bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: An international study.
Authors: Casadei-Gardini Andrea , Rimini Margherita , Rimassa Lorenza , Burgio Valentina , Kudo Masatoshi , Tada Toshifumi , Shimose Shigeo , Suda Goki , Yoo Changhoon , Cheon Jaekyng , Pinato David J. James , Scartozzi Mario , Cascinu Stefano 
Published: June 2022

4069 Background: Recently, several evidences have suggested that patients with a no-viral hepatocellular carcinoma (HCC) might be less responsive to immunotherapy and more response to Lenvatinib. Methods: The study population derived from prospectively collected retrospectively analyzed data of patients treated with atezolizumab plus bevacizumab (AB) or lenvatinib (L) or sorafenib (S) as first-line treatment for advanced HCC or intermediate HCC deemed not eligible for loco-regional therapies. The overall cohort included Western and Eastern patient populations from 36 centers located in 4 countries(Italy, Japan, Republic of Korea, and United Kingdom) undergoing treatment with L or AB or with S. The primary endpoint was OS of AB versus L; the secondary endpoints were OS of AB versus S. Results: 569 patients received L, 190 patients received AB and 210 received S. In the whole population OS was 17.8 months (95%CI:15.8-43.8) for patients receiving L, and 12.1 months(95%CI:11.1-16.8)for patients treated with AB (HR 0.71; 95% CI:0.50-1.06; p=0.1028); multivariate analysis for imbalance patients characteristic highlighted that L is an independent prognostic factor for OS (HR 0.65; 95% CI:0.44-0.95; p=0.0268), compared AB. In the population affected by NASH/NAFLD, 254 patients were treated with L and 82 patients were treated with AB. OS was 21.2 months (95% CI:18.4-30.6) for patients receiving L, and 12.2 months (95% CI:10.0-16.8) for patients treated with AB (HR 0.46; 95% CI:0.25-0.88; p = 0.0181); multivariate analysis for imbalance patients characteristic highlighted that L is an independent prognostic factor for OS (HR 0.46; 95% CI:0.26-0.84; p=0.031),compared AB. In the cohort of no viral and no NASH/NAFLD patients, no statistically significant differences were reported in terms of OS between patients treated with L versus AB. All these results were confirmed following propensity score matching analysis. By comparing patients receiving AB versus S, no significant differences were found in terms of OS in the whole population, in the NASH/NAFLD population and in no viral/no NASH/NAFLD population. Conclusions: The present analysis conducted on a large number of non-viral HCC patients showed for the first time a significant survival benefit from lenvatinib over atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.
Patient-reported outcomes from the phase 3 HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.
Authors: Sangro Bruno , Galle Peter R , Kelley Robin Kate , Charoentum Chaiyut , De Toni Enrico N , Ostapenko Yuriy , Heo Jeong , Cheng Ann-Lii , Vogel Arndt , Marcovitz Michelle , Abraham Jayne , Patel Nikunj , Negro Alejandra , Abou-Alfa Ghassan K. 
Published: June 2022

4074 Background: In the Phase 3 HIMALAYA study (NCT03298451) of patients (pts) receiving first-line treatment for unresectable hepatocellular carcinoma (uHCC), a single priming dose of tremelimumab (T; anti-CTLA-4) plus durvalumab (D; anti-PD-L1) in the STRIDE regimen significantly improved overall survival (OS) vs sorafenib (S), and D monotherapy was noninferior to S for OS (Abou-Alfa et al. J Clin Oncol 2022;40[suppl 4]. Abs 379). Methods: A pre-planned secondary objective of HIMALAYA was to assess pt-reported outcomes (PROs) in pts receiving STRIDE (T 300 mg plus D 1500 mg [one dose] plus D 1500 mg once every 4 weeks [Q4W]; N=393) or D (1500 mg Q4W; N=389) vs S (400 mg twice daily; N=389). The European Organisation for Research and Treatment of Cancer (EORTC) 30-item Quality of Life (QoL) Questionnaire and the EORTC 18-item HCC QoL questionnaire were used to assess disease-related symptoms, physical functioning (PF), and Global Health Status (GHS)/QoL. Time to deterioration (TTD), defined as time from randomization to first clinically meaningful deterioration (worsening ≥10 points) confirmed at a subsequent visit or death, was assessed in pts with baseline scores ≤90 for symptoms or ≥10 for PF and GHS/QoL. Results: Across treatment arms, compliance rates for PROs were >77% at baseline and >70% overall. Baseline scores were comparable across treatment arms. TTD in fatigue, appetite loss, abdominal pain, PF, and GHS/QoL were significantly longer for both STRIDE and D vs S (Table). TTD in nausea and abdominal swelling were significantly longer for STRIDE vs S. Conclusions: The positive OS outcomes for STRIDE and D in pts receiving first-line treatment for uHCC in HIMALAYA were associated with clinically meaningful, pt-centered benefits, demonstrated by delayed worsening of disease-related symptoms, PF, and GHS/QoL vs S. Median TTD in months (95% CI) in PROs for STRIDE and D vs S. Clinical trial information: NCT03298451. [Table: see text]
Phase 1b results of a multicenter, randomized phase 1b/2 study of gemcitabine and cisplatin +/- CPI-613 as first-line therapy for patients with advanced biliary tract cancer (BilT-04).
Authors: Sahai Vaibhav , Zhen David Bing , Crysler Oxana V. , Beg Shaalan Shaalan , Enzler Thomas , Griffith Kent A. , Zalupski Mark 
Published: June 2022

4094 Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis despite systemic chemotherapy. Gemcitabine (G) and cisplatin (C) is a standard first-line systemic therapy with a reported overall response rate (ORR) of 26% and median overall survival (OS) of 11.7 months (mo). CPI-613/Devimistat (D) is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and a-ketoglutarate dehydrogenase enzymes of the tricarboxylic (TCA) cycle, preferentially within the mitochondria of cancer cells augmenting chemotherapeutic cytotoxicity. Methods: An investigator-initiated, multi-institutional phase 1b/2 trial is underway across 10 sites in the US investigating the combination of G 1000 mg/m2, C 25 mg/m2 and D (dose levels: (-1) 500, (1) 1000, (2) 1500 and (3) 2000 mg/m2) (GCD) on days 1 and 8 every 21 days in pts with previously untreated advanced BTC. The primary objective of the phase 1b portion (n = 20 pts; TiTE-CRM methodology) was to determine the recommended phase 2 dose (RP2D). The primary objective of the ongoing phase 2 portion (n = 48-58 pts; 2:1 randomization with Bayesian control arm) is to determine the best ORR with an alternative hypothesis of 43% (null of 25%); with 80% power and one-sided alpha of 0.05. Secondary objectives include evaluation of progression-free survival (PFS), OS, and safety. Exploratory objectives include targeted exome/ transcriptomic analysis using tissue, and metabolomic analysis using plasma (pre-, on- and post-treatment). Results: 20 pts were enrolled on phase 1b; median age 65 years (range 43-75), ECOG PS 0/1 (9/11), male/female (11/9), Caucasian (85%), intrahepatic/hilar/distal cholangiocarcinoma and gallbladder (9/5/3/3), and metastatic/locally advanced stage (15/5). CPI-613 dose level assignments were 1 pt each for (-1) and (1), 2 pts on (2), and 16 pts on (3). Median follow-up was 9.4 mos and median number of cycles was 9. Only 1 pt had dose-limiting toxicity (grade 2 creatinine elevation). RP2D for CPI-613 was 2000 mg/m2. In phase 1b, ORR was 40% (7 PR, 1 CR). Median PFS not estimable (NE) but probability of PFS at 9 months was 68.1% [95% CI, 38.1%-85.8%]. Median OS is 16.3 months [95% CI, 9.1-NE]. One locally advanced pt was resected with pathologic CR. Conclusions: The combination of GCD was well tolerated and demonstrates encouraging efficacy with ORR, PFS and OS in phase 1b. The randomized phase 2 portion of the trial is open and accruing patients. Clinical trial information: NCT04203160.
A multicenter, non-randomized, controlled trial to evaluate the efficacy of surgery versus radiofrequency ablation for small hepatocellular carcinoma (SURF-Cohort Trial): Analysis of overall survival.
Authors: Yamashita Tatsuya , Kawaguchi Yoshikuni , Kaneko Shuichi , Takayama Tadatoshi , Izumi Namiki , Yamanaka Naoki , Kudo Masatoshi , Shimada Mitsuo , Inomata Masafumi , Baba Hideo , Koike Kazuhiko , Omata Masao , Makuuchi Masatoshi , Matsuyama Yutaka , Kokudo Norihiro , Hasegawa Kiyoshi 
Published: June 2022

4095 Background: We conducted a multicenter prospective study (SURF trial) to compare the efficacy of surgery vs. radiofrequency ablation (RFA) for small hepatocellular carcinoma (HCC). SURF trial consisted of a randomized controlled trial (SURF-RCT) and a non-randomized prospective observational study (SURF-Cohort), including patients who did not consent to randomization. The initial report of the SURF-Cohort trial showed that recurrence-free survival (RFS) did not differ significantly between patients undergoing surgery and RFA. The focus of the present report was to assess the efficacy for overall survival (OS). Methods: The SURF-Cohort trial was a prospective multicenter study conducted in 49 institutions in Japan. Patients (aged between 29 and 79 years) with Child-Pugh scores ≤ 7, largest HCC diameter ≤ 3 cm, and ≤ 3 HCC nodules were considered eligible. Before the enrollment, both liver surgeons and hepatologists who perform RFA confirm that all the patients can be treated using both surgery and RFA. The co-primary endpoints were RFS and OS. OS was assessed at 5 years after the last accrual as per the protocol. Inverse probability of treatment weighted (IPTW) analysis was used to balance the characteristics of the groups. This trial is registered in UMIN000001796. Results: During 2009–2015, 782 patients were enrolled. After excluding ineligible patients, the surgery and RFA groups included 382 and 371 patients, respectively. In the surgery group, median platelet count (13.7x104 vs. 11.5x104, P< 0.01) was significantly greater, and the median largest HCC diameter was significantly greater (2.0 cm vs. 1.8 cm, P< 0.01) than in the RFA group. The median (range) follow-up period was 6.8 years in the surgery group and 6.7 years in the RFA group. The IPTW-adjusted OS did not differ significantly between the surgery and RFA groups: the 5-year OS, 79.7% vs. 79.3%; HR 0.98; 95% CI 0.75–1.30; P= 0.906. The analysis after long-term follow-up in the current report showed that RFS was not significantly different between the surgery and RFA groups: the 5-year RFS, 44.6% vs. 39.3%; HR 0.86; 95% CI 0.71–1.06; P= 0.155. Conclusions: SURF-Cohort trial revealed that OS and RFS after the IPTW adjustment were not significantly different between patients undergoing surgery and RFA for early stage HCC (≤ 3 cm and 3 nodules). Clinical trial information: UMIN000001796.
Genomic characterization and translational immunotherapy of microsatellite instability-high (MSI-H) in cholangiocarcinoma.
Authors: Yang Xu , Lian Baofeng , Li Yiran , Xue Jinnan , Wang Yunchao , Wang Yanyu , Xun Ziyu , Zhang Nan , Sun Huishan , Long Junyu , Song Zhijian , Lu Leilei , Pan Jie , Zhao Lin , Guan Mei , Yang Xiaobo , Mao Yilei , Sang Xinting , Wang Kai , Zhao Hai-Tao 
Published: June 2022

4101 Background: Microsatellite instability-high (MSI-H) status is a unique genomic state with encouraging effects of PD-1-based therapy in patients with advanced cancer. Cholangiocarcinoma is often driven by genetic mutations. However, the genomic characterization and translational medicine of MSI-H are not clear. Methods: In this study, 881 Chinese patients with cholangiocarcinoma (582 intrahepatic cholangiocarcinoma and 299 extrahepatic cholangiocarcinoma) were enrolled and their genomes were investigated using panel sequencing or whole-exome sequencing. Clinicopathological and genomic features as well as PD-1 inhibitor-based immunotherapy were analyzed by MSI status in patients with cholangiocarcinoma. Results: Overall, 47 (5.3%) cholangiocarcinoma patients were identified as MSI-H patients after enrichment enrollment. Intrahepatic cholangiocarcinoma (ICC) accounted for 74.47% (35/47) of MSI-H patients. Clinicopathological parameters showed younger, ICC-dominated, and more positive PD-L1 expression in MSI-H patients. In the genome of MSI-H cholangiocarcinoma, ACVR2A (75.00%), ARID1A (75.0%), KMT2D (72.2%), TGFBR2 (63.9%), PBRM1 (58.3%), RNF43 (55.6%), TP53 (52.8%) ), ARID1B (47.2%) had a higher mutation frequency. Comparing the SNV and INDEL mutation in the genome, the differential genes between MSI-H and MSS were ARID1A, ACVR2A, KMT2D, TGFBR2, PBRM1, RNF43, LRP1B, ARID1B, etc., respectively. In addition, the differential mutation pathways of MSI-H showed that the mutation rate of DDR, SWI/SNF CellCycle, HRD and other pathways was significantly higher than that of MSS samples. The tumor mutation burden (TMB) in MSI-H patients was significantly higher than that in MSS (P<0.001). In a cohort of 151 CCA patients who received PD-1 inhibitor-based immunotherapy, 19 patients with MSI-H cholangiocarcinoma were found to have a favorable prognosis (1-year survival rate 68.4%). Compared with 132 MSS cholangiocarcinoma patients, Patients with MSI-H cholangiocarcinoma had significantly prolonged OS (Not reach vs. 13.4m, P<0.001, HR=0.17, P <0.001) and high clinical benefit (CBR) (OR=8.16, P <0.001). In this immunotherapy cohort, ≥2 DDR pathway genes and ≥2 SWI/SNF pathway genes mutations, positive PD-L1 expression and TMB-H were also associated with better OS and CBR (both P<0.05). Conclusions: MSI-H cholangiocarcinoma has distinct genomic features, and the effect of PD-1 inhibitors immunotherapy is excellent to these patients. Clinical trial information: NCT03892577.
A descriptive study on the treatment and outcomes of patients with platinum-sensitive, advanced, BRCA- or PALB2-related pancreatic cancer who have progressed on rucaparib.
Authors: Brown Timothy J , O'Hara Mark H. , Teitelbaum Ursina R. , Karasic Thomas Benjamin , Schneider Charles John , Izgur Natallia , Nathanson Katherine L. , Domchek Susan M. , Reiss Kim Anna 
Published: June 2022

4131 Background: We recently reported the results of a single arm phase II study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic variant in BRCA1, BRCA2, or PALB2 (NCT 03140670; Reiss, JCO 2021). However, optimal treatment following progression on PARP inhibitors (PARPi) has not been defined. Here, we report a descriptive study of post-progression treatment and outcomes of this patient population. Methods: Patients with advanced pancreatic cancer and germline or somatic BRCA1, BRCA2, or PALB2mutations treated with at least 16 weeks of platinum-based chemotherapy without progression were enrolled and treated with rucaparib until progression or unacceptable toxicity. At the time of progression, patients were treated with physician-choice chemotherapy. Here we evaluate the objective response rates (ORR) by RECIST 1.1. Overall survival (OS) and time to second progression (PFS2) calculated from trial enrollment and progression free survival on chemotherapy (PFS) by regimen were secondary endpoints. Time-to-event was analyzed by the Kaplan-Meier method and censored at date of last clinic visit, with a cutoff date of 12/10/21. Results: The trial enrolled 42 patients; 31 patients had progressed. Of these, 22 received second-line chemotherapy: nine were treated with an oxaliplatin-based regimen, nine were treated with a cisplatin-based regimen, and four were treated with non-platinum regimens. Demographics were balanced between those who received platinum versus non-platinum. All patients who received second-line chemotherapy regimens met the PFS2 endpoint and all but one patient had died at time of data cutoff. No patients had a complete response, five patients had a partial response (PR). By regimen, 1/9 patients treated with cisplatin had a PR, 3/9 treated with oxaliplatin had a PR, and 1/4 patients treated with non-platinum had a PR. OS, PFS2, PFS, and ORR results by regimen are shown in the table. Conclusions: In this small sample of patients with advanced pancreatic cancer with progressive disease on PARPi, chemotherapy retains some activity. Further study to identify predictors of response and/or resistance to post-PARPi treatment are underway. [Table: see text]
Responses to immune checkpoint inhibition among MSI-H pancreatic ductal adenocarcinoma: A multi-institutional case series.
Authors: Coston Tucker , Starr Jason S. , Sonbol Bassam Bassam , Babiker Hani M. , Mahipal Amit , Chakrabarti Sakti , McWilliams Robert R. , Bekaii-Saab Tanios S. , Desai Aakash , Jones Jeremy Clifton , Ma Wen Wee 
Published: June 2022

4145 Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death. Outcomes remain poor, due to irresectability at diagnosis for many and sub-optimal responses to systemic therapy. Cytotoxic chemotherapy remains the standard of care. High microsatellite instability (MSI-H) predicts response to immune checkpoint inhibition (ICI) in many cancers. Detecting high MSI is rare in PDAC (incidence <2%), but case reports demonstrate potential therapeutic benefit with ICI. Here, we present multi-institutional data to characterize the clinical behavior of MSI-H PDAC, with special attention to response to ICI. Methods: Cases of MSI-H PDAC were obtained by reviewing data of all PDAC patients from our tertiary cancer center who had undergone genomic sequencing by one commercially available platform. The resulting cohort was supplemented with MSI-H PDAC cases identified by GI oncology specialists at multiple institutions. De-identified patient data were compiled and analyzed. Results: 15 MSI-H PDAC patients were identified. 20% had stage II disease at diagnosis, 27% stage III, and 53% stage IV. 73% of patients received ICI (n=11); 40% as 1st line and 33% as 2nd line. These patients demonstrated 100% overall response rate; 45% complete response (1 pathologic CR, 4 radiographic CR) and 55% partial response. No patient that received ICI had lost response or died after a median follow-up of 18 months (range 6-89 mos). 1 patient had oligoprogression of a single hepatic lesion after 7 mos that was then irradiated; this patient retained radiographic CR for 17 subsequent mos (ongoing). In this cohort, we observe poor responses to cytotoxic chemotherapy. In total, 12 regimens were trialed among 9 patients. Overall response rate was 0%. 42% achieved disease stability, with median duration of response of 2 mos; only 2 cases maintained disease stability for >5 mos. 4 patients did not receive ICI; all patients died, with a median survival of 7.5 mos. Conclusions: MSI-H PDAC represents a rare but important subtype of PDAC with unique clinical behavior. Given its rarity, large-scale analyses and trials are unlikely to be performed, making case series such as ours crucial. In our cohort, we observe impressive, durable responses to ICI, along with very poor responses to cytotoxic chemotherapy. Our data argues for consideration of ICI in any patient presenting with MSI-H PDAC, including in the first-line and neoadjuvant settings.
Discrimination of mucinous pancreatic cysts using an enzymatic turnover assay to improve clinical diagnostic accuracy.
Authors: Sheik Daniel , Suresh Vallabh , Byers Kaleb , Rajesh U. Chinna , Caiazza Francesco , Zhu Gina , Craik Charles , Kirkwood Kimberly S. , Davisson V. Jo 
Published: June 2022

4151 Background: One impact of medical imaging technology has been an approximately 3-fold increase in the incidental detection of pancreatic cysts during routine clinical examinations. To reduce burden on the healthcare system and patients, clinicians desire accurate classification of pancreatic cysts into benign non-mucinous or potentially malignant, mucinous populations. Using EUS-FNA, fluid from these cysts can provide molecular biomarkers of predictive value. However, current in vitro diagnostics lack the desired sensitivity and specificity for clinicians to accurately stratify patients for risk of pre-malignant cancers. This situation can be improved by introducing new biomarkers and novel assay platforms. An enzymatic biomarker, pepsin C, has shown high accuracy for diagnosing mucinous cysts. The use of enzymatic activity assays is applicable to clinical workflows without disruption of current standards of care. Methods: A pepsin C activity assay using a magnetic bead-based platform was developed, with both fluorescent and surface-enhanced Raman spectroscopy (SERS) readouts. The assay platform utilizes selective peptide substrates, and a dimeric Rhodamine-6G-based dye, which allows ultrasensitive detection and significantly decreases the sample volume requirement for analysis, down to 1 µL of cyst fluid. The dye-labeled substrate is immobilized on magnetic beads and reacted with enzyme-containing samples to produce a quantitative assay signal that is standardized and expressed in true enzyme activity units. Results: While both readouts were quantitative and produced linear standard curves, SERS-based analysis was more robust against established biological matrix effects than fluorescence. Nevertheless, both assay modes successfully differentiated mucinous and non-mucinous cysts in a retrospective cohort of 69 cyst fluid samples. Compared with the standard of care CEA assay, this activity-based assay displays much improved sensitivity in diagnosing mucinous pancreatic cysts (Table). Conclusions: This pepsin c activity assay differentiates between mucinous and non-mucinous cysts better than the CEA assay and provides a quantifiable standardized readout. This work establishes a path to a true rule-out assay enabling clinicians to better stratify patients into low risk vs. potential malignancy thus impacting treatment and monitoring plans. [Table: see text]
Supportive care (SC) utilization for patients with locally advanced pancreatic cancer: Review of the National Cancer Data Base (2004-2018).
Authors: Cann Christopher G , Shen Chan , LaPelusa Michael Brian , Agarwal Rajiv , Cardin Dana Backlund , Eng Cathy 
Published: June 2022

4154 Background: Pancreatic cancer is a formidable malignancy, with an estimated 62,000 new cases in 2022 and approximately 50,000 deaths. Five-year overall survival remains low at 11%; 14.4% for locally advanced disease. Nearly one-third of newly diagnosed patients (pts) present with locally advanced pancreatic cancer (LAPC) and only a minority of pts (<25%) are eligible for surgical resection. Given the significant morbidity and mortality associated with LAPC, timely integration of SC into the treatment care plan is vital. Methods: Pts diagnosed with Stage II-III LAPC (2004-2018) recorded in the National Cancer Data Base were included, stratified by stage and use of SC (defined as procedures or therapy provided for palliative intent symptom control) from time of diagnosis throughout the disease trajectory. Analyses included tumor characteristics, demographics, and socioeconomic parameters. Multivariate logistic regressions were performed on three sets of data: Stage II, Stage III, and Stage II/III combined. Results: 158,340 pts were included in the cohort [stage II (70.6%); stage III (29.4%)]. Only a minority of pts (2.9%) received SC treatment despite > 65% of pts receiving care at an academic program; 95% living in or near a metro area, and nearly 60% living < 20 miles of their primary treatment center (p <0.001). Medicare (58%) and private insurance (32.8%) was consistent across both stages and SC use. The table depicts selected significant factors and the respective adjusted odds of receiving SC from the three logistic regressions. Conclusions: Our analysis demonstrates the underutilization of SC in LAPC population over the past decade and potential specific demographic/social areas of unmet need. Future work should focus on practice patterns across cancer centers and the significant impact SC has on both survival and quality of life outcomes for LAPC pts. SC should be an integral component incorporated early on in the care of pancreatic cancer regardless of stage. [Table: see text]