bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining the role of lymphadenectomy for pancreatic neuroendocrine tumors: An eight institution study of 695 patients from the U.S. Neuroendocrine Tumor Study Group.
Authors: Lopez-Aguiar Alexandra G , Zaidi Mohammad , Dillhoff Mary , Beal Eliza W , Poultsides George A. , Makris Eleftherios , Rocha Flavio G. , Kanji Zaheer S. , Idrees Kamran , Marincola Smith Paula , Cho Clifford , Beems Megan , Weber Sharon M. , Fisher Alexandra V. , Fields Ryan C , Krasnick Bradley A. , Cardona Kenneth , Maithel Shishir 
Published: January 2019

212 Background: Preoperative factors that reliably predict lymph node (LN) metastases in pancreatic neuroendocrine tumors (PanNETs) are unclear. The number of LNs needed to accurately stage PanNETs has not been defined. Methods: Patients who underwent curative-intent resection of primary non-functional PanNETs at 8 institutions from 2000-2016 were analyzed. Tumors with poor differentiation and Ki-67 > 20% were excluded. Preoperative factors associated with LN metastases were identified. A procedure specific target for LN retrieval to accurately stage patients was determined. Results: Of 2182 pts with GI NETs, 695 underwent resection of PanNETs. 33% of tumors were proximal (head/uncinate), and 67% were distal (neck/body/tail). 26% of pts (n = 158) had LN+ disease, which was associated with worse 5-yr recurrence-free survival (RFS) (60% vs 86%; p < 0.001). Increasing number of +LNs was not associated with worse RFS. Preoperative factors associated with +LNs included tumor size ≥2 cm (OR 6.6; p < 0.001), proximal location (OR 2.5; p < 0.001), moderate vs well differentiation (OR 2.1; p = 0.006), and Ki-67≥3% (OR 3.1; p < 0.001). LN metastases were also present in tumors without these risk factors: < 2cm (9%), distal location (19%), well differentiated (23%), and Ki-67 < 3% (16%). Median LN retrieval was 13 for pancreatoduodenectomy (PD), but only 9 for distal pancreatectomy (DP). Given that PD routinely includes a complete regional lymphadenectomy, a minimum number of LNs to accurately stage pts was not identified. For DP, however, removal of < 7 LNs failed to discriminate 5-yr RFS between LN (+) and (-) pts ( < 7 LNs: 72% vs 83%, p = 0.198; ≥7 LNs: 67% vs 86%, p = 0.002). Conclusions: Tumor size ≥2 cm, proximal location, moderate differentiation, and Ki-67≥3% are preoperative factors that predict LN positivity in resected non-functional PanNETs. Given the 9-23% incidence of LN metastases in patients without such risk factors, routine regional lymphadenectomy should be considered. Pancreatoduodenectomy inherently includes sufficient LN retrieval, while distal pancreatectomy should aim to remove ≥7 LNs for accurate staging.
Multiomic molecular comparison of primary versus metastatic pancreatic tumors.
Authors: Brar Gagandeep , Blais Edik , Bender R Joseph , Brody Jonathan , Sohal Davendra , Madhavan Subha , Picozzi Vincent J. , Hendifar Andrew Eugene , Chung Vincent M. , Halverson David , Mikhail Sameh , Matrisian Lynn McCormick , Rahib Lola , Petricoin Emanuel , Pishvaian Michael J. 
Published: January 2019

213 Background: Pancreatic cancer metastasizes very early, as evidenced by the fact that > 70% of patients with operable disease ultimately develop metastases. Thus, it is likely that the molecular characteristics of primary pancreatic tumors are similar to metastatic lesions. We compared the frequency of genetic alterations and protein expression from primary vs. metastatic pancreatic tumors, and from metastases from different sites. By focusing on actionable genetic and proteomic information, we sought to explore whether targeted therapies could be tailored to patients at metastatic progression based on primary surgical material. Methods: Next generation DNA sequencing (NGS) data of 208 genes and a limited set of protein markers were analyzed from pancreatic tumors of 431 patients enrolled in the Know Your Tumor initiative. Of the 208 genes tested, mutations in 70 were considered potentially actionable based on preclinical and clinical evidence. We compared 146 primary pancreatic tumors against 285 metastatic lesions, and examined subgroups for liver vs. lung vs. other metastatic lesions. Molecular alterations were compared between independent groups for each gene/protein using Fisher’s exact test. Significance was assessed using a false discovery rate adjusted q-value threshold of 0.05. Results: No differences in the specific mutation or expression pattern were observed between primary vs. metastatic lesions, nor across the site of metastasis after correcting for multiple hypotheses. Even the proportion of actionable alterations (including mutations in the homologous recombination DNA repair pathway) was similar across subgroups. Conclusions: Comparison of the muli-omic profile of primary vs. metastatic pancreatic adenocarcinoma reveals that the molecular architecture is very similar, and that actionable alterations are identified at the same frequency. This is unlike the data observed from other solid tumors, (e.g. colon and breast cancer), in which substantial molecular discordance and heterogeneity exists between primary tumors and metastatic sites, but is consistent with the belief that primary pancreatic cancers metastasize early and thus are molecularly indistinguishable from metastatic lesions.
Association of preoperative monocyte-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio with overall survival after resection of pancreatic neuroendocrine tumors.
Authors: Panni Roheena Z. , Davidson Jesse T , Krasnick Bradley A. , McGilvray Martha , Zarate Rodriguez Jorge , Lopez-Aguiar Alexandra G , Dillhoff Mary , Poultsides George A. , Winslow Emily , Rocha Flavio G. , Idrees Kamran , Hammill Chet , Cho Clifford , Doyle Maria Majella , Chapman William C. , Hawkins William G. , Strasberg Steven M. , Trikalinos Nikolaos A , Maithel Shishir , Fields Ryan ,   US-NETSG Group
Published: January 2019

216 Background: Neutrophil, monocyte and lymphocyte counts are important biomarkers of the tumor-induced systemic inflammatory response. A lower monocyte-to-lymphocyte ratio (MLR) and neutrophil-to-lymphocyte ratio (NLR) is associated with a favorable prognosis for certain tumors. However, this association has not yet been demonstrated in resected pancreatic neuroendocrine tumors (PNETs). The aim of this study was to investigate the prognostic significance of MLR and NLR in patients with resectable PNETs with regards to overall survival (OS). Methods: Eligible patients undergoing surgery for PNETs between 2000 and 2016 were identified using a national multi-center cohort dataset. Their pre-operative neutrophil, monocyte and lymphocyte counts were imported and NLR and MLR were calculated. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut offs for NLR and MLR. Univariate analyses were used to compare patient factors and tumor characteristics in different groups. The difference in OS between high and low groups was explored with the use of Kaplan Meier curves and compared using log-rank tests. Results: A total of 635 patients were analyzed. Univariate analysis revealed that higher lymphocyte, low monocyte and low neutrophil counts were associated with improved OS (P = 0.0002, 0.014 and 0.011 respectively). The mean NLR and MLR level was 4.11 ± 0.219 and 0.4295 ± 0.0196, respectively. Lower NLR ( < 4) and lower MLR ( < 0.25) were significantly associated with improved OS (p < 0.001 & p < 0.0001). Median survival was 141 months in the low NLR group (n = 474) and 119 months in the high NLR group (n = 161). The median survival in the high MLR group (n = 464) was 120 months and has not been reached in the low MLR group (n = 171). On multivariate analysis, low MLR was independent predictor of improved OS when controlling for age, race and comorbidities (p < 0.001). Conclusions: For resectable PNETs, low pre-operative NLR and MLR levels are significantly associated with improved survival. NLRs and MLRs may serve as valuable markers to stratify PNET patients for subsequent therapies and clinical trial enrollment.
HCC incidence in patients treated with DAA for chronic hepatitis C compared to PEG-interferon/ribavirin treated patients: HORRID study.
Authors: Siebenhuener Alexander Rheinhard 
Published: January 2019

219 Background: Direct antiviral agents (DAA) have revolutionized the treatment of chronic hepatitis C (CHC) and have quickly become the standard of care. Despite this effective treatment CHC patients are known to have an increased risk to develop hepatocellular carcinoma (HCC). The incidence of HCC is about 3-5% in this population and regular surveillance is highly recommended. To date the correlation between eradication of viral hepatitis and the risk of HCC development in CHC patients is not well understood. Surprisingly several studies show a frequent incidence of HCC after DAA treatment. The aim of this study is to demonstrate treatment of CHC with DAA or PEG-INF/RBV and patients' outcome into context of HCC development and success of CHC treatment. Methods: We performed a retrospective analysis of 300 patients that received treatment with PEG-IFN and RBV and 346 patients that received DAA treatment for CHC in our institution. HCC viral load, genotype, treatment type, duration and outcome, fibrosis grade, age, gender, BMI as well as AFP and serum albumin were recorded. A Cox-proportional hazard model was fit to compare survival in patients treated with PEG-IFN and patients that received DAA regarding HCC, need for liver transplantation and death. Results: While death and need for liver transplantation was not different in both groups, there was a significant difference in the incidence of HCC. Patients that received DAA developed HCC post-treatment significantly earlier than PEG-IFN/RBV treated patients. In a Cox-proportional hazard model, DAA treatment remained a significant predictor for occurrence of HCC after adjusting for confounders. Conclusions: Our data demonstrates a significantly increased incidence of HCC in patients that were cured from CHC with DAA compared to patients after PEG-IFN/RBV treatment. In contrast to earlier studies using historic data, our study limited confounders by directly comparing HCC differential incidence of HCC after PEG-INF/RBV and DAA treatment within the same institution. Further prospective studies are warranted to precisely determine the HCC risk in patients that receive DAA for CHC.
The impact of C-reactive protein to albumin ratio on survivals in patients with esophageal cancer.
Authors: Hayashi Masato , Kawakubo Hirofumi , Mayanagi Shuhei , Nakamura Rieko , Fukuda Kazumasa , Suda Koichi , Wada Norihito , Kitagawa Yuko 
Published: January 2019

22 Background: C-reactive protein to albumin (CRP/Alb) ratio is a novel inflammation-based prognostic score. It was originally reported as a prognostic score in septic patients, however, recent reports show CRP/Alb can be a prognostic score in some cancer patients. There are a few reports about CRP/Alb in patients with esophageal cancer. The usefulness of CRP/Alb in patients with esophageal cancer is still unclear. Methods: The aim of this study is to ensure the evidence of CRP/Alb in patients with esophageal cancer as a prognostic score. One hundred and sixty patients with esophageal cancer were reviewed in the current study. CRP/Alb was calculated before the treatment: In neoadjuvant chemotherapy (NAC) patients, CRP/Alb was calculated before NAC, in non-NAC patients, CRP/Alb was calculated before surgery. CRP/Alb was divided into high group and low group, using cut off value 0.035. The number of 0.035 was determined, referred from other reports of CRP/Alb. Results: The distributions of postoperative pathologic stages 0, 1, 2, 3, and 4 were respectively 4, 51, 33, 56, and 16. The number of high CRP/Alb group was 58 (36.3%). That of low CRP/Alb group was 102 (63.7%). In the survival analysis, the patients with high CRP/Alb showed a significantly shorter overall survival. In the multivariate analysis with pathological stage, neoadjuvant treatment, field of lymph node dissection, and CRP/Alb as covariates, CRP/Alb was detected as a significantly independent prognostic score (hazard ratio 2.602; P < 0.001). Conclusions: In this study, CRP/Alb was thought to be a prognostic score with statistical significance in esophageal cancer. Therefore, further investigation of reducing preoperative inflammation and increasing preoperative nutrition in esophageal cancer is needed.
Microsatellite instability in resectable colorectal liver metastasis: An international multi-institutional analysis.
Authors: Margonis Georgios Antonios , Buettner Stefan , Wagner Doris , McVey John , Andreatos Nikolaos , Beer Andrea , Sasaki Kazunari , He Jin , Kaczirek Klaus , Poultsides George A. , Cameron John L. , Mischinger Hans Jörg , Aucejo Federico , Wolfgang Christopher Lee , Weiss Matthew J. 
Published: January 2019

220 Background: Microsatellite instability (MSI) is associated with favorable prognosis and distinct response to chemotherapy and immunotherapy for non-metastatic colorectal cancer (CRC). However, studies suggest that MSI may have minimal prognostic impact for widely metastatic CRC. Whether MSI is prognostic for the subset of patients with resectable colorectal liver metastases (CRLM) remains unknown. In this study, we analyze the impact of MSI status on patients with CRLM in the largest cohort reported to date. Methods: Patients who underwent curative-intent resection for CRLM between 2003 and 2017 in five participating tertiary centers and had available data on MSI status were included. Standard clinicopathologic and outcome data were collected. Survival was calculated using Kaplan-Meier analysis. Results: A total of 332 patients who met inclusion criteria were identified, of which 198 (59.6%) were male and 133 (40.7%) had rectal primary tumors. Sixteen patients (4.8%) were MSI positive. The majority of patients had T3 tumors (n = 193; 61.3%) and lymph node metastasis were present in 202 patients (64.5%). The median number of hepatic lesions was 1 [inter-quartile range (IQR):1-3] and median tumor diameter was 2.0 cm (1.2-3.5). Extrahepatic disease was present in 51 (15.7%) patients. Preoperative chemotherapy was administered to 220 (68.8%) patients. Of note, data on KRAS mutation status were available for the majority of the patients (95.5%). Baseline characteristics were similar between MSI positive and negative patients. At a median follow-up of 22.1 months, 154 (47.5%) patients experienced disease recurrence and 70 (21.1%) died. Importantly, neither disease-free survival (DFS, p = 0.168) nor overall survival (OS) were associated with MSI status (p = 0.759). Conclusions: MSI status did not appear to impact survival for patients with resectable CRLM. Additional research in larger cohorts from additional participating institutions is currently underway to assess these preliminary findings.
Survival after surgery for metastatic small bowel compared to pancreatic neuroendocrine tumors.
Authors: Concors Seth Jason , Ecker Brett , Sinnamon Andrew , Fraker Douglas L. , Karakousis Giorgos , Vollmer Charles M. , Roses Robert 
Published: January 2019

221 Background: Surgical management of small bowel (mSBNET) and pancreatic (mPNET) neuroendocrine tumors with hepatic metastases remains controversial. Previous studies, often drawn from single institution experiences, combine outcomes mSBNET and mPNET cohorts, despite ample evidence indicating discreet biology and natural history. This study aimed to define and contrast survival outcomes after surgery in patients with mSBNET and mPNET using a large national dataset. Methods: Patients with hepatic metastases from SBNET and PNET who underwent surgical (n = 1063; n = 556, respectively) or non-surgical management (n = 456; n = 2593, respectively) were identified in the National Cancer Database (1998-2014). Surgical and non-surgical cohorts were matched (1:1) by propensity scores based on the likelihood of receiving surgery and survival hazard. Kaplan-Meier estimates of overall survival (OS) were compared. Results: After adjustment for potential cofounders (age, Charleston comorbidity index, tumor differentiation and administration of chemotherapy or radiotherapy), nonsurgical management was associated with poorer survival in SBNET (HR 2 95%CI 1.5-2.7) and in PNET (HR 3.6, 98%CI 2.8-4.5). In the propensity matched cohort, there was a significant survival advantage for patients who received surgery for both SBNET and PNET (p < 0.001). In SBNET, mean survival in the non-surgical cohort was 33.9 months (SD 1.3, 95%CI 31.5-36.4), and 39.3 months in the surgical cohort (SD 0.8, 95%CI 36.1-39.1). In PNET, mean survival in the non-surgical cohort was 32.7 months (SD 1.6, 95%CI 29.5-35.8), and 55.1 months in the surgical cohort (SD 1.4, 95%CI 52.4-57.7). Conclusions: Surgical selection or management are associated with a survival advantage in both mPNET and mSBNET; this advantage is greater in mPNET. The relative contributions of patient selection and therapeutic benefit require further elucidation.
Survival for small, well-differentiated PNETs in relation to treatment.
Authors: Julian bao-Quynh , Ituarte Philip HG , Jutric Zeljka , Singh Gagandeep , Paz Isaac Benjamin , Lewis Aaron G 
Published: January 2019

222 Background: Management of small well-differentiated pancreatic neuroendocrine tumors (PNETs) is controversial, and the malignant potential remains uncertain. Treatment options include observation (OB), enucleation (ENUC), and formal resection (Distal pancreatectomy – DP, Whipple/Total pancreatectomy – PD). Our objective was to analyze the association between treatment types of small PNETs and overall survival (OS). Methods: The California Cancer Registry linked with the Office of Statewide Health Planning and Development inpatient database was queried from 2000-2012 for patients with < 3 cm, nonfunctional, stage I–II PNETs. Exclusion: poorly-differentiated PNETs or metastases within 6 months. Non-parametric statistics (Kruskal-Wallis) or Fisher’s exact test were used to determine if any patient characteristics were associated with type of treatment (surgery or observation). Ten-year OS was estimated by the Kaplan-Meier method. A multivariate model was performed using Cox proportional hazards. Results: Of 1,862 patients with PNETs, 204 were small, well-differentiated. Treatments include: OB n = 41, EN n = 20, DP n = 106, or PD n = 67. Few patients developed distant recurrences past 6 months (OB, n = 0; EN, n = 0; DP, n = 2; PD, n = 1). On bivariate analysis, comorbidities (2 or more, p = 0.024), insurance type (p = 0.018), and mean number of lymph nodes retrieved (EN = 1.8 +/- 4.1; DP = 6.3 +/- 7.63; PD = 11.0 +/-8.5) were associated with treatment. Patient gender, race, socio-economic status, hospital type, tumor size, grade (well vs. moderate), and lymph node status at diagnosis were not associated with treatment type. On multivariate analysis, treatment type was not associated with worse OS (p = 0.098). Ten-year OS was similar between treatment groups (OB = 92%, EN = 100%, DP = 95%, PD = 95%, p= 0.1828). Conclusions: In this unique study accounting for time of metastasis in patients who present with early stage, well-differentiated PNETs, observation, enucleation, and resection are equally associated with long-term survival. In the appropriately selected patient group, enucleation or observation may be alternatives to more aggressive surgery.
Tumor-normal sequencing to reveal frequency of false positive error rates with tumor-only sequencing in GI cancers and with RNA sequencing as a new standard of precision molecular profiling.
Authors: Garner Chad , Reddy Sandip , Sanborn John Z , Benz Stephen Charles , Soon-Shiong Patrick , Rabizadeh Shahrooz 
Published: January 2019

224 Background: Tumor-only sequencing to identify somatic tumor genomic variants increases the risk of mistakenly identifying germline mutations as somatically derived driver mutations. Simultaneous bioinformatics analysis of both normal germline and the tumor genome with RNA analysis is necessary for precise identification of molecular targets for cancer therapy. The objective of this study was to compare the accuracy and precision of tumor somatic SNV calling with a 45-gene GI cancer molecular actionability panel, analyzing tumor tissue alone versus analyzing tumor DNA with normal germline DNA and tumor RNA. Methods: The study included 204 cancer patients with 11 GI cancer types with whole genome sequencing of tumor and normal genomes. True positive and false positive rates were measured for single nucleotide variants (SNVs). RNA sequencing was available for 139 patients to determine SNVs expressed in messenger RNA. SNVs were identified using well-established and published bioinformatics methods. False positive results were SNVs identified as being somatic origin that were of germline origin. Results: 92% SNVs identified from sequencing tumor genomes alone were of germline origin (false positives) rather than true somatic mutations. Filtering the SNVs using a public database with reported population allele frequencies < 0.001 still resulted in a false positive rate of 41%. Furthermore, 71% of GI cancer patients had at least one false positive SNV after filtering. RNA analysis showed 10% of true somatic variants were not expressed and 17% of patients had at least one true somatic variant that was not expressed. Conclusions: Simultaneous sequencing and analysis of both normal germline and tumor genomes is necessary for accurate identification of molecular targets. Analysis of tumor genome alone results in a high false positive rate. Higher precision is achieved with simultaneous tumor-normal DNA and RNA sequencing analysis. Treatment decisions based on tumor-only DNA analysis or in the absence of RNA analysis can result in administration of ineffective therapies and increasing risk of negative drug-related side effects.
Emerging value of multigene panels for germline testing in patients with neuroendocrine tumors.
Authors: Whitman Julia , Shih Brandon , Blanco Amie , Chan Salina , Paciorek Alan , Desjardin Jacqueline , Dhawan Mallika Sachdev , Zhang Li , Bergsland Emily 
Published: January 2019

226 Background: Neuroendocrine tumors (NETs) are known to be associated with hereditary syndromes stemming from MEN1, VHL, SDH or TSC mutations. Recent data suggest that additional germline mutations may be relevant, implying a role of germline testing with multigene panels. We examined genetic counseling (GC) referral and testing patterns, test results, and their changes over time in NET patients (pts). Methods: Retrospective chart review was conducted in 236 NET pts referred to UCSF Cancer Genetics and Prevention Program 2004-2017. Univariate logistic models were used to assess relationship between binary outcome and covariate. STATA was used for analysis and statistical significance was based on p < 0.05. Results: 139 referred pts (59%) followed up with GC. Pts with >1 family members diagnosed with cancer were more likely to attend GC [OR=2.75, p=0.010]. Among 107 pts tested, small bowel NETs were less associated with testing than pancreatic NETs [OR=0.15, p=0.001]. Single-gene tests were routine until 2015, when panels up to 130 genes became standard. Overall, 31 pts (29% of 107 tested) had a pathogenic/likely pathogenic (P/LP) result. There was no significant difference between single and multi-gene tests in identifying P/LP mutations (likely due to changes in threshold for testing over time), but greater diversity in P/LP mutations was noted with larger panels. Functional tumors showed lower rate of P/LP mutations than non-functional [OR=0.17, p=0.037]. Conclusions: Only 59% of referred pts followed up with GC, suggesting significant barriers to testing exist. Of those tested, 29% harbored a P/LP mutation. Germline mutations not traditionally associated with NETs were identified, highlighting the potential importance of larger panels to detect rare mutations. [Table: see text]