bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic significance of tumor infiltrating natural killer cells in periampullary adenocarcinoma.
Authors: Lundgren Sebastian , Elebro Jacob , Heby Margareta , Nodin Bjorn , Eberhard Jakob , Jirstrom Karin 
Published: February 2017

267 Background: Adenocarcinomas in in the pancreas and the periampullary region are heterogenous with the shared trait of having dismal prognosis. Despite recent progress in cancer therapy this has not been reflected in better prognosis for this patient group. Research has thus begun to explore the role of the immune system in pancreatic cancer. The aim of this study was to analyze the prognostic value of CD56+ natural killer (NK) cells in periampullary cancer, with particular reference to morphological type. Methods: Immunohistochemical expression of CD56 in lymphocytes and tumor cells was analyzed in tissue microarrays with tumors from 175 consecutive cases of operated periampullary adenocarcinoma, 110 of pancreatobiliary-type (PB type) and 65 of intestinal-type (I type) morphology. Kaplan-Meier and Cox regression analysis, unadjusted and adjusted for sex, age, stage, grade, size, growth in peripancreatic fat, perineural tissue and blood vessels, adjuvant chemotherapy and resection margins, were applied to determine the impact of CD56 expression on 5-year overall survival (OS). Results: A high density of CD56+ NK cells correlated significantly with low T- and N-stage (p = 0.003; p = 0.009), absent lymphatic, vascular and perineural infiltration (p = 0.007; p = 0.006; p = 0.023) and growth in peripancreatic fat (p = 0.016). High density of CD56+ NK cells was associated with a prolonged OS in univariable, but not multivariable, analysis in PB type, but not in I type, tumors (HR = 0.60; 95% CI 0.37-0.98). Interestingly, high density of CD56+ NK cells was a negative predictor of response to adjuvant chemotherapy in patients with PB-type tumors (p for interaction = 0.020). Tumor specific CD56 expression was significantly associated with reduced OS in univariable, but not in multivariable analysis, in patients with PB type but not in I type tumors (HR = 1.65; 95% CI 1.09-2.49). Conclusions: These results demonstrate that stromal CD56+ NK cell infiltration has a significant favorable impact on prognosis in PB type, but not in I type, periampullary cancer. Of note, this beneficial effect was only seen in patients not receiving chemotherapy, indicating that chemotherapy may modulate the beneficial prognostic effect of NK cells.
PD-1/PD-L1 expression and molecular associations in HPB malignancies.
Authors: Mody Kabir , Feldman Rebecca , Reddy Sandeep K. , Reynolds Gina A , McMillan Jessica M , Johnson Elizabeth 
Published: February 2017

289 Background: Cholangiocarcinoma (CC), hepatocellular carcinoma (HCC), and pancreatic ductal adenocarcinoma (PDAC) are all devastating malignancies. Limited data exists about PD-1 and PDL1 expression in these cancers. We assessed expression of PD1/PDL1 in a large cohort of patients with hepato-pancreatico-biliary (HPB) cancers and explored the existence of accompanying genomic mutations associated with expression of PD-1/PD-L1. Methods: 524 patients with HPB cancers (354 PDAC, 58 HCC, 54 intrahepatic (ICC), 18 extrahepatic (ECC), and 40 gallbladder (GBC)) were included in the study and tumors tested centrally at a CLIA lab (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (next generation sequencing, Illumina TruSeq), protein expression (immunohistochemistry [IHC]) and gene amplification). PD-1 (SP142 antibody) and PD-L1 (MRQ-22 antibody) status was tested in all samples. Two-tailed Fisher's exact test was performed to test where proportions of positive results were different by subgroup (p²0.05). Results: Among those with PDAC, HCC, ICC, ECC, and GBC, rates of PD1 expression on tumor infiltrating lymphocytes (TILs) and PD-L1 expression on tumor cells is detailed in the Table. In PD-1+, compared with PD-1- HPB cancers, mutations in the following were more prevalent, though not statistically significant: BRCA2, ATM, CTNNB1, and PIK3CA. Among all theranostic biomarkers tested, TOP2A expression (IHC) was significantly increased in PD-L1+ versus PD-L1- tumors (82% vs 60%; p=0.0083). Conclusions: HPB tumors express PD-L1 at a frequency of 4-18%, and PD-1 at a frequency of 29-45%. A statistically significant association of mutations with PD-1+ or PD-L1+ tumors was not identified in this group of tumors. PD-L1 expression associates with TOP2a expression, a marker of proliferation and also anthracycline sensitivity. Further evaluation of this correlation and PDL1/PD-1 + anthracycline combination therapy may be warranted. [Table: see text]
Phase II study of fixed dose-rate gemcitabine plus S-1 as second-line treatment in advanced biliary tract cancer.
Authors: Kobayashi Satoshi , Sugimori Kazuya , Morizane Chigusa , Kojima Yasushi , Ueno Makoto , Morimoto Manabu , Ohkawa Shinichi 
Published: February 2017

301 Background: Cisplatin plus gemcitabine (GC) is considered as standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC). However, no standard therapy is established for second-line setting. Some clinical studies showed that gemcitabine was more effective if administered by the fixed dose rate method, and S-1 had anti-tumor effect as second-line chemotherapy for BTC. We evaluated the efficacy and safety of combination therapy of fixed dose-rate gemcitabine and S-1 after failure of GC or gemcitabine alone. Methods: This study was a single arm phase II study, and primary endpoint was response rate (RR) with MinMax two stage design to test the hypothesis that RR was more than 7%. Number of patients needed was 35 with a power of 90% and two-sided α value of 0.05. Patients received gemcitabine (1,000 mg/m2, div, over 100 minutes, day 1) and S-1 (40 mg/m2 twice daily, oral, day 1-7), every two weeks until disease progression or intolerable adverse events. Results: Forty patients were enrolled from July, 2011 to Nov., 2014. Of 23 patients in the first stage, two patients showed response and proceeded to the second stage. Overall response rate was 7.5%. Overall survival, progression-free survival and disease control rate were 7.7 months, 2.6 months, and 47.5%, respectively. Common adverse events were anemia (97.2%), thrombocytopenia (66.7%), leukopenia (47.2%), neutropenia (41.7%), anorexia (39.0%) and fatigue (37.8%). Grade 3–4 adverse events were leukopenia (19.5%), neutropenia (19.5%), anemia (14.6%), thrombocytopenia (7.3%) and anorexia (4.8%). Biliary tract infection led to death in two patients; however, these were reported as not related to this study treatment. Conclusions: Fixed dose-rate gemcitabine plus S-1 was tolerable as second-line settings in BTC; however, its activity was modest for patients refractory to the standard gemcitabine. Clinical trial information: UMIN000005918 Clinical trial information: UMIN000005918.
Prognosis of unresectable hepatocellular carcinoma: Comparison of seven staging systems (TNM, Okuda, BCLC, CLIP, CUPI, JIS, CIS) in a Chinese cohort.
Authors: Zhang Feng JIN , Shu JUN ZHI , Xie YI CHUN , LI QI , Jin Hong XI , GU Wei , Jiang Jian FANG , Ling Quan CHANG 
Published: February 2017

305 Background: Many liver staging systems that include the tumor stage and the extent of liver function have been developed. However, Prognosis assessment for hepatocellular carcinoma (HCC) remains controversial. In this study, the performances of 7 staging systems were compared in a cohort of patients with HCC who underwent non-surgical treatment. Methods: A total of 196 consecutive patients with HCC who underwent non-surgical treatment seen between January 1, 2004, and December 31, 2007, were included. Performances of TNM sixth edition, Okuda, Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Chinese University Prognostic Index (CUPI), Japan Integrated Staging (JIS), and China integrated score (CIS) have been compared and ranked using concordance index (c-index). Predictors of survival were identified using univariate and multivariate Cox model analyses. Results: The median survival time for the cohort was 7.6 months (95% CI 5.6-9.7). The independent predictors of survival were performance status (P <.001), serum sodium (P <.001), alkaline phosphatase (P <.001), tumor diameter greater than 5 cm (P =.001), portal vein invasion (P <.001), lymph node metastasis (P =.025), distant metastasis (P =.004). CUPI staging system had the best independent predictive power for survival when compared with the other six prognostic systems. Performance status and serum sodium improved the discriminatory ability of CUPI. Conclusions: In our selected patient population whose main etiology is hepatitis B, CUPI was the most suitable staging systems in predicting survival in patients with unresectable HCC. BCLC was the second top-ranking staging system. CLIP, JIS, CIS, and TNM sixth edition were not helpful in predicting survival outcome, and their use is not supported by our data. Clinical trial information: 1103-10.
Comparative effectiveness of FOLFIRINOX (FOL) versus gemcitabine and nab-paclitaxel (GNP) for the first-line treatment of metastatic pancreatic cancer.
Authors: Cheng Wei-Han , Sadeghi Sarmad , Lenz Heinz-Josef , Hay Joel W , Barzi Afsaneh 
Published: February 2017

306 Background: ACCORD-11 and IMPaCT established the efficacy of combination chemotherapy with FOL and GNP in metastatic pancreatic cancer (mPC). These two regimens have different administration schedule and toxicity profile. In this study we compare the effectiveness and costs of the two regimens including the costs of toxicities and supportive medications from a societal perspective. Methods: A Markov model was developed to simulate a cohort of mPC patients to estimate the cost per life-year gained (LYG) and per quality-adjusted life-year (QALY) for treatment with FOL and GNP. The model has three states: stable disease, progressive disease, and death. The cohorts were modeled over a 3-year time horizon in a one-month cycle length. Efficacy data were obtained from respective trials. Drug acquisition costs were extracted from Veteran Affairs Federal Supply Schedules. Other costs including visits, tests, and procedures were derived from the Medicare physician-fee-schedule. Literature was reviewed to estimate the adverse event costs and the utility scores for each health state. One-way sensitivity analyses were performed to determine the robustness of the model to changes in key parameters. Results: The model projected a life expectancy of 9 months and 7 months for FOL and GNP, respectively. FOL group showed a higher QALY than GNP group (0.51 vs. 0.40). Although the drug acquisition costs were significantly lower in FOL compared with GNP, FOL yielded a slightly higher cost after 3-years period ($55,944 vs. $56,628). FOL treatment incurred an incremental cost of $1,334 per additional life-month ($16,012 per life-year) and an incremental cost of $30,870 per QALY gained. The median overall survival and progression-free survival point estimate greatly influenced model results based on the results of sensitivity analysis. Conclusions: Compared with GNP, FOL showed a slightly higher cost but higher life expectancy and QALY as a first-line treatment in mPC. Given that the toxicity profile account for a significant portion of cost for FOL providing best supportive care and management of side effects can significantly impact the overall costs of treatment.
Outcomes of multimodality therapy for gallbladder cancer in the United States (US): Analysis of the National Cancer Data Base (NCDB).
Authors: Hamid Fatima , Shafqat Hammad , Mantripragada Kalyan , Guerrero Thomas , Somasundar Ponnandai , Olszewski Adam J. 
Published: February 2017

313 Background: Management of gallbladder cancer (GBCA) is largely based on small observational studies, and it is unknown how various treatment modalities are applied in the community. The objective of this study was to describe the utilization of surgery (S), chemotherapy (Ct) and chemoradiation (CRT), and associated overall survival (OS) in the US. Methods: We selected adult patients (pts) with GBCA diagnosed in 2004-2012 from the NCDB—a population-wide registry capturing > 70% of incident cancers in the US. We identified pts undergoing S, Ct and concurrent CRT. We assumed adjuvant (Adj) therapy if it was started within 4 months (mo) of S. Stage was grouped as: T1-T3N0, node-positive (N+), T4 (N0 or N+) or metastatic (M1). OS was calculated from diagnosis, with 95% confidence intervals (CI). Results: We identified 22,574 GBCA pts. Median age was 71 years. There were 69% women, 71% white non-Hispanic, 10% white Hispanic, 14% black and 4% Asian pts. Distribution of stage groups was: in situ, 4%; T1N0, 8%; T2N0, 16%; T3N0, 13%; N+, 14%; T4, 3%; M1, 38%; unknown, 4%. Most non-metastatic pts underwent S, but only a minority received Adj Ct or CRT (Table). Among M1 and T4 pts, 44% received Ct, but 29% got no cancer-directed therapy. Median OS for M+ or T4 pts was 4 and 7 mo, respectively. It was 8 and 11 mo, respectively, if Ct was given. Conclusions: These OS estimates provide realistic prognosis for GBCA pts treated with various modalities in the US. Adj therapy is rarely delivered in locally advanced (T3N0 or T1-3N+) GBCA. Survival in T4 and M1 GBCA remains poor even with palliative Ct. Novel therapeutic approaches for GBCA of all stages are needed. [Table: see text]
Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the gastrointestinal (GI) tract and unknown primary: A subgroup analysis of the phase III RADIANT-4 trial.
Authors: Singh Simron , Carnaghi Carlo , Buzzoni Roberto , Pommier Rodney F. , Raderer Markus , Tomasek Jiri , Lahner Harald , Valle Juan W. , Voi Maurizio , Bubuteishvili-Pacaud Lida , Lincy Jeremie , Sachs Carolin , Okita Natsuko , Libutti Steven K. , Oh Do-Youn , Kulke Matthew H. , Strosberg Jonathan R. , Yao James C. , Pavel Marianne E. , Fazio Nicola ,   RAD001 in Advanced Neuroendocrine Tumors, Fourth Trial (RADIANT-4) Study Group
Published: February 2017

315 Background: In the groundbreaking, phase 3 RCT RADIANT-4 study, everolimus (EVE) significantly prolonged median progression-free survival (PFS) by 7.1 mo in patients (pts) with advanced, progressive, nonfunctional NET of GI or lung vs placebo (PBO); HR, 0.48 (95%CI, 0.35-0.67), P<0.00001 [Yao JC et al, ECC-ESMO, 2015]. Methods: InRADIANT-4, pts with advanced, progressive, well-differentiated (G1/G2), nonfunctional GI or lung NET were randomized (2:1) to EVE (10 mg/d) or PBO. In this analysis, pts with NET of GI tract (stomach, colon, rectum, appendix, caecum, ileum, duodenum, jejunum, or small intestine) and unknown primary were included. Results: Of 302 pts, 175 had GI NET (EVE [n=118], PBO [n=57]); 36 had NET of unknown primary (EVE [23], PBO [13]). In GI NET pts, median age was 63 y; females: 55%; G1/G2: 75%/25%; WHO PS: 0, 78% or 1, 22%; Caucasian: 73%. Similar baseline characteristics were observed in pts with NET of unknown primary. Ileum (41%), rectum (23%) and jejunum (13%) were the most common locations in GI subgroup. The table below lists prior treatments. In pts with GI NET, median PFS (95% CI) by central review (EVE vs PBO) was 13.1 (9.2-17.3) mo vs 5.4 (3.6-9.3) mo with an estimated 44% risk-reduction in favor of EVE (HR, 0.56; 95% CI, 0.37-0.84). In pts with NET of unknown primary, median PFS (95% CI) by central review (EVE vs PBO) was 13.6 (4.1-not evaluable) mo vs 7.5 (1.9-18.5) mo (HR, 0.60; 95% CI, 0.24-1.51). The most frequent G3/4 adverse events irrespective of drug-relationship reported in ≥5% pts in GI subgroup were diarrhea, hypertension, stomatitis, abdominal pain, fatigue, and acute renal failure. Conclusions: The present subgroup analysis of RADIANT-4 study demonstrated improvement in PFS with EVE for pts with GI NET, and suggests efficacy in NET of unknown primary, with an estimated 40% to 44% risk-reduction in favor of EVE vs PBO. Safety profile for EVE is consistent with that previously reported. Clinical trial information: NCT01524783. [Table: see text]
Phase 1 dose escalation study of MEDI-565, a bispecific T-cell engager that targets human carcinoembryonic antigen (CEA), in patients with advanced gastrointestinal (GI) adenocarcinomas.
Authors: Pishvaian Michael J. , Morse Michael , McDevitt Jennifer T. , Ren Song , Robbie Gabriel , Ryan Patricia C. , Soukharev Serguei , Bao Haifeng , Denlinger Crystal Shereen 
Published: February 2017

320 Background: MEDI-565, a bispecific single-chain antibody, targets human CEA on tumor cells and the CD3 epsilon subunit of the human T-cell receptor complex. In murine models, MEDI-565 showed antitumor activity in CEA-expressing tumors (J Immunother 2009;34:341-52). Methods: This phase 1, multicenter, open-label, dose-escalation study enrolled adults with GI adenocarcinomas (including esophageal, gastric, small intestine, colorectal, biliary tract, and pancreatic). MEDI-565 was given intravenously over 3 h on days 1–5 in 28-day cycles, with 4 single-patient (pt) (0.75–20 μg) and 5 standard 3+3 escalation (60 μg–3 mg; 1.5–7.5 mg with dexamethasone [dex]) cohorts. Primary objective was to determine the maximum tolerated dose (MTD); secondary objectives were to evaluate pharmacokinetics (PK), antidrug antibody (ADA), and antitumor activity. Results: Study enrolled39 pts: mean age 59 y; 56% male; 28 (72%) colorectal, 6 (15%) pancreatic, 5 (13%) other. Dose-limiting toxicities (grade ≥ 3 nonhematologic) were seen in 4 pts (2 at 3-mg; 2 at 7.5-mg + dex): hypoxia (n = 2), diarrhea, and cytokine release syndrome (CRS). Grade 3 treatment-related adverse events (AEs) seen in 5 pts: diarrhea, CRS, increased alanine aminotransferase, hypertension (all n = 1), and hypoxia (n = 2). Treatment-related serious AEs seen in 6 pts: diarrhea, vomiting, pyrexia, CRS (all n = 1), and hypoxia (n = 2). Five pts discontinued treatment due to AEs: diarrhea, CRS, central nervous system metastases, and hypoxia (n = 2). MEDI-565 exposures increased in approximately dose-proportional manner, with clearance (35–77 L/d) and half-life (2–7 h) typical of drug class. ADA had minor impact; 19 pts (48.7%) had ADAs, 5/39 (12.8%) with high titer, with decreased MEDI-565 concentrations in 2 pts. Plasma inflammatory cytokines were elevated posttreatment in several pts at 1.5- and 3-mg (no dex) dose levels. No objective responses were observed; 11 (28%) pts had stable disease as best response. Conclusions: The MTD of MEDI-565 in pts with GI adenocarcinomas was 5 mg with dex. PK was linear, with fast clearance and short half-life. No objective responses were observed. Clinical trial information: NCT01284231.
Unresectable hepatocellular carcinoma: Is radio-embolization an alternative for chemo-embolization?
Authors: Lobo Laila , Yakoub Danny , Picado Omar , Ripat Caroline , Pendola Fiorella , Sharma Rishika , Venkat Shree , Yechieli Raphael 
Published: February 2017

323 Background: Transarterial Radio-embolization (TARE) has emerged as a newer regional technique to Transarterial Chemo-embolization (TACE) for treatment of unresectable hepatocellular carcinoma (HCC). The aim of this study is to evaluate clinical outcomes of both techniques. Methods: Online search for studies comparing TARE to TACE from 2005 to present was performed. Primary outcome was overall survival rate for up to 4 years. Secondary outcomes included post-treatment complications and treatment response. Quality of included studies was evaluated by STROBE criteria. Relative Risk (RR) and 95% Confidence Intervals (CI) were calculated from pooled data. Results: The search strategy yielded 172 studies, 5 met our selection criteria and included 653 patients undergoing embolization for unresectable HCC. Of these patients, 284 underwent TACE and 269 underwent TARE. Median age was 63 and 64 years for TACE and TARE, respectively. Meta-analysis showed no statistically significant difference in survival for up to 4 years between the two groups (HR = 1.06; 95% CI: 0.81-1.46, p = 0.567). TACE required at least one day of hospital stay compared to TARE which was mostly an outpatient procedure. TACE had more post-treatment pain than TARE (RR = 1.96, 95% CI: 1.40-2.75, p < 0.01), but less subjective fatigue (RR = 0.62, 95% CI: 0.48-0.80, p < 0.01). There was no difference between the two groups in the incidence of post-treatment nausea, vomiting, fever or other complications. In addition, there was no difference in partial or complete response rates between the two groups. Conclusions: TARE appears to be a safe alternative treatment to TACE with similar complication profile and survival rates. Larger prospective randomized trials, focusing on patient-reported quality-of-life are required to consolidate these results, and to evaluate cost vs benefit for both techniques.
The characteristics of pancreatic neck cancer.
Authors: Yamaue Hiroki , Hirono Seiko , Kawai Manabu , Okada Ken-Ichi , Miyazawa Motoki , Shimizu Atsushi , Kitahata Yuji , Ueno Masaki , Hayami Shinya , Shigekawa Yoshinobu , Miyamoto Atsushi 
Published: February 2017

337 Background: Pancreatic neck cancer occurs in the small region surrounded by the common hepatic artery (CHA), gastroduodenal artery (GDA), and portal vein (PV). The specific clinicopathological characteristics of pancreatic neck cancer remain unclear. This study aimed to identify specific biological behaviors of pancreatic neck cancer for the improvement of treatment outcomes. Methods: This study was a retrospective cohort study and comparative outcomes design. In 63 (19.4%) of 325 consecutive pancreatic cancer patients who underwent surgery, the tumor was located in the pancreatic neck. Clinicopathological characteristics and prognostic factors specific to pancreatic neck cancer were analyzed by comparison to those of pancreatic head or body/tail cancers. Results: The rates of radiographic and pathological PV and/or superior mesenteric vein (PV/SMV) invasion were higher in patients with pancreatic neck cancer (radiographic: 84.1%, pathological: 36.5%) than those with pancreatic head and body/tail cancers (radiographic, head: 67.3%, body/tail: 25.0%, pathological, head: 26.0%, body/tail: 6.3%). The most frequent lymph node metastasis was found in the region along the CHA in pancreatic neck cancer, and the spots most likely to show a positive surgical margin were the dissected surface of the PV and the root of the GDA and/or CHA. For pancreatic neck cancer patients, five independent poor prognostic factors were found: pathological PV/SMV invasion (P= 0.005), moderately or poorly differentiation (P= 0.001), positive lymph node ratio ≥ 0.1 (P< 0.001), surgical margin length ≤ 1 mm (P= 0.018), and no completion of planned postoperative adjuvant therapy (P< 0.001). Conclusions: Pancreatic neck cancer showed specific clinicopathological characteristics and prognostic factors after resection. Patients with these risk factors might need multimodality treatment strategies, including neoadjuvant therapy, in order to prolong the survival, although further studies will be necessary to confirm our findings.