bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regorafenib combined with transarterial chemoembolization and PD-1 antibody as a second-line therapy for hepatocellular carcinoma: A real-world study.
Authors: Pan Tao , Huang Mingsheng 
Published: June 2022

e16167 Background: The benefits and tolerability of regorafenib combined with transarterial chemoembolization (TACE) and programmed death-1 (PD-1) antibody as a second-line therapy for advanced hepatocellular carcinoma (HCC) is unclear. We aimed to determine the efficacy and safety of regorafenib combined with TACE and PD-1 antibody as second-line treatment for advanced HCC. Methods: This study was approved by our institutional review board. In this retrospective study, a total of 55 consecutive advanced HCC patients who had tumor progression after first-line sorafenib treatment, and then treated with regorafenib plus TACE and programmed death-1 (PD-1) antibody between January 2017 and December 2020 were evaluated. The overall survival (OS), tumor response and adverse events (AEs) were analyzed. Statistical analysis was performed with the Kaplan-Meier method using the log-rank test and Cox regression models. Results: The median follow-up period was 35.5 months (range 6.0-52.0 months). The median age was 50 (range 18, 72) years. There were 49 (89.0%) males. The initial doses of regorafenib were 80 mg/d (n = 18, 32.7%) and 120 mg/d (n = 37, 67.3%). The patients underwent a median of two TACE sessions (range 1–5). The median OS after second-line treatment was 16.0 months (range 3.6-33.5 months), and the median PFS was 9.0 months (95%CI 6.1-11.7 months). According to modified RECIST criteria, complete response and partial response were found in 3 (5.5%) and 29 (45.5%) patients. The incidence of all grade 3/4 AEs was 29.6%, and the three main AEs were abdominal pain (10.9%), hypertension (7.3%) and hand-foot-skin reaction (5.5%). Two patients stopped PD-1 antibody and one stopped regorafenib due to AEs. Conclusions: Regorafenib combined with TACE and PD-1 antibody were tolerable and resulted in a promising OS and ORR in the second-line treatment of advanced HCC.
Role of organ-specific response to immune checkpoint inhibitor in survival for advanced hepatocellular carcinoma.
Authors: Huang Kuo Wei , Lee Pei-Chang , Chao Yee , Lee I-Cheng , Hou Ming-Chih , Huang Yi-Hsiang 
Published: June 2022

e16172 Background: Immune checkpoint inhibitors (ICIs) are encouraging treatment for advanced hepatocellular carcinoma. However, it is unclear which organ has the best response to ICIs as well as the role of individual organ response in survival for advanced HCC. We aimed to delineate tumor response to ICIs in different involved organs and its impact on survival. Methods: From May 2017 to October 2021, 224 patients received ICIs for advanced HCC were retrospectively reviewed. 174 patients who had follow-up images after ICIs, including 91 intrahepatic tumors only, 19 extrahepatic tumors only, and 66 concurrent intra- and extrahepatic tumors, were enrolled. Organ-specific responses were evaluated according to RECIST 1.1 and mRECIST criteria. Results: Of the 174 patients, 77 underwent anti-PD-1 monotherapy, the others received ICI combinations. The median overall survival (mOS) was 13.3 months (95% confidence interval [CI]: 11.4–15.3 months). Patients with concurrent intra- and extra-hepatic tumors had the lowest ORR and worse overall survival. The objective response rate (ORR) was the highest for metastatic lymph nodes (26%), followed by liver (24.2%), intra-abdominal tumors (21.4%), lung (12.1%), and bone (11.8%). Of the 66 patients with concurrent intra- and extrahepatic HCC, intrahepatic tumor response (HR: 0.247, P = 0.002) and ICI combinations (HR:0.403, p = 0.041) were significantly associated with a better OS in multivariate analysis. Conclusions: The response rate to ICIs was lower for lung and bone metastasis than liver and lymph nodes in advanced HCC. For patients with concurrent intra- and extrahepatic HCC, intrahepatic tumor response determines overall survival. [Table: see text]
A novel m6A-based HCC prognosis signature and potential mechanisms in predicting immune and anti-angiogenic response.
Authors: Wang Xiang-Xu , Wu Li-Hong , Dou Qiong-Yi , Liu Qing-Qing , Deng Shi-Zhou , Lu Yajie , Ai Li-Ping , Ji Hong-Chen , Pan Wei , Zhang Hong-Mei 
Published: June 2022

e16174 Background: The combination of immune checkpoint inhibitors and anti-angiogenic drugs has been approved as the preferred first-line treatment for advanced hepatocellular carcinoma (HCC). However, only a small subset of HCC patients could benefit from this combination treatment. Methods: The m6A clusters were identified by consistent cluster analysis via R package “consense-cluster plus” based on the expression of 26 m6A regulators. The immune cells infiltration was estimation of by ssGSEA, MCPCOUNT and TIMER 2.0 algorithm. The m6A-related prognosis significant genes were screened by univariate Cox, lasso-Cox and multivariate Cox regression, and the prognosis signature was constructed by multivariate Cox regression. The IC50s of anti-angiogenic drugs in GDSC (Genomics of Drug Sensitivity in Cancer) database were calculated by “pRRophetic” package. The packages “Celldex” and “SingleR” were used to annotate cell types, and to present the expression landscapes of 5 hub genes in different sites and immune cell subpopulations of HCC patients. Results: We identified three m6A clusters with distinct immune and angiogenesis microenvironments. We further constructed a 5-gene prognosis signature (termed as m6Asig-Score) which could predict both immune and anti-angiogenic responses. We illustrated that high m6Asig-Score is associated with poor prognosis, advanced TNM stage, and high TP53 mutation frequency. Besides, the m6Asig-Score was negatively associated with immune checkpoint inhibitors and anti-angiogenic drugs response. We further found that two of the five m6Asig-Score inner genes, B2M and SMOX, were associated with immune cell infiltration, immune response and the sensitivity to sorafenib, which were validated in two independent immunotherapy cohorts and the GDSC database. Conclusions: The m6Asig-Score, B2M and SMOX might have a significant impact on guiding the combined strategy of immunotherapy and anti-angiogenic therapy in HCC.
Combined 18F-FDG and 11C-acetate positron emission tomography/computed tomography in staging and treatment decision in patients with hepatocellular carcinoma: A cost-effectiveness analysis.
Authors: Chan Sik-Kwan , Chiu Wan Hang Keith , Lee Ho Fun Victor , Vardhanabhuti Varut , Cheung Tan To , Chan Albert , Chan Stephen L. , Khong Pek-Lan , Ng Kelvin Kwok Chai , Seto Wai-Kay , Kong Feng-Ming Spring , Chiang Chi Leung 
Published: June 2022

e16176 Background: Dual-tracer positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose and 11C-acetate is increasingly used in the management of hepatocellular carcinoma (HCC). However, considering the high cost of dual-tracer PET/CT, there is a need to assess its value by considering both the efficacy and cost. Methods: In this retrospective cohort study, 223 dual-tracer PET/CT scans were performed in 206 patients between 2014 and 2020 for tumor staging for radiologically or histologically confirmed HCC. New lesion detection rate, changes in the Barcelona Clinic Liver Cancer (BCLC) classification, and changes in treatment allocation based on dual-tracer PET/CT were evaluated. Validation was performed on a cohort of staging patients from another institution (n = 48). A cost-benefit analysis model was built for the incurred costs and the impact of dual-tracer PET/CT findings on treatment strategy over conventional imaging was studied. Results: Of the 223 patients that underwent dual-tracer PET/CT for staging, new lesions were detected in 33 (14.8%) patients, resulting in BCLC upstaging in 26 (11.6%) and treatment modification in 16 (7.2%) cases. The external staging cohort showed similar findings where dual-tracer PET/CT resulted in 12.5% (6/48) BCLC upstaging and 10.4% (5/48) treatment modifications (concordance-index: 0.85; 95% CI: 0.82-0.88). In subgroup analysis of 200 patients performed for pre-treatment metastatic screening, dual-tracer PET/CT detected extra-hepatic metastasis in 11, 10, and 16 patients, respectively, and led to treatment modifications in all of these patients. Sixteen locoregional therapies (8%) were avoided (8 resections, 3 transplantations, and 5 TACEs), with an estimated cost saving of US$161,665 (US$808 / patient) from the use of dual-tracer PET/CT. Sensitivity analyses suggested that dual-tracer PET/CT is consistently more cost-saving than conventional imaging, irrespective of the changes in the cost of imaging, procedures, and the duration of hospital stay (range: US$112,945-210,385). The cost of PET/CT had the greatest influence on the cost savings. Conclusions: Comparing to conventional imaging, dual-tracer PET/CT improves tumor staging, alters treatment allocation and is cost-saving in patients undergoing pre-treatment metastatic screening. Our results demonstrated that the use of dual-tracer PET/CT provides additional value and improves patient care.
Immunotherapy treatment responses in hepatocellular carcinoma patients with nonalcoholic fatty liver disease cirrhosis.
Authors: Chang Jeremy , Ryan Joseph S , Ajmera Veeral , Fowler Kathryn J , Ting Stephanie , Tamayo Pablo , Burgoyne Adam 
Published: June 2022

e16199 Background: Primary liver cancer is the third most frequent cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) composing 75% of cases. Recent preclinical models suggest that immunotherapy targeting programmed cell death protein 1 (PD-1) leads to CD8+ T-cell activation but not tumor regression in nonalcoholic fatty liver disease (NAFLD) induced HCC. However, additional studies are required to understand the response of NAFLD-associated HCC patients to PD-1 and programmed death-ligand 1 (PD-L1) therapies. Methods: Our team conducted a retrospective, single center study to determine the best responses to anti-PD-1/PD-L1 containing regimens in patients with HCC and underlying NAFLD cirrhosis. There were 2 groups included in this study: patients with HCC associated with NAFLD cirrhosis and those who had HCC without NAFLD cirrhosis. All patients included in this study received either an anti-PD-1/PD-L1 targeted agent as monotherapy or combined with other systemic treatment. Radiologic evaluations were conducted between February 2018 and January 2022. Results: There were 81 patients were included in this study: 15 in the NAFLD cirrhosis HCC group and 66 in the HCC group without NAFLD cirrhosis. When determining the best responses to anti-PD-1/PD-L1 therapies, 6 patients (40%) with HCC and NAFLD cirrhosis had disease progression as their best responses versus 7 patients (10.6%) who had HCC without NAFLD cirrhosis (risk ratio 3.8, p = 0.012). Furthermore, in the HCC group without NAFLD cirrhosis, 59 patients (89.4%) experienced disease control (defined as stable disease, partial response, or complete response) from anti-PD-1/PD-L1 containing regimens compared to 9 patients (60%) in the NAFLD cirrhosis-related HCC group (risk ratio 1.5, p = 0.012). No significant differences were found in gender, patient age, or treatment regimens received between the two groups. See the table below for details on immunotherapy regimens and treatment responses. Conclusions: In this study, HCC patients with NAFLD cirrhosis experienced significantly higher rates of disease progression as the best response to anti-PD-1/PD-L1 therapies compared to HCC patients without NAFLD cirrhosis. As the use of immunotherapy in the HCC population continues to expand, additional prospective studies are necessary to clarify the impact of underlying liver disease on treatment response.[Table: see text]
Artisan trial protocol: A single center, open-label, phase II trial of the safety and efficacy of TheraSphere selective internal radiation therapy (SIRT) in the treatment of inoperable metastatic (liver) neuroendocrine neoplasia (NENs).
Authors: Sharma Rohini , Evans Joanne , Ward Caroline , Wernig Florian , Thomas Robert 
Published: June 2022

e16208 Background: Patients(pts) with NENs present with advanced, unresectable disease, with liver metastases. Liver metastases dictates prognosis. SIRT allows targeted high dose radiation directly to tumours, with relative sparing of the surrounding liver tissue. ArTisaN is a phase II study assessing efficacy and tolerability of SIRT using TheraSpheres for management of liver metastases secondary to NENs. Methods: Pts with liver dominant NENs will receive up to 2 TheraSphere treatments. Pts will be followed until disease progression for up to 2-years. Primary endpoints: objective response rate (ORR) within the treated liver volume, incidence of adverse events. Secondary endpoints: progression-free survival (PFS), overall (OS) and quality of life (EORTC QLQ-C30 and QLQ-GI.NET21). Assuming ORR 40%, sample size 24 patients-95% confidence interval will extend 20% in either direction. Results: 13 pts completed therapy: 69% female, primary site: 23% pancreatic, 31% small bowel. Grade: 54%-1, 46% - 2. 69% had previously received more than one line of systemic therapy including 7 who had previously received peptide receptor radiotherapy. 92% received bilobar treatment-average dose 2.49GBq administered. Hepatic ORR-69%. Grade 3 treatment related events occurred in 2 patients–1 ischaemic limb and 1 radiation induced hepatitis. Quality of life-maintained across all parameters. At the time of analysis, 5 pts had progressed, 3 had extrahepatic progression. Median PFS was 15.4 months (95%CI 11.5-19.4) and median OS was 18.5months (95%CI 7.4-29.6). Conclusions: Theraspheres is a safe and effective therapy for the management of patients with liver dominant disease from NENs. Clinical trial information: NCT04362436.
Platinum-doublet chemotherapy for advanced gastroenteropancreatic neuroendocrine carcinoma: A systematic review and meta-analysis.
Authors: Ohmoto Akihiro , Fujiwara Yu , Horita Nobuyuki , Nakano Kenji , Takahashi Shunji 
Published: June 2022

e16217 Background: Neuroendocrine carcinoma (NEC) is a poorly differentiated pathological neuroendocrine neoplasm exhibiting aggressive clinical behaviors; the most common extrapulmonary site is the gastroenteropancreatic (GEP) system. Treatment strategies for GEP-NEC are primarily based on those employed for small cell lung cancer, and platinum-doublet chemotherapy, such as platinum plus etoposide (EP) or platinum plus irinotecan (IP), has been widely used as initial systemic therapy for patients with advanced/metastatic disease; however, clinical data for GEP-NEC are chiefly derived from small-scale retrospective studies, and the reported efficacy is heterogenous among studies. Methods: We conducted a systematic database search using PubMed/MEDLINE and EMBASE. Eligible studies included randomized trials, single-arm trials, prospective observational studies, and retrospective studies documenting the clinical efficacy of platinum-doublet chemotherapy (EP and IP) for advanced GEP-NEC. The pooled overall response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were calculated and weighted using generic inverse variance in a random-effects meta-analysis model. Results: Based on initial screening and eligibility assessment, 19 studies with a combined total of 1,157 patients were identified through a systematic review. Studies included 3 comparative studies between EP and IP with 1 randomized phase II trial and 2 retrospective studies. The pooled ORR in all patients who received the platinum-doublet regimen was 49.1% (95% confidence interval [CI], 41.8–56.5), and subgroup analysis for EP and IP groups showed ORRs of 44.4% (95% CI, 35.9–53.0) and 59.4% (95% CI, 48.0–70.8), respectively. According to the three studies directly comparing EP to IP, the odds ratio of ORR using EP as reference was 1.95 (95% CI, 0.86–4.39, P = 0.11). The pooled median OS in all patients who received the platinum-doublet regimen was 12.9 (95% CI, 10.9–15.3) months, where EP and IP subgroups had median OS of 12.9 (95% CI, 10.8–15.4) and 12.9 (95% CI, 6.0–27.8) months, respectively. The pooled median PFS was 5.4 (95% CI, 4.5–6.4) months in all patients with platinum-regimen, 5.4 (95% CI, 4.5–6.5) months in the EP subgroup, and 4.0 (95% CI, 1.4–11.7) months in IP subgroup, respectively. Conclusions: This study was the first systematic review and meta-analysis assessing patients with GEP-NEC; it has revealed considerable ORR following platinum-doublet chemotherapy. EP and IP regimens can be reasonably employed in patients with advanced GEP-NEC. These results can serve as reference information for clinicians in deciding a suitable chemotherapy regimen. Larger randomized trials and individual patient data meta-analyses are warranted to obtain robust clinical evidence.
Carcinoid syndrome and valvular heart disease: A national perspective on patient characteristics and cardiovascular outcomes.
Authors: Dalal Shivani , Patel Krunalkumar , Hussein Atif Mahmoud , Isaac Krista , Patel Akash , Gattas Boula , Dalal Misha 
Published: June 2022

e16218 Background: Carcinoid is a well differentiated neuroendocrine tumor (NET) arising most commonly in the gastrointestinal tract or bronchopulmonary system. Carcinoid syndrome is a constellation of symptoms mediated by a myriad of vasoactive substances elaborated by the Carcinoid tumor, of which serotonin is most prominent in the pathophysiology of Carcinoid heart disease (CHD). CHD is characterized by pathognomonic plaque-like deposits of fibrous tissue on the endocardium of valvular cusps, leaflets, papillary muscles and cords. Clinical manifestations include valvular heart disease(VHD), arrhythmias and coronary heart disease. We aim to determine the impact of co-existing VHD in patients with CHD on morbidity, mortality, length of stay and mean hospitalization costs as compared to patients without coexisting VHD. Methods: We identified hospitalized adult patients with Carcinoid syndrome and divided them into patients with and without VHD from October 2015 to December 2018 from the National Inpatient Sample Database using ICD 10 Codes. We further determined demographics, baseline characteristics, associated comorbidities, mortality, length of stay (LOS) and hospitalization costs among patients with carcinoid syndrome with and without documented VHD. SAS 9.4 software was used for statistical analysis. Results: We captured 10,135 patients hospitalized with carcinoid syndrome, amongst which 705 patients were found to have VHD. The group with VHD were predominantly males (51.8 vs 48.2%), had a higher prevalence of CAD (26.2 vs 16.8%), heart failure with reduced ejection fraction(17.7 vs 3.7%), heart failure with preserved ejection fraction (13.5 vs 6%), atrial fibrillation (28.4 vs 15.3%), pleural effusion (13.5 vs 7.1%), pericardial effusion (2.8 vs 1%) as compared with patients without VHD. They were also noted to have higher inpatient mortality (9.2 vs 5.2%), length of stay (8.8 vs 6.6 days) and mean hospitalization cost (31973 vs 17734$). In the cohort with CHD and co-existing VHD, we noted mortality was highest amongst patients with involvement of pulmonary valve (13.5%) followed by tricuspid, mitral and aortic valves(13%, 8.3% and 4% respectively). Conclusions: Carcinoid tumor involves the heart in about 60% of the patients and is associated with poor long-term prognosis and is a major cause of morbidity and mortality. With mounting epidemiological evidence of poor outcomes in patients with carcinoid syndrome and VHD, our study shines light on the importance of a concerted effort to develop an algorithm for early screening, diagnosis and treatment of CHD. This necessitates multidisciplinary approach control of progressive heart failure, treatment of systemic malignancy and surgical correction of right sided valvular heart disease by utilizing services of a team consisting of surgeons, oncologists and cardiologists to guide management.
Can CA 19-9 predict inferior surgical and pathological outcomes for resectable pancreatic cancer?
Authors: Jabbal Iktej Singh , Nagarajan Arun , Roy Mayank , Rivera Carlos , Yaghi Marita , Liang Hong , Nguyen Timmy Q. , George Tiffany L. , Nahleh Zeina A. , Simpfendorfer Conrad H 
Published: June 2022

e16228 Background: Previous data have established that patients with pancreatic surgical specimens showing lymphovascular invasion (LVI) and positive surgical resection margins are associated with poor survival outcomes. However, there are no biomarkers to identify these high-risk patients preoperatively. In this study, we hypothesized that increased carbohydrate antigen 19-9 (CA 19-9) levels could be used to predict high-risk resectable pancreatic cancer features, including LVI and positive residual margins, thereby guiding the surgical decision-making process. Methods: We sampled the National Cancer Database for patients undergoing pancreatic cancer resection between 2004-2018. Logistic regression analysis was performed to analyze sociodemographic and disease characteristics associated with elevated CA 19-9 levels (> 98 U/ml) versus low CA 19-9 levels (< 98 U/ml). Additionally, Cox regression analyses were used to compare hazard ratios for demographic and disease characteristics. A p < 0.05 was considered statistically significant. Results: 12208 patients (50.76% males) with pancreatic cancer were sampled. Pathological findings of LVI (n = 5963), microscopic residual tumor margins (R1) (n = 1547), and residual margins (R), not otherwise specified (NOS) (n = 885) had a stronger association with high preoperative CA 19-9 levels when compared to those with low CA 19-9 levels (LVI: OR 1.212, 95% CI 1.125–1.305, p < 0.001, R1: OR 1.260, 95% CI 1.129–1.408, p = 0.001 and R NOS: OR 1.212, 95% CI 1.052–1.395, p = 0.008). Macroscopic residual margins (R2) (n = 85) were also associated with high CA 19-9 but statistically not significant (OR 1.242, 95% CI 0.802–1.924, p = 0.332) probably due to the low sample size for this subpopulation. Furthermore, all the factors listed below were independently associated with poor prognosis: (A) Elevated CA 19-9 levels: HR 1.411, 95% CI 1.350–1.475, p < 0.001, (B) LVI: HR 1.333, 95% CI 1.275–1.394, p < 0.001, (C) R NOS: HR = 1.517, 95% CI = 1.401–1.643, p < 0.001, (D) R1: HR 1.594, 95% CI 1.499–1.695, p < 0.001, (E) R2: HR 2.015, 95% CI 1.597–2.543, p < 0.001. Conclusions: Elevated CA 19-9 can be used as a biomarker to identify a subset of pancreatic cancer patients with high-risk surgical pathological features such as LVI or residual tumor margins. In these patients, perhaps neoadjuvant chemotherapy can facilitate downstaging and provide superior surgical and oncological outcomes.