bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-1 blockade in mismatch repair deficient non-colorectal gastrointestinal cancers.
Authors: Le Dung T. , Uram Jennifer N. , Wang Hao , Kemberling Holly , Eyring Aleksandra , Bartlett Bjarne , Goldberg Richard M. , Crocenzi Todd S. , Fisher George A. , Lee James J. , Greten Tim F. , Laheru Dan , Azad Nilofer Saba , Donehower Ross C. , Luber Brandon , Koshiji Minori , Eshleman James R. , Anders Robert A , Vogelstein Bert , Diaz Luis A. 
Published: February 2017

195 Background: Mismatch repair (MMR) deficient tumors harbor hundreds to thousands of mutations that may produce neoantigens that can be recognized and targeted by T cells. We have shown that MMR deficiency can serve as a predictive biomarker for selection of tumors across tumor histologies that may respond to programmed death-1 (PD-1) blockade. MMR deficiency is present in 15% of colorectal (CRC) however is also detected in 2-20% of gastric, small bowel, and hepatobiliary cancers. Methods: We conducted a phase II study to evaluate anti-PD-1, pembrolizumab, in patients with previously-treated, progressive, advanced cancer. Twenty-one patients with MMR deficient tumors were enrolled onto the non-CRC cohort with an additional 50 patient expansion underway. The pembrolizumab dose is 10mg/kg intravenously every 2 weeks. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) will be reported in at least the first 17 patients with non-CRC gastrointestinal (GI) cancers. Results: As of September 18, 2015, 17 patients with non-CRC GI cancers have been enrolled on the protocol with additional patients identified. The diseases represented are ampullary (N=4), pancreas (N=4), biliary (N=3), small bowel (N=3), and gastric (N=3) cancers. For the 10 evaluable patients at the time of abstract admission, ORR is 50 % (N=5/10), disease control rate is 70% (N=7/10), OS is 21 months and the median duration of response (range 5.5-17+ months) and PFS have not been reached. The median follow up duration is 7.6 months. Conclusions: PD-1 blockade shows promising activity in mismatch repair deficient GI cancers. Clinical trial information: NCT01876511.
A phase Ib/II study of BBI608 combined with weekly paclitaxel in advanced pancreatic cancer.
Authors: Bekaii-Saab Tanios S. , Mikhail Sameh , Langleben Adrian , Becerra Carlos , Jonker Derek J. , Asmis Timothy R. , Cote Gregory Michael , Wu Christina Sing-Ying , Kwak Eunice Lee , Spira Alexander I. , Braiteh Fadi S. , Richey Stephen Lane , Hume Stephanie , Hitron Matthew , Li Chiang 
Published: February 2017

196 Background: Cancer stemness is thought to be associated with resistance to chemotherapies. BBI608, a first-in-class cancer stemness inhibitor that works through inhibiting the Stat3 pathway, has shown potent synergistic anti-tumor activity with paclitaxel in vivo. In a phase Ib dose escalation study in patients with advanced solid tumors, BBI608 plus weekly paclitaxel was well tolerated and a RP2D of BBI608 480 mg BID was determined. Methods: Patients with heavily pretreated metastatic pancreatic adenocarcinoma were enrolled in a phase Ib/II extension study to assess safety, tolerability, and preliminary anti-cancer activity in patients with this diagnosis. BBI608 was administered orally at a starting dose of 480 mg or 500 mg twice daily along with paclitaxel 80 mg/m2 IV weekly 3 of every 4 weeks. A sample size of 40 set the bounds of the 90% CI at ±10% to 14%, assuming a DCR of 60% to 80%. Safety and efficacy results for the cohort will be presented as late breaking data. Results: 41 patients were enrolled. Patients had received a median of 2 prior lines of treatment including FOLFIRINOX (71%), gemcitabine/nab-paclitaxel (44%), or both (37%). Overall, prior therapy included gemcitabine in 90%, a thymidylate synthetase inhibitor (eg 5FU, capecitabine) in 81%, platinum in 76%, irinotecan in 73%, and taxane in 44%. Protocol therapy was well tolerated. Related grade 3 AE included diarrhea (N = 2, 4.9%), abdominal pain (N = 2, 4.9%), and nausea (N = 1, 2.4%), and were rapidly reversible. For evaluable patients (N = 31), response rate (PR+CR) was 7% and disease control rate (SD+PR+CR) was 52%. In evaluable taxane-naïve patients (N = 19), response rate was 11%, disease control rate was 63%, and 16% were progression free at 24 weeks. Overall (ITT, N = 41) mPFS was 10 weeks and mOS was 24 weeks. For the taxane-naïve patients (ITT, N = 23) mPFS was 16 weeks and mOS was 30 weeks. Conclusions: BBI608 plus weekly paclitaxel has demonstrated safety, tolerability, and promising activity in patients with refractory, heavily pretreated pancreatic cancer; particularly in taxane-naïve patients. Durable disease control and prolonged overall survival in this pre-treated population are notable. Clinical trial information: NCT01325441.
Small bowel neuroendocrine tumors: A critical analysis of diagnostic work-up and operative approach.
Authors: Ethun Cecilia Grace , Postlewait Lauren McLendon , Baptiste Gillian G. , Le Nina , McInnis Mia R. , Cardona Kenneth , Russell Maria C. , Kooby David A. , Staley Charles A. , Maithel Shishir Kumar 
Published: February 2017

203 Background: Small bowel neuroendocrine tumors (SB-NET) are rare, and often small and multifocal. They are difficult to localize preoperatively and can be overlooked during operative exploration. The optimal work-up and operative approach is not known. Methods: Patients who underwent resection of SB-NET at a single institution from 2000-2014 were included. Primary aim was to describe the diagnostic work-up, pathologic characteristics, and compare minimally-invasive (MIS) to open resection. Results: 93pts underwent resection for SB-NET. Median age was 61yrs; 52% were male. On presentation, 71% of pts were symptomatic and underwent an average of 3 diagnostic tests prior to resection: 45% had octreoscans, which identified the region of primary disease in 85%; 11% had small bowel enteroscopy, with a 10% diagnostic yield; 19% had capsule endoscopy, which saw a lesion in 83%, but in only 21% was the correct number of tumors seen. The diagnostic yield of capsule was 28% overall, but 82% in pts presenting with GI bleeding. 79pts (85%) underwent curative-intent resections. Median tumor size was 1.8cm and multiple primary tumors were seen in 34pts(42%), of whom 50% had > 3 tumors. 37% had metastatic and 70% had LN positive disease. 27pts underwent MIS resections vs 66 open. MIS pts were younger (56vs61yrs;p0.035) and less likely to have obstructive symptoms (4vs24%;p = 0.19) and metastatic disease at resection (19vs44%;p = 0.038). Compared to open, the MIS group had smaller (1.7vs2.4cm;p = 0.03) and fewer tumors resected (2vs5;p = 0.049), but similar LN yield (13vs12;p = 0.7). In pts without metastases undergoing curative-intent resection, MIS approach was still associated with fewer tumors removed compared to open (1.5vs4;p = 0.034). Conclusions: Capsule endoscopy appears to be better than small bowel enteroscopy at identifying occult small bowel neuroendocrine tumors, particularly when pts present with bleeding, but still may underestimate tumor burden. While MIS may be appropriate in select patients, recognizing the limitations of preoperative evaluation is critical when selecting the operative approach for these tumors, as heightened operative vigilance is often required.
Noninvasive markers to predict malignant intraductal papillary mucinous neoplasms of the pancreas.
Authors: Orcutt Sonia Tewani , Permuth-Wey Jennifer , Choi Jung W. , Chen Dung-Tsa , Chen Lu , Malafa Mokenge Peter 
Published: February 2017

204 Background: Despite guidelines to preoperatively distinguish malignant from benign intraductal papillary mucinous neoplasms (IPMN), many patients undergo invasive testing and morbid pancreatic resection but ultimately have benign disease on pathology. A blood-based microRNA signature (SIG, including miR-200a-3p, miR-1185-5p, miR-33a-5p, miR-574-4p, and miR-664b) has been shown to preoperatively discriminate malignant from benign IPMN, with expression lower in malignant IPMN. This study was designed to develop a model to improve preoperative prediction of IPMN pathologic status combining radiographic markers and SIG values. Methods: An institutional database was used to identify patients undergoing resection for IPMN (2006-2011) with preoperative computed tomography (CT) scans and SIG values. CTs were read by a single radiologist blinded to pathology to assess predetermined radiographic features. The outcome was malignant pathology (MP, invasive carcinoma and high-grade dysplasia) vs. benign pathology (BP, low- and moderate-grade). Results: Of 38 eligible patients, 20 (53%) had MP and 18 (47%) had BP. 72% with MP had main pancreatic duct (PD) involvement vs. 20% with BP, p = 0.003. Median cyst size was higher in the MP group (3.9 vs. 2.8cm), p = 0.018. 83% of those with MP had ≥ 1 “high-risk stigmata” (PD size ≥ 10mm, enhancing solid component, or obstructive jaundice), vs. 15% of those with BP (p < 0.001), yet ≥ 1 “worrisome” feature (acute pancreatitis, PD size 5-9mm, cyst size > 3cm, thickened enhanced cyst walls, or non-enhanced mural nodules) was not associated with malignancy (p = 0.734). SIG was significantly lower in the MP group, p < 0.001. Multivariate logistic regression analyses revealed that high risk stigmata and SIG retained significance (43.0 [4.64-398.8], p = 0.001 and 0.30 [0.10-0.86], p = 0.026, respectively). The area under the receiver operating characteristic curve resulted in 0.950 for the model with both variables, compared to 0.841 and 0.836 for each variable independently. Conclusions: Combining high-risk stigmata from preoperative CT scans with a blood-based miRNA genomic classifier may improve the ability to noninvasively predict IPMN status preoperatively.
Presentation, clinical behavior, outcomes and therapies for patients with advanced pancreas adenocarcinoma (PAC) who present with or develop ascites.
Authors: Mier Hicks Angel , O'Reilly Eileen Mary , Capanu Marinela , Lowery Maeve Aine , Yu Kenneth H. 
Published: February 2017

209 Background: Ascites develops in a subset of patients with PAC at presentation or as the disease advances. Limited data exist on the prognostic importance of malignant ascites in PAC. Our hypothesis is that this information will provide an understanding of the natural history and facilitate management decisions. Methods: We conducted a retrospective analysis of N = 180 patients treated at Memorial Sloan Kettering Cancer Center diagnosed between January 1, 2009 and December 31, 2014, with PAC and ascites either at presentation or which developed during the disease course. Results: For the 180 patients, overall survival was 15 months. Time from diagnosis to ascites presentation was 11 months and survival time after ascites development was 4 months. Of 62 patients (34%) who had ascitic fluid analyzed, N = 36 (58%) had positive cytology, N = 51 (82%) patients had a serum ascites albumin gradient (SAAG) ≥ 1 and N = 11 (18%) had SAAG < 1.1. Sixty-four (36%) of patients had their ascites managed solely by serial paracenteses. A total of 116 patients required a catheter, from these, N = 108 (93%) had a Tenckhoff catheter, N = 4 (3%) Pleurx catheter, N = 3 (2%) Pigtail catheter and one (1%) a Denver catheter. Eight (4%) patients required two catheters to be placed and N = 6 (3%) Tenckhoff catheters had to be removed. Main observed complications: spontaneous bacterial peritonitis in N = 7 (11%) of patients managed with paracenteses vs. N = 34 (19%) who had a catheter placed, catheter malfunction in N = 8 (4%), acute renal failure in N = 6 (3%). After ascites development N = 79 (44%) of patients received active therapy and N = 101 (56%) patients were managed with supportive care alone. Conclusions: In patients with PAC the presence of ascites is a poor prognostic factor. Serial paracenteses and indwelling catheters are common methods used for alleviating patients’ discomfort. The complication rate was higher with indwelling catheters, primarily associated with infections (e.g. bacterial peritonitis) with low rates of complications occurring related to catheter malfunction, acute renal failure or bowel perforation.
Recurrent feature after radiofrequency ablation therapy for hepatocelluar carcinoma: Risk of increasing malignant behavior.
Authors: Yamada Shinichiro , Shimada Mitsuo 
Published: February 2017

213 Background: Radiofrequency ablation (RFA) is a widely used therapy for hepatocellular carcinoma (HCC). However, several reports demonstrated the aggressive local recurrence after RFA, suggesting the induction of further malignant transformation of HCC. Methods: Eighty-eight patients with HCC who underwent hepatic resection were included in this study. Hepatectomy was indicated for local recurrence of HCC after RFA (n = 10, RFA group) and for the HCC without prior RFA (n = 78, non-RFA group). Clinicopathological data and patient’s prognosis after hepatectomy were compared between the two groups. Expression levels of HIF-1, EpCAM, CD44, VEGF and EMT markers mRNA in the tumor tissues were examined. We also investigated miR-34a and miR-200c expressions in the two groups. Results: RFA group showed higher frequency of portal vein invasion and less tumor differentiation compared with the non-RFA group (p < 0.05). Overall and disease-free survival rates in the RFA group were significantly worse than those in the non-RFA group (p < 0.05). HIF-1 and EpCAM mRNA expression levels in the RFA group were significantly higher than those in the non-RFA group (p < 0.05). The expressions of TGF-β, Twist and Snail-1 in RFA group were significantly higher than those in non-RFA group (P < 0.05), and Vimentin expression in RFA group tended to be higher than that in non-RFA group (P = 0.07). Regarding to miRNA, miR-200c and miR-34a expressions in RFA group were significantly lower than those in non-RFA group (miR-200c: P = 0.04, miR-34a: P < 0.01). Conclusions: Recurrent HCC after RFA showed the highly malignant potential through the expressions of HIF-1, cancer stem cell and EMT markers.
Could the PD-1 pathway be a potential target for treating small intestinal adenocarcinoma?
Authors: Shi Chanjuan , Thota Ramya , Berlin Jordan 
Published: February 2017

233 Background: The programmed death 1 (PD-1) pathway is up-regulated in the immune microenvironment of many cancers. PD-1 blockage has been shown to be effective in treating some malignancies. In colorectal cancers, inhibition of PD-1 pathway appears to be selectively efficacious in microsatellite instable (MSI) tumors. In this study, we examined the immune microenvironment of small intestinal adenocarcinoma by immunohistochemistry. Methods: Twenty two small intestinal adenocarcinomas were identified from our Pathology Archives from 01/01/2002 to 05/01/2014. Immunohistochemical studies were employed to evaluate expression of CD3, CD4, CD8, CD20, CD56, PD-1 and programmed death ligand 1 (PD-L1). CD3+, CD4+, and CD8+ T cells were estimated under high power fields (HPF) and compared between PD-L1+ and PD-L1- tumors. Results: The 22 cases included 9 females and 13 males, with age ranging from 38 to 92 years. PD-1 was expressed in 18 of 22 (82%) cases, by tumor surrounding lymphocytes and lymphoid aggregates as well as tumor infiltrating lymphocytes if present. PD-L1 expression was observed in 10 of 22 (45%) cases, including 2 MSI, 2 microsatellite stable (MSS) and 6 tumors with unknown MSI status. PD-L1 was mainly expressed by histiocytes capping cancerous glands/nests at the infiltrating front. Expression of PD-L1 was also seen in tumor cells surrounding by the histiocytic caps. All the 10 cancers also expressed PD-1. The tumors expressing PD-L1 contained more CD3+ (440±22/HPF versus 238±31/HPF, p < 0.01), CD4+ (172±26/HPF versus 287±25/HPF, p < 0.01) and CD8+ T cells (58±17/HPF versus 153±33/HPF, p = 0.013) than those without expression of PD-L1. CD20+ cells were mainly seen in lymphoid aggregates. There were rare or none C56+ inflammatory cells. Conclusions: PD-1 and PD-L1 are expressed by inflammatory cells (mainly histiocytes) and tumors cells in most small intestinal adenocarcinoma. Blockage of the PD-1 pathway should be evaluated in the treatment of small intestinal adenocarcinomas.
Non-invasive monitoring of patient-derived orthotopic xenograft: An optimal system for rapid in vivotesting.
Authors: Rios Perez Mayrim V. , Pratt Michael , Kang Ya'an , Fleming Jason B. 
Published: February 2017

235 Background: Heterotopic patient-derived xenografts (PDX) have been used to assess response to therapy however they underrepresent the role of tumor microenvironment and rarely develop metastasis, both of which are overcome by orthotopic models. Fluorescent orthotopic mouse models require invasive measures to determine tumor bioluminescence. Ultrasonography (US) is a cost-effective, non-invasive imaging technique that has been used in genetically engineered mouse models of pancreatic cancer for a three-dimensional (3D) acquisition of tumor volume, which allows rapid and safe in vivo drug testing. We intend to demonstrate that this technique allows real time monitoring of in vivo response to therapy using patient-derived orthotopic xenograft (PDOX) of pancreatic ductal adenocarcinoma (PDAC). Methods: A non-survival study using PDOX was designed with control (n = 5) and treatment (n = 5) groups. Weekly 3D US images were obtained pre and post-treatment over 4 weeks. Tumor growth curves were generated to monitor progression of disease. Metastatic burden was determined during necropsy. Results: One mouse was excluded from control and treatment groups due to baseline tumor size exceeding 300mm3 and drug toxicity, respectively. Pre-treatment average tumor volumes for control and treatment groups were (36±12)mm3 and (34±12)mm3, respectively. No difference was found in average tumor growth over time between groups (p = 0.9120). A 20% tumor regression was observed per group. Both groups exhibited gross metastasis to spleen, peritoneum, and omentum. Liver, periportal metastasis and local extension to the gastrointestinal and genitourinary system were present on the treatment group. Conclusions: This study describes a rapid technique for in vivo drug response by using 3D US to monitor PDOX; failure of response to therapy correlated with metastatic burden observed. PDOX regression could be explained by tumor heterogeneity. PDOX models, as challenging as they could be, remain to be necessary in vivo models to show therapeutic response to human PDAC, which could be easily monitored using 3D US imaging.
The value of endoscopic ultrasonography in a PET/CT upfront model in staging esophageal cancer with respect to treatment decision.
Authors: Hulshoff Jan-Binne , de Boer Hiske E.M. , Noordzij Walter , Nagengast Wouter B. , van Dullemen Hendrik M. , Mul Veronique E.M. , Plukker John Theodorus 
Published: February 2017

25 Background: The optimal sequence of endoscopic ultrasonography (EUS) and positron emission tomography with computed tomography (PET/CT) in esophageal cancer (EC) is a matter of debate. The use of EUS with fine needle aspiration (FNA) after PET/CT seems to increase the efficacy of curative intended neoadjuvant or definitive chemoradiotherapy. Retrospectively, we assessed the impact of EUS in the PET/CT upfront model on the treatment decision making in EC patients. Methods: In the period 2009 to 2015, 298 EC patients were staged with hybrid PET/CT or PET with CT, and EUS if applicable, in a non-specific order to assess curability (T1-4a,N0-3M0). We determined the feasibility of EUS and whether the initial or additional EUS changed the primary decision suspicious incurable (T4b and M+) into curable disease or added extra nodal information leading to up/downstaging or exhibit suspected nodes at different lymph node stations. In addition, we assessed if EUS changed the radiation area (i.e. lymph nodes > 3.5 cm from the defined radiation target volumes) in the PET/CT “upfront model”. Results: EUS was complete in 185 (62.1%) and incomplete due to stricture from a relative obstructing tumor in 59 (19.8%) patients. Fifty-four patients (18.1%) did not receive EUS because of stenosis (n = 46; 15.4%), patient dependent reasons (n = 4; 1.3%) or other reasons (n = 4; 1.3%). EUS after hybrid PET/CT or PET with CT (n = 244) gave additional information in 166 patients (68.0%); it changed the curability in 4 (1.6%), lead to nodal up and downstaging in respectively, 81 (33.2%) and 27 (11.1%) patients, changed the number of or lymph node station of suspected lymph nodes in an additional 58 patients (n = 23.8%), and FNA gave additional information in 34 (13.9%) patients. EUS after PET/CT ”upfront” changed the treatment plan in 90 patients (36.9%), including alteration in the radiation field (86; 35.2%) and curability (4; 1.6%). Conclusions: EUS gave additional information after PET/CT “up front” and altered the radiation field in about one third of the EC patients, suggesting a better yield of “EUS on indication” after PET/CT upfront.
A multi-institutional analysis of duodenal neuroendocrine tumors: Tumor biology rather than extent of resection to dictate prognosis.
Authors: Margonis Georgios A , Samaha Mario , Kim Yuhree , Postlewait Lauren McLendon , Maithel Shishir Kumar , Poultsides George A. , Tran Thuy , Gamblin T. Clark , Berger Nicholas Gerard , Pawlik Timothy M. 
Published: February 2017

255 Background: Duodenal neuroendocrine tumors (NETs) are rare neoplasms and their management is poorly defined. As such, we sought to evaluate the management and outcomes of patients undergoing resection of duodenal NETs. Methods: Using a multi-institutional database, 132 patients who underwent curative-intent resection for duodenal NETs between 1998 and 2015 were identified. Data on clinical characteristics, comorbidities, procedural details, as well as recurrence-free survival (RFS) were collected and analyzed. Results: Median age was 63 years and most patients were male(52.3%). Two-thirds(66.7%) of patients had symptomatic disease. Most patients presented with abdominal pain(47.8%), while 17(19.3%) patients presented with GI bleeding/anemia. Lesions were located in first/second(94.5%) or third/fourth(5.5%) portion of the duodenum. Median tumor size was 1.7 cm. Local surgical resection(LSR) was performed in 55(42.0%) patients, while 47(35.9%) patients underwent pancreaticoduodenectomy(PD) and 29(22.1%) underwent an endoscopic resection(ER). Most patients had an R0 surgical margin(88.4%)(LSR, 88.7% vs. PD, 95.7% vs. ER, 71.4%; P = 0.02). Among patients who had at least one lymph node examined(n = 86), 49(57.0%) had a metastatic lymph node; lymph node metastasis were more common among patients with tumors ≥ 2cm(OR = 3.21, P = 0.02). Median length-of-stay was longer for PD(11 days) versus LSR(7 days)(P < 0.001). PD patients had more complications(LSR, 52.7% vs. PD, 63.8% vs. ER, 6.9%; P < 0.001). 3- and 5-year RFS was 80.1%, and 69.6%, respectively (site of recurrence: locoregional, n = 8 vs. distant, n = 14). Factors associated with worse RFS included tumor grade(moderate-to-poor: HR 4.12) and presence of metastasis at diagnosis (HR 5.66)(both P < 0.05). PD versus LSR versus ER approach was not associated with RFS (P > 0.05). Conclusions: Recurrence of duodenal NETs was dependent on tumor biology rather than procedure type. PD was associated with a longer hospital stay and higher risk of perioperative complications. For patients with tumors < 2cm, LSR or ER may be appropriate with PD reserved for larger lesions and those not amenable to a more local approach.