bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic analyses of esophageal cancer patients with brain metastases.
Authors: Aguirre Luis E. , Yao Jiqiang , Mesa Tania , Wloch Marek , Yoder Sean J. , Brass Shawn , Cen Ling , Fontaine Jacques , Pimiento Jose Mario , Mehta Rutika 
Published: January 2022

341 Background: Brain metastases from esophageal cancer are extremely rare with an estimated incidence of 1.7% but limited survival. Some reports highlight the rich microvascular density of such tumors and their distinctive degree of HER2, HIF1-a and EGFR expression, further emphasizing the potential role of angiogenesis in their neurotropic behavior. With this in mind, we aimed to illustrate the transcriptomic landscape of brain metastases from esophageal cancers and better understand the disease biology. Methods: Following IRB approval, we collected retrospective data on patients with a diagnosis of esophageal cancer with histology-proven brain metastases treated at our institution between 2008 and 2020. We identified 10 adequate, paired samples with available tissue for RNA extraction. Expression data was generated using NanoString TS 360 panels to characterize gene signatures of interest and analyzed using GSEA_4.1.0. Results: All 10 patients were Caucasian, 90% were male. Median age was 63 years. All had adenocarcinoma with G2-G3 histology. Median follow-up was 39.4 mos (95%CI, 27.4 to 51.4). At data cutoff, 6 patients had died. Median OS was 24.6 mos. Median time from curative surgery to CNS recurrence was 8.3 mos. Ninety percent of patients developed brain metastases within 24 mos of surgery. Median time from brain metastases to death was 4.7 mos. Almost a third of patients had HER2 positive disease. 48 gene signatures were analyzed; 5 being significantly enriched between metastatic and primary site accounting for cell cycle, DNA damage repair, MYC, mTOR signaling and immortality and stemness. Out of a pool of 760, significant overlap was seen between 12 genes across the 5 signatures of interest: POLE, LIG1, FEN1 (involved in DNA repair and replication); AURKA and PLK1 (cell proliferation and triggers for G2/M transition), BUB1 (establishment of the mitotic spindle checkpoint and chromosome congression), MCM2 and MCM4 (initiation of genome replication); BRIP1 and RAD51 (critical in homologous recombinational repair); CCNE1 (cell cycle G1/S transition) and WRAP53 (dual role as p53 regulator and protein involved in telomere elongation and DNA repair). ERBB2 was similarly enriched in primary and metastatic sites. Conclusions: These preliminary data demonstrate that the genomic basis of brain metastases in esophageal cancer goes beyond EGFR/ERBB2 signaling. A complex genomic interaction is present in brain metastases as compared to primary site that offers these cells the advantage for neurotropism. To our knowledge this is the first study attempting to illustrate genomic differences between primary and matched brain metastasis sites in esophageal cancer.
Efficacy of immune checkpoint inhibitors for gastrointestinal cancers with SWI/SNF complex genetic alterations.
Authors: Nakata Akinobu , Narita Yukiya , Kumanishi Ryosuke , Nakazawa Taiko , Ogata Takatsugu , Matsubara Yuki , Kodama Hiroyuki , Honda Kazunori , Masuishi Toshiki , Taniguchi Hiroya , Kadowaki Shigenori , Andoh Masashi , Yamaguchi Rui , Tajika Masahiro , Muro Kei 
Published: January 2022

346 Background: SWI/SNF chromatin-remodeling complex is encoded by multi-gene families that are recurrently mutated in cancer. Previous studies reported that tumors harboring SWI/SNF complex genetic alterations (GA) are sensitive to immune checkpoint inhibitors (ICIs), but the clinical significance of SWI/SNF complex GA in patients with gastrointestinal cancers (GICs) is unclear. Methods: We reviewed patients with metastatic GICs who underwent comprehensive genomic profiling (CGP) and received ICIs at our institution between July 2014–June 2021. SWI/SNF complex GA were defined as ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1 alterations. Results: Of 292 patients receiving CGP, 136 patients received ICIs, of which 10 (7.4%) had SWI/SNF GA, including 8 ARID1A (5.9%), 1 ARID2 (0.7%) and 2 SMARCA4 (1.5%) alterations. The subjects included 50 esophageal cancers, 84 gastric cancers, and 2 small intestine cancers. The patients with SWI/SNF complex GA had significantly higher proportions of microsatellite instability-high ( p = 0.004) and lower proportions of esophageal cancer ( p = 0.002), compared with patients without SWI/SNF complex GA. During the median follow-up time of 7.5 months (M), the median overall survival (OS), time-to-treatment failure (TTF), and progression-free survival (PFS) in all patients was 13.2 M ([95% confidence interval [CI] 7.7-21.8 M), 2.2 M (95%CI, 1.8-2.5 M), and 2.3 M (95%CI, 1.9-2.8 M), respectively. The patients with SWI/SNF complex GA had better OS (median, not reached vs 10.3 M; hazard ratio [HR], 0.40 [95% confidence interval [CI] 0.19–0.86]; p = 0.019) than those without SWI/SNF complex GA. The patients with SWI/SNF complex GA tended to have longer TTF (median, 4.7 M vs 2.1 M; HR, 0.67 [95%CI 0.38–1.17]; p = 0.16) and PFS (median, 5.4 M vs 2.2 M; HR, 0.70 [95%CI 0.39–1.27], p = 0.24) than those without SWI/SNF GA. The objective response rate (ORR) and disease control rate (DCR) in all patients was 13.2% (95%CI, 8.0-20.1) and 40.4% (95%CI, 32.1-49.2), respectively. The ORR and DCR of patients with SWI/SNF complex GA tended to be higher than those without SWI/SNF complex GA (ORR, 30.0% vs 11.9%; p = 0.13: DCR, 70.0% vs 38.1%; p = 0.09), with 1 complete response and 2 partial responses in the patients with SWI/SNF complex GA. Conclusions: The patients with GICs who had SWI/SNF complex GA were more likely to benefit from ICI therapy, suggesting that novel ICI-containing chemotherapies targeting SWI/SNF complex GA are needed for GICs.[Table: see text]
Tumor regression grade and overall survival following gastrectomy with neoadjuvant therapy for gastric cancer.
Authors: Savoldy Michelle A , Sinnamon Andrew J , Mehta Rutika , Pena Luis , Dineen Sean P. , Lauwers Gregory Y , Pimiento Jose Mario 
Published: January 2022

355 Background: Perioperative chemotherapy is the standard of care for locoregional gastric cancers in western populations. However, the impact of response to therapy as a biomarker of cancer survival has not been fully defined. This study focuses on the pathological response to neoadjuvant chemotherapy, as measured by tumor regression grade (TRG), for gastric cancer and its impact on patient outcomes, primarily overall survival. Methods: Patients undergoing gastrectomy for nonmetastatic invasive gastric adenocarcinoma following perioperative chemotherapy (clinical T2+/N+cM0) were identified from an institutional database (2000-2021). Demographics, clinical staging including histologic grade, surgical factors and survival outcomes were included. The association between TRG and overall survival from time of surgery was assessed. OS was estimated using the Kaplan Meier method with adjustment for covariates using Cox regression. Results: One hundred seventeen patients were identified. Median age was 65 years (IQR 57–73). The majority of the patients were male (n = 64, 55%). Seventy-six patients underwent total gastrectomy, 22 subtotal gastrectomy, and 19 distal gastrectomy. Six patients (5.1%) had a TRG of 0, 18 patients (15.4%) had a TRG of 1, 25 patients (21.4%) had a TRG of 2, and 68 patients (58.1%) had a TRG of 3. Median survival overall was 40.9 months (95% CI 28.7–66.4). TRG status was not significantly different between chemotherapy regimens (doublet vs triplet, p = 0.96). Median survival was longest in the TRG 0 group (86.9 months), followed sequentially by TRG 1 (74.5 months), TRG 2 (51.5 months), and lastly, TRG 3 group with 27.0 months. Increased tumor regression (lower TRG) was significantly associated with prolonged survival (p < 0.01 by log-rank for trend). After adjustment for clinical patient factors and tumor factors, TRG remained significantly associated with overall survival (Table; TRG hazard ratio 1.62, p = 0.007). In addition to TRG status, clinical T4 tumors and diffuse histology were associated with poor survival (cT4 hazard ratio 2.09, p = 0.039, diffuse histology hazard ratio 1.82 (p = 0.071). Conclusions: In patients receiving perioperative chemotherapy for treatment of gastric cancer, response to therapy as defined by TRG is independently prognostic of survival.[Table: see text]
Characteristics and trends in treatment utilization in young-onset cholangiocarcinoma.
Authors: Reddy Sarah , Goksu Suleyman Yasin , Chowattukunnel Nivan , Hsieh David , Al Matar Salwan , Sanford Nina Niu , Beg Muhammad Shaalan , Kazmi Syed Mohammad Ali 
Published: January 2022

386 Background: Although the incidence of cholangiocarcinoma is rising, little is known about the demographic and clinical characteristics of patients with young-onset cholangiocarcinoma (YOCC), diagnosed at age < 50 years. The objective of this study was to compare patients with YOCC, and patients with typical-onset cholangiocarcinoma (TOCC; diagnosed age >50 years), and to describe trends in treatment utilization and factors associated with survival in YOCC. Methods: We identified patients diagnosed with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and hilar cholangiocarcinoma from the National Cancer Database (NCDB) between 2004 and 2016. Patients were classified as either having YOCC or TOCC. Categorical variables were compared using the chi-square test with Bonferroni correction. Multivariate survival analyses were performed using the Cox-regression model after adjusting for age, gender, race/ethnicity, comorbidity index, insurance status, laterality, definitive surgery, radiotherapy, and chemotherapy. Results: We identified 26,346 patients, of which 2,520 had YOCC (9.6%, median age 44 years) and 23,826 had TOCC (90.4%, median age 68 years). Patients with YOCC were more likely to be non-White (YOCC 35.0% vs. TOCC 27.4%, p <0.01) and had lower overall comorbidity burden. Patients with YOCC were more likely to present with stage IV disease (YOCC 50.5% vs. TOCC 43.5%, p <0.001) and have intrahepatic cholangiocarcinoma (YOCC 56.0% vs. TOCC 45.5%, p<0.001). Patients with YOCC were more likely to receive definitive surgery (YOCC 30.9% vs. TOCC 25.0%, p <0.001) radiation (YOCC 27.7% vs. TOCC 19.0%, p<0.001), and chemotherapy (YOCC 73.1% vs. TOCC 50.4%, p<0.001). In adjusted analyses, patients with YOCC had a 21% decreased risk of death compared to patients with TOCC [HR 0.79 (95% CI 0.75-0.83), p<0.001)]. This remained true for subgroups of patients with intrahepatic disease and those who underwent definitive surgery. Conclusions: YOCC constitutes a small but distinct subgroup of cholangiocarcinoma. Patients with YOCC were more likely to be non-White and present with intrahepatic cholangiocarcinoma disease. Despite being more likely to be diagnosed with advanced stage cholangiocarcinoma, patients with YOCC had better overall survival.
Natural history of patients with advanced cholangiocarcinoma and FGFR2 gene fusions/rearrangements.
Authors: Shroff Rachna T. , Avogadri Francesca , Weng Richard , Li Ai , Dambkowski Carl L. , Lamarca Angela 
Published: January 2022

391 Background: Cholangiocarcinoma (CCA) is a rare malignancy associated with poor survival. Molecular profiling is important to inform treatment choices and FGFR2 fusions or other rearrangements are common, occurring in 10–16% of patients with intrahepatic CCA (iCCA). There is limited real-world data on the natural history of patients with advanced CCA and FGFR2 fusions/rearrangements receiving therapies for advanced disease. The primary objective of this retrospective, observational natural history study was to compare real-world overall survival in patients with advanced CCA and FGFR2 fusions/rearrangements vs. those with wild-type (WT) FGFR2 from the index date of diagnosis of advanced CCA to date of death. A secondary objective was to analyze overall survival in the subgroup of patients with CCA and FGFR2 fusions/rearrangements from the index date of start of second-line therapy to date of death. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine clinico-genomic database. Data originated from approx. 280 US cancer clinics (̃800 sites of care). Patients were ≥18 years of age, had chart-confirmed advanced CCA, comprehensive genomic profiling demonstrating FGFR2 fusion/rearrangement, and had ≥2 visits within the Flatiron Health network since January 1, 2011. Results: As of May 2020, 571 patients met the inclusion criteria; 75 patients with FGFR2 fusions/rearrangements (median age 63 years; 64% female; 95% iCCA; 68% stage IV at initial diagnosis), and 496 patients with WT FGFR2 (median age 65 years; 48% female; 74% iCCA; 55% stage IV at initial diagnosis). Median overall survival from the index date of diagnosis was numerically higher, but not statistically different, for patients with FGFR2 fusions/rearrangements vs. WT FGFR2 (12.1 months [95% CI 8.5−17.1] vs. 7.1 months [95% CI 5.7−8.8]; log rank p = 0.184). 50 patients with FGFR2 fusions/rearrangements (median age 62 years; 70% female; 94% iCCA; 70% stage IV at diagnosis) received second-line therapy. Median real-world overall survival from the index date of second-line therapy was 8.5 months (95% CI 4.1−12.4 months). Conclusions: These real-world overall survival findings did not demonstrate a survival advantage for patients with CCA and FGFR2 fusions/rearrangements vs. WT FGFR2 receiving therapies for advanced disease, although a non-significant trend towards longer overall survival was observed in patients with FGFR2 fusions/rearrangements. FGFR2 status was not a significant predictor of overall survival after adjusting for potential prognostic covariates. An additional analysis is ongoing to compare overall survival from the start of second-line therapy in patients with advanced CCA and FGFR2 fusions/rearrangements vs. those with WT FGFR2.
Ramucirumab for HCC patients who experienced two or more systemic therapy: A multicenter study.
Authors: Yasui Yutaka , Kurosaki Masayuki , Tsuchiya Kaoru , Hayakawa Yuka , Hasebe Chitomi , Abe Masami , OGAWA CHIKARA , Joko Kouji , Tada Toshifumi , Nakamura Shinichiro , Furuta Koichiro , Kimura Hiroyuki , Tsuji Keiji , Kojima Yuji , Akahane Takehiro , Tamada Takashi , Uchida Yasushi , Kondo Masahiko , Mitsuda Akeri , Izumi Namiki ,   Japanese Red Cross Hospital Liver Study Group
Published: January 2022

395 Background: Ramucirumab has been approved for hepatocellular carcinoma (HCC) patients whose α-fetoprotein was≥400 ng/mL as a second-line agent after sorafenib. The present study aimed to clarify the efficacy and safety of ramucirumab including patients who experienced two or more systemic treatments or whose hepatic reserve was deteriorated. Methods: We enrolled 76 unresectable HCC patients from 14 institutes. The data, regarding survival, radiological response, and adverse events were retrospectively collected. This cohort included 35 patients who received more than two molecular targeted agents and 29 Child-Pugh B or C patients. The radiological response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Median overall survival (OS) in the total cohort was 7.5 months (m), whereas it was 7.5 m, 9.8 m, and 6.8 m in patients who were administered ramucirumab as the second-, third-, and fourth-line therapies, respectively. The overall survival of Child-Pugh A patients (n = 47) was significantly longer than that of Child-Pugh B/C patients (n = 29) (OS 10.3 m vs. 6.7m, p = 0.04). Progression-free survival in the second-, third-, and fourth-line therapies was 3.7, 2.2, and 3.4 m, respectively. The best response identified by RECIST version 1.1 was partial response (PR) in one patient and stable disease (SD) in 25 patients, and the disease control rate (DCR) in the study was 49.1%. There were no statistically significant differences in DCR between the treatment courses. Regarding adverse events, there was no difference between the treatment courses. However, peripheral edema, the development of ascites that required the administration of diuretics (Grade ≥ 2), and diarrhea were significantly more frequent in Child-Pugh B/C patients than in Child-Pugh A patients (peripheral edema; 65.5% vs . 31.9%, p = 0.005, ascites; 62.0% vs . 19.1%, p < 0.001, diarrhea; 27.6% vs . 8.5%, p = 0.05). Conclusions: Ramucirumab was useful as a second-line therapy and feasible as a third- or fourth-line treatment for HCC.
Single-center real-world treatment and outcomes in patients with hepatocellular carcinoma receiving immunotherapy.
Authors: Habib Diane , Patel Ronak , Algaze Sandra , Iqbal Syma , Chiu Victor Yundeh , El-Khoueiry Anthony B. 
Published: January 2022

401 Background: Immune checkpoint inhibitor (ICI) based therapy has emerged as a therapeutic option in hepatocellular carcinoma (HCC). Approvals were based on clinical trials with strict eligibility criteria limiting generalizability to clinical practice. Further, there is no established post ICI treatment standard. Methods: Patients (pts) with advanced HCC treated with ICI as single agent (ICI-SA) or in combination (ICI-C) across lines of therapy were included in this retrospective study. Results: The cohort consisted of 118 pts: median age 63 years (24, 88); 84% male; 35% Hispanic/Latino, 26% Asian, 19% Non-Hispanic White, 5% Black and 15% unknown. Etiology of cirrhosis: 13% Hepatitis B, 45% Hepatitis C, 16 % alcohol liver disease, 10% NAFLD and 16 % mixed/other; 73% had baseline Child Pugh (CP) A, 25% had CP-B, and 2% had CP-C; ALBI Scores were ≤ -2.60 in 32%, 2.60 < and ≤-1.39 in 48%, and ≥-1.39 in 19% pts; 62% had extrahepatic disease and/or portal invasion; AFP was ≥ 400 ng/mL in 25% of pts. 81% of pts had prior local therapy. First line systemic therapies were: TKIs in 52 pts (44%), ICI-SA in 42 (36%), ICI-C in 15 (13%), clinical trial agent (CTA) in 8 (7%) and chemotherapy in 1 (1%), with a median duration (dur) of 4 months (95% CI 2.3 to 4). Ninety one (77%) and 61 pts (52%) received ≥ 2 or 3 lines of therapy, respectively. Fifty seven pts had ICI-SA and 14 ICI-C in second line or beyond. Median dur of ICI therapy was 4 months (95% CI 3-5) for all lines. Post-ICI therapies included 11% ICI, 30% CTA and 59% TKIs. TKIs included sorafenib (46%), cabozantinib (27%), lenvatinib (15%), and regorafenib (27%). For the 118 pt cohort, mOS was 14 months (95% CI 12-19). For pts treated with ICI in first line, mOS was 11 months (0, 74); post-ICI mOS was 6 months (95% CI 3-9) and mPFS was 3 months (95% CI 2-3). Thirty one pts received a TKI post ICI; mOS for this subset was 19 months (15, 22); mOS from start of TKI post ICI was 6.5 months (4, 12). On multivariable regression analysis, ALBI score was associated with OS (HR 1.63, p=0.02, CI: 1.08-2.27). Conclusions: Pts with advanced HCC and CP-A or B cirrhosis are able to receive sequential systemic therapy including ICI. Survival outcomes in this cohort are impacted by the inclusion of patients with more compromised liver function and less restrictive pt selection compared to clinical trials. Usage of TKIs post ICI is feasible with suggestion of clinical activity but this is an area in need of prospective studies.
A phase 1 study of ABX196 in combination with nivolumab in patients with previously treated hepatocellular carcinoma (HCC).
Authors: Sigal Darren , Bhangoo Munveer Singh , Frenette Catherine T. , Lee Sunyoung S. , Fark Christine , Gineste Paul , Vissian Anais , Teyton Luc , Pearce Tillman E. , Kaseb Ahmed Omar 
Published: January 2022

429 Background: ABX196, a synthetically modified α-galactosylceramide (α-GalCer), activates invariant NKT (iNKT) cells and produced anti-tumor activity in Hepa 106 xenograft HCC models. Pre-administration of anti-PD1 antibodies prevented α-GalCer-induced iNKT cell anergy and may also enhance iNKT cell-induced T cell response. We report on a phase 1 study evaluating the combination of ABX196 plus nivolumab (N) in HCC patients previously treated with at least 1 line of prior systemic therapy. Methods: In a 3+3 dose escalation design, intramuscular ABX196 was dosed at 0.1, 0.2, or 0.4 µg 120 mins after N infusion on day 1 of every other 28-day cycle. N (240mg) was administered intravenously on day 1 and 15 of each cycle. Key objectives were to assess safety, MTD, and signs of clinical benefit. Study endpoints included incidence and severity of AEs, laboratory parameters, DLTs, ORR, and PFS. Results: 10 patients (8 males, 2 females) were enrolled: median age, 66y (49-76y); median # of prior systemic therapies, 2 (1-3), including 9 patients with prior immune checkpoint inhibitor (ICI) therapy; median # of ABX196 doses, 2.5 (1-8). There were 76 AEs (95% G1/G2) and 1 non-treatment related SAE. Common non-serious AEs included diarrhea (6), malaise/fatigue (6), AST/ALT increase (6), and only 1 injection site reaction. Maximum administered dose was 0.4 μg; MTD not reached. Clinical benefit was observed in 5 patients (50%) including 1 patient with a PR (ORR 10%) and 4 patients with SD (40%). Of these 5 patients, 3 had viral hepatitis. Median PFS for all patients was 113.5 days (49-450 days), but for those with clinical benefit it was 276 days (172-450 days). Conclusions: ABX196 plus N was very well tolerated without any DLTs or treatment emergent SAEs. In this small but heavily pre-treated HCC population, ABX196 plus N demonstrated promising signals of clinical benefit, including in patients with previous ICI therapy. These results support further clinical development of ABX196 in the front-line HCC setting. Clinical trial information: NCT03897543. [Table: see text]