bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel therapeutic avenues for cholangiocarcinoma treatment: A meta-analysis.
Authors: Aljabban Nabeal , Aljabban Jihad , Gurakar Merve , Khorfan Kamal , Syed Saad A. , Gayar Adam , Khan Hajra , Hadley Dexter , Saberi Behnam 
Published: February 2020

584 Background: Cholangiocarcinoma (CCA) is a rare cancer of the bile ducts but has been increasing in incidence. The mainstay of treatment of CCA is resection or chemoradiation for more advanced disease, with immunotherapy being an evolving field in treatment. A better understanding of CCA pathogenesis will pave new avenues for treatment. Methods: We employed our STARGEO platform to conduct a meta-analysis of public data from NCBI's Gene Expression Omnibus. We performed meta-analysis with 259 CCA tumor samples against 16 normal intrahepatic duct samples as a control. We then analyzed the signature in Ingenuity Pathway Analysis. Results: Our analysis revealed FXR/RXR and LXR/RXR activation as top canonical pathways. Top upstream regulators identified included HNF1A (with predicted inhibition) and ERBB2 (with predicted activation). The most upregulated genes included several extracellular matrix proteins implicated in cancer including COL1A1, LAMC2 (correlated with poor prognosis in CCA), KRT17 (a keratin implicated in various malignancies but not well described in CCA), and LAMB3 (exerts tumorigenesis through PI3k/Akt signaling). Additionally, we found stark upregulation of the immunophillin FKPBP1A, which is involved in mTOR activation. We also noted upregulation of ubiquitin-associated gene UBASH3B, which inhibits endocytosis in EGFR and has been described in breast cancer but not CCA. From our investigation of immune checkpoint inhibitors, we found upregulation of classically described inhibitors such as CTLA4, TIGIT, and BTLA. In addition, we found upregulation of SIGLEC7, which has been recently shown to suppress immune function by binding to terminal sialic acid on glycans on the surface of immune cells. Conclusions: Our analysis highlights the possible role of ERBB2 and several extracellular genes in the pathogenesis of CCA. We also identify the role of genes not previously described in CCA such as FKBP1A and UBASH3B. Lastly, our results promote the promise of immunotherapy in CCA treatment.
The world-wide incidence of biliary tract cancer (BTC).
Authors: Wang Huifen , Sun Ping , Baria Katherine 
Published: February 2020

585 Background: Existing epidemiologic research for BTC is limited to certain subtypes, eg gallbladder cancer (GBC), or combines BTC with liver cancer, and only reports regional statistics. Main sources for global BTC epidemiology (particularly anatomic sites) are literature reviews, which can be subject to limitations like inconsistent classification of subtypes, and varying standard population adjustment and comparison timeframes. Given the increasing incidence of BTC, it is critical to monitor global epidemiology to provide insight to public health management and clinical program development. Methods: We evaluated BTC incidence in 15 countries using the Cancer Incidence in Five Continents database Volume XI (CI5 XI) from the International Agency for Research on Cancer. Most CI5 XI registries cover data from 2008-12 with some variations. Incidence was examined by country, region, and anatomic site (extrahepatic cholangiocarcinoma, ECC; intrahepatic cholangiocarcinoma, ICC; GBC; ampulla of Vater cancer, AVC; and unspecified BTCs). Incidence was adjusted to standard world population and reported as age-standardized rate (ASR; per 100,000 person-years) with standard error (SE). Results: The highest incidence of total BTC was in South Korea (SK; ASR = 3.00, SE = 0.02) and lowest in the UK (ASR = 0.66, SE = 0.01). Overall, BTC incidence was higher in Asian countries than Western, and in Asian-Americans than the general US population (ASR = 1.00, SE = 0.02 and 0.77, SE > 0.01, respectively). In Thailand, BTC incidence was higher in the North than South (ASR = 1.93, SE = 0.05 and 1.05, SE = 0.03, respectively). GBC and ECC are the top common subtypes in most countries reported. SK had the highest incidence of all subtypes, with ASR > 2 in GBC, ECC, and ICC. Outside of SK, GBC and ECC were most common in Japan (ASR = 1.93, SE = 0.02 and 2.66, SE = 0.03, respectively); ICC was most common in Thailand (ASR = 1.73, SE = 0.05) and high in France (ASR = 1.01, SE = 0.03). Conclusions: These registry data support past reports of higher BTC incidence in Asian vs Western countries as well as regional variation within countries. Data also suggests that high BTC rates in Asian populations may not be entirely geographical as Asian-Americans suffer a higher BTC incidence than the overall US population.
Increased frequency of PD-1+CD57+Siglec-7- dysfunctional NK cells in patients with nonalcoholic fatty liver disease.
Authors: Sakamoto Yuzuru , Yoshio Sachiyo , Nagatsu Akihisa , Asahi Yoh , Shimada Shingo , Orimo Tatsuya , Kamachi Hirofumi , Kamiyama Toshiya , Kanto Tatsuya , Taketomi Akinobu 
Published: February 2020

589 Background: The proportion of non-alcoholic fatty liver disease (NAFLD) has been increasing as a cause of hepatocellular carcinoma (HCC) worldwide. Natural killer (NK) cells are involved in the first line of immune defense against cancer. NK cell function is regulated by activating and inhibitory NK cell receptors. However, the role of NK cells in the pathogenesis of NAFLD and NAFLD-HCC is still largely unknown. In this study, we aimed to clarify the phenotypic and functional features of NK cells in NAFLD and NAFLD-HCC patients. Methods: We performed mass cytometry (CyTOF) and flow cytometry analysis of NK cells in 33 NAFLD patients (22 chronic hepatitis (CH), 8 liver cirrhosis (LC), 3 with HCC (HCC)) and 9 healthy donors (HDs). We compared surface markers on NK cells in cancerous and non-cancerous intrahepatic lymphocytes (IHLs). We also measured NK cell function in the presence of IL-12 and IL-18. Results: The frequency of NK cells was lower in NAFLD patients compared to HDs. PD-1, CD57, ILT2 were highly expressed, and Siglec-7, NKp30, NKp46 were downregulated on NK cells from NAFLD patients, compared with those of HDs. In NAFLD patients, Siglec-7 levels on NK cells were negatively correlated with PD-1 and CD57, and positively correlated with NKp30 and NKp46. The other inhibitory markers (NKG2A, KIR3DL1 and KIRDL2/L3), activating markers (CD69 and NKG2D) and checkpoint markers (Tim-3 and TIGIT) were comparable between NAFLD patients and HDs. PD-1 and CD57 expression levels on NK cells were also significantly upregulated in NAFLD-HCC patients than those in HDs. CD57 was rarely expressed on NK cells in non-cancerous IHLs, on the other hand, highly expressed in cancerous IHLs. The IFNγ production and CD107a expression on NK cells were also decreased in NAFLD patients. PD-1+CD57+Siglec-7− NK cells were observed in NAFLD patients, rarely in HDs. PD-1+CD57+Siglec-7− NK cells were functionally impaired compared to other NK subsets. Conclusions: In patients with NAFLD, NK cells are reduced and functionally impaired, the reason of which may be the increased proportion of dysfunctional PD-1+CD57+Siglec-7− NK subset, and dysfunctional NK cells might be related to impairment of surveillance for HCC.
First results for Australasian Gastrointestinal Trials Group (AGITG) control net study: Phase II study of 177Lu-octreotate peptide receptor radionuclide therapy (LuTate PRRT) +/- capecitabine, temozolomide (CAPTEM) for midgut neuroendocrine tumors (mNETs).
Authors: Pavlakis Nick , Ransom David Turner , Wyld David , Sjoquist Katrin Marie , Asher Rebecca , Gebski Val , Wilson Kate , Kiberu Andrew Ddembe , Burge Matthew E. , Macdonald William , Roach Paul , Pattison David A , Butler Patrick , Price Timothy Jay , Michael Michael , Lawrence Benjamin James , Bailey Dale L. , Leyden John Charles , Zalcberg John Raymond , Turner J. Harvey 
Published: February 2020

604 Background: Single agent 177Lu-octreotate peptide receptor radionuclide therapy is now a standard of care for progressive mNETS. High activity was seen with LuTate and concurrent CAPTEM chemotherapy in a single arm Phase I/II trial. This study was undertaken to determine the relative activity of adding CAPTEM to LuTate PRRT in patients with mNETs. Methods: Non-comparative randomised open label phase II trial of PRRT +/- CAPTEM in patients with mNETs, with 2:1 randomisation: PRRT /CAPTEM (experimental arm) vs. PRRT (control). PRRT /CAPTEM: 7.8GBq LuTate day(D) 10, 8 weekly (wkly) x 4, with b.i.d. oral CAP 750mg/m2 D1-14 & TEM 75mg/m2 D10-14, 8 wkly x 4, vs. PRRT 8 wkly x 4. Primary endpoint: progression free survival (PFS) at 15 months assuming 15 month PFS of 66.4% in the control arm, aiming for PFS rate > 80%; secondary endpoints: objective tumour response rate (complete or partial response) (OTRR), clinical benefit rate (complete or partial response, stable disease) (CBR), toxicity, and QOL. Results: 47 patients enrolled (Dec 2015 - Feb 2018): 33 PRRT/CAPTEM and 14 PRRT. Two patients withdrew prior to treatment. Patient characteristics were balanced except gender (female 58% vs. 14%). Two patients received 2 prior systemic regimens. After a median follow-up of 32 months, the 15 month PFS was 90% (95% CI: 73-97%) v 92% (95% CI: 57-99%); OTRR 25% vs 15%; and CBR 97% vs 92% for PRRT/CAPTEM v PRRT respectively. For treatment related adverse events 22/32 CAPTEM patients experienced one Grade 3 event (69%) vs 5/13 (38%, PRRT); 4/32 pts experienced one Grade 4 event (13%) v 1/13 (8%) respectively. Only one patient failed to complete therapy due to toxicity (PRRT/CAPTEM). Conclusions: This initial planned analysis demonstrates similarly high 15 month PFS for CAPTEM/PRRT relative to PRRT alone. OTRR is numerically higher but at the cost of greater toxicity. Longer follow up is required to determine if the activity of PRRT/CAPTEM is sufficient to warrant Phase III evaluation. Clinical trial information: ACTRN12615000909527.
ENETS single center of excellence experience with the NETest: A real-world assessment of 565 patients.
Authors: Malczewska Anna , Rydel Mateusz , Robek Amanda , Kusnierz Katarzyna , Les-Zielinska Izabela , Czyzewski Damian , Ziora Dariusz , Pilch-Kowalczyk Joanna , Zajecki Wojciech , Kos-Kudla Beata , Modlin Irvin Mark 
Published: February 2020

605 Background: There is a substantial clinical unmet need for an accurate and effective blood biomarker of NET disease. We therefore evaluated under real-world conditions the clinical utility of the NETest in a NET Center of Excellence and compare it with the biomarker CgA. Methods: Cohorts: GEP-NET (253), BP-NET (49), colon cancer (37), lung cancers (80), benign lung disease (59) and controls (86). GEP-NETs: 164 (65%) had image-detectable disease or were resection-margin (R1) positive. Grading included G1 [106], G2 [49] and G3 [9]. BP-NETs, 28 of 49 (57%) had evidence of disease. Grading was TC [14], AC [14]. Disease status (stable [SD] or progressive [PD]) determined by RECIST 1.1. Blood sampling: NETest ( n= 565) and NETest/CgA matched samples (135). NETest (PCR) (0-100 score) with positive > 20; progressive > 40. CgA (ELISA). All samples deidentified, and measurement/ analyses blinded. Statistics: Mann-Whitney U-test, McNemar’s test and AUROC. Results: GEPNET: NETest was significantly higher (34.4±1.8, p< 0.0001) in NET disease versus no NET disease (10.5±1, p< 0.0001), non-NET disease (18±4, p= 0.0004) or controls (7±0.5, p< 0.0001). Diagnostic sensitivity was 89%, and specificity 94%. NETest levels were not related to grade (G1: 32±2 vs. G2: 38±3, p= 0.09). BPNET: NETest was significantly higher (30±1.3) vs no NET disease (24.1±1.3, p= 0.0049). Diagnostic sensitivity 100%. Levels were elevated vs controls ( p< 0.0001) and non-NET disease (20±2, p= 0.0001). NETest levels were not related to grade (TC 30±2 vs. AC: 30±2, p= NS). Levels were elevated in PD (55±5.5) vs SD (33.6±2, p= 0.0005). AUCs for detecting disease ranged between 0.89 (GEP-NET) to 1.0 (BE-NET) ( p< 0.0001). Matched GEP-NETS (135): NETest was significantly more accurate for detecting NETS (99%) than CgA (53%, McNemar’s test Chi2= 87, p= 0.0001). sensitivity (99%) and specificity (96%) were better than CgA (37% and 96% respectively). Conclusions: The NETest is an accurate diagnostic test for both GEP- and BP-NEN. It defines clinical status (stable or progressive disease). NETest is significantly more accurate than CgA. The multianalyte genomic blood assessment of NET disease provided clinical information of utility in management.
Time from first symptoms to diagnosis in GEP-NET patients: Results from a large German tertiary referral center.
Authors: Koca Esra , Koch Christine , Husmann Gabriele , Bojunga Jörg 
Published: February 2020

610 Background: Patients with neuroendocrine tumors (NET) often go through a long phase between onset of symptoms and initial diagnosis. Methods: Retrospective analysis of 486 patients with GEP-NET (488 tumors) at tertiary referral center from 1984-2019; inclusion criteria: Patients > 18 years, diagnosis of GEP-NET; descriptive analysis using SPSS; Cox regression, Log rank test. Results: Demographics: Male 54% / 52.9% (all/GEP-NET), median age at first diagnosis 63y/58y (all /GEP-NET). Localizations: small intestine 145/488 (29.7%), pancreas 143/488 (29.3%), CUP 53/488 (10.9%), colon 49/488 (10%), stomach 45/488 (9.2%), rectum 27/488 (5.5%), other digestive organs 11/488 (2.3%), esophagus 5/488 (1%), other 10/488 (2%). Ki67 in 330/488 (67.6%) evaluable patients: < 3%: 155/330; 46.9%; ≥ 3%: 111/330; 33.6%; > 20%: 64/330;19.3%. 128/488 (26.2%) of patients had NET specific symptoms (abdominal pain 77/128; 60.2%, diarrhea 51/128; 39.8%, flush 19/128; 14.8%, carcinoid syndrome 8/128; 6.3% tachycardia 6/128; 4.7%). 122/488 (25%) patients showed other tumor-specific symptoms (weight loss 48/122; 39.3%, stool irregularity 21/122; 17.2%, hypoglycemia 10/122; 8.2%, painless jaundice 8/122; 6.6%). 154/ 488 (32%) of NET were incidental findings (imaging 39.6%, endoscopy 23.4%, surgery for other causes 18.8%, appendectomy 15.6%). 221/279 (initial diagnosis/any time; 79.2%) patients had distant metastases at initial diagnosis (187/221 liver metastases). Time from tumor manifestation to initial diagnosis: pNET 360 ± 116 days, siNET 309 ± 87 days, gastric NET 66 ± 47 days, colonic NET 98 ± 67 days. Time from onset of symptoms to diagnosis in symptomatic patients was significantly longer than in asymptomatic patients (388 ± 86 days vs. 174 ± 58 days, p = 0.001). No significant difference in patients with or without distant metastases (223 ± 78 days vs. 259 ± 57 days, p = 0.355). Conclusions: A large proportion of NET are incidental findings and only about half of all patients are symptomatic at the time of diagnosis. Diagnosis for symptomatic patients takes significantly longer than for asymptomatic, which might be due to mainly unspecific symptoms. Presence of metastases has no influence on time to diagnosis.
Usefulness and applicability of next generation sequencing in neuroendocrine neoplasms.
Authors: Manyanont Sorrapong , Winter Kyle , Trikalinos Nikolaos 
Published: February 2020

626 Background: Neuroendocrine neoplasms (NENs) are rare tumors that can arise anywhere in the body and treatment options are limited due to their rarity. Knowledge of their mutational status might allow for tumor agnostic treatments or aid in enrollment in clinical trials, especially in the metastatic setting. Methods: Eligible NEN patients on an institutional, IRB approved protocol, who had NGS as standard of care and were treated in the past 24 months were included. Tumors were categorized by location and histologic grade. We explored the actual and theoretical eligibility for tumor agnostic treatments and enrollment in clinical trials as available on clinicaltrials.gov. Results: Between August 2017 and July 2019 a total of 107 patients were eligible. Globally 102 clinical trials included patients with NEN and specific mutations.NGS detected one (1%) case of MSI high and one (1) TRK fusion positive tumor, eligible for checkpoint inhibitor and TRK inhibitor therapy respectively. Moreover, NGS identified 16 (15%) cases of MEN1, 1 (1%) of RET, 2 (2%) of NF1 and 3 (2.8%) of MUTYH, 2 (2%) TSC or TSC2, BRCA in 1(1%). These patients were appropriately referred to genetic counseling. About 51.5% of patients would in theory be eligible for an investigational treatment based on mutations and clinical trial availability. Fifty two of 107 patients (48.5%) would not have been eligible for a clinical trial with reasons varying between no mutations (24%), sample failure (8.4%) or nonactionable mutations (15.9%). Conclusions: NGS can point to clinical trial eligibility and guide genetic counseling and should probably be a standard approach in the evaluation of new metastatic NEN patients.
Out-of-pocket spending (OOPS) and financial toxicity survey for neuroendocrine tumor (NET) patients.
Authors: Chauhan Aman , Agrawal Rohitashva , Edwins Rebecca , Wahmann Maryann , Wahmann Bob , Corum Lauren , Anthony Lowell Brian 
Published: February 2020

632 Background: Incidence and prevalence of neuroendocrine tumors (NETs) are on the rise. However, with the increasing burden of the disease, there is a need to understand financial toxicity associated with NET management. Especially the out of pocket spending or expenses made by patients and family members, which affects the management and treatment adherence. We report results of our prospective online survey based study looking into determinants and the burden of financial toxicity in NET patients. Methods: We collaborated with NCAN (Neuroendocrine Cancer Awareness Network) a national NET patient support group for our prospective online questionnaire-based survey. After IRB approval, NCAN disseminated online link to the survey on their webpage. The survey had twenty-one questions with the goal of at least 200 complete responses. Results: We received 215 responses before we decided to stop the survey for analysis. The average age of the respondents was 58.4 years. 75% of respondents were females with most repsondents of the survey (37%) being graduates. About 41% of respondents had small bowel NET while 27% had pancreas NET as their NET diagnosis. The median income of the respondents was $65000/year. Median oncology visits were reported to be 4 per year. Median co-pay for the NET specialist visit was found to be $30. The median spending on travel for the physician`s appointment was $250 per visit to see NET specialists. Median monthly insurance premium was $300. Study participants reported spending $75 out of pocket on NET related care every month on top of insurance premiums. More than half of the respondents were on Somatostatin analogues only as their main treatment. About 21% mentioned that they were not able to get required treatment due to cost related issues. Conclusions: The preliminary analysis of the survey gave us an insight into financial toxicity related to NET management. Although most NETs are indolent, the chronic nature of disease and associated, symptom management is often time and resource-intensive. Many patients mentioned having issues with the coverage of insurance and having to travel a long distance to see a NET specialist, which demonstrate a lack of access to NET specialists.
Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of gastrointestinal (GI) tract: A single institution experience.
Authors: Amin Manik A. , Trikalinos Nikolaos 
Published: February 2020

633 Background: MiNENs are heterogeneous group of rare tumors and represent less than 1% of all GI malignancies. These are pathologically classifiable according to neuroendocrine component into low grade, intermediate grade and high grade MiNENs but and managed based upon non-neuroendocrine component rather than true NENs. They have poor prognosis and less is known about treatment options. Methods: We identified 34 cases of MiNENs from 1/1/2000 to 1/1/2018 from Siteman Cancer Registry Database at Siteman Cancer Center, Washington University, St. Louis. Treatment and follow up information was obtained from medical charts of patients. Results: Of 34 identified cases of MiNENs, our database showed equal distribution of MiNENs in male and female patients (N = 17 each). Site of origin included appendix (N = 14), colon (N = 10), esophageal (N = 2), stomach (N = 3), rectum (N = 3), small intestine (N = 1) and ampulla of Vater (N = 1) locations. Histology was high grade (N = 22), intermediate grade (N = 8), low grade (N = 3) and unknown (1). Twenty nine (85%) underwent surgical resection with curative intent and 13 (40%) patients were disease free at five years of follow up. Disease was localized in 15 patients (44%) and distant metastasis were reported in 13 patients (40%). Ten out of 15 patient with localized disease were disease free with combined modality therapy of surgery and chemotherapy. Most common chemotherapy regimen used in the metastatic setting was FOLFOX (11), 5FU/capecitabine (3), and carboplatin plus etoposide (5). Next generation sequencing analysis was available on limited patients which showed MMR proficient (3), MMR deficiency (1), BRAF V600E mutation (1) and KRAS wild type (1). Conclusions: MiNENs of GI tract are rare and aggressive tumors and represent a distinct entity. Surgical resection whenever possible offers curative option. Our database of GI MiNENs showed efficacy with commonly used GI chemotherapy regimens. Patients with low grade tumor histology had better survival as compared to moderately and poorly differentiated tumors. Genomic testing through NGS would be recommended for personalized treatment decisions given poor prognosis in these patients.
Metachronous colorectal pathology among survivors of young-onset colorectal cancer: Implications for postresection colonoscopic surveillance.
Authors: Peacock Oliver , Yang Yun , Thirumurthi Selvi , Nguyen Sa Thi Nguyen , Lum Phillip , Rodriguez-Bigas Miguel A. , Bednarski Brian K. , Messick Craig , Skibber John Michael , Chang George J. , Vilar Sanchez Eduardo , You Y. Nancy 
Published: February 2020

64 Background: Patients with sporadic young-onset colorectal cancer (CRC) are postulated to have a more biologically active colorectum prone to malignant transformation earlier in life. It is unknown whether there is elevated risk for metachronous colorectal pathology after the index cancer. We aimed to define this risk, to inform their post-resection endoscopic surveillance. Methods: Consecutive CRC patients (aged 18-50, n = 728) were prospectively followed after surgical resection between 2009 and 2017. Patients presenting with hereditary CRC, recurrent disease, or without endoscopy follow-up were excluded. All endoscopy records were subjected to natural language processing and further reviewed. Metachronous colorectal pathology of interest included: high-risk adenoma (≥1cm in size, > 3 in number, or tubulovillious/high-grade dysplasia histology), second CRC, and endoscopically detectable local recurrence. Results: During a 48-month (median) follow-up, 457 patients underwent 1,192 person-years of colonoscopic follow-up. The median age at CRC diagnosis was 44 years. Disease arose from the proximal colon in 9.4%, distal colon in 23.0% and rectum in 67.6%, and was stages I/II in 191 (41.8%), III in 185 (40.4%), and IV in 81 (17.7%). The majority (95.8%) underwent segmental resection, while the remainder had extended resections for synchronous pathology not amendable to preoperative endoscopic clearance. The overall incidence of metachronous pathology was 32 per 1000 person-years: 31 patients developed high-risk adenomas (6.8%), 1 had a second CRC (0.2%), and 7 had luminal recurrences (1.5%). The median time to metachronous pathology was 13.9 (IQR: 11.8-33.1) months, with 21 (53.8%) detected between 12 and 48 months post-resection. Conclusions: For young-onset CRC survivors, the incidence of metachronous colorectal pathology was 32 per 1000 person-years of follow-up. Given the time pattern of detection, adding an interval colonoscopy between the current recommended post-resection surveillance at 12 and 48 months may be beneficial. [Table: see text]