bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized, open-label, perioperative phase II study evaluating nivolumab alone versus nivolumab plus ipilimumab in patients with resectable HCC.
Authors: Kaseb Ahmed Omar , Carmagnani Pestana Roberto , Vence Luis M. , Blando Jorge M. , Singh Shalini , Ikoma Naruhiko , Vauthey Jean-Nicolas , Allison James Patrick , Sharma Padmanee 
Published: January 2019

185 Background: In HCC, surgical resection is associated with high recurrence rate, and no effective neoadjuvant or adjuvant therapies currently exist. On the basis of previous reports on the efficacy and safety of anti–PD-1 and anti–CTLA-4 antibodies against HCC, we initiated a randomized pilot trial of perioperative immunotherapy for resectable HCC. Methods: This is a randomized, phase II trial of nivolumab (Arm A) or nivolumab + ipilimumab (Arm B) as peri-operative treatment for patients (pt) with HCC who are eligible for surgical resection. Pt are given nivolumab 240 mg every 2 weeks (wk) for a total of 6 wk. Pt in Arm B are treated concurrently with ipilimumab 1 mg/kg every 6 wk. Surgical resection occurs within 4 wkafter last cycle of therapy. Pt continue adjuvant immunotherapy for up to 2 years after resection. Primary objective is the safety and tolerability of nivolumab +/- ipilimumab. Secondary objectives include overall response rate, complete response rate and time to progression. Exploratory objectives include evaluating the pre- and post-treatment immunological changes in tumor tissues and peripheral blood. Results: 9 pt were enrolled at the time of first interim analysis, and 8 pt were evaluable (5 in Arm A, 3 in Arm B). Pt were 60-69 yo, and males (78%). 5 pt were HCV-positive and 1 had chronic hepatitis B infection. 8 pt proceeded with resection as planned; surgery was aborted for 1 pt due to frozen abdomen from previous surgery. Pathologic complete response (pCR) was observed in 3/8 pt – 2 in Arm A and 1 Arm B (37.5% pCR). 2 pt in Arm B and 1 in Arm A experienced grade 3 or higher toxicity which did not affect their resectability. No grade 4 or higher toxicity were observed. Immune analysis of the first case with a pCR in Arm B demonstrated that clinical response correlated with an increase in CD8+ T cell infiltration, notably an increase in two effector T cell clusters. Conclusions: We report a pCR rate of 37.5% in the first interim analysis of a phase II pilot trial of perioperative immunotherapy for resectable HCC. Treatment was deemed safe and surgical resection was not delayed. The study is ongoing and results may contribute to a paradigm shift in the perioperative treatment of HCC. Clinical trial information: NCT03222076.
Distribution of insulin growth factor-1 (IGF-1) binding proteins in hepatocellular carcinoma with and without cirrhosis.
Authors: Abdelhakeem Ahmed , Kaseb Ahmed Omar , Hatia Rikita , Abdel-Wahab Reham , Amin Hesham M. , Hassan Manal 
Published: January 2019

193 Background: Circulating insulin-like growth factor-1 (IGF-1) significantly declines in patients (pts) with cirrhosis and hepatocellular carcinoma (HCC), reflecting damaged hepatocytes. The bioavailability of IGF-1 is controlled by insulin-like growth factor binding proteins (IGFBPs), which bind IGF-1. IGFBPs transcription is cell specific, and are secreted mainly by the liver. Variations in circulating IGFBPs in HCC pts, especially those with non-cirrhotic HCC, has not been elucidated. We investigated the expression of these proteins in HCC with and without cirrhosis. Methods: Under Institutional Review Board approval, we measured plasma levels of seven IGFBPs in 489 cirrhotic HCC pts, 274 non-cirrhotic HCC pts, 75 pts with cirrhosis without HCC, and 200 healthy controls. Also, we assessed variations in IGFBPs plasma level between early and advanced stage HCC in the presence and absence of cirrhosis. Levels of circulating biomarkers were summarized by descriptive statistics, and both Chi-square and ANOVA tests were used to compare levels between groups. Results: IGFBPs levels varied significantly between groups (Table). Moreover, IGFBP-3 was lower in HCC pts than in healthy controls ( P ≤ 0.001), and IGFBP-1, -2, -4, and -7 were higher in HCC without cirrhosis than in healthy controls ( P = 0.001 for all). Additionally, in non-cirrhotic HCC pts, a similar pattern was observed in advanced Stage HCC compared with early stage HCC. Conclusions: Levels of circulating IGFBPs may be associated with risk of non-cirrhotic HCC and could be used as markers for underlying liver damage. [Table: see text]
Development of a nomogram to predict overall survival in patients presenting with gastrointestinal neuroendocrine carcinoma (WHO G3).
Authors: Lin Zhenyu , Wang Haihong , Zhang Dejun , Yu Dandan , Zhang Tao 
Published: January 2019

197 Background: To evaluate the prognostic factors in patients with gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) and develop a nomogram to predict 1-year overall survival (OS). Methods: We performed a retrospective analysis of 122 patients with GI-NEC. Nomogram for 1-year OS was created as visualizations of Cox proportional hazards regression models and internally validated by use of bootstrap and cross-validation. We assessed nomogram model performance by examining overall accuracy (Brier score), calibration (calibration plot), and discrimination (Harrell C index). Results: The median survival was 9 months in 122 patients, and 51 (41.8%) patients died in the development cohort. A 1-year OS was chosen because 82% of the patients who died from disease did so within 1 year. Multivariable analysis identified prognostic factors including performance status, stage, Ki-67 index and LDH, all of which were included in the final model. In the development cohort, the Harrell C index for overall survival was 0·887 (95% CI 0·810-0·964), and calibration curves showed adequate calibration (judged by eye) of the observed and predicted probabilities. Conclusions: Prognostic factors were used to develop nomograms for 1-year OS for GI-NEC. The nomogram can be offered to clinicians to improve their abilities to assess patient prognosis, strengthen the prognosis-based decision making, enhance patient stratification, and inform patients in the clinic.
Hepatocellular carcinoma (HCC) survival by etiology: A SEER-Medicare database analysis.
Authors: Brar Gagandeep , McNeel Tim , McGlynn Katherine , Graubard Barry , Floudas Charalampos S. , Morelli M. Pia , Xie Changqing , Greten Tim F. , Altekruse Sean 
Published: January 2019

201 Background: HCC is the 6thmost common occurring cancer worldwide and the 4th leading cause of cancer mortality, with a survival of 6-9 months. While survival varies by stage at diagnosis and treatment, the effect of HCC etiology on survival is unclear. We analyzed the SEER-Medicare database to evaluate whether HCC survival varied by etiology, after adjusting for stage, treatment, and survival. Methods: A total of 11,522 SEER-Medicare HCC cases (ICD-O-3 codes C22 for topography, 8170-8175 for morphology) met criteria for the Cox proportional hazard analyses to assess survival differences among the risk factors for hepatitis C virus (HCV) infection, hepatitis B virus (HBV) infection, alcohol disorders, and metabolic disorders. These analyses were adjusted for covariates for gender, age at diagnosis, race, ethnicity, tumor size and extent of disease, a modified Charlson Index of comorbidities, and treatments that included resection, transplantation, ablation, arterial directed therapy and radiotherapy. Cases with multiple and unknown etiologies were included in analyses, however genetic disorders and primary biliary cirrhosis were excluded due to their rarity. Results: HBV associated cases had the highest proportion of single nodules (40% vs 33% overall), localized stage disease (57% vs 49%), treatment (40% vs 27%), and greatest frequency of resection (18.6% vs 9%). Non-Hispanic Asians/Pacific Islanders accounted for 69% of HBV infection-related HCC cases but only 16% of all cases. HBV associated cases had better survival than did HCC cases with other etiologies. Specifically, after adjusting for demographic and clinical attributes, compared to cases with HBV infection, the risk of death was highest for alcohol-related HCC (HR=1.69; 95%CI:1.42-2.01) followed by multiple etiologies (HR = 1.40; 95% CI: 1.20-1.64), metabolic disorders (HR = 1.32; 95% CI: 1.13-1.55), HCV infection (HR = 1.30; 95% CI: 1.10-1.53), and HCC of unknown etiology (HR = 1.22; 95% CI: 1.04-1.43). Conclusions: Persons with HBV associated HCC had better survival than persons with HCC of other etiologies. Efforts to identify people with any etiologic risk factors for HCC, treat their conditions, and screen for HCC may improve overall survival.
Characteristics and epidemiology of gastric cancer in Korea: Disparity in sex and age according to histologic classification.
Authors: Kim Dongwoo , Lee Sang Woo , Hwang Su Hyun , Kim Seung Young , Hyun Jong Jin , Jung Sung Woo , Koo Ja Seol 
Published: January 2019

21 Background: Gastric cancer (GC) is one of the most common cancers worldwide. The overall incidence of gastric cancer is higher in males, but signet ring cell carcinoma (SRC) is more common in younger females. However, the sex disparity according to the histological classification of GC in Korea has not studied much. The aim of this study is to analyze the difference of clinical manifestation between sex groups and to assess sex disparity to gastric cancer. Methods: We retrospectively analyzed 1488 patients (459 females (30.8%) and 2017 males (69.0%)) who diagnosed with gastric cancer at Korea University Ansan Hospital from 2009 to 2017. The patients were divided into three groups according to Lauren’s classification: Intestinal type GC (IGC), diffuse type GC (DGC), mixed type. The difference of clinicopathologic characteristics between these groups and sex groups were compared. Results: The age-group-specific annual incidence rates for intestinal and diffuse type GC were analyzed. The incidence of IGC increased from 40s in males. In females, the incidence of DGC was higher in young age and the proportion of IGC was increased rapidly after age 60 in females. Most of IGC appeared after age 60. (19.3% in below 60 vs. 80.7% in above 60 in females, 35.1% vs. 64.9% in males, p < 0.001) IGC seemed to appear 10-20 years earlier in male than female. Female patients were associated with poorly differentiated adenocarcinoma, SRC and DGC. Diffuse and mixed type GC was more frequent with younger, female patients and associated with advanced GC and TNM stage. Kaplan-Meier analysis revealed that the patients with IGC had a higher cumulative survival rate than those with DGC (5-year survival rate 88.2% vs. 80.5%, p < 0.001). Conclusions: Female patients with IGC were older than male patient and appeared about 10-20 years later. But this difference did not observed in DGC. Therefore, unlike DGC, sex hormones such as estrogen may act in development of IGC. This is supported by an increase of IGC in females after menopause. Further studies on role of estrogen in the development of gastric cancer are needed.
Prevalence of pancreaticobiliary cancer in Irish families with BRCA1 and BRCA2 mutations.
Authors: Power Robert , Leavy Cristin , Nolan C. , White Niamh , Clarke R. M. , Gallagher David James , Lowery Maeve Aine 
Published: January 2019

210 Background: Germline mutations in BRCA1 and BRCA2 genes are associated with pancreatic ductal adenocarcinoma (PDAC), and more recently associated with increased risk of biliary tract cancers (BTC). This study assessed the prevalence, age and gender distribution of PDAC/BTC in BRCA1/2 positive families; compared to those of the Irish population. Methods: A review of all families referred to a national genetics clinic from 09/11/1997-01/06/2018 was performed following institutional ethics board approval. Demographics including age, sex and BRCA mutation status was collected in each case of PDAC/BTC. The BOADICEA algorithm was used to estimate the probability that an untested relative of a known BRCA1/2 mutation carrier with PDAC was a carrier. Results: 3252 distinct family pedigrees were reviewed, of which 1193 contained a proband who underwent testing for BRCA1/2 based on Manchester score ≥ 15. Among 128 BRCA2 positive families, 27 (21%) contained a 1st/2nd or 3rd degree relative with PDAC, of 116 BRCA1 positive families, 11 (9%) contained a 1st/ 2nd or 3rd degree relative with PDAC (male: female (m:f) = 1:0.9). Of these 38 families, 25 pts with PDAC had ≥ 50% likelihood of being a mutation carrier by BODICEA analysis. This cohort had a median age at diagnosis of 55 (33-75), with a mean (55) significantly lower than that of 8364 unselected patients with PDAC identified through the National Cancer Registry Ireland (71, p < 0.0001). Six BRCA2 positive (5%) and 2 BRCA1 positive pedigrees (2%) contained an individual with BTC; median age at diagnosis was 65 (33-99, m:f = 1:7). Additional pedigrees with Lynch Syndrome (n = 3), FAP (n = 1) and ATM (n = 2) and PDAC were identified. Conclusions: PDAC and BTC are prevalent in Irish families with a BRCA1/2 mutation and are associated with early onset malignancy. This consolidates evidence of PDAC and BTC as BRCA- associated cancers in the Irish population and supports current guidelines recommending universal germline testing for PDAC patients. [Table: see text]
Preoperative evaluation with computed tomography (CT) of the resectability of mesenteric lymph node metastases in small intestine neuroendocrine neoplasms (si-NENs): New criteria for clinicians and surgeons.
Authors: Funicelli Luigi , Bertani Emilio , Zugni Fabio , Bellomi Massimo , Fazio Nicola 
Published: January 2019

212 Background: The 2016 European Neuroendocrine Tumor Society consensus guidelines update recommends resection of the primary tumor and all mesenteric lymph-nodes for all patients with si-NENs, both with curative and palliative purposes. Current resectability criteria are based on the degree of involvement of the superior mesenteric artery (SMA) by the metastatic lymph nodes. The aim of this work was to test these criteria for the evaluation of our patients; we included as additional criteria the degree of involvement of the superior mesenteric vein (SMV) and peritoneum, two features not covered by current literature. Methods: We retrospectively reviewed the pre-operative CT-scans of all patients with si-NENs operated at IEO (European Institute of Oncology) between 2008 and April 2018. A first analysis classified tumors as “resectable” or “unresectable” according to SMA involvement. A second analysis classified tumors as resectable or unresectable according to SMA involvement, SMV involvement (infiltration of the peripheral or proximal portion) and peritoneal involvement (presence or absence of fibrosis and retraction of the mesentery). We finally reviewed all surgery reports assessing radicality and completeness of the operation. Results: Abdominal CT-scan were available for analysis in 42 out of 47 operated patients. According to the first analysis, all three tumors classified as unresectable underwent incomplete resection, whereas out of the 39 tumors classified as resectable, six received an incomplete resection and 33 were completely resected. According to the second analysis, the nine tumors classified as unresectable underwent an incomplete resection, whereas 33 tumors classified as resectable were completely resected. Conclusions: Our retrospective analysis confirmed that SMA involvement may be useful to evaluate the resectability of the primary tumor and mesenteric lymph nodes. Furthermore, it suggested that the additional evaluation of the SMV and peritoneum involvement can allow to identify further cases of tumors for which complete resection is not possible.
Prognostic significance of nutritional and inflammatory markers in patients with unresectable pancreatic ductal adenocarcinoma treated with chemotherapy.
Authors: Kobiyama Ryosuke , Yoshioka Isaku , Ando Takayuki , Kajiura Shinya , Shibuya Kazuto , Sekine Shinichi , Hirano Katsuhisa , Baba Hayato , Arai Mie , Sukegawa Kenta , Watanabe Toru , Hashimoto Isaya , Hojo Shozo , Okumura Tomoyuki , Nagata Takuya , Murotani Kenta , Yasuda Ichiro , Fujii Tsutomu 
Published: January 2019

219 Background: Recently, several nutritional and inflammatory markers have been reported to be involved in cancer progression. The aim of this study is to evaluate whether nutritional and inflammatory biomarkers such as the modified Glasgow prognostic score (mGPS), the neutrophil‐to-lymphocyte ratio (NLR), the platelet‐to-lymphocyte ratio, the systemic-immune-inflammation index (SIII), controlling nutritional status (CONUT) score, prognostic nutritional index, and the lymphocyte‐to-monocyte ratio (LMR) could predict the prognosis in patients with unresectable pancreatic ductal adenocarcinoma (UR-PDAC) who underwent chemotherapy as first-line therapy, using disease-specific survival as the primary outcome. Methods: All UR-PDAC patients were retrospectively evaluated between January 2011 and May 2017 at Toyama University Hospital. Baseline clinicopathological characteristics and pre-treatment laboratory values such as absolute neutrophil, lymphocyte and platelet counts, C-reactive protein, albumin and CA19-9 levels, were collected. Results: A total of 184 patients were diagnosed as UR-PDAC. Among them, 151 patients who underwent chemotherapy were enrolled in this study. There were significant relationships between survival and elevated mGPS, elevated NLR, elevated SIII, decreased LMR, decreased serum cholinesterase level, and low CONUT score (p < 0.001, p < 0.001, p = 0.001, p < 0.001, p = 0.026 and p < 0.001, respectively, by log-rank test). The median survival time of patients with metastatic lesions was significantly shorter than that of patients with unresectable locally advanced PDAC (9.0 vs 15.5 months, respectively; p = 0.033). There was no significant difference in survival in pre-treatment CA19-9 level and tumor location. Multivariate analysis using Cox regression model revealed that NLR and CONUT score were independent prognostic factors. Conclusions: Pre-treatment NLR and CONUT score may predict clinical outcome in patients with UR-PDAC undergoing chemotherapy as first-line therapy.
IGF-Child-Pugh score as a predictor of treatment outcome in Child-Pugh A, advanced hepatocellular carcinoma patients undergoing sorafenib therapy.
Authors: Abugabal Yehia I. , Hassan Manal , Xiao Lianchun , Morris Jeffrey , Carmagnani Pestana Roberto , Abdel-Wahab Reham , Hatia Rikita , Chang Ping , Girard Lauren , Rashid Asif , Bhawana George , Raghav Kanwal Pratap Singh , Abdelhakeem Ahmed , Wolff Robert A. , Amin Hesham M. , Kaseb Ahmed Omar 
Published: January 2019

223 Background: Sorafenib is the first systemic therapy approved for advanced HCC treatment; with no accurate tool available to help predict survival and treatment outcome and to guide therapy decisions. Our novel blood-based IGF-Child-Pugh (CP) score comprises levels of IGF-1, bilirubin, INR, and albumin. IGF-CP score significantly improved the prediction of HCC survival in our recently published studies. The current prospective study aimed to compare the overall survival (OS) and progression free survival (PFS) of 101 patients with CP-A HCC treated with sorafenib whose score is reclassified as IGF-A (AA) to that of patients whose score is reclassified as IGF-B/C (AB/AC). Methods: Between 2014 and 2018, after the approval of the institutional review boards and signing written informed consent, a total of 101 patients with HCC, CP-A were prospectively enrolled and started on sorafenib and followed until progression or death. Results: Sixty-three patients were evaluable. Patients who were reclassified by the IGF-CTP scoring system were better stratified by their new risk groups. Forty-two of patients were classified as IGF-CTP-A and had median PFS of 4.87 months (95% CI=2.3 to 6.84), and median OS of 15.43 (95% CI = 12.04 to 31.18 months), whereas 21 patients were reclassified as intermediate risk (IGF-CTP-B) and had significantly shorter OS of 7.6 months (p-value<0.0001) and shorter PFS of 2.86 months (p-value=0.0021). Conclusions: The results of this study confirms our biologically driven hypothesis that: among HCC patients with “old CP-A” class treated with sorafenib, some will be reclassified as “new CP-B/C” will have poorer prognosis in terms of shorter OS and PFS. Thus, our study provides an objective non-invasive strategy to better predict the outcome in HCC patients undergoing systemic therapy. Future validation of our IGF score may lead to adopting it as a stratification tool in trials to predict HCC outcome and guide therapy decision in routine practice. [Table: see text]
Designing clinical trials in 3L+ pancreatic cancer.
Authors: Manax Victoria G. , Chatikhine Valery , Kirven Saundra , Taylor Ben R 
Published: January 2019

226 Background: An increasing percentage of pancreatic cancer (PC) patients are looking for 3L+ options. As patient outcomes are improving with advances in treatment for PC, more patients need 3L+ treatments. Few trials focus on this patient segment as evaluation of drug effects can be complicated by comorbidity rates and disease-related SAEs. Having exhausted SOC chemotherapy backbones, patients increasingly search for novel therapies and clinical trial options. This assessment was to evaluate 3L+ PC trials for 1) sufficient patient interest, 2) a clinically evaluable patient population, and 3) guidelines/restrictions that could improve clinical assessment. Methods: Initiated as a retrospective evaluation of consenting patients screened for a prospective 2L+ pancreatic cancer Phase II trial with SM-88. A comparison of recurrent PC trials was performed by Novella to assess industry wide enrollment characteristics. Results: 32% of patients searching for clinical trials YTD 2018 in PanCAN’s database were looking for 3L+ treatments, up from 25% in 2016. In the sample trial, rate of consents (n=72) increased hyperbolically, reaching ~1/pt/day by end of analysis (24 sites). Inc/exc criteria were broadly standard for sponsor-initiated trials, however ECOG PS 2 were eligible. 38% screen failed, with hepatic labs (esp Alb & ALP) as most common reason. Industry analysis indicated expected 0.35 p/s/m for refractory PC trials and 20% screen fail. 93% (37/40) of SAEs were unrelated to study drug, including 11 G4 or G5 prior to receiving drug. Preliminary safety and efficacy results for the trial are reported elsewhere. Conclusions: Rapid enrollment from 3L+ patients demonstrated significant interest among this patient segment. The screen failure rate was within reasonable expectations, implying a majority of the patients were within standard inc/exc criteria. The high level of unrelated SAEs during the consent period and initial enrollment period indicate this may not be a suitable population to properly assess drug safety. Subgroup statistical analyses may be more relevant than ITT medians since several comorbidities, such as biliary obstruction, have elsewhere been demonstrated to have a dramatic impact on OS. Clinical trial information: NCT03512756.