bluuebunny/crossref_metadata_2025 huggingface dataset:
The association of chromosome 11q13 amplification with the hyperprogressive disease in unresectable hepatocellular carcinoma patients underwent the immunotherapy.
Authors: Zhang Haibin , Yan Kai , Zhang Ding , Chen Yanan , Huang Mengli , Fu Yong , Lu Wenfeng
Published: June 2022

e16156

Background: Hyperprogressive disease (HPD) is characterized by an acceleration of tumor growth during systemic therapy, which usually refers to immunotherapy. The incidence of HPD in patients with hepatocellular carcinoma (HCC) is reported to be 12.7%. Amplification of the chromosome 11q13 locus, including cyclin D1 (CCND1), FGF3, FGF4 and FGF19, is frequent in many cancers and correlates with inferior outcomes with immunotherapy. However, little is known about the association between chromosome 11q13 amplification and HPD of HCC. Methods: 58 HCC patients who underwent the next-generation sequencing (NGS) in our institution from September 2017 to April 2018 were enrolled in this study. Among them, 30 patients had unresectable advanced or recurrent HCC and received anti-tumoral therapy, including 18 cases (Group 1) receiving programmed cell death-1 (PD-1) monoclonal antibody immunotherapy (with or without tyrosine kinase inhibitors, TKIs) and 12 cases (Group 2) receiving local regional therapy (with or without TKIs). Based on radiological surveillance, HPD was defined as: 1. Tumor growth kinetics (TGK) or tumor growth rate (TGR) > 2; 2. Time to treatment failure < 2 months. Results: In our dataset, chromosome 11q13 amplification (11q13 Amp) was seen in 11 patients (19.0%). 11q13 Amp was associated with worse clinical baseline, with a significant concentration in patients with BCLC C stage, tumor numbers of ≥ 3 and ECOG 1 score. Group 1 had an objective response rate (ORR) of 50.0% and Group 2 had an ORR of 54.5%. There was no significant difference in progression-free survival (PFS) between these two groups. 3 patients showed HPD in Group 1, all of whom carried 11q13 Amp. Compared to non-11q13 Amp patients, patients with 11q13 Amp had worse PFS (log-rank P= 0.001) in Group 1. While there was no significant difference of PFS between 11q13 Amp and non-11q13 Amp patients in Group 2. We further investigated the efficacy of different treatment strategies based on 11q13 Amp status. These 11q13 Amp patients in Group 1 showed worse PFS, compared to Group 2 (log-rank P= 0.025). However, patients with non-11q13 Amp showed similar outcomes between these two groups (log-rank P= 0.70). Conclusions: Our findings suggested that 11q13 Amp was associated with HPD of HCC. PD-1 monoclonal antibody showed poor efficacy in patients with 11q13 Amp, therefore targeted treatment strategies might be more suitable for such patients. Meanwhile, the role of 11q13 Amp as putative predictive biomarkers of HPD needs further validation in larger cohorts.
Characterization of molecular and immune landscape of microvascular invasion in hepatocellular carcinoma and prognostic significance.
Authors: Zhang Kai , Tao Changcheng , Wu Fan , WANG Liming , Zheng Linlin , Wang Yaru , Wu Anke , Wu Jianxiong , Xiao Ting , Rong Weiqi
Published: June 2022

e16162

Background: Partial hepatectomy is potentially curative treatment in selected patients (pts) with hepatocellular carcinoma (HCC). Microvascular invasion (MVI) is one of the strongest predictors of prognosis and recurrence of HCC. In this study, we analyzed the gene mutation signature and immune factors associated with MVI, and the prognostic value. Methods: Pts who were diagnosed with HCC between Jan 2018 and Sep 2020 in Cancer Hospital of Chinese Academy of Medical Sciences were retrospectively enrolled in this study. Next-generation sequencing (NGS) was performed on tumor tissues after radical partial hepatectomy. The different immune makers (PD1, PD-L1, CD3, CD8, CD68, and CD163) of tumor-infiltrating lymphocytes (TILs) were identified with immunofluorescence-based microenvironment analysis panel (MAP). Results: In the MVI+ group (n = 39, 59.1 %), there were significantly more pts with larger tumor size, and capsules invasion by tumors. The mutation spectra revealed that 61 (92.4%) pts harbored somatic mutations and the most frequently mutated gene was telomerase reverse transcriptase (TERT), which was present in 31.8% (n = 20) HCC pts. Mutations in the promoter of TERT were found in 95.2% (20/21) pts. 90.0% (18/20) had one hotspot point mutation located 124bp upstream of the translation start site. The mutation frequency in the TERT promoter was significantly higher in the MVI+ group compared with the MVI- group (41.0% vs. 14.8%, p < 0.05). Pts with TERT promoter mutations tend to be MVI+ rather than MVI- and more HCC driver mutations were detected in MVI+ pts with TERT promoter mutations (p < 0.05). Based on MAP, we found MVI+ pts had significantly lower CD3+ TILs (p < 0.05). The multivariable analysis indicated that pts with copy number variations (CNV, hazard ratios [HR] 2.62, 95% confidence interval [CI] 1.07-6.40; p = 0.028), elevated PT/INR (HR 0.29, 95% CI 0.11-0.77; p = 0.008), and lower serum prealbumin concentration (PALB, HR 3.03, 95% CI 1.08-8.51; p = 0.027) had significantly shorter recurrence-free survival (RFS) after surgery. Similar findings were also observed for immune factors within cancer parenchyma, including CD68+ (HR 7.14, 95% CI 0.95-53.55; p = 0.025), CD163+ (HR 3.07, 95% CI 1.10-8.53; p = 0.023), CD68+/CD163- (HR 11.35, 95% CI 1.51-85.05; p = 0.003), CD68+/CD163+ (HR 3.51, 95% CI 1.4-8.79; p = 0.004), which indicated tumor-associated macrophage (TAM) infiltration was independent risk factor for RFS. Conclusions: In this study, we characterized the molecular and immune landscape of MVI in HCC patients. MVI presence highly correlated with adverse biological markers, mutations in the promoter of TERT, and higher CD3+ TILs. Some risk factors of HCC recurrence were identified, including CNV, PT/INR, CA 19-9, PALB, and TAM. Transcriptional alterations and immune tumor microenvironment change may contribute to MVI in HCC.
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.
Isolation and culture of circulating pancreatic cancer tumor cells using a microfilter.
Authors: Furukawa Atsuko , Shimomura Osamu , Araki Kazuhisa , Mori Tomoko , Oda Tatsuya , Matsusaka Satoshi
Published: June 2022

e16230

Background: The presence and number of circulating tumor cells (CTCs) are reportedly associated with prognosis but the rarity of CTCs in peripheral circulation limits the ability of conventional technologies to provide fully accurate analyses. The purpose of this study was thus to establish a novel approach to capture and culture the CTCs using a microfilter device. Methods: This was a prospective study in preoperative patients with pancreatic cancer at the University of Tsukuba Hospital after approved by the Institutional Review Board. Five ml of whole blood was collected from each patient into an EDTA-treated collection tube before pumping through an 8μm pore microfilter. Cells isolated on the filter were stained with PE-conjugated anti-EpCAM, FITC-conjugated anti-CD45 and Hoechst 33342. The filter was then transferred to a 35mm dish and cultured with 20%FBS-IMDM-F12 medium containing 2%Matrigel- EGF-FGF-B27 for 4-6 weeks. Cells were visualized with an automatic fluorescence microscope. A CTC was defined as an intact round oval cell with a visible nucleus, positive staining for EpCAM and negative staining for CD45. Results: A total of 9 patients [male/female; 4/5, median age;71 (39-78), Stage 0/IA/IIA/IIB; 1/3/3/2, preoperative chemotherapy/chemoradiation; 1/2] were enrolled. CTCs were captured in 8 out of 9 cases and cultured CTCs were kept viable for 4-6 weeks in 6 out of 9 cases. CTCs formed colonies by 4-6 weeks of culture, colonies were expanding and blood cells disappeared. No cultured CTCs were observed in the two cases who received preoperative chemotherapy. Conclusions: We successfully developed a novel culture method of patient CTC using a microfilter device. Our system supports the possibility of accurate detection and proliferation of CTCs on microfilters. Cultured CTCs could be used for patient-specific drug susceptibility testing and mutational profiles for future cancer patients.
Emerging immuno-therapies for advanced pancreatic cancer: An overview of available literature.
Authors: Masood Adeel , Ehsan Hamid , Iqbal Qamar , Amin Saher Nasir , Wilson Melissa
Published: June 2022

e16231

Background: Pancreatic cancer is the 11th most common cancer and represents 3.2% of all new cancer cases. But it is the third leading cause of cancer-related deaths with a five-year relative survival of only 10.8%. More than 50% of patients diagnosed with metastatic disease at initial presentation have 5-year relative survival of only 3.0%. Here, we explore the recent literature for the emerging role of immunotherapies and their outcomes for advanced pancreatic cancer. Methods: The literature search was conducted on PubMed, Embase, Cochrane, and ClinicalTrials.gov from inception to January 2022 using MeSH terms' pancreatic neoplasms', 'immunotherapy,' and 'therapeutics'. The final analysis includes nine clinical trials that meet the inclusion criteria regarding immunotherapy for metastatic pancreatic cancer. Results: The combination of pembrolizumab and trametinib with stereotactic radiotherapy (SBRT) reported a median progression-free survival (PFS) and overall survival (OS) of 25 and 18 months compared to gemcitabine and SBRT combination of 22 and 16 months, respectively. Another study reported a median OS of 18 months with nivolumab along with operative irreversible electroporation to increase the bioavailability of nivolumab in the cancer cells. The EGFR targeted CAR T cells therapy was evaluated in 14 patients with advanced pancreatic cancer with a median OS of five months and an overall response rate (ORR) of 29%. Sotigalimab, an agonistic CD40 antibody combined with nivolumab, was found to have an ORR of 58%, PFS of 12 months, and OS of 20 months after a follow-up of almost 18 months. On the contrary, Bruton's tyrosine kinase inhibitors such as Acalabrutinib and Ibrutinib were found to have no OS benefit (median OS 3.8 and 5.3 months, respectively). Conclusions: Due to the high mortality associated with advanced pancreatic cancer, there is increasing interest in Novel immunotherapies-based approaches, with some showing promising results.[Table: see text]
Toripalimab combined with nab-paclitaxel/gemcitabine as first-line treatment for advanced pancreatic adenocarcinoma: Updated results of a phase Ib/II clinical study.
Authors: Cheng Ke , Lv Wanrui , Li Xiaofen , Chang Chen , Cao Dan
Published: June 2022

e16244

Background: Much controversy remains regarding the immune-checkpoint-inhibitor plus Nab-paclitaxel/gemcitabine (AG) as the treatment in advanced pancreatic ductal adenocarcinoma (aPDAC). We assess safety and efficacy of toripalimab plus AG in aPDAC, this was the updated results of the study. Methods: This was a phase Ib/II clinical study of toripalimab plus AG as first-line treatment for aPDAC. Toripalimab (240mg, Q3W), combined with AG (nab-paclitaxel 125 mg/m2, d1, d8 plus gemcitabine 1000 mg/m2, d1, d8) were administrated until the disease progresses/unacceptable toxicity or receiving toripalimab maintenance treatment. The primary endpoints were safety and OS; the secondary endpoints were ORR, DCR and PFS. Predictive biomarkers including gene mutations based on next-generation sequencing and PD-L1 expression were assessed. Results: Until January 2022, 55 chemotherapy-naïve aPDAC evaluable patients (beyond 90% patients with metastatic lesions) to safety and response, ECOG PS≤2 were enrolled. The ORR was 29.1%, the DCR was 90.9%, including 15 patients with PR and 1 patient with CR, 34 patients with SD respectively. 33 patients were alive and 16 patients were still ongoing study. Median PFS was 5.0 months (95% CI: 4.033-5.967), the 6-month PFS rate was 56.4%; median OS was 10.0 months (95% CI: 6.321-13.679), the 1-year OS rate was 69.1%. 2 cases of pseudoprogression were observed. The most frequent treatment related adverse events (TRAE) were anemia (90.1%, G3/4: 9.1%), hypoproteinemia (73%, G3/4: 5.5%), AST elevation (61.0%, G3/4: 3.6%), ALT elevation (60%, G3/4: 5.5%), hypothyroidism (51%, G3/4: 0%), leukocytopenia (45.4%, G3/4: 5.5%), neutropenia (44%, G3/4: 9.1%), nausea (44%, G3/4: 3.6%), rash (38.1%, G3/4: 0%). And 23 patients (41.8%) experienced grade 3/4 TRAE. In the biomarker analysis, all 55 patients were MMR-proficient status; 37 patients were evaluated for PD-L1 expression, PD-L1 positive cases (PD-L1 TPS > 1% and/or CPS > 2, n = 12, 6 patients achieved PR) compared with PD-L1 negative cases (n = 25) presented higher ORR (50% vs 16%). 44 patients were investigated for NGS in 55 evaluable patients, KRAS mutation (86.4%) was the most frequently mutated genes (KRAS G12D = 20 patients, KRAS G12V = 13 patients, KRAS G12R = 4 patients, KRAS G12C = 1 patients), and germline BRCA2 mutation was observed in one patient. The correlation between gene mutation and efficacy and prognosis is under analyzed. Conclusions: The updated results of this phase Ib/II study has met our preset primary endpoint with 69.1% in 1-year OS rate, provided promising evidence that toripalimab in combination with AG has a manageable safety profile and expected antitumor activity. The correlation between biomarkers with clinical efficacy are under investigation. The results supported ongoing combined treatment in aPDAC patients. Clinical trial information: ChiCTR2000032293.
Racial disparities in surgical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) undergoing pancreas surgery.
Authors: Saad Mariam , Gartrelle Kendyll , Shah Rupen A. , Clark Julie , Steffes Christopher P. , Kwon David S.
Published: June 2022

e16255

Background: Previous studies have suggested disparity in PDAC survival in African American (AA) compared to non-AA patients. Pancreas surgery is associated with significant morbidity, and technical outcomes are known to impact survival; however, there is little reported data on surgical outcomes by race. We sought to evaluate the effect of race on surgical outcomes and survival in an urban tertiary care center for patients with PDAC undergoing pancreas surgery. Methods: A retrospective single-center analysis of PDAC patients undergoing pancreas resection between January 2013 and September 2021 was performed. Patient demographics, Clavien-Dindo (CD) complications, readmission, and mortality in the 30- and 90- day period were collected and stratified by race. Univariate and multivariate analyses were performed. Results: Among 180 patients, 145 (81%) were non-AA and 35 (19%) were AA. Demographic and pre-operative characteristics were found to be similar between the two groups. 30-day ED visits, postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE), and intra-abdominal abscess (IAA) were found to be significant on univariate analysis in the AA cohort. On multivariate analysis, 30-day ED visit (OR 4.5; 95% CI 1.3-15.8; p = 0.02), POPF (OR 4.5; 95% CI 1.3-14.8; p = 0.015), and IAA (OR 4.4; 95% CI 1.12-17.3; p = 0.033) were still significantly higher in the AA cohort while DGE lost its significance. Median overall survival and disease-free survival showed no significant difference on Kaplan-Meier curves. There was no statistical difference in local, regional, or metastatic recurrence patterns between the two groups (distant metastasis 36% in non-AA and 37% in AA). Conclusions: AA undergoing pancreas surgery for PDAC were noted to have higher incidence of POPF and IAA as well as ED visits compared to non-AA patients. However, no significant difference was seen in reoperation rates, major CD complications, recurrences, or survival. Exploring tumor biology, and preoperative treatment algorithms may shed additional insight on the differences in surgical outcomes in this patient cohort.[Table: see text]
Do patients with metastatic pancreatic adenocarcinoma to the lung have improved survival?
Authors: Ebrahimi Aren , Shadarevian Melanie , Cham Jason , Hermel David Jacob , Spierling Bagsic Samantha R. , Sigal Darren
Published: June 2022

e16257

Background: Pancreatic ductal adenocarcinoma (PDAC) is a genetically heterogeneous disease often diagnosed with synchronous metastatic disease involving the liver. Tumors with extra-abdominal spread that bypass the liver are thought to represent a unique molecular subgroup of the disease. Specifically, those with isolated pulmonary metastatic disease are thought to have a more favorable clinical phenotype. We sought to retrospectively investigate whether patients with isolated pulmonary metastases had improved survival compared to those with disease involving the liver. Methods: We conducted a retrospective review of patients with pathologically confirmed PDAC treated between the years 2010 and 2020 at a Scripps Health hospital. The final study sample included only patients with pulmonary and/or liver primary metastases (N = 175). Analyses were conducted on subgroups defined by metastatic sites of disease in the liver only, lung only and combined liver+lung. Primary and secondary outcome analyses compared isolated lung versus liver/liver+lung. Primary endpoint was overall survival (OS), defined as from the date of diagnosis to date of death or most recent follow up. Progression free survival (PFS) was also analyzed as a secondary endpoint and defined as from the date of diagnosis to date of radiographic progression. Each survival outcome was analyzed using Cox Proportional Hazards tests. Results: No statistically significant differences were seen in OS (HR 0.67, CI 0.44–1.03; p= 0.069) or PFS (HR 1.05, CI 0.68–1.65; p= 0.816) between patients with primary lung metastases compared to those with either liver or liver+lung metastases (reported as hazard ratios of liver/liver+lung relative to lung only). However, a trend towards improved OS was seen for patients with isolated lung metastasis and the kaplan-meier curve for OS showed improved survival for these patients at 3 years, with crossing of the survival curves around 5 years from time of diagnosis. Conclusions: There appears to be a unique clinical phenotype in patients with PDAC presenting with isolated pulmonary disease. Though there was not a statistically significant difference in OS and PFS seen in our population, there was a trend towards improved overall survival compared to those with hepatic involvement. These findings highlight a potential prognostic indicator of metastatic PDAC and further subgroup analysis will help characterize clinical variations that may lead to these differences in tumor biology.[Table: see text]
A phase I study of gemcitabine/nab-paclitaxel/S-1 chemotherapy in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma.
Authors: Chang Chen , Li Xiaofen , Cheng Ke , Cai Zhaolun , Xiong Junjie , Lv Wanrui , Li Ruizhen , Zhang Pei , Cao Dan
Published: June 2022

e16261

Background: Systemic chemotherapy is the primary treatment in patients with locally advanced or metastatic pancreatic ductal adenocarcinomas (PDAC). More effective treatment options are highly awaited . The aim of this study was to evaluate the toxicity and feasibility of triweekly gemcitabine/nab-paclitaxel/S-1 (GAS) chemotherapy in patients with locally advanced or metastatic PDAC, determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of S-1 in this regimen, and explore the preliminary efficacy. Methods: Eligible patients with locally advanced or metastatic PDAC received GAS chemotherapy on a 21-day cycle. Fixed-dose of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) were given intravenously on days 1 and 8. Different doses of S-1 were given orally twice daily from day 1 to day 14 within a 3+3 dose escalation design. According to patients` body surface area, the dose-escalation design was as follows: patients with a body surface area of 1.25–1.5 m2 received S-1 40 mg/d initially and the dose was increased to 60 mg or 80 mg. Patients with a body surface area of more than 1.5 m2 received S-1 60 mg/d initially and the dose was increased to 80 mg or 100 mg. The primary endpoints were to evaluate the toxicity and determine the DLT and MTD of S-1. The secondary endpoint was to evaluate efficacy. Results: A total of 21 eligible patients were included. Due to the infrequence of patients with a body surface area of 1.25–1.5 m2, only 2 patients were included in cohort of S-1 40 mg. The dose-escalation for patients in this group failed to be enrolled completely. For patients with a body surface area of more than 1.5 m2, 3 DLTs in 7 patients were detected at cohort of S-1 100 mg (grade 3 thrombocytopenia with hemorrhage, grade 3 rash, and grade 3 mucositis/stomatitis). S-1 80 mg/d (body surface area: > 1.5 m2) was considered to be the MTD in GAS chemotherapy (21-day cycle). No grade 4 adverse events (AEs) or treatment-related deaths were observed. The most common occurring hematologic AE of any grade was anemia (38.1%). The most frequent nonhematologic AEs of any grade were peripheral neuropathy (38.1%), dyspepsia (23.8%), constipation (23.8%), and alopecia (23.8%). After 2 cycles of GAS chemotherapy, the objective response rate was 36.8% and the disease control rate was 94.7%. The median progression-free survival was 5.3 (95% CI, 4.6 to 6.0) months and the median overall survival was 10.3 (95% CI, 8.1 to 12.5) months. Conclusions: GAS chemotherapy (21-day cycle) with nab-paclitaxel 125 mg/m2, gemcitabine 1000 mg/m2, and S-1 80 mg/d (body surface area: > 1.5 m2) was detected with the acceptable toxicity and significant clinical control in patients with locally advanced or metastatic PDAC. It is valuable to conduct further phase II trials. Clinical trial information: ChiCTR1900027833.
Impact of site-specific metastases on survival outcomes in pancreatic adenocarcinoma (PDAC) patients: A national analysis.
Authors: Nikravesh Nima , Gresham Gillian , Anderson Eric , Elmadbouh Omer , Thomassian Shant , Moshayedi Natalie , Davelaar John , Lo Simon , Gaddam Srinivas , Nissen Nicholas , Kosari Kambiz , Gangi Alexandra , Pandol Stephen Jacob , Gong Jun , Hendifar Andrew Eugene , Osipov Arsen
Published: June 2022

e16270

Background: PDAC is the third most fatal cancer, where most patients present with metastases at diagnosis. Previous studies, including a retrospective analysis from our single-center experience, suggests survival rates are significantly higher for those with lung-only metastases (mets) when compared to liver metastasis or other sites of metastases (liver+other). The objective of this analysis is to explore this difference based on sites and metastasis and the impact of chemotherapy from a national cohort. Methods: We identified PDAC patients (>18years) from with metastases to either 1) lung-only; 2) liver+other sites in the National Cancer Database diagnosed between 2010 and 2015.We analyzed patient characteristics, demographics, type of chemotherapy, and survival outcomes. Kaplan Meir survival curves were generated, and Cox proportional hazard models adjusted for age and sex were fit to evaluate associations between met site and survival. Survival was calculated from time of diagnosis to death and compared across mets site, receipt of chemotherapy, and treatment and type (single versus multi-agent). Results: 15359 PDAC patients were included in the analysis [51.6% male 48.4% female, mean age 69 years] of which 4512 (29.4%) patients had lung only mets and 10847 (70.6%) had liver + other mets. Median survival was 5.72 and 2.37 months for lung only vs. liver+other mets, respectively (log rank p<0.001). From a subset population of 8440 patients who received chemotherapy, median survival of 9.4 and 4.9 months for lung only and liver+other mets was observed, respectively [Table]. Median OS for single agent chemotherapy was 4.4 months (n=2637), with patients with lung only mets having a median OS of 7.1 months and those with liver+other mets having a median OS of 3.6 months. Median OS for patients treated with multi-agent chemotherapy (n=5380) was 7.4 months, with lung only met patients having a median OS of 11.6 months and those with liver+other mets having a median OS of 6.1 months. Hazard ratios (HR) and 95% confidence intervals (CI) are displayed in the table. Conclusions: In a national cohort, patients with metastatic PDAC and lung-only metastasis had improved survival when compared with liver +other metastasis. Further contemporary research is needed to understand the underlying biology that dictates the survival difference between lung metastasis vs other sites of metastatic disease in pancreatic cancer.[Table: see text]