bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of IP-10/CXCL10 induction in human pancreatic cancer stroma on lymphocytes recruitment and correlation with survival.
Authors: Brunner Thomas B , Lunardi Serena , Jamieson Nigel B , Lim Su Yin , Griffiths Kristin L , Carvalho-Gaspar Manuela Maria , Al-Assar Osama , Carter Ross , McKay Colin J , Spoletini Gabriele , D'Ugo Stefano , Silva Michael A , Samson Owen J , Janssen Klaus Peter , Muschel Ruth J 
Published: February 2017

290 Background: Pancreatic ductal adenocarcinoma is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Methods: Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines, chemokines and growth factors. Gene expression analysis of human pancreatic ductal adenocarcinoma samples was used to verify expression of cytokines and their correlation with markers of immunoresponse and with clinical outcome. Finally, we tested chemotaxis of leukocytes isolated from peripheral blood mononuclear cells of pancreatic cancer patients. Results: IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 expression was consistently upregulated in human pancreatic cancer specimens, and positively correlated with high stroma content. Furthermore, expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, the survival of patients with high IP-10 levels was 18.1 months less than those with low IP-10 levels (HR=2.14, 95% CI 1.05 -4.42). Importantly, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with pancreatic cancer. Conclusions: Our findings suggest that, in pancreatic cancer patients, CXCR3+ Tregs are recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.
Prognostic value of tumor-infiltrating lymphocytes (TILs) and expression of PD-L1 in cholangiocarcinoma.
Authors: Suleiman Yaman , Coppola Domenico , Zibadi Sherma , Dalia Samir , Juan TzuHua , Lee Jae K , Malafa Mokenge Peter , Soliman Hatem Hussein , Kim Richard D. 
Published: February 2017

294 Background: Cholangiocarcinoma is a malignancy arising from the epithelial cells of the biliary tract with poor prognosis. Tumor-infiltrating lymphocytes (TILs) have a prognostic impact in various solid tumors. We aimed to investigate TIL expression and programmed cell death ligand PD-L1 and their clinical relevance in cholangiocarcinoma. Methods: Formalin-fixed paraffin-embedded tumor samples from thirty seven patients with resected and histologically verified cholangiocarcinoma between 1990 and 2011 were identified and immunohistochemically (IHC) stained with anti CD8, anti CD45RO and the anti-PDL1 mouseIgG1 (clone 5H1; Thompson) antibodies on a Leica automated IHC platform. The stains were semiquantitatively analyzed using the AllRed score system (range 1 to 8). Cases with IHC score > 3 were considered positive. The association between PDL1, CD45R0, overall survival (OS) and progressive free survival (PFS) was investigated using Kaplan-Meier survival and COX proportional hazard regression analyses. Results: The median age of patients was 64 (41-85) with 51% male. 25%, 59%, 10% and 5% were stage I, II, III, and IV respectively. CD8 was positive in 10/37 (27%) with median IHC of 5, CD45R0 (specimen with lymph node like structure) was positive in 16/37 (43%) with median IHC score of 4, PD-L1 was positive in 35/37 (94 %) with median IHC score of 8. Pts with tumors exhibiting lymph node (LN) like structures (CD45RO+) has better median OS (63 months vs 18 months, P = 0.0065) and median PFS (29 months vs 14.6 months, P = 0.05) than patients lacking LN like structures (CD45RO-). 5 yrs. OS in CD45RO+ was 64% vs 20% in CD45RO- (P 0.006) whereas 5 yrs. PFS in CD45RO+ was 41% vs. 8% in in CD45RO- pts (P value 0.05). Correlating PDL1 with OS and PFS was not done due to high expression of PD-L1 in most of the samples (94%). Conclusions: Presence of lymph node like structures (CD45RO+) was associated with significant better outcome reflecting the immune-mediated killing of tumor cells. The high expression of PD-L1 on cholangiocarcinoma cells represents a potential therapeutic target which may improve the prognosis for this dismal cancer. Future trials involving PD-L1 inhibitors in cholangiocarcinoma are warranted.
Clinical activity and correlative DCE-MRI imaging of G-202, a thapsigargin-based prostate-specific membrane antigen-activated prodrug, in progressive hepatocellular cancer.
Authors: Mahalingam Devalingam , Tubb Benjamin , Nemunaitis John J. , Cen Putao , Rowe Julie Haewon , Sarantopoulos John , Kurman Michael R. , Allgood Victoria , Campos Luis T. 
Published: February 2017

301 Background: G-202 is a thapsigargin-based prodrug whose cytotoxic activity is blocked by a masking peptide that is cleaved by prostate-specific membrane antigen (PSMA), a membrane-bound protease expressed in prostate cancer and the endothelium of tumor vasculature but not in most other tissues or normal tissue vasculature. In a Phase I study of G-202, prolonged disease stabilization was observed in the subset of patients with hepatocellular carcinoma (HCC) and prompted development of a Phase II study to further evaluate activity of G-202 in patients with HCC who have progressed on sorafenib. Methods: G-202 is administered by iv infusion on Days 1, 2 and 3 of a 28-day cycle; prophylactic hydration is administered with infusion to ameliorate incidence of creatinine elevations. HCC is typically highly-vascularized, and DCE-MRI is performed in consenting patients at baseline and after treatment on approximately Day 6 of Cycle 2 to evaluate possible effects of G-202 on blood flow metrics in hepatic lesions. DCE-MRI is a non-invasive method of investigating vascular structure and function and is sensitive to alterations in vascular permeability and blood flow. DCE-MRI measurements were made on 1.5 Tesla MRI and the volume transfer coefficients, Ktrans, of HCC tumor lesions were calculated using arterial input function derived from signal in abdominal aorta. Results: Among the 22 patients treated to date, G-202 related SAEs in this patient population have been creatinine increase/acute renal failure/acute kidney injury (3 pts) and congestive heart failure (1 pt). While objective responses (CR, PR) have not been observed in these patients with advanced disease, the rate of disease stabilization has been remarkable, with >70% of patients exhibiting SD. In patients undergoing DCE-MRI, an average 56% decrease in Ktranshas been observed after administration of G-202. Conclusions: G-202 is generally well-tolerated and promotes disease stabilization in patients with advanced HCC who have progressed on sorafenib. DCE-MRI findings of decreased tumor Ktrans values suggests that G-202 reduces early arterial blood flow in hepatic lesions. Clinical trial information: NCT01777594.
Evolution of phase 1 trials for patients with advanced pancreatic cancer: An update on the experience from MD Anderson Cancer Center.
Authors: Goldstein Jennifer Brooke , Tang Chad , Hong David S. , Subbiah Vivek , Janku Filip , Hess Kenneth R. , Fu Siqing , Karp Daniel D. , Naing Aung , Tsimberidou Apostolia Maria , Wheler Jennifer J. , Zinner Ralph , Javle Milind M. , Varadhachary Gauri R. , Wolff Robert A. , Fogelman David R. , Meric-Bernstam Funda , Piha-Paul Sarina Anne 
Published: February 2017

320 Background: Pancreatic cancer is a disease that generally presents in advanced stage and is nearly fatal in all cases. In 2011, we reported our experience with pancreatic cancer patients enrolled on phase 1 clinical trials from 2004-2009. At the time, gemcitabine and erlotinib were the only US FDA approved drugs for pancreatic cancer. Median overall survival from presentation in the phase 1 clinic was 5 months. After an additional 5 years of progress, we queried the impact of novel cancer therapeutics, evolving molecular profiling, and targeted therapy on pancreatic cancer patient outcomes in the phase 1 setting. Methods: A retrospective review of advanced pancreatic adenocarcinoma patients from the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center, was conducted for patients treated from 1/2009 to 1/2014. Statistical analyses utilized the Kaplan-Meier method. Results: A total of 90 patients were identified in 50 trials reviewed. Median age was 62 years (40-84), 57% were male, and 40% had stage IV disease at presentation. Median documented PS was 1 (range 0-3). The median time from diagnosis to treatment on a phase I protocol was 15 months (0.2-119). Patients were treated with an average of 4 prior regimens prior to Phase 1 referral (0-10) with 8% having undergone >5 treatments. The median overall survival from the first phase I treatment was 5.2 months, 95% CI = (4.4-6.3) and the 1 year overall survival from the first phase 1 treatment was 15% (9%- 25%). The median duration on regimen with best phase I response was 1.9 months (0.2-21.3). Of 88 evaluable, the best responses were PR in 1 patient and SD (> 6 months) in 5 patients. Although 47 patients had biomarker profiling performed and 61 patients were treated with targeted therapy alone or in combination with cytotoxic therapy, only 6 patients (5 PD, 1 SD currently on protocol) were placed on trials based on biomarker testing results. Conclusions: Pancreatic cancer remains a difficult disease to treat with poor outcome. Referral to phase 1 occurs late in the disease course. Biomarker based therapies may be more successful with more stringent patient selection and when referred earlier or used prior to cytotoxic treatment.
Prognostic and predictive potential of omics studies from blood in pancreatic cancer patients treated with concurrent radiotherapy, gemcitabine, and cetuximab.
Authors: Huber Peter E , Timke Carmen , Nicolay Nils H , Lopez Ramon 
Published: February 2017

326 Background: Pancreatic cancer is a cancer with dismal prognosis. Multimodal therapy approaches integrating targeted drugs into radiochemotherapy regimens may be promising concepts for patients with locally advanced disease. It would be desirable to better understand patterns of therapy response, clinical outcome and side effect spectra by performing gene expression and protein analyses from blood samples before, during and after actual treatments. Methods: At defined time points before, during and after neoadjuvant triple therapy consisting of IMRT +/-gemcitabine chemotherapy +/-cetuximab EGFR antibodies, blood samples were collected from 21 patients with advanced pancreatic cancer. Whole blood transcriptomics was performed using Agilent’s human genome wide microarray platform. Quantitative serum protein analysis was performed using the ‘FastQuant’ (sandwich antibody) system on 20 selected proteins with a focus on cytokines and angiogenesis related proteins. Cluster analyses were performed and array data were correlated to local control, survival, CA19-9 response, and side effects e.g. acne grading and hematotoxicity. Results: Whole blood transcriptomics was feasible and showed statistically significant prognostic and predictive value for therapy specific and patient specific expression signatures. RNA expression signatures obtained before and during treatment course appeared to have significant statistical power to predict CA19-9 response, clinical outcome and side effect parameters. Similarly, the serum proteomic time course correlated with clinical outcome. Moreover, cetuximab increased e.g. PDGF, MCP-1, Rantes, Il-6, Angiopoietin, serum and downregulated TIMP-1, Il-8, and Angiogenin levels while radiochemotherapy had primarily the respective opposite effects. Conclusions: Whole blood analyses provides a promising tool to monitor pancreatic cancer patients undergoing radiotherapy+gemcitabine+cetuximab, and the protein and gene expression “signatures” from blood may be prognostic and predictive for clinical endpoints.
Exploring phosphatase and tensin homolog (PTEN) loss via immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) as a potential predictive marker for response to everolimus in patients (pts) with neuroendocrine tumors (NET).
Authors: Khushman Moh'd M. , Gomez Arteaga Alexandra , Diaz Liege , Tinoco Gabriel , Dawar Richa , Bustinza Ernesto , Garcia Monica T. , Fan Yao-Shan , Restrepo Maria , Merchan Jaime R. , Sussman Daniel A. , Slingerland Joyce , Rocha Lima Caio Max S. , Hosein Peter Joel 
Published: February 2017

333 Background: Identification of pts with exquisite sensitivity and/or durable responses to targeted therapies may lead to improved patient selection and allow for more rational treatment designs. Exceptional responders to everolimus in NET including pancreatic (PNET) were observed in our cohort of pts. PTEN is a key negative regulator of the phosphatidylinositol 3-kinase(PI3K)/Akt and mammalian target of rapamycin (mTOR) pathway. Loss of PTEN tumor suppressor gene function, usually due to deletion, leads to PI3K/Akt/mTOR pathway activation. Inthis study, we explored the role of PTEN as a potential predictive marker of everolimus in pts with NET including PNET. Methods: Between 2010 and 2014, pts with well-differentiated unresectable and metastatic gastrointestinal NET treated at our institution with everolimus were identified. 17 patients had pathology specimens available for testing. PTEN loss detection by FISH was carried out using a commercially available probe for cytoband 10q23, and by IHC using a commercially available antibody. Patients’ response to everolimus was evaluated through August 2014. The primary outcome was PFS and PTEN status was correlated with PFS for any potential association. Results: The median age was 59 years (range 45-78); 7 were male; 8 had PNET (2 gastrinomas, 1 insulinoma and 5 non-functional); 7 had small bowel NET and 2 unknown primary. All pts received everolimus starting at 10mg daily and octreotide LAR. Of the pts with PNETs, 3 had PTEN loss by FISH. Of those, one did not tolerate everolimus. The PFS for the other two pts was 8 and 24 months respectively. Among the 4 pts with intact PTEN; PFS was 14, 26, 3 and 12 months. 1 patient had insufficient tumor for testing. PTEN FISH is ongoing in the 9 non-pancreatic NET pts. PTEN expression by IHC is also ongoing and will be reported at the meeting. Conclusions: Testing for PTEN loss by FISH is feasible. Due to the small sample size, the role of PTEN loss could not be defined as a predictive marker in PNET. Testing on additional cases is ongoing and will be presented at the meeting.
Outcomes of therasphere radioembolization for neuroendocrine metastases.
Authors: Abbott Andrea M. , Hoffe Sarah E. , Strosberg Jonathan R. , Almhanna Khaldoun , Biebel Benjamin , Choi Junsung , El-Haddad Ghassan , Kis Bela , Sweeney Jennifer , Fulp William J. , Shridhar Ravi 
Published: February 2017

371 Background: Neuroendocrine tumors (NET) are a rare group of tumors with variable biologic activity that have a propensity for hepatic metastases. Complete surgical resection or debulking is the standard of care while chemotherapy is reserved for unresectable disease. However, liver directed therapy utilizing radioembolization with yttrium-90 (y90) may offer an alternative modality of treatment to patients with unresectable hepatic disease while minimizing systemic toxicity and providing acceptable overall survival (OS). Methods: A retrospective review of all patients undergoing y90 microsphere treatment for metastatic NET (mNET) from 2009-2013 was conducted. Patient, treatment, and post-treatment variables from initial diagnosis and y90 treatment were collected. Multivariable analysis (MVA) of factors related to OS and treatment toxicity was performed by the Cox proportional hazard model using Wald test and OS estimates were calculated using the Kaplan-Meier method. Results: We identified 74 patients with a median follow-up of 21 months. Median and 2 year OS was 26 months and 56%. Tumor burden was a significant predictor of survival. Two year OS for patients with ≤ 25%, 25-50%, 50-75%, and >75% tumor burden was 63%, 59%, 40%, and 34%, respectively (log-rank p = 0.027). MVA revealed that female gender and higher disease burden were associated with increased mortality; age, location of primary tumor, resection status of the primary tumor, prior chemotherapy, and presence of extrahepatic metastases at the time of treatment were not significant predictors of OS. The majority of patients (88%) experienced a treatment related toxicity; however 72% were Grade 1/2 and only 16% were Grade 3/4. Male gender and prior liver therapy were associated with higher rates of toxicity. Conclusions: Y90 was associated with acceptable OS with minimal severe morbidity in this series of patients with mNET. Lower tumor burden and male gender were associated with better OS. These results suggest that y90 may be a potential treatment alternative for patients with unresectable mNET. Prospective studies evaluating y90 in the treatment of unresectable chemo-refractory mNET are needed.
Phase II study evaluating the association of gemcitabine, trastuzumab, and erlotinib as first-line treatment in patients with metastatic pancreatic adenocarcinoma (GATE 1).
Authors: Assenat Eric , Mineur Laurent , Mollevi Caroline , Lombard-Bohas Catherine , Mazard Thibault , Samalin Emmanuelle , Portales Fabienne , Walter Thomas , Ychou Marc 
Published: February 2017

379 Background: This study aimed to assess the efficacy and tolerance of the combinationof chemotherapy and two targeted therapies as a first-line treatment in metastatic pancreatic cancer patients. Methods: We designed a phase 2 open-label, non-comparative, multicenter study (NCT01204372). Patients received weekly 1000 mg/m² gemcitabine (3 weeks out of 4), weekly trastuzumab (4 mg/kg the first week, 2 mg/kg afterwards) and erlotinib 100 mg/day per os. The primary endpoint was the disease control rate (DCR) according to RECIST. Using a Fleming’s single-stage procedure, the trial was considered positive if 29 patients had a controlled disease (out of 57 evaluable patients). Secondary endpoints included the safety, the progression-free survival (PFS) and the overall survival (OS). An ancillary study addressed the EGFR, HER2 and KRAS status of the patients. Results: Between June 2010 and July 2013, 62 patients were recruited (37 men). The median age was 62 years (range 35-77). Performance status was 0 (n=27) and 1 (n=35). 10 patients had had a surgery of the primary tumor (PT), of whom 6 had been treated with a gemcitabine-based adjuvant chemotherapy (> 6-month delay). PT were localized in the head (n=25), corpus (n=22) and tail (n=15) of pancreas. The number of metastatic sites varied from 1 (n=25) to ≥ 3 (n=15). The baseline median left ventricular ejection fraction was 65% (range 51-86%). All patients were evaluable for safety and 59 patients for efficacy. Main first cycle treatment-related toxicities included: grade 3 anorexia (27%), asthenia (13%), diarrhea (10%), anemia (6%), and thrombocytopenia (3%); grade 3-4 neutropenia (24%), and mucositis (6%); grade 2-3 cutaneous events (35%). No complete responses were observed. 11 patients had a partial response, 33 a stable disease and 15 a disease progression. Therefore, the DCR was 74.6% (95%CI: 61.6-85.0%). Definitive results for the secondary endpoints will be presented at the meeting. Conclusions: Our results showed that combining gemcitabine, trastuzumab and erlotinib is efficient in terms of DCR. A further study is necessary to investigate this promising association. Funding (Roche SAS). Clinical trial information: NCT01204372.
Neoadjuvant chemoradiation (NACRT) and the prognostic effect of surgical margin (SM) status in pancreatic adenocarcinoma (PAC).
Authors: Wang Lora S , Hoffman John Parker , Handorf Elizabeth , Murphy Colin T. , Cooper Harry S. , Cohen Steven J. , Meyer Joshua E. 
Published: February 2017

407 Background: Many studies have associated a R0 resection to have significantly improved survival compared with a R1 resection in PAC. Patients (pts) who undergo NACRT often go to surgery 4-8 weeks after the end of therapy, before the effects of NACRT can be fully manifested. The goal of this study is to evaluate if a positive SM (+SM) after NACRT has the same poor prognosis as a +SM after upfront surgery. Methods: After IRB approval, we retrospectively reviewed all cases of surgically resected PAC at a single institution from Dec 1996 to Jan 2014. Pts were stratified by receipt of NACRT as well as by SM status. We excluded pts treated with palliative intent, metastatic disease at presentation, death within 90 days of surgery, and biliary or ampullary tumors. The primary endpoint was overall survival (OS). We assessed the relationship between pt and tumor variables with treatment/margin combination using Chi-squared tests. OS was examined using Kaplan-Meier curves, and we tested association with treatment/margin using log-rank tests. Results: A total of 213 pts met inclusion criteria; 111 received upfront surgery (group I) with 94 (85%) receiving adjuvant chemotherapy or CRT and 102 received NACRT (group II) with either concurrent 5-fluorouracil (n=18) or gemcitabine (n=84). There were 31 pts with +SM in group I and 29 pts in group II. Pt demographics were balanced. There was more vessel involvement in group II (81%) at diagnosis than group I (11%) (p<0.01) with a trend towards improved OS in group II vs group I (p=0.09). Pathological evaluation revealed more PNI (61% vs 42%, p<0.01) and more lymph node positivity (71% vs 33%, p<0.01) in group I vs group II, respectively. Median OS for group I SM+/SM- and group II SM+/SM- were 15/25 months and 26/32 months respectively. OS is significantly improved with a negative SM (-SM) compared with a +SM (p<0.01). If the SM is positive, pts in group II had improved OS compared with group I (p=0.02). OS was not significantly different for group II +SM vs group I –SM (p=0.34). Conclusions: The negative impact of a +SM on survival is partially mitigated by NACRT. This data further supports the use of NACRT, although it is limited by its retrospective nature and small sample size.