bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monitoring of neuroendocrine tumors in elderly patients in the Brittany region.
Authors: Metges Jean-Philippe , Deniel Lagadec Delphine , Pracht Marc , Lievre Astrid , Robinet Gilles , Estivin Sandrine , Corre Romain 
Published: May 2019

e15690 Background: NeuroEndocrine Tumors (NETs) remain a poorly known entity, especially in older patients. The therapeutic management is multidisciplinary combining surgery, interventional radiology, chemotherapy, cancer supportive care and also geriatrics oncology. The aim of this study performed by the OncoGeriatry Coordination Unit (UCOG) of Brittany, in collaboration with the National Reference Network for the management of NET (RENATEN), was to analyze the current management of NETs in older patients (more than 75 years old) and to develop recommandations to optimize the management of elderly patients with NENs. RENATEN’s guidelines mean systematic discussion of the cases in Regional Multidiscplinary Tumor Board (MTB) dedicated to NETs (RENATEN MTB). Methods: This study is a retrospective observational study including patients aged 75 years and over, with a NET that has been diagnosed in an pathological laboratory or whose file has been discussed in a MTB (usual MTB or RENATEN MTB) between 2014 and 2017 in the Brittany area. Results: 51 patients with a median age of 79 years [75-92] have been included up until now, among whom 77% had digestive NET, 12% urological, 8% dermatological (Merkel tumor), 4% pulmonary, 2% gynecological and 2% NETs of unknown origin. Tumor grade was 1, 2, 3 and unkown in 20%, 14%, 37% and 29% respectively. Overall, 33% of the tumors were well differentiated and 63% were metastatic (synchronous metastases :78%). Only 20% of patients benefited from a geriatric oncology consultation to help the clinician in the therapeutic decision. File of 53% of patients has been discussed one time in a specialized RENATEN MTB and 57% in another MTB. No proof of discussion in MTB was found in 12%. The treatment proposed in the RENATEN MTB was effective in 85% of patients (2 patients died immediately after RENATEN MTB, 2 patients did not wish to be treated). Only 14% of patients received initial surgery, 10% radiotherapy and 41% chemotherapy. The overall survival of this cohort is 11.3 months [0.3 -89] (for grade 3, 7.9 months [0.8-21.7]). Conclusions: The rate of multidisciplinary meeting presentation has to be improved, as well as the geriatric oncology management. A cohort of more than 100 patients will be presented at the meeting and treatment response and survival data based on age class, tumor grade, histological subtypes and therapeutic strategy will be shown.
A retrospective series of centralized reviewed GEP MANECs receiving a first-line adenocarcinoma-oriented chemotherapy.
Authors: Spada Francesca , Milione Massimo , Maisonneuve Patrick , Prinzi Natalie , Smiroldo Valeria , Bolzacchini Elena , Carnaghi Carlo , La Rosa Stefano , Capella Carlo , Sessa Fausto , Fazio Nicola 
Published: May 2019

e15695 Background: Mixed adeno-neuroendocrine carcinomas (MANECs) are very rare malignancies. Due to their biological and clinical heterogeneity, there is not a universally shared clinical approach. Methods: We retrospectively analyzed clinical records of 22 patients from 4 Italian referral centers with advanced MANEC of the gastro-entero-pancreatic (GEP) tract who received a first line chemotherapy and were part of a previously published series of 160 patients (M. Milione et al, Endocrine Related Cancer 2018). Surgical specimens were centrally reviewed by a team of 7 expert pathologists. Clinical and biological data were correlated with outcomes. Results: All patients developed distant metastases (32% synchronous, 68% metachronous). Primary sites were colorectal in 13 patients, esophago-gastro-duodenal in 6, and pancreato-biliary in 3. Ki-67 index in the NEC component was ≥55% in 77% of the patients. Three patients (2 colorectal) received neo-adjuvant chemotherapy, 4 adjuvant (2 colorectal), and 2 peri-operative (one colorectal, one pancreas). The most common regimen was adenocarcinoma-oriented (59% fluoropyrimidines /oxaliplatin). Overall, 14% of patients had a partial response (PR) and 18% stable disease (SD). The median OS in the whole cohort was 0.9 years (95% CI 0.3-1.4). It was longer in patients with Ki-67 < 55% in the NEC component (median 2.5 years; 95% CI 0.5-2.5) than in those with Ki-67 ≥ 55% (median 0.9 years; 95% CI 0.3-1.0) (Wilcoxon P =0.10), regardless of the type of therapy. Mutations in either KRAS (codons 12 and 13) or TP53 (exons 5-8) genes performed by NGS were observed in 9 (8 colorectal, one pancreas) out of 19 patients. Only one of them, (colon primary site), experienced SD. Conclusions: This analysis suggested that an adenocarcinoma-oriented regimen could be active as first line chemotherapy in patients with advanced GEP-MANECs especially with Ki-67 index < 55% in the NEC component. Since its descriptive design and various clinical management, this study cannot either suggest a specific therapy or a real impact of chemotherapy on prognosis. However, it produced solid hypotheses for future prospective-interventional studies in selected populations.
Characterization of a novel entity of high-grade well-differentiated colorectal neuroendocrine tumors.
Authors: Punekar Salman Rafi , Masri-Lavine Lena , Hajdu Cristina , Newman Elliot , Becker Daniel Jacob 
Published: May 2019

e15696 Background: Small studies suggest that a new pathologic entity of high-grade (by Ki-67 or mitotic index) well-differentiated (by histologic features) neuroendocrine tumors (NETs) exist throughout the GI tract, but the prognosis and characteristics of affected patients are unknown. We sought to further characterize the prognosis and demographics of patients with high-grade (HG) well-differentiated (WD) colorectal NET. Materials and Methods: We used the Surveillance Epidemiology and End Results (SEER) database to study patients with NETs of the colon and rectum diagnosed from 2000 to 2015. We identified patient demographics, clinical and tumor characteristics, and studied associations with tumor grade. We compared overall survival (OS) between patients with low-grade (LG)(grade 1-2) well-differentiated (ICD-0-3 = carcinoid), high-grade (grade 3-4) well-differentiated, and high-grade poorly-differentiated NETs (ICD-0-3 = small cell neuroendocrine). We used logistic regression to detect associations with grade and Cox proportional hazards models to examine predictors of survival. Results: We identified 5,894 cases with colorectal carcinoid tumor (5780 [98.1%] LG and 114 [1.9%] HG); the cohort was 68% white, 48% male, and had a median age of 54. Patients diagnosed with HG carcinoid tumors were more likely to be of older age (OR 2.23; 95% CI 1.19-4.19 for age 60-69 vs < 50) and unmarried (OR 1.56; 95% CI 1.02-2.38), and less likely to be diagnosed after 2010 (OR 0.09; 95% CI 0.06-0.15). OS for patients with HG carcinoids (median 36 m; 95% CI 13-92) fell in between OS for those with HG small cell NETs (median 7 m; 95% CI 6-8), and LG carcinoid tumor (median not reached, > 120 m). Among patients with carcinoid tumors, black patients (HR 1.31; 95% CI 1.03-1.67, older patients (HR 3.60; 95% CI 2.50-5.19 for age 60-69 vs < 50), unmarried patients (HR 1.52; 95% CI 1.24-1.87), and those with HG features (HR 3.85; 95% CI 2.88-5.15) had worse survival. Conclusions: We defined a subset of high-grade well-differentiated NETs, more commonly diagnosed in older, unmarried patients, with a prognosis between that of high grade small cell NETs and low grade carcinoid tumors. Our analysis adds the first national registry study to the literature in support of a new classification of non-pancreatic high-grade well differentiated NETs.
Comprehensive characterization of pseudomyxoma peritonei.
Authors: Malouf Gabriel G. , Dohan Anthony , Yao Hui , Mouawad Roger , Carapito Raphael , Bahram Seiamak , KHAYAT INSTITUT CANCEROLOGIE Meyer , Kurtz Jean-Emannuel , Su Xiaoping , Pocard Marc 
Published: May 2019

e15701 Background: Pseudomyxoma peritonei (PMP) is a rare malignant tumor characterized by the infiltration of the peritoneum by mucus-secreting tumor cells. The genetic landscape of these tumors and correlation with clinico-pathological tumor features is unclear to date. Methods: We performed whole-exome sequencing (WES) on 8 PMPs and matched normal. We then validated our finding using ultra-deep sequencing of hotspot mutations (~82.270 x) in 45 clinically annotated samples. In addition, bulk RNAseq was performed on 10 samples and MCP-counter was used to infer absolute abundance of eight immune and two stromal cell populations. Results: Overall, 323 somatic mutations were identified through WES with most frequent mutations involving GNAS (R186H) (50%), KRAS (G12D) (50%), AHNAK2 (25%) and ATXN1 (25%). Furthermore, ultra-deep sequencing uncovered KRAS, GNAS and IDH1/2 hotspots mutations in 16 (35.5%), 11 (24.4%) and 2 (4.4%) PMPs, respectively. Strikingly, KRAS mutations were enriched in females (79% vs 39%, p = 0.03) while GNAS in males (67% vs 28%, p = 0.04). No other significant associations were identified between mutations and other clinico-pathological features. Using MCP-counter, fibroblasts, endothelial cells and moncoytic cells were the most frequent inferred cells. Unsupervised clustering using expression of most variable cells identified two PMP clusters, namely C1 (n = 4) and C2 (n = 6). C2 cluster displayed higher T cells as compared to C1 (p < 0.0001), consistent with increased cytotoxic lymphocytes (p = 0.04). Notably, C2 was enriched for tumors with higher grade as compared to C1 (80% vs 0%; p = 0.04). Conclusions: Our study represents the largest study to data exploring genetic and immune alterations in PMPs. We uncovered puzzling associations between genetic landscape of PMPs and patients gender, which deserve further validation in an independent cohort. The association of high-grade tumors with increased tumor infiltrating lymphocytes suggests the existence of an immunogenic microenvironment; PD-1/PD-L1 blockade might represent a therapeutic option for these patients.
Analysis of feasibility and survival in repeated cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in appendiceal cancer with peritoneal dissemination.
Authors: Karpes Josh , Parikh Roneil , Shamavonian Raphael , Alzahrani Nayef , Morris David L. 
Published: May 2019

e15702 Background: CRS/HIPEC has been established as the method of choice for the management of peritoneal dissemination from appendiceal cancer. With recurrence rates after first surgery as high as 44%, re-do CRS/HIPEC is evolving as an effective recurrent treatment regime. This analysis examines the feasibility of repeated CRS/HIPEC for patients with appendiceal cancer with peritoneal dissemination and evaluates the survival outcomes. Methods: A retrospective cohort study of 1074 patients who had CRS/HIPEC procedures and had a recorded tumour grade from 1996 to 2017 was performed. Morbidity and mortality as well as the survival effect was analysed. Tumour grade was divided into low grade: diffuse peritoneal adenomucinosis (DPAM); and high grade: peritoneal mucinous carcinomatosis (PMCA). Results: Initial CRS/HIPEC comprised of 991 patients, with 148 of those undergoing repeated CRS/HIPEC for appendiceal cancer with peritoneal dissemination. The overall survival for patients with DPAM who had only one CRS/HIPEC was 248 months with a five-year survival of 80%, compared to an overall survival of 75 months and five-year survival of 54% in those who had repeated CRS/HIPEC. For patients with PMCA, the overall survival of those who only had one CRS/HIPEC was 63 months with a five-year survival of 47%, compared to an overall survival of 52 months and five-year survival of 44% in those who had repeated CRS/HIPEC. There was no statistically significant difference in the morbidity and mortality for patients who had repeated CRS/HIPEC for management of appendiceal cancer with peritoneal metastases when compared to those who only had one. Conclusions: This study suggests that re-do CRS/HIPEC is a feasible and effective treatment regime in the management of tumour recurrence in appendiceal cancer with peritoneal dissemination, with no difference in the morbidity and mortality of patients who had repeated CRS/HIPEC compared to only one procedure.
Identifying mechanisms of macrophage-induced metastasis in pancreatic ductal adenocarcinoma.
Authors: Wu Tony James 
Published: May 2019

e15705 Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal, incurable disease. Macrophages are one of the most abundant, multifunctional immune cell populations in the tumor microenvironment and a major component of the immune infiltrate in many solid tumors. Methods: Employing a multi-omics approach, PDAC cell lines and primary macrophages were CTAP (cell-type specific labelling using amino acid precursors)-labelled and admixed together for a prolonged period of time. To identify cell-of-origin of novel RNA and proteins, these mixed co-cultures were FACS sorted for downstream RNA-sequencing analysis or harvested in bulk for downstream proteome and secretome analysis. Results: Here, we provide new insight into the dichotomous relationship between epithelial and mesenchymal phenotypes of PDAC cells in 3D culture. We report the ability of PDAC mesenchymal cells to form vascular mimicry-like structures in a 3D in vitro assay of invasion. Additionally, we demonstrate that macrophages have the ability to impart a pro-invasive phenotype to PDAC cells when co-cultured in 3D, regardless of EMT (epithelial-to-mesenchymal transition) status. Preliminary integration of cell culture transcriptomes with CTAP-TMT proteomes and secretomes implicates several key epithelial- and macrophage-derived signalling molecules as principal instructing signals for mediating the observed pro-invasive phenotype. Conclusions: Blockade of these signalling molecules or their receptors disrupted the crosstalk between PDAC cells and macrophages within the tumor microenvironment and impaired the ability of macrophages to induce a pro-invasive phenotype to PDAC cells.
Prognostic factors associated with short-term survival (STS) in advanced pancreatic cancer (APC): A Canadian multicenter analysis from the CHORD Consortium.
Authors: Cardoso Miguel , Mehta Sakshi , Kim Christina , Armstrong Dawn Elizabeth , Ramjeesingh Ravi , Renouf Daniel John , Ahmed Shahid , Ko Yoo-Joung , Harb Mohammed , Kong Shiying , Cheung Winson Y. , Meyers Brandon M. ,   on behalf of the CHORD Consortium
Published: May 2019

e15717 Background: The survival of patients (pts) with APC (locally advanced/metastatic) is slowly improving; however in some pts it remains extremely short. Few studies have evaluated the clinical, pathologic and treatment characteristics associated with STS in APC. Methods: Pts with APC (between 2011-2017) were included in the analysis. Descriptive analyses were conducted for demographic, tumor and treatment characteristics between pts who survived ≤ and > 90 days using Wilcoxon rank-sum test and Chi-square test for continuous and categorical variables respectively. Multivariable logistic regression was performed to identify association between pts’ characteristics and STS. Results: A total of 580 pts were included in the analysis: median age 68, 53% male, 92% metastatic and 53% ECOG 0/1. STS ≤90 days occurred in 152 pts (26.2%), with 65.1% not receiving any chemotherapy. Median overall survival for STS was 49 days vs. 276 for non-STS. At least 1 cycle of chemotherapy was administered to 358 pts; mean duration of 1st line chemotherapy for pts with STS ≤90 was 1.5(SD 2.5) cycles (N = 53), compared to 7.6(SD 11.1) cycles (N = 305) for pts surviving > 90 days. Prognostic factors associated with STS ≤90 days were neutrophil:lymphocyte ratio, LDH, metastatic disease, ECOG and not receiving chemotherapy (Table). Other clinical factors (BMI, smoking history, diabetes) and laboratory values (platelet, baseline CA19-9, estimated GFR) were not prognostic. Conclusions: In a multicenter database of Canadian academic centers, < 2/3 of pts received at least 1 cycle of chemotherapy. STS ≤90 days occurred most often in pts who did not receive chemotherapy. Prognostic factors associated with STS include routine laboratory values, receipt of chemotherapy, ECOG and the presence of metastatic disease. Further analyses of these factors may help improve survival in APC. [Table: see text]
Predictors of neoadjuvant chemotherapy efficacy in localized pancreatic head cancer: A 15-year experience at a high volume pancreatic cancer center.
Authors: Al Abbas Amr I. , Hodges Jacob , Varley Patrick , Buchholz Connor , Bellon Johanna E , Bahary Nathan , Singhi Aatur D. , Hogg Melissa , Zeh Herbert , Zureikat Amer H. 
Published: May 2019

e15724 Background: Surgery followed by adjuvant chemotherapy (SF) is the standard approach for localized pancreatic adenocarcinoma (PC). Although neoadjuvant chemotherapy (NC) is being increasingly used, its efficacy remains debatable. This study aims to identify baseline factors associated with benefit from NC as compared to SF for PC. Methods: Review of a prospectively maintained database of resected localized head PC undergoing NC or SF at a tertiary referral hospital from 2002 to 2018. Baseline factors investigated included clinical stage by EUS (7th edition AJCC), CT vessel involvement, and serum CA19-9. Baseline CA19-9 levels were grouped into mild (37-200), moderate (200-900), and marked elevations (≥ 900). Patients with baseline serum CA19-9 < 37 IU/dL were excluded from the analysis. Results: In total, 269 patients were evaluated: 165 (61%) received NC and 104 (39%) had SF. Mean patient age was 68.3 years and 50% were females. Of these, 42% had stage IIB, 44% had N1 disease, and 38% had vascular involvement. Compared to SF approach, NC was associated with improved median survival for CA19-9 of < 200 IU/dL (30 vs 21 months, p = 0.08), 200-900 IU/dL (32 vs 17 months, p < 0.01), and the ≥900 IU/dL (33 vs 12 months, p < 0.01) groups. On Cox regression, NC was the only baseline factor predictive of improved survival in the groups with moderate (HR:0.35,[95% CI:0.20-0.62];p < 0.01) and marked (HR:0.36,[95% CI:0.18-0.71];p < 0.01) pretreatment CA19-9 elevation. Notably, NC was not predictive of improved survival in the cohort with mild CA19-9 elevation. Conclusions: This study identifies a cohort of patients that benefits from neoadjuvant chemotherapy over a surgery first approach for localized pancreatic head cancer. Elevation in baseline CA19-9 may serve as the strongest indicator for chemotherapy before resection.
Prediction of response to pelareorep plus pembrolizumab in pancreatic ductal adenocarcinoma (PDAC).
Authors: Fountzilas Christos , Wilkinson Grey A , Eng Kevin H. , Fields Paul , Arora Sukeshi Patel , Kalinski Pawel , Raber Patrick , Nuovo Gerard , Coffey Matthew C. , Mahalingam Devalingam 
Published: May 2019

e15726 Background: Pelareorep is an oncolytic reovirus that can induce an inflamed T-cell-infiltrated (hot) phenotype in PDAC. In a phase Ib trial, pelareorep was administered in combination with pembrolizumab and chemotherapy in patients (pts) with advanced, pre-treated PDAC. The safety profile was acceptable and efficacy results were encouraging (Mahalingam ASCO GI 2018). Here we present the results of immune analysis in peripheral blood. Methods: Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 day 1 (C1D1, pre-pelareorep), C1D8 (pre-pembrolizumab) and C2D1 (pre-pelareorep). RNA from PBMCs was analyzed using a customized Nanostring panel. The research-use only immunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA) was used to characterize T-cell receptors from PBMCs. Results: Eleven pts were enrolled. Disease control was achieved in 50% of the 6 efficacy-evaluable pts. One pt achieved PR that lasted 17.4m. Two additional pts achieved SD, lasting 277 and 126 days. Downregulation (relative change < -1.5) of CD1b (C1D1), HLA-C, MAPK14 (C1D8), CD63, LY96, LTF, TXK, TNFSF13, IL25, C1QB (C2D1) and upregulation ( > 1.5) of IL17F (C1D1), MAGEA4, CCL7 (C1D8), CSF1, ICOS, LILRA4, TICAM2 (C2D1) was observed in pts with clinical benefit vs. no clinical benefit (raw p < 0.05). Increase in clonal diversity was noted during therapy overall (Table). C2D1 had significantly more clonal expansion than C1D8; ~30% of expanded clones from C1D8 were also expanded at C2D1 (durable). High numbers of early expanded (C1D8 only) and durable clones were associated with longer survival. Conclusions: Pts with disease control had higher baseline IL17F compared to non-responders. On-treatment relative decrease in IL25 (Th2), increase in LILRA4, TICAM2 (antiviral response) and ICOS were noted in these pts. There was new clone expansion after treatment overall; ~30% of expanded clones at C1D8 were durable. Early and durable clonal expansion correlated with survival. A phase II trial with pelareorep plus pembrolizumab in advanced PDAC is ongoing. Clinical trial information: NCT02620423. [Table: see text]
The prevalence of hereditary pancreatitis mutations in families with pancreatic cancer.
Authors: Seedor Rino S. , Savage Michelle J. , Iqbal Waleed , Arora Sanjeevani , Rainey Kim , Forman Andrea , Lincoln Steven , Garcia John , Truty Rebecca , Esplin Edward D. , Handorf Elizabeth A. , Hall Michael J. 
Published: May 2019

e15728 Background: Germline pathogenic variants (PV) in hereditary cancer risk genes are found in ~10-15% of pancreatic adenocarcinomas/cancers (PC), but most cases of familial PC have no identifiable genetic cause. Chronic pancreatitis is an established risk factor for PC, with a lifetime risk of PC of 10-30%, and has been associated with germline mutations in several genes: PRSS1, SPINK1, CASR, CTRC, and CFTR. Few studies have examined the prevalence of PV in the pancreatitis risk genes among patients reporting a personal or family history (FHx) of PC. Methods: The FCCC Risk Assessment Program (RAP) database was queried to identify patients tested for PRSS1, SPINK1, CASR, CTRC, and CFTR as part of risk assessment. Pedigrees, demographic and cancer history data were reviewed. De-identified data from Invitae on patients found to be CFTR+ on hereditary pancreatitis testing were also reviewed for personal/FHx of PC. Results: 26 patients with PC and 48 patients with a FHx of PC underwent germline testing for the pancreatitis genes at FCCC. 7 of 26 (26.9%) patients with PC carried at least one CFTR mutation, while 3 of 48 (6.3%) patients with a FHx of PC carried a CFTR mutation. Interestingly, 8 patients carried an intronic variant in the CFTR gene. No patients with PC and 2 of 48 (4.2%) patients with a FHx of PC carried a SPINK1 mutation. The CFTR mutation rate in PC patients exceeded the expected carrier rate (2.6-3.6%)(p < 0.001). The SPINK1 mutation rate in PC patients also exceeded the expected carrier rate but was not statistically significant (1.9%)(p = 0.23). CaSR, PRSS1, and CTRC mutations were not identified in our population. Personal/FHx data were available to review for 175 of the 496 CFTR+ patients tested through Invitae. 49 of 175 (28%) had a personal history of PC and 105 of 175 (60%) had a reported FHx of PC. Strikingly, 23% of CFTR+ patients carried pathogenic mutations in other genes (most commonly SPINK1). Conclusions: In our select sample, CFTR mutations, and in particular a known intronic variant, were highly enriched in a population of patients undergoing risk assessment for hereditary PC. Commercial data suggest a substantial minority of CFTR+ carriers with a personal/FHx of PC may also carry SPINK1 mutations.