bluuebunny/crossref_metadata_2025_split huggingface dataset:
NTRK gene fusions in biliary tract cancers.
Authors: Demols Anne , Rocq Laureen , Charry Manon , De Nève Nancy , Verrellen Audrey , Ramadhan Ali , Van Campenhout Claude , De Clercq Sarah , Salmon Isabelle , D'Haene Nicky 
Published: February 2020

574 Background: Gene fusions involving one of the 3 neurotrophic tyrosine receptor kinases ( NTRK) have been identified in approximately 1% of solid tumors and inhibitors of TRK (e.g. larotrectinib) have been shown to have anti-tumor activity regardless of tumor type. NTRK gene fusions have been previously reported in bilio-pancreatic cancers. It is of interest therefore to determine the incidence and molecular characteristics of NTRK gene fusions in patients with bilio-pancreatic cancers. Methods: Formalin-fixed paraffin-embedded archival blocks from surgical resections, biopsies or cytological samples of biliary tract tumors including intra-hepatic cholangiocarcinoma (IH), extra-hepatic cholangiocarcinoma (EH), perihilar cholangiocarcinoma (PH) and gallbladder tumors (G) were selected/retrieved from the tumor bank of the CUB Hôpital Erasme between January 2010 and July 2019. A two-step diagnostic method incorporating immunohistochemistry (IHC) screening followed by NGS analysis was used. Pan–TRK IHC (monoclonal antibody clone EPR17341 [AbCam, Cambridge, MA]) was used for the screening method. Staining intensity (negative, weak, moderate or strong) and localization (cytoplasmic or nuclear) were evaluated. The presence of at least weak staining tumor cells led to testing by a RNA-based NGS panel (Oncomine Focus Assay, ThermoFisher scientific). Results: 145 archival tumors samples (81 surgical resections, 48 biopsies and 16 cytology) have been selected, including 61 IH, 32 PH, 26 EH and 26 G (67 female and 78 male). 134 samples were suitable to perform IHC. 17 samples were IHC positive. Intensity of staining was weak in 16 samples and moderate in one. Staining location was cytoplasmic (14/17), nuclear (2/17), and nuclear+cytoplasmic (1/17). NGS testing of the 17 IHC positive samples revealed a single NTRK3 gene fusion ( ETV6(4)- NTRK3(14)). In this case (female patient with a poorly differentiated PH, deceased), IHC had a weak focal cytoplasmic and nuclear staining. Overall in the patients screened by IHC and confirmed by NGS, the percentage of NTRK fusions was 0.75%. Conclusions: NTRK gene fusions are rare in biliary cancers but testing is of high interest due to the emergence of possible treatment with specific TRK inhibitors.
Beta-catenin mutations in hepatocellular cancer, tumor cell metabolism, and the response of these tumors to mTOR inhibition.
Authors: Monga Satdarshan , Borad Mitesh J. , Tao Junyan 
Published: February 2020

583 Background: Hepatocellular cancer (HCC) continues to grow in incidence despite approval of many new therapies including immune checkpoint inhibitors (ICIs) and TKIs. Genomic landscape of HCC is becoming increasing apparent through WGS and WES. One major driver of HCC is the Wnt/b-catenin pathway. Mutations in CTNNB1, which encodes for b-catenin, are evident in 26-37% of all human HCCs. However, expression of mutant-b-catenin in liver in mice is insufficient for HCC development. Indeed, analysis of HCC cases has revealed CTNNB1 mutations to significantly co-exist with other aberrations including activation/overexpression of Met and Myc and mutations in TERT promoter or mutations in NFE2L2/KEAP1, APOB and ARID2. Methods: Using sleeping beauty transposon/transposase and hydrodynamic tail vein injection, we co-expressed mutant-CTNNB1 (S45Y, S33Y or T41A) and one other clinically relevant co-occurrence to study significance and biology of HCC. Any novel findings in the preclinical model were validated in HCC patient cohorts. Results: Co-expression of mutant-CTNNB1 and one relevant co-occurrence led to development of HCC in mice in 6-10 weeks. All HCC in these models showed a dramatic increase in glutamine synthetase (GS), encoded by Glul, a known target of the Wnt/b-catenin signaling pathway in the liver. This led to an increase in glutamine levels in the tumor-bearing livers. Increased glutamine in the tumors in turn led to increased levels of phospho-mTOR-S2448, a marker of mTORC1 activation. In fact, examination of ~400 patient HCCs showed a significant correlation between positive GS and p-mTOR-S2448 staining. Treatment of Met-b-catenin model with Rapamycin led to notable and significant decrease in HCC burden. Conclusions: Our studydemonstrates b-catenin-mutated HCC to be positive for both GS and in turn mTORC1 active. This provides a novel opportunity for personalized medicine in HCC and CTNNB1-mutated HCCs may be vulnerable to therapeutic targeting by mTOR and more specially, mTORC1 inhibitors.
Neuroendocrine and carcinoid tumors of the gastrointestinal tract: Epidemiology and outcomes from the National Cancer Database.
Authors: Uhlig Johannes , Nie James , Stein Stacey , Cecchini Michael , Lacy Jill , Kim Hyun S. 
Published: February 2020

609 Background: While carcinoid and neuroendocrine tumors (NET) can manifest throughout the human body, approximately 2/3 of these tumors arise in the gastrointestinal (GI) tract. Methods: The 2019 version of the National Cancer Database was searched for adult patients with carcinoid or neuroendocrine tumors of the GI tract. Tumor incidence, patient demographics, treatment and cancer variables of GI carcinoid/NETs were compared to other GI cancers. Cox proportional hazards models were used to evaluate overall survival (OS). Results: A total of 101,744 patients were included. Carcinoid/NET incidence varied with primary location, with highest proportion in the small intestine (55.7% of all small intestinal cancers). Compared to other histologies, carcinoid/NETs were more common in younger patients (median age 60 vs. 68years, p < 0.001) and African Americans (18 vs 12%, p < 0.001). Median carcinoid/NET diameter 15mm vs. 40mm for other cancers (p < 0.001). Carcinoid/NETs were diagnosed at lower stages than other histologies (AJCC stage 3/4, 30% vs. 47%, p < 0.001), with most metastases in the liver (8.9%). Stage 1/2 carcinoid/NETs were most often treated by surgical resection with or without concurrent chemotherapy (65%; 22%), whereas stage 3/4 patients received chemotherapy alone or in combination with surgical resection more commonly (39%; 25%). After multivariable adjustment, primary cancer site emerged as an independent prognosticator: longest OS was observed in patients with carcinoid/NET of the small intestines (vs. colonic frame HR = 0.40, 95% CI: 0.37-0.44, p < 0.001). Comparable results were evident in patients with hepatic metastases (small intestines vs. colonic frame carcinoid/NETs; HR = 0.20, 95% CI: 0.17-0.24, p < 0.001). Other independent OS prognosticators were patient age, gender, race and comorbidities, as well as tumor size, stage and treatment. Conclusions: Compared to other GI-associated tumors, carcinoid/NETs are more common in younger patients, African Americans, diagnosed with smaller diameter at low stage. Carcinoid/NETs of the small intestines are associated with improved overall survival compared to other primary disease sites.
The benefits of upfront primary tumor resection for metastatic small bowel neuroendocrine tumors: A population-based analysis.
Authors: Bennett Sean , Coburn Natalie , Law Calvin , Zuk Victoria , Mahar Alyson , Singh Simron , Myrehaug Sten , Zhao Haoyu , Davis Laura E , Gupta Vaibhav , Hallet Julie 
Published: February 2020

620 Background: Early resection of the primary tumor in metastatic small bowel neuroendocrine (SB-NET) remains controversial. Conflicting data exist regarding its clinical and survival benefits. We compared the long-term outcomes of upfront small bowel resection (USBR) and non-operative management (NOM) for metastatic SB-NETs. Methods: A population-based analysis of patients with SB-NET metastatic at diagnosis between 2001-2017 was conducted by linking administrative datasets. USBR was defined as resection within 6 months of diagnosis. Primary outcomes were subsequent unplanned acute care admissions and small bowel related surgery. Secondary outcome was overall survival (OS). USBR and NOM patients were matched 2:1 using a propensity-score including age, sex, year of diagnosis, socioeconomic status, institution academic status, and functional status. We used time-to-event analyses with cumulative incidence functions and univariate Andersen-Gill regression for primary outcomes, and Kaplan-Meier methods and univariate Cox regression for OS. E-value methods assessed the potential for residual confounding. Results: Of 1000 patients identified, 785 (78.5%) had USBR. The matched cohort included 348 patients with USBR and 174 with NOM. Matched groups were well balanced with standardized mean differences <10% for matched variables. Patients with USBR had lower 3-year risk of subsequent admissions (72.6% vs 86.4%, p<0.001) than those with NOM, with hazard ratio (HR) 0.72 (95%CI 0.57-0.91). USBR was associated with lower risk of subsequent small bowel related surgery (15.4% vs 40.3%, p<0.001), with HR 0.41 (95%CI 0.30-0.56). OS was superior for USBR patients compared to NOM (HR 0.55, 95%CI 0.41-0.74). E-values indicated it was unlikely that the observed risk estimates could be explained by an unmeasured confounder. Sensitivity analysis excluding emergent resections to define USBR did not alter the results. Conclusions: USBR for metastatic SB-NETs was associated with clinical benefits over NOM, in terms of decreased subsequent admissions and interventions, and improved survival. USBR should be considered for metastatic SB-NETs to improve patient outcomes.
PRRT neuroendocrine tumor response assessment using blood transcript analysis: The NETest.
Authors: Bodei Lisa , Kidd Mark A. , Singh Aviral , van der Zwan Wouter A , Severi Stefano , Drozdov Ignat A. , Malczewska Anna , Baum Richard P. , Kwekkeboom Dik J. , Paganelli Giovanni , Krenning Eric , Modlin Irvin Mark 
Published: February 2020

625 Background: Peptide receptor radionuclide therapy (PRRT) is effective for metastatic/inoperable neuroendocrine tumors (NETs). Imaging response assessment is most effective after treatment completion. Blood biomarkers such as PRRT Predictive Quotient (PPQ) and NETest are effective in real-time. PPQ predicts PRRT efficacy, NETest monitors disease. We prospectively evaluated: 1) NETest as a surrogate biomarker for RECIST; 2) Correlation of NETest levels, PPQ prediction and treatment efficacy. Methods: Three independent 177Lu-PRRT-treated GEP-NET and BPNEN cohorts (Rotterdam, Netherlands: n=41; Bad-Berka, Germany: n=44; Meldola, Italy: n=72). Treatment response: RECIST1.1 [Responder (stable, partial/complete response) vs Non-Responder]. Blood sampling: pre-PRRT, prior to each cycle and 6 months (median) after completion of all cycles. PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable<40; progressive >40). CgA (ELISA) as comparator. Samples deidentified, measurement and analyses blinded. Kaplan-Meier survival and Mann-Whitney analyses. Results: 122 of 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly ( p<0.0001) decreased in RECIST-“responders” (-47±3%); in “non-responders” it elevated (+79±19%, p<0.0005). NETest monitoring accuracy 98% (119/122). Follow-up levels >40 (progressive) vs stable (<40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04, 95%CI: 0.02-0.07). PPQ response prediction was accurate in 118 (97%); 99% accurate positive and 93% accurate negative prediction. NETest significantly ( p<0.0001) decreased in PPQ-predicted responders (-46±3%) and remained increased in PPQ-predicted non-responders (+75±19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06, 95%CI: 0.03-0.12). CgA failed to identify response to PRRT ( p=NS). Conclusions: NETest accurately (98%) monitors PRRT response and is an effective surrogate marker for radiological response (image concordance 98%). A NETest decrease identified responders and correlated (>97%) with the pretreatment PPQ response predictor.
Allele frequencies of two MUTYH variants, Y179C, and G396D, in a direct-to-consumer genetic database.
Authors: Nhan Hoang , Zhan Jianan , Kosinski Cindy , Hampel Heather , Wu Shirley ,   23andMe Health Team
Published: February 2020

63 Background: MUTYH-associated polyposis (MAP) is an autosomal recessive condition that accounts for about 0.3-0.7% of all colorectal cancer (CRC) cases. The two most common variants among people of Northern European descent are MUTYH Y179C (rs34612342) and G396D (rs36053993), with a carrier frequency of 1-2%. However, understanding the frequency of these variants in other populations can better inform population health approaches for CRC screening and prevention. This study assessed the frequency of these two variants in a generally unselected group of genotyped individuals who have used direct-to-consumer (DTC) genetic testing (23andMe, Inc. Sunnyvale, CA). Methods: Study participants were genotyped on Illumina genotyping arrays, which included the Y179C and G396D variants. Eligible subjects were 23andMe customers who were at least 18 years of age and who consented to participate in research. IRB approval was obtained from Ethical and Independent Review Services. Results: Out of the 3,617,279 eligible participants included in this study, the overall allele frequencies of Y179C and G396D were 0.18% and 0.51%, respectively. People of European descent had the highest frequencies (0.22% and 0.59%), while people of Ashkenazi Jewish, East Asian, and South Asian descent had the lowest frequencies ( < 0.015% for both variants). The allele frequencies for people of Hispanic/Latino descent were 0.15% and 0.51%. Conclusions: This is the first description of an unselected cohort of individuals with MUTYH Y179C and G396D variants identified through DTC genetic testing. While these two variants were most common among people of European descent, they were also observed at relatively high frequency among people of Hispanic/Latino descent. These results may help guide CRC screening and prevention strategies in different ethnicities.
Implementation of systematic genetic counseling (GC) and multigene germline testing (MGT) for pancreatic cancer (PC) patients (pts).
Authors: Yurgelun Matthew B. , Chittenden Anu B. , Ukaegbu Chinedu I. , Perez Kimberly , Madigan Audrey P. , Gaonkar Shraddha , Cleary James M. , Aguirre Andrew , Wolpin Brian M. , Syngal Sapna 
Published: February 2020

678 Background: MGT identifies cancer susceptibility gene variants in 4-10% of unselected PC pts. Such data have prompted national guidelines to recommend GC and MGT of all PC pts, but the benefits and barriers to implementing systematic testing are unknown. This study’s aim was to study the implementation of universal GC for all PC pts seen in an academic oncology practice. Methods: In 12/2016, all Dana-Farber Cancer Institute (DFCI) gastrointestinal oncologists were recommended to refer all PC pts for GC and MGT. In 10/2018, workflows were changed such that PC patients were automatically scheduled for GC consultation on the same day as their initial oncologic evaluation (unless patients opted out), rather than relying on provider referral. Clinical and germline data were collected on a consecutive cohort of PC pts undergoing GC and MGT from 3/1/2017-3/31/2019. Two additional months (4/1/2019-5/31/2019) were collected for clinical quality assessment purposes. Results: 1305 (48.3/month) PC pts were seen for oncologic new patient visits, 318 (25.1%; 12.1/month) of whom underwent GC. Rates of GC/MGT increased significantly after the 10/2018 workflow change (8.2 PC pts/month [17.2% of all new PC pts seen] versus 20.3 PC pts/month, [40.9% of all new PC pts seen]; p<0.01). Of the 318 PC pts who underwent GC, 29 (9.1%; 95% CI 6.4-11.9%; 2.2% of all PC pts seen) were found to carry germline PC susceptibility gene mutations on MGT. Rates of mutation carrier identification increased after the clinical workflow change from 0.79 mutation carriers/month (1.6% of all new PC pts seen) to 1.75 mutation carriers/month (3.5% of all new PC pts seen). The majority of identified mutation carriers have either received therapy targeted towards their germline mutation or are undergoing first-line palliative systemic therapy with potential for future targeted therapy. Conclusions: Clinical implementation of routine GC/MGT in PC pts is feasible and results in the detection of mutations that are actionable for PC pts and at-risk family members. Systematized workflows for GC evaluation not reliant on active referral result in markedly higher uptake of MGT and mutation carrier identification. Clinical trial information: NCT03060720.
Efficacy and safety of second-line nab-paclitaxel plus gemcitabine (nab-P+GEM) after progression on first-line FOLFIRINOX in advanced pancreatic ductal adenocarcinoma (PDAC): Multicenter retrospective analysis.
Authors: Yoo Changhoon , Jeong Hyehyun , Chae Heejung , Cheon Jaekyung , Chon Hong Jae , Ryu Hyewon , Kim Il-Hwan , Jeong Jae Ho , Kim Kyu-Pyo , Ryoo Baek-Yeol 
Published: February 2020

689 Background: FOLFIRINOX is one of standard 1st-line regimens for patients (pts) with advanced PDAC. However, there is no globally established 2nd-line regimen after failure of FOLFIRINOX. Although gemcitabine-based regimens are recommended by multiple guidelines and widely used in daily practice, further analysis is needed to reveal the magnitude of clinical benefit with these regimens. Nab-P+Gem is another standard 1st-line regimen for PDAC, but there are limited data as 2nd-line therapy in PDAC. Therefore, we conducted multicenter retrospective analysis of 2nd-line nab-P+Gem after progression on FOLFIRINOX in pts with advanced PDAC. Methods: Between Feb 2016 and Feb 2019, a total of 103 pts with histologically documented PDAC who received nab-P+GEM after progression on 1st-line FOLFIRINOX were identified among 5 referral cancer centers in South Korea. Results: Median age was 60 years and 50 pts (49%) were male. All but one pts had ECOG performance status of 0-1 at the time of nab-P+GEM. At the time of nab-P+GEM, 25 (24%) and 78 (76%) patients had locally advanced and metastatic disease, respectively. Median overall survival (OS) and progression-free survival (PFS) with nab-P+GEM was 9.8 months (95% CI: 8.9-10.6) and 4.6 months (95% CI: 3.7-5.5), respectively. Among pts with measurable disease (n = 95), partial response and stable disease were achieved in 8 (8%) and 56 (54%), respectively. Median OS from the start of 1st-line FOLFIRINOX was 20.9 months (95% CI: 15.2-26.6). Most common adverse event of all grade was anemia (77%), followed by neutropenia (60%), fatigue (52%), thrombocytopenia (45%), and peripheral neuropathy (30%). Most common grade 3-4 adverse events were neutropenia (36%), anemia (9%), and peripheral neuropathy (8%). Conclusions: In medically fit pts with advanced PDAC who failed on 1st-line FOLFIRINOX, nab-P+GEM was effective and well tolerated as 2nd-line therapy.
A pilot clinical trial of p53/p16-independent epigenetic therapy for pancreatic ductal adenocarcinoma (PDA).
Authors: Sohal Davendra , Krishnamurthi Smitha S. , Tohme Rita , Shepard Dale Randall , Khorana Alok A. , Saunthararajah Yogen 
Published: February 2020

699 Background: PDA treatment is limited to cytotoxic drugs. A key factor limiting their efficacy is TP53 mutations, omnipresent in PDA, which counter apoptosis-mediated cell kill. We evaluated a novel epigenetic approach using decitabine (Dec) to inhibit DNA methyltransferase 1 (DNMT1) and effect cancer cell cycle exits by epithelial-differentiation, combined with tetrahydrouridine (THU) to inhibit cytidine deaminase (CDA) and thereby permit oral bioavailability and solid-tissue distribution of Dec. Methods: Open-label single-arm, IRB-approved clinical trial at Cleveland Clinic and University Hospitals for patients with metastatic PDA that had progressed on prior chemotherapy, ECOG PS of 0-2. Treatment was oral, weight-based, with Dec 10-20 mg, and THU 500-1000 mg daily, 5 days/week. Primary endpoint was DNMT1 protein levels at 16-week vs baseline biopsies. Results: From Apr to Aug 2017, we enrolled 13 patients. Median age was 65 (range 44-74) years; 7 (54%) males; 11 (85%) Caucasians. Median time from diagnosis was 13 (3.9-53.5) months, with a median of 2 (1-3) prior lines of therapy. Baseline ECOG PS was 0/1 in 12 (92%) patients. All patients started study drugs; median time on treatment was 35 (4-63) days, and on study 72 (25-105) days. The most frequent adverse events attributable to the study drugs were anemia (n=5), and anorexia, dehydration, nausea, fatigue, febrile neutropenia and decreased lymphocyte count, in 3 patients each; no deaths. Eight (62%) patients underwent evaluation scans at 8 weeks, showing stable disease in 1 patient and progression in 7. Common reasons for coming off of study drugs were progression (n=6), physician discretion (n=3), and adverse events (n=2). Overall, 6 patients died; median survival was 3.1 months, and patients did not reach the 16-week biopsy. Shifts in blood counts, a sensitive indicator of Dec systemic activity, were unexpectedly mild, and plasma CDA enzyme activity was increased versus other cancer and normal controls. Conclusions: This first-of-its-kind study demonstrated feasibility and safety of the novel oral epigenetic therapy. Systemically elevated CDA in these patients requires higher doses of THU; a trial accordingly refined is planned. Clinical trial information: NCT02847000.