bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of low-dose cyclophosphaminde followed by low-dose tumoral radiation, intratumoral poly-ICLC combined with local-regional therapy, followed by systemic immune boosting with intramuscular poly-ICLC in patients with cancers of the liver.
Authors: de la Torre Andrew N , Castaneda Ismael , Contractor Sohail , Salazar Andres M. 
Published: February 2017

327 Background: Cancers in the liver are susceptible immune evasion due to the liver’s role in self-tolerance. Eliminating liver cancers may require multiple steps to reduce tumor tolerance, increase expression of tumor-associated antigens, and turn on immunity against such tumor antigens. Methods: Phase I-II trial to 1) reduce tumor tolerance with oral cyclophosphamide 50 mg/day x 21 days, 2) increase tumor antigen visibility with low dose radiation (2.5 Gy x 3 days), 3) induce a “danger” response with intra-tumoral injection of the TLR3 agonist poly-ICLC (1mg) and concurrent hepatic artery embolization and 4) enhance immunity with intramuscular poly-ICLC (20 mcg/kg). Results: From 2/17/2007 to 7/27/12, 25 patients were enrolled. Cancers were 17 hepatoma (HCC), 3 metastatic pancreas (mPANC), 2 metastatic neuroendocrine (mNEURO), and 2 cholangiocarcinoma (CC). Patients were not liver transplant eligible at enrollment. Patient 1 with cirrhosis died after embolization of a 13 cm HCC. Patients 2-25 had no adverse events (AE) greater than grade 2. The most common AEs were fatigue (13), anorexia (7), injection site rash (7), fever (6), and diarrhea (3). Of 17 HCC patients, the mean survival was 737 days. Two patients were downstaged and underwent liver transplant. One patient was transplanted after 203 days and is still alive. The second patient was transplanted after 1433 days, but died 10 days following transplant. We had one patient who presented with multiple large HCCs and portal vein invasion surviving 984 days and another patient with multiple large HCCs still alive after 2451 days. Both patients with mNEURO tumors are still alive after 1905 and 736 days. All patients with CC and mPANC cancer died. Conclusions: This approach is well tolerated. Caution should be used with embolization of large tumors. Although the overall survival was just over two years, several patients with advanced HCC and mNEURO tumors lived beyond our expectations. Further investigation is needed to optimize this method and identify patients who will benefit most from this immunotherapeutic approach. Clinical trial information: NCT00553683.
Efficacy markers for cisplatin and S-1 in biliary tract carcinoma.
Authors: Sakamoto Yasunari , Ojima Hidenori , Morizane Chigusa , Yamagishi Seri , Hosoi Hiroko , Kondo Shunsuke , Ueno Hideki , Okusaka Takuji , Kanai Yae 
Published: February 2017

334 Background: Gemcitabine (GEM) + cisplatin (CDDP) combination chemotherapy is the first choice for advanced biliary tract carcinoma (BTC). In Japan, the GEM + S-1 therapy has shown promise for the treatment of BTC. Our aim was to investigate the cytotoxic effects of GEM, CDDP and S-1 on BTC cell lines and find an immunohistochemical marker for predicting the efficacy of chemotherapy. Methods: We evaluated the efficacy of GEM, CDDP, and S-1 by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of 17 BTC cell lines. Furthermore, we subdivided the cell lines into sensitive and insensitive groups on the basis of the sensitivity of each drug. Moreover, pairwise studies were conducted using the MTT assay, Bliss additivism model, and Combination Index for analysis. Immunohistochemical expression analysis of excision repair cross-complementation group 1 (ERCC1), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), and thymidine phosphorylase (TP) were also performed in each cell line to compare the results of the cytotoxic effects of CDDP and S-1. Results: In the single-agent MTT assays, among the 17 tumor cell lines, 11 were sensitive to GEM, 13 to CDDP, and 11 to S-1. In 5 cell lines, <30% of the cells showed ERCC1 expression; these lines belonged to the CDDP-sensitive group. Conversely, the cell lines with >30% ERCC1-positive cells mostly belonged to the CDDP-insensitive group. CDDP IC50 correlated with the percentage of ERCC1-positive cells (P <.05). In contrast, none of the immunohistochemical markers could be used to select a cutoff level that would point to the sensitivity to S-1. In pairwise MTT assays (combination therapy), we demonstrated the synergy of GEM with CDDP in 9 tumor cell lines (53%) and the synergy of GEM with S-1 in 4 tumor cell lines(24%). Although 3 cell lines with the synergy of GEM with CDDP showed <30% ERCC1-positive cells, there was no correlation between them. Conclusions: ERCC1 expression in <30% of cells may help to identify CDDP-sensitive tumors; however, it is unknown whether expression of ERCC1 can help to predict efficacy of treatment with GEM + CDDP.
Cost description of chemotherapy regimens for the treatment of metastatic pancreas cancer (mPC).
Authors: Goldstein Daniel A. , Krishna Kavya , Flowers Christopher , El-Rayes Bassel F. , Bekaii-Saab Tanios S. , Noonan Anne M. 
Published: February 2017

368 Background: Multiple chemotherapy regimens are now available for the treatment of mPC. With these regimens median overall survival ranges between 6-11 months. Choice of regimen is often based on the patient’s performance status (PS) and toxicity profile of the regimen. Newer combinations may be associated with high financial costs. The objective of this study was to analyze the costs of first-line regimens to further aid in decision-making and develop a platform upon which to assess value. Methods: We calculated the monthly cost for individual standard regimens. These included gemcitabine (G), FOLFIRINOX (5-FU, irinotecan and oxaliplatin), and gemcitabine/nab-paclitaxel (GN-P). Furthermore, we evaluated other novel regimens. These included our institutional experience with dose-modified GN-P (dmG-NP) which will be presented at the ASCO GI conference. We additionally evaluated the cost of 3-weekly carboplatin/paclitaxel (CP) which formed the control arm of a phase II trial in mPC (NCT01280058). The results of this trial are to be presented as Late Breaking Abstract 19 at the upcoming ESMO conference. In addition to the cost of drugs, we included administration costs, and costs of toxicities (including growth factor support, blood product transfusion and hospitalization for toxicities). Costs for administration and management of adverse events were based on Medicare reimbursement rates for hospital and physician services. Drug costs were based on Medicare average sale prices (all 2014 US $). Results: The monthly cost of GN-P is $12,221. FOLFIRINOX costs $3.865 per month. G alone costs $1,363 per month. DmGN-P costs $6.716 per month. CP was the cheapest combination regimen ($2,154 per month) and in a recent phase II trial has been shown to have a similar efficacy to GN-P. Conclusions: Choice of chemotherapy regimen for mPC is usually based on tolerability and efficacy of the regimen individualized to patient’s PS. Healthcare systems have finite resources, thus, there is increasing emphasis on metrics to define value in healthcare These data provide useful financial information to incorporate into the decision-making process.
Treatment strategy for borderline resectable pancreatic cancer with artery involvement.
Authors: Hirono Seiko , Kawai Manabu , Okada Ken-Ichi , Miyazawa Motoki , Shimizu Atsushi , Kitahata Yuji , Ueno Masaki , Hayami Shinya , Yamaguchi Shunsuke , Takifuji Katsunari , Hotta Tsukasa , Nakamura Masaki , Matsuda Kenji , Yamaue Hiroki 
Published: February 2017

373 Background: It has been still controversial to perform surgical resection with borderline resectable pancreatic cancer with artery involvement (BR-A), because an aggressive surgery leads to high morbidity and mortality with low R0 rate for the BR-A patients. In this study, we evaluated whether or not neoadjuvant therapy followed by surgical resection improves survival benefits for BR-A patients. Methods: There were 138 patients with BR-A among 330 pancreatic cancer patients underwent surgical resection at Wakayama Medical University Hospital. We compared clinicopathological factors between 38 BR-A patients with neoadjuvant therapy followed by surgical resection and 100 BR-A patients with upfront surgery to evaluate the clinical impacts of neoadjuvant therapy. Results: The overall survival (OS) of BR-A patients was significantly shorter than that of the patients with borderline resectbale pancreatic cancer with portal vein/ superior mesenteric vein (PV/SMV) involvement (n=76) and resectable pancreatic cancer (n=105) who underwent surgical resection (median OS: 13.6 vs. 20.6 months, P<0.001). The OS of BR-A patient with neoadjuvant therapy followed by surgical resection was significantly longer than those with upfront surgery (median OS: 20.2 vs. 12.9 months, P=0.047). Multivariate analysis showed that older age (P=0.027), pathological PV/SMV invasion (P=0.031), moderated or poor differentiated tumor (P=0.008), positive lymph node ratio ³a0.1 (P=0.018), and no postoperative adjuvant chemotherapy (P<0.001) were independent poor prognostic factors for BR-A patients. Conclusions: Neoadjuvant treatment might bring the clinical benefits for BR-A patients, and it is important to develop the appropriate regimen of neoadjuvant therapy and postoperative adjuvant therapy for longer survival in BR-A patients. Clinical trial information: 000003795.
Outcomes of a clinical pathway for borderline resectable pancreatic cancer.
Authors: Rashid Omar Maen , Pimiento Jose Mario , Springett Gregory M. , Malafa Mokenge Peter 
Published: February 2017

374 Background: While multimodality therapy for borderline resectable pancreatic adenocarcinoma (BPA) is advocated, treatment regimens vary by institution without a standardized approach supported by prospective randomized data. We implemented a multidisciplinary multimodality clinical pathway (CP) for the management of BPA and examined outcomes to investigate optimal therapy. Methods: From January 1, 2006, to December 31, 2013, BPA cases as defined by the NCCN and AHPBA consensus guidelines were managed prospectively along CP. Resection rates, margin status, pathologic response, and overall survival were retrospectively examined. Standard statistical and survival analysis were used. Results: 121 patients were classified as BPA and 101 entered the CP. The neoadjuvant chemoradiation (NT) completion rate was 93.1%. Of those who entered the CP, 55 patients (54.5%) underwent pancreatectomy. R0, R1 and R2 margin rates were 96.3%, 3.7% and 0%, respectively. Of the 55 patients who underwent resection, 22 (40%) required vascular reconstruction, with R0, R1 and R2 margin rates of 95.2%, 4.8%, and 0%, respectively. Pathologic response to treatment was found in 70.8%, with a complete response rate of 15.9%. Median overall survival in the resected group versus the non-resected group was 34.2 months versus 14.7 months, p<0.001. Conclusions: Our series represents one of the largest reports of BPA in the literature and implementation of our CP resulted in a high NT completion rate and pancreatectomy with negative margin rate. Although 41.4% of cases were not resectable after NT, there was a high rate of negative margin resection with >70% pathologic response rate and a favorable median survival.
Efficacy of sorafenib in patients with oligometastatic hepatoceulluar carcinoma (HCC).
Authors: Thillai Kiruthikah , Ziogas Dimitrios , Korantzis Ippokratis , Chowdhury MH Ruhe , Papadatos-Pastos Dionysios , Suddle Abid , O'Grady John , Heaton Nigel , Ross Paul J. , Sarker Debashis 
Published: February 2017

389 Background: HCC is the second leading cause of cancer related mortality worldwide. Standard treatment for advanced disease is sorafenib, which is associated with a modest improvement in overall survival. We hypothesized that patients with oligometastatic disease treated with sorafenib have improved outcomes over those with extensive metastases. Methods: A retrospective analysis of all patients with advanced HCC treated with sorafenib at a large HCC centre. 190 patients were identified (177 patients with sorafenib alone, 13 patients treated with a combination of sorafenib and erlotinib/placebo as part of the SEARCH trial). Disease distribution was defined as intra-hepatic, oligometastatic (3 or fewer extra-hepatic metastases) and extensive (more than 3 metastases) at the time of starting sorafenib. Overall survival (OS), progression free survival (PFS) and toxicities were recorded. Results: The median age for all patients was 66 years (26-87), 157 male and 33 female. Underlying liver disease included hepatitis B (N=39, 20.4%,) hepatitis C (N=38, 19.9%), alcoholic liver disease (N=38, 19.9%), non-alcoholic fatty liver disease (N=27, 14.1%), unknown aetiology (N=42, 21.9%) and other (N=7, 3.6%). 157 patients had Child-Pugh A status, 33 patients Child-Pugh B. 113 patients had intra-hepatic disease, 45 patients had extensive disease and 32 patients had oligometastatic disease. Median OS for all patients treated with sorafenib was 7.6months(m) and PFS was 4.3m. For patients with oligometastatic disease, OS was significantly longer than those with extensive disease (10.4m vs. 6.3m p=0.034). PFS was also increased at 5.9m vs. 2.8m p=0.028). 50 patients (26%) developed grade 3 or greater toxicity, including diarrhea (N=10, 5.2%), fatigue (N=15, 7.8%) and skin (N=12, 6.3%). There were no statistically significant differences in toxicities amongst patients with oligometastatic disease compared with those with extensive disease. Conclusions: This study suggests that patients with oligometastatic disease have improved survival outcomes compared with patients with extensive disease. Further prospective research is needed to confirm these findings.
The Glasgow whipple risk score to predict pancreas-specific complications after pancreaticoduodenectomy.
Authors: Palani Velu Lavanniya Kumar , Chandrabalan Vishnuvardhan , Carter Ross , McKay Colin , McMillan Donald , Jamieson Nigel B , Dickson Euan 
Published: February 2017

394 Background: Pancreas-specific complications (PSC), comprising postoperative pancreatic fistula, post-pancreatectomy haemorrhage, and intra-abdominal collections, are drivers of morbidity following pancreaticoduodenectomy (PD). Intra-operatively derived pancreatic gland texture is a major determinant of postoperative PSC. We have previously demonstrated that a postoperative day 0 (PoD0) serum amylase ≥ 130 IU/L is an objective surrogate of pancreatic texture, and is associated with PSC. We sought to refine the PSC risk prediction model by including serial measurements of serum C-reactive protein (CRP). Methods: 230 consecutive patients undergoing PD between 2008 and 2014 were included in the study. Routine serum investigations, including amylase and CRP were performed from the pre-operative day. Receiver operating characteristic (ROC) curve analysis was used to identify a threshold value of serum CRP associated with clinically significant PSC. Results: 95 (41.3%) patients experienced a clinically significant PSC. ROC analysis identified post-operative day 2 (PoD2) serum CRP of 180 mg/L as the optimal threshold (P=0.005) associated with clinically significant PSC, a prolonged stay in critical care (P =0.032), and a relaparotomy (P = 0.045). Patients with a PoD0 serum amylase ≥ 130 IU/L who then developed a PoD2 serum CRP ≥ 180 mg/L had a higher incidence of postoperative complications. Patients were categorised into high, intermediate and low risk groups based on PoD0 serum amylase and PoD2 serum CRP. Patients in the high risk group (PoD0 serum amylase ≥ 130 IU/L and PoD2 serum CRP ≥ 180 mg/l) had significantly higher incidence of PSC, a return to theatre, prolonged lengths stay (all P≤ 0.05) and a four-fold increase in perioperative mortality compared patients in the intermediate and low risk groups (7 deaths in the high risk group versus 2 and nil in the intermediate and low risk groups respectively). Conclusions: A high risk profile, defined as PoD0 serum amylase ≥ 130 IU/L and PoD2 serum CRP ≥ 180 mg/l, should raise the clinician’s awareness of the increased risk of clinically significant PSC and a complicated postoperative course following pancreaticoduodenectomy.
Final analysis of a phase II study of Yale-modified FOLFIRINOX (mFOLFIRINOX) in metastatic pancreatic cancer (MPC).
Authors: James Edward Samuel , Cong Xiangyu , Yao Xiaopan , Hahn Carol , Kaley Kristin , Li Jia , Kortmansky Jeremy S. , Fischbach Neal A. , Cha Charles , Salem Ronald R , Stein Stacey , Hochster Howard S. , Lacy Jill 
Published: February 2017

395 Background: Although FOLFIRINOX is superior to gemcitabine in MPC, the regimen is associated with significant toxicities (Conroy et al. N Engl J Med 2011;364:1817). In our prior retrospective analysis, efficacy was not compromised by dose attenuations of FOLFIRINOX (Gunturu et al. Med Oncol 2013;30:361). Based on this analysis, a prospective phase II open label study to evaluate the efficacy and tolerability of mFOLFIRINOX in pts with locally advanced (LAPC) and MPC was conducted. Herein, we report the final analysis of the toxicity in LAPC and MPC, and the efficacy in MPC. Methods: Previously untreated pts with MPC or LAPC received mFOLFIRINOX every two wks with 25% dose reductions of irinotecan & bolus 5FU until progression, unacceptable toxicity, or surgical resection. All pts received prophylactic pegfilgrastim. CAT scans were obtained every 4 cycles for response assessment by RECIST. Toxicities in the entire cohort, and response rate (RR) & pt characteristics in the MPC cohort were compared to historical data reported by Conroy. PFS was determined for MPC cohort. Results: 31 pts with LAPC and 43 pts with MPC with ECOG PS 0/1 were enrolled between 11/11 and 01/14. Characteristics of evaluable (37/43) MPC pts were: med age, 61 yrs (range 50-76); male, 21; ECOG PS 0, 17; med # metastatic sites, 2; peritoneal disease, 14; biliary stent, 9; med # of cycles 10 (range 4-31). Grade 3/4 toxicities in entire cohort were: vomiting & peripheral neuropathy, 2.7%; ALT elevated, thromboembolism and febrile neutropenia, 4.1%; anemia, 5.4%; diarrhea,16.2% (no grade 4 diarrhea reported); neutropenia & fatigue, 12.2%; thrombocytopenia, 9.5%. Neutropenia (p<0.0001), vomiting (p=0.0014), and fatigue (0.0194) were significantly decreased compared to historical data. RR in 37 pts with MPC was 35.1% (0 CR, 13 PR, 19 SD, 5 PD) and similar to historical data (36.9%; p 0.86). PFS in MPC pts was 6.11 mo with 95% CI (5.29, 8.31). Conclusions: mFOLFIRINOX with prophylactic pegfilgrastim in pts with MPC is associated with improved tolerability compared to full dose FOLFIRINOX, while RR and PFS in pts with MPC is similar to that reported by Conroy et all using full dose FOLFIRINOX. MPC pts are in follow-up for OS. Follow up for LAPC patients is ongoing. Clinical trial information: NCT01523457.
Phase I trial of sorafenib following liver transplantation in patients with high-risk hepatocellular carcinoma.
Authors: Siegel Abby B. , El-Khoueiry Anthony B. , Finn Richard S. , Guthrie Katherine , Venook Alan P. , Blanke Charles David , Brown Robert S. 
Published: February 2017

401 Background: Liver transplantation (LT) offers excellent long-term survival for hepatocellular carcinoma (HCC) patients who are within established criteria. For those outside such criteria, or with high risk pathologic features in the explant, HCC recurrence rates after LT are high. No treatment has been shown to decrease risk of recurrence post-LT. We conducted a multicenter phase I trial of sorafenib in LT patients with high-risk HCC. Methods: Subjects had pathologically proven high-risk HCC defined as outside Milan (pre- or post-transplant), poorly differentiated tumors, or tumors with vascular invasion. We used a standard 3+3 phase I design, beginning drug between 4 and 16 weeks after LT, with planned duration of treatment of 24 weeks. Cohort dosages were: 1) 200 mg per day, 2) 200 mg twice a day, 3) 200 mg/400 mg per day 4) 400 mg BID. Correlative studies included circulating endothelial cells (CECs) and plasma biomarkers collected prior to treatment, at 1 month, and at recurrence in a subset of subjects, and tumor expression of p-Erk, p-Akt, and c-Met in tissue microarrays. Results: We enrolled 14 patients. Median age was 63 years, and 93% were men. 71% had underlying HCV and 21% had HBV. Maximum tolerated dose (MTD) was 200 mg BID; only 43% of patients received >80% of planned dose. Grade 3-4 toxicities seen in >10% of subjects included: leukopenia (29%), LFT abnormalities (21%), hypertension (14%), hand-foot syndrome (14%) and diarrhea (14%). Over a median follow-up of 953 days, 1 patient died and 4 recurred, with a median recurrence-free survival of 716 days for the 4 patients who recurred. Mean CEC number at baseline was 21 cells/4 ml for those who recurred, and 80 cells/4 ml for those who did not (p=0.10). Mean sVEGFR2 levels decreased after 1 month on sorafenib (p=0.09), but did not correlate with recurrence. There was a trend for tumor c-Met expression with increased risk of recurrence. Conclusions: Post-transplant sorafenib is feasible and tolerable at 200 mg PO BID. Recurrence-free survival appears longer than expected but needs further validation in a larger study. Clinical trial information: NCT00997022.
Neoadjuvant chemoradiation therapy for cholangiocarcinoma to improve R0 resection rate: The first report of phase II study.
Authors: Katayose Yu , Nakagawa Kei , Yoshida Hiroshi , Morikawa Takanori , Hayashi Hiroki , Okada Takaho , Mizuma Masamichi , Sakata Naoaki , Ohtsuka Hideo , Fukase Koji , Yabuuchi Shinichi , Ishida Masaharu , AOki Takeshi , Okada Ryo , Masuda Kunihiro , Kawaguchi Kei , Motoi Fuyuhiko , Naitoh Takeshi , Unno Michiaki 
Published: February 2017

402 Background: With the much-improved surgical techniques of hepatic lobectomy, but the long-term survival of patients undergoing such surgery remains far from satisfactory. Then, to improve the prognosis of cholangiocarcinoma patients, we have applied neoadjuvant chemoradiation therapy followed by conventional resection for possibly resectable cholangiocarcinoma, named NACRAC. Here, we analyzed and evaluated the Phase II (P-2) study. Methods: Patients with histologically or cytologically confirmed adenocarcinoma of the extra- and hilar cholangiocarcinoma were enrolled from 2008 to 2013 at Department Surgery, Tohoku University Hospital. The dose of gemcitabine was determined 600mg/m2 of gemcitabine with external beam radiation therapy (1.8-Gy daily fractions to a total dose of 45 Gy) ( Hepatogastroenterology. 2011;58(112):1866-72.). The primary endpoint of P-2 is R0-resection rate. We hypothesized that R0-resection rate become from 60% to 80%. Results: Total numbers of enrolled patients were 25 cases. 22 cases were operated, and 20 cases were resected. After chemoradiation, 3 cases were not operated by liver metastases, tumor progression, and heart failure. 2 cases were not resected by peritoneal carcinomatosis. One case was diagnosed as pancreatic cancer at the final pathological diagnosis. R0-resectinn cases were 17 cases. R0 resection rate was 89.6% (17/19) among operated cases. In recruited 24 cases (A pancreatic cancer was not included), R0 resection rate was 70.8% (17/24). Grade 3 and 4 adverse events (AE) were neutropenia, leukocytopenia, and Thrombocytopenia. No grade 5 AE and no fatal AE in this P-2 study. Conclusions: Neoadjuvant chemoradiation therapy with conventional resections appears to be effective and well tolerated. After both disease free survival and overall survival are going to be fixed, we will decide a proper indication of neoadjuvant therapy for cholangiocarcinoma. Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR) UMIN UMIN000000992 and UMIN000001754 Clinical trial information: 000001754.