bluuebunny/crossref_metadata_2025 huggingface dataset:
TP53 mutation analysis in gastric cancer and clinical outcomes of patients with metastatic disease treated with anti-angiogenic or standard chemotherapy regimens.
Authors: Fischer Nicholas William , Graziano Francesco , Bagaloni Irene , Di Bartolomeo Maria , Lonardi Sara , Vincenzi Bruno , Fornaro Lorenzo , Ongaro Elena , Aprile Giuseppe , Bisonni Renato , Prisciandaro Michele , Gariépy Jean , Loupakis Fotios , Sarti Donatella , Del Prete Michela , Catalano Vincenzo , Magnani Mauro , Ruzzo Annamaria
Published: May 2020

e16571

Background: Current data support the angiogenic potential of cancer cells with mutant p53 and VEGF-A up-regulation in solid tumors. These findings have renewed interest in the p53 role as a predictive/prognostic factor in cancer therapy. We investigated TP53 mutations in gastric adenocarcinoma (GA) samples of metastatic patients (pts) who underwent anti-angiogenic Paclitaxel-Ramucirumab (PR) therapy. The analysis was also performed in a control group of pts who received first-line chemotherapy (CT) with platinum derivates and fluoropyrimidines. Methods: TP53 mutations were identified by next-generation sequencing in 110 GA primary tumors of two retrospective metastatic series including 48 pts who were treated with second-line PR and 62 pts who received first-line CT with Cisplatin or Oxaliplatin plus 5-Fluorouracil or Capecitabine. Detected TP53 mutations were classified for TP53 mutant-specific residual transcriptional activity scores ( TP53 RTAS) (Fischer NW et al JCI Insight 2018). TP53 RTAS results were used for stratifying pts in survival analyses. Primary end-point was overall survival (OS). Results: In the PR group, TP53 mutations were detected in 29 out of 48 tumor samples (60.4%) with 10 having TP53 RTAS 0%-to-<1%. In the CT group, TP53 mutations were found in 40 out of 62 tumor samples (64.5%) with 11 having TP53 RTAS 0%-to-<1%. In the PR group, the 10 cases with a TP53 mutation causing no residual or minimal activity ( TP53 RTAS 0%-to-<1%) showed better OS in comparison with pts in the remaining groups (wild-type and TP53 RTAS > 1%). This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval 0.17-0.85, p = 0.02). An opposite effect was seen in the CT group with the worst OS in carriers of TP53 RTAS 0%-to-<1% mutations (Hazard Ratio = 2.64, 95% confidence interval 1.17-5.95, p = 0.02). Notably, in the whole group of 110 pts, TP53 mutations (any type) occurred more frequently in the intestinal-type GA group (p = 0.02). Conclusions: Additional studies are warranted to explore the favorable role of TP53 mutations in cancer pts undergoing anti-angiogenic therapies. TP53 mutations frequently occur in GA and these findings would lead to novel tailored therapy strategies in this lethal disease.
Safety Run-In Phase (SRP) cohorts 1 and 2 of the IMMUNIB trial (AIO-HEP-0218/ass): An open-label, single-arm phase II study evaluating safety and efficacy of immunotherapy with PD-L1/L2 inhibition (nivolumab) in combination with receptor tyrosine kinase inhibition (lenvatinib) in advanced stage hepatocellular carcinoma (HCC).
Authors: Mueller Daniel Wilhelm , Siegler Gabriele Margareta , de Toni Enrico , Lindig Udo , Siebler Jurgen , Walker Martin , Al-Batran Salah-Eddin , Vogel Arndt
Published: May 2020

e16601

Background: Immuno-oncology (I-O) drug nivolumab binds to T-cell PD-1 receptor and overcomes tumor induced inhibition of T-cell proliferation and cytokine release caused by PD-L1/L2 interaction. It so enhances the immune system’s natural tumor erasing capacity. In combination with selective targeting of oncogenic signaling pathways by receptor tyrosine kinase inhibitor (TKI) lenvatinib, a markedly improved response rate is expected in patients suffering from advanced stage HCC. Methods: This investigator-initiated phase II trial is designed as a signal generating, single-armed trial. 50 patients are planned in total. Primary endpoints are efficacy (objective response rate acc. to investigator assessed RECIST 1.1) and safety of combination treatment. The trial comprises two successive Safety Run-in Phase (SRP) cohorts, each consisting of 3 consecutively recruited patients, to evaluate safety of defined dose level 0: 240 mg nivolumab i.v. q2w along with 12 mg (≥ 60 kg bw) respectively 8 mg ( < 60 kg bw) lenvatinib p.o. qd. This abstract focuses on safety data from SRP cohort 1 and 2 (6 patients) in which all AEs were evaluated after patients received 2 cycles of IMP in dose level 0. In total, 10 patients have been enrolled into the trial up to now. Results: Summarized over both SRP cohorts, no dose limiting toxicities (DLTs) i.e. selected grade 4 events occurred in the six evaluated patients. 2 SAEs (abdominal infection; not IMP-related; grade 3 / fever; IMP-related; grade 1) and 21 AEs have been documented in 6 patients (most common AEs: hypertension [3x (14%); IMP-related], pain [3x (14%) (flank; extremity; unspecified); not IMP-related] - in total 12 AEs IMP-related and 9 AEs not IMP-related). No grade 5 AE, one grade 4 AE (AST increase; IMP-related) and three grade 3 AEs (Abdominal infection and hepatic encephalopathy; not IMP-related / ALT increase; IMP-related) in two patients have been reported. All other AEs were of grades 1 or 2. No patient discontinued treatment during SRP. Conclusions: Combination treatment with nivolumab 240 mg and lenvatinib 12/8 mg was assessed as safe and well tolerated from the data obtained from 6 patients in two cohorts, each received two combination cycles. Regular recruitment was thus opened in January 2020 and is planned to be completed in Q3/2020. Clinical trial information: NCT03841201 .
Significance of Inter aorto-caval lymph nodes in gall bladder cancer management.
Authors: Singh Kishore , Srivastava Anurita , Srivastava Siddharth , Aggarwal Aditi , Goel Varshu , Rathi Arun Kumar , Saluja Sundeep , Sakhuja Pooja
Published: May 2020

e16607

Background: Gallbladder cancer (GBC) is one of the three leading cancer among women of North and North-east India. The age standardized rate (ASR) for GBC in women of North and north-east India are 11.8/100,000 population and 17.1/100,000 population respectively It is one of the most fatal cancer, characterized by early spread, both local as well as distant. Radical resection is associated with the highest control rates. Presence of inter-aorto-caval lymph nodes (IAC) during preoperative workup is designated as metastatic disease in GBC and radical surgery is deferred. This study attempts to confirm the validity of such an approach. Methods: Between January 2017 and December 2018, 178 patients of GBC were registered at our hospital. Of these, 108 patients with radiologically resectable disease were evaluated preoperatively with endoscopic ultrasound (EUS) to look for IAC lymph nodes lying below the level of the renal vein. Patients with IAC involvement were taken up for chemotherapy while the others underwent upfront surgery. Results: Mean age at presentation was 51.1 (±10.9) years with a female predominance (N = 77, 71.2%). Presenting symptoms were either pain (N = 91, 84.2%) or jaundice (N = 42, 38.8%) in majority cases. Patients with jaundice presented earlier with mean of 53.27 days (Range2-240 days) while those with pain presented at a mean of 71.5 days (1-360 days) prior to diagnosis. Pathologically positive IAC cases (n = 12) of resectable GBC received systemic therapy upfront rather than immediate radical surgery. Rest of the patients underwent surgical resection followed by adjuvant treatment as indicated. Mean follow up was 179 days with a mortality of 62%(n = 67). No significant difference was seen in the stage distribution in IAC positive versus negative group. Median survival with Kaplan Meier method of IAC positive patients was 239 days versus 190 days in IAC negative patients. Conclusions: IAC lymph node may not necessarily portend poor prognosis. It needs to be validated in large sample size.
Efficacy and safety of anlotinib combined with transarterial chemoembolization versus transarterial chemoembolization alone in patients with unresectable hepatocellular carcinoma: A retrospective study.
Authors: Guo Wenbo , Chen Song
Published: May 2020

e16611

Background: HCC is one of the most common cancer among all the malignant tumor, while the efficacy of TACE alone for unresectable HCC patients still remains unsatisfactory. With the development of targeted drug, more and more targeted drugs are applying to the treatment of HCC. Objective: The aim of the stidy is to investigate the efficacy and safety of transarterial chemoembolization (TACE) combined with Anlotinib versus TACE alone in patients with unresectable HCC. Methods: This single-center retrospective study involved 82 patients with unresectable HCC who underwent TACE alone (TA group; n=46) or TACE combined with Anlotinib (TC group; n=36) between Jan 2018 and Jan 2019. The primary outcomes were progression-free survival (PFS) and overall survival (OS), while the secondary outcomes included the objective response rate (ORR), the disease control rate (DCR) and main complications. Results: The TC group showed relatively higher PFS than the TA group (7.35months vs. 5.54 months, p=0.035). The 3-month survival rate was not statistically different between the two groups (97.2% vs. 93.5%, p=0.627), while both the 6-month survival rate and 1-year survival rate were significantly higher in the TC group than in the TA group (83.3% vs. 56.5%, p=0.016; 66.7% vs. 19.6%, p<0.01). ORR in the TA group was significantly higher than in the TC group (77.8% vs. 32.6%, p<0.01), while the two groups showed no statistical difference in DCR (94.4% vs. 82.6%, p=0.17). No treatment-related mortality or grade 4 adverse event was observed, but grade 3 adverse events occurred in two patients in the TC group (one suffered with erythra, and another suffered with hand-foot-skin reaction). Both of them disappeared after prompt treatment. Conclusions: TACE combined with Anlotinib is safe and may improve outcomes for unresectable HCC patients comparing with TACE alone. It still needs more further randomized controlled trials to clarify the potential role of Anlotinib in hepatocellular carcinoma. Key words: Hepatocellular carcinoma; Anlotinib; Transarterial chemoembolization
Impact of tumor histology and socioeconomic factors on survival of patients suffering from malignant vascular tumors of liver and hepatocellular carcinomas: A SEER database analysis.
Authors: Shreenivas Aditya Varnam , Guru Murthy Guru Subramanian , George Ben , Thomas James P. , Chakrabarti Sakti , Kamgar Mandana , Ritch Paul S.
Published: May 2020

e16612

Background: Primary malignant vascular tumors of the liver are rare, aggressive and poorly understood subtypes of liver cancers. In this analysis, we aim to determine the impact of tumor histology and other socio economic factors on survival of these tumors and hepatocellular carcinomas. Methods: Patients with malignant histopathological diagnoses of hepatocellular carcinoma not otherwise specified (HCC NOS), hepatocellular carcinoma with spindle cell (HCC SP), fibrolamellar (HCC F), clear cell (HCC CL), scirrhous (HCC SC) and pleomorphic variants ( HCC PL), combined hepatocellular carcinoma and cholangiocarcinoma (Mixed), hepatic angiosarcoma (AS), hemangioendothelioma (HE), its epithelioid variant (EHE) and hemangiopericytoma (HP) were identified using the SEER (version 2018) database. Overall survival was studied with Kaplan–Meier with the log rank method. Multivariable analysis was performed to assess the impact of race, ethnicity, marital and insurance status on survival of these patients. Results: We analyzed de-identified data of 104502 patients from the year 1973 to 2016 with hepatocellular carcinomas and malignant vascular tumors of liver (including 101851 patients with HCCNOS, 70 with HCC SP, 378 with HCC F, 104 with HCC SC, 593 with HCC CL, 23 with HCC PL, 950 with Mixed, 367 with AS, 36 with HE, 120 with EHE and 10 with HP ) respectively. Median overall survival (OS) of HCC NOS was calculated to be 7 months. Among hepatocellular carcinoma patients HCC F had the longest median OS of 29 months and HCC SP had the shortest median OS of 3months (P < 0.001). Additionally, among patients with malignant vascular tumors, AS had the shortest median OS (1 month) while patients with EHE had the longest median OS of 81 months (P < 0.001). Overall, married and insured patients had a better overall survival than unmarried and uninsured patients (P < 0.04). Conclusions: Malignant vascular tumors of liver are rare in comparison to hepatocellular carcinomas. Spindle cell variant of HCC and liver angiosarcomas carry the worst prognosis and fibrolamellar variant of HCC, hemangioendothelioma (HE) and its epithelioid variant (EHE) have the best prognosis. Insurance and marital status has a positive impact on overall survival of liver cancer patients.
Effect of an lncRNA-associated ceRNA regulatory network in MVI-positive hepatocellular carcinoma on their sensitivity to sorafenib.
Authors: Luo Zhiwen , Bi Xinyu
Published: May 2020

e16615

Background: Microvascular invasion (MVI) is a histological feature of hepatocellular carcinoma (HCC) related to aggressiveness. But different sensitivity to first line targeted drug, sorafenib, in MVI+ HCC has been observed. Long noncoding RNAs (lncRNAs) can act as microRNA (miRNA) sponges to regulate protein-coding gene expression; so lncRNAs are considered as a major part of competitive endogenous RNA (ceRNA) network and have attracted growing attention. We explored the regulatory mechanisms and functional roles of lncRNAs as ceRNAs in MVI+ HCC, and ceRNA network’s potential impact on prognosis and sensitivity to sorafenib in MVI+ HCC patient. Methods: We studied the expression profiles, prognostic value of lncRNA, miRNA, and mRNA from MVI+ HCC patients, established a prognosis-related network of dysregulated ceRNAs and analyzed its role in sensitivity to sorafenib and radiomics features by bioinformatics methods. Results: A ceRNA network including 13 lncRNAs, 3 miRNAs, and 2 mRNAs specific to MVI+ HCC was established. 6 lncRNAs ( ARHGEF7-AS1, ATP2B2-IT1, LINC00330, MUC2, TLR8-AS1 and ZNF385D-AS1), 2 miRNAs ( hsa-mir-206 and hsa-mir-373) and two mRNAs ( PAX3, SIK1) were prognostic biomarkers for MVI+ HCC. PAX3 was an unfavorable prognostic gene (HR = 1.9, 95%CI 1.01 ~ 3.60), while SIK1 favored the prognosis (HR = 0.4, 95%CI 0.19 ~ 0.85). PAX3 as a stratification in recurrence predicting model was used to identify MVI+ HCC with high or low recurrence risk. Datamining into the dataset of phase 3 STORM trial showed no difference in the influence of PAX3 level on the outcome between sorafenib HCC group and placebo HCC group. However, deep datamining into GDSC dataset revealed our high PAX3 group in MVI+ HCC related to resistance to sorafenib ( P = 0.0039). Radiomics features were extracted from CT of MVI+ HCC, and texture analysis in MVI+ HCCs is ongoing. Conclusions: The proposed ceRNA network may help elucidate the regulatory mechanism by which lncRNAs function as ceRNAs and contribute to the pathogenesis of MVI in HCC. Importantly, the candidate lncRNAs, miRNAs, and mRNAs involved in the ceRNA network have shown to be potential therapeutic targets and prognostic biomarkers for MVI+ HCC. PAX3 might play a vital role in the mechanism of sorafenib resistance in MVI+ HCC, exclusively, this aggressive HCC subtype. The ongoing experiments on radiomics might add potent supports to identify sorafenib sensitive MVI+ HCC.
A risk scoring system to predict overall survival for patients with liver cancer.
Authors: Xin Haibei , Zhang Guanxiong , Zhou Wei , Chen Huan , Liang Dandan , Zhang Henghui , Li Nan
Published: May 2020

e16635

Background: Surgical resection is a common curative treatment for patients with primary hepatocellular carcinoma (HCC), and conventional strategies of assessing clinical and pathologic risk factors have been adopted to predict clinic outcomes in patients after curative surgery. We hypothesized that an ensemble learning approach which incorporates multidimensional features would enable effective prediction of patient survival. Methods: We analyzed data from 222 stage II-III HCC patients who underwent surgical resection at Eastern Hepatobiliary Surgery Hospital (Shanghai, China). Baseline information for each patient includes clinical and pathologic risk factors, laboratory tests and in situ immunological profiles. Using machine learning, we developed CoxPH, GBS, CGBS, FSVM and NSVM models for patient overall survival (OS). Models were trained on 155 cases with 48 features. Thirteen-fold cross-validation (CV) was used to measure performance with area under the ROC curve (AUC) and C-Index (CI). The ensemble model was used to predict patient OS and validated on the subsequent 67 cases. Results: For all models tested, immune features, including the fraction of CD68+ and CD8+ cells in tumor, and CD8+ cells in stroma, play a crucial role in predicting patient OS. Using the ensemble CoxPH model (with superior value of AUC and CI), a risk scoring system for patient OS was developed. The scoring system could stratify patients into high-risk or low-risk groups, revealing different prognosis (validation cohort: HR, 6.5, 95% CI, 2.4-18, P = 3.4e-05). The CoxPH model was also predictive of the time to-recurrence (p < 0.0001). In validation set, the scoring system predicted half-year mortality of patients with AUC of 0.9, and 1-year mortality of patients with AUC of 0.897. The scoring system could also predict half-year recurrence and 1-year recurrence with AUC more than 0.83. Conclusions: The machine learning-based risk scoring system offers a novel strategy for incorporating multidimensional risk factors to predict clinic outcome and may help medical practitioners to optimize clinical follow-up or therapeutic interventions. [Table: see text]
Hepatocellular carcinoma with ARID1A mutation is associated with higher TMB and poor survival.
Authors: Peng Yaorong , Gao Bowen , Zhou Zhenyu , Chen Tingting , Xie Wenzhuan , Huang Mengli , Li Wenbin
Published: May 2020

e16667

Background: Hepatocellular carcinoma (HCC) is a heterogeneous disease that lacks molecular predictors of response to available treatments. AT-rich interactive domain 1A (ARID1A), a SWI/SNF chromatin remodeling gene, is commonly mutated in human cancers and hypothesized to be a tumor suppressor gene. In recent years, immune checkpoint blockade immunotherapies (ICIs) are promising therapies for multiple cancers including HCC, and tumor mutation burden (TMB) was an important biomarker to predict the efficacy of ICIs. Besides, previous research reported that ARID1A deficiency was associated with mismatch repair (MMR) in cancer, and may cooperated with ICIs. Methods: Whole exome sequencing data of 10336 pan-cancer patients including 353 HCC patients was obtained from the Cancer Genome Altas (TCGA). Next generation sequencing (NGS) data of 15849 pan-cancer patients including 1926 HCC patients from Chinese clinical dataset were analyzed to explore the correlation between ARID1A gene mutation and TMB. TMB was defined as total number of somatic non-synonymous mutations in coding region. Prognostic data of 136 HCC patients were obtained from the MSK-IMPACT Clinical Sequencing Cohort (MSKCC). Results: In total, 8.62% (891/10336) of pan-cancer patients in TCGA harboring ARID1A mutation and 8.47% (3188/37628) in Chinese cohort, while mutant percentage of HCC was 9.35% (33/353) in TCGA, 9.03% (174/1926) in Chinese cohort, the alternation frequency of ARID1A in two cohorts was no significant difference (P = 0.3334). The medium TMB level of ARID1A mutant group was higher than wild-type group with significant difference both in Chinese pan-cancer and HCC (medium TMB level, P < 0.0001). Results of 18 kinds of ARID1A mutated tumors patients in TCGA cohort indicated that ARID1A mutation was an independent risk factor in liver cancer affecting overall survival (OS, HR 2.43, 95% IC 1.07-5.54, P = 0.0286). Besides, Kaplan-Meier analysis was performed on HCC patients in MSKCC cohort, ARID1A statue resulted in significantly shorter OS (median, 12.2 vs 21.43 months; HR 2.5; P = 0.0092). Conclusions: The results indicated that ARID1A gene mutation was a poor prognostic factor in hepatocellular carcinoma, and these mutational states were associated with higher TMB level, which might be a potential positive biomarker of immunotherapy.
Cabozantinib in advanced hepatocellular carcinoma: Efficacy and safety data from an international multicenter real-world cohort.
Authors: Finkelmeier Fabian , Scheiner Bernhard , Leyh Catherine , Best Jan , Fründt Thorben Wilhelm , Czauderna Carolin , Beutel Alica , Bettinger Dominik , Weiß Johannes , Meischl Tobias , Kuetting Fabian , Waldschmidt Dirk Thomas , Schultheiß Michael , Ettrich Thomas Jens , Weinmann Arndt , Wege Henning , Venerito Marino , Lange Christian , Pinter Matthias , Waidmann Oliver
Published: May 2020

e16668

Background: The multikinase inhibitor cabozantinib has been approved by the European Medicines Agency in November 2018 for hepatocellular carcinoma (HCC) prior treated with sorafenib. We report, to our knowledge, for the first time safety and efficacy data of an international, multicenter, real-world cohort of patients with advanced HCC treated with cabozantinib. Methods: Patients with HCC who were treated with cabozantinib were retrospectively identified across 10 centers in Austria and Germany. Patients´ characteristics, side effects, duration of treatment and survival data were analyzed until January 17, 2020. Results: 74 patients were identified of whom 65 patients were male (88%) and 9 were female (12%). The median age at the start of cabozantinib treatment was 66 years. The most common underlying liver diseases included hepatitis C in 15 (20%), hepatitis B in 6 (8%), alcohol in 17 (23%) and NAFLD/NASH in 20 (27%) patients, respectively. 64 patients (86%) had BCLC stage C and 43 patients (58%) were Child Pugh A. Cabozantinib was used as systemic second- and third-line treatment in 37 (50%), and 25 (34%) patients, respectively. In the remaining patients cabozantinib was used in further lines. The median starting dose was 40 mg (20-60 mg). In 26 patients (35%) a dose reduction due to side effects was performed. Following best responses under cabozantinib were documented: partial response in 4 (5%), stable disease in 22 (30%), and progressive disease in 24 (32%) patients, respectively. 24 patients (32%) had not yet been evaluable. The median duration of cabozantinib treatment was 4.4 months. 35 patients (47%) had died at day of data analysis. The median overall survival from start of cabozantinib treatment was 7.7 months. Most common adverse events were fatigue and diarrhea. Conclusions: Cabozantinib treatment was effective, safe and feasible in patients with advanced HCC. Patients in the real life setting had more advanced liver disease – only 58% of patients were Child A. Duration of treatment was similar to the phase 3 trial (CELESTIAL). However, overall survival was shorter, probably due to more advanced liver disease.
CFL1 to promote proliferation and invasiveness and to regulate NF-κB-mediated inflammatory factors in hepatocellular carcinoma.
Authors: Zhang Chunyan , Dai Qian , Ma Xiaolu , Yang Wenjing , Lv Lihua , Zhu Jie , Zhou Yan , Pan Baishen , Wang Beili , Yang Xinrong , Guo Wei
Published: May 2020

e16669

Background: Cofilin1 (CFL1) is an actin-binding protein that plays an essential role in cytoskeleton regulation. However, its function in hepatocellular carcinoma (HCC) is largely unknown. The aim of study was to investigate the role of CFL1 in HCC. Methods: We used qRT-PCR and western blot assays to detect CFL1 expression. The role of CFL1 in regulating HCC cell growth and invasion were assessed by forced expression and downregulation. A tissue microarray study containing 189 HCC cases was conducted to evaluate the clinical relevance and prognostic significance of CFL1. Results: The expression level of CFL1 in high metastasis cell lines was significantly higher than that in low metastasis lines ( P < 0.05). Knockdown of CFL1 reduced the proliferation and invasion activities of Huh7 and MHHC97H cells ( P < 0.05). Western blot revealed that the cytoplasmic level of the p65 subunit of NF-κB was significantly elevated along with reduced nuclear levels and NF-κB-targeted genes MMP9, BCL2, EZH2, COX2 and VCAM1 levels significantly inhibited n HCC cells silenced for CFL1. Immunohistochemistry in a primary tissue array revealed that CFL1 expression correlated with Tumor encapsulation and microvascular invasion ( P < 0.05). High CFL1 expression patients had significantly higher recurrence and deaths rates (recurrence: 72.9% vs. 42.9%, death: 20.8% vs. 51.1%) than low CFL1 expression patients ( P < 0.001). Conclusions: CFL1 regulate the proliferation and dissemination of HCC and TNF-α induced NF-κB nuclear translocation. CFL1 may serve as a prognostic marker in HCC and might be a promising therapeutic target for suppressing metastasis.
Clinical utility of comprehensive genomic profiling and targeted therapy in biliary tract cancers: A real-world experience.
Authors: Shahid Mahum , Abdallah Mohamed A. , Ellithi Moataz , Abdullah Hafez Mohammad , Nelson Morgan , Solomon Benjamin Maurice , Bleeker Jonathan
Published: May 2020

e16671

Background: Biliary tract cancers (BTC) are a highly aggressive group of malignancies with high mortality and poor prognosis. Chemotherapy is the mainstay of treatment for advanced disease. The role of molecular targeted therapy and immunotherapy using comprehensive genomic profiling (CGP) is evolving. We investigated the role of CGP directed therapy in patients with BTC. Methods: A multi-center retrospective study of CGP done on 35 patients with BTC at Sanford USD Medical Center and Avera McKennan Hospital, Sioux Falls, SD, between 2014 and 2019. 27 patients had cholangiocarcinoma (fifteen intrahepatic, two extrahepatic and ten unclassified), two had gallbladder carcinoma and six had ampullary carcinoma. Results: 22 of 35 BTC (63%) had potentially actionable genetic alterations(GA). Nine of these 22 (41%) received molecular therapy based on CGP. Four patients had microsatellite instability (MSI-H) and two of them received immunotherapy (Table). CDKN2A/B was the most common mutation (23%) followed by PIK3CA (13%), ARID1A (13%) and Tp53(13%). By the end of the follow up period, median overall survival (OS) was 569 days(19 months) for those who received targeted therapy compared to 315 days(10.5 months) for those who did not. (P = 0.051). Conclusions: In this multi-center cohort, 63% of patients had at least one targetable GA. Furthermore, CGP guided treatment decisions in 41% of patients. CGP has the potential to provide clinically meaningful treatment options for patients with BTC. New studies are warranted to further investigate this promising prospect for BTC management. [Table: see text]
Real-world use of second-line treatments in patients with advanced hepatocellular carcinoma (HCC) of varying liver dysfunction: Analysis at a Hispanic-majority cancer center.
Authors: Xia Jeffrey , Arora Sukeshi Patel
Published: May 2020

e16676

Background: Hispanics have a higher incidence of HCC but are underrepresented in clinical trials leading to approvals of new therapies for HCC. Further, there is a lack of prospective trials comparing second-line treatments for HCC. Therefore, we reviewed the treatment patterns and tolerability of second-line treatments for HCC at our Hispanic-majority NCI-designated cancer center. Methods: Retrospective analysis of patients with advanced HCC, diagnosed at Mays Cancer Center at UT Health San Antonio from 1/2015-3/2019, who received second-line therapies, including, tyrosine kinase inhibitors (TKIs; Ie, cabozantinib, regorafenib) and immunotherapy (IO; ie, nivolumab), clinical trials, hospice/best supportive care (BSC). Child Pugh cirrhosis and adverse events were be compared. Results: Median age 59 (n = 58), Hispanics n = 43 (74%), Cause of cirrhosis: HCV 42 (74%), HBV 1, EtOH 33, NAFLD/NASH 13. BMI overweight/obese 33 (57%). Child-Pugh: A 9 (16%), B 30 (52%), C 16 (28%) (Table). BCLC B 6 (10%), C 47 (81%). CLIP: 1-2 (16%), 3 (38%), 4+ (41%). Second-line treatments: TKI (4, 7%), IO (24, 41%), Clinical trials (3, 5%), BSC (24, 41%). Toxicities (Table). Dose interruptions or reductions: All 18 (31%), TKIs 3 (75%), IOs (58%), trials (33%). Conclusions: In our Hispanic-majority cohort, 41% of patients with HCC were not candidates for second-line treatments (BSC). Of those who received second-line treatments, most received IOs, including patients with Child-Pugh B and C cirrhosis, with 58% requiring dose interruptions. Only 5% enrolled on clinical trials. Real-world patients are significantly different than clinical trial populations, and we need more prospective real-world analyses of these treatments to better understand efficacy, tolerability and quality of life. [Table: see text]
PD-L1 expression as a prognostic marker in patients with advanced biliary tract cancer.
Authors: Kim Hyera , Hong Jung Yong , Lee Jeeyun , Park Se Hoon , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki , Kim Seung Tae
Published: May 2020

e16679

Background: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered as a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients. Methods: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score (CPS) positivity. Results: In all 186 patients, the median age was 62 years (range 38-82), and the primary tumor location was intrahepatic cholangiocarcinoma (IH-CCC) in 72 patients (38.7%), extrahepatic (EH)-CCC in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). There were 158 (84.9%) patients with recurrent disease and 28 (15.1%) with metastatic disease. Among the 186 patients, 53 (28.5%) had PD-L1 CPS positivity, and 133 were CPS negative. The median overall survival (OS) of patients with PD-L1 CPS positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. The OS and PFS were not statistically different between groups. In sub-group analysis, EH-CCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p= 0.002) and PFS (7.8 vs. 5.4 months, p= 0.005) than those that were PD-L1 negative. However, this finding was not reproduced in patients with IH-CCC or GB cancer. Univariate analysis of the association between PD-L1 expression and OS in patients with advanced BTC indicated that PD-L1 CPS positivity has a prognostic role in sub-populations older than 60 years (HR 1.743, CI 1.001-3.034, p = 0.050), those with EH-CCC (HR 2.449, CI 1.355-4.426, p = 0.003), and those with liver metastasis (HR 2.511, CI 1.362-4.626, p = 0.003). Conclusions: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EH-CCC but not for patients with IH-CCC or GB cancer.
Sequential treatment with sorafenib (SOR) followed by regorafenib (REG) in patients (pts) with unresectable hepatocellular carcinoma (HCC): Interim analysis of the observational REFINE study.
Authors: Merle Philippe , Lim Ho Yeong , Finn Richard S. , Ikeda Masafumi , Kudo Masatoshi , Frenette Catherine T , Masi Gianluca , Kim Yoon Jun , Gerolami René , Kurosaki Masayuki , Numata Kazushi , Klümpen Heinz-Josef , Zebger-Gong Hong , Fiala-Buskies Sabine , Ozgurdal Kirhan , Qin Shukui ,   on behalf of the REFINE Investigators
Published: May 2020

e16680

Background: REG is approved for the treatment of pts with HCC who previously received SOR, based on results of the phase 3 RESORCE trial. The REFINE study was designed to evaluate the safety and effectiveness of REG in pts with HCC in real-world practice. Methods: This prospective, observational study aims to recruit 1000 pts with unresectable HCC for whom a decision to treat with REG was made by the treating physician prior to enrollment according to the local health authority approved label. The primary endpoint is the incidence of treatment-emergent adverse events (TEAEs) and dose modifications due to TEAEs (NCI-CTCAE v4.03). Secondary endpoints include overall survival (OS) and progression-free survival (investigator assessed). This interim analysis includes the first 500 pts on study for ≥4 months. Results: Of 500 pts enrolled and observed for ≥4 months, 498 received REG and were evaluable (data cut-off: November 11, 2019). Pts were Child-Pugh A 67%, B 11%, C 1%, and missing/not evaluable 21%. Most pts (98%; n = 490) had received prior systemic therapy; 97% (n = 482) had received prior SOR. REG was second line treatment in 81% of pts (n = 403), third line or higher in 17% (n = 87), and first line in 2% (n = 8). Of the 403 pts who received REG second line, 398 (99%) received prior SOR. Among the 482 pts who received SOR in any prior line, the median duration of prior SOR was 4.8 months (interquartile range 2.5–9.6), 45% (n = 216) had a last daily SOR dose of 800 mg, and 8% (n = 40) had a TEAE leading to SOR discontinuation (SOR-intolerant). OS by treatment line is shown in the Table. Among all treated pts, the most frequent TEAEs (any grade) were hand–foot skin reaction (HFSR; 30%), diarrhea (21%), fatigue (16%), and decreased appetite (14%). In SOR-intolerant pts (n = 40), the most frequent TEAEs (any grade) were diarrhea (25%), HFSR (20%), abdominal pain (15%), and decreased appetite (13%). Conclusions: In this interim analysis of REFINE, most pts received REG second line after SOR versus other lines of therapy. Median OS in this subgroup was longer than OS in RESORCE, but the proportion of censored pts was high. The most common TEAEs were similar to those in RESORCE in both the overall cohort and in SOR-intolerant pts. Clinical trial information: NCT03289273 . [Table: see text]
The natural history of fibroblast growth factor receptor (FGFR)-altered cholangiocarcinoma (CCA).
Authors: Goyal Lipika , Lamarca Angela , Strickler John H. , Cecchini Michael , Ahn Daniel H. , Baiev Islam , Boileve Alice , Tazdait Melodie , Hannan Lindsay Marie , Jia Jingquan , Marble Hetal Desai , Barzi Afsaneh , Sahai Vaibhav , Lennerz Jochen K , Kelley Robin Kate , Bekaii-Saab Tanios S. , Javle Milind M. , Uboha Nataliya Volodymyrivna , Harris William P. , Hollebecque Antoine
Published: May 2020

e16686

Background: Genetic alterations in the FGFR pathway are emerging as promising therapeutic targets in CCA. The clinical and molecular features of patients (pts) with CCA harboring FGFR genetic alterations are reported here. Methods: A retrospective chart review was performed in pts with CCA who were found to have an FGFR alteration on tumor molecular profiling as part of routine care between 9/2007 and 12/2019. Data on demographics, risk factors, pathology, molecular characteristics, systemic therapies, radiographical response, time on treatment, and overall survival (OS) were collected in a multi-center collaborative effort across seven academic centers. Results: Among 135 pts with FGFR-altered CCA, the median age at diagnosis was 57 years old (range = 25-92 years), and 80 (59.3%) pts were female, 129 (95.6%) had intrahepatic CCA, and 6 (5.6%) had chronic HBV. At presentation, 28.2% of pts had resectable disease, including 65.0% with Stage I-II, 22.5% with Stage III, and 5.0% with Stage IV. At the time of initial diagnosis, CA19-9 was < 35U/mL in 42.6% of pts. Bone metastases were observed in 41 (30.6%) pts with advanced disease. FGFR2 fusions were the most common FGFR alteration (68.2%), followed by FGFR2 mutations (21.5%), FGFR3 mutations (3.7%), FGFR2 rearrangements (1.5%), FGFR1 amplification (1.5%), and FGFR2 amplification (1.5%). The most common FGFR2 fusion partners were BICC1 (28.3%), SORBS1 (4.4%), POC1B (3.3%), and TACC2 (3.3%). The median lines of palliative systemic therapies received was 3 (range = 0-8), and 40/135 (29.6%) pts received a liver-directed therapy. For the 55 (59.8%) pts with FGFR2 fusions who received gemcitabine/cisplatin as first-line palliative systemic therapy, the median time on treatment was 6.2 months (95% CI: 4.1-9.3). The median OS from time of initial diagnosis was 36.1 months (95% CI: 28.3-51.6) in the FGFR2 fusion positive cohort. Among the 92 pts with FGFR2 fusions, 70 (76.1%) pts received an FGFR inhibitor on a clinical trial; 12 (17.1%) were subsequently treated with a second FGFR inhibitor, and 58.3% stayed on the second FGFR inhibitor for ≥4 months. Pts with a BICC1 fusion partner (n = 16) had an overall response rate of 42.9% on FGFR-selective inhibitors compared to 30.8% in non-BICC1 fusion partners (n = 54). Conclusions: Pts with CCA harboring FGFR alterations were found to have a high rate of normal CA19-9, high rate of bone metastases, and short median time on treatment on first-line palliative gemcitabine/cisplatin. Additional comparative studies are necessary to evaluate these findings.
Diagnostic criteria of pancreatic pathology.
Authors: Neskubina Irina V. , Frantsiyants Elena M. , Kaplieva Irina V. , Surikova Ekaterina I. , Bandovkina Valeria A. , Trepitaki Lidia K. , Nemashkalova Ludmila A. , Aleynov Viacheslav A. , Trifanov Vladimir S. , Mezentsev Stanislav S. , Chernyak Maksim N. , Kit Oleg I. , Snezhko Aleksandr V. , Petrov Dmitry S. , Fomenko Yuriy A.
Published: May 2020

e16696

Background: Vascular endothelial growth factors (VEGF) and their receptors provide malignant tumors with new blood and lymphatic vessels. However, it is unknown whether their level in the blood can help to determine the tumor nature or to distinguish malignant pathology from chronic organ inflammation. The purpose of the study was to reveal the dynamics of VEGF in the blood of patients with chronic pancreatitis and pancreatic cancer. Methods: The study included male patients with chronic pancreatitis (n = 9), pancreatic adenocarcinoma T1-3N0-1M0 (n = 10) and pancreatic neuroendocrine tumors T1-3N0-1M0 (n = 12) before treatment. Healthy males (n = 21) were controls. Blood levels of VEGF-A, VEGF-C, VEGF-R1 and VEGF-R3 were determined by ELISA using standard test systems (Cusabio, China). Results: VEGF-A in the blood of patients with pancreatic cancer increased: in adenocarcinoma by 2.6 times, in neuroendocrine tumors by 1.7 times (p < 0.05), while chronic pancreatitis was characterized with reduced VEGF-A in the blood – 2.2 times lower than in healthy people. Serum concentration of VEGF-C increased only in patients with adenocarcinoma – 1.3 times higher than the norm (p < 0.05). The amount of VEGF-R1 and VEGF-R3 receptors increased in the blood of patients with chronic pancreatitis (by 2.2 and 1.6 times respectively, p < 0.05) and pancreatic neuroendocrine tumors (2.2 and 1.3 times, p < 0.05). Conclusions: The rise of VEGF-A in the blood is a sign of malignant pancreatic pathology; its combination with the accumulation of VEGF-C in the blood is a diagnostic criterion for pancreatic adenocarcinoma, and a combination with an increase in VEGF-R1 and VEGF-R3 is a diagnostic criterion for pancreatic neuroendocrine tumors. In contrast, chronic pancreatitis is characterized by reduced VEGF-A together with the increase in both types of receptors in the blood.
Germline and somatic DNA damage repair gene mutations potentially predict the efficacy of relevant treatment in Chinese patients with pancreatic ductal adenocarcinoma.
Authors: Shui Lin , Peng Yang , Li Shuangshuang , Tian Jiangfang , Cao Dan
Published: May 2020

e16732

Background: PDAC is a fatal disease with molecular heterogeneity, inducing differences in biological behaviour and therapeutic strategy. We conducted a study to reveal the mutation landscape of Chinese PDAC patients, and investigate the predictive role of germline and somatic DNA damage repair (DDR) status in precise treatment. Methods: 195 PDAC patients were enrolled from multiple medical centers of China between Jan 2016 to Nov 2019. Baseline clinical or genetic characteristics, and survival status were collected. NGS were performed on paraffin-embedded resected tissues or peripheral blood using a panel of 417 genes, including 50 DDR-related genes. Survival analysis was conducted using Kaplan-Meier, and Cox proportional hazard regression model. Results: The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Patients with KRAS mutation showed worse OS than those without (p = 0.048). DDR deficiency were identified in 15.38% of overall patients, mainly occurred in BRCA2 (4.62%), ATM (4.10%), RAD50 (1.54%) and MLH1 genes (1.03%). No significant improvement of OS existed between patients with or without DDR mutations (p = 0.88). Treatment with olaparib (adjusted HR, 0.2550; P = 0.0720) or platinum-based chemotherapy (adjusted HR, 0.1308; P = 0.0185) respectively decreased hazard of death in patients with DDR mutation. Besides BRCA gene, ATM mutant patients treated with olaparib harbored prolonged median OS than those without olaparib treatment (22.25 vs 15.2 month). Despite a little higher PD-L1 expression rate were seen in DDR mutant patients (29.17% vs 20.51%), no statistical correlation between tumor mutation burden level and DDR mutation was identified. And in patients treated with PD-1 blockade, 2 patients of DDR wild-type group both had SD, whereas of the remaining 5 patients with DDR deficiency, 1 was evaluated as PR, 3 as SD, and 1 as PD (ORR, 0 wt vs 20% mut). Conclusions: In this multi-center retrospective study, we deciphered the intra-tumoral genetic heterogeneity in Chinese PDAC population, which differs from western patients cohort to some extent. We found the potential role of germline and somatic DDR mutation status in predicting the response to olaparib and platinum-based chemotherapy, especially with BRCA or ATM mutation. However, DDR alteration was limited in prediction of hypermutational status and sensitivity to PD-1 blockade. Our study may provide a valuable evidence for clinical application of DDR mutation as a potential biomarker for precise treatment.
Metabolism-based GP-2250 in combination with gemcitabine as a novel approach to pancreatic cancer: A mouse xenograft study.
Authors: Braumann Chris , Buchholz Marie , Majchrzak - Stiller Britta , Hahn Stephan , Uhl Waldemar , Kasi Anup , Mueller Dr. Thomas
Published: May 2020

e16750

Background: GP-2250, a novel oxathiazine derivative, displayed apoptotic cytotoxicity against various tumor cell lines but not normal cells. It was therefore tested whether its antineoplastic potential - alone or in combination – could be leveraged specifically against pancreatic cancer. Methods: GP-2250 is a cancer metabolism-based therapeutic. It depleted metabolic energy through inhibition of the enzyme GAPDH (glyceraldehyde-3-phosphate dehydrogenase) which is rate limiting for aerobic glycolysis. ATP was decreased in a time- and dose-dependent manner in pancreatic tumor cell lines and ROS was increased. Mitochondrial dysfunction was triggered by an increased expression of Bax and decreased expression of Bcl2, leading to apoptosis. Cytotoxicity of GP-2250 was ROS-dependent. It was blocked by N-acetylcysteine. Results: GP-2250 substantially increased the sensitivity of pancreatic tumor cells to various chemotherapeutics in particular to gemcitabine (Gem). At doses which were inactive or barely active per se, the combination of GP-2250 and Gem caused striking cytotoxicity in patient-derived primary tumor cells in vitro, pointing to a strong synergy between the two agents. This finding was substantiated in vivo by patient-derived xenograft (PDX) studies in nude mice. While GP-2250 and Gem, given as monotherapy (500 mg/kg and 50 mg/kg respectively, 2x/week), showed only a limited antineoplastic response, the combination treatment resulted in a significantly higher anti-tumor activity as shown in further PDX. Tumor regression was found in 5 out of 9 PDX based on RECIST criteria. Stable disease was reached in 3 of the remaining grafts. In 1 xenograft, which was unresponsive to Gem, the combination treatment nevertheless achieved a reduction in tumor growth which significantly exceeded that of GP-2250 monotherapy. Conclusions: GP-2250 is a novel cancer metabolism-based therapeutic. GP-2250, in combination with Gem, strongly reduces tumor growth in patient-derived xenografts exceeding by far the response to monotherapy. GP-2250 is being evaluated in a Phase I clinical trial in patients diagnosed with advanced pancreatic cancer (Clinical Trial NCT03854110).
Osteoclast-like giant cell tumors of the pancreas: Clinical characteristics, genetic testing, and treatment modalities.
Authors: Ueberroth Benjamin Edward , Liu Alex John , Graham Rondell P. , Sonbol Mohamad Bassam , Halfdanarson Thorvardur Ragnar
Published: May 2020

e16752

Background: Undifferentiated osteoclast-like giant cell carcinoma of the pancreas is an aggressive malignancy only described by a few case reports in the literature. In this study, we sought to better characterize this entity by examining patients seen at Mayo Clinic. Methods: This study identified patients with osteoclast-like giant cell carcinoma of the pancreas using Mayo Clinic databases (MN, AZ, FL) from the year 2000 to present. Patient demographics, genetic data, and treatment modalities were reviewed. Kaplan-Meier analysis was used to evaluate median overall survival (mOS) for the cohort as well as mOS and mPFS for treatment subgroups. Results: 15 patients were identified (9 female, 6 male). Median age at diagnosis was 59 years and mOS for all patients was 11.0 mos (95% CI 6.2-15.7 mos). 3 patients (20%) had metastatic disease at diagnosis with the liver being the most common site (n = 3). Metastatic disease was associated with significantly shorter OS (3.5 vs. 14.1 mos, p = 0.005; HR 7.98 [95% CI 1.43-44.4]) compared to locoregional disease (LRD). 4 patients underwent genetic testing. The most common mutation was CDKN2A (n = 3), followed by TP53 (n = 2) and KRAS (n = 2). 13/15 patients had detailed follow-up information. 6/7 patients undergoing chemotherapy received a gemcitabine-based regimen as first line: with capecitabine (n = 2), with nab-paclitaxel (n = 2), or as monotherapy (n = 2). 1 patient received FOLFIRINOX. In patients with LRD and adequate follow-up (n = 11), 8/11 underwent surgical resection and had longer OS compared to those without resection (17.0 vs. 8.4 mos, p = 0.09). No surgical patients received neoadjuvant chemotherapy. 5/8 received adjuvant chemotherapy, 2 did not undergo chemotherapy, and 1 was lost to follow-up after surgery. PFS from time of surgery was 15.3mos (95% CI 5.0-25.6mos). 6 patients (40%) were alive at time of analysis; all 6 underwent surgical resection. Conclusions: Osteoclast-like giant cell carcinoma of the pancreas is a rare malignancy with a poor prognosis, even when diagnosed at an early stage. OS for patients of all stages in this study was less than 1 year suggesting prognosis may be even worse than that of pancreatic adenocarcinoma. The optimal therapy remains unknown but most patients received similar chemotherapy as in adenocarcinoma. Patients with LRD amenable to surgical resection experienced a PFS over 1 year from surgery, possibly associated with OS benefit, however overall prognosis is poor. Further study is warranted on a larger scale to better understand disease course and treatment options.