that is currently being tested in clinical trials for hematological malignancies, impairs PDA tumorigenesis by both mimicking some and inhibiting other Brg1-mediated functions. In summary, our study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA. PMID:25792600

  10. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation

    PubMed Central

    Fokas, E; Prevo, R; Pollard, J R; Reaper, P M; Charlton, P A; Cornelissen, B; Vallis, K A; Hammond, E M; Olcina, M M; Gillies McKenna, W; Muschel, R J; Brunner, T B

    2012-01-01

    Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC. PMID:23222511

  11. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation.

    PubMed

    Fokas, E; Prevo, R; Pollard, J R; Reaper, P M; Charlton, P A; Cornelissen, B; Vallis, K A; Hammond, E M; Olcina, M M; Gillies McKenna, W; Muschel, R J; Brunner, T B

    2012-01-01

    Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC. PMID:23222511

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

    PubMed

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

    2013-06-01

    Studies in animal models of cancer have demonstrated that targeting tumor metabolism can be an effective anticancer strategy. Previously, we showed that inhibition of glucose metabolism by the pyruvate analog, 3-bromopyruvate (3-BrPA), induces anticancer effects both in vitro and in vivo. We have also documented that intratumoral delivery of 3-BrPA affects tumor growth in a subcutaneous tumor model of human liver cancer. However, the efficacy of such an approach in a clinically relevant orthotopic tumor model has not been reported. Here, we investigated the feasibility of ultrasound (US) image-guided delivery of 3-BrPA in an orthotopic mouse model of human pancreatic cancer and evaluated its therapeutic efficacy. In vitro, treatment of Panc-1 cells with 3-BrPA resulted in a dose-dependent decrease in cell viability. The loss of viability correlated with a dose-dependent decrease in the intracellular ATP level and lactate production confirming that disruption of energy metabolism underlies these 3-BrPA-mediated effects. In vivo, US-guided delivery of 3-BrPA was feasible and effective as demonstrated by a marked decrease in tumor size on imaging. Further, the antitumor effect was confirmed by (1) a decrease in the proliferative potential by Ki-67 immunohistochemical staining and (2) the induction of apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphospate nick end labeling staining. We therefore demonstrate the technical feasibility of US-guided intratumoral injection of 3-BrPA in a mouse model of human pancreatic cancer as well as its therapeutic efficacy. Our data suggest that this new therapeutic approach consisting of a direct intratumoral injection of antiglycolytic agents may represent an exciting opportunity to treat patients with pancreas cancer. PMID:23529644

  13. Focused Ultrasound Surgery Control Using Local Harmonic Motion: VX2 Tumor Study

    NASA Astrophysics Data System (ADS)

    Curiel, Laura; Chopra, Rajiv; Goertz, David; Hynynen, Kullervo

    2009-04-01

    The objective of this study was to develop a real-time method for controlling focused ultrasound surgery using ultrasound imaging. The approach uses measurements of localized harmonic motion (LHM) in order to perform controlled FUS exposures by detecting changes in the elastic properties of tissues during coagulation. Methods: Nine New Zealand rabbits with VX2 tumors implanted in the thigh were used for this study. LHM was generated within the tumors by periodic induction of radiation force using a FUS transducer (80-mm focal length, 100-mm diameter, 20-mm central hole, 1.485-MHz). Tissue motion was tracked by collecting and cross-correlating RF signals during the motion using a separate diagnostic transducer (3-kHz PRF, 5-MHz). After locating the tumor in MR images, a series of sonications were performed to treat the tumors using a reduction in LHM amplitude to control the exposure. Results: LHM was successfully used to control the sonications. A LHM amplitude threshold value was determined at which changes were considered significant and then the exposure was started and stopped when the LHM amplitude dropped below the threshold. The appearance of a lesion was then verified by MRI. The feasibility of LHM measurements to control FUS exposure was validated.

  14. Focused Ultrasound Surgery Control Using Local Harmonic Motion: VX2 Tumor Study

    SciTech Connect

    Curiel, Laura; Chopra, Rajiv; Goertz, David; Hynynen, Kullervo

    2009-04-14

    The objective of this study was to develop a real-time method for controlling focused ultrasound surgery using ultrasound imaging. The approach uses measurements of localized harmonic motion (LHM) in order to perform controlled FUS exposures by detecting changes in the elastic properties of tissues during coagulation. Methods: Nine New Zealand rabbits with VX2 tumors implanted in the thigh were used for this study. LHM was generated within the tumors by periodic induction of radiation force using a FUS transducer (80-mm focal length, 100-mm diameter, 20-mm central hole, 1.485-MHz). Tissue motion was tracked by collecting and cross-correlating RF signals during the motion using a separate diagnostic transducer (3-kHz PRF, 5-MHz). After locating the tumor in MR images, a series of sonications were performed to treat the tumors using a reduction in LHM amplitude to control the exposure. Results: LHM was successfully used to control the sonications. A LHM amplitude threshold value was determined at which changes were considered significant and then the exposure was started and stopped when the LHM amplitude dropped below the threshold. The appearance of a lesion was then verified by MRI. The feasibility of LHM measurements to control FUS exposure was validated.

  15. Recovery of biological motion perception and network plasticity after cerebellar tumor removal.

    PubMed

    Sokolov, Arseny A; Erb, Michael; Grodd, Wolfgang; Tatagiba, Marcos S; Frackowiak, Richard S J; Pavlova, Marina A

    2014-10-01

    Visual perception of body motion is vital for everyday activities such as social interaction, motor learning or car driving. Tumors to the left lateral cerebellum impair visual perception of body motion. However, compensatory potential after cerebellar damage and underlying neural mechanisms remain unknown. In the present study, visual sensitivity to point-light body motion was psychophysically assessed in patient SL with dysplastic gangliocytoma (Lhermitte-Duclos disease) to the left cerebellum before and after neurosurgery, and in a group of healthy matched controls. Brain activity during processing of body motion was assessed by functional magnetic resonance imaging (MRI). Alterations in underlying cerebro-cerebellar circuitry were studied by psychophysiological interaction (PPI) analysis. Visual sensitivity to body motion in patient SL before neurosurgery was substantially lower than in controls, with significant improvement after neurosurgery. Functional MRI in patient SL revealed a similar pattern of cerebellar activation during biological motion processing as in healthy participants, but located more medially, in the left cerebellar lobules III and IX. As in normalcy, PPI analysis showed cerebellar communication with a region in the superior temporal sulcus, but located more anteriorly. The findings demonstrate a potential for recovery of visual body motion processing after cerebellar damage, likely mediated by topographic shifts within the corresponding cerebro-cerebellar circuitry induced by cerebellar reorganization. The outcome is of importance for further understanding of cerebellar plasticity and neural circuits underpinning visual social cognition. PMID:25017648

  16. miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor

    SciTech Connect

    Park, Jong-Kook; Henry, Jon C.; Jiang, Jinmai; Esau, Christine; Gusev, Yuriy; Lerner, Megan R.; Postier, Russell G.; Brackett, Daniel J.; Schmittgen, Thomas D.

    2011-03-25

    Research highlights: {yields} The expression of miR-132 and miR-212 are significantly increased in pancreatic cancer. {yields} miR-132 and miR-212 target the tumor suppressor pRb, resulting in enhanced proliferation. {yields} miR-132 and miR-212 expression is increased by a {beta}2 adrenergic receptor agonist, suggesting a novel mechanism for pancreatic cancer progression. -- Abstract: Numerous microRNAs (miRNAs) are reported as differentially expressed in cancer, however the consequence of miRNA deregulation in cancer is unknown for many miRNAs. We report that two miRNAs located on chromosome 17p13, miR-132 and miR-212, are over-expressed in pancreatic adenocarcinoma (PDAC) tissues. Both miRNAs are predicted to target the retinoblastoma tumor suppressor, Rb1. Validation of this interaction was confirmed by luciferase reporter assay and western blot in a pancreatic cancer cell line transfected with pre-miR-212 and pre-miR-132 oligos. Cell proliferation was enhanced in Panc-1 cells transfected with pre-miR-132/-212 oligos. Conversely, antisense oligos to miR-132/-212 reduced cell proliferation and caused a G{sub 2}/M cell cycle arrest. The mRNA of a number of E2F transcriptional targets were increased in cells over expressing miR-132/-212. Exposing Panc-1 cells to the {beta}2 adrenergic receptor agonist, terbutaline, increased the miR-132 and miR-212 expression by 2- to 4-fold. We report that over-expression of miR-132 and miR-212 result in reduced pRb protein in pancreatic cancer cells and that the increase in cell proliferation from over-expression of these miRNAs is likely due to increased expression of several E2F target genes. The {beta}2 adrenergic pathway may play an important role in this novel mechanism.

  17. Feasibility of using respiratory correlated mega voltage cone beam computed tomography to measure tumor motion.

    PubMed

    Chen, Mingqing; Siochi, R Alfredo

    2011-01-01

    The purpose of this study was to test the feasibility of using respiratory correlated mega voltage cone-beam computed tomography (MVCBCT), taken during patient localization, to quantify the size and motion of lung tumors. An imaging phantom was constructed of a basswood frame embedded with six different-sized spherical pieces of paraffin wax. The Quasar respiratory motion phantom was programmed to move the imaging phantom using typical respiratory motion. The moving imaging phantom was scanned using various MVCBCT imaging parameters, including two beam line types, two protocols with different ranges of rotation and different imaging doses. A static phantom was also imaged as a control. For all the 3D volumetric images, the contours of the six spherical inserts were measured manually. Compared with the nominal sphere diameter, the average relative error in the size of the respiratory correlated MVCBCT spheres ranged from 5.3% to 12.6% for the four largest spheres, ranging in size from 3.6 cc to 29 cc. Larger errors were recorded for the two smallest inserts. The average relative error in motion was 5.1% smaller than the programmed amplitude of 3.0 cm. We are able to conclude that it is feasible to use respiratory correlated MVCBCT to quantify tumor motion for lung cancer patients. PMID:21587196

  18. Pancreatic Cancer Genetics

    PubMed Central

    Amundadottir, Laufey T.

    2016-01-01

    Although relatively rare, pancreatic tumors are highly lethal [1]. In the United States, an estimated 48,960 individuals will be diagnosed with pancreatic cancer and 40,560 will die from this disease in 2015 [1]. Globally, 337,872 new pancreatic cancer cases and 330,391 deaths were estimated in 2012 [2]. In contrast to most other cancers, mortality rates for pancreatic cancer are not improving; in the US, it is predicted to become the second leading cause of cancer related deaths by 2030 [3, 4]. The vast majority of tumors arise in the exocrine pancreas, with pancreatic ductal adenocarcinoma (PDAC) accounting for approximately 95% of tumors. Tumors arising in the endocrine pancreas (pancreatic neuroendocrine tumors) represent less than 5% of all pancreatic tumors [5]. Smoking, type 2 diabetes mellitus (T2D), obesity and pancreatitis are the most consistent epidemiological risk factors for pancreatic cancer [5]. Family history is also a risk factor for developing pancreatic cancer with odds ratios (OR) ranging from 1.7-2.3 for first-degree relatives in most studies, indicating that shared genetic factors may play a role in the etiology of this disease [6-9]. This review summarizes the current knowledge of germline pancreatic cancer risk variants with a special emphasis on common susceptibility alleles identified through Genome Wide Association Studies (GWAS). PMID:26929738

  19. Clinical study on the influence of motion and other factors on stereotactic radiotherapy in the treatment of adrenal gland tumor

    PubMed Central

    Wang, Jingsheng; Li, Fengtong; Dong, Yang; Song, Yongchun; Yuan, Zhiyong

    2016-01-01

    Background The aim of this study was to investigate the adrenal tumor motion law and influence factors in the treatment of adrenal gland tumor and provide a reference value basis for determining the planning target volume margins for therapy. Materials and methods The subjects considered in this study were 38 adrenal tumor patients treated with CyberKnife with the placement of 45 gold fiducials. Fiducials were implanted into each adrenal tumor using β-ultrasonic guidance. Motion amplitudes of gold fiducials were measured with a Philips SLS simulator and motion data in the left–right, anterior–posterior, and cranio–caudal directions were obtained. Multiple linear regression models were used to analyze influencing factors. t-Test was used for motion amplitude comparison of different tumor locations along the z-axis. Results The motion distances were 0.1–0.4 cm (0.27±0.07 cm), 0.1–0.5 cm (0.31±0.11 cm), and 0.5–1.2 cm (0.87±0.21 cm) along the x-, y-, and z-axes, respectively. Motion amplitude along the z-axis may be affected by tumor location, but movement along the other axes was not affected by age, height, body mass, location, and size. Conclusion The maximum motion distance was along the z-axis. Therefore, this should be the main consideration when defining the planning target volume safety margin. Due to the proximity of the liver, adrenal gland tumor motion amplitude was smaller on the right than the left. This study analyzed adrenal tumor motion amplitude data to evaluate how motion and other factors influence the treatment of adrenal tumor with a goal of providing a reference for stereotactic radiotherapy boundary determination. PMID:27486331

  20. Quantifying Rigid and Nonrigid Motion of Liver Tumors During Stereotactic Body Radiation Therapy

    SciTech Connect

    Xu, Qianyi; Hanna, George; Grimm, Jimm; Kubicek, Gregory; Pahlajani, Niraj; Asbell, Sucha; Fan, Jiajin; Chen, Yan; LaCouture, Tamara

    2014-09-01

    Purpose: To quantify rigid and nonrigid motion of liver tumors using reconstructed 3-dimensional (3D) fiducials from stereo imaging during CyberKnife-based stereotactic body radiation therapy (SBRT). Methods and Materials: Twenty-three liver patients treated with 3 fractions of SBRT were used in this study. After 2 orthogonal kilovoltage images were taken during treatment, the 3D locations of the fiducials were generated by the CyberKnife system and validated using geometric derivations. A total of 4824 pairs of kilovoltage images from start to end of treatment were analyzed. For rigid motion, the rotational angles and translational shifts were reported by aligning 3D fiducial groups from different image pairs, using least-squares fitting. For nonrigid motion, we quantified interfractional tumor volume variations by using the proportional volume derived from the fiducials, which correlates to the sum of interfiducial distances. The individual fiducial displacements were also reported (1) after rigid corrections and (2) without angle corrections. Results: The proportional volume derived by the fiducials demonstrated a volume-increasing trend in the second (101.9% ± 3.6%) and third (101.0 ± 5.9%) fractions among most patients, possibly due to radiation-induced edema. For all patients, the translational shifts in left-right, anteroposterior, and superoinferior directions were 2.1 ± 2.3 mm, 2.9 ± 2.8 mm, and 6.4 ± 5.5 mm, respectively. The greatest translational shifts occurred in the superoinferior direction, likely due to respiratory motion from the diaphragm. The rotational angles in roll, pitch, and yaw were 1.2° ± 1.8°, 1.8° ± 2.4°, and 1.7° ± 2.1°, respectively. The 3D individual fiducial displacements with rigid corrections were 0.2 ± 0.2 mm and increased to 0.5 ± 0.4 mm without rotational corrections. Conclusions: Accurate 3D locations of internal fiducials can be reconstructed from stereo imaging during treatment. As an

  1. Major Vascular Abutment, Involvement or Encasement is not a Contraindication to Pancreatic Endocrine Tumor Resection

    PubMed Central

    Norton, Jeffrey A.; Harris, E. John; Chen, Yijun; Visser, Brendan C; Poultsides, George A; Kunz, Pamela C.; Fisher, George A; Jensen, Robert.T.

    2010-01-01

    Background There is considerable controversy about the treatment of patients with malignant functional or nonfunctional pancreatic endocrine tumors (PETs). Aggressive surgery with dissection and/or reconstruction of major vascular structures is a potentially efficacious antitumor therapy, but is rarely performed, and considered a contraindication to surgery by many. Hypothesis Aggressive resection of locally advanced PETs in which preoperative studies suggest major vascular involvement can be performed with acceptable morbidity and mortality rates and may lead to extended survival. Design The combined databases of the prospective NIH study on PETs (gastrinomas) (from 1982) and Stanford (all PETs)(from 2004) were queried. All patients with possible involvement of major vascular structures were reviewed and preoperative studies, operative findings and surgical results/outcomes correlated. Main Outcome Measures Surgical procedure, pathologic characteristics, complications, mortality rates, and disease-free and overall survival rates. Results Of 273 patients with PETs, 46 (17%) had preoperative CT evidence of major vascular involvement. There were 21 men (45%). Mean age was 42 years (range 24-76). 32 (57%) had functional tumors with 30 gastrinomas and 2 glucagonomas; the remainder (n=14) had nonfunctional PETs. 12 patients (26%) had MEN-1. 44 of 46 underwent surgery. The mean size for the primary PET on preoperative CT was 5.8 cm. The involved major vessel was as follows: portal vein (n=20, 43%), SMV or SMA (n=16, 35%), IVC (n=4, 9%), splenic vein (n=4, 9%) and heart (n=2, 4%). 42 (91%) patients had PET removed: 12 (27%) primary only, 30 (68%) with lymph nodes, and 18 (41%) with liver metastases. PETs were removed by either enucleation (n=5, 12%) or resection (n=36, 86%). Resections included distal or subtotal pancreatectomy in 23 (55%), Whipple in 10 (23%) and total in 2 (5%). 19 (45%) patients had concomitant liver resection: 10 (23%) wedge resection and 9 (21

  2. Resolution of Hyperreninemia, Secondary Hyperaldosteronism, and Hypokalemia With 177Lu-DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy in a Patient With Pancreatic Neuroendocrine Tumor.

    PubMed

    Makis, William; McCann, Karey; Riauka, Terence A; McEwan, Alexander J B

    2015-11-01

    A 54-year-old woman presented with a history of nausea, vomiting, diarrhea, and recurrent episodes of severe hypokalemia requiring hospitalization. Imaging revealed a pancreatic mass with liver metastases, histologically confirmed to be a neuroendocrine tumor. Elevated active renin and aldosterone levels were identified, and the patient was treated with 4 induction cycles of Lu-DOTATATE, which resolved the diarrhea, nausea, and hypokalemia, and normalized the renin and aldosterone levels. After 3 additional maintenance Lu-DOTATATE treatments, the pancreatic tumor had decreased in size, was deemed operable, and was resected. She remains on maintenance Lu-DOTATATE therapy with progression-free survival of 45 months thus far. PMID:26359564

  3. Unusual suspects: pulmonary opportunistic infections masquerading as tumor metastasis in a patient with adrenocorticotropic hormone-producing pancreatic neuroendocrine cancer.

    PubMed

    Chowdry, Rajasree P; Bhimani, Chandar; Delgado, Maria A; Lee, Daniel J; Dayamani, Priya; Sica, Gabriel L; Owonikoko, Taofeek K

    2012-11-01

    Pancreatic neuroendocrine tumors (p-NETs) are a rare group of neoplasms but with increasing incidence. The atypical complications that arise in the setting of functional endocrine tumors are underreported and therefore have not received sufficient attention and the necessary mention in the oncology literature. The clinical implications of these complications pose management challenges starting with the difficulty in establishing diagnosis, accurate staging and optimal treatment of the primary process. We present the case of a middle-aged woman diagnosed with adrenocorticotropic hormone-producing carcinoma arising from the pancreas whose case was complicated by excessive uncontrolled hypercortisolism and reactivation of pulmonary opportunistic infections that confounded her management. We believe that this case illustration will be of value to practicing oncologists and other groups of physicians who are called upon to participate in the multidisciplinary treatment of these relatively rare but highly challenging cases. PMID:23118805

  4. Unusual suspects: pulmonary opportunistic infections masquerading as tumor metastasis in a patient with adrenocorticotropic hormone-producing pancreatic neuroendocrine cancer

    PubMed Central

    Chowdry, Rajasree P.; Bhimani, Chandar; Delgado, Maria A.; Lee, Daniel J.; Dayamani, Priya; Sica, Gabriel L.

    2012-01-01

    Pancreatic neuroendocrine tumors (p-NETs) are a rare group of neoplasms but with increasing incidence. The atypical complications that arise in the setting of functional endocrine tumors are underreported and therefore have not received sufficient attention and the necessary mention in the oncology literature. The clinical implications of these complications pose management challenges starting with the difficulty in establishing diagnosis, accurate staging and optimal treatment of the primary process. We present the case of a middle-aged woman diagnosed with adrenocorticotropic hormone-producing carcinoma arising from the pancreas whose case was complicated by excessive uncontrolled hypercortisolism and reactivation of pulmonary opportunistic infections that confounded her management. We believe that this case illustration will be of value to practicing oncologists and other groups of physicians who are called upon to participate in the multidisciplinary treatment of these relatively rare but highly challenging cases. PMID:23118805

  5. Rasfonin, a novel 2-pyrone derivative, induces ras-mutated Panc-1 pancreatic tumor cell death in nude mice

    PubMed Central

    Xiao, Z; Li, L; Li, Y; Zhou, W; Cheng, J; Liu, F; Zheng, P; Zhang, Y; Che, Y

    2014-01-01

    Rasfonin is a novel 2-pyrone derivative reported to induce apoptosis in ras-dependent cells. In this study, its effects on ras-mutated pancreatic cancer cells were investigated in vitro and in vivo. Two human pancreatic cancer cell lines Panc-1 (mutated K-ras) and BxPC-3 (wild-type K-ras) were selected to test the effects of rasfonin on cell proliferation, clone formation, migration and invasion in vitro. Immunoblotting was used to detect the expressions of EGFR–Ras–Raf–MEK–ERK signaling pathway proteins. Ras activity was measured using a pull-down ELISA kit and guanine exchange factor (GEF)/GTPase-activating proteins (GAP) activity was measured by [3H]-GDP radiometric ligand binding. For an in vivo study, CD1 nude mice bearing Panc-1 cells were treated with rasfonin or Salirasib (FTS). We found that rasfonin suppressed proliferation more strongly in Panc-1 cells (IC50=5.5 μM) than BxPC-3 cells (IC50=10 μM) in vitro. Clone formation, migration and invasion by Panc-1 cells were also reduced by rasfonin. Rasfonin had little effect on the farnesylation of Ras, but it strongly downregulated Ras activity and consequently phosphorylation of c-Raf/MEK/ERK. Further experiments indicated that rasfonin reduced Son of sevenless (Sos1) expression but did not alter GEF and GAP activities. The in vivo experiments also revealed that rasfonin (30 mg/kg) delayed the growth of xenograft tumors originating from Panc-1 cells. Tumor weight was ultimately decreased after 20 days of treatment of rasfonin. Rasfonin is a robust inhibitor of pancreatic cancers with the K-ras mutation. The reduction of Sos1 expression and the consequently depressed Ras–MAPK activity could be important in its anticancer activity. PMID:24853419

  6. Rasfonin, a novel 2-pyrone derivative, induces ras-mutated Panc-1 pancreatic tumor cell death in nude mice.

    PubMed

    Xiao, Z; Li, L; Li, Y; Zhou, W; Cheng, J; Liu, F; Zheng, P; Zhang, Y; Che, Y

    2014-01-01

    Rasfonin is a novel 2-pyrone derivative reported to induce apoptosis in ras-dependent cells. In this study, its effects on ras-mutated pancreatic cancer cells were investigated in vitro and in vivo. Two human pancreatic cancer cell lines Panc-1 (mutated K-ras) and BxPC-3 (wild-type K-ras) were selected to test the effects of rasfonin on cell proliferation, clone formation, migration and invasion in vitro. Immunoblotting was used to detect the expressions of EGFR-Ras-Raf-MEK-ERK signaling pathway proteins. Ras activity was measured using a pull-down ELISA kit and guanine exchange factor (GEF)/GTPase-activating proteins (GAP) activity was measured by [(3)H]-GDP radiometric ligand binding. For an in vivo study, CD1 nude mice bearing Panc-1 cells were treated with rasfonin or Salirasib (FTS). We found that rasfonin suppressed proliferation more strongly in Panc-1 cells (IC50=5.5 μM) than BxPC-3 cells (IC50=10 μM) in vitro. Clone formation, migration and invasion by Panc-1 cells were also reduced by rasfonin. Rasfonin had little effect on the farnesylation of Ras, but it strongly downregulated Ras activity and consequently phosphorylation of c-Raf/MEK/ERK. Further experiments indicated that rasfonin reduced Son of sevenless (Sos1) expression but did not alter GEF and GAP activities. The in vivo experiments also revealed that rasfonin (30 mg/kg) delayed the growth of xenograft tumors originating from Panc-1 cells. Tumor weight was ultimately decreased after 20 days of treatment of rasfonin. Rasfonin is a robust inhibitor of pancreatic cancers with the K-ras mutation. The reduction of Sos1 expression and the consequently depressed Ras-MAPK activity could be important in its anticancer activity. PMID:24853419

  7. Tumor Size on Abdominal MRI Versus Pathologic Specimen in Resected Pancreatic Adenocarcinoma: Implications for Radiation Treatment Planning

    SciTech Connect

    Hall, William A.; Mikell, John L.; Mittal, Pardeep; Colbert, Lauren; Prabhu, Roshan S.; Kooby, David A.; Nickleach, Dana; Hanley, Krisztina; Sarmiento, Juan M.; Ali, Arif N.; Landry, Jerome C.

    2013-05-01

    Purpose: We assessed the accuracy of abdominal magnetic resonance imaging (MRI) for determining tumor size by comparing the preoperative contrast-enhanced T1-weighted gradient echo (3-dimensional [3D] volumetric interpolated breath-hold [VIBE]) MRI tumor size with pathologic specimen size. Methods and Materials: The records of 92 patients who had both preoperative contrast-enhanced 3D VIBE MRI images and detailed pathologic specimen measurements were available for review. Primary tumor size from the MRI was independently measured by a single diagnostic radiologist (P.M.) who was blinded to the pathology reports. Pathologic tumor measurements from gross specimens were obtained from the pathology reports. The maximum dimensions of tumor measured in any plane on the MRI and the gross specimen were compared. The median difference between the pathology sample and the MRI measurements was calculated. A paired t test was conducted to test for differences between the MRI and pathology measurements. The Pearson correlation coefficient was used to measure the association of disparity between the MRI and pathology sizes with the pathology size. Disparities relative to pathology size were also examined and tested for significance using a 1-sample t test. Results: The median patient age was 64.5 years. The primary site was pancreatic head in 81 patients, body in 4, and tail in 7. Three patients were American Joint Commission on Cancer stage IA, 7 stage IB, 21 stage IIA, 58 stage IIB, and 3 stage III. The 3D VIBE MRI underestimated tumor size by a median difference of 4 mm (range, −34-22 mm). The median largest tumor dimensions on MRI and pathology specimen were 2.65 cm (range, 1.5-9.5 cm) and 3.2 cm (range, 1.3-10 cm), respectively. Conclusions: Contrast-enhanced 3D VIBE MRI underestimates tumor size by 4 mm when compared with pathologic specimen. Advanced abdominal MRI sequences warrant further investigation for radiation therapy planning in pancreatic adenocarcinoma before

  8. A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

    PubMed Central

    Sadanandam, Anguraj; Wullschleger, Stephan; Lyssiotis, Costas A.; Grötzinger, Carsten; Barbi, Stefano; Bersani, Samantha; Körner, Jan; Wafy, Ismael; Mafficini, Andrea; Lawlor, Rita T.; Simbolo, Michele; Asara, John M.; Bläker, Hendrik; Cantley, Lewis C.; Wiedenmann, Bertram; Scarpa, Aldo; Hanahan, Douglas

    2016-01-01

    Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation–enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities. SIGNIFICANCE This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy. PMID:26446169

  9. A case of pancreatic heterotopy of duodenal wall, intraductal papillary mucinous tumor and intraepithelial neoplasm of pancreas, papillary carcinoma of kidney in a single patient.

    PubMed

    Nobili, Cinzia; Franciosi, Claudio; Degrate, Luca; Caprotti, Roberto; Romano, Fabrizio; Perego, Elisa; Trezzi, Rosangela; Leone, Biagio Eugenio; Uggeri, Franco

    2006-01-01

    We report a case of the contemporaneous presence of two histologically different pancreatic neoplasms, one renal cancer and one embryogenic duodenal anomaly in a single patient. A 66-year-old man underwent ultrasound examination because of urinary disorders; a solid neoformation within the inferior pole of the left kidney was observed. Computed tomography confirmed the renal lesion, but also a heterogeneous mass within the pancreatic head appeared without bile ducts dilatation. Abdominal magnetic resonance revealed a multiloculated cystic component of the pancreatic mass. A second CT scan confirmed the renal and biliary findings, but it revealed a modest enlargement of the pancreatic asymptomatic mass. A resection of the left kidney inferior pole and a pylorus-preserving pancreaticoduodenectomy were performed. Histopathologic analysis of the surgical specimen revealed mild differentiated papillary renal carcinoma, intraductal papillary mucinous adenoma of the pancreatic head, foci of intraepithelial pancreatic neoplasm and pancreatic heterotopy of duodenal muscular and submucosal layers. The coexistence of several primaries and anomalies in one patient led us to suppose a genetic predisposition to different lesions, even in the absence of known familial genetic syndromes. The study of such cases may help to improve the investigation of molecular correlations and etiological factors of different solid tumors. Nowadays, surgery is the only effective cure. PMID:17168444

  10. High ROR2 expression in tumor cells and stroma is correlated with poor prognosis in pancreatic ductal adenocarcinoma

    PubMed Central

    Huang, Jianfei; Fan, Xiangjun; Wang, Xudong; Lu, Yuhua; Zhu, Huijun; Wang, Wei; Zhang, Shu; Wang, Zhiwei

    2015-01-01

    RTK-like orphan receptor 2 (ROR2) is overexpressed in several cancers and has tumorigenic activity. However, the expression of ROR2 and its functional and prognostic significance have yet to be evaluated in pancreatic ductal adenocarcinoma (PDAC). Quantitative real-time polymerase chain reaction was used to characterize the expression of ROR2 mRNA in PDAC, corresponding peritumoral tissues, and PDAC cell lines. Immunohistochemical analysis with tissue microarrays was used to evaluate ROR2 expression in PDAC and to investigate the relationship of this expression to clinicopathological factors and prognosis. The expression of ROR2 mRNA and protein was significantly higher in PDAC than in normal pancreatic tissues. High cytoplasmic ROR2 expression in cancer cells was significantly associated with a primary tumor, distant metastasis, and TNM stage, and high stromal ROR2 expression was significantly associated with regional lymph node metastasis and TNM stage. The Kaplan–Meier method and Cox regression analyses showed that high ROR2 expression in tumor cytoplasm or stromal cells was significantly associated with malignant attributes and reduced survival in PDAC. We present strong evidence that ROR2 could be used as an indicator of poor prognosis and could represent a novel therapeutic target for PDAC. PMID:26259918

  11. SELEX Aptamer Used as a Probe to Detect Circulating Tumor Cells in Peripheral Blood of Pancreatic Cancer Patients

    PubMed Central

    Zhang, Jinqiang; Li, Shaohua; Liu, Fang; Zhou, Lanping; Shao, Ningsheng; Zhao, Xiaohang

    2015-01-01

    Many studies have shown that the quantity and dynamics of circulating tumor cells (CTCs) in peripheral blood of patients afflicted with solid tumours have great relevance in therapeutic efficacy and prognosis. Different methods based on various strategies have been developed to isolate and identify CTCs, but their efficacy needs to be improved because of the rarity and complexity of CTCs. This study was designed to examine the possibility of using a SELEX aptamer (BC-15) as a probe to identify rare CTCs out of background nucleated cells. Aptamer BC-15 was selected from a random oligonucleotide library screened against human breast cancer tissue. Fluorescence staining showed that BC-15 had a high affinity for nuclei of human cancer cell lines of various origins as well as CTCs isolated from pancreatic cancer patients, whereas its binding capacity for non-tumor breast epithelial cells and leukocytes was almost undetectable. BC-15+/CD45- cells in cancer patient blood were also found to be cytokeratins 18-positive and aneuploid by immunofluorescence staining and fluorescent in situ hybridization, respectively. Finally, the aptamer method was compared with the well-established anti-cytokeratin method using 15 pancreatic cancer patient blood samples, and enumeration indicated no difference between these two methods. Our study establishes a novel way to identify CTCs by using a synthetic aptamer probe. This new approach is comparable with the anti-cytokeratin-based CTC identification method. PMID:25799539

  12. Distal Pancreatectomy With En Bloc Resection of the Celiac Trunk for Extended Pancreatic Tumor Disease: An Interdisciplinary Approach

    SciTech Connect

    Denecke, Timm; Andreou, Andreas; Podrabsky, Petr; Grieser, Christian; Warnick, Peter; Bahra, Marcus; Klein, Fritz; Hamm, Bernd; Neuhaus, Peter; Glanemann, Matthias

    2011-10-15

    Purpose: Infiltration of the celiac trunk by adenocarcinoma of the pancreatic body has been considered a contraindication for surgical treatment, thus resulting in a very poor prognosis. The concept of distal pancreatectomy with resection of the celiac trunk offers a curative treatment option but implies the risk of relevant hepatic or gastric ischemia. We describe initial experiences in a small series of patients with left celiacopancreatectomy with or without angiographic preconditioning of arterial blood flow to the stomach and the liver. Materials and Methods: Between January 2007 and October 2009, six patients underwent simultaneous resection of the celiac trunk for adenocarcinoma of the pancreatic body involving the celiac axis. In four of these cases, angiographic occlusion of the celiac trunk before surgery was performed to enhance collateral flow from the gastroduodenal artery. Radiologic and surgical procedures, findings, and outcome were analyzed retrospectively. Results: Complete tumor removal (R0) succeeded in two patients, whereas four patients underwent R1-tumor resection. After surgery, one of the two patients without angiographic preparation experienced an ischemic stomach perforation 1 week after surgery. The other patient died from severe bleeding from an ischemic gastric ulcer. Of the four patients with celiac trunk embolization, none presented ischemic complications after surgery. Mean survival was 371 days. Conclusion: In this small series, ischemic complications after celiacopancreatectomy occurred only in those patients who did not receive preoperative celiac trunk embolization.

  13. SU-E-J-60: Evaluation of Temporal Lag in Radiotherapy Gating for Tumor Motion Trajectories

    SciTech Connect

    Belcher, AH; McCabe, B; Wiersma, RD

    2015-06-15

    Purpose: Evaluating timing differences between LINAC beam ON/OFF and the estimation of tumor positioning using gating systems is essential for establishing confidence when treating with gating during radiotherapy, and is an annual requirement of TG-142. Temporal discrepancies between the trajectories of external marker surrogates and beam delivery may vary depending upon the type of external marker motion, which is quantified in this work for several trajectories. Methods: A precise robotic 3D motion stage performed several trajectories typically used for gating phantoms, including sinusoidal and Lujan-type motion; a commercial respiratory motion simulator was also employed. The true motions were monitored using variable resistors. The beam ON/OFF was controlled separately by two RPM (Varian) systems, an integrated version delivered by a Varian Truebeam LINAC and version 1.6 delivered by a Varian Trilogy, and measured using a diode. The resistor and diode signals were read by a multichannel digital oscilloscope, and timing differences between beam ON/OFF as measured by the diode and the phantom motion were determined using a peak detection algorithm. Results: Timing differences between beam ON/OFF and 3D stage motion peaks (diode—true motion timing) were computed to be 79.4 & 57.7ms for sinusoidal motion and 109.1 & 63.6ms for Lujan-type motion on the Truebeam LINAC, for beam ON and OFF, respectively. Timing differences for the Trilogy LINAC were 34.4 & 55.2ms for the sinusoidal motion and 29.0 & 26.3ms for the Lujan-type motion, for beam ON and OFF, respectively. With the commercial motion simulator, the timing differences were found to be −9ms and −78ms for beam ON/OFF, respectively, with the Truebeam, and −97.6ms and −60.9ms for beam ON/OFF, respectively, with the Trilogy. Conclusion: Setup-dependent temporal lags were found using this methodology. These discrepancies have the potential to influence quality assurance on gating systems and ultimately

  14. Ligand stimulation of ErbB4 and a constitutively-active ErbB4 mutant result in different biological responses in human pancreatic tumor cell lines

    SciTech Connect

    Mill, Christopher P.; Gettinger, Kathleen L.; Riese, David J.

    2011-02-15

    Pancreatic cancer is the fourth leading cause of cancer death in the United States. Indeed, it has been estimated that 37,000 Americans will die from this disease in 2010. Late diagnosis, chemoresistance, and radioresistance of these tumors are major reasons for poor patient outcome, spurring the search for pancreatic cancer early diagnostic and therapeutic targets. ErbB4 (HER4) is a member of the ErbB family of receptor tyrosine kinases (RTKs), a family that also includes the Epidermal Growth Factor Receptor (EGFR/ErbB1/HER1), Neu/ErbB2/HER2, and ErbB3/HER3. These RTKs play central roles in many human malignancies by regulating cell proliferation, survival, differentiation, invasiveness, motility, and apoptosis. In this report we demonstrate that human pancreatic tumor cell lines exhibit minimal ErbB4 expression; in contrast, these cell lines exhibit varied and in some cases abundant expression and basal tyrosine phosphorylation of EGFR, ErbB2, and ErbB3. Expression of a constitutively-dimerized and -active ErbB4 mutant inhibits clonogenic proliferation of CaPan-1, HPAC, MIA PaCa-2, and PANC-1 pancreatic tumor cell lines. In contrast, expression of wild-type ErbB4 in pancreatic tumor cell lines potentiates stimulation of anchorage-independent colony formation by the ErbB4 ligand Neuregulin 1{beta}. These results illustrate the multiple roles that ErbB4 may be playing in pancreatic tumorigenesis and tumor progression.

  15. Six Degrees-of-Freedom Prostate and Lung Tumor Motion Measurements Using Kilovoltage Intrafraction Monitoring

    SciTech Connect

    Huang, Chen-Yu; Tehrani, Joubin Nasehi; Ng, Jin Aun; Booth, Jeremy; Keall, Paul

    2015-02-01

    Purpose: Tumor positional uncertainty has been identified as a major issue that deteriorates the efficacy of radiation therapy. Tumor rotational movement, which is not well understood, can result in significant geometric and dosimetric inaccuracies. The objective of this study was to measure 6 degrees-of-freedom (6 DoF) prostate and lung tumor motion, focusing on the more novel rotation, using kilovoltage intrafraction monitoring (KIM). Methods and Materials: Continuous kilovoltage (kV) projections of tumors with gold fiducial markers were acquired during radiation therapy for 267 fractions from 10 prostate cancer patients and immediately before or after radiation therapy for 50 fractions from 3 lung cancer patients. The 6 DoF motion measurements were determined from the individual 3-dimensional (3D) marker positions, after using methods to reject spurious and smooth noisy data, using an iterative closest point algorithm. Results: There were large variations in the magnitude of the tumor rotation among different fractions and patients. Various rotational patterns were observed. The average prostate rotation angles around the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) axes were 1.0 ± 5.0°, 0.6 ± 3.3°, and 0.3 ± 2.0°, respectively. For 35% of the time, the prostate rotated more than 5° about the LR axis, indicating the need for intrafractional adaptation during radiation delivery. For lung patients, the average LR, SI, and AP rotation angles were 0.8 ± 4.2°, −0.8 ± 4.5°, and 1.7 ± 3.1°, respectively. For about 30% of the time, the lung tumors rotated more than 5° around the SI axis. Respiration-induced rotation was detected in 2 of the 3 lung patients. Conclusions: The prostate and lung tumors were found to undergo rotations of more than 5° for about a third of the time. The lung tumor data represent the first 6 DoF tumor motion measured by kV images. The 6 DoF KIM method can enable rotational and translational

  16. Imaging the distribution of an antibody-drug conjugate constituent targeting mesothelin with 89Zr and IRDye 800CW in mice bearing human pancreatic tumor xenografts

    PubMed Central

    ter Weele, Eva J.; van Scheltinga, Anton G.T. Terwisscha; Kosterink, Jos G.W.; Pot, Linda; Vedelaar, Silke R.; Lamberts, Laetitia E.; Williams, Simon P.; Hooge, Marjolijn N. Lub-de; de Vries, Elisabeth G.E.

    2015-01-01

    Mesothelin is a tumor differentiation antigen expressed by epithelial tumors, including pancreatic cancer. Currently, mesothelin is being targeted with an antibody-drug conjugate (ADC) consisting of a mesothelin-specific antibody coupled to a highly potent chemotherapeutic drug. Considering the toxicity of the ADC and reduced accessibility of pancreatic tumors, non-invasive imaging could provide necessary information. We therefore developed a zirconium-89 (89Zr) labeled anti-mesothelin antibody (89Zr-AMA) to study its biodistribution in human pancreatic tumor bearing mice. Biodistribution and dose-finding of 89Zr-AMA were studied 144 h after tracer injection in mice with subcutaneously xenografted HPAC. MicroPET imaging was performed 24, 72 and 144 h after tracer injection in mice bearing HPAC or Capan-2. Tumor uptake and organ distribution of 89Zr-AMA were compared with nonspecific 111In-IgG. Biodistribution analyses revealed a dose-dependent 89Zr-AMA tumor uptake. Tumor uptake of 89Zr-AMA was higher than 111In-IgG using the lowest tracer dose. MicroPET showed increased tumor uptake over 6 days, whereas activity in blood pool and other tissues decreased. Immunohistochemistry showed that mesothelin was expressed by the HPAC and CAPAN-2 tumors and fluorescence microscopy revealed that AMA-800CW was present in tumor cell cytoplasm. 89Zr-AMA tumor uptake is antigen-specific in mesothelin-expressing tumors. 89Zr-AMA PET provides non-invasive, real-time information about AMA distribution and tumor targeting. PMID:26536664

  17. A Fast Neural Network Approach to Predict Lung Tumor Motion during Respiration for Radiation Therapy Applications

    PubMed Central

    Slama, Matous; Benes, Peter M.; Bila, Jiri

    2015-01-01

    During radiotherapy treatment for thoracic and abdomen cancers, for example, lung cancers, respiratory motion moves the target tumor and thus badly affects the accuracy of radiation dose delivery into the target. A real-time image-guided technique can be used to monitor such lung tumor motion for accurate dose delivery, but the system latency up to several hundred milliseconds for repositioning the radiation beam also affects the accuracy. In order to compensate the latency, neural network prediction technique with real-time retraining can be used. We have investigated real-time prediction of 3D time series of lung tumor motion on a classical linear model, perceptron model, and on a class of higher-order neural network model that has more attractive attributes regarding its optimization convergence and computational efficiency. The implemented static feed-forward neural architectures are compared when using gradient descent adaptation and primarily the Levenberg-Marquardt batch algorithm as the ones of the most common and most comprehensible learning algorithms. The proposed technique resulted in fast real-time retraining, so the total computational time on a PC platform was equal to or even less than the real treatment time. For one-second prediction horizon, the proposed techniques achieved accuracy less than one millimeter of 3D mean absolute error in one hundred seconds of total treatment time. PMID:25893194

  18. Intrafraction tumor motion management techniques in imaging, treatment planning, and IMRT delivery

    NASA Astrophysics Data System (ADS)

    Ehler, Eric Drew

    Anatomic motion can affect the radiation treatment of disease sites in the thorax and abdomen. With four dimensional (4D) imaging modalities, respiratory motion can be defined on a patient specific basis. From 4D data sets, radiotherapy techniques can be devised to account for tissue motion. Systematic and random uncertainties must be characterized for each 4D imaging modality utilized. Some modalities, such as 4D-CT, require multiple motion trajectories in order to fully define the uncertainties associated with the imaging system. This is investigated in this work for a clinical 4D-CT scanning protocol and the methods used can be applied to any 4D imaging modality. Once all of the relevant tissues and their associated motion have been defined, with corrections to account for any associated uncertainties in the 4D data sets, treatment plans can be generated. For lung cancer, unique challenges arise when inverse planning is used, typically in the case of IMRT, because density differences between lung tissue and other tissues can result in quite different dose distributions. Because inverse planning is an optimization algorithm, the degree of optimization is dependent on the input parameters. One important input factor is the image set that is used for the dose calculation. For three image sets supplied to a commercial inverse planning algorithm (Average Image and an exhale phase image with motion envelope defined from a maximum intensity projection image, both with and without a density override to the motion envelope), dose calculated on the Average Image was found to be in best agreement with the dose calculated on the 4D-CT. Finally, when IMRT is delivered to mobile tumors, it is possible for the dose to the tumor to vary from treatment to treatment. Therefore, numerous methods have been investigated in order to reduce this variation. A computer simulation algorithm has been developed to predict the variation on a two spatial dimension plane and comparisons are

  19. Mechanoregulatory tumor-stroma crosstalk in pancreatic cancer: Measurements of the effects of extracellular matrix mechanics on tumor growth behavior, and vice-versa, to inform therapeutics

    NASA Astrophysics Data System (ADS)

    Celli, Jonathan; Jones, Dustin; El-Hamidi, Hamid; Cramer, Gwendolyn; Hanna, William; Caide, Andrew; Jafari, Seyedehrojin

    The rheological properties of the extracellular matrix (ECM) have been shown to play key roles in regulating tumor growth behavior through mechanotranduction pathways. The role of the mechanical microenvironment may be particularly important tumors of the pancreas, noted for an abundance of rigid fibrotic stroma, implicated in therapeutic resistance. At the same time, cancer cells and their stromal partners (e.g. tumor associated fibroblasts) continually alter the mechanical microenvironment in response to extracellular physical and biochemical cues as part of a two-way mechanoregulatory dialog. Here, we describe experimental studies using 3D pancreatic cell cultures with customized mechanical properties, combined with optical microrheology to provide insight into tumor-driven matrix remodeling. Quantitative microscopy provides measurements of phenotypic changes accompanying systematic variation of ECM composition in collagen and laminin-rich basement membrane admixtures, while analysis of the trajectories of passive tracer particles embedded in ECM report dynamic changes in heterogeneity, microstructure and local shear modulus accompanying both ECM stiffening (fibrosis) processes, and ECM degradation near invading cells. We gratefully acknowledge funding from the National Cancer Institute, R00CA155045 (PI: Celli).

  20. SU-E-J-182: Reproducibility of Tumor Motion Probability Distribution Function in Stereotactic Body Radiation Therapy of Lung Using Real-Time Tumor-Tracking Radiotherapy System

    SciTech Connect

    Shiinoki, T; Hanazawa, H; Park, S; Takahashi, T; Shibuya, K; Kawamura, S; Uehara, T; Yuasa, Y; Koike, M

    2015-06-15

    Purpose: We aim to achieve new four-dimensional radiotherapy (4DRT) using the next generation real-time tumor-tracking (RTRT) system and flattening-filter-free techniques. To achieve new 4DRT, it is necessary to understand the respiratory motion of tumor. The purposes of this study were: 1.To develop the respiratory motion analysis tool using log files. 2.To evaluate the reproducibility of tumor motion probability distribution function (PDF) during stereotactic body RT (SBRT) of lung tumor. Methods: Seven patients having fiducial markers closely implanted to the lung tumor were enrolled in this study. The positions of fiducial markers were measured using the RTRT system (Mitsubishi Electronics Co., JP) and recorded as two types of log files during the course of SBRT. For each patients, tumor motion range and tumor motion PDFs in left-right (LR), anterior-posterior (AP) and superior-inferior (SI) directions were calculated using log files of all beams per fraction (PDFn). Fractional PDF reproducibility (Rn) was calculated as Kullback-Leibler (KL) divergence between PDF1 and PDFn of tumor motion. The mean of Rn (Rm) was calculated for each patient and correlated to the patient’s mean tumor motion range (Am). The change of Rm during the course of SBRT was also evluated. These analyses were performed using in-house developed software. Results: The Rm were 0.19 (0.07–0.30), 0.14 (0.07–0.32) and 0.16 (0.09–0.28) in LR, AP and SI directions, respectively. The Am were 5.11 mm (2.58–9.99 mm), 7.81 mm (2.87–15.57 mm) and 11.26 mm (3.80–21.27 mm) in LR, AP and SI directions, respectively. The PDF reproducibility decreased as the tumor motion range increased in AP and SI direction. That decreased slightly through the course of RT in SI direction. Conclusion: We developed the respiratory motion analysis tool for 4DRT using log files and quantified the range and reproducibility of respiratory motion for lung tumors.

  1. Identification and characterization of a tumor infiltrating CD56(+)/CD16 (-) NK cell subset with specificity for pancreatic and prostate cancer cell lines.

    PubMed

    Frankel, Timothy L; Burns, William; Riley, John; Morgan, Richard A; Davis, Jeremy L; Hanada, Kenichi; Quezado, Martha; Rosenberg, Steven A; Royal, Richard E

    2010-12-01

    In a recent clinical trial, a patient exhibited regression of several pancreatic cancer metastases following the administration of the immune modulator Ipilimumab (anti-CTLA-4 antibody). We sought to characterize the immune cells responsible for this regression. Tumor infiltrating lymphocytes (TIL-2742) and an autologous tumor line (TC-2742) were expanded from a regressing metastatic lesion excised from this patient. Natural killer (NK) cells predominated in the TIL (92% CD56(+)) with few T cells (12% CD3(+)). A majority (88%) of the NK cells were CD56(bright)CD16(-). TIL-2742 secreted IFN-γ and GM-CSF following co-culture with TC-2742 and major histocompatibility complex mismatched pancreatic tumor lines. After sorting TIL-2742, the purified CD56(+)CD16(-)CD3(-) subset showed reactivity similar to TIL-2742 while the CD56(-)CD16(-)CD3(+) cells exhibited no tumor recognition. In co-culture assays, TIL-2742 and the NK subset expressed high reactivity to several pancreatic and prostate cancer cell lines and could lyse the autologous tumor as well as pancreas and prostate cancer lines. Reactivity was partially abrogated by blockade of TRAIL. We thus identified a unique subset of NK cells (CD56(bright)CD16(dim)) isolated from a regressing metastatic pancreatic cancer in a patient responding to Ipilimumab. This represents the first report of CD56(+)CD16(-) NK cells with apparent specificity for pancreatic and prostate cancer cell lines and associated with tumor regression following the treatment with an immune modulating agent. PMID:20734041

  2. Amblyomin-X induces ER stress, mitochondrial dysfunction, and caspase activation in human melanoma and pancreatic tumor cell.

    PubMed

    Morais, Katia L P; Pacheco, Mario Thiego Fernandes; Berra, Carolina Maria; Bosch, Rosemary V; Sciani, Juliana Mozer; Chammas, Roger; de Freitas Saito, Renata; Iqbal, Asif; Chudzinski-Tavassi, Ana Marisa

    2016-04-01

    During the last two decades, new insights into proteasome function and its role in several human diseases made it a potential therapeutic target. In this context, Amblyomin-X is a Kunitz-type FXa inhibitor similar to endogenous tissue factor pathway inhibitor (TFPI) and is a novel proteasome inhibitor. Herein, we have demonstrated Amblyomin-X cytotoxicity to different tumor cells lines such as pancreatic (Panc1, AsPC1BxPC3) and melanoma (SK-MEL-5 and SK-MEL-28). Of note, Amblyomin-X was not cytotoxic to normal human fibroblast cells. In addition, Amblyomin-X promoted accumulation of ER stress markers (GRP78 and GADD153) in sensitive (SK-MEL-28) and bortezomib-resistant (Mia-PaCa-2) tumor cells. The intracellular calcium concentration [Ca(2+)] i was slightly modulated in human tumor cells (SK-MEL-28 and Mia-PaCa-2) after 24 h of Amblyomin-X treatment. Furthermore, Amblyomin-X induced mitochondrial dysfunction, cytochrome-c release, PARP cleavage, and activation of caspase cascade in both human tumor (SK-MEL-28 and Mia-PaCa-2) cells. These investigations might help in further understanding of the antitumor properties of Amblyomin-X. PMID:27015684

  3. Reduced dissemination of circulating tumor cells with no-touch isolation surgical technique in patients with pancreatic cancer.

    PubMed

    Gall, Tamara M H; Jacob, Jimmy; Frampton, Adam E; Krell, Jonathan; Kyriakides, Charis; Castellano, Leandro; Stebbing, Justin; Jiao, Long R

    2014-05-01

    Circulating tumor cells (CTCs) disseminate from the primary tumor and travel through the bloodstream and lymphatic system. The detection of and/or increase in the number of CTCs during a patient’s clinical course may be a harbinger of forthcoming overt metastasis. We aimed to examine the impact of 2 different surgical techniques, standard (ST) pancreaticoduodenectomy (PD) and no-touch isolation (NT) PD, on tumor behavior and outcome in patients with pancreatic cancer by using CTCs as biomarkers. In this pilot study, patients were randomized to either ST-PD (n = 6) or NT-PD (n = 6). Intraoperatively, blood samples were taken from the portal vein for measurement of CTCs before and immediately after removal of the tumor. An increase in CTCs was seen in 5 of 6 patients (83%) with ST-PD but no patients with NT-PD (P = .003). In the ST-PD and NT-PD groups, median overall survival was 13.0 and 16.7 months, respectively (P = .33); there was no difference in disease-free survival (P = .42). The use of NT-PD significantly reduced the number of CTCs in the portal vein with no benefit in survival outcomes compared with ST-PD, although more extensive studies are required. PMID:24599353

  4. Antibody-mediated neutralization of autocrine Gas6 inhibits the growth of pancreatic ductal adenocarcinoma tumors in vivo.

    PubMed

    Moody, Gordon; Belmontes, Brian; Masterman, Stephanie; Wang, Wei; King, Chadwick; Murawsky, Chris; Tsuruda, Trace; Liu, Shuying; Radinsky, Robert; Beltran, Pedro J

    2016-09-15

    Gas6 and its receptors Axl, Mer and Tyro-3 (TAM) are highly expressed in human malignancy suggesting that signaling through this axis may be tumor-promoting. In pancreatic ductal adenocarcinoma (PDAC), Gas6 and the TAM receptor Axl are frequently co-expressed and their co-expression correlates with poor survival. A strategy was devised to generate fully human neutralizing antibodies against Gas6 using XenoMouse® technology. Hybridoma supernatants were selected based on their ability to inhibit Gas6 binding to the receptor Axl and block Gas6-induced Axl phosphorylation in human cells. Two purified antibodies isolated from the screened hybridomas, GMAB1 and GMAB2, displayed optimal cellular potency which was comparable to that of the soluble extracellular domain of the receptor Axl (Axl-Fc). In vivo characterization of GMAB1 was conducted using a pharmacodynamic assay that measured inhibition of Gas6-induced Akt activation in the mouse spleen. Treatment of mice with a single dose (100-1000 µg) of GMAB1 led to greater than 90% inhibition of Gas6-induced phosphorylated Akt (pAkt) for up to 72 hr. Based on the target coverage observed in the PD assay, the efficacy of GMAB1 was tested against human pancreatic adenocarcinoma xenografts. At doses of 50 µg and 150 µg, twice weekly, GMAB1 was able to inhibit 55% and 76% of tumor growth, respectively (p < 0.001 for both treatments vs. control Ig). When combined with gemcitabine, GMAB1 significantly inhibited tumor growth compared to either agent alone (p < 0.001). Together, the data suggest that Gas6 neutralization may be important as a potential strategy for the treatment of PDAC. PMID:27170265

  5. Early Response to Everolimus Therapy Detected on 68Ga-DOTATATE PET/CT in a Patient With Pancreatic Neuroendocrine Tumor.

    PubMed

    Ozkan, Elgin; Soydal, Cigdem; Ucak Semirgin, Sibel; Yapici, Oktay; Atmaca, Aysegul; Demirag, Guzin

    2016-07-01

    Everolimus is a mammalian target of rapamycin inhibitor that has been recently approved for the treatment of patients with advanced progressive pancreatic neuroendocrine tumor. Here, we present a case in which an early therapy response to everolimus was effectively demonstrated by Ga-DOTATATE PET/CT. PMID:27163457

  6. Probing tumor-stroma interactions and response to photodynamic therapy in a 3D pancreatic cancer-fibroblast co-culture model

    NASA Astrophysics Data System (ADS)

    Glidden, Michael D.; Massodi, Iqbal; Rizvi, Imran; Celli, Jonathan P.; Hasan, Tayyaba

    2012-02-01

    Pancreatic ductal adenocarcinoma is a lethal disease that is often unresectable by the time of diagnosis and is typically non-responsive to chemo- and radiotherapy, resulting in a five year survival of only 3%. Tumors of the pancreas are characterized by a dense fibrous stroma rich in extracellular matrix proteins, which is implicated in poor therapeutic response, though its precise roles remain poorly understood. Indeed, while the use of therapeutics that target the stroma is an emerging paradigm in the clinical management of this disease, the primary focus of such efforts is to enhance drug penetration through dense fibrous stroma and it is unclear to what extent the characteristically rigid stroma of pancreatic tumors imparts drug resistance by acting as a complex signaling partner, or merely as a physical barrier for drug delivery. Here we use 3D in vitro co-cultures of pancreatic cancer cells and normal human fibroblasts as a model system to study heterotypic interactions between these populations. Leveraging this in vitro model along with image-based methods for quantification of growth and therapeutic endpoints, we characterize these co-cultures and examine the role of verteporfin-based photodynamic therapy (PDT) for targeting tumor-fibroblast interactions in pancreatic tumors.

  7. Dosimetric Impact of Intrafractional Patient Motion in Pediatric Brain Tumor Patients

    SciTech Connect

    Beltran, Chris Trussell, John; Merchant, Thomas E.

    2010-04-01

    The purpose of this study was to determine the dosimetric consequences of intrafractional patient motion on the clinical target volume (CTV), spinal cord, and optic nerves for non-sedated pediatric brain tumor patients. The patients were immobilized for treatment using a customized thermoplastic full-face mask and bite-block attached to an array of reflectors. The array was optically tracked by infra-red cameras at a frequency of 10 Hz. Patients were localized based on skin/mask marks and weekly films were taken to ensure proper setup. Before each noncoplanar field was delivered, the deviation from baseline of the array was recorded. The systematic error (SE) and random error (RE) were calculated. Direct simulation of the intrafractional motion was used to quantify the dosimetric changes to the targets and critical structures. Nine patients utilizing the optical tracking system were evaluated. The patient cohort had a mean of 31 {+-} 1.5 treatment fractions; motion data were acquired for a mean of 26 {+-} 6.2 fractions. The mean age was 15.6 {+-} 4.1 years. The SE and RE were 0.4 and 1.1 mm in the posterior-anterior, 0.5 and 1.0 mm in left-right, and 0.6 and 1.3 mm in superior-inferior directions, respectively. The dosimetric effects of the motion on the CTV were negligible; however, the dose to the critical structures was increased. Patient motion during treatment does affect the dose to critical structures, therefore, planning risk volumes are needed to properly assess the dose to normal tissues. Because the motion did not affect the dose to the CTV, the 3-mm PTV margin used is sufficient to account for intrafractional motion, given the patient is properly localized at the start of treatment.

  8. Dosimetric impact of intrafractional patient motion in pediatric brain tumor patients.

    PubMed

    Beltran, Chris; Trussell, John; Merchant, Thomas E

    2010-01-01

    The purpose of this study was to determine the dosimetric consequences of intrafractional patient motion on the clinical target volume (CTV), spinal cord, and optic nerves for non-sedated pediatric brain tumor patients. The patients were immobilized for treatment using a customized thermoplastic full-face mask and bite-block attached to an array of reflectors. The array was optically tracked by infra-red cameras at a frequency of 10 Hz. Patients were localized based on skin/mask marks and weekly films were taken to ensure proper setup. Before each noncoplanar field was delivered, the deviation from baseline of the array was recorded. The systematic error (SE) and random error (RE) were calculated. Direct simulation of the intrafractional motion was used to quantify the dosimetric changes to the targets and critical structures. Nine patients utilizing the optical tracking system were evaluated. The patient cohort had a mean of 31 +/- 1.5 treatment fractions; motion data were acquired for a mean of 26 +/- 6.2 fractions. The mean age was 15.6 +/- 4.1 years. The SE and RE were 0.4 and 1.1 mm in the posterior-anterior, 0.5 and 1.0 mm in left-right, and 0.6 and 1.3 mm in superior-inferior directions, respectively. The dosimetric effects of the motion on the CTV were negligible; however, the dose to the critical structures was increased. Patient motion during treatment does affect the dose to critical structures, therefore, planning risk volumes are needed to properly assess the dose to normal tissues. Because the motion did not affect the dose to the CTV, the 3-mm PTV margin used is sufficient to account for intrafractional motion, given the patient is properly localized at the start of treatment. PMID:19931014

  9. SU-E-J-79: Internal Tumor Volume Motion and Volume Size Assessment Using 4D CT Lung Data

    SciTech Connect

    Jurkovic, I; Stathakis, S; Li, Y; Patel, A; Vincent, J; Papanikolaou, N; Mavroidis, P

    2014-06-01

    Purpose: To assess internal tumor volume change through breathing cycle and associated tumor motion using the 4DCT data. Methods: Respiration induced volume change through breathing cycle and associated motion was analyzed for nine patients that were scanned during the different respiratory phases. The examined datasets were the maximum and average intensity projections (MIP and AIP) and the 10 phases of the respiratory cycle. The internal target volume (ITV) was delineated on each of the phases and the planning target volume (PTV) was then created by adding setup margins to the ITV. Tumor motion through the phases was assessed using the acquired 4DCT dataset, which was then used to determine if the margins used for the ITV creation successfully encompassed the tumor in three dimensions. Results: Results showed that GTV motion along the superior inferior axes was the largest in all the cases independent of the tumor location and/or size or the use of abdomen compression. The extent of the tumor motion was found to be connected with the size of the GTV. The smallest GTVs exhibited largest motion vector independent of the tumor location. The motion vector size varied through the phases depending on the tumor size and location and it was smallest for phases 20 and 30. The smaller the volume of the delineated GTV, the greater its volume difference through the different respiratory phases was. The average GTV volume change was largest for the phases 60 and 70. Conclusion: Even if GTV is delineated using both AIP and MIP datasets, its motion extent will exceed the used margins especially for the very small GTV volumes. When the GTV size is less than 10 cc it is recommended to use fusion of the GTVs through all the phases to create the planning ITV.

  10. Early Therapy Evaluation of Combined Cetuximab and Irinotecan in Orthotopic Pancreatic Tumor Xenografts by Dynamic Contrast-Enhanced Magnetic Resonance Imaging

    PubMed Central

    Kim, Hyunki; Folks, Karri D.; Guo, Lingling; Sellers, Jeffery C.; Fineberg, Naomi S.; Stockard, Cecil R.; Grizzle, William E.; Buchsbaum, Donald J.; Morgan, Desiree E.; George, James F.; Zinn, Kurt R.

    2014-01-01

    Early pancreatic cancer response following cetuximab and/or irinotecan therapies was measured by serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) before and during therapy. Groups 1 to 4 (n = 6/group) of SCID mice bearing orthotopic pancreatic adenocarcinoma xenografts expressing luciferase were treated with phosphate-buffered saline, cetuximab, irinotecan, or cetuximab combined with irinotecan, respectively, twice weekly for 3 weeks. DCE-MRI was performed on days 0, 1, 2, and 3 after therapy initiation, whereas anatomic magnetic resonance imaging was performed on days 0, 1, 2, 3, 6, and 13. Bioluminescence imaging was performed on days 0 and 21. At day 21, all tumors were collected for further histologic analyses (Ki-67 and CD31 staining), whereas tumor dimensions were measured by calipers. The Ktrans values in the 0.5 mm–thick peripheral tumor region were calculated, and the changes in Ktrans during the 3 days posttherapy were compared to tumor volume changes, bioluminescent signal changes, and histologic findings. The Ktrans changes in the peripheral tumor region after 3 days of therapy were linearly correlated with 21-day decreases in tumor volume (p < .001), bioluminescent signal (p = .050), microvessel densities (p = .002), and proliferating cell densities (p = .001). This study supports the clinical use of DCE-MRI for pancreatic cancer patients for early assessment of an anti–epidermal growth factor receptor therapy combined with chemotherapy. PMID:21496446

  11. Differences and Similarities in the Clinicopathological Features of Pancreatic Neuroendocrine Tumors in China and the United States

    PubMed Central

    Zhu, Li-Ming; Tang, Laura; Qiao, Xin-Wei; Wolin, Edward; Nissen, Nicholas N.; Dhall, Deepti; Chen, Jie; Shen, Lin; Chi, Yihebali; Yuan, Yao-Zong; Ben, Qi-Wen; Lv, Bin; Zhou, Ya-Ru; Bai, Chun-Mei; Chen, Jie; Song, Yu-Li; Song, Tian-Tian; Lu, Chong-Mei; Yu, Run; Chen, Yuan-Jia

    2016-01-01

    Abstract The presentation, pathology, and prognosis of pancreatic neuroendocrine tumors (PNETs) in Asian patients have not been studied in large cohorts. We hypothesized that the clinicopathological features of PNETs of Chinese patients might be different from those of US patients. The objectives of this study were to address whether PNETs in Chinese patients exhibit unique clinicopathological features and natural history, and can be graded and staged using the WHO/ENETS criteria. This is a retrospective review of medical records of patients with PNETs in multiple academic medical centers in China (7) and the United States (2). Tumor grading and staging were based on WHO/ENETS criteria. The clinicopathological features of PNETs of Chinese and US patients were compared. Univariate and multivariate analyses were performed to find associations between survival and patient demographics, tumor grade and stage, and other clinicopathological characteristics. A total of 977 (527 Chinese and 450 US) patients with PNETs were studied. In general, Chinese patients were younger than US patients (median age 46 vs 56 years). In Chinese patients, insulinomas were the most common (52.2%), followed by nonfunctional tumors (39.7%), whereas the order was reversed in US patients. Tumor grade distribution was similar in the 2 countries (G1: 57.5% vs 55.0%; G2: 38.5% vs 41.3%; and G3: 4.0% vs 3.7%). However, age, primary tumor size, primary tumor location, grade, and stage of subtypes of PNETs were significantly different between the 2 countries. The Chinese nonfunctional tumors were significantly larger than US ones (median size 4 vs 3 cm) and more frequently located in the head/neck region (54.9% vs 34.8%). The Chinese and US insulinomas were similar in size (median 1.5 cm) but the Chinese insulinomas relatively more frequently located in the head/neck region (48.3% vs 26.1%). Higher grade, advanced stage, metastasis, and larger primary tumor size were significantly associated with

  12. Changes in gene expression of tumor necrosis factor alpha and interleukin 6 in a canine model of caerulein-induced pancreatitis.

    PubMed

    Song, Ruhui; Yu, Dohyeon; Park, Jinho

    2016-07-01

    Acute pancreatitis is an inflammatory process that frequently involves peripancreatic tissues and remote organ systems. It has high morbidity and mortality rates in both human and veterinary patients. The severity of pancreatitis is generally determined by events that occur after acinar cell injury in the pancreas, resulting in elevated levels of various proinflammatory mediators, such as interleukin (IL) 1β and 6, as well as tumor necrosis factor alpha (TNF-α). When these mediators are excessively released into the systemic circulation, severe pancreatitis occurs with systemic complications. This pathophysiological process is similar to that of sepsis; thus, there are many striking clinical similarities between patients with septic shock and those with severe acute pancreatitis. We induced acute pancreatitis using caerulein in dogs and measured the change in the gene expression of proinflammatory cytokines. The levels of TNF-α and IL-6 mRNA peaked at 3 h, at twice the baseline levels, and the serum concentrations of amylase and lipase also increased. Histopathological examination revealed severe hyperemia of the pancreas and hyperemia in the duodenal villi and the hepatic sinusoid. Thus, pancreatitis can be considered an appropriate model to better understand the development of naturally occurring sepsis and to assist in the effective treatment and management of septic patients. PMID:27408338

  13. Therapeutic designed poly (lactic-co-glycolic acid) cylindrical oseltamivir phosphate-loaded implants impede tumor neovascularization, growth and metastasis in mouse model of human pancreatic carcinoma

    PubMed Central

    Hrynyk, Michael; Ellis, Jordon P; Haxho, Fiona; Allison, Stephanie; Steele, Joseph AM; Abdulkhalek, Samar; Neufeld, Ronald J; Szewczuk, Myron R

    2015-01-01

    Poly (lactic-co-glycolic acid) (PLGA) copolymers have been extensively used in cancer research. PLGA can be chemically engineered for conjugation or encapsulation of drugs in a particle formulation. We reported that oseltamivir phosphate (OP) treatment of human pancreatic tumor-bearing mice disrupted the tumor vasculature with daily injections. Here, the controlled release of OP from a biodegradable PLGA cylinder (PLGA-OP) implanted at tumor site was investigated for its role in limiting tumor neovascularization, growth, and metastasis. PLGA-OP cylinders over 30 days in vitro indicated 20%–25% release profiles within 48 hours followed by a continuous metronomic low dose release of 30%–50% OP for an additional 16 days. All OP was released by day 30. Surgically implanted PLGA-OP containing 20 mg OP and blank PLGA cylinders at the tumor site of heterotopic xenografts of human pancreatic PANC1 tumors in RAGxCγ double mutant mice impeded tumor neovascularization, growth rate, and spread to the liver and lungs compared with the untreated cohort. Xenograft tumors from PLGA and PLGA-OP-treated cohorts expressed significant higher levels of human E-cadherin with concomitant reduced N-cadherin and host CD31+ endothelial cells compared with the untreated cohort. These results clearly indicate that OP delivered from PLGA cylinders surgically implanted at the site of the solid tumor show promise as an effective treatment therapy for cancer. PMID:26309402

  14. Diverse effects of LPA4, LPA5 and LPA6 on the activation of tumor progression in pancreatic cancer cells.

    PubMed

    Ishii, Shuhei; Hirane, Miku; Fukushima, Kaori; Tomimatsu, Ayaka; Fukushima, Nobuyuki; Tsujiuchi, Toshifumi

    2015-05-22

    Lysophosphatidic acid (LPA) is an extracellular biological lipid which interacts with G protein-coupled LPA receptors (LPA1 to LPA6). LPA signaling via LPA receptors mediates several cellular responses. In the present study, to assess the roles of LPA4, LPA5 and LPA6 in cellular functions of pancreatic cancer cells, we generated LPA receptor knockdown cells from PANC-1 cells (PANC-sh4, PANC-sh5 and PANC-sh6 cells, respectively). In cell motility assay, PANC-sh4 and PANC-sh5 cells enhanced the cell motile activities, compared with control cells. In contrast, the cell motile activity of PANC-sh6 cells was suppressed. The invasive activities of PANC-sh4 and PANC-sh5 cells were markedly stimulated, while PANC-sh6 cells showed the low invasive activity. In colony assay, PANC-sh4 and PANC-sh5 cells formed the large sized colonies, but not PANC-sh6 cells. When endothelial cells were incubated with supernatants from PANC-sh4 and PANC-sh5 cells, the cell motility and tube formation of endothelial cells were significantly induced, but not PANC-sh6 cells. These results suggest that the diverse roles of LPA4, LPA5 and LPA6 are involved in the activation of tumor progression in pancreatic cancer cells. PMID:25849892

  15. Optical characterization of pancreatic normal and tumor tissues with double integrating sphere system

    NASA Astrophysics Data System (ADS)

    Kiris, Tugba; Akbulut, Saadet; Kiris, Aysenur; Gucin, Zuhal; Karatepe, Oguzhan; Bölükbasi Ates, Gamze; Tabakoǧlu, Haşim Özgür

    2015-03-01

    In order to develop minimally invasive, fast and precise diagnostic and therapeutic methods in medicine by using optical methods, first step is to examine how the light propagates, scatters and transmitted through medium. So as to find out appropriate wavelengths, it is required to correctly determine the optical properties of tissues. The aim of this study is to measure the optical properties of both cancerous and normal ex-vivo pancreatic tissues. Results will be compared to detect how cancerous and normal tissues respond to different wavelengths. Double-integrating-sphere system and computational technique inverse adding doubling method (IAD) were used in the study. Absorption and reduced scattering coefficients of normal and cancerous pancreatic tissues have been measured within the range of 500-650 nm. Statistical significant differences between cancerous and normal tissues have been obtained at 550 nm and 630 nm for absorption coefficients. On the other hand; there were no statistical difference found for scattering coefficients at any wavelength.

  16. Chronic pancreatitis

    MedlinePlus

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... abuse over many years. Repeated episodes of acute pancreatitis can lead to chronic pancreatitis. Genetics may be ...

  17. Glucagonoma Pancreatic Neuroendocrine Tumor Treated With 177Lu DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy.

    PubMed

    Makis, William; McCann, Karey; Riauka, Terence A; McEwan, Alexander J B

    2015-11-01

    A 56-year-old man presented with a history of 2 prior resections of a recurrent pancreatic glucagonoma in the past 4 years. Workup revealed new liver and abdominal nodal metastases with a rising serum glucagon level. He was started on peptide receptor radionuclide therapy with Lu DOTATATE, and his disease stabilized, while his glucagon levels decreased and also stabilized. After 4 induction and 2 maintenance cycles, he remains progression free for 23 months. PMID:26204206

  18. Up-regulation of fatty acid synthase induced by EGFR/ERK activation promotes tumor growth in pancreatic cancer

    SciTech Connect

    Bian, Yong; Yu, Yun; Wang, Shanshan; Li, Lin

    2015-08-07

    Lipid metabolism is dysregulated in many human diseases including atherosclerosis, type 2 diabetes and cancers. Fatty acid synthase (FASN), a key lipogenic enzyme involved in de novo lipid biosynthesis, is significantly upregulated in multiple types of human cancers and associates with tumor progression. However, limited data is available to understand underlying biological functions and clinical significance of overexpressed FASN in pancreatic ductal adenocarcinoma (PDAC). Here, upregulated FASN was more frequently observed in PDAC tissues compared with normal pancreas in a tissue microarray. Kaplan–Meier survival analysis revealed that high expression level of FASN resulted in a significantly poor prognosis of PDAC patients. Knockdown or inhibition of endogenous FASN decreased cell proliferation and increased cell apoptosis in HPAC and AsPC-1 cells. Furthermore, we demonstrated that EGFR/ERK signaling accounts for elevated FASN expression in PDAC as ascertained by performing siRNA assays and using specific pharmacological inhibitors. Collectively, our results indicate that FASN exhibits important roles in tumor growth and EGFR/ERK pathway is responsible for upregulated expression of FASN in PDAC. - Highlights: • Increased expression of FASN indicates a poor prognosis in PDAC. • Elevated FASN favors tumor growth in PDAC in vitro. • Activation of EGFR signaling contributes to elevated FASN expression.

  19. KLF4 is a novel candidate tumor suppressor gene in pancreatic ductal carcinoma.

    PubMed

    Zammarchi, Francesca; Morelli, Mariangela; Menicagli, Michele; Di Cristofano, Claudio; Zavaglia, Katia; Paolucci, Alessandra; Campani, Daniela; Aretini, Paolo; Boggi, Ugo; Mosca, Franco; Cavazzana, Andrea; Cartegni, Luca; Bevilacqua, Generoso; Mazzanti, Chiara Maria

    2011-01-01

    Ductal pancreatic carcinoma (DPC) is a deadly disease with an incidence of 9 cases in 100,000 people per year and a mortality rate close to 100%. Allelic losses in the long arm of chromosome 9 are commonly encountered in many human malignancies but no data are yet available about DPC. We screened 40 laser-microdissected DPC samples and 6 pre-invasive lesions for 9 microsatellite mapping markers of region 9q21.3 through 9q34.2. A small overlapping region of deletion, spanning 8 million base pairs, was identified between D9S127 and D9S105. Two genes, RSG3 and KLF4, mapped to 9q31.1 through 9q32, were further investigated. A highly significant association was found between KLF4 gene expression levels and genomic status. Similarly, absence of immunohistochemical expression of KLF4 protein was found in 86.8% cases of DPC (33/38). Overexpression of KLF4 in a human pancreatic carcinoma cell line induced a significant decrease in the proliferation associated with up-regulation of p21 and the down-regulation of cyclin D1. In conclusion, we identified a novel oncosuppressor region located at the 9q 31.1-3 locus that is lost in DPC at high frequency. Loss of KLF4 expression is closely related to the genomic loss, and its restoration inhibits cancer cell proliferation, suggesting a key suppressor role in pancreatic tumorigenesis. PMID:21224073

  20. A Method to Estimate Mean Position, Motion Magnitude, Motion Correlation, and Trajectory of a Tumor From Cone-Beam CT Projections for Image-Guided Radiotherapy

    SciTech Connect

    Poulsen, Per Rugaard Cho, Byungchul; Keall, Paul J.

    2008-12-01

    Purpose: To develop a probability-based method for estimating the mean position, motion magnitude, and trajectory of a tumor using cone-beam CT (CBCT) projections. Method and Materials: CBCT acquisition was simulated for more than 80 hours of patient-measured trajectories for thoracic/abdominal tumors and prostate. The trajectories were divided into 60-second segments for which CBCT was simulated by projecting the tumor position onto a rotating imager. Tumor (surrogate) visibility on all projections was assumed. The mean and standard deviation of the tumor position and motion correlation along the three axes were determined with maximum likelihood estimation based on the projection data, assuming a Gaussian spatial distribution. The unknown position component along the imager axis was approximated by its expectation value, determined by the Gaussian distribution. Transformation of the resulting three-dimensional position to patient coordinates provided the estimated trajectory. Two trajectories were experimentally investigated by CBCT acquisition of a phantom. Results: The root-mean-square error of the estimated mean position was 0.05 mm. The root-mean-square error of the trajectories was <1 mm in 99.1% of the thorax/abdomen cases and in 99.7% of the prostate cases. The experimental trajectory estimation agreed with the actual phantom trajectory within 0.44 mm in any direction. Clinical applicability was demonstrated by estimating the tumor trajectory for a pancreas cancer case. Conclusions: A method for estimation of mean position, motion magnitude, and trajectory of a tumor from CBCT projections has been developed. The accuracy was typically much better than 1 mm. The method is applicable to motion-inclusive, respiratory-gated, and tumor-tracking radiotherapy.

  1. GFRα2 prompts cell growth and chemoresistance through down-regulating tumor suppressor gene PTEN via Mir-17-5p in pancreatic cancer.

    PubMed

    Gu, Jiangning; Wang, Di; Zhang, Jiaqiang; Zhu, Yi; Li, Ying; Chen, Hao; Shi, Minmin; Wang, Xuelong; Shen, Baiyong; Deng, Xiaxing; Zhan, Qian; Wei, Gang; Peng, Chenghong

    2016-10-01

    Nerve growth factors and their receptors have received an increasing attention in certain cancers since they play an important role in regulating tumorigenesis, biological process and metastasis. Here we aimed at characterizing a new function of one of the subtypes of growth factor receptors (GFR), GFRα2, in pancreatic cancer. In this study, we showed that GFRα2 was up-regulated in pancreatic adenocarcinoma and was positively correlated with tumor size and perineural invasion, which indicated that it may be associated with cell growth and apoptosis. Mechanically, we discovered that high GFRα2 expression level leads to PTEN inactivation via enhancing Mir-17-5p level. PMID:27400681

  2. Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies

    PubMed Central

    Reid, Michelle D; Bagci, Pelin; Ohike, Nobuyuki; Saka, Burcu; Seven, Ipek Erbarut; Dursun, Nevra; Balci, Serdar; Gucer, Hasan; Jang, Kee-Taek; Tajiri, Takuma; Basturk, Olca; Kong, So Yeon; Goodman, Michael; Akkas, Gizem; Adsay, Volkan

    2015-01-01

    Ki67 index is now an essential part of classification of pancreatic neuroendocrine tumors. However, its adaptation into daily practice has been fraught with challenges related to counting methodology. In this study, three reviewers used four counting methodologies to calculate Ki67 index in 68 well-differentiated pancreatic neuroendocrine tumors: (1) ‘eye-ball’ estimation, which has been advocated as reliable and is widely used; (2) automated counting by image analyzer; (3) manual eye-counting (eye under a microscope without a grid); and (4) manual count of camera-captured/printed image. Pearson’s correlation (R) was used to measure pair-wise correlation among three reviewers using all four methodologies. Average level of agreement was calculated using mean of R values. The results showed that: (1) ‘eye-balling’ was least expensive and fastest (average time <1 min) but had poor reliability and reproducibility. (2) Automated count was the most expensive and least practical with major impact on turnaround time (limited by machine and personnel accessibility), and, more importantly, had inaccuracies in overcounting unwanted material. (3) Manual eye count had no additional cost, averaged 6 min, but proved impractical and poorly reproducible. (4) Camera-captured/printed image was most reliable, had highest reproducibility, but took longer than ‘eye-balling’. In conclusion, based on its comparatively low cost/benefit ratio and reproducibility, camera-captured/printed image appears to be the most practical for calculating Ki67 index. Although automated counting is generally advertised as the gold standard for index calculation, in this study it was not as accurate or cost-effective as camera-captured/printed image and was highly operator-dependent. ‘Eye-balling’ produces highly inaccurate and unreliable results, and is not recommended for routine use. PMID:25412850

  3. 18F-FDG PET/CT Imaging Detects Therapy Efficacy of Anti-EMMPRIN Antibody and Gemcitabine in Orthotopic Pancreatic Tumor Xenografts

    PubMed Central

    Shah, Nemil; Zhai, Guihua; Knowles, Joseph A.; Stockard, Cecil R.; Grizzle, William E.; Fineberg, Naomi; Zhou, Tong; Zinn, Kurt R.; Rosenthal, Eben L.; Kim, Hyunki

    2013-01-01

    Purpose To evaluate by sequential 18F-FDG PET/CT imaging the therapeutic response to a novel monoclonal antibody targeting human EMMPRIN (extracellular matrix metalloproteinase inducer) in combination with gemcitabine in a pancreatic-tumor xenograft murine model. Procedures Four groups of SCID mice bearing orthotopic pancreatic tumor xenografts were injected with PBS, gemcitabine (120mg/kg BW), anti-EMMPRIN antibody (0.2mg), or combination, respectively twice weekly for 2 weeks, while 18F-FDG PET/CT imaging was performed weekly for 3 weeks. Changes in mean standardized uptake value (SUVmean) of 18F-FDG and volume of tumors were determined. Results The tumor SUVmean change in the group receiving combination therapy was significantly lower than those of the other groups. Tumor-volume changes of groups treated with anti-EMMPRIN monotherapy or combined therapy were significantly lower than that of the control group. Conclusions These data provide support for clinical studies of anti-EMMPRIN therapy with gemcitabine for pancreatic cancer treatment. PMID:21494920

  4. Assessment of different 3D culture systems to study tumor phenotype and chemosensitivity in pancreatic ductal adenocarcinoma.

    PubMed

    Zeeberg, Katrine; Cardone, Rosa Angela; Greco, Maria Raffaella; Saccomano, Mara; Nøhr-Nielsen, Asbjørn; Alves, Frauke; Pedersen, Stine Falsig; Reshkin, Stephan Joel

    2016-07-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis, due to the influence of the tumor stroma, which promotes tumor growth, early invasion and chemoradiation resistance. Efforts to develop models for identifying novel anticancer therapeutic compounds have been hampered by the limited ability of in vitro models to mimic these in vivo tumor-stroma interactions. This has led to the development of various three-dimensional (3D) culture platforms recapitulating the in vivo tumor-stroma crosstalk and designed to better understand basic cancer processes and screen drug action. However, a consensus for different experimental 3D platforms is still missing in PDAC. We compared four PDAC cell lines of different malignancy grown in 2D monolayers to three of the more commonly used 3D techniques (ultralow adhesion concave microwells, Matrigel inclusion and organotypic systems) and to tumors derived from their orthotopic implantation in mice. In these 3D platforms, we observed that cells grow with very different tumor morphologies and the organotypic setting most closely resembles the tumor cytoarchitecture obtained by orthotopically implanting the four cell lines in mice. We then analyzed the molecular and cellular responses of one of these cell lines to epidermal growth factor receptor (EGFR) stimulation with EGF and inhibition with erlotinib and found that only in the 3D platforms, and especially the organotypic, cells: i) responded to EGF by changing the expression of signalling components underlying cell-stroma crosstalk and tissue architecture, growth, invasion and drug resistance (E-cadherin, EGFR, ezrin, β1 integrin, NHERF1 and HIF-1α) similar to those reported in vivo; ii) had stimulated growth and increased erlotinib sensitivity in response to EGF, more faithfully mimicking their known in vivo behaviour. Altogether, these results, indicate the organotypic as the most relevant physiological 3D system to study the

  5. A pancreatic tumor-specific biomarker characterized in humans and mice as an immunogenic onco-glycoprotein is efficient in dendritic cell vaccination

    PubMed Central

    Collignon, Aurélie; Perles-Barbacaru, Adriana Teodora; Robert, Stéphane; Silvy, Françoise; Martinez, Emmanuelle; Crenon, Isabelle; Germain, Sébastien; Garcia, Stéphane; Viola, Angèle; Lombardo, Dominique

    2015-01-01

    Oncofetal fucose-rich glycovariants of the pathological bile salt-dependent lipase (pBSDL) appear during human pancreatic oncogenesis and are detected by themonoclonal antibody J28 (mAbJ28). We aimed to identify murine counterparts onpancreatic ductal adenocarcinoma (PDAC) cells and tissue and investigate the potential of dendritic cells (DC) loaded with this unique pancreatic tumor antigen to promote immunotherapy in preclinical trials. Pathological BSDLs purified from pancreatic juices of patients with PDAC were cleaved to generate glycosylated C-terminal moieties (C-ter) containing mAbJ28-reactive glycoepitopes. Immunoreactivity of the murine PDAC line Panc02 and tumor tissue to mAbJ28 was detected by immunohistochemistry and flow cytometry. C-ter-J28+ immunization promoted Th1-dominated immune responses. In vitro C-ter-J28+-loaded DCskewed CD3+ T-cells toward Th1 polarization. C-ter-J28+-DC-vaccinations selectively enhanced cell immunoreactivity to Panc02, as demonstrated by CD4+- and CD8+-T-cell activation, increased percentages of CD4+- and CD8+-T-cells and NK1.1+ cells expressing granzyme B, and T-cell cytotoxicity. Prophylactic and therapeutic C-ter-J28+-DC-vaccinations reduced ectopic Panc02-tumor growth, provided long-lasting protection from Panc02-tumor development in 100% of micebut not from melanoma, and attenuated progression of orthotopic tumors as revealed by MRI. Thusmurine DC loaded with pancreatic tumor-specific glycoepitope C-ter-J28+ induce efficient anticancer adaptive immunity and represent a potential adjuvant therapy for patients afflicted with PDAC. PMID:26405163

  6. A pancreatic tumor-specific biomarker characterized in humans and mice as an immunogenic onco-glycoprotein is efficient in dendritic cell vaccination.

    PubMed

    Collignon, Aurélie; Perles-Barbacaru, Adriana Teodora; Robert, Stéphane; Silvy, Françoise; Martinez, Emmanuelle; Crenon, Isabelle; Germain, Sébastien; Garcia, Stéphane; Viola, Angèle; Lombardo, Dominique; Mas, Eric; Béraud, Evelyne

    2015-09-15

    Oncofetal fucose-rich glycovariants of the pathological bile salt-dependent lipase (pBSDL) appear during human pancreatic oncogenesis and are detected by themonoclonal antibody J28 (mAbJ28). We aimed to identify murine counterparts onpancreatic ductal adenocarcinoma (PDAC) cells and tissue and investigate the potential of dendritic cells (DC) loaded with this unique pancreatic tumor antigen to promote immunotherapy in preclinical trials. Pathological BSDLs purified from pancreatic juices of patients with PDAC were cleaved to generate glycosylated C-terminal moieties (C-ter) containing mAbJ28-reactive glycoepitopes. Immunoreactivity of the murine PDAC line Panc02 and tumor tissue to mAbJ28 was detected by immunohistochemistry and flow cytometry. C-ter-J28+ immunization promoted Th1-dominated immune responses. In vitro C-ter-J28+-loaded DCskewed CD3+ T-cells toward Th1 polarization. C-ter-J28+-DC-vaccinations selectively enhanced cell immunoreactivity to Panc02, as demonstrated by CD4+- and CD8+-T-cell activation, increased percentages of CD4+- and CD8+-T-cells and NK1.1+ cells expressing granzyme B, and T-cell cytotoxicity. Prophylactic and therapeutic C-ter-J28+-DC-vaccinations reduced ectopic Panc02-tumor growth, provided long-lasting protection from Panc02-tumor development in 100% of micebut not from melanoma, and attenuated progression of orthotopic tumors as revealed by MRI. Thusmurine DC loaded with pancreatic tumor-specific glycoepitope C-ter-J28+ induce efficient anticancer adaptive immunity and represent a potential adjuvant therapy for patients afflicted with PDAC. PMID:26405163

  7. Evaluation of Hepatic Tumors Using Intravoxel Incoherent Motion Diffusion-Weighted MRI

    PubMed Central

    Wang, Mingjie; Li, Xudan; Zou, Jianxun; Chen, Xugao; Chen, Shuyan; Xiang, Wanqing

    2016-01-01

    Background This study aimed to evaluate the diagnostic value of the D value, D* value, and f magnitude for identifying benign and malignant hepatic tumors using intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI). Material/Methods Data of 89 cases (123 lesions) with hepatic tumor confirmed by surgical pathology and postoperative follow-up were retrospectively collected. Among these cases, 40 cases were benign hepatic tumors (57 lesions) and 49 cases were malignant hepatic tumors (66 lesions). All subjects underwent conventional MRI with T1WI, T2WI, multi-b-value DWI, and dynamic enhanced LAVA scan. Diffusion-weighted images with 11 b values (0, 10, 20, 30, 50, 80, 100, 200, 400, 800, and 1000 s/mm2) were obtained to calculate true molecular diffusion (D), perfusion-related diffusion coefficient (D*), and perfusion fraction (f). The diagnostic performance in differentiating between malignant and benign hepatic lesions was analyzed. Results Malignant lesions had a significantly lower D value ([1.04±0.34]×10−3 mm2/s) and D* value ([16.5±7.7]×10−3 mm2/s) compared to benign lesions (D value: [1.70±0.55]×10−3 mm2/s, P<0.01; D* value: [21.7±9.9]×10−3 mm2/s, P<0.01). There was no statistically significant difference in f values between malignant (23.3±9.5) and benign lesions (33.5±14.9, P=0.13). In addition, D exhibited a better diagnostic performance than D* in terms of the area under the curve, sensitivity, and specificity when identifying malignancies from benign lesions. Conclusions D and D* are significant parameters for diagnosing hepatic tumors. Moreover, the D value is a more reliable parameter in distinguishing benign and malignant hepatic tumors. PMID:26931063

  8. Compensating for Tumor Motion by a 6-Degree-of-Freedom Treatment Couch: Is Patient Tolerance an Issue?

    SciTech Connect

    Sweeney, Reinhart A. Arnold, Winfried; Steixner, Eva; Nevinny-Stickel, Meinhard; Lukas, Peter

    2009-05-01

    Purpose: To determine whether patients could tolerate the motion of a robotic couch that compensates for breathing-induced tumor motion. Methods and Materials: A total of 10 healthy subjects and 23 radio-oncology patients underwent simulated extracranial stereotactic radiotherapy (two 30-min sessions) on a robotic couch programmed to follow a fictitious tumor trajectory of 20x5x5 mm (cranio-caudal, left-right, and anterior-posterior directions, respectively) while rotating 2 deg. around a cranio-caudal axis at a frequency of 5 seconds per loop. Results: No session had to be interrupted and no nausea was induced. However, one patient refused the second session due to general deterioration and not all patients could keep their arms elevated for the entire session. Conclusions: Our findings showed that most patients tolerated compensatory couch motion and that motion sickness should not pose a problem in the investigation of this tumor-tracking method.

  9. Preoperative Volume-Based PET Parameter, MTV2.5, as a Potential Surrogate Marker for Tumor Biology and Recurrence in Resected Pancreatic Cancer.

    PubMed

    Kang, Chang Moo; Lee, Sung Hwan; Hwang, Ho Kyoung; Yun, Mijin; Lee, Woo Jung

    2016-03-01

    This study aims to evaluate the role of volume-based positron emission tomography parameters as potential surrogate markers for tumor recurrence in resected pancreatic cancer. Between January 2008 and October 2012, medical records of patients who underwent surgical resection for pancreatic ductal adenocarcinoma and completed ¹⁸F-fluorodeoxyglucose positron emission tomography/CT as a part of preoperative staging work-up were retrospectively reviewed. Not only clinicopathologic variables but also positron emission tomography parameters such as SUVmax, MTV2.5 (metabolic tumor volume), and TLG (total lesion glycolysis) were obtained. Twenty-six patients were women and 31 were men with a mean age of 62.9 ± 9.1 years. All patients were preoperatively determined to resectable pancreatic cancer except 1 case with borderline resectability. R0 resection was achieved in all patients and 45 patients (78.9%) received postoperative adjuvant chemotherapy with or without radiation therapy. Median overall disease-free survival was 12.8 months with a median overall disease-specific survival of 25.1 months. SUVmax did not correlate with radiologic tumor size (P = 0.501); however, MTV2.5 (P = 0.001) and TLG (P = 0.009) were significantly associated with radiologic tumor size. In addition, MTV2.5 (P < 0.001) and TLG (P < 0.001) were significantly correlated with a tumor differentiation. There were no significant differences in TLG and SUVmax according to lymph node ratio; only MTV2.5 was related to lymph node ratio with marginal significance (P = 0.055). In multivariate analysis, lymph node ratio (Exp [β] = 2.425, P = 0.025) and MTV2.5 (Exp[β] = 2.273, P = 0.034) were identified as independent predictors of tumor recurrence following margin-negative resection. Even after tumor size-matched analysis, MTV2.5 was still identified as significant prognostic factor in resected pancreatic cancer (P < 0.05). However, preoperative

  10. Preoperative Volume-Based PET Parameter, MTV2.5, as a Potential Surrogate Marker for Tumor Biology and Recurrence in Resected Pancreatic Cancer

    PubMed Central

    Kang, Chang Moo; Lee, Sung Hwan; Hwang, Ho Kyoung; Yun, Mijin; Lee, Woo Jung

    2016-01-01

    Abstract This study aims to evaluate the role of volume-based positron emission tomography parameters as potential surrogate markers for tumor recurrence in resected pancreatic cancer. Between January 2008 and October 2012, medical records of patients who underwent surgical resection for pancreatic ductal adenocarcinoma and completed 18F-fluorodeoxyglucose positron emission tomography/CT as a part of preoperative staging work-up were retrospectively reviewed. Not only clinicopathologic variables but also positron emission tomography parameters such as SUVmax, MTV2.5 (metabolic tumor volume), and TLG (total lesion glycolysis) were obtained. Twenty-six patients were women and 31 were men with a mean age of 62.9 ± 9.1 years. All patients were preoperatively determined to resectable pancreatic cancer except 1 case with borderline resectability. R0 resection was achieved in all patients and 45 patients (78.9%) received postoperative adjuvant chemotherapy with or without radiation therapy. Median overall disease-free survival was 12.8 months with a median overall disease-specific survival of 25.1 months. SUVmax did not correlate with radiologic tumor size (P = 0.501); however, MTV2.5 (P = 0.001) and TLG (P = 0.009) were significantly associated with radiologic tumor size. In addition, MTV2.5 (P < 0.001) and TLG (P < 0.001) were significantly correlated with a tumor differentiation. There were no significant differences in TLG and SUVmax according to lymph node ratio; only MTV2.5 was related to lymph node ratio with marginal significance (P = 0.055). In multivariate analysis, lymph node ratio (Exp [β] = 2.425, P = 0.025) and MTV2.5 (Exp[β] = 2.273, P = 0.034) were identified as independent predictors of tumor recurrence following margin-negative resection. Even after tumor size-matched analysis, MTV2.5 was still identified as significant prognostic factor in resected pancreatic cancer (P < 0.05). However, preoperative

  11. Incidence of Changes in Respiration-Induced Tumor Motion and Its Relationship With Respiratory Surrogates During Individual Treatment Fractions

    SciTech Connect

    Malinowski, Kathleen; McAvoy, Thomas J.; George, Rohini; Dietrich, Sonja; D'Souza, Warren D.

    2012-04-01

    Purpose: To determine how frequently (1) tumor motion and (2) the spatial relationship between tumor and respiratory surrogate markers change during a treatment fraction in lung and pancreas cancer patients. Methods and Materials: A Cyberknife Synchrony system radiographically localized the tumor and simultaneously tracked three respiratory surrogate markers fixed to a form-fitting vest. Data in 55 lung and 29 pancreas fractions were divided into successive 10-min blocks. Mean tumor positions and tumor position distributions were compared across 10-min blocks of data. Treatment margins were calculated from both 10 and 30 min of data. Partial least squares (PLS) regression models of tumor positions as a function of external surrogate marker positions were created from the first 10 min of data in each fraction; the incidence of significant PLS model degradation was used to assess changes in the spatial relationship between tumors and surrogate markers. Results: The absolute change in mean tumor position from first to third 10-min blocks was >5 mm in 13% and 7% of lung and pancreas cases, respectively. Superior-inferior and medial-lateral differences in mean tumor position were significantly associated with the lobe of lung. In 61% and 54% of lung and pancreas fractions, respectively, margins calculated from 30 min of data were larger than margins calculated from 10 min of data. The change in treatment margin magnitude for superior-inferior motion was >1 mm in 42% of lung and 45% of pancreas fractions. Significantly increasing tumor position prediction model error (mean {+-} standard deviation rates of change of 1.6 {+-} 2.5 mm per 10 min) over 30 min indicated tumor-surrogate relationship changes in 63% of fractions. Conclusions: Both tumor motion and the relationship between tumor and respiratory surrogate displacements change in most treatment fractions for patient in-room time of 30 min.

  12. Circulating Tumor Cells as a Biomarker of Response to Treatment in Patient-Derived Xenograft Mouse Models of Pancreatic Adenocarcinoma

    PubMed Central

    Torphy, Robert J.; Tignanelli, Christopher J.; Kamande, Joyce W.; Moffitt, Richard A.; Herrera Loeza, Silvia G.; Soper, Steven A.; Yeh, Jen Jen

    2014-01-01

    Circulating tumor cells (CTCs) are cells shed from solid tumors into circulation and have been shown to be prognostic in the setting of metastatic disease. These cells are obtained through a routine blood draw and may serve as an easily accessible marker for monitoring treatment effectiveness. Because of the rapid progression of pancreatic ductal adenocarcinoma (PDAC), early insight into treatment effectiveness may allow for necessary and timely changes in treatment regimens. The objective of this study was to evaluate CTC burden as a biomarker of response to treatment with a oral phosphatidylinositol-3-kinase inhibitor, BKM120, in patient-derived xenograft (PDX) mouse models of PDAC. PDX mice were randomized to receive vehicle or BKM120 treatment for 28 days and CTCs were enumerated from whole blood before and after treatment using a microfluidic chip that selected for EpCAM (epithelial cell adhesion molecule) positive cells. This microfluidic device allowed for the release of captured CTCs and enumeration of these cells via their electrical impedance signatures. Median CTC counts significantly decreased in the BKM120 group from pre- to post-treatment (26.61 to 2.21 CTCs/250 µL, p = 0.0207) while no significant change was observed in the vehicle group (23.26 to 11.89 CTCs/250 µL, p = 0.8081). This reduction in CTC burden in the treatment group correlated with tumor growth inhibition indicating CTC burden is a promising biomarker of response to treatment in preclinical models. Mutant enriched sequencing of isolated CTCs confirmed that they harbored KRAS G12V mutations, identical to the matched tumors. In the long-term, PDX mice are a useful preclinical model for furthering our understanding of CTCs. Clinically, mutational analysis of CTCs and serial monitoring of CTC burden may be used as a minimally invasive approach to predict and monitor treatment response to guide therapeutic regimens. PMID:24586805

  13. PI3K/AKT/mTOR and sonic hedgehog pathways cooperate together to inhibit human pancreatic cancer stem cell characteristics and tumor growth

    PubMed Central

    Sharma, Narinder; Nanta, Rajesh; Sharma, Jay; Gunewardena, Sumedha; Singh, Karan P.; Shankar, Sharmila; Srivastava, Rakesh K.

    2015-01-01

    Cancer stem cells (CSCs) play major roles in cancer initiation, progression, and metastasis. It is evident from growing reports that PI3K/Akt/mTOR and Sonic Hedgehog (Shh) signaling pathways are aberrantly reactivated in pancreatic CSCs. Here, we examined the efficacy of combining NVP-LDE-225 (PI3K/mTOR inhibitor) and NVP-BEZ-235 (Smoothened inhibitor) on pancreatic CSCs characteristics, microRNA regulatory network, and tumor growth. NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting pancreatic CSC's characteristics and tumor growth in mice by acting at the level of Gli. Combination of NVP-LDE-225 and NVP-BEZ-235 inhibited self-renewal capacity of CSCs by suppressing the expression of pluripotency maintaining factors Nanog, Oct-4, Sox-2 and c-Myc, and transcription of Gli. NVP-LDE-225 co-operated with NVP-BEZ-235 to inhibit Lin28/Let7a/Kras axis in pancreatic CSCs. Furthermore, a superior interaction of these drugs was observed on spheroid formation by pancreatic CSCs isolated from Pankras/p53 mice. The combination of these drugs also showed superior effects on the expression of proteins involved in cell proliferation, survival and apoptosis. In addition, NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting EMT through modulation of cadherin, vimentin and transcription factors Snail, Slug and Zeb1. In conclusion, these data suggest that the combined inhibition of PI3K/Akt/mTOR and Shh pathways may be beneficial for the treatment of pancreatic cancer. PMID:26451606

  14. 1H NMR Based Serum Metabolic Profiles Associated with Pathological Progression of Pancreatic Islet β Cell Tumor in Rip1-Tag2 Mice

    PubMed Central

    Yang, Yongxia; Liu, Ying; Zheng, Lingyun; Zhang, Qianqian; Gu, Quliang; Wang, Linlin; Wang, Lijing

    2015-01-01

    Pancreatic islet β cell tumor is the most common islet cell tumor. A well-characterized tumor progression in Rip1-Tag2 mice undergoes five stages, involving normal, hyperplasia, angiogenic islets, tumorigenesis and invasive carcinoma. 1H NMR based metabonomics was applied to identify potential biomarkers for monitoring pancreatic islet β cell tumor progression in Rip1-Tag2 mice. Multivariate analysis results showed the serum metabonome at hyperplasia stage shared the similar characteristics with the ones at normal stage as a result of slight proliferation of pancreatic islet β cells. At angiogenic islets stage, the up-regulated glycolysis, disturbed choline and phospholipid metabolism composed the metabolic signature. In addition to the changes mentioned above, several metabolites were identified as early biomarkers for tumorigenesis, including increased methionine, citrate and choline, and reduced acetate, taurine and glucose, which suggested the activated energy and amino acid metabolism. All the changes were aggravated at invasive carcinoma stage, coupled with notable changes in alanine, glutamate and glycine. Moreover, the distinct metabolic phenotype was found associated with the implanting of SV40 large T antigen in Rip1-Tag2 mice. The combined metabolic and multivariate statistics approach provides a robust method for screening the biomarkers of disease progression and examining the association between gene and metabolism. PMID:25892966

  15. Correlation between Ultrasound Reflection Intensity and Tumor Ablation Ratio of Late-Stage Pancreatic Carcinoma in HIFU Therapy: Dynamic Observation on Ultrasound Reflection Intensity

    PubMed Central

    Ge, Hui-Yu; Miao, Li-Ying; Wang, Jin-Rui; Xiong, Liu-Lin; Yan, Fang; Zheng, Cui-Shan; Jia, Jian-Wen; Cui, Li-Gang; Chen, Wen

    2013-01-01

    The minimally invasive high-intensity focused ultrasound (HIFU) therapy is thermal ablation treatment for late-stage pancreatic carcinoma with widely recognized safety and effectiveness, but there are currently no instant assessment methods for its ablation effect. It is vital to find a real-time high-sensitive assessment method. This research aims to dynamically observe the variation rules of ultrasound reflection intensity, analyze the correlation between ultrasound reflection intensity and tumor ablation ratio, and find out the value of ultrasound reflection intensity in prognosis of HIFU ablation effect. HIFU intermittent therapies were retrospectively analyzed for 31 subjects with late-stage pancreatic carcinoma from March 2007 to December 2009 in the study. The variation rules of the ultrasound reflection intensity during HIFU therapy were summarized and the correlation between ultrasound reflection intensity and tumor ablation ratio was analyzed based on the tumor ablation ratio indicated by CT scanning. The conclusion is that variation of ultrasound reflection intensity can be used for initial assessment of tumor ablation in HIFU therapy and early prognosis of overall HIFU ablation, providing important clinical basis for improving safety and effectiveness of HIFU therapy. Ultrasound can work as a real-time imaging instrument for observation of HIFU ablation effect in treating late-stage pancreatic carcinoma. PMID:24453916

  16. In vivo molecular imaging of somatostatin receptors in pancreatic islet cells and neuroendocrine tumors by miniaturized confocal laser-scanning fluorescence microscopy.

    PubMed

    Fottner, C; Mettler, E; Goetz, M; Schirrmacher, E; Anlauf, M; Strand, D; Schirrmacher, R; Klöppel, G; Delaney, P; Schreckenberger, M; Galle, P R; Neurath, M F; Kiesslich, R; Weber, M M

    2010-05-01

    The aim of the study was to evaluate real time in vivo molecular imaging of somatostatin receptors (sstrs) using a handheld miniaturized confocal laser scan microscope (CLM) in conjunction with fluorescein-labeled octreotate (OcF) in healthy mice and murine models of neuroendocrine tumors. For CLM a small rigid probe (diameter 7 mm) with an integrated single line laser (488 nm) was used (optical slice thickness 7 mum; lateral resolution 0.7 mum). OcF was synthesized via Fmoc solid-phase peptide synthesis and purified by HPLC showing high-affinity binding to the sstr2 (IC(50) 6.2 nmol). For in vitro evaluation, rat and human pancreatic cancer cells were used and characterized with respect to its sstr subtype expression and functional properties. For in vivo confocal imaging, healthy mouse pancreatic islet and renal tubular cells as well as immunoincompetent nude mice harboring sstr-expressing tumors were evaluated. Incubation of sstr-positive cells with OcF showed a specific time- and dose-dependent staining of sstr-positive cells. CLM showed rapid internalization and homogenous cytoplasmatic distribution. After systemic application to mice (n = 8), specific time-dependent internalization and cytoplasmatic distribution into pancreatic islet cells and tubular cells of the renal cortex was recorded. After injection in tumor-harboring nude mice (n = 8), sstr-positive cells selectively displayed a cell surface and cytoplasmatic staining. CLM-targeted biopsies detected sstr-positive tumor cells with a sensitivity of 87.5% and a specificity of 100% as correlated with ex vivo immunohistochemistry. CLM with OcF permits real-time molecular, functional, and morphological imaging of sstr-expressing cell structures, allowing the specific visualization of pancreatic islet cells and neuroendocrine tumors in vivo. PMID:20233796

  17. Detection of circulating tumor cells in patients with esophagogastric or pancreatic adenocarcinoma using the CellSearch® system: An observational feasibility study

    PubMed Central

    Piegeler, Tobias; Winder, Thomas; Kern, Sabine; Pestalozzi, Bernhard; Schneider, Paul Magnus; Beck-Schimmer, Beatrice

    2016-01-01

    Circulating tumor cells (CTCs) in the blood of cancer patients have been demonstrated to be of prognostic value regarding metastasis and survival. The CellSearch® system has been certified for the detection of CTCs and as a prognostic tool in patients with metastatic breast, colon and prostate cancer. Few studies have evaluated the detection of CTCs originating from esophagogastric or pancreatic cancer with the CellSearch® system. In the present small pilot study, a total of 16 patients with either esophagogastric (n=8) or pancreatic (n=8) adenocarcinomas at various disease stages were randomly screened and included. A total of 7.5 ml of blood was drawn from each patient and analyzed for CTCs using the CellSearch® device. CTCs could be detected in 1 out of 8 patients (12.5%) with esophagogastric and in 7 out of 8 patients (87.5%) with pancreatic cancer. The preliminary data obtained from this observational feasibility study suggested that the CellSearch® system may become a valuable tool for the detection of CTCs in patients with pancreatic adenocarcinoma, whereas the usefulness in patients with early-stage esophagogastric adenocarcinoma may be limited. This study clearly points towards a requirement for larger studies focusing on patients with pancreatic adenocarcinoma at various disease stages and assessing CTCs, whereas patients with esophagogastric adenocarcinomas should be part of further pilot studies. PMID:27446462

  18. LincRNA-ROR promotes invasion, metastasis and tumor growth in pancreatic cancer through activating ZEB1 pathway.

    PubMed

    Zhan, Han-Xiang; Wang, Yao; Li, Ce; Xu, Jian-Wei; Zhou, Bin; Zhu, Jian-Kang; Han, Hai-Feng; Wang, Lei; Wang, Yun-Shan; Hu, San-Yuan

    2016-05-01

    Pancreatic cancer (PC) remains one of the most lethal malignant tumors; early distant metastasis commonly results in poor prognosis. Recent studies confirmed the pivotal role of the long non-coding RNAs (lncRNAs) in tumorigenesis and metastasis of malignant tumors, including PC. However, little is known about the role of LincRNA-ROR (linc-ROR) in PC. In the present study, we found that linc-ROR was upregulated in PC tissues. Overexpression of linc-ROR promoted cells proliferation, migration, invasion and metastasis both in vitro and in a mouse model. Contrarily, knockdown of linc-ROR attenuated proliferation, invasion and distant metastasis. Mechanistically, we confirmed that linc-ROR up-regulates ZEB1 and then induces epithelial-mesenchymal transition (EMT), which promotes the aggressive biological behaviors of PC. Together, these results indicate that linc-ROR acts as an important regulator of ZEB1, can promote invasion and metastasis in PC, and may represent a novel therapeutic target. PMID:26898939

  19. RNA interference against MDM2 suppresses tumor growth and metastasis in pancreatic carcinoma SW1990HM cells.

    PubMed

    Shi, Weidong; Meng, Zhiqiang; Chen, Zhen; Hua, Yongqiang; Gao, Huifeng; Wang, Peng; Lin, Junhua; Zhou, Zhenhua; Luo, Jianmin; Liu, Luming

    2014-02-01

    In our previous study, the mouse double minute 2 (MDM2) was identified as one of the leading genes that promote the metastasis of pancreatic cancer (PC). However, the mechanism by which MDM2 promotes metastasis of PC is not understood. In this study, we show that down-regulation of MDM2 through lentivirus-mediated RNA interference could also suppress in vitro proliferation and in vivo tumor growth, and led to an obvious inhibition of both in vitro invasion and in vivo live metastases of SW1990HM cells which had an over-expression of MDM2 and a higher metastatic potential. Moreover, we also show that the down-regulation of MDM2 induced a significant decrease in MMP9, Ki-67 and increase in P53, E-Cadherin expression, and results in an altered expression of genes involved in metastasis, apoptosis, and cell proliferation. Our results suggest that MDM2 plays an important role in metastasis as well as tumor growth of PC. MDM2 could be a hopeful target for the control of PC. PMID:22200978

  20. MicroRNA-148b and microRNA-152 reactivate tumor suppressor genes through suppression of DNA methyltransferase-1 gene in pancreatic cancer cell lines

    PubMed Central

    Azizi, Masoumeh; Teimoori-Toolabi, Ladan; Arzanani, Mohsen Karimi; Azadmanesh, Kayhan; Fard-Esfahani, Pezhman; Zeinali, Sirous

    2014-01-01

    Overexpression of DNA methyltransferase 1 (DNMT-1) is observed mostly in pancreatic cancer and it can cause tumor suppressor genes silencing in this disease. Recent studies suggest that abnormal expressions of microRNAs (miRs) are involved in pathogenesis of different types of human cancers including pancreatic cancer. In this study we aimed to investigate the effect of miR-148b and -152 on reverting the tumorigenic phenotype of pancreatic cancer cell lines. In order to investigate whether miR-148b and -152 are involved in the regulation of DNMT-1, luciferase reporter assay was used and confirmed that the DNMT-1 mRNA could be a target for miR-148b and miR-152. Furthermore, overexpression of miR-148b and -152 in pancreatic cancer cell lines (MIA PaCa-2 and AsPC-1) decreased DNMT-1 expression (53% and 59% respectively), returned DNA methylation to normal patterns and induced re-expression of tumor suppressor genes, like BNIP3 (4.7- and 3.8-fold) and SPARC (5.3- and 2.9-fold) for miR-148b and -152 respectively. Moreover, the introduced miR-148b and -152 could inhibit the proliferation of MIA PaCa-2 (35% and 37% respectively) and AsPC-1 (39% and 40% respectively) cell lines. The apoptosis rates of MIA PaCa-1 after treatment with miR-148b and -152 were 10% and 8% respectively; while these rates in AsPC-1 were 16% and 11% respectively. Conclusively these findings mean that miRs that are targeting DNMT-1 and modifying methylation status of tumor suppressor genes such as BNIP3 and SPARC can be applied in killing the pancreatic cancer cells and decreasing the tumorigenicity of these cells. PMID:24448385

  1. A GPU-based framework for modeling real-time 3D lung tumor conformal dosimetry with subject-specific lung tumor motion

    NASA Astrophysics Data System (ADS)

    Min, Yugang; Santhanam, Anand; Neelakkantan, Harini; Ruddy, Bari H.; Meeks, Sanford L.; Kupelian, Patrick A.

    2010-09-01

    In this paper, we present a graphics processing unit (GPU)-based simulation framework to calculate the delivered dose to a 3D moving lung tumor and its surrounding normal tissues, which are undergoing subject-specific lung deformations. The GPU-based simulation framework models the motion of the 3D volumetric lung tumor and its surrounding tissues, simulates the dose delivery using the dose extracted from a treatment plan using Pinnacle Treatment Planning System, Phillips, for one of the 3DCTs of the 4DCT and predicts the amount and location of radiation doses deposited inside the lung. The 4DCT lung datasets were registered with each other using a modified optical flow algorithm. The motion of the tumor and the motion of the surrounding tissues were simulated by measuring the changes in lung volume during the radiotherapy treatment using spirometry. The real-time dose delivered to the tumor for each beam is generated by summing the dose delivered to the target volume at each increase in lung volume during the beam delivery time period. The simulation results showed the real-time capability of the framework at 20 discrete tumor motion steps per breath, which is higher than the number of 4DCT steps (approximately 12) reconstructed during multiple breathing cycles.

  2. Comparative Assessment of Liver Tumor Motion Using Cine–Magnetic Resonance Imaging Versus 4-Dimensional Computed Tomography

    SciTech Connect

    Fernandes, Annemarie T.; Apisarnthanarax, Smith; Yin, Lingshu; Zou, Wei; Rosen, Mark; Plastaras, John P.; Ben-Josef, Edgar; Metz, James M.; Teo, Boon-Keng

    2015-04-01

    Purpose: To compare the extent of tumor motion between 4-dimensional CT (4DCT) and cine-MRI in patients with hepatic tumors treated with radiation therapy. Methods and Materials: Patients with liver tumors who underwent 4DCT and 2-dimensional biplanar cine-MRI scans during simulation were retrospectively reviewed to determine the extent of target motion in the superior–inferior, anterior–posterior, and lateral directions. Cine-MRI was performed over 5 minutes. Tumor motion from MRI was determined by tracking the centroid of the gross tumor volume using deformable image registration. Motion estimates from 4DCT were performed by evaluation of the fiducial, residual contrast (or liver contour) positions in each CT phase. Results: Sixteen patients with hepatocellular carcinoma (n=11), cholangiocarcinoma (n=3), and liver metastasis (n=2) were reviewed. Cine-MRI motion was larger than 4DCT for the superior–inferior direction in 50% of patients by a median of 3.0 mm (range, 1.5-7 mm), the anterior–posterior direction in 44% of patients by a median of 2.5 mm (range, 1-5.5 mm), and laterally in 63% of patients by a median of 1.1 mm (range, 0.2-4.5 mm). Conclusions: Cine-MRI frequently detects larger differences in hepatic intrafraction tumor motion when compared with 4DCT most notably in the superior–inferior direction, and may be useful when assessing the need for or treating without respiratory management, particularly in patients with unreliable 4DCT imaging. Margins wider than the internal target volume as defined by 4DCT were required to encompass nearly all the motion detected by cine-MRI for some of the patients in this study.

  3. Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway.

    PubMed

    Wang, Yongwei; Wu, Xiangsong; Zhou, Yinan; Jiang, Hongchi; Pan, Shangha; Sun, Bei

    2016-03-01

    Pancreatic cancer is an aggressive malignancy, which generally respond poorly to chemotherapy. Hence, novel agents that are safe and effective are highly needed. The aim of this study was to investigate whether piperlongumine, a natural product isolated from the fruit of the pepper Piper longum, has any efficacy against human pancreatic cancer when used either alone or in combination with gemcitabine in vitro and in a xenograft mouse model. In vitro, piperlongumine inhibited the proliferation of pancreatic cancer cell lines, potentiated the apoptotic effects of gemcitabine, inhibited the constitutive and inducible activation of NF-κB, and suppressed the NF-κB-regulated expression of c-Myc, cyclin D1, Bcl-2, Bcl-xL, Survivin, XIAP, VEGF, and matrix metalloproteinase-9 (MMP-9). Furthermore, in an in vivo xenograft model, we found piperlongumine alone significantly suppressed tumor growth and enhanced the antitumor properties of gemcitabine. These results were consistent with the downregulation of NF-κB activity and its target genes, decreased proliferation (PCNA and Ki-67), decreased microvessel density (CD31), and increased apoptosis (TUNEL) in tumor remnants. Collectively, our results suggest that piperlongumine alone exhibits significant antitumor effects against human pancreatic cancer and it further enhances the therapeutic effects of gemcitabine, possibly through the modulation of NF-κB- and NF-κB-regulated gene products. PMID:26667450

  4. Mid-Ventilation Concept for Mobile Pulmonary Tumors: Internal Tumor Trajectory Versus Selective Reconstruction of Four-Dimensional Computed Tomography Frames Based on External Breathing Motion

    SciTech Connect

    Guckenberger, Matthias Wilbert, Juergen; Krieger, Thomas; Richter, Anne; Baier, Kurt; Flentje, Michael

    2009-06-01

    Purpose: To evaluate the accuracy of direct reconstruction of mid-ventilation and peak-phase four-dimensional (4D) computed tomography (CT) frames based on the external breathing signal. Methods and Materials: For 11 patients with 15 pulmonary targets, a respiration-correlated CT study (4D CT) was acquired for treatment planning. After retrospective time-based sorting of raw projection data and reconstruction of eight CT frames equally distributed over the breathing cycle, mean tumor position (P{sub mean}), mid-ventilation frame, and breathing motion were evaluated based on the internal tumor trajectory. Analysis of the external breathing signal (pressure sensor around abdomen) with amplitude-based sorting of projections was performed for direct reconstruction of the mid-ventilation frame and frames at peak phases of the breathing cycle. Results: On the basis of the eight 4D CT frames equally spaced in time, tumor motion was largest in the craniocaudal direction, with 12 {+-} 7 mm on average. Tumor motion between the two frames reconstructed at peak phases was not different in the craniocaudal and anterior-posterior directions but was systematically smaller in the left-right direction by 1 mm on average. The 3-dimensional distance between P{sub mean} and the tumor position in the mid-ventilation frame based on the internal tumor trajectory was 1.2 {+-} 1 mm. Reconstruction of the mid-ventilation frame at the mean amplitude position of the external breathing signal resulted in tumor positions 2.0 {+-} 1.1 mm distant from P{sub mean}. Breathing-induced motion artifacts in mid-ventilation frames caused negligible changes in tumor volume and shape. Conclusions: Direct reconstruction of the mid-ventilation frame and frames at peak phases based on the external breathing signal was reliable. This makes the reconstruction of only three 4D CT frames sufficient for application of the mid-ventilation technique in clinical practice.

  5. Identification of pancreatic tumors in vivo with ligand-targeted, pH responsive mesoporous silica nanoparticles by multispectral optoacoustic tomography.

    PubMed

    Gurka, Marie K; Pender, Dillon; Chuong, Phillip; Fouts, Benjamin L; Sobelov, Alexander; McNally, Molly W; Mezera, Megan; Woo, Shiao Y; McNally, Lacey R

    2016-06-10

    Despite significant efforts to translate nanotechnology for cancer application, lack of identification of biodistribution/accumulation of these nanovehicles in vivo remains a substantial barrier for successful implementation of theranostic nanoparticles in the clinic. The purpose of the study was to develop a tumor-targeted theranostic nanovehicle for pancreatic cancer detectable by multispectral optoacoustic tomography (MSOT). To improve the tumor specificity of our mesoporous silica nanoparticle (MSN), we utilized a dual targeting strategy: 1) an elevated tumor receptor, urokinase plasminogen activator receptor (UPAR), and 2) the acidic tumor microenvironment. The tumor specificity of the MSN particle was improved with the addition of both chitosan, targeting acidic pH, and urokinase plasminogen activator (UPA), targeting UPAR. Drug release assays confirmed pH responsive release of gemcitabine in vitro. The UPAR specific binding of MSN-UPA nanoparticles was confirmed by reduction in fluorescence signal following MSN-UPA nanoparticle treatment in UPAR positive cells blocked with a UPAR-blocking antibody. Based upon Indocyanine Green encapsulation within the nanoparticles, UPA ligand targeted MSNs demonstrated increased intensity compared to untargeted MSNs at both pH7.4 (7×) and 6.5 (20×); however the signal was much more pronounced at a pH of 6.5 using tissue phantoms (p<0.05). In vivo, MSN-UPA particles demonstrated orthotopic pancreatic tumor specific accumulation compared to liver or kidney as identified using multispectral optoacoustic tomography (p<0.05) and confirmed by ex vivo analysis. By tracking in vivo nanoparticle biodistribution with MSOT, it was shown that pH responsive, ligand targeted MSNs preferentially bind to pancreatic tumors for payload delivery. PMID:26763377

  6. SU-C-210-06: Quantitative Evaluation of Dosimetric Effects Resulting From Positional Variations of Pancreatic Tumor Volumes

    SciTech Connect

    Yu, S; Sehgal, V; Wei, R; Lawrenson, L; Kuo, J; Hanna, N; Ramsinghani, N; Daroui, P; Al-Ghazi, M

    2015-06-15

    Purpose: The aim of this study is to quantify dosimetric effects resulting from variation in pancreatic tumor position assessed by bony anatomy and implanted fiducial markers Methods: Twelve pancreatic cancer patients were retrospectively analyzed for this study. All patients received modulated arc therapy (VMAT) treatment using fiducial-based Image Guided Radiation Therapy (IGRT) to the intact pancreas. Using daily orthogonal kV and/or Cone beam CT images, the shift needed to co-register the daily pre-treatment images to reference CT from fiducial to bone (Fid-Bone) were recorded as Left-Right (LR), Anterior-Posterior (AP) and Superior-Inferior (SI). The original VMAT plan iso-center was shifted based on KV bone matching positions at 5 evenly spaced fractions. Dose coverage of the planning target volumes (PTVs) (V100%), mean dose to liver, kidney and stomach/duodenum were assessed in the modified plans. Results: A total of 306 fractions were analyzed. The absolute fiducial-bone positional shifts were greatest in the SI direction, (AP = 2.7 ± 3.0, LR = 2.8 ± 2.8, and SI 6.3 ± 7.9 mm, mean ± SD). The V100% was significantly reduced by 13.5%, (Fid-Bone = 95.3 ± 2.0 vs. 82.3 ± 11.8%, p=0.02). This varied widely among patients (Fid-Bone V100% Range = 2–60%), where 33% of patients had a reduction in V100% of more than 10%. The impact on OARs was greatest to the liver (Fid-Bone= 14.6 vs. 16.1 Gy, 10%), and stomach, (Fid-Bone = 23.9 vx. 25.5 Gy, 7%), however was not statistically significant (p=0.10 both). Conclusion: Compared to matching by fiducial markers, matching by bony anatomy would have substantially reduced the PTV coverage by 13.5%. This reinforces the importance of online position verification based on fiducial markers. Hence, implantation of fiducial markers is strongly recommended for pancreatic cancer patients undergoing intensity modulated radiation therapy treatments.

  7. Interfractional Position Variation of Pancreatic Tumors Quantified Using Intratumoral Fiducial Markers and Daily Cone Beam Computed Tomography

    SciTech Connect

    Horst, Astrid van der; Wognum, Silvia; Dávila Fajardo, Raquel; Jong, Rianne de; Hooft, Jeanin E. van; Fockens, Paul; Tienhoven, Geertjan van; Bel, Arjan

    2013-09-01

    Purpose: The aim of this study was to quantify interfractional pancreatic position variation using fiducial markers visible on daily cone beam computed tomography (CBCT) scans. In addition, we analyzed possible migration of the markers to investigate their suitability for tumor localization. Methods and Materials: For 13 pancreatic cancer patients with implanted Visicoil markers, CBCT scans were obtained before 17 to 25 fractions (300 CBCTs in total). Image registration with the reference CT was used to determine the displacement of the 2 to 3 markers relative to bony anatomy and to each other. We analyzed the distance between marker pairs as a function of time to identify marker registration error (SD of linear fit residuals) and possible marker migration. For each patient, we determined the mean displacement of markers relative to the reference CT (systematic position error) and the spread in displacements (random position error). From this, we calculated the group systematic error, Σ, and group random error, σ. Results: Marker pair distances showed slight trends with time (range, −0.14 to 0.14 mm/day), possibly due to tissue deformation, but no shifts that would indicate marker migration. The mean SD of the fit residuals was 0.8 mm. We found large interfractional position variations, with for 116 of 300 (39%) fractions a 3-dimensional vector displacement of >10 mm. The spread in displacement varied significantly (P<.01) between patients, from a vector range of 9.1 mm to one of 24.6 mm. For the patient group, Σ was 3.8, 6.6, and 3.5 mm; and σ was 3.6, 4.7 and 2.5 mm, in left–right, superior–inferior, and anterior–posterior directions, respectively. Conclusions: We found large systematic displacements of the fiducial markers relative to bony anatomy, in addition to wide distributions of displacement. These results for interfractional position variation confirm the potential benefit of using fiducial markers rather than bony anatomy for daily online

  8. [Somatostatin-producing endocrine pancreatic tumor in Recklinghausen's neurofibromatosis. Case report and literature review].

    PubMed

    Saurenmann, P; Binswanger, R; Maurer, R; Stamm, B; Hegglin, J

    1987-07-25

    Somatostatin-producing tumors of the pancreas were first described in 1977. In 1983 a syndrome involving multiple endocrine neoplasias (MEN) was named type III A. This syndrome consists of carcinoid of the duodenum, often producing somatostatin, and von Recklinghausen's disease (neurofibromatosis) or pheochromocytoma. The case is reported of a 62-year-old man with familial neurofibromatosis and a tumor of the head of the pancreas spreading into pars II of the duodenum. After Whipple's duodenopancreatectomy the patient exhibited no further symptoms. Immunohistochemistry served to prove the production of somatostatin and small amounts of calcitonin in the tumor. PMID:2890200

  9. Potent antitumor effect of neurotensin receptor-targeted oncolytic adenovirus co-expressing decorin and Wnt antagonist in an orthotopic pancreatic tumor model.

    PubMed

    Na, Youjin; Choi, Joung-Woo; Kasala, Dayananda; Hong, JinWoo; Oh, Eonju; Li, Yan; Jung, Soo-Jung; Kim, Sung Wan; Yun, Chae-Ok

    2015-12-28

    Pancreatic cancer is highly aggressive, malignant, and notoriously difficult to cure using conventional cancer therapies. These conventional therapies have significant limitations due to excessive extracellular matrix (ECM) of pancreatic cancer and poor cancer specificity. The excess ECM prevents infiltration of drugs into the inner layer of the solid tumor. Therefore, novel treatment modalities that can specifically target the tumor and degrade the ECM are required for effective therapy. In the present study, we used ECM-degrading and Wnt signal-disrupting oncolytic adenovirus (oAd/DCN/LRP) to achieve a desirable therapeutic outcome against pancreatic cancer. In addition, to overcome the limitations in systemic delivery of oncolytic Ad (oAd) and to specifically target pancreatic cancer, neurotensin peptide (NT)-conjugated polyethylene glycol (PEG) was chemically crosslinked to the surface of Ad, generating a systemically injectable hybrid system, oAd/DCN/LRP-PEG-NT. We tested the targeting and therapeutic efficacy of oAd/DCN/LRP-PEG-NT toward neurotensin receptor 1 (NTR)-overexpressing pancreatic cancer cells, both in vitro and in vivo. The oAd/DCN/LRP-PEG-NT elicited increased NTR-selective cancer cell killing and transduction efficiency when compared with a cognate control lacking NT (oAd/DCN/LRP-PEG). Furthermore, systemic administration of oAd/DCN/LRP-PEG-NT significantly decreased induction of innate and adaptive immune responses against Ad, and blood retention time was markedly prolonged by PEGylation. Moreover, NTR-targeting oAd elicited greater in vivo tumor growth suppression when compared with naked oAd and 9.5 × 10(6)-fold increased tumor-to-liver ratio. This significantly enhanced antitumor effect of oAd/DCN/LRP-PEG-NT was mediated by active viral replication and viral spreading, which was facilitated by ECM degradation and inhibition of Wnt signaling-related factors (Wnt, β-catenin, and/or vimentin) in the tumor tissues. Taken together, these

  10. An Increased Abundance of Tumor-Infiltrating Regulatory T Cells Is Correlated with the Progression and Prognosis of Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Tang, Yichen; Xu, Xuejun; Guo, Shixiang; Zhang, Chaobin; Tang, Yan; Tian, Yi; Ni, Bing; Lu, Binfeng; Wang, Huaizhi

    2014-01-01

    CD4+CD25+Foxp3+ regulatory T cells (Tregs) can inhibit cytotoxic responses. Though several studies have analyzed Treg frequency in the peripheral blood mononuclear cells (PBMCs) of pancreatic ductal adenocarcinoma (PDA) patients using flow cytometry (FCM), few studies have examined how intratumoral Tregs might contribute to immunosuppression in the tumor microenvironment. Thus, the potential role of intratumoral Tregs in PDA patients remains to be elucidated. In this study, we found that the percentages of Tregs, CD4+ T cells and CD8+ T cells were all increased significantly in tumor tissue compared to control pancreatic tissue, as assessed via FCM, whereas the percentages of these cell types in PBMCs did not differ between PDA patients and healthy volunteers. The percentages of CD8+ T cells in tumors were significantly lower than in PDA patient PBMCs. In addition, the relative numbers of CD4+CD25+Foxp3+ Tregs and CD8+ T cells were negatively correlated in the tissue of PDA patients, and the abundance of Tregs was significantly correlated with tumor differentiation. Additionally, Foxp3+ T cells were observed more frequently in juxtatumoral stroma (immediately adjacent to the tumor epithelial cells). Patients showing an increased prevalence of Foxp3+ T cells had a poorer prognosis, which was an independent factor for patient survival. These results suggest that Tregs may promote PDA progression by inhibiting the antitumor immunity of CD8+ T cells at local intratumoral sites. Moreover, a high proportion of Tregs in tumor tissues may reflect suppressed antitumor immunity. PMID:24637664

  11. Evaluation of tumor localization in respiration motion-corrected cone-beam CT: Prospective study in lung

    SciTech Connect

    Dzyubak, Oleksandr; Kincaid, Russell; Hertanto, Agung; Hu, Yu-Chi; Pham, Hai; Yorke, Ellen; Zhang, Qinghui; Mageras, Gig S.; Rimner, Andreas

    2014-10-15

    Purpose: Target localization accuracy of cone-beam CT (CBCT) images used in radiation treatment of respiratory disease sites is affected by motion artifacts (blurring and streaking). The authors have previously reported on a method of respiratory motion correction in thoracic CBCT at end expiration (EE). The previous retrospective study was limited to examination of reducing motion artifacts in a small number of patient cases. They report here on a prospective study in a larger group of lung cancer patients to evaluate respiratory motion-corrected (RMC)-CBCT ability to improve lung tumor localization accuracy and reduce motion artifacts in Linac-mounted CBCT images. A second study goal examines whether the motion correction derived from a respiration-correlated CT (RCCT) at simulation yields similar tumor localization accuracy at treatment. Methods: In an IRB-approved study, 19 lung cancer patients (22 tumors) received a RCCT at simulation, and on one treatment day received a RCCT, a respiratory-gated CBCT at end expiration, and a 1-min CBCT. A respiration monitor of abdominal displacement was used during all scans. In addition to a CBCT reconstruction without motion correction, the motion correction method was applied to the same 1-min scan. Projection images were sorted into ten bins based on abdominal displacement, and each bin was reconstructed to produce ten intermediate CBCT images. Each intermediate CBCT was deformed to the end expiration state using a motion model derived from RCCT. The deformed intermediate CBCT images were then added to produce a final RMC-CBCT. In order to evaluate the second study goal, the CBCT was corrected in two ways, one using a model derived from the RCCT at simulation [RMC-CBCT(sim)], the other from the RCCT at treatment [RMC-CBCT(tx)]. Image evaluation compared uncorrected CBCT, RMC-CBCT(sim), and RMC-CBCT(tx). The gated CBCT at end expiration served as the criterion standard for comparison. Using automatic rigid image

  12. Pancreatic cancer risk in hereditary pancreatitis

    PubMed Central

    Weiss, Frank U.

    2014-01-01

    Inflammation is part of the body's immune response in order to remove harmful stimuli—like pathogens, irritants or damaged cells—and start the healing process. Recurrent or chronic inflammation on the other side seems a predisposing factor for carcinogenesis and has been found associated with cancer development. In chronic pancreatitis mutations of the cationic trypsinogen (PRSS1) gene have been identified as risk factors of the disease. Hereditary pancreatitis (HP) is a rare cause of chronic pancreatic inflammation with an early onset, mostly during childhood. HP often starts with recurrent episodes of acute pancreatitis and the clinical phenotype is not very much different from other etiologies of the disease. The long-lasting inflammation however generates a tumor promoting environment and represents a major risk factor for tumor development This review will reflect our knowledge concerning the specific risk of HP patients to develop pancreatic cancer. PMID:24600409

  13. Pancreatitis - discharge

    MedlinePlus

    Chronic pancreatitis - discharge; Pancreatitis - chronic - discharge; Pancreatic insufficiency - discharge; Acute pancreatitis - discharge ... You were in the hospital because you have pancreatitis. This is a swelling of the pancreas. You ...

  14. Using an external surrogate for predictor model training in real-time motion management of lung tumors

    SciTech Connect

    Rottmann, Joerg; Berbeco, Ross

    2014-12-15

    Purpose: Precise prediction of respiratory motion is a prerequisite for real-time motion compensation techniques such as beam, dynamic couch, or dynamic multileaf collimator tracking. Collection of tumor motion data to train the prediction model is required for most algorithms. To avoid exposure of patients to additional dose from imaging during this procedure, the feasibility of training a linear respiratory motion prediction model with an external surrogate signal is investigated and its performance benchmarked against training the model with tumor positions directly. Methods: The authors implement a lung tumor motion prediction algorithm based on linear ridge regression that is suitable to overcome system latencies up to about 300 ms. Its performance is investigated on a data set of 91 patient breathing trajectories recorded from fiducial marker tracking during radiotherapy delivery to the lung of ten patients. The expected 3D geometric error is quantified as a function of predictor lookahead time, signal sampling frequency and history vector length. Additionally, adaptive model retraining is evaluated, i.e., repeatedly updating the prediction model after initial training. Training length for this is gradually increased with incoming (internal) data availability. To assess practical feasibility model calculation times as well as various minimum data lengths for retraining are evaluated. Relative performance of model training with external surrogate motion data versus tumor motion data is evaluated. However, an internal–external motion correlation model is not utilized, i.e., prediction is solely driven by internal motion in both cases. Results: Similar prediction performance was achieved for training the model with external surrogate data versus internal (tumor motion) data. Adaptive model retraining can substantially boost performance in the case of external surrogate training while it has little impact for training with internal motion data. A minimum

  15. Interfractional Reproducibility of Lung Tumor Location Using Various Methods of Respiratory Motion Mitigation

    SciTech Connect

    Starkschall, George; Balter, Peter; Britton, Keith; McAleer, Mary F.; Cox, James D.; Mohan, Radhe

    2011-02-01

    Purpose: To determine interfractional reproducibility of the location of lung tumors using respiratory motion mitigation. Methods and Materials: Free-breathing four-dimensional computed tomography (CT) data sets and CT data sets during breath hold were acquired weekly for 17 patients undergoing treatment for non-small-cell lung cancer. Distances between the center of the gross tumor volume (GTV) and a reproducible bony reference point under conditions of breath hold on end inspiration (EI) and end expiration (EE) and during free breathing on the 0% phase (corresponding to EI) and 50% phase (corresponding to EE) were analyzed for interfractional reproducibility. Systematic uncertainties in tumor location were determined as the difference in distance between the GTV center on the first CT data set and the mean location of GTV centers on the subsequent data sets. Random uncertainties in tumor location were determined as the standard deviation of the distances between the GTV centers and the bony reference points. Margins to account for systematic and random interfractional variations were estimated based on these uncertainties. Results: Mean values of interfractional setup uncertainties were as follows: systematic uncertainties-EI, 0.3 cm; EE, 0.2 cm; 0% phase, 0.3 cm; and 50% phase, 0.3 cm; and random uncertainties-EI, 0.3 cm; EE, 0.3 cm; 0% phase, 0.3 cm; and 50% phase, 0.3 cm. There does not appear to be any correlation between uncertainties and GTV size, but there appears to be a weak positive correlation between uncertainties and the magnitude of GTV excursion. Conclusions: Voluntary breath hold and gating on either EI or EE appear to be equally reliable methods of ensuring the reproducibility of lung tumor position. We recommend setup margins of 0.3 cm if using cone-beam CT or kilovoltage X-ray with fiducials and aligning directly to the tumor and 0.8 cm when aligning to a nearby bony surrogate using cone-beam CT or kilovoltage X-ray.

  16. Tumor Tracking Method Based on a Deformable 4D CT Breathing Motion Model Driven by an External Surface Surrogate

    SciTech Connect

    Fassi, Aurora; Schaerer, Joël; Fernandes, Mathieu; Riboldi, Marco; Sarrut, David; Baroni, Guido

    2014-01-01

    Purpose: To develop a tumor tracking method based on a surrogate-driven motion model, which provides noninvasive dynamic localization of extracranial targets for the compensation of respiration-induced intrafraction motion in high-precision radiation therapy. Methods and Materials: The proposed approach is based on a patient-specific breathing motion model, derived a priori from 4-dimensional planning computed tomography (CT) images. Model parameters (respiratory baseline, amplitude, and phase) are retrieved and updated at each treatment fraction according to in-room radiography acquisition and optical surface imaging. The baseline parameter is adapted to the interfraction variations obtained from the daily cone beam (CB) CT scan. The respiratory amplitude and phase are extracted from an external breathing surrogate, estimated from the displacement of the patient thoracoabdominal surface, acquired with a noninvasive surface imaging device. The developed method was tested on a database of 7 lung cancer patients, including the synchronized information on internal and external respiratory motion during a CBCT scan. Results: About 30 seconds of simultaneous acquisition of CBCT and optical surface images were analyzed for each patient. The tumor trajectories identified in CBCT projections were used as reference and compared with the target trajectories estimated from surface displacement with the a priori motion model. The resulting absolute differences between the reference and estimated tumor motion along the 2 image dimensions ranged between 0.7 and 2.4 mm; the measured phase shifts did not exceed 7% of the breathing cycle length. Conclusions: We investigated a tumor tracking method that integrates breathing motion information provided by the 4-dimensional planning CT with surface imaging at the time of treatment, representing an alternative approach to point-based external–internal correlation models. Although an in-room radiograph-based assessment of the

  17. Vasohibin-1 Expression Is Regulated by Transforming Growth Factor-β/Bone Morphogenic Protein Signaling Pathway Between Tumor-Associated Macrophages and Pancreatic Cancer Cells

    PubMed Central

    Seppänen, Hanna; Kauttu, Tuuli; Vainionpää, Sanna; Ye, Yingjiang; Mustonen, Harri

    2013-01-01

    Vasohibin-1 has been detected in endothelial cells as an intrinsic angiogenesis inhibitor. Both tumor-associated macrophages (TAMs) and transforming growth factor-β (TGF-β)/bone morphogenic protein (BMP) signaling have been reported to promote angiogenesis in cancer. However, whether vasohibin-1 expression is regulated by TGF-β/BMP signaling between TAMs and cancer cells remains unclear. The expression of TGF-β1, TGF-β2, BMP-4, and BMP-7 in TAMs and the expression of vasohibin-1, vascular endothelial growth factor-A (VEGF-A), and VEGF-C in two pancreatic cancer cell lines (a nonmetastatic cell line Panc-1 and a distant metastatic cell line HPAF-II) were measured by real-time reverse transcription-polymerase chain reaction (RT-PCR). The TGF-β receptor 1 and BMP receptor 1 were inhibited by the inhibitor SB-431542 and LDN193189, respectively. Thereafter, vasohibin-1, VEGF-A, and VEGF-C expression was detected by real-time RT-PCR. We found that the expression of TGF-β1, TGF-β2, BMP-4, and BMP-7 was upregulated in TAMs cocultured with pancreatic cancer cells. Vasohibin-1, VEGF-A, and VEGF-C mRNA expression in pancreatic cancer cells was upregulated by TAMs. Vasohibin-1 expression in pancreatic cancer cells cocultured with TAMs was upregulated significantly when TGF-β receptors or BMP receptors were inhibited, but VEGF-C expression was downregulated. Therefore, Vasohibin-1 expression is regulated by the TGF-β/BMP signaling between TAMs and pancreatic cancer cells. These results might shed a new light on the antiangiogenesis therapy in the pancreatic cancer. PMID:23651239

  18. K-Ras mutation detection in liquid biopsy and tumor tissue as prognostic biomarker in patients with pancreatic cancer: a systematic review with meta-analysis.

    PubMed

    Li, Tao; Zheng, Yuanting; Sun, Hong; Zhuang, Rongyuan; Liu, Jing; Liu, Tianshu; Cai, Weimin

    2016-07-01

    K-Ras gene mutations have been found in most pancreatic cancers; however, conflicting data on the prognostic value of K-Ras mutations in pancreatic cancer have been published. We conducted a meta-analysis to assess its prognostic significance. Literature searches of PubMed, EMBASE, Cochrane Library, Web of Science and Google Scholar were performed through December 2015 to identify publications exploring the association of K-Ras mutation with overall survival. Forty eligible studies involving 3427 patients with pancreatic cancer were included in the present meta-analysis. Our analysis showed a hazard ratio (HR) of negative association with survival of 1.61 [95 % confidence interval (CI) 1.36-1.90; p < 0.01] in K-Ras mutant pancreatic cancer patients. In subgroup analyses, K-Ras mutations detected in tumor tissues and in liquid biopsies had HRs of 1.37 (95 % CI 1.20-1.57; p < 0.01) and 3.16 (95 % CI 2.1-4.71; p < 0.01), respectively. In addition, the HR was higher when K-Ras mutations were detected in fresh frozen samples (HR = 2.01, 95 % CI 1.28-3.16, p = 0.002) than in formalin-fixed, paraffin-embedded (FFPE) samples (HR = 1.29, 95 % CI 1.12-1.49, p < 0.01). Though K-Ras alterations are more frequent among non-East Asian individuals than East Asian individuals, there were no significant differences in HRs of survival between the two ethnic subgroups. In conclusion, this meta-analysis suggests that K-Ras mutations are associated with a worse overall survival in pancreatic cancer patients, especially when mutations are detected in liquid biopsies or fresh frozen tumor tissue samples. PMID:27225938

  19. SU-E-J-175: Comparison of the Treatment Reproducibility of Tumors Affected by Breathing Motion

    SciTech Connect

    Adamczyk, M; Piotrowski, T; Adamczyk, S

    2015-06-15

    Purpose: The aim of the dose distribution simulations was to form a global idea of intensity-modulated radiation therapy (IMRT) realization, by its comparison to three-dimensional conformal radiation therapy (3DCRT) delivery for tumors affected by respiratory motion. Methods: In the group of 10patients both 3DCRT and IMRT plans were prepared.For each field the motion kernel was generated with the largest movement amplitude of 4;6 and 8mm.Additionally,the sets of reference measurements were made in no motion conditions(0 mm).The evaluation of plan delivery,using a diode array placed on moving platform,was based on the Gamma Index analysis with distance to agreement of 3mm and dose difference of 3%. Results: IMRT plans tended to spare doses delivered to lungs compared to 3DCRT.Nonetheless,analyzed volumes showed no significant difference between the static and dynamic techniques,except for the volumes of both lungs receiving 10 and 15Gy.After adding the components associated with the respiratory movement,all IMRT lung parameters evaluated for the ipsilateral,contralateral and both lungs together,revealed considerable differences between the 0vs.6, 0vs.8 and 4vs.8-mm amplitudes.Similar results were obtained for the 3DCRT lung measurements,but without significance between the 0vs.6-mm amplitude.Taking into account the CTV score parameter in 3DCRT and IMRT plans,there was no statistically significant difference between the motion patterns with the smallest amplitudes.The differences were found for the 8-mm amplitude when it was compared both with static conditions and 4-mm amplitude (for 3DCRT) and between 0vs.6, 0vs.8 and 4vs.8-mm amplitudes (for IMRT).All accepted and measured 3DCRT and IMRT doses to spinal cord,esophagus and heart were always below the QUANTEC limits. Conclusion: The application of IMRT technique in lung radiotherapy affords possibilities for reducing the lung doses.For maximal amplitudes of breathing trajectory below 4mm,the disagreement between CTV

  20. SU-E-J-61: Monitoring Tumor Motion in Real-Time with EPID Imaging During Cervical Cancer Treatment

    SciTech Connect

    Mao, W; Hrycushko, B; Yan, Y; Foster, R; Albuquerque, K

    2015-06-15

    Purpose: Traditional external beam radiotherapy for cervical cancer requires setup by external skin marks. In order to improve treatment accuracy and reduce planning margin for more conformal therapy, it is essential to monitor tumor positions interfractionally and intrafractionally. We demonstrate feasibility of monitoring cervical tumor motion online using EPID imaging from Beam’s Eye View. Methods: Prior to treatment, 1∼2 cylindrical radio opaque markers were implanted into inferior aspect of cervix tumor. During external beam treatments on a Varian 2100C by 4-field 3D plans, treatment beam images were acquired continuously by an EPID. A Matlab program was developed to locate internal markers on MV images. Based on 2D marker positions obtained from different treatment fields, their 3D positions were estimated for every treatment fraction. Results: There were 398 images acquired during different treatment fractions of three cervical cancer patients. Markers were successfully located on every frame of image at an analysis speed of about 1 second per frame. Intrafraction motions were evaluated by comparing marker positions relative to the position on the first frame of image. The maximum intrafraction motion of the markers was 1.6 mm. Interfraction motions were evaluated by comparing 3D marker positions at different treatment fractions. The maximum interfraction motion was up to 10 mm. Careful comparison found that this is due to patient positioning since the bony structures shifted with the markers. Conclusion: This method provides a cost-free and simple solution for online tumor tracking for cervical cancer treatment since it is feasible to acquire and export EPID images with fast analysis in real time. This method does not need any extra equipment or deliver extra dose to patients. The online tumor motion information will be very useful to reduce planning margins and improve treatment accuracy, which is particularly important for SBRT treatment with long

  1. TAILS N-Terminomics and Proteomics Show Protein Degradation Dominates over Proteolytic Processing by Cathepsins in Pancreatic Tumors.

    PubMed

    Prudova, Anna; Gocheva, Vasilena; Auf dem Keller, Ulrich; Eckhard, Ulrich; Olson, Oakley C; Akkari, Leila; Butler, Georgina S; Fortelny, Nikolaus; Lange, Philipp F; Mark, Jennifer C; Joyce, Johanna A; Overall, Christopher M

    2016-08-01

    Deregulated cathepsin proteolysis occurs across numerous cancers, but in vivo substrates mediating tumorigenesis remain ill-defined. Applying 8-plex iTRAQ terminal amine isotopic labeling of substrates (TAILS), a systems-level N-terminome degradomics approach, we identified cathepsin B, H, L, S, and Z in vivo substrates and cleavage sites with the use of six different cathepsin knockout genotypes in the Rip1-Tag2 mouse model of pancreatic neuroendocrine tumorigenesis. Among 1,935 proteins and 1,114 N termini identified by TAILS, stable proteolytic products were identified in wild-type tumors compared with one or more different cathepsin knockouts (17%-44% of 139 cleavages). This suggests a lack of compensation at the substrate level by other cathepsins. The majority of neo-N termini (56%-83%) for all cathepsins was consistent with protein degradation. We validated substrates, including the glycolytic enzyme pyruvate kinase M2 associated with the Warburg effect, the ER chaperone GRP78, and the oncoprotein prothymosin-alpha. Thus, the identification of cathepsin substrates in tumorigenesis improves the understanding of cathepsin functions in normal physiology and cancer. PMID:27477282

  2. Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C82(OH)22 and its implication for de novo design of nanomedicine

    SciTech Connect

    Kang, S. -g.; Zhou, G.; Yang, P.; Liu, Y.; Sun, B.; Huynh, T.; Meng, H.; Zhao, L.; Xing, G.; Chen, C.; Zhao, Y.; Zhou, R.

    2012-09-18

    Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth-leading cause of cancer-related death in North America. Matrix metalloproteinases (MMPs) have long been targeted as a potential anticancer therapy because of their seminal role in angiogenesis and extracellular matrix (ECM) degradation of tumor survival and invasion. However, the inhibition specificity to MMPs and the molecular-level understanding of the inhibition mechanism remain largely unresolved. Here, we found that endohedral metallofullerenol Gd@C82(OH)22 can successfully inhibit the neoplastic activity with experiments at animal, tissue, and cellular levels. Gd@C82(OH)22 effectively blocks tumor growth in human pancreatic cancer xenografts in a nude mouse model. Enzyme activity assays also show Gd@C82(OH)22 not only suppresses the expression of MMPs but also significantly reduces their activities. We then applied large-scale molecular-dynamics simulations to illustrate the molecular mechanism by studying the Gd@C82(OH)22–MMP-9 interactions in atomic detail. Our data demonstrated that Gd@C82(OH)22 inhibits MMP-9 mainly via an exocite interaction, whereas the well-known zinc catalytic site only plays a minimal role. Steered by nonspecific electrostatic, hydrophobic, and specific hydrogen-bonding interactions, Gd@C82(OH)22 exhibits specific binding modes near the ligand-specificity loop S1', thereby inhibiting MMP-9 activity. Both the suppression of MMP expression and specific binding mode make Gd@C82(OH)22 a potentially more effective nanomedicine for pancreatic cancer than traditional medicines, which usually target the proteolytic sites directly but fail in selective inhibition. Finally, our findings provide insights for de novo design of nanomedicines for fatal diseases such as pancreatic cancer.

  3. Bundled assembly of helical nanostructures in polymeric micelles loaded with platinum drugs enhancing therapeutic efficiency against pancreatic tumor.

    PubMed

    Mochida, Yuki; Cabral, Horacio; Miura, Yutaka; Albertini, Francesco; Fukushima, Shigeto; Osada, Kensuke; Nishiyama, Nobuhiro; Kataoka, Kazunori

    2014-07-22

    Supramolecular assemblies of amphiphilic block copolymers having polypeptide segments offer significant advantages for tailoring spatial arrangement based on secondary structures in their optically active backbones. Here, we demonstrated the critical effect of α-helix bundles in cisplatin-conjugated poly(L- (or D-)glutamate) [P(L(or D)Glu)-CDDP] segment on the packaging of poly(ethylene glycol) (PEG)-P(L(or D)Glu)-CDDP block copolymers in the core of polymeric micelles (CDDP/m) and enhanced micelle tolerability to harsh in vivo conditions for accomplishing appreciable antitumor efficacy against intractable pancreatic tumor by systemic injection. CDDP/m prepared from optically inactive PEG-poly(D,L-glutamate) (P(D,LGlu)), gradually disintegrated in the bloodstream, resulting in increased accumulation in liver and spleen and reduced antitumor efficacy. Alternatively, CDDP/m from optically active PEG-P(L(or D)Glu) maintained micelle structure during circulation, and eventually attained selective tumor accumulation while reducing nonspecific distribution to liver and spleen. Circular dichroism and small-angle X-ray scattering measurements indicated regular bundled assembly of α-helices in the core of CDDP/m from PEG-P(L(or D)Glu), which is suggested to stabilize the micelle structure against dilution in physiological condition. CDDP/m suffered corrosion by chlorides in medium, yet the optically active micelles with α-helix bundles kept the micelle structure for prolonged time, with slowly releasing unimers and dimers from the surface of the bundled core in an erosion-like process, as verified by ultracentrifugation analysis. This is in sharp contrast with the abrupt disintegration of CDDP/m from PEG-P(D,LGlu) without secondary structures. The tailored assembly in the core of the polymeric micelles through regular arrangement of constituting segments is key to overcome their undesirable disintegration in bloodstream, thereby achieving efficient delivery of loaded

  4. Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone

    PubMed Central

    Chakrabarti, Gaurab; Silvers, Molly A.; Ilcheva, Mariya; Liu, Yuliang; Moore, Zachary R.; Luo, Xiuquan; Gao, Jinming; Anderson, Glenda; Liu, Lili; Sarode, Venetia; Gerber, David E.; Burma, Sandeep; DeBerardinis, Ralph J.; Gerson, Stanton L.; Boothman, David A.

    2015-01-01

    Base excision repair (BER) is an essential pathway for pancreatic ductal adenocarcinoma (PDA) survival. Attempts to target this repair pathway have failed due to lack of tumor-selectivity and very limited efficacy. The NAD(P)H:Quinone Oxidoreductase 1 (NQO1) bioactivatable drug, ß-lapachone (ARQ761 in clinical form), can provide tumor-selective and enhanced synergy with BER inhibition. ß-Lapachone undergoes NQO1-dependent futile redox cycling, generating massive intracellular hydrogen peroxide levels and oxidative DNA lesions that stimulate poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Rapid NAD+/ATP depletion and programmed necrosis results. To identify BER modulators essential for repair of ß-lapachone-induced DNA base damage, a focused synthetic lethal RNAi screen demonstrated that silencing the BER scaffolding protein, XRCC1, sensitized PDA cells. In contrast, depleting OGG1 N-glycosylase spared cells from ß-lap-induced lethality and blunted PARP1 hyperactivation. Combining ß-lapachone with XRCC1 knockdown or methoxyamine (MeOX), an apyrimidinic/apurinic (AP)-modifying agent, led to NQO1-dependent synergistic killing in PDA, NSCLC, breast and head and neck cancers. OGG1 knockdown, dicoumarol-treatment or NQO1- cancer cells were spared. MeOX + ß-lapachone exposure resulted in elevated DNA double-strand breaks, PARP1 hyperactivation and TUNEL+ programmed necrosis. Combination treatment caused dramatic antitumor activity, enhanced PARP1-hyperactivation in tumor tissue, and improved survival of mice bearing MiaPaca2-derived xenografts, with 33% apparent cures. Significance: Targeting base excision repair (BER) alone has limited therapeutic potential for pancreatic or other cancers due to a general lack of tumor-selectivity. Here, we present a treatment strategy that makes BER inhibition tumor-selective and NQO1-dependent for therapy of most solid neoplasms, particularly for pancreatic cancer. PMID:26602448

  5. Pretreatment Carbohydrate Antigen 19-9 Level Indicates Tumor Response, Early Distant Metastasis, Overall Survival, and Therapeutic Selection in Localized and Unresectable Pancreatic Cancer

    SciTech Connect

    Yoo, Tae; Lee, Woo Jin; Woo, Sang Myung; Kim, Tae Hyun; Han, Sung-Sik; Park, Sang-Jae; Moon, Sung Ho; Shin, Kyung Hwan; Kim, Sang Soo; Hong, Eun Kyung; Kim, Dae Yong; Park, Joong-Won

    2011-11-15

    Purpose: The use of chemoradiotherapy (CRT) for localized and unresectable pancreatic cancer has been disputed because of high probability of distant metastasis. Thus, we analyzed the effect of clinical parameters on tumor response, early distant metastasis within 3 months (DM{sup 3m}), and overall survival to identify an indicator for selecting patients who would benefit from CRT. Methods and Materials: This study retrospectively analyzed the data from 84 patients with localized and unresectable pancreatic cancer who underwent CRT between August 2002 and October 2009. Sex, age, tumor size, histological differentiation, N classification, pre- and post-treatment carbohydrate antigen (CA) 19-9 level, and CA 19-9 percent decrease were analyzed to identify risk factors associated with tumor response, DM{sup 3m}, and overall survival. Results: For all 84 patients, the median survival time was 12.5 months (range, 2-31.9 months), objective response (complete response or partial response) to CRT was observed in 28 patients (33.3%), and DM{sup 3m} occurred in 24 patients (28.6%). Multivariate analysis showed that pretreatment CA 19-9 level ({<=}400 vs. >400 U/ml) was significantly associated with tumor response (45.1% vs. 15.2%), DM{sup 3m} (19.6% vs. 42.4%), and median overall survival time (15.1 vs. 9.7 months) (p < 0.05 for all three parameters). Conclusion: For patients with localized and unresectable pancreatic cancer, pretreatment CA 19-9 level could be helpful in predicting tumor response, DM{sup 3m}, and overall survival and identifying patients who will benefit from CRT.

  6. Suppression of pancreatic tumor growth by targeted arsenic delivery with anti-CD44v6 single chain antibody conjugated nanoparticles.

    PubMed

    Qian, Chenchen; Wang, Yong; Chen, Yinting; Zeng, Linjuan; Zhang, Qiubo; Shuai, Xintao; Huang, Kaihong

    2013-08-01

    Arsenic trioxide (As2O3) is a promising anticancer agent for solid tumors. However, the high toxicity to normal tissues resulting from the lack of tumor specificity remains a huge challenge in its systemic application. Targeted vectors enabling drug delivery to specific cancer cells bring about great potential for better therapeutic efficacy whereas low side effects in cancer treatments. Our previous work has demonstrated that the anti-CD44v6 single chain variable fragment (scFv(CD44v6)) screened out from the human phage-displayed scFv library possesses high specificity and affinity to membrane antigen CD44v6 over-expressing in a subset of epithelium-derived cancers, such as pancreatic, hepatocellular, colorectal and gastric cancers. Herein, a maleimide-functionalized amphiphilic diblock copolymer of poly (ethylene glycol) and poly (D, L-lactide) (mal-PEG-PDLLA) was synthesized and assembled to vesicles with arsenite ion (As) encapsulated in their cores (As-NPs). Conjugation of scFv(CD44v6) with mal-PEG-PDLLA (scFv-As-NPs) enabled more efficient delivery of As and exhibited higher cytotoxic activity than non-targeted ones (As-NPs) in human pancreatic cancer cells PANC-1. Furthermore, the targeted delivery of As induced more significant gene suppression in terms of the expression of anti-apoptotic Bcl-2 protein. Consequently, the expression level of cleaved caspase-3 which is a molecular indicator of cell apoptosis was remarkably elevated. In animal tests, scFv-As-NPs were found to greatly increase accumulation of drug in tumor site and potentiate the efficacy of As in inhibiting tumor growth owing to the enhanced cell apoptosis. These results imply that our tumor specific nanocarriers provide a highly efficient and safe platform for pancreatic cancer therapy. PMID:23721794

  7. Diabetes and Pancreatic Cancer

    PubMed Central

    Li, Donghui

    2011-01-01

    Type 2 diabetes mellitus is likely the third modifiable risk factor for pancreatic cancer after cigarette smoking and obesity. Epidemiological investigations have found that long-term type 2 diabetes mellitus is associated with a 1.5- to 2.0-fold increase in the risk of pancreatic cancer. A causal relationship between diabetes and pancreatic cancer is also supported by findings from prediagnostic evaluations of glucose and insulin levels in prospective studies. Insulin resistance and associated hyperglycemia, hyperinsulinemia, and inflammation have been suggested to be the underlying mechanisms contributing to development of diabetes-associated pancreatic cancer. Signaling pathways that regulate the metabolic process also play important roles in cell proliferation and tumor growth. Use of the antidiabetic drug metformin has been associated with reduced risk of pancreatic cancer in diabetics and recognized as an antitumor agent with the potential to prevent and treat this cancer. On the other hand, new-onset diabetes may indicate subclinical pancreatic cancer, and patients with new-onset diabetes may constitute a population in whom pancreatic cancer can be detected early. Biomarkers that help define high-risk individuals for clinical screening for pancreatic cancer are urgently needed. Why pancreatic cancer causes diabetes and how diabetes affects the clinical outcome of pancreatic cancer have yet to be fully determined. Improved understanding of the pathological mechanisms shared by diabetes and pancreatic cancer would be the key to the development of novel preventive and therapeutic strategies for this cancer. PMID:22162232

  8. Applications of a novel tumor-grading-metastasis staging system for pancreatic neuroendocrine tumors: An analysis of surgical patients from a Chinese institution.

    PubMed

    Yang, Min; Tan, Chun-Lu; Zhang, Yi; Ke, Neng-Wen; Zeng, Lin; Li, Ang; Zhang, Hao; Xiong, Jun-Jie; Guo, Zi-Heng; Tian, Bo-Le; Liu, Xu-Bao

    2016-07-01

    The ability to stratify patients with pancreatic neuroendocrine tumors (p-NETs) into prognostic groups has been hindered by the absence of a commonly accepted staging system. Both the 7th tumor-node-metastasis (TNM) staging guidelines by the American Joint Committee on Cancer (AJCC) and the 2010 grading classifications by the World Health Organization (WHO) were validated to be unsatisfactory.We aim to evaluate the feasibility of combining the latest AJCC and WHO criteria to devise a novel tumor-grading-metastasis (TGM) staging system. We also sought to examine the stage-specific survival rates and the prognostic value of this new TGM system for p-NETs.Data of 120 patients with surgical resection and histopathological diagnosis of p-NETs from January 2004 to February 2014 in our institution were retrospectively collected and analyzed. Based on the AJCC and WHO criteria, we replaced the stage N0 and N1 with stage Ga (NET G1 and NET G2) and Gb (NET G3 and MANEC) respectively, without changes of the definition of T or M stage. The present novel TGM staging system was grouped as follows: stage I was defined as T1-2, Ga, M0; stage II as T3, Ga, M0 or as T1-3, Gb, M0; stage III as T4, Ga-b, M0 and stage IV as any T, M1.The new TGM staging system successfully distributed 55, 42, 12, and 11 eligible patients in stage I to IV, respectively. Differences of survival compared stage I with III and IV for patients with p-NETs were both statistically significant (P < 0.001), as well as those of stage II with III and IV (P < 0.001). Patients in stage I showed better a survival than those in stage II, whereas difference between stages III and IV was not notable (P = 0.001, P = 0.286, respectively). In multivariate models, when the TGM staging system was evaluated in place of the individual T, G, and M variables, this new criteria were proven to be an independent predictor of survival for surgically resected p-NETs (P < 0.05).Stratifying patients well, the current

  9. Residual motion of lung tumors in end-of-inhale respiratory gated radiotherapy based on external surrogates

    SciTech Connect

    Berbeco, Ross I.; Nishioka, Seiko; Shirato, Hiroki; Jiang, Steve B.

    2006-11-15

    It has been noted that some lung tumors exhibit large periodic motion due to respiration. To limit the amount of dose to healthy lung tissues, many clinics have begun gating radiotherapy treatment using externally placed surrogates. It has been observed by several institutions that the end-of-exhale (EOE) tumor position is more reproducible than other phases of the breathing cycle, so the gating window is often set there. From a treatment planning perspective, end-of-inhale (EOI) phase might be preferred for gating because the expanded lungs will further decrease the healthy tissue within the treatment field. We simulate gated treatment at the EOI phase, using a set of recently measured internal/external anatomy patient data. This paper attempts to answer three questions: (1) How much is the tumor residual motion when we use an external surrogate gating window at EOI? (2) How could we reduce the residual motion in the EOI gating window? (3) Is there a preference for amplitude- versus phase-based gating at EOI? We found that under free breathing conditions the residual motion of the tumors is much larger for EOI phase than for EOE phase. The mean values of residual motion at EOI were found to be 2.2 and 2.7 mm for amplitude- and phase-based gating, respectively, and, at EOE, 1.0 and 1.2 mm for amplitude- and phase-based gating, respectively. However, we note that the residual motion in the EOI gating window is correlated well with the reproducibility of the external surface position in the EOI phase. Using the results of a published breath-coaching study, we deduce that the residual motion of a lung tumor at EOI would approach that at EOE, with the same duty cycle (30%), under breath-coaching conditions. Additionally, we found that under these same conditions, phase-based gating approaches the same residual motion as amplitude-based gating, going from a 28% difference to 11%, for the patient with the largest difference between the two gating modalities. We conclude

  10. Technical Note: Intrafractional changes in time lag relationship between anterior–posterior external and superior–inferior internal motion signals in abdominal tumor sites

    SciTech Connect

    Regmi, Rajesh; Lovelock, D. Michael; Zhang, Pengpeng; Pham, Hai; Xiong, Jianping; Yorke, Ellen D.; Mageras, Gig S.; Goodman, Karyn A.; Wu, Abraham J.

    2015-06-15

    Purpose: To investigate constancy, within a treatment session, of the time lag relationship between implanted markers in abdominal tumors and an external motion surrogate. Methods: Six gastroesophageal junction and three pancreatic cancer patients (IRB-approved protocol) received two cone-beam CTs (CBCT), one before and one after treatment. Time between scans was less than 30 min. Each patient had at least one implanted fiducial marker near the tumor. In all scans, abdominal displacement (Varian RPM) was recorded as the external motion signal. Purpose-built software tracked fiducials, representing internal signal, in CBCT projection images. Time lag between superior–inferior (SI) internal and anterior–posterior external signals was found by maximizing the correlation coefficient in each breathing cycle and averaging over all cycles. Time-lag-induced discrepancy between internal SI position and that predicted from the external signal (external prediction error) was also calculated. Results: Mean ± standard deviation time lag, over all scans and patients, was 0.10 ± 0.07 s (range 0.01–0.36 s). External signal lagged the internal in 17/18 scans. Change in time lag between pre- and post-treatment CBCT was 0.06 ± 0.07 s (range 0.01–0.22 s), corresponding to 3.1% ± 3.7% (range 0.6%–10.8%) of gate width (range 1.6–3.1 s). In only one patient, change in time lag exceeded 10% of the gate width. External prediction error over all scans of all patients varied from 0.1 ± 0.1 to 1.6 ± 0.4 mm. Conclusions: Time lag between internal motion along SI and external signals is small compared to the treatment gate width of abdominal patients examined in this study. Change in time lag within a treatment session, inferred from pre- to post-treatment measurements is also small, suggesting that a single measurement of time lag at the session start is adequate. These findings require confirmation in a larger number of patients.

  11. Technical Note: Intrafractional changes in time lag relationship between anterior–posterior external and superior–inferior internal motion signals in abdominal tumor sites

    PubMed Central

    Regmi, Rajesh; Lovelock, D. Michael; Zhang, Pengpeng; Pham, Hai; Xiong, Jianping; Yorke, Ellen D.; Goodman, Karyn A.; Wu, Abraham J.; Mageras, Gig S.

    2015-01-01

    Purpose: To investigate constancy, within a treatment session, of the time lag relationship between implanted markers in abdominal tumors and an external motion surrogate. Methods: Six gastroesophageal junction and three pancreatic cancer patients (IRB-approved protocol) received two cone-beam CTs (CBCT), one before and one after treatment. Time between scans was less than 30 min. Each patient had at least one implanted fiducial marker near the tumor. In all scans, abdominal displacement (Varian RPM) was recorded as the external motion signal. Purpose-built software tracked fiducials, representing internal signal, in CBCT projection images. Time lag between superior–inferior (SI) internal and anterior–posterior external signals was found by maximizing the correlation coefficient in each breathing cycle and averaging over all cycles. Time-lag-induced discrepancy between internal SI position and that predicted from the external signal (external prediction error) was also calculated. Results: Mean ± standard deviation time lag, over all scans and patients, was 0.10 ± 0.07 s (range 0.01–0.36 s). External signal lagged the internal in 17/18 scans. Change in time lag between pre- and post-treatment CBCT was 0.06 ± 0.07 s (range 0.01–0.22 s), corresponding to 3.1% ± 3.7% (range 0.6%–10.8%) of gate width (range 1.6–3.1 s). In only one patient, change in time lag exceeded 10% of the gate width. External prediction error over all scans of all patients varied from 0.1 ± 0.1 to 1.6 ± 0.4 mm. Conclusions: Time lag between internal motion along SI and external signals is small compared to the treatment gate width of abdominal patients examined in this study. Change in time lag within a treatment session, inferred from pre- to post-treatment measurements is also small, suggesting that a single measurement of time lag at the session start is adequate. These findings require confirmation in a larger number of patients. PMID:26127033

  12. MR guided thermal therapy of pancreatic tumors with endoluminal, intraluminal and interstitial catheter-based ultrasound devices: preliminary theoretical and experimental investigations

    NASA Astrophysics Data System (ADS)

    Prakash, Punit; Salgaonkar, Vasant A.; Scott, Serena J.; Jones, Peter; Hensley, Daniel; Holbrook, Andrew; Plata, Juan; Sommer, Graham; Diederich, Chris J.

    2013-02-01

    Image-guided thermal interventions have been proposed for potential palliative and curative treatments of pancreatic tumors. Catheter-based ultrasound devices offer the potential for temporal and 3D spatial control of the energy deposition profile. The objective of this study was to apply theoretical and experimental techniques to investigate the feasibility of endogastric, intraluminal and transgastric catheter-based ultrasound for MR guided thermal therapy of pancreatic tumors. The transgastric approach involves insertion of a catheter-based ultrasound applicator (array of 1.5 mm OD x 10 mm transducers, 360° or sectored 180°, ~7 MHz frequency, 13-14G cooling catheter) directly into the pancreas, either endoscopically or via image-guided percutaneous placement. An intraluminal applicator, of a more flexible but similar construct, was considered for endoscopic insertion directly into the pancreatic or biliary duct. An endoluminal approach was devised based on an ultrasound transducer assembly (tubular, planar, curvilinear) enclosed in a cooling balloon which is endoscopically positioned within the stomach or duodenum, adjacent to pancreatic targets from within the GI tract. A 3D acoustic bio-thermal model was implemented to calculate acoustic energy distributions and used a FEM solver to determine the transient temperature and thermal dose profiles in tissue during heating. These models were used to determine transducer parameters and delivery strategies and to study the feasibility of ablating 1-3 cm diameter tumors located 2-10 mm deep in the pancreas, while thermally sparing the stomach wall. Heterogeneous acoustic and thermal properties were incorporated, including approximations for tumor desmoplasia and dynamic changes during heating. A series of anatomic models based on imaging scans of representative patients were used to investigate the three approaches. Proof of concept (POC) endogastric and transgastric applicators were fabricated and experimentally

  13. Surgery for Pancreatic Cancer

    MedlinePlus

    ... the abdomen. The surgeon can look at the pancreas and other organs for tumors and take biopsy ... pancreatic cancers appear to be confined to the pancreas at the time they are found. Even then, ...

  14. Association between Genetic Subgroups of Pancreatic Ductal Adenocarcinoma Defined by High Density 500 K SNP-Arrays and Tumor Histopathology

    PubMed Central

    Gutiérrez, María Laura; Muñoz-Bellvis, Luís; Abad, María del Mar; Bengoechea, Oscar; González-González, María

    2011-01-01

    The specific genes and genetic pathways associated with pancreatic ductal adenocarcinoma are still largely unknown partially due to the low resolution of the techniques applied so far to their study. Here we used high-density 500 K single nucleotide polymorphism (SNP)-arrays to define those chromosomal regions which most commonly harbour copy number (CN) alterations and loss of heterozygozity (LOH) in a series of 20 PDAC tumors and we correlated the corresponding genetic profiles with the most relevant clinical and histopathological features of the disease. Overall our results showed that primary PDAC frequently display (>70%) extensive gains of chromosomes 1q, 7q, 8q and 20q, together with losses of chromosomes 1p, 9p, 12q, 17p and 18q, such chromosomal regions harboring multiple cancer- and PDAC-associated genes. Interestingly, these alterations clustered into two distinct genetic profiles characterized by gains of the 2q14.2, 3q22.1, 5q32, 10q26.13, 10q26.3, 11q13.1, 11q13.3, 11q13.4, 16q24.1, 16q24.3, 22q13.1, 22q13.31 and 22q13.32 chromosomal regions (group 1; n = 9) versus gains at 1q21.1 and losses of the 1p36.11, 6q25.2, 9p22.1, 9p24.3, 17p13.3 and Xp22.33 chromosomal regions (group 2; n = 11). From the clinical and histopathological point of view, group 1 cases were associated with smaller and well/moderately-differentiated grade I/II PDAC tumors, whereas and group 2 PDAC displayed a larger size and they mainly consisted of poorly-differentiated grade III carcinomas. These findings confirm the cytogenetic complexity and heterogenity of PDAC and provide evidence for the association between tumor cytogenetics and its histopathological features. In addition, we also show that the altered regions identified harbor multiple cancer associate genes that deserve further investigation to determine their relevance in the pathogenesis of PDAC. PMID:21811587

  15. Motion.

    ERIC Educational Resources Information Center

    Gerhart, James B.; Nussbaum, Rudi H.

    This monograph was written for the Conference on the New Instructional Materials in Physics held at the University of Washington in summer, 1965. It is intended for use in an introductory course in college physics. It consists of an extensive qualitative discussion of motion followed by a detailed development of the quantitative methods needed to…

  16. Motion.

    ERIC Educational Resources Information Center

    Brand, Judith, Ed.

    2002-01-01

    This issue of Exploratorium Magazine focuses on the topic of motion. Contents include: (1) "First Word" (Zach Tobias); (2) "Cosmic Collisions" (Robert Irion); (3) "The Mobile Cell" (Karen E. Kalumuck); (4) "The Paths of Paths" (Steven Vogel); (5) "Fragments" (Pearl Tesler); (6) "Moving Pictures" (Amy Snyder); (7) "Plants on the Go" (Katharine…

  17. A High Circulating Tumor Cell Count in Portal Vein Predicts Liver Metastasis From Periampullary or Pancreatic Cancer: A High Portal Venous CTC Count Predicts Liver Metastases.

    PubMed

    Tien, Yu Wen; Kuo, Hsun-Chuan; Ho, Be-Ing; Chang, Ming-Chu; Chang, Yu-Ting; Cheng, Mei-Fang; Chen, Huai-Lu; Liang, Ting-Yung; Wang, Chien-Fang; Huang, Chia-Yi; Shew, Jin-Yuh; Chang, Ying Chih; Lee, Eva Y H P; Lee, Wen-Hwa

    2016-04-01

    Circulating tumor cells (CTCs) released from a periampullary or pancreatic cancer can be more frequently detected in the portal than the systemic circulation and potentially can be used to identify patients with liver micrometastases. Aims of this study is to determine if CTCs count in portal venous blood of patients with nonmetastatic periampullary or pancreatic adenocarcinoma can be used as a predictor for subsequent liver metastases. CTCs were quantified in portal and peripheral venous blood samples collected simultaneously during pancreaticoduodenectomy in patients with presumed periampullary or pancreatic adenocarcinoma without image-discernible metastasis. Postoperatively patients were monitored for liver metastasis by abdominal magnetic resonance imaging or computed tomography every 3 months for 1 year. Sixty patients with a pathological diagnosis of periampullary or pancreatic adenocarcinoma were included in the study. Multivariate analysis indicated that portal CTC count was a significant predictor for liver metastases within 6 months after surgery. Eleven of 13 patients with a high portal CTCs count (defined as >112 CMx Platform estimated CTCs in 2 mL blood) developed liver metastases within 6 months after surgery. In contrast, only 6 of 47 patients with a low portal CTC count developed liver metastases (P < 0.0001). A value of 112 CMx Platform estimated CTCs had 64.7% sensitivity and 95.4% specificity to predict liver metastases within 6 months after surgery. We concluded that a high CTC count in portal venous blood collected during pancreaticoduodenectomy in patients with periampullary or pancreatic adenocarcinoma without metastases detected by currently available imaging tools is a significant predictor for liver metastases within 6 months after surgery. PMID:27100430

  18. Enhanced transcellular penetration and drug delivery by crosslinked polymeric micelles into pancreatic multicellular tumor spheroids.

    PubMed

    Lu, Hongxu; Utama, Robert H; Kitiyotsawat, Uraiphan; Babiuch, Krzysztof; Jiang, Yanyan; Stenzel, Martina H

    2015-07-01

    Many attempts have been made in the application of multicellular tumor spheroids (MCTS) as a 3D tumor model to investigate their biological responses upon introduction of polymeric micelles as nanocarriers for therapeutic applications. However, the micelle penetration pathways in MCTS are not yet known. In this study, micelles (uncrosslinked, UCM) were prepared by self-assembly of block copolymer poly(N-(2-hydroxypropyl) methacrylamide-co-methacrylic acid)-block-poly(methyl methacrylate) (P(HPMA-co-MAA)-b-PMMA). Subsequently, the shells were crosslinked to form relatively stable micelles (CKM). Both UCM and CKM penetrated deeper and delivered more doxorubicin (DOX) into MCTS than the diffusion of the free DOX. Additionally, CKM revealed higher delivery efficiency than UCM. The inhibition of caveolae-mediated endocytosis, by Filipin treatment, decreased the uptake and penetration of the micelles into MCTS. Treatment with Exo1, an exocytosis inhibitor, produced the same effect. Furthermore, movement of the micelles through the extracellular matrices (ECM), as modelled using collagen micro-spheroids, appeared to be limited to the peripheral layer of the collagen spheroids. Those results indicate that penetration of P(HPMA-co-MAA)-b-PMMA micelles depended more on transcellular transport than on diffusion through ECM between the cells. DOX-loaded CKM inhibited MCTS growth more than their UCM counterpart, due to possible cessation of endocytosis and exocytosis in the apoptotic peripheral cells, caused by faster release of DOX from UCM. PMID:26221942

  19. Maximum Standard Uptake Value as a Clinical Biomarker for Detecting Loss of SMAD4 Expression and Early Systemic Tumor Recurrence in Resected Left-Sided Pancreatic Cancer

    PubMed Central

    Kang, Chang Moo; Hwang, Ho Kyoung; Park, Jiae; Kim, Changsoo; Cho, Seong-Kyoung; Yun, Mijin; Lee, Woo Jung

    2016-01-01

    Abstract This study investigated the oncologic impact of loss of SMAD4 expression in resected left-sided pancreatic cancer and its correlation with tumor metabolism. From 2005 to 2011, the medical records of patients who underwent radical distal pancreatectomy for resectable pancreatic cancer were retrospectively reviewed. Formalin-fixed, paraffin embedded tissue from 32 patients was investigated. Clinicopathological characteristics, immunostaining of SMAD4, and positron emission tomography-based parameters were analyzed in relation to oncologic outcomes. Thirteen patients were women and 19 were men, with a mean age of 63 ± 9.4 years. Mean resected tumor size was 3.3 ± 1.5 cm. Ten patients (31.3%) showed loss of SMAD4 expression. No significant clinicopathological differences were noted according to SMAD4 expression (P > 0.05); however, patients with loss of SMAD4 showed significantly poorer disease-free survival (mean 57.4 months vs mean 17.6 months, P = 0.006). As a cut-off value, a SUVmax of 4.5 was found to be predictive of loss of SMAD4 with a sensitivity of 75% and a specificity of 84.6%. In logistic regression analysis, SUVmax>4.5 was found to infer a 16-fold higher risk for loss of SMAD4 in resected left-sided pancreatic cancers (Exp[β] = 16.5, P = 0.012, 95% confidence interval: 1.832–148.606). Loss of SMAD4 is associated with poor oncologic outcomes. SUVmax can predict loss of SMAD4 in resected left-sided pancreatic cancer. SUVmax may be a clinical biomarker for detecting loss of SMAD4 expression and predicting early systemic metastasis. PMID:27124039

  20. Hormonally defined pancreatic and duodenal neuroendocrine tumors differ in their transcription factor signatures: expression of ISL1, PDX1, NGN3, and CDX2.

    PubMed

    Hermann, Gratiana; Konukiewitz, Björn; Schmitt, Anja; Perren, Aurel; Klöppel, Günter

    2011-08-01

    We recently identified the transcription factor (TF) islet 1 gene product (ISL1) as a marker for well-differentiated pancreatic neuroendocrine tumors (P-NETs). In order to better understand the expression of the four TFs, ISL1, pancreatico-duodenal homeobox 1 gene product (PDX1), neurogenin 3 gene product (NGN3), and CDX-2 homeobox gene product (CDX2), that mainly govern the development and differentiation of the pancreas and duodenum, we studied their expression in hormonally defined P-NETs and duodenal (D-) NETs. Thirty-six P-NETs and 14 D-NETs were immunostained with antibodies against the four pancreatic hormones, gastrin, serotonin, calcitonin, ISL1, PDX1, NGN3, and CDX2. The TF expression pattern of each case was correlated with the tumor's hormonal profile. Insulin-positive NETs expressed only ISL1 (10/10) and PDX1 (9/10). Glucagon-positive tumors expressed ISL1 (7/7) and were almost negative for the other TFs. Gastrin-positive NETs, whether of duodenal or pancreatic origin, frequently expressed PDX1 (17/18), ISL1 (14/18), and NGN3 (14/18). CDX2 was mainly found in the gastrin-positive P-NETs (5/8) and rarely in the D-NETs (1/10). Somatostatin-positive NETs, whether duodenal or pancreatic in origin, expressed ISL1 (9/9), PDX1 (3/9), and NGN3 (3/9). The remaining tumors showed labeling for ISL1 in addition to NGN3. There was no association between a particular TF pattern and NET features such as grade, size, location, presence of metastases, and functional activity. We conclude from our data that there is a correlation between TF expression patterns and certain hormonally defined P-NET and D-NET types, suggesting that most of the tumor types originate from embryologically determined precursor cells. The observed TF signatures do not allow us to distinguish P-NETs from D-NETs. PMID:21739268

  1. CA19-9-related tumor kinetics after first-line chemotherapy of patients with advanced pancreatic cancer: a monoinstitutional experience.

    PubMed

    Colloca, Giuseppe; Venturino, Antonella; Guarneri, Domenico

    2016-09-01

    The absolute value of carbohydrate antigen 19-9 (CA19-9) pretreatment and its reduction after chemotherapy are established prognostic variables for patients with advanced pancreatic cancer. The present study is a retrospective monoinstitutional evaluation of the prognostic role of the CA19-9 reduction and some CA19-9-related tumor kinetics parameters, such as tumor growth rate constant (G), kinetic tumor response and log ratio. Forty-one cases met the selection criteria. After 8 weeks only G reported an inverse relationship with OS (r = -0.494) that was confirmed by regression analysis (R (2) = 0.192). G after 8 weeks of chemotherapy appears as a possible surrogate end point of overall survival. PMID:27522503

  2. CSF1/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T Cell Checkpoint Immunotherapy in Pancreatic Cancer Models

    PubMed Central

    Zhu, Yu; Knolhoff, Brett L.; Meyer, Melissa A.; Nywening, Timothy M.; West, Brian L.; Luo, Jingqin; Wang-Gillam, Andrea; Goedegebuure, S Peter; Linehan, David C.; DeNardo, David G.

    2014-01-01

    Cancer immunotherapy generally offers limited clinical benefit without coordinated strategies to mitigate the immunosuppressive nature of the tumor microenvironment. Critical drivers of immune escape in the tumor microenvironment include tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC), which not only mediate immune suppression but also promote metastatic dissemination and impart resistance to cytotoxic therapies. Thus, strategies to ablate the effects of these myeloid cell populations may offer great therapeutic potential. In this report, we demonstrate in a mouse model of pancreatic ductal adenocarcinoma (PDAC) that inhibiting signaling by the myeloid growth factor receptor CSF1R can functionally reprogram macrophage responses that enhance antigen presentation and productive anti-tumor T cell responses. Investigations of this response revealed that CSF1R blockade also upregulated T cell checkpoint molecules, including PDL1 and CTLA4, thereby restraining beneficial therapeutic effects. We found that PD1 and CTLA4 antagonists showed limited efficacy as single agents to restrain PDAC growth, but that that combining these agents with CSF1R blockade potently elicited tumor regressions, even in larger established tumors. Taken together, our findings provide a rationale to reprogram immunosuppressive myeloid cell populations in the tumor microenvironment under conditions that can significantly empower the therapeutic effects of checkpoint-based immunotherapeutics. PMID:25082815

  3. NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by β-lapachone

    PubMed Central

    Moore, Z; Chakrabarti, G; Luo, X; Ali, A; Hu, Z; Fattah, F J; Vemireddy, R; DeBerardinis, R J; Brekken, R A; Boothman, D A

    2015-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (e.g., FK866) target the most active pathway of NAD+ synthesis in tumor cells, but lack tumor-selectivity for use as a single agent. Reducing NAD+ pools by inhibiting NAMPT primed pancreatic ductal adenocarcinoma (PDA) cells for poly(ADP ribose) polymerase (PARP1)-dependent cell death induced by the targeted cancer therapeutic, β-lapachone (β-lap, ARQ761), independent of poly(ADP ribose) (PAR) accumulation. β-Lap is bioactivated by NADPH:quinone oxidoreductase 1 (NQO1) in a futile redox cycle that consumes oxygen and generates high levels of reactive oxygen species (ROS) that cause extensive DNA damage and rapid PARP1-mediated NAD+ consumption. Synergy with FK866+β-lap was tumor-selective, only occurring in NQO1-overexpressing cancer cells, which is noted in a majority (∼85%) of PDA cases. This treatment strategy simultaneously decreases NAD+ synthesis while increasing NAD+ consumption, reducing required doses and treatment times for both drugs and increasing potency. These complementary mechanisms caused profound NAD(P)+ depletion and inhibited glycolysis, driving down adenosine triphosphate levels and preventing recovery normally observed with either agent alone. Cancer cells died through an ROS-induced, μ-calpain-mediated programmed cell death process that kills independent of caspase activation and is not driven by PAR accumulation, which we call NAD+-Keresis. Non-overlapping specificities of FK866 for PDA tumors that rely heavily on NAMPT-catalyzed NAD+ synthesis and β-lap for cancer cells with elevated NQO1 levels affords high tumor-selectivity. The concept of reducing NAD+ pools in cancer cells to sensitize them to ROS-mediated cell death by β-lap is a novel strategy with potential application for pancreatic and other types of NQO1+ solid tumors. PMID:25590809

  4. Maximum-Intensity Volumes for Fast Contouring of Lung Tumors Including Respiratory Motion in 4DCT Planning

    SciTech Connect

    Rietzel, Eike Liu, Arthur K.; Chen, George T.Y.; Choi, Noah C.

    2008-07-15

    Purpose: To assess the accuracy of maximum-intensity volumes (MIV) for fast contouring of lung tumors including respiratory motion. Methods and Materials: Four-dimensional computed tomography (4DCT) data of 10 patients were acquired. Maximum-intensity volumes were constructed by assigning the maximum Hounsfield unit in all CT volumes per geometric voxel to a new, synthetic volume. Gross tumor volumes (GTVs) were contoured on all CT volumes, and their union was constructed. The GTV with all its respiratory motion was contoured on the MIV as well. Union GTVs and GTVs including motion were compared visually. Furthermore, planning target volumes (PTVs) were constructed for the union of GTVs and the GTV on MIV. These PTVs were compared by centroid position, volume, geometric extent, and surface distance. Results: Visual comparison of GTVs demonstrated failure of the MIV technique for 5 of 10 patients. For adequate GTV{sub MIV}s, differences between PTVs were <1.0 mm in centroid position, 5% in volume, {+-}5 mm in geometric extent, and {+-}0.5 {+-} 2.0 mm in surface distance. These values represent the uncertainties for successful MIV contouring. Conclusion: Maximum-intensity volumes are a good first estimate for target volume definition including respiratory motion. However, it seems mandatory to validate each individual MIV by overlaying it on a movie loop displaying the 4DCT data and editing it for possible inadequate coverage of GTVs on additional 4DCT motion states.

  5. Contribution of microRNAs in understanding the pancreatic tumor microenvironment involving cancer associated stellate and fibroblast cells

    PubMed Central

    Ali, Shadan; Suresh, Raagini; Banerjee, Sanjeev; Bao, Bin; Xu, Zhihong; Wilson, Jeremy; Philip, Philip A; Apte, Minoti; Sarkar, Fazlul H

    2015-01-01

    Understanding of molecular events associated with tumor microenvironment in pancreatic cancer (PC) is an active area of research especially because of the rich desmoplasia seen in human PC. Desmoplasia is contributed by several cell types including cancer-associated fibroblast (CAF) and stellate cells (PSCs), which are believed to play critical roles in conferring aggressiveness to PC. The aberrant expression of microRNAs (miRNAs) in PSCs and CAF cells appears to play a pivotal role in the development and progression of PC. In this study, expression analysis of miR-21/miR-221 in conditioned media derived from PSCs/CAF cells, and from PSCs/CAF cells showed up-regulation of both miRNAs compared to MIAPaCa-2 PC cells. In addition, miR-21 expression in stellate cells derived from normal pancreas was substantially lower when compared to PSCs or CAF cells. COLO-357 PC cells cultured in the presence of conditioned media derived from PSC/CAF cells led to a significant increase in clonogenicity and pancreatosphere formation. Furthermore, inhibition of miR-21 with antisense oligonucleotide (ASO) transfection resulted in decreased migration/invasive capacity of PSCs. Similarly, the effect of ASO-miR-221 transfection in CAF cells reduced the expression of NF-κB and K-Ras (target of miR-221) along with inhibition of migration/invasion. Moreover, miRNA expression profiling of PSCs, MIAPaCa-2, and COLO-357 cells, and further validation by real-time PCR, showed several differentially expressed miRNAs, among which four was significantly up-regulated. Collectively, these results suggest a crosstalk between PSCs/CAF cells and PC cells, resulting in the up-regulation of miR-21/miR-221 expression which in part may confer aggressiveness to PC. We conclude that targeting these miRNAs could be useful for developing precision medicine for the prevention of tumor progression and/or for the treatment of PC. PMID:26046003

  6. Cancer Stem Cells in Pancreatic Cancer

    PubMed Central

    Bao, Qi; Zhao, Yue; Renner, Andrea; Niess, Hanno; Seeliger, Hendrik; Jauch, Karl-Walter; Bruns, Christiane J.

    2010-01-01

    Pancreatic cancer is an aggressive malignant solid tumor well-known by early metastasis, local invasion, resistance to standard chemo- and radiotherapy and poor prognosis. Increasing evidence indicates that pancreatic cancer is initiated and propagated by cancer stem cells (CSCs). Here we review the current research results regarding CSCs in pancreatic cancer and discuss the different markers identifying pancreatic CSCs. This review will focus on metastasis, microRNA regulation and anti-CSC therapy in pancreatic cancer. PMID:24281178

  7. Nuclear expression of Y-box binding protein-1 is associated with poor prognosis in patients with pancreatic cancer and its knockdown inhibits tumor growth and metastasis in mice tumor models.

    PubMed

    Shinkai, Kentaro; Nakano, Kenji; Cui, Lin; Mizuuchi, Yusuke; Onishi, Hideya; Oda, Yoshinao; Obika, Satoshi; Tanaka, Masao; Katano, Mitsuo

    2016-07-15

    The objective of this study was to examine the implication of Y-box-binding protein-1 (YB-1) for the aggressive phenotypes, prognosis and therapeutic target in pancreatic ductal adenocarcinoma (PDAC). YB-1 expression in PDAC, pancreatic intraepithelial neoplasia (PanIN) and normal pancreas specimens was evaluated by immunohistochemistry, and its correlation with clinicopathological features was assessed in patients with PDAC. The effects of YB-1 on proliferation, invasion and expressions of cell cycle-related proteins and matrix metalloproteinases (MMPs) were analyzed by WST-8, cell cycle and Matrigel invasion assays, Western blotting and quantitative RT-PCR in PDAC cells transfected with YB-1-siRNAs. To verify the significance of YB-1 for tumor progression in vivo, the growth and metastasis were monitored after intrasplenic implantation of ex vivo YB-1 siRNA-transfected PDAC cells, and YB-1-targeting antisense oligonucleotides were intravenously administered in nude mice harboring subcutaneous tumor. The intensity of YB-1 expression and positivity of nuclear YB-1 expression were higher in PDAC than PanIN and normal pancreatic tissues. Nuclear YB-1 expression was significantly associated with dedifferentiation, lymphatic/venous invasion and unfavorable prognosis. YB-1 knockdown inhibited cell proliferation via cell cycle arrest by S-phase kinase-associated protein 2 downregulation and consequent p27 accumulation, and decreased the invasion due to downregulated membranous-type 2 MMP expression in PDAC cells. Tumor growth and liver metastasis formation were significantly suppressed in nude mice after implantation of YB-1-silenced PDAC cells, and the YB-1 targeting antisense oligonucleotide significantly inhibited the growth of subcutaneous tumors. In conclusion, YB-1 may be involved in aggressive natures of PDAC and a promising therapeutic target. PMID:26939718

  8. Hand-Held High-Resolution Fluorescence Imaging System for Fluorescence-Guided Surgery of Patient and Cell-Line Pancreatic Tumors Growing Orthotopically in Nude Mice

    PubMed Central

    Hiroshima, Yukihiko; Maawy, Ali; Sato, Sho; Murakami, Takashi; Uehara, Fuminari; Miwa, Shinji; Yano, Shuya; Momiyama, Masashi; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M.

    2014-01-01

    Background In this study, we investigated the advantages for fluorescence-guided surgery (FGS) in mice of a portable hand-sized imaging system compared to a large chamber fluorescing imaging system or a long-working-distance fluorescence microscope. Methods Mouse models of human pancreatic cancer for FGS included (1) MiaPaCa-2-expressing green fluorescent protein (GFP), (2) BxPC3 labeled with anti-CEA antibody conjugated with Alexa 488, (3) patient-derived orhotopic xenograft (PDOX)™ labeled with anti-CA19-9 antibody conjugated with Alexa 488. Results Each device could clearly detect the primary MiaPaCa-2-GFP. tumor and any residual tumor after FGS. In the BxPC3 model labeled with Alexa 488-conjugated anti-CEA, each device could detect the primary tumor, but the MVX10 could not clearly detect the residual tumor remaining after FGS while the other devices could. In the PDOX™ model labeled with Alexa 488 conjugated with anti CA19-9, only the portable hand-held device could distinguish the residual tumor from the background, and complete resection of the residual tumor was achieved under fluorescence navigation. Conclusions The results described in the present report suggest the hand-held mobile imaging system can be able to be applied to the clinic for FGS due to its convenient size and high sensitivity and help make FGS widely-used. PMID:24373959

  9. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models.

    PubMed

    Zhu, Yu; Knolhoff, Brett L; Meyer, Melissa A; Nywening, Timothy M; West, Brian L; Luo, Jingqin; Wang-Gillam, Andrea; Goedegebuure, S Peter; Linehan, David C; DeNardo, David G

    2014-09-15

    Cancer immunotherapy generally offers limited clinical benefit without coordinated strategies to mitigate the immunosuppressive nature of the tumor microenvironment. Critical drivers of immune escape in the tumor microenvironment include tumor-associated macrophages and myeloid-derived suppressor cells, which not only mediate immune suppression, but also promote metastatic dissemination and impart resistance to cytotoxic therapies. Thus, strategies to ablate the effects of these myeloid cell populations may offer great therapeutic potential. In this report, we demonstrate in a mouse model of pancreatic ductal adenocarcinoma (PDAC) that inhibiting signaling by the myeloid growth factor receptor CSF1R can functionally reprogram macrophage responses that enhance antigen presentation and productive antitumor T-cell responses. Investigations of this response revealed that CSF1R blockade also upregulated T-cell checkpoint molecules, including PDL1 and CTLA4, thereby restraining beneficial therapeutic effects. We found that PD1 and CTLA4 antagonists showed limited efficacy as single agents to restrain PDAC growth, but that combining these agents with CSF1R blockade potently elicited tumor regressions, even in larger established tumors. Taken together, our findings provide a rationale to reprogram immunosuppressive myeloid cell populations in the tumor microenvironment under conditions that can significantly empower the therapeutic effects of checkpoint-based immunotherapeutics. PMID:25082815

  10. MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice

    PubMed Central

    Cogoi, Susanna; Zorzet, Sonia; Rapozzi, Valentina; Géci, Imrich; Pedersen, Erik B.; Xodo, Luigi E.

    2013-01-01

    KRAS mutations are primary genetic lesions leading to pancreatic cancer. The promoter of human KRAS contains a nuclease-hypersensitive element (NHE) that can fold in G4-DNA structures binding to nuclear proteins, including MAZ (myc-associated zinc-finger). Here, we report that MAZ activates KRAS transcription. To knockdown oncogenic KRAS in pancreatic cancer cells, we designed oligonucleotides that mimic one of the G-quadruplexes formed by NHE (G4-decoys). To increase their nuclease resistance, two locked nucleic acid (LNA) modifications were introduced at the 3′-end, whereas to enhance the folding and stability, two polycyclic aromatic hydrocarbon units (TINA or AMANY) were inserted internally, to cap the quadruplex. The most active G4-decoy (2998), which had two para-TINAs, strongly suppressed KRAS expression in Panc-1 cells. It also repressed their metabolic activity (IC50 = 520 nM), and it inhibited cell growth and colony formation by activating apoptosis. We finally injected 2998 and control oligonucleotides 5153, 5154 (2 nmol/mouse) intratumorally in SCID mice bearing a Panc-1 xenograft. After three treatments, 2998 reduced tumor xenograft growth by 64% compared with control and increased the Kaplan–Meier median survival time by 70%. Together, our data show that MAZ-specific G4-decoys mimicking a KRAS quadruplex are promising for pancreatic cancer therapy. PMID:23471001

  11. Two Chitotriose-Specific Lectins Show Anti-Angiogenesis, Induces Caspase-9-Mediated Apoptosis and Early Arrest of Pancreatic Tumor Cell Cycle.

    PubMed

    Singh, Ruby; Nawale, Laxman; Sarkar, Dhiman; Suresh, C G

    2016-01-01

    The antiproliferative activity of two chito-specific agglutinins purified from Benincasa hispida (BhL) and Datura innoxia (DiL9) of different plant family origin was investigated on various cancer cell lines. Both lectins showed chitotriose specificity, by inhibiting lectin hemagglutinating activity. On further studies, it was revealed that these agglutinins caused remarkable concentration-dependent antiproliferative effect on human pancreatic cancerous cells but not on the normal human umbilical vein endothelial cells even at higher doses determined using MTT assay. The GI50 values were approximately 8.4 μg ml(-1) (0.247 μM) and 142 μg ml(-1) (14.8 μM) for BhL and DiL9, respectively, against PANC-1 cells. The growth inhibitory effect of these lectins on pancreatic cancer cells were shown to be a consequence of lectin cell surface binding and triggering G0/G1 arrest, mitochondrial membrane depolarization, sustained increase of the intracellular calcium release and the apoptotic signal is amplified by activation of caspases executing cell death. Interestingly, these lectins also showed anti-angiogenic activity by disrupting the endothelial tubulogenesis. Therefore, we report for the first time two chito-specific lectins specifically binding to tumor glycans; they can be considered to be a class of molecules with antitumor activity against pancreatic cancer cells mediated through caspase dependent mitochondrial apoptotic pathway. PMID:26795117

  12. Two Chitotriose-Specific Lectins Show Anti-Angiogenesis, Induces Caspase-9-Mediated Apoptosis and Early Arrest of Pancreatic Tumor Cell Cycle

    PubMed Central

    Sarkar, Dhiman; Suresh, C. G.

    2016-01-01

    The antiproliferative activity of two chito- specific agglutinins purified from Benincasa hispida (BhL) and Datura innoxia (DiL9) of different plant family origin was investigated on various cancer cell lines. Both lectins showed chitotriose specificity, by inhibiting lectin hemagglutinating activity. On further studies, it was revealed that these agglutinins caused remarkable concentration-dependent antiproliferative effect on human pancreatic cancerous cells but not on the normal human umbilical vein endothelial cells even at higher doses determined using MTT assay. The GI50 values were approximately 8.4 μg ml-1 (0.247 μM) and 142 μg ml-1(14.8 μM) for BhL and DiL9, respectively, against PANC-1 cells. The growth inhibitory effect of these lectins on pancreatic cancer cells were shown to be a consequence of lectin cell surface binding and triggering G0/G1 arrest, mitochondrial membrane depolarization, sustained increase of the intracellular calcium release and the apoptotic signal is amplified by activation of caspases executing cell death. Interestingly, these lectins also showed anti-angiogenic activity by disrupting the endothelial tubulogenesis. Therefore, we report for the first time two chito-specific lectins specifically binding to tumor glycans; they can be considered to be a class of molecules with antitumor activity against pancreatic cancer cells mediated through caspase dependent mitochondrial apoptotic pathway. PMID:26795117

  13. Chronic Pancreatitis and Pancreatic Cancer

    PubMed Central

    Kong, Xiangyu; Sun, Tao; Kong, Fanyang; Du, Yiqi; Li, Zhaoshen

    2014-01-01

    Background Pancreatic cancer (PC) is one of the most lethal diseases with an incidence rate almost equal to the rate of mortality. Chronic pancreatitis (CP) is a common chronic inflammatory disease of unknown etiology that affects the pancreas. Epidemiological studies have identified CP to be a major risk factor for PC. Summary A greater understanding of the molecular mechanisms linking CP and PC has identified several common pathways that provide targets for future interventions. This article reviews those components in the CP-PC connection, including the role of macrophages, the maintenance of genome stability, cytokines, and other nodal factors such as nuclear factor kappa B, COX-2 and reactive oxygen species. Key Message The molecular mechanisms that underlie CP and PC provide novel targets for future therapies for PC. Practical Implications The stromal-desmoplastic reaction plays an important role in initiating and sustaining chronic inflammation and tumor progression. Recently, two targeted anti-tumor agents, erlotinib and nab-paclitaxel, have shown promising therapeutic efficacy. Notably, both these agents target components (EGFR and SPARC) within the inflammatory stroma surrounding malignant cells, underscoring the importance of inflammation in pancreatic carcinogenesis. Identifying the common pathways linking CP and PC may help uncover additional novel targets for future therapies. PMID:26674754

  14. Pancreatic adenocarcinoma: Outstanding problems

    PubMed Central

    Zakharova, Olga P; Karmazanovsky, Grigory G; Egorov, Viacheslav I

    2012-01-01

    Pancreatic adenocarcinoma remains the fourth leading cause of cancer-related death and is one of the most aggressive malignant tumors with an overall 5-year survival rate of less than 4%. Surgical resection remains the only potentially curative treatment but is only possible for 15%-20% of patients with pancreatic adenocarcinoma. About 40% of patients have locally advanced nonresectable disease. In the past, determination of pancreatic cancer resectability was made at surgical exploration. The development of modern imaging techniques has allowed preoperative staging of patients. Institutions disagree about the criteria used to classify patients. Vascular invasion in pancreatic cancers plays a very important role in determining treatment and prognosis. There is no evidence-based consensus on the optimal preoperative imaging assessment of patients with suspected pancreatic cancer and a unified definition of borderline resectable pancreatic cancer is also lacking. Thus, there is much room for improvement in all aspects of treatment for pancreatic cancer. Multi-detector computed tomography has been widely accepted as the imaging technique of choice for diagnosing and staging pancreatic cancer. With improved surgical techniques and advanced perioperative management, vascular resection and reconstruction are performed more frequently; patients thought once to be unresectable are undergoing radical surgery. However, when attempting heroic surgery, a realistic approach concerning the patient’s age and health status, probability of recovery after surgery, perioperative morbidity and mortality and life quality after tumor resection is necessary. PMID:22655124

  15. Evaluation of template matching for tumor motion management with cine-MR images in lung cancer patients

    PubMed Central

    Shi, Xiutao; Diwanji, Tejan; Mooney, Karen E.; Lin, Jolinta; Feigenberg, Steven; D’Souza, Warren D.; Mistry, Nilesh N.

    2014-01-01

    Purpose: Accurate determination of tumor position is crucial for successful application of motion compensated radiotherapy in lung cancer patients. This study tested the performance of an automated template matching algorithm in tracking the tumor position on cine-MR images by examining the tracking error and further comparing the tracking error to the interoperator variability of three human reviewers. Methods: Cine-MR images of 12 lung cancer patients were analyzed. Tumor positions were determined both automatically with template matching and manually by a radiation oncologist and two additional reviewers trained by the radiation oncologist. Performance of the automated template matching was compared against the ground truth established by the radiation oncologist. Additionally, the tracking error of template matching, defined as the difference in the tumor positions determined with template matching and the ground truth, was investigated and compared to the interoperator variability for all patients in the anterior-posterior (AP) and superior-inferior (SI) directions, respectively. Results: The median tracking error for ten out of the 12 patients studied in both the AP and SI directions was less than 1 pixel (= 1.95 mm). Furthermore, the median tracking error for seven patients in the AP direction and nine patients in the SI direction was less than half a pixel (= 0.975 mm). The median tracking error was positively correlated with the tumor motion magnitude in both the AP (R = 0.55, p = 0.06) and SI (R = 0.67, p = 0.02) directions. Also, a strong correlation was observed between tracking error and interoperator variability (y = 0.26 + 1.25x, R = 0.84, p < 0.001) with the latter larger. Conclusions: Results from this study indicate that the performance of template matching is comparable with or better than that of manual tumor localization. This study serves as preliminary investigations towards developing online motion tracking techniques for hybrid MRI

  16. Synchronized moving aperture radiation therapy (SMART): superimposing tumor motion on IMRT MLC leaf sequences under realistic delivery conditions

    NASA Astrophysics Data System (ADS)

    Xu, Jun; Papanikolaou, Nikos; Shi, Chengyu; Jiang, Steve B.

    2009-08-01

    Synchronized moving aperture radiation therapy (SMART) has been proposed to account for tumor motions during radiotherapy in prior work. The basic idea of SMART is to synchronize the moving radiation beam aperture formed by a dynamic multileaf collimator (DMLC) with the tumor motion induced by respiration. In this paper, a two-dimensional (2D) superimposing leaf sequencing method is presented for SMART. A leaf sequence optimization strategy was generated to assure the SMART delivery under realistic delivery conditions. The study of delivery performance using the Varian LINAC and the Millennium DMLC showed that clinical factors such as collimator angle, dose rate, initial phase and machine tolerance affect the delivery accuracy and efficiency. An in-house leaf sequencing software was developed to implement the 2D superimposing leaf sequencing method and optimize the motion-corrected leaf sequence under realistic clinical conditions. The analysis of dynamic log (Dynalog) files showed that optimization of the leaf sequence for various clinical factors can avoid beam hold-offs which break the synchronization of SMART and fail the SMART dose delivery. Through comparison between the simulated delivered fluence map and the planed fluence map, it was shown that the motion-corrected leaf sequence can greatly reduce the dose error.

  17. Speed and amplitude of lung tumor motion precisely detected in four-dimensional setup and in real-time tumor-tracking radiotherapy

    SciTech Connect

    Shirato, Hiroki . E-mail: hshirato@radi.med.hokudai.ac.jp; Suzuki, Keishiro; Sharp, Gregory C.; Fujita, Katsuhisa R.T.; Onimaru, Rikiya; Fujino, Masaharu; Kato, Norio; Osaka, Yasuhiro; Kinoshita, Rumiko; Taguchi, Hiroshi; Onodera, Shunsuke; Miyasaka, Kazuo

    2006-03-15

    Background: To reduce the uncertainty of registration for lung tumors, we have developed a four-dimensional (4D) setup system using a real-time tumor-tracking radiotherapy system. Methods and Materials: During treatment planning and daily setup in the treatment room, the trajectory of the internal fiducial marker was recorded for 1 to 2 min at the rate of 30 times per second by the real-time tumor-tracking radiotherapy system. To maximize gating efficiency, the patient's position on the treatment couch was adjusted using the 4D setup system with fine on-line remote control of the treatment couch. Results: The trajectory of the marker detected in the 4D setup system was well visualized and used for daily setup. Various degrees of interfractional and intrafractional changes in the absolute amplitude and speed of the internal marker were detected. Readjustments were necessary during each treatment session, prompted by baseline shifting of the tumor position. Conclusion: The 4D setup system was shown to be useful for reducing the uncertainty of tumor motion and for increasing the efficiency of gated irradiation. Considering the interfractional and intrafractional changes in speed and amplitude detected in this study, intercepting radiotherapy is the safe and cost-effective method for 4D radiotherapy using real-time tracking technology.

  18. Exosomal lipids induce human pancreatic tumoral MiaPaCa-2 cells resistance through the CXCR4-SDF-1α signaling axis.

    PubMed

    Beloribi-Djefaflia, Sadia; Siret, Carole; Lombardo, Dominique

    2015-01-01

    We previously reported that exosomes secreted by human pancreatic tumor cells induce cell death through the inhibition of the Notch-1 survival pathway (Ristorcelli et al., 2009). We demonstrated that exosomal lipids evoked apoptosis of human pancreatic cancer SOJ-6 cells. Based on the lipid composition of efficient exosomes we designed Synthetic Exosome-Like Nanoparticles (SELN) in which the ratio ordered lipids versus disordered lipids was equal to 6.0 (SELN6.0). These SELN decreased SOJ-6 cells survival by inhibiting the Notch-1 pathway. However MiaPaCa-2 cells were resistant to exosomes (Ristorcelli et al., 2008) and to SELN6.0 (Beloribi et al.,2012). In this paper we aimed at deciphering the reason(s) of this resistance. We observed, in presence of SELN6.0, that the expression of the Notch IntraCytoplasmic Domain (NICD) decreases in MiaPaCa-2 cells but neither Hes-1, the nuclear target of NICD, nor the ratio Bax/Bcl-2 were affected. We further showed that in MiaPaCa-2 cells SELN6.0 induced the activation of NF-kB, which promotes the expression and the secretion of SDF-1α. This chemokine interacts with its receptor CXCR4 on MiaPaCa-2 cells and activates the Akt survival pathway protecting cells from death. This activation process promoted by exosomal lipids could have implications in tumor progression and drug resistance. PMID:25821841

  19. Exosomal lipids induce human pancreatic tumoral MiaPaCa-2 cells resistance through the CXCR4-SDF-1α signaling axis

    PubMed Central

    Beloribi-Djefaflia, Sadia; Siret, Carole; Lombardo, Dominique

    2015-01-01

    We previously reported that exosomes secreted by human pancreatic tumor cells induce cell death through the inhibition of the Notch-1 survival pathway (Ristorcelli et al., 2009). We demonstrated that exosomal lipids evoked apoptosis of human pancreatic cancer SOJ-6 cells. Based on the lipid composition of efficient exosomes we designed Synthetic Exosome-Like Nanoparticles (SELN) in which the ratio ordered lipids versus disordered lipids was equal to 6.0 (SELN6.0). These SELN decreased SOJ-6 cells survival by inhibiting the Notch-1 pathway. However MiaPaCa-2 cells were resistant to exosomes (Ristorcelli et al., 2008) and to SELN6.0 (Beloribi et al.,2012). In this paper we aimed at deciphering the reason(s) of this resistance. We observed, in presence of SELN6.0, that the expression of the Notch IntraCytoplasmic Domain (NICD) decreases in MiaPaCa-2 cells but neither Hes-1, the nuclear target of NICD, nor the ratio Bax/Bcl-2 were affected. We further showed that in MiaPaCa-2 cells SELN6.0 induced the activation of NF-kB, which promotes the expression and the secretion of SDF-1α. This chemokine interacts with its receptor CXCR4 on MiaPaCa-2 cells and activates the Akt survival pathway protecting cells from death. This activation process promoted by exosomal lipids could have implications in tumor progression and drug resistance. PMID:25821841

  20. PEG-detachable cationic polyaspartamide derivatives bearing stearoyl moieties for systemic siRNA delivery toward subcutaneous BxPC3 pancreatic tumor.

    PubMed

    Kim, Hyun Jin; Oba, Makoto; Pittella, Frederico; Nomoto, Takahiro; Cabral, Horacio; Matsumoto, Yu; Miyata, Kanjiro; Nishiyama, Nobuhiro; Kataoka, Kazunori

    2012-01-01

    For systemic siRNA delivery into tumor tissues, a safe and efficient vehicle is strongly required. Therefore, we designed a block copolymer of detachable poly(ethylene glycol) (PEG) polycation bearing low pKa amines and hydrophobic moieties in the side chain to develop a smart siRNA complex possessing biocompatibility, high complex stability, and endosomal escaping functionality. A disulfide linkage (-SS-) was inserted as a linker between PEG and a cationic polyaspartamide derivative, poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (PAsp(DET)), with a flanking stearoyl moiety, where PAsp(DET) segment provides the excellent ability of endosome destabilization by direct interaction with the membrane. The resulting polymer, stearoyl PEG-SS-PAsp(DET), was confirmed to form the siRNA complex with an environment-responsive PEG palisade, which was detached from the complex surface under reductive conditions mimicking tumor tissues and cytoplasm because of the disulfide cleavage. The smart siRNA complex allowed significant gene silencing against cultured pancreatic cancer cells without considerable cytotoxicity and erythrocyte disruption, whereas such significant gene silencing was not observed in a control siRNA complex without the disulfide linkage. This enhanced gene silencing activity might be because of the enhanced cellular uptake and subsequent translocation of siRNA into cytoplasm facilitated by PEG detachment around and/or in the cancer cells. Further, intravital real-time confocal laser scanning microscopic observation revealed the effect of hydrophobic stearoyl modification on the stabilization of the siRNA complex for longevity in the blood. Significant in vivo gene silencing of the smart siRNA complex was achieved by systemic administration of vascular endothelial growth factor siRNA in a mouse model bearing a subcutaneous pancreatic tumor, leading to 40% regression in tumor growth. These results demonstrate the strong potential of stearoyl PEG

  1. Heteroclitic XBP1 peptides evoke tumor-specific memory cytotoxic T lymphocytes against breast cancer, colon cancer, and pancreatic cancer cells

    PubMed Central

    Bae, Jooeun; Samur, Mehmet; Munshi, Aditya; Hideshima, Teru; Keskin, Derin; Kimmelman, Alec; Lee, Ann-Hwee; Dranoff, Glen; Anderson, Kenneth C; Munshi, Nikhil C

    2015-01-01

    XBP1 is a critical transcriptional activator of the unfolded protein response (UPR), which increases tumor cell survival under prolonged endoplasmic reticulum (ER) stress and hypoxic conditions.This study was designed to evaluate the immunogenicity of heteroclitic XBP1 unspliced (US)184–192 (YISPWILAV) and heteroclictic XBP1 spliced (SP)367–375 (YLFPQLISV) HLA-A2 peptides, and to characterize the specific activities of XBP1 peptides-specific cytotoxic T lymphocytes (XBP1-CTL) against breast cancer, colon cancer, and pancreatic cancer cells.The XBP1-CTL had upregulated expression of critical T cell markers and displayed HLA-A2-restricted and antigen-specific activities against breast cancer, colon cancer and pancreatic cancer cells. XBP1-CTL were enriched withCD45RO+ memory CTL, which showed high expression of critical T cell markers (CD28, ICOS, CD69, CD40L), cell proliferation and antitumor activities as compared to CD45RO− non-memory CTL. The effector memory (EM: CD45RO+CCR7−) subset had the highest level of cell proliferation while the central memory (CM: CD45RO+CCR7+) subset demonstrated enhanced functional activities (CD107a degranulation, IFNγ/IL-2 production) upon recognition of the respective tumor cells. Furthermore, both the EM and CM XBP1-CTL subsets expressed high levels of Th1 transcription regulators Tbet and Eomes. The highest frequencies of IFNγ or granzyme B producing cells were detected within CM XBP1-CTL subset that were either Tbet+ or Eomes+ in responding to the tumor cells.These results demonstrate the immunotherapeutic potential of a cocktail of immunogenic HLA-A2 specific heteroclitic XBP1 US184–192 and heteroclictic XBP1 SP367–375 peptides to induce CD3+CD8+ CTL enriched for CM and EM cells with specific antitumor activities against a variety of solid tumors. PMID:25941601

  2. Formation of the tetraploid intermediate is associated with the development of cells with more than four centrioles in the elastase-simian virus 40 tumor antigen transgenic mouse model of pancreatic cancer.

    PubMed Central

    Levine, D S; Sanchez, C A; Rabinovitch, P S; Reid, B J

    1991-01-01

    The development of pancreatic cancer in transgenic mice expressing the simian virus 40 tumor antigen placed under controlling regions of the elastase I gene is characterized by the sequential appearance of tetraploid and then multiple aneuploid cell populations