bluuebunny/crossref_metadata_2025 huggingface dataset:
A prognostic model to predict survival after hepatic arterial infusion chemotherapy for hepatocellular carcinoma with portal vein invasion.
Authors: He Jian , Mo Zhiqiang , Mai Qicong , Shi Feng , Chen Xiaoming
Published: June 2021

e16157

Background: We aimed to establish a prognostic model to predict survival for the patient with advanced hepatocellular carcinoma (HCC) after the treatment with hepatic arterial infusion chemotherapy (HAIC) of oxaliplatin plus fluorouracil/leucovorin. Methods: 164 patients diagnosed of HCC with portal vein invasion and treated with HAIC of oxaliplatin plus fluorouracil/leucovorin between 1/2018 and 1/2021 at the Guangdong provincial people’s hospital and were randomly divided to training(N=82) and validation(N=82) cohort. We investigated the impact of baseline characteristics and tumour load on overall survival (OS, log-rank test) and developed a prognostic model in the training cohort by using a stepwise Cox regression model and validated in validation cohort. Results: The final presentation of the model was “NCV-score= 0.974* serum neutrophil/lymphocyte ratio+ 1.239* Child-pugh stage+ 0.661* portal Vein invasion grade”, which further selected the first quartile of the linear predictor, namely 5.7, as cut-off values. The NCV-score differentiated two risk categories(≥5.7, ＜5.7) with distinct prognosis (median OS: 6.6 vs. 11.2 months, p <0.001). The prognostic model was used to develop nomogram for predicting individual survival of HAIC candidates and was validated in validation cohort to identify patients who obtain satisfying survival benefit for HAIC. Conclusions: The NCV-score identifies advanced HCC patients who obtain satisfying survival benefit for HAIC of oxaliplatin plus fluorouracil/leucovorin and provides individual survival predicting.[Table: see text]
Comparative mutational analysis of biliary tract cancers.
Authors: Qiu Zhiquan , Ji Jun , Xu Yu , Zhu Yan , Gao Chun-Fang , Wang Guoqiang , Li Chengcheng , Cai Shangli , Liu Hao , Li Bin , Jiang Xiaoqing
Published: June 2021

e16164

Background: Traditional classifications of tumors have utilized tissue of origin and histologic types. These categories have been refined with comprehensive molecular characterizations across large numbers of tumors. We hereby aimed to identify the similarities and differences of mutational profiles among the cancers along biliary tract, and investigate their prognostic effects. Methods: Mutation and clinical data from 99 BTC patients who received surgical resection (gallbladder cancer [GBC], n=42; cholangiocarcinoma [CCA], n=57) were analyzed. Capture-based targeted deep sequencing was performed using a 520-gene panel, spanning 1.64 Mb of the human genome (Burning Rock Biotech). Results: The mutational frequencies of TP53, BRCA1/2, ATM, and PI3K, WNT, HRR, and cell cycle pathway, gradually decreased with the order of the anatomical position (GBC, dCCA, pCCA, iCCA-large duct, and iCCA-small duct), while the changing trend of BRAF mutational frequency was the opposite (Table). In addition, CCND1/E1 and APC mutations were enriched in metastatic BTCs. As for prognostic effect, mutations of BRAF, TGFBR1/2, ARID1A, and MMR pathway were associated with shorter OS, and these association remained significant after adjustment for tissue of origin, TNM stage, histological grade, surgical margin, and serum CEA level. Conclusions: The differentially mutated genes among the cancers along biliary tract may indicate the potential mechanism of tumor development in different anatomic locations. Deeper understanding of the prognosis-related mutational events might change the postoperative management of BTC by enabling risk stratification, ACT monitoring, and early relapse detection. Mutational rate of the differentially mutated genes among the cancers along biliary tract.[Table: see text]
Characteristics, management and outcomes of patients with hepatocarcinoma in a low-income country.
Authors: Dominguez Jennifer , Macario Bonnie , Ramirez Rixci , Castro Mario Daniel
Published: June 2021

e16166

Background: Worldwide, every year, there are nearly 905,000 patients diagnosed with liver cancer; it is the sixth most common malignancy and the third most lethal malignancy. Almost three quarters of new patients live in areas with low and medium-income country. Guatemala has the highest mortality and incidence of liver cancer. Objectives: Describe the clinical characteristics, main risk factors, treatment and outcomes of patients with hepatocarcinoma (HCC) in Guatemala. Methods: A retrospective review was performed among patients with HCC from January 2002 to December 2019 in the Instituto Guatemalteco de Seguridad Social (IGSS). Kaplan Meier curves, Cox regression and log-rank test were used to calculate overall survival (OS) and mortality. Results: 140 patients with HCC were analyzed, 114 women and 26 men with a median age of 60 years (20 - 99), 102 patients (73%) have history of excessive alcohol consumption and 11 (8%) has history of chronic hepatitis B or C virus infection. All of the patients have liver cirrhosis, Child-Pugh A 100 patients (71%), B 34 (24%) and C 6 (5%). 10 patients (7%) have HCC BCLC A, 0 (0%) BCLC B, 121 (81%) BCLC C and 9 (6%) BCLC D. All patients with HCC BCLC A received surgical treatment with a median OS of 123 months (95% CI 89 - 156 p < 0.001). 122 patients (89%) received target therapy with Sorafenib with a median OS of 17 months (95% CI 12 - 21 p < 0.001) and 8 patients (6%) underwent to chemoembolization with a median OS of 32 months (95% CI 12 - 52 p < 0.001). At this time, 111 patients (79%) died from the disease, 11 (8%) are alive with the disease and 8 (6%) are alive without disease. Conclusions: The most frequent risk factor for HCC is the excessive alcohol consumption, survival of patients with HCC are associated with treatment at the beginning of the disease.
Prognostic value of dickkopf-1 and ß-catenin expression according to the antitumor immunity of CD8-positive tumor-infiltrating lymphocytes in biliary tract cancer.
Authors: Kim Seoree , Ko Yoon Ho , Won Hye Sung , Yang Ji Hyun , Sun Der Sheng , Yim Kwangil , Hong Soon Auck , Chun Sang Hoon , Kim Kee-Hwan Michael
Published: June 2021

e16172

Background: Despite recent advancements in the understanding of the molecular biology of biliary tract cancer (BTC), target therapy and immunotherapy have demonstrated only limited efficacy, with cytotoxic systemic therapy still being the most effective treatment in BTC, except for surgery. Thus, this study aimed to analyze the role of DKK1 or β-catenin as a prognostic factor in BTC and determine the clinical association of ß-catenin and DKK1 with CD8+ tumor-infiltrating lymphocyte (TIL). Methods: We used data in The Cancer Genome Atlas (TCGA) Research Network and the clinicopathological data of 145 patients with BTC who had undergone primary radical resection between 2006 and 2016. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections, and whole tissue sections of representative tumor samples were used for antigen retrieval. Results: CD8+TIL expression was a significant predictor of favorable overall survival (OS) and recurrence-free survival (RFS) (median OS, 34.9months in TIL-high, 16.7months in TIL-low, P < 0.0001 respectively; median RFS, 27.1months in TIL-high, 10months in TIL-low, P < 0.0001 respectively). Positive ß-catenin expression and high DKK1 expression was also associated with a shorter OS (median OS, 23.95months in positive ß-catenin, 26.1months in negative ß-catenin, P = 0.1009 respectively; median OS, 19.4months in high DKK1, 31.65months in Low DKK1, P = 0.0093 respectively), but not RFS (p = 0.1466, at ß-catenin respectively; p = 0.2924, in DKK1 respectively). In the CD8+TIL-high BTC group, the tumor expression of β-catenin and DKK1 had a significant negative impact on either OS or RFS (p = 0.0146 and p = 0.0112, at ß-catenin respectively; p = 0.0950 and p = 0.3904, in DKK1 respectively). However, in the TIL-low BTC group, there were no differences in OS or RFS according to ß-catenin and DKK1 expression (p = 0.5108 and p = 0.8431, at ß-catenin respectively; p = 0.1127 and p = 0.1095, in DKK1 respectively). Cox regression multivariate analysis demonstrated that CD8+ TIL (hazard ratio [HR], 0.490; 95% confidence interval (CI), 0.303-0.791; p = 0.004) and β-catenin (HR, 1.652; 95% CI, 1.035-2.639; p = 0.036) retained significant association with OS after adjustment for all variables. Conclusions: Among patients with resected BTC, β-catenin and DKK1 protein levels are associated with poor clinical outcomes, whereas high CD8+ TIL levels are associated with good clinical outcomes. This confirms the differential clinical role of Wnt/β-catenin and DKK1 proteins according to TIL expression in BTC.
Cabozantinib in advanced HCC patients previously treated with immune checkpoint inhibitors: A territory-wide cohort study.
Authors: Wong Jeffrey Sum Lung , Dong Yawen , Tang Vikki , Leung Thomas Wai-Tong , Yeung Cynthia SY , Tai Anna , Law Ada , Shum Tracy Cy , Kwok Gin Wai , Li Bryan , Leung Roland Ching-Yu , Chiu Joanne Wing Yan , Ma Ka Wing , She Wong-Hoi , Tsang Wing Yan Josephine , Cheung Tan To , Yau Thomas
Published: June 2021

e16179

Background: Cabozantinib is licensed for use as second- or third-line treatment for sorafenib-exposed advanced hepatocellular carcinoma (aHCC) based on the phase III CELESTIAL trial. However, its use in the post-immune checkpoint inhibitors (ICI) setting has yet to be described. We evaluated the pattern of use, efficacy, survival and tolerability of cabozantinib in aHCC patients with previous treatment by ICIs. Methods: We did a multi-centre, territory-wide study analysing aHCC patients who received cabozantinib after prior ICIs. Objective response rate (ORR), disease control rate (DCR), time-to-progression (TTP), overall survival (OS) and treatment related adverse events (TRAEs) were assessed. Results: Thirty-one patients were included. The median age was 58.0 (range 41-85) and 77.4% had Child-Pugh A cirrhosis. 51.6% of patients received single agent cabozantinib and 48.4% received cabozantinib in combination with ICIs. ≥80% of patients received cabozantinib beyond the second-line and 93.5% of patients had prior TKIs. All patients received prior anti-PD-1 and 61.3% had prior anti-CTLA-4. The median follow-up was 15.2 months. For single agent cabozantinib patients, the ORR was 6.3%, DCR was 31.3% and median TTP was 3.5 months (95% C.I. 1.2-5.8). For cabozantinib-ICI combination patients, the ORR was 6.7%, DCR was 26.7% and median TTP was 2.3 months (95% C.I. 1.4-3.1). The overall median OS was 8.9 months (95% C.I. 5.7-11.9). Single agent cabozantinib patients had a significantly shorter OS compared to cabozantinib-ICI combination patients (8.3 months (95% C.I. 1.3-15.2) vs. 15.1 months (95% C.I. 11.1-19.2), p = 0.047). There was no significant difference in OS among patients with primary resistance to prior ICI regimes compared to those with acquired resistance (primary resistance 8.28 months (95% C.I. 5.04-11.5) vs. acquired resistance 8.90 months (95% C.I. 3.49-14.3), p = 0.472). Overall, 67.7% and 6.5% of patients experienced TRAEs of all grade and grade ≥3 respectively. The most common TRAE was hand-foot syndrome. 62.5% of single agent cabozantinib patients had any grade TRAE and no such patients had grade ≥3 TRAE. Conclusions: Cabozantinib had good anti-tumour activity and survival outcomes with acceptable toxicity in aHCC patients with previous treatment by ICIs.
Comprehensive genomic profiling analysis of HBV-infected hepatocellular carcinoma patients.
Authors: Liu Xiaoliang , Wang Xiaohui , Yao Jianfei , Chen Shifu , Li Yu
Published: June 2021

e16180

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of tumor-related death worldwide which is dominantly caused by chronic infection of hepatitis B virus (HBV) and hepatitis C virus (HCV). Recent studies have shown that immune checkpoint inhibitors may enter the first-line treatment of HCC. Comprehensive investigation of the genetic alterations and their correlation with microsatellite instability (MSI) and PD-L1 expression in HBV-infected HCC is helpful to determine the therapy strategy for patients. Methods: The genomic information of HCC patients was obtained from HapLab database. HaploX 605- gene panel was performed to analyze the genomic data of patients. PD-L1 expression was detected by immunochemistry. Results: A total of 349 mutations were found by analyzing the genomic profiles of 115 HBV-infected HCC patients. The frequently mutated genes included TP53 (63%), TERT (27%), CTNNB1 (16%), CSMD3 (15%), LRP1B (14%), AXIN1 (13%), CDKN2A (13%), KIT (13%), MDM4 (12%) and CCND1 (12%). Besides, 279 mutations were identified by analyzing the genomic profiles of 82 HCC patients without HBV-infection. Mutation frequencies for several genes were relatively higher in the HBV-positive patients than that in HBV-negative HCC patients, including TP53 (63% versus 39%), CCND1 (12% versus 5%), RB1(12% versus 4%) and BRCA2 (11% versus 4%). The proportion of MSI-H/L in HBV-infection patients were higher than that in HBV-negative ones (7.83% versus 4.88%). Notably, the proportion of high PD-L1 expression in patients with HBV-infection was 40.57% (43/106), while it was 28.95% (22/76) in patients without HBV-infection. Conclusions: These results highlighted a potential impact of viral infection on the mutational signatures in hepatocarcinogenesis. The PD-L1 expression status and MSI were closely related to HBV-infected HCC. These results may contribute to understanding the mechanism of HBV-infected HCC and the selection of therapy for relative patients.
Nivolumab/pembrolizumab in Child-Pugh grade B/C patients with advanced HCC.
Authors: Wong Jeffrey Sum Lung , Kwok Gin Wai , Tang Vikki , Li Bryan , Leung Roland Ching-Yu , Chiu Joanne Wing Yan , Ma Ka Wing , She Wong-Hoi , Tsang Wing Yan Josephine , Cheung Tan To , Yau Thomas
Published: June 2021

e16184

Background: Hepatic derangement commonly accompanies advanced HCC (aHCC) and limits the use of systemic therapies. We aimed to evaluate the use of single agent anti-PD-1 nivolumab or pembrolizumab in Child-Pugh (CP) grade B or C patients with aHCC. Methods: Consecutive aHCC patients with CP grade B (CPB) or C (CPC) liver function who received single agent nivolumab or pembrolizumab were analysed. Objective response rate (ORR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Between May 2015 and June 2020, 61 patients were included. The median age was 60 (range 28-82). 81% and 4.8% had hepatitis-B and hepatitis-C related HCCs respectively. 72.1% (n = 44) were of CPB and 27.9% (n = 17) were of CPC. Amongst CPB patients, 19 (31.1% of all patients) had CP score 7 (CP7) and 25 (41.0% of all patients) had CP score 8 or 9. The median follow-up was 2.3 months. The ORR of CPB and CPC patients were 6.8% and 0% respectively (p = 0.553). The TTP of CPB and CPC patients were 2.1 months (95% C.I. 1.4-2.8) and 1.4 months (95% C.I. 0.6-2.1) respectively (p = 0.204). CPB patients had significantly better OS than CPC patients (3.1 months (95% C.I. 1.4-4.7), vs. 1.7 months (95% C.I. 1.0-2.4), p = 0.041). Compared to CP score ≥8 (CP≥8) patients, CP7 patients had significantly better OS (median OS CP7 6.7 months (95% C.I. 4.0-9.3), vs. CP≥8 1.8 months (1.2-2.4), p = 0.002). Patients with diuretic-refractory ascites had significantly worse OS compared to those without (1.7 months (95% C.I. 1.0-2.5) vs. 3.7 months (95% C.I. 0.1-7.3), p = 0.004). Portal vein (PV) thrombosis was also significantly associated with inferior survival, with median OS of patients with any PV thrombosis being 1.8 months (95% C.I. 1.0-2.5), compared to 5.3 months (95% C.I. 2.4-8.1) of those without (p = 0.004). The median number of doses given was 3 (range 1-34). Median treatment duration was 5.0 weeks (range 0-77). Overall, 25.4% of patients experienced TRAEs and 4.8% experienced grade ≥3 TRAEs. The most common TRAEs were skin-related (13.1%) and constitutional symptoms (6.6%). Conclusions: Nivolumab/pembrolizumab had acceptable safety in CPB/C patients with aHCC. CP7, absence of diuretic-refractory ascites and lack of PV thrombosis were associated with better survival.
Metronomic oral cyclophosphamide & low dose nivolumab for advanced hepatocellular carcinoma (HCC).
Authors: Chen Jo-Pai , Kao Tsui-Mai , Hsueh Fu-Jen , Lu Wei-Chen , Ma Wei-li , Wu Hsu , Chiang Keng-Man , Chen Hsing-wu , Kuo Sung-Hsin
Published: June 2021

e16190

Background: Metronomic oral cyclophosphamide would suppress Treg and low dose nivolumab(0.1 mg/kg biweekly) might be still effective for immunogenic cancers. We try to introduce this regimen for immunogenic advanced HCC. Methods: From 2016 to 2021, 65 advanced HCC patients receiving ICIs in Yun-lin Branch of National Taiwan University Hospital were reviewed. Results: In these patients, 46 failed sorafenib; 35 (54%) HBV infected, 23 (35%) HCV infected, 7 (11%) alcoholism. The objective response rate was 48% (31/65) and disease control rate was 74% (48/65), with favorable toxicity profiles. In 43 nivolumab users, dosage from 0.3 to 3 mg/kg biweekly with 58% in 3 mg/kg; 15 receiving second-line low dose biweekly 20 mg nivolumab with oral metronomic cyclophosphamide 50 mg per day produced response rate 53% (8/15) & clinical benefit 73% (11/15). For this special regimen, in 10 HCV-infected patients, ORR was 70% & DCR was 90%; in 4 HBV-infected patients, ORR was 25%. In 10 with lung/LN metas only, ORR was 80%. 7 receiving bevacizumab, nivolumab, & cisplatin had 57% (4/7) response rate. In 7 atezolizumab users, combined with low dose bevacizumab (100 to 200 mg per 3 weeks) for first-line use, 6 were responders (86%). 19 front-line immunotherapy users had 68% (13/19) response rate (5 bevacizumab & atezolizumab; 4 lenvatinib & pembrolizumab; 2 bevacizumab, cisplatin, & nivolumab; 2 nivolumab with SBRT on MPV); 47 later line users had 38% (18/47) response rate (some receiving nivolumab combined with CT; bevacizumab with nivolumab & CT; sorafenib or regorafenib). 13 patients had MPV involvement (7 responders to immunotherapy-54%): 3 patients, using nivolumab after sorafenib failure, all suffered from rapid progression; 3 patients, receiving front-line SBRT over portal vein tumors and nivolumab, had response rate in 67% (2/3) and 100% clinical benefit; 2 responders to front-line lenvatinib & pembrolizumab (ORR 2/2-100%); 1 responder to front-line bevacizumab & atezolizumab (ORR 1/2-100%; another patient responded to second-line lenvatinb & pembrolizumab); 1 responder to front-line bevacizumab, cisplatin, & nivolumab. Conclusions: In our institution, ICIs combined with metronomic chemotherapy, low dose bevacizumab, multi-targeted VEGFR2 TKI, CT(platinum, anthracycline, and 5-fluorouracil), & SBRT could produce favorable response rates(first line 68%; later line 38%)/clinical benefits and toxicity profiles in advanced HCCs, even in heavily-treated patients, MPV involvement, and fulminant spreading status. Metronomic oral cyclophosphamide & low dose nivolumab, all failing sorafenib, seemed feasible and effective with lower toxicity/cost. Patients with HCV infection or lung/lymph nodes metastasis only seemed to respond better. Immune-modulation mechanisms of metronomic oral cyclophosphamide, nivolumab biologically-effective dose, clinical trial design, & biomarkers research are warranted.
Methylation status of eight tumor suppressors in neuroendocrine pancreatic tumors.
Authors: Kit Oleg I. , Trifanov Vladimir S. , Timoshkina Natalya N. , Gvaldin Dmitry Yu. , Mesheryakova Milana Yu. , Kolesnikov Evgeniy N. , Kozhushko Mikhail A. , Averkin Mikhail A. , Mezentsev Stanislav S. , Gabrichidze Petr N.
Published: June 2021

e16197

Background: Aberrant DNA methylation is a characteristic feature of cancer, affecting gene expression and tumor phenotype. In this study, we quantified the methylation of promoters of eight tumor suppressor genes in pancreatic neuroendocrine tumors (Pan-NET). Methods: The method of pyrosequencing was used to quantity level (Met,%) of methylation of gene promoters - tumor suppressors AHRR, APC1A, DAPK, MGMT, MLH1, P16, RASSF1A, RUNX3 in tumor samples from 55 patients with pancreatic NET (G1-G3) and in the blood of 10 healthy donors. Met for each sample was calculated as the median methylation of CpG sites in triplicate. Results: Hypermethylation was observed for AHRR (75%), APC1A (25%), RASSF1A (30%). In contrast, DAPK, MGMT, MLH1, P16, RUNX3 had low methylation levels ( < 20%). The median of methylation in the blood of healthy donors for AHRR was 91% (76-98); for all other loci it did not exceed 6%. A high incidence of methylation in excess of blood levels in healthy donors was identified for RASSF1A (0.96); AHRR (0.75); MGMT (0.65); RUNX3 (0.41), APC1A (0.25). For tumor suppressor P16, only one case of increased methylation was recorded (Met = 15%), despite the fact that this phenomenon is not uncommon for NETs of other localizations. In 66% of pancreatic NET cases, hypermethylation of more than two promoters of tumor suppressor genes was noted. An association tendency was found between the presence of MEN1 mutations and the RASSF1A methylation level (p = 0.08). Correlation analysis revealed a significant level of negative association between changes in methylation of MLH1 and AHRR (p < 0.01); for the latter, the prognostic value of a high methylation status and a better prognosis for many malignant neoplasms were described. Conclusions: In the present study, significant methylation of the promoters of the APC1A, DAPK, MGMT, RASSF1A, and RUNX3 genes in well-differentiated pancreatic NETs was identified with a high frequency. At the same time, isolated cases of hypermethylation were noted for the well-known tumor suppressors MLH1 and P16.
Dual immune checkpoint blockade in advanced well-differentiated neuroendocrine tumors, a phase II clinical trial.
Authors: Scott Susan Combs , De Jesus-Acosta Ana , Hu Chen , Levy Benjamin Philip , Anagnostou Valsamo , Brahmer Julie R. , Illei Peter Bela , Jaffee Elizabeth M. , Marrone Kristen , Forde Patrick M. , Hann Christine L.
Published: June 2021

e16201

Background: Limited systemic treatment options are available for progressive well-differentiated neuroendocrine tumors (NET), also called carcinoid tumors. Given emerging evidence for immunotherapy response in high grade NET including small cell lung cancer, we sought to determine the efficacy of combination immunotherapy with ipilimumab and nivolumab in patients with advanced, progressive, well-differentiated NET in an open label phase II clinical trial. Methods: Eligible patients had well-differentiated, nonfunctional NET of lung, pancreas, or GI origin that had progressed within the past 12 months after at least one line of prior therapy. Patients received nivolumab 240 mg every 2 weeks and ipilimumab 1mg/kg every 6 weeks for up to 2 years. Primary endpoint was objective response rate (ORR) by RECIST v1.1. Using a Simon’s 2-stage design, the study planned to accrue up to 56 patients. Based on published response rates to everolimus of 5%, we hypothesized that this regimen would be considered promising if the true ORR is > 15%. Results: Nine patients were enrolled prior to study closure due to funding, including 6 patients with NET of lung origin, 2 pancreatic, and 1 small bowel (Table). Median age was 71 years. All patients had distant metastatic disease at enrollment, with an average of 2 prior lines of therapy. Four of 9 patients achieved the primary endpoint of confirmed objective response, all of whom have ongoing response with a median duration of 15.4 months. Five of 9 patients, including all 4 responders, experienced immune-related toxicity requiring treatment modification or discontinuation. The trial did not accrue the target of 56 patients, however, objective response in 4 of 9 patients (ORR 44.4%, 90% CI: 16.9-74.9%) excluded the response rate target (15%). Conclusions: The impressive ORR of 44% with a median duration of response exceeding 15 months in this small clinical trial warrants further study of combination CTLA-4 and PD-1 inhibition in previously treated well-differentiated NET. Our ongoing immunologic and genomic correlative analysis in responders and non-responders will help inform future study of immunotherapy in this patient population in need of new systemic therapy approaches. Clinical trial information: NCT03420521. [Table: see text]
INTENSIVE: InterNaTional rEgistry oN Sars-cov-2 posItiVe nEuroendocrine neoplasm patients.
Authors: Spada Francesca , Gervaso Lorenzo , La Salvia Anna , Garcia-Carbonero Rocio , Hernando Jorge , Capdevila Jaume , Hofland Johannes , de Herder Wouter , Koumarianou Anna , Rossi Maura , Boselli Sabrina , Tamayo Darina , Bagnardi Vincenzo , Laffi Alice , Rubino Manila , Sonbol Mohamad Bassam , Fazio Nicola , Halfdanarson Thorvardur Ragnar
Published: June 2021

e16205

Background: Data about neuroendocrine neoplasms (NENs) patients with SARS-CoV-2 are scanty and specific indications for clinical practice are missing. Our aim is to create an international registry about NENs patients affected by SARS-CoV-2 positivity to give a worldwide representation of the situation. Methods: This is an observational retrospective/prospective multicenter survey based on a direct email invitation. All types of NEN are eligible except SCLC and MiNEN. Patients fulfilling the inclusion criteria from March 1st, 2020 up to the end pf pandemic will be recruited. Electronic CRFs are filled out using the REDCap database. Local Institutional Review Board approval is required before data entry. Results: Eighty-one centers, 24 in and 57 outside Italy, representing 39 countries and 5 continents, were contacted. Fourteen centers did not respond and 15 declined the invitation. Among the remaining 52, 6 centers are currently recruiting and 8 are active but not recruiting yet. As of the current abstract submission deadline, 67 patients have been included, mostly GEP-NET (75%), non-functioning (86%), metastatic (85%) and on active treatment [47% somatostatin analogs (SSAs), 10% everolimus, 12% tirosin-kinase inhibitors (TKIs), 10% peptide receptor radionuclide therapy (PRRT), 15% chemotherapy]. Median age at NEN diagnosis was 57 years whilst the median age at SARS-CoV-2 diagnosis was 62 years. Almost all patients reported COVID-19-related symptoms, more commonly fever (67% of patients), cough (55%) and dyspnea (51%), in 28% of cases exertional and in 22% at rest. More than one third of patients (n, 24) had a pneumonia. The most common therapies for COVID-19 were antibiotics, steroids and hydroxychloroquine. Eleven patients (16%) needed oxygen therapy, three (4%) sub-intensive care and none intensive care. Fifty-six patients (84%) clinically recovered, six (9%) with sequelae, whereas five (7%) died. Among these latter 4 had a NET and 1 a NEC, and no patients have been receiving chemotherapy. With regard to the anti-tumor therapy no change occurred in 66% of patients, temporary interruption in 30%, and definitive discontinuation in 3%, 2% missing. Conclusions: Most of the NEN patients completely recovered from COVID-19, in many cases without any anti-tumor therapy adjustment. No clear correlations were observed with type, primary site and treatment of NEN. The recruitment is ongoing.
Outcomes of pancreatic ductal adenocarcinoma (PDAC) patients treated with neoadjuvant stereotactic body radiation therapy (SBRT) or conventionally fractionated radiation therapy (CFRT).
Authors: Zhu Fan , Wang Haoyu , Ashamalla Hani
Published: June 2021

e16209

Background: Hypothesis: Neoadjuvant SBRT can improve survival when compared to CFRT in PDAC patients who received chemotherapy. Past retrospective studies have shown improved outcomes of definitive SBRT when compared to CFRT without accounting for chemotherapy.1 We aim to study the outcomes of neoadjuvant SBRT vs CFRT accounting for chemotherapy. Methods: The National Cancer Database (NCDB) was queried for cases of PDAC from 2004-2015. Patients who received surgery and chemotherapy were included. Exclusion criteria were prior hormonal therapy or immunotherapy, lack of pathological confirmation or lack of information about chemotherapy. Log-rank test and Cox proportional hazards model were used to compare survival by radiation modalities. Predictors for overall survival (OS) were identified. Propensity score-matched (PSM) analysis balancing for different variables including type of chemotherapy was conducted. Results: Among 1604 patients, 223 (13.9%) had SBRT, and 1381 (86.1%) had CFRT. The median survivals were 30.0 and 26.0 months ( P = 0.010), while the 2-year survival rates were 63.4% and 53.7% for SBRT and CFRT patients, respectively. SBRT tended to be offered to older patients (age≥65: 56.1% vs 47.3%, P = 0.018), healthier patients (CCI=0: 72.2% vs 63.6%, P = 0.016), patients with worse cT staging (cT3 and cT4: 80.7% vs 69.7%, P = 0.008) and patients who got more multi-agent chemotherapy (89.2% vs 50.5%, P < 0.001). In the cohort with positive clinical lymph nodes (cN+), CFRT tended to decrease the pN staging more when compared to SBRT ( P = 0.032) (Table). In multivariate analysis, multi-agent chemotherapy (HR, 0.72; P < 0.001) was associated with better OS. SBRT did not show significantly better OS when compared to CFRT (HR, 0.81; P = 0.13) after accounting for other covariates including chemotherapy. PSM (1:1 match) analysis matched 223 pairs. SBRT did not show significant OS benefit (HR, 0.80; P = 0.17) when compared to CFRT. Conclusions: SBRT may be superior to CFRT in univariate analysis. However, after accounting for multi-agent chemotherapy, there is no significant survival difference between neoadjuvant SBRT and CFRT. Studies with larger sample size are desired. Neoadjuvant CFRT offers more significant nodal down-staging in patients with clinically positive lymph nodes (cN+) when compared to SBRT. Reference: Zhong J, Patel K, Switchenko J, et al. Outcomes for patients with locally advanced pancreatic adenocarcinoma treated with stereotacticbody radiation therapy versus conventionally fractionated radiation. Cancer2017 Sep 15;123(18):3486-3493. pN staging of cN+ cohort[Table: see text]
Immunoregulation related gene of CSMD2 and RNA activity as potential predicter of 2-year survival in pancreatic cancer: A DNA and RNA sequencing analysis.
Authors: Yan Jiafei , Li Si , Xi Wenjing , Chen Dongsheng , Xiao Mingzhe
Published: June 2021

e16212

Background: The 5-year survival rate of pancreatic cancer remains as low as 3%-15%. One of the key approaches to enrich current treatment options or improve effectiveness is new biomarker probing. We conducted DNA and RNA sequencing analysis to reveal potential biomarkers related to overall survival. Methods: Whole-exome sequencing, RNA sequencing and clinical data for 209 patients with pancreatic cancer were downloaded from TCGA. Clinical factors and mutational landscape (insertion/ deletion/ single nucleotide variant) were compared between group of OS2+ (OS longer than 2 years) and OS2- (OS longer than 2 years) with T test and Chi-square Test. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted with RNA sequencing data to clarify the functional differences between the two groups. Results: The rates of OS2+ for patients in stage of I/II/III/IV was 43% (9/21), 17.8% (27/152), 0% (0/4), 0% (0/5), respectively. 152 patients in stage II were included for further analysis. No difference of sex and age were found between group of OS2+ and OS2-. Tumor mutation burden was comparable between the two groups. Mutation landscape showed the two groups had the accordance of 50% in top 10 genes. Mutations of CSMD2(18.5% vs. 5.0% , P = 0.026), CMYA5(14.8% vs, 2.5% , P = 0.019) and KCNA6(14.8% vs, 3.3%, P = 0.034) were more frequent in OS2+ group. CSMD2 is thought to be involved in the control of complement cascade of the immune system, and its low expression was significantly associated with differentiation, lymphatic invasion, and tumor size in colorectal cancer. CMYA5 was predicted as novel oncogene in breast cancer with the tool of Moonlight, it may also participate tumor activity in pancreatic cancer. The role of KCNA6 in cancer cell activity is barely known yet. Evaluation of differentially expressed genes between the two groups detected difference in leukocyte differentiation and T cell activation (GO analysis) and MAPK signal pathway (KEGG panalysis), these immunoregulation and MAPK pathways may play critical roles in tumor development and progression and affect the prognosis of pancreatic cancer. Conclusions: Pancreatic cancer with 2-year survival presented significant different DNA and RNA alterations, in which CSMD2 and pathway of leukocyte differentiation and T cell activation are closely associated with immunoregulation. These might provide guidance for prognose management and development of new therapeutic targets. Further mechanistic insights and prospective validation studies are warranted.
Pancreatic cancer outcomes in Nova Scotia: Searching for small windows of opportunity.
Authors: Sun Peiran , Ramjeesingh Ravi
Published: June 2021

e16219

Background: While pancreatic cancer (PC) globally has poor outcomes, there are still regional variation in PC outcomes in Canada. Nova Scotia (NS) has been documented to have some of the worst outcomes in PC but the details and barriers to the care of PC in NS have never been analyzed. Methods: A retrospective chart review was performed on PC patients (pts) diagnosed in NS from 2013 to 2017 for patient characteristics, referral pattern, treatments and wait times. Cox proportional hazards methods were used to analyze overall survival (OS) with Age, Stage, Eastern Cooperative Oncology Group Performance Status (PS), Charleston Comorbidity Index (CCI), receiving ERCP and receiving chemotherapy as covariates in the multivariate analysis. Results: 667 consecutive pts were identified, which included 357 males and 310 females with a median age of 71 at diagnosis. 42 (6.25%) lived beyond 2 years, while 163 (24.4%) survived for under 30 days and 260 (39%) survived for under 60 days. Patients with a limited survival (under 30 days) when compared to pts who survived > 60 days are older (mean 75 vs 71, P < 0.05), had a higher proportion of ECOG > 2 (81.6% vs 20.3%, P < 0.01), and a higher proportion of stage 4 disease (73.9% vs 41.2%, P < 0.01). There was no significant difference in any measure of wait times. Pts with limited survival were less likely to be seen by Medical Oncology (MO) (20.9% vs 70.9%, P < 0.001), and less likely to receive chemotherapy (1.2% vs 45%, P < 0.001) or ERCP (27% vs 53.8%, P < 0.01). Multivariate analysis showed that receiving ERCP (P = 0.027) and chemotherapy(P < 0.001) are independent predictors of survival, even when accounting for PS, CCI, stage, and age. Conclusions: Analysis of PC outcomes in NS demonstrates a large proportion of pts dying within 30 days of diagnosis. Those pts are older and present with higher stage and worse PS but did not have any significant difference in diagnostic and referral wait times. Those pts receive fewer referrals to Oncology services, fewer potentially life prolonging treatments and we uniquely discovered ERCP as an independent predictor of survival in our population. While further work is needed, this study characterized some of the unique challenges of PC care in NS as a province with a higher proportional of older adults and highlights potential opportunities to improve early healthcare delivery in older adults with limited windows for care.
Primary pancreatic adenocarcinoma (PPDA) and metastatic pancreatic adenocarcinoma (MPDA): Are they genomically distinct?
Authors: Singh Sunny R. K. , Leonard-Murali Shravan , She Ruicong , Lin Chun-Hui , Freaney Jonathan , Poisson Laila , Khan Gazala
Published: June 2021

e16226

Background: PDA is an aggressive disease with a dismal prognosis. Advances in next-generation sequencing (NGS) have enabled targeted therapies, revolutionizing treatments of several solid tumors. Their role in the management of PDA is limited, in part due to the paucity in our understanding of targetable genomic events. We sought to evaluate genomic differences between PPDA and MPDA in the tumor and tumor immune microenvironment (TIME). The genomic changes after chemotherapy (CTX) administration were also evaluated. Methods: NGS data derived from tumor samples of 150 unique patients was analyzed. Targeted 648 gene DNA sequencing was performed using the Tempus xT and xO assays. Patients were allocated into 2 cohorts: PPDA (n = 75) and MPDA (n = 75), which were overall similar in terms of their demographics. The frequencies of somatic mutations were compared. The immune infiltrate was imputed from RNAseq. Proportions of immune cells (IC), and the tumor mutational burden (TMB) relative to the proportion of IC in the TIME, were also analyzed. Kaplan Meier Survival estimates for most frequent mutations and TMB were calculated. Results: The most frequently mutated genes amongst the 150 study subjects were: KRAS (92.7%), TP53 (76.7%), CDKN2A (45.3%), SMAD4 (31.3%), ATM (12.7%) and ARID1A (10.7%). Patients in the MPDA cohort had a higher rate of mutation in several genes when compared to PPDA, most notably in TP53 (85.3% vs 68.0%, p = 0.010), ARID1A (16.0 vs 5.3%, p = 0.037) CDKN2A (49.3 vs. 41.3%, p = 0.3) and SMAD4 (33.3 vs. 29.3 p = 0.7). We also evaluated if the genetic changes between PPDA and MPDA are associated with alterations in the TMB and differences in the TIME. A higher TMB was seen amongst patients in the MPDA vs PPDA cohort (2.73 vs 1.73 Mut/Mb, p = 0.008). TMB was also significantly increased after CTX (2.22 vs 1.63 Mut/Mb p = 0.049). TMB ≥ 3 was associated with decreased odds of progression free survival ≥ 12 months (OR 0.26 95% CI 0.078-0.822, p = 0.023). Regarding immune infiltrate, the proportion of CD4 and CD8 T cells were higher in the PPDA cohort. Macrophages and NK cells were more prevalent the MPDA cohort. TMB had a positive correlation with the degree of macrophage infiltration in the TIME (Multivariate estimate: 1.70, p value 0.01). Conclusions: PPDA and MPDA are biologically dissimilar entities with genomic disparity. Associated differences were observed in TMB and TIME. There is a differential increase in the spectrum of mutations in MPDA as compared to PPDA, specifically in p53, ARID1A, CDKN2A and SMAD4. The burden of increased mutations in MPDA is associated with an increase in the TMB and tumor associated macrophages. The role of serial NGS in the management of PDA both in early and late disease should be investigated further to identify evolving genomic changes that correlate with outcome.
Positive association between Helicobacter pylori infection and pancreatic cancer: A case-control study.
Authors: Otieno Steve , Jain Amit L , Mohammed Omar , Patel Jay R , Collyer John , Deleeuw Peter , Husain Arshad , Weir Alva Bowen
Published: June 2021

e16243

Background: Pancreatic adenocarcinoma is a malignancy with a very poor prognosis. The 5-year overall survival is about 9%. Helicobacter pylori ( H. pylori) is a known risk factor for gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Whether H.pylori is a risk factor for pancreatic adenocarcinoma is still unclear. Previous observational retrospective studies trying to see if there is an association between H.pylori and pancreatic adenocarcinoma have used serology as a marker for H.pylori infection, but these have yielded mixed results. We seek to probe the association of H.pylori infection and pancreatic adenocarcinoma in a case-control study using histology for H.pylori bacteria from esophagogastroduodenoscopy (EGD) biopsies. Methods: A database for patients diagnosed with pancreatic adenocarcinoma at the Veterans Affairs Medical Center in Memphis, TN, from 1988 to 2018 was analyzed to obtain suitable cases. Pathology was reviewed to confirm the diagnosis and then the charts were reviewed to determine if the patient had undergone an EGD and if biopsies done obtained were tested for H.pylori. H.pylori positivity was determined using Steiner staining of the biopsy samples. 402 charts were reviewed and 51 cases meeting the above criteria were obtained. Controls were obtained by reviewing charts for all EGDs that were tested for H.pylori. Care was taken to make sure patients did not have any history of pancreatobiliary malignancy. 130 matched controls fit the screening criteria. Univariate and multivariate logistic regression analysis was done to analyze the risk factors. Results: Significantly more subjects in the case group (53%) were found to have H.Pylori infection compared to the control group (18%). Risk factors associated with pancreatic cancer in the literature, including age, race, smoking history, obesity, alcohol consumption, chronic pancreatitis, and diabetes, were analyzed using multivariate logistic regression. The results revealed that pancreatic cancer was significantly associated with a positive family history of pancreatic cancer (OR = 11.2, 95%CI 2.8-44.4, p = 0.001) and H.Pylori infection (OR = 5.5), 95%CI 2.4-12.7,p < 0.001). Conclusions: A positive association was found between H.pylori infection and pancreatic adenocarcinoma.
An internal review of rates of palliative medicine referral for patients with advanced pancreatic cancer.
Authors: Huffman Deanna , Shankar Karthik , Alnimer Lynna , Samhouri Yazan , Vusqa Urwat , Srinivasamaharaj Srividya , Monga Dulabh K.
Published: June 2021

e16245

Background: Patients diagnosed with advanced pancreatic cancer face many challenges in addition to symptom burden including psychological stressors and often the need for supportive care at home. In recent years, both clinical trials and retrospective reviews have confirmed the benefits of early integration of palliative care services such as improved quality of life and reduced symptom intensity. The American College of Clinical Oncology recommends patients with advanced cancer receive directed palliative care services early after diagnosis and in concurrence with active treatment. While the benefit of palliative care services is clear, the best way to integrate palliative services has not been determined. Our project aims to review the rates of palliative care consultation in patients with advanced pancreatic cancer intending to improve patient outcomes. Methods: We retrospectively reviewed the electronic medical records of all patients diagnosed with pancreatic cancer at Allegheny General Hospital diagnosed between 2009-2020. Summary statistics are presented as percentages for categorical data and median with interquartile range for quantitative data. Results: Of the 171 patients reviewed, 121 competed all treatment and evaluation within our health network. Median age was 63 years (IQR 40-91 years); 55 patients (45%) were male. The majority were white (88%). At the time of diagnosis, 28% of our patients had stage IV disease and 19.8% of patients with stage IV disease had documented palliative care referrals. Eight patients had pain documented at diagnosis, six patients underwent celiac plexus neurolysis, 31 underwent palliative radiation and 43 patients had documented opiate use. Of the 6 patients who underwent celiac plexus neurolysis, only 4 documented pain at 6-month follow-up. Of the 31 patients who underwent palliative radiation, 6 documented pain at 6-month follow-up. Conclusions: Palliative care is an integral part of usual care for pancreatic cancer. Our analysis showed that palliative care is underutilized in our hospital with only 19.8% of patients having documented palliative care visits. While patients may refuse palliative care consult, other contributing factors are likely the lack of access or lack of early involvement of palliative care team members. Integration of palliative care has been proven repeatedly to improve quality of life in patients diagnosed with advanced pancreatic cancer. We aim to improve palliative care integration in out patients’ care by adding a hard stop to electronic medical records to remind physicians to offer palliaitive care to the patients, in addition to arranging medical grand rounds and various lectures to increase awareness of the importance of palliative care in this setting.
Real-world safety and medication use of second-line (2L) 5-fluorouracil (5-FU)–based regimens among patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Kim George P. , Cockrum Paul , Surinach Andy , Wang Shu , Wainberg Zev A.
Published: June 2021

e16248

Background: Chemotherapy-related adverse events (AEs) can negatively impact the treatment of pts. Managing and preventing these toxicities often require additional medications. This study examined the proportion of pts with mPDAC treated with 5-FU–based regimens in 2L who experienced AEs during treatment, and the proportion who received medication to manage those AEs. Methods: Data were extracted for pts diagnosed with mPDAC who initiated 2L treatment Jan 2016 to Aug 2020 from the Flatiron Health database. Pts included were treated with FOLFIRINOX (FFX), FOLFOX, FOLFIRI, or liposomal irinotecan (nal-IRI). The occurrence of grade 3 (G3) and grade 4 (G4) neutropenia and G3/G4 thrombocytopenia were determined using lab results and the grading criteria from the CTCAE v4.03. The occurrence of diarrhea and nausea/vomiting (N/V) were identified via ICD-10-CM codes. The use of atropine and granulocyte colony stimulating factor (G-CSF) during treatment was assessed. Duration of therapy (DOT) was assessed for each regimen. Descriptive statistics for AEs, medication use, and DOT were reported. Results: Of the 825 eligible pts, 29.0% (n=239) received FFX, 40.2% (n=332) received regimens containing nal-IRI, 24.0% (n=198) received FOLFOX, and 6.8% (n=56) received FOLFIRI. The median DOT (IQR) was 15.1 weeks (wks) (7.1 – 30.1), 12.9 wks (6.0 – 24.8), 11 wks (6.4 – 24.0), and 12.7 wks (8.3 – 24.6) for pts who received FFX, nal-IRI, FOLFOX, and FOLFIRI, respectively. G3/G4 thrombocytopenia (<50,000/mm3) presented in 9.6%, 2.4%, 8.1%, and 14.3% of pts treated with FFX, nal-IRI, FOLFOX, and FOLFIRI, respectively. G3/G4 neutropenia (<1000/mm3) presented in 22.6%, 12.3%, 14.6%, and 19.6% of pts treated with FFX, nal-IRI, FOLFOX, and FOLFIRI, respectively. The median (Q1-Q3) cumulative dose of the G-CSF pegfilgrastim was 18mg (12 – 45), 18mg (12 – 48), 24mg (12 – 36), and 30mg (13 – 48) for pts treated with FFX, nal-IRI, FOLFOX, and FOLFIRI, respectively. Atropine use was higher in pts treated with FFX and FOLFIRI (90.8% and 94.6%, respectively) than for pts treated with nal-IRI (75.6%). The full study results are reported in the table. Conclusions: In this study of AEs among pts with mPDAC treated in 2L, pts who received liposomal irinotecan had the lowest proportion of thrombocytopenia and neutropenia. Diarrhea was similar across the cohorts despite the high proportion of use in atropine for pts treated with FFX and FOLFIRI.[Table: see text]