bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of durvalumab following multimodality therapy for locally advanced esophageal and GEJ adenocarcinoma: Two-year follow-up results from Big Ten Cancer Research Consortium study.
Authors: Mamdani Hirva , Schneider Bryan J. , Kasi Pashtoon Murtaza , Abushahin Laith I. , Birdas Thomas J. , Kesler Kenneth , Burney Heather , Perkins Susan , Jalal Shadia Ibrahim
Published: February 2020

404

Background: Concurrent chemoradiation(CRT) followed by esophagectomy is a standard of care for locally advanced esophageal(LA-EAC) and GEJ adenocarcinoma. Approximately 50% of patients(pts) experience disease relapse within the 1st yr after treatment(tx) completion. No adjuvant tx has been shown to improve survival in these pts. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown radiation +/- chemotherapy upregulate PD-1/PD-L1 pathway. Methods: We conducted a phase II trial evaluating safety and efficacy of durvalumab(durva) in pts with LA-EAC and GEJ adenocarcinoma who have residual disease in surgical specimen after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1yr. Results: 24 pts were enrolled from 4/2016-1/2018(median age: 60yrs (range, 43-70). 18 received carbo/paclitaxel and 6 received cis/5-FU concurrently with radiation. Staging at diagnosis: T2N0(n = 3, 12.5%), T2N2(n = 3, 12.5%),T3N0(n = 6, 25%), T3N1(n = 6, 25%), T3N2(n = 4, 17%), T3N3(n = 1, 4%), T3Nx(n = 1, 4%).19 pts(79%) had positive lymph nodes(LNs) at the time of surgery following CRT. 12 pts completed 1yr of tx, 12 came off tx because of relapse(6), AEs(5), and consent withdrawal(1). Most common AEs were fatigue(n = 8, 33.3%) and nausea(n = 6, 25%). 3pts (12.5%) developed grade 3 irAEs: pneumonitis(1), hepatitis(1), colitis(1). At median follow up of 21.9mo(range, 1.7-23.9mo), 11 pts have relapsed: 9 distant and 2 locoregional. Two of 3 pts with grade 3 irAEs are alive and disease free at 17 and 23 mo respectively. 1-yr RFS and OS were 79.2% and 95.5%, respectively. RFS at 26 mo was 20.6%. Overall mOS and mOS after relapse were 28.1mo(range, 22.9-28.1) and 11.1 mo(range, 0.1-11.3mo) respectively. The study was expanded to enroll 14 additional pts who are currently undergoing tx. Conclusions: Adjuvant durvalumab following trimodality therapy for LA-EAC and GEJ adenocarcinoma is safe with improvement in 1-yr RFS to 79.2% compared to historical rate of 50%. RFS was 20.6% at 26 months. Evaluation of predictive biomarkers of RFS with durva is underway. Clinical trial information: NCT02639065.
Tumor treating fields (TTFields; 150 kHz) and FOLFOX combination treatment effects on gastric cancer in vitro.
Authors: Zeevi Einav , Gotlib Karnit , Schneiderman Rosa S , Munster Mijal , Porat Yaara , Voloshin Tali , Davidi Shiri , Shteingauz Anna , Kaynan Noa , Giladi Moshe , Kirson Eilon D. , Weinberg Uri , Kinzel Adrian , Palti Yoram
Published: February 2020

406

Background: Gastric cancer is the third most common cause of cancer mortality worldwide, yet long-term survival in gastric cancer remains poor despite systemic therapeutic advances. FOLFOX (oxaliplatin, fluorouracil [5-FU], and leucovorin) is an approved chemotherapy regimen for gastric cancer treatment. Tumor Treating Fields (TTFields) are an antimitotic, loco-regional anticancer treatment delivered via non-invasive application of low intensity (1-3V/cm), intermediate frequency (100-500 kHz), alternating electrical fields. TTFields targets rapidly dividing cancer cells by disrupting microtubules leading to mitotic catastrophe, abnormal chromosome segregation, and apoptosis induction. We investigated the potential use of TTFields alone and in combination with FOLFOX for gastric carcinomas. Methods: Gastric cells (AGS and KATO III) were treated for 72 hours with TTFields (1.1 and 1.7 V/cm, respectively) at frequencies of 100-400 kHz using the inovitro system. Efficacy of TTFields and FOLFOX and its individual components was tested by applying TTFields at the optimal frequency in combination with various drug concentrations. Cell counts, apoptosis induction, clonogenic potential, and overall effect were determined. Results: The optimal TTFields frequency that led to the greatest cell count reduction (AGS, 55%; KATO III, 52%) was 150 kHz. The clonogenic potential was reduced by > 70% in both cell lines. TTFields combined with each FOLFOX component (oxaliplatin, 5-FU, or leucovorin) led to a significant reduction in AGS and KATO III cell survival (2-way ANOVA, P < 0.001 for each cell line) versus each treatment alone. In AGS, TTFields plus FOLFOX combination treatment led to a further reduction in the overall effect (cytotoxic and clonogenic; 79%) versus TTFields alone (65%) and FOLFOX alone (34%). Similar results were observed in KATO III cells. Conclusions: These results suggest that TTFields (150 kHz; optimal frequency) are an effective gastric cancer treatment; and combining TTFields with FOLFOX may further enhance efficacy. There is a strong rational to continue exploring the use of TTFields in combination with standard of care for gastric cancer treatment in the clinical settings.
Impact of postoperative complications on oncologic outcomes after rectal cancer surgery: An analysis of the United States Rectal Cancer Consortium.
Authors: Gamboa Adriana C. , Lee Rachel M. , Turgeon Michael K. , Varlamos Christopher , Regenbogen Scott E. , Hrebinko Katherine , Holder-Murray Jennifer , Wiseman Jason T. , Ejaz Aslam , Feng Michael P. , Hawkins Alexander , Bauer Philip , Silviera Matthew , Maithel Shishir K. , Balch Glen C.
Published: February 2020

41

Background: Postoperative complications (POCs) are associated with worse oncologic outcomes in several cancer types. The implications of complications after rectal cancer surgery are not known. Methods: The US Rectal Cancer Consortium (2007-17) was reviewed for patients with primary rectal adenocarcinoma who underwent R0/R1 low anterior resection (LAR) or abdominoperineal resection (APR). 90-day POCs were categorized as major vs minor and grouped into infectious, cardiopulmonary (CP), thromboembolic (TE), renal, or intestinal dysmotility. Primary outcomes were 5-yr overall survival (OS) and recurrence-free survival (RFS). Results: Of 1136 pts, median age was 59 yrs (IQR 51-67), 61% were male (n = 693), median f/u was 31 mos (IQR 13-54). 70% underwent LAR (n = 799) and 30% APR (n = 337). Complication rate was 46% (n = 527), with 63% minor (n = 330) and 32% major (n = 170). Of all POCs, infectious complications comprised 20% (n = 105), cardiopulmonary 3% (n = 14), thromboembolic 5% (n = 25), renal 9% (n = 46) and intestinal dysmotility 19% (n = 100). When compared to minor or no POCs, major POCs were associated with both worse RFS (48 vs 63 vs 76% p < 0.01) and OS (64 vs 76 vs 80% p < 0.01). While a single POC was associated with worse RFS (61 vs 76% p < 0.01), multiple POCs were associated with worse OS (62% vs 79% p = 0.02). Regardless of complication grade, infectious POCs were associated with worse RFS (56 vs 76% p < 0.01) while CP and TE POCs were associated with worse OS (CP 40 vs 78% p < 0.01; TE 63 vs 78% p < 0.01). Postoperative renal dysfunction was associated with both worse RFS (26 vs 76%, p < 0.001) and OS (62 vs 78% p = 0.01). This persisted on MV analysis for OS when accounting for pathologic stage, receipt of neoadjuvant therapy, and final margin status (CP: HR 3.6 p = 0.01; TE: HR 19.4 p < 0.01; renal: HR 2.4 p = 0.01) and for RFS (infectious: HR 2.1 p < 0.01; renal: HR 3.2 p < 0.01). Conclusions: Major complications after proctectomy for cancer are associated with decreased recurrence-free and overall survival. Given the association of infectious complications and postoperative renal dysfunction with earlier recurrence of disease, efforts must be directed towards defining best practices and standardizing care.
Correlation of tumor mutation with efficacy in patients with gastric cancer who received nivolumab and ramucirumab combination therapy.
Authors: Nakayama Izuma , Shoji Hirokazu , Hara Hiroki , Esaki Taito , Machida Nozomu , Nagashima Kengo , Aoki Kazunori , Honda Kazufumi , Takahari Daisuke , Miyamoto Takahiro , Boku Narikazu , Kato Ken
Published: February 2020

413

Background: Nivolumab (Nivo) plus ramucirumab (Ram) showed promising efficacy in the second-line chemotherapy for advanced gastric cancer (AGC) in NIVORAM study with the 44% of objective response rate (ORR) and 38.6% of 6-month progression free survival (PFS) rate. We investigated the correlation of tumor mutation load and efficacy. Methods: Patients received Nivo (3mg/kg, Q2W) in combination with Ram (8mg/kg, Q2W) until unacceptable toxicity or disease progression. Tissue samples were collected before the treatment, and analyzed for tumor mutation load using Oncomine Tumor Mutation Load Assay. Efficacy included ORR, overall survival (OS), PFS and duration of response. OS and PFS curves were estimated using the Kaplan-Meier method. Hazard ratio (HR) was estimated using the Cox proportional hazards model. Results: By the data cut off of December 15, 2018, the median follow duration on therapy was 13.7 month. Thirty AGC pts who obtained tissue sample were analyzed. Median tumor mutation load (TML) was 6.755 mutation/Mb (range 0.84-19.67). Higher TML (cut-off median) related to better tendency of efficacy with ORR (40.0% vs 20.0%), PFS (5.32 vs 2.33 months) and OS (18.1 vs 10.6 months). 6-month PFS rate was better in TML higher group (48%) compared to TML lower group (18%). In multivariate analysis, higher TML showed 2.030 of hazard ratio (95% CI; 0.849-4.855, p-0.112) for PFS, and 1.915 (95% CI; 0.578-6.343, p=0.287) for OS. Conclusions: The patients with higher tumor mutation load have a better tendency for OS and PFS, among AGC patients who received Nivo and Ram combination therapy. Clinical trial information: NCT02999295.
Molecular landscape of gastric cancer (GC) harboring mutations of histone methyltransferases.
Authors: Wang Jingyuan , Xiu Joanne , Baca Yasmine , Goldberg Richard M. , Philip Philip Agop , Seeber Andreas , Battaglin Francesca , Arai Hiroyuki , Soni Shivani , Tokunaga Ryuma , Zhang Wu , Hwang Jimmy J. , Shields Anthony Frank , Marshall John , Astsaturov Igor A. , Lockhart Albert Craig , Gatalica Zoran , Korn W. Michael , Lenz Heinz-Josef
Published: February 2020

418

Background: Alteration of histone modifications participating in transcription and genomic instability, has been recognized as an important role in tumorigenesis. Aberrant expression of histone-lysine N-methyltransferase 2 ( KMT2) family, which methylate histone H3 on lysine 4, is significantly correlated with poor survival in GC. Understanding how gene mutations of KMT2 family interact to affect cancer progression could lead to new treatment strategies. Methods: A total of 1,245 GC were analyzed using next-generation sequencing (NGS) and immunohistochemistry (IHC; Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations, and MSI status was evaluated by a combination of IHC, fragment analysis and NGS. PD-L1 status was analyzed by IHC (SP142). Gene fusions were detected by Archer (N = 59) or whole-transcriptome sequencing (N = 129). Results: The overall mutation rate of genes in KMT2 family was 10.6% ( KMT2A: 1.7 %, KMT2C: 4.7%, KMT2D: 7.1%). Overall, the mutation rates were significantly higher in KMT2-mutated (MT) GC than KMT2-wild type (WT) GC, except for TP53 (43% vs 63%, p < .0001). Interestingly, among the genes with significant higher mutation rates in KMT2-MT GC, 28% (21/76) of them were related to DNA damage repair (including BRCA1/ 2, RAD50) and 33% (25/76) of them were related to chromatin remodeling (including ARID1A/ 2, SMARCA4). Overexpression of HER2, amplifications of KRAS, CDK6 and HER2 were significant lower, while PCM1 and BCL3 amplifications were significant higher in KMT2-MT, compared to KMT2-WT GC ( p < .05). Significantly higher prevalence of TMB-high ( > 17mut/MB) (49% vs 3%), MSI-H (53% vs 2%), and PD-L1 overexpression (20% vs 7%) were present in KMT2-MT GC, compared to KMT2-WT GC ( p < .001). The rates of fusions involving ARHGAP26 (19% vs 3%, p < .01)and RELA (29% vs 0%, p < .0001) were significantly higher in KMT2-MT than those in KMT2-WT GC. Conclusions: This is the largest study to investigate the distinct genomic landscape between KMT2-MT and WT GC. Our data indicates that KMT2-MT GC patients could potentially benefit from agents targeting DNA damage repair and immunotherapy, which warrants further in-vitro and in-vivo investigation.
Utility of PET-CT CMR after neoadjuvant chemotherapy with DCF for esophageal cancer as a predictive factor of recurrence.
Authors: Kosuke Suzuki , Tomotaka Shibata , Kohei Nishiki , Shoichi Fumoto , Takahiro Hirarsuka , Kohei Kono , Tomonori Akagi , Manabu Tojigamori , Yoshitake Ueda , Hidefumi Shiroshita , Tsuyoshi Etoh , Norio Shiraishi , Masafumi Inomata
Published: February 2020

434

Background: PET-CT is considered as standard modality for evaluating metastasis of esophageal cancer before treatment. On the other hand, it is unclear whether PET-CT CMR (complete metabolic response) could be useful for assessment after neoadjuvant chemotherapy. To clarify the utility of PET-CT CMR as an adequate modality of prediction for recurrence after neoadjuvant chemotherapy with DCF for esophageal cancer. Methods: Fifty-eight cases of esophageal cancer (cStageII-IVa) who received the esophagectomy with neoadjuvant chemotherapy of DCF since June 2013 in Oita University. We evaluated the clinicopathological factors, RFS and OS between CMR group (n=22, 38%) and non-CMR group (n=36, 62%). Results: In the clinical stage before chemotherapy, T-factor was higher in the non-CMR group (p = 0.044), but there were no significant differences of lymph node metastasis (p = 0.27) and stage (p = 0.94) between the two groups. There was no significant difference of the SUV max (16.4 ± 6.5 vs 15.7 ± 6.5, p = 0.98) of the main lesion before chemotherapy and the FDG accumulation rate of lymph nodes (14 cases (63.6%) vs 21 cases) (58.3%), p = 0.69) between the two groups. There were no significant differences of the surgical procedure, lymph node dissection area, number of harvested lymph nodes, amount of bleeding, operation time, curability, and intra/post-operative complications between the two groups. There were 5 cases (15%) with postoperative recurrence in the CMR group (lung 1 case, extra-regional lymph nodes 3 cases, bone 1 case), 17 cases (47%) in the non-CMR group (local 4 cases, lung 3 cases, livers 5 cases, extra regional lymph nodes 6 cases, bone 4 cases, pleura 2 cases), but there was no significant difference between the two groups (p = 0.062). There were significant differences between the two groups for 3-year RFS (81.3 vs 65.3 months, p=0.021) and 3-year OS (93.8 vs 61.6 months, p=0.011). Conclusions: PET-CR CMR could not predict recurrence at present. PET-CR CMR cases had better prognosis compared to non-CMR cases in terms of 3-year RFS and 3-years OS.
Etiological involvement of weak acid reflux in the development of esophageal carcinoma.
Authors: Kono Toru , Sadatomi Daichi , Fujitsuka Naoki , Miyashita Tomoharu , Kaneko Atsushi , Yamamoto Masahiro
Published: February 2020

435

Background: Patients with gastroesophageal reflux disease (GERD) with mixed gastric acid–bile acid reflux are at a high risk of developing reflux-induced esophageal cancer. Increased local production of prostaglandin E2 (PGE2) is etiologically associated with reflux-induced esophageal cancer pathogenesis; however, the underlying mechanism remains unclear. Our aim was to investigate the relationship between PGE2 production in esophageal cells and reflux fluids, particularly gastric acid. The effect of the Kampo medicine Hangeshashinto (HST), which reduced the incidence of reflux-induced esophageal cancer in rats (Surgery 2018), on PGE2 production was also examined. Methods: Esophageal squamous cell carcinoma were treated for 2 h with acidic culture condition (pH 3.5 – 6.5) and chenodeoxycholic acid (CDCA; 200, 400 μmol/L), followed by measurement of PGE2 production in the culture medium for the additional 6 h by enzyme-linked immunosorbent assay. Results: CDCA induced PGE2 production and significantly increased cyclooxygenase-2 (cox-2) expression. However, in weak acidic conditions (pH 4–5), a pH-specific and significant increase in PGE2 production with no increase in cox-2 expression was observed. cPLA2 inhibitor decreased the effect of weak acid stimulation, indicating that the mechanism underlying PGE2 production differs between weak acid and CDCA. In addition, HST significantly inhibited both weak acid- and CDCA-induced PGE2 production. Conclusions: The synergistic effect of bile acid-induced cox-2 expression and weak acid-induced arachidonic acid production via cPLA2 can cause excessive PGE2 production. Therefore, mixed reflux showing pH 4–5 could contribute to the high incidence of esophageal cancer, which might be prevented by HST treatment. Weak acid reflux around pH 4–5 has been observed in PPI-treated patients, who could exhibit excessive PGE2 production as well as increased risk of reflux-induced esophageal cancer.
Genomic correlates of extreme pathologic response following neoadjuvant chemotherapy in locally advanced gastric cancer to reveal distinct vulnerabilities.
Authors: Datta Jashodeep , Walch Henry S. , Russo Ashley , Chatila Walid Khaled , Vos Elvira , Bhanot Umesh , Janjigian Yelena Yuriy , Schultz Nikolaus , Tang Laura H. , Strong Vivian E.
Published: February 2020

441

Background: Clinical factors associated with pathologic response (PResp) following neoadjuvant chemotherapy (NCT) in locally advanced gastric cancer (LAGC) are well studied; however, genomic correlates of such response have not been previously investigated. Methods: Evaluable pre-NCT tumor samples from patients with LAGC who underwent resection and demonstrated extreme pathologic response (EPR; ≤10% PResp: n = 21, ≥80% PResp: n = 19) were sequenced using a targeted exome capture platform. Gene- and signaling pathway-level correlates of EPR and disease-specific survival (DSS) were examined. Results: Of 40 patients, a majority had ≥cT2/N+ disease and were treated with predominantly platinum (98%) or 5-FU (88%) based NCT regimens. Two patients with MSI-high tumors had ≤10% PResp and were excluded from analysis. The EPR cohorts did not differ significantly in demographic or clinical (i.e., tumor location, cT/N status, NCT regimen, extent of gastrectomy, number of lymph nodes examined, or margin status) characteristics. Although EPR cohorts did not differ with respect to tumor differentiation/grade, Lauren classification, proportions of TCGA consensus CIN or GS subtypes, tumors with ≤10% PResp were more likely to have vascular (P < 0.001) and perineural (P = 0.007) invasion. At median follow-up of 31m (IQR 21-57), ≥80% PResp was associated with improved DSS compared with ≤10% PResp (median NR vs. 32m, P = 0.04). On gene-level analysis, tumors with ≤10% PResp were significantly more likely to be ERBB2-altered (32% vs 5%, P = 0.04) compared with ≥80% PResp tumors. Conversely, ARID1A truncating mutations were enriched in tumors with ≥80% vs ≤10% PResp (32% vs 5%, P = 0.04). There was no difference in pathway-level alteration frequency between EPR cohorts. While frequency of oncogenic TP53 alterations was similar between EPR cohorts, TP53-altered tumors were associated with worse DSS vs TP53-wildtype tumors (median 80m vs 24m, P = 0.005) in patients demonstrating ≤10%, but not ≥80%, PResp. Conclusions: Genomic comparison of cohorts demonstrating EPR after NCT in LAGC reveal molecular vulnerabilities with distinct prognostic and therapeutic implications.
Abdominal obesity and risk for esophageal cancer: A nationwide population-based cohort study of South Korea.
Authors: Lee Dong Ho , Cho Jae Ho , Shin Cheol Min , Han Kyungdo , Yoon Hyuk , Park Young Soo , Kim Nayoung
Published: February 2020

446

Background: The relationship between overall obesity, as measured by body mass index (BMI), and risk of esophageal squamous cell carcinoma (ESCC) has been reported, and it has a negative correlation. However, the relationship with abdominal obesity, as measured by waist circumference, may be different. We investigated the association between abdominal obesity and ESCC. Methods: Retrospective cohort study with 22,809,722 individuals who had undergone regular health check-ups provided by the National Health Insurance Corporation between 2009 and 2012 (median follow-up period was 6.4 years) in South Korea. Abdominal obesity was defined as a waist circumference over 90 cm for men and 85 cm for women. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Chi-squared test and Cox proportional hazard model adjusted for confounding factors. Primary outcome was newly developed esophageal cancer. Results: After adjusting for BMI, abdominal obesity increased the risk of ESCC (HR 1.29, 95% CI 1.23–1.36). Waist circumference is associated with increased risk of ESCC in a dose-dependent manner ( P for trend < 0.0001). We analyzed individuals divided into five categories of BMI. Among individuals with overweight (BMI 23–24.9 kg/m2) and obese I (BMI 25–29.9 kg/m2), abdominal obesity was a risk factor associated with developing ESCC (HR 1.22, 95% CI 1.11–1.34; HR 1.28, 95% CI 1.18–1.39, respectively). Conclusions: Abdominal obesity, not BMI itself, is associated with an increased risk for ESCC. Therefore, reducing abdominal obesity may affect decreasing the development of ESCC.
Levels of oncofetal proteins in pathological tissues of patients with gastric cancer.
Authors: Kit Oleg Ivanovich , Frantsiyants Elena M. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Samoylenko Nikolay S.
Published: February 2020

449

Background: Spread to the peritoneal cavity and lymphatic system is the most important factor of gastric cancer prognosis. Successful implantation of cancer cells in a distant place is possible only when cancer cells accept a special kind of molecular invitation sent by some organs. Our purpose was to study levels of CA-19.9, CA-125, CA-72.4 and He-4 in tissues of tumors, peritoneum and omentum in patients with gastric cancer (GC) T3-4aN0-3M1 and T3-4aN0-3M0. Methods: Levels of CA-19.9, CA-125 and CA-72.4 were determined by ELISA in primary tumors, the omentum and peritoneum of patients from main groups 1 (M0) – GC T3-4aN0-3M0 (n = 24) and 2 (M1) – GC T3-4aN0-3M1 (n = 21) and in the stomach, omentum and peritoneum of non-cancer controls (n = 17). Results: Levels of CA-19.9, CA-125 and CA-72.4 were increased, compared to control values, in all studied samples from 1.6 times (CA-72.4) to 180.1 times (СA-19.9). Only CA-19.9 levels differed depending on the metastatic spread: 1.8 times (p˂0.05) higher in T3-4aN0-3M1 than in T3-4aN0-3M0. In the omentum tissues, CA-19.9 levels in T3-4aN0-3M1 exceeded the control values by 20 times; in 20 patients with T3-4aN0-3M0, the value was only 4.1 times higher than in controls and 4.8 times lower than in T3-4aN0-3M1, while in 4 patients it did not differed significantly from the value in T3-4aN0-3M1. In the peritoneal tissues, CA-19.9 levels in T3-4aN0-3M1 exceeded the control values by 19.2 times; in 21 patients with T3-4aN0-3M0, the value was only 2.2 times higher than in controls and 8.5 times lower than in T3-4aN0-3M1, while in 3 patients it did not differed significantly from the value in T3-4aN0-3M1. Conclusions: Saturation of peritoneal and omentum tissues with marker oncoproteins is one of the factors associated with metastatic characteristics of gastric cancer, while the CA-19.9 level can serve as informative laboratory tests to predict the nature of the further disease development.
Prognostic factors in patients with nonmetastatic gastric cancer treated with contemporary multimodality strategies.
Authors: Alfaro Ariceli , Hoang Tuyen , Huynh Jasmine , Ji Jingran , Ko Andrew H. , Cho May Thet , Hiyama Darryl , Dayyani Farshid
Published: February 2020

451

Background: We conducted a retrospective study to evaluate clinical outcomes in patients with non-metastatic gastric adenocarcinoma (nmGA) treated at two high-volume academic institutions within the University of California (UC) system. Methods: Electronic Health Records and California Cancer Registry of demographic and clinical data were collected for pts with nmGA who underwent surgery with curative intent from 2010-2017. Medical chart reviews were conducted to validate outcomes. We used multivariate Cox regression to determine prognostic factors for cancer recurrence and overall survival. Results: Demographics of study cohort (n = 406): mean age 65 years; 71% male; 58% Caucasian, 26% Asian, 13% Latino. There was an even distribution between pts with locoregionally advanced (defined as pT4 or pN1+) vs. localized (pT1-3, pN0) disease. Tumor histology: 49% intestinal, 19% diffuse, 13% mixed, 19% unknown. Type of surgery: 27% open gastrectomy, 59% laparoscopic, 14% unknown. Multimodality therapy: 29% received perioperative systemic rx alone (48% adjuvant only, 52% neoadjuvant +/- adjuvant), 35% received perioperative systemic rx plus radiation (40% adjuvant only, 60% neoadjuvant +/- adjuvant), 36% underwent surgery only. With median f/u time after surgery of 5 years, 21% of pts developed cancer recurrence and 43% had died. Weight loss prior to diagnosis, locoregional stage, and positive resection margins were a/w recurrence (HR = 1.6-2.5, p < .05). Only locoregional stage was prognostic for worse survival (HR = 2.7, p < .0001). Positive resection margins were seen in 6% of pts and were a/w diffuse histology and tumor size > 4cm (odds ratio = 2.9-8.8, p < .02). Multimodality therapy was not a/w recurrence but was a/w longer survival after adjusting for stage (HR = 0.3, p < .0001). Addition of radiation to systemic rx did not confer further improvements in either recurrence or survival. Conclusions: This study highlights contemporary practice patterns for pts with nmGA and demonstrates a survival benefit with multimodality rx. Additional data are being gathered from other UC medical centers to confirm these findings and explore differences across institutions and ethnicities.
Relationship between PET response and pathologic response in distal esophageal/gastroesophageal junction (DE/GEJ) cancers.
Authors: Yu Irene S. , Liu Shiru Lucy , Zhao Yizhou , Lau Sally CM , Lim Howard John
Published: February 2020

452

Background: The utility of PET scans (PETs) to predict outcomes after neoadjuvant treatment of DE/GEJ cancers is unclear. We aimed to explore the relationship between PET response and pathologic/clinical outcomes in a real-world setting. Methods: Patients (pts) with DE/GEJ cancer treated with curative intent perioperative chemotherapy or neoadjuvant chemoradiation followed by surgery in British Columbia from 2009-2018 were included. Retrospective chart review was conducted; pts were stratified into PET responder (R, ≥ 35% decrease in max SUV) and non-responder (NR, < 35%) groups. Chi-square and Kaplan Meier were used to test for associations between variables and outcomes. Results: Of 576 pts identified, 52% had pre- and post-induction PETs; 232 pts proceeded to surgery and were included for analysis. Treatment regimens comprised of CROSS (72%), MAGIC (24%) and FLOT (4%). Median age was 66 (IQR 57-72), 85% male, 91% ECOG 0/1, 62% GEJ involvement, and 81% adenocarcinoma histology. Characteristics and treatment regimens were balanced between the PET-R and PET-NR groups (all p>0.05). Median time from end of treatment to PET was 30 days (IQR 22-36); 67% were PET-R. Pathologic complete response (PCR) rates were similar for PET-R vs. PET-NR (14% vs. 13%, p=0.08). The discordance rate between PET vs. pathologic response was 34% (Table). Aborted surgery rate was higher in the PET-NR group (8% vs. 3%, p=0.03); 70% of aborted cases were due to peritoneal involvement. Median overall survival was similar between the two groups (PET-R 31.5 mo vs. PET-NR 36.1 mo, p=0.62). Conclusions: In our population-based cohort, PET response did not demonstrate prognostic utility and was associated with a significant pathology discordance rate. The role of PET/CT is evolving and the use of post-induction imaging for response assessment and prognostic value may be questionable.

[Table: see text]
Preoperative muscle strength as a predictor of complications after esophagectomy.
Authors: Colcord Madison , Watson Michael D , Gower Nicole Lee , Benbow Jennifer H , Trufan Sally Jeanne , Hill Joshua , Salo Jonathan C.
Published: February 2020

454

Background: Sarcopenia has been associated with post-operative complications and length of stay (LOS) in patients undergoing esophagectomy. A variety of methods exist to measure muscle mass and strength, with few comparisons between methods. We compared hand-grip strength (HGS), muscle mass and intramuscular adipose tissue as predictors of post-operative outcomes. Methods: Patients with esophageal cancer undergoing esophagectomy were identified between January 2015 – June 2019 at Levine Cancer Institute. Skeletal muscle index (SMI) and skeletal muscle density (SMD), a measure of intramuscular adipose tissue, were derived from CT. HGS was measured using a dynamometer. Uni- and multivariable GLM analyses were performed. Results: 115 patients (100 male, 15 female) underwent esophagectomy with an average age of 64.3 +/- 9.8. The analysis was stratified by sex due to significant differences in HGS, SMI, and SMD. Among men, univariable analysis revealed a significant association between pre-operative HGS <25 kg and increased risk of post-operative pneumonia ( p=0.02), ventilation >48hrs ( p=0.02), LOS ( p=0.002), discharge to home ( p=0.001), and one-year mortality ( p=0.005). All associations except discharge home remained significant in multivariable analyses (Table). Among women, no factors analyzed were significantly associated with postoperative outcomes. Conclusions: HGS is a more powerful predictor of postoperative complications and LOS than either muscle mass or intramuscular adipose tissue among men undergoing esophagectomy. HGS is cost-effective and easily incorporated into routine clinical care, allowing for preoperative intervention to optimize patients for esophagectomy. To better understand the implications in women, additional research with a larger cohort is needed. [Table: see text]
Effect of age on swallowing dysfunction after esophagectomy.
Authors: Mann Della , Raj Vishwa , Colcord Madison , Watson Michael D , Trufan Sally Jeanne , Benbow Jennifer H , Gower Nicole Lee , Hill Joshua , Salo Jonathan C.
Published: February 2020

455

Background: Patients undergoing esophagectomy frequently experience malnutrition, which in combination with the catabolic effects of surgery can result in loss of muscle mass and function. Safe swallowing requires the preservation of muscle mass. Modified barium swallow (MBS) enables assessment of postoperative swallowing impairments. We assessed the incidence and risk factors of swallowing dysfunction post-esophagectomy. Methods: Patients with a MBS post-esophagectomy were identified between January 2015-June 2019 at Levine Cancer Institute at Carolinas Medical Center. Swallowing was evaluated with the Penetration Aspiration Scale. Muscle loss was evaluated with pre-operative hand-grip strength (HGS) and skeletal muscle index (SMI) and skeletal muscle density (SMD) from axial CT images. Uni- and multivariable GLM analyses were performed. Results: 91 patients (79 men, 12 women) underwent esophagectomy with an average age of 64.0 + 10.1. Pre-operative HGS, SMI, and SMD all decreased with age. Significant differences existed between sexes in HGS, SMI, and SMD, so the cohort was stratified by sex for analysis. Univariate analysis of male patients revealed older age, lower body mass index (BMI), smoking history, prior feeding tube, and lower pre-operative HGS and SMI were associated with aspiration or penetration on MBS. Among women, no factors analyzed were significantly associated with swallowing dysfunction. Conclusions: Swallowing dysfunction after esophagectomy is correlated with increased age and lower BMI. The role of muscle loss in the risk of aspiration after esophagectomy is not clear. Further research is needed to determine the relationship between these factors with the goal of enabling preoperative physiologic optimization and patient selection. [Table: see text]
A prediction model for pathological findings after neoadjuvant chemoradiotherapy for resectable locally advanced esophageal cancer based on PET images using radiomics and machine-learning.
Authors: Murakami Yuji , Nagata Yasushi , Kawahara Daisuke
Published: February 2020

456

Background: The pathologic complete response (PCR) rate by neoadjuvant chemoradiotherapy (NCRT) for resectable locally advanced esophageal squamous cell carcinoma (ESCC) is about 40%. If we could predict a PCR from pre-treatment image data, it might be possible to select patients who can be cured by organ-preserving CRT. The purpose of this study is to construct a predictive model for PCR by NCRT in patients with locally advanced ESCC using radiomics and machine-learning. Methods: We used data of 98 ESCC patients who underwent NCRT and surgery from 2003 to 2016. Firstly, we fused the radiotherapy treatment planning CT images and PET images scanned before treatment. Then using target delineations on planning CT images, we created eight kinds of target regions on PET images. Secondly, we generated a total of 6968 features per patient using the PET image data within these target regions that were preprocessed by radiomics technique. Among them, we extracted the optimal features for machine-learning using the least absolute shrinkage and selection operator (LASSO) logistic regression. Thirdly, artificial neural networks were used as a machine-learning method to create a predictive model. The extracted radiomics features were used as input values, and the information of ‘PCR’ or ‘not PCR’ was used as output values. We used data of randomly selected 58 patients for training and constructed a predictive model. Then we used data of 15 patients to validate the models and created the optimal model. Finally, we evaluated the predictive model using the test data of 25 patients. Results: By the LASSO analysis, 32 radiomics features were extracted for machine-learning classification. This predictive model predicted pathological findings after NCRT in 24 of 25 test data. The accuracy, specificity and sensitivity in the prediction of PCR after NCRT by this predictive model were 96.0%, 93.8%, and 100%, respectively. Conclusions: A prediction model based on PET images using radiomics and machine-learning could predict pathological findings after NCRT for resectable locally advanced ESCC.
Effect of baseline medications on response to immunotherapy in hepatocellular carcinoma.
Authors: Jun Tomi , Dharmapuri Sirish , Marron Thomas Urban , Sung Max W. , Ang Celina
Published: February 2020

484

Background: Immunotherapy (IO) response rates in advanced hepatocellular carcinoma (HCC) are less than 20%. The microbiome has been shown to mediate IO response in experimental models, and clinical studies have observed that antibiotics, especially prior to IO initiation, are associated with reduced IO response. We reasoned that commonly prescribed antacid medications, such as proton pump inhibitors (PPIs) and histamine receptor antagonists (H2RAs), which are known to influence the microbiome, may also influence IO response. Methods: This is a retrospective chart review-based study of 95 patients with advanced HCC treated with IO at a single academic medical center. The primary outcome was overall survival (OS). The secondary outcome was overall response rate (ORR). The primary predictors were antibiotic or antacid exposure in the 60 days prior to IO. A secondary predictor was antibiotic or antacid exposure in the 30 days prior to IO. Results: The cohort was predominantly male (84%), was racially diverse (31% White, 23% Black, 23% Asian, 13% Hispanic), and had a median age of 65 years. There were 49 deaths with a median follow up of 0.96 years. The most common underlying liver diseases were HCV (49%), HBV (31%), and NASH (11%). The majority of patients had cirrhosis (80%), with a median Child Pugh score of 6. Within 60 days before IO, 25 patients received antibiotics, 40 received PPIs and 5 received H2RAs. Most patients receiving antibiotics also received a PPI (92%). The median duration of antibiotics was 5 days. Neither antibiotic nor antacid exposure within 60 or 30 days prior to IO was significantly correlated with OS in univariate or multivariate analyses, nor were they correlated with ORR. Conclusions: No significant associations between baseline exposure to antibiotics and antibiotics and OS or ORR were identified in this single-institution study. Larger observational studies or mechanistic studies are needed to clarify interactions between medications, the microbiome, and IO response.

[Table: see text]
IGF-1 Child-Turcotte-Pugh score as a predictor of overall survival to therapy in CTP-A, BCLC stage C patients with advanced hepatocellular carcinoma.
Authors: Abugabal Yehia I. , Qayyum Aliya , Hassan Manal , Xiao Lianchun , Duda Dan G. , Hatia Rikita , Lee Sunyoung S. , Wolff Robert A. , Pestana Roberto , Morris Jeffrey , Yao James C. , Amin Hesham M. , Kaseb Ahmed Omar
Published: February 2020

488

Background: Child-Turcotte-Pugh (CTP) A is the standard population for active HCC therapy. The IGF-CTP score, comprises levels of type 1 insulin-like growth factor (IGF-1), bilirubin, INR, and albumin, significantly improved the prediction of overall survival (OS) in recently published studies. Our current study aimed to investigate the accuracy of the IGF-CTP score in predicting OS in HCC Child-Pugh A patients (pts) treated with local and/or systemic therapies (tx). The overall hypothesis is that the IGF-CTP score can further distinguish CP-A pts in terms of overall survival, PFS. Methods: Between 2014 and 2018, a total of 274 pts with new advanced HCC BCLC stage who had available baseline plasma IGF-1 level were retrospectively enrolled. Clinicopathologic features and treatment history were collected. We calculated IGF-CTP scores, used Kaplan-Meier method and log rank test to estimate and compare time to event outcomes between subgroups of patients. Results: 198 pts were CTP Class A, 209 patient underwent systemic tx, 65 underwent local tx [see table]; 161 were re-classified as IGF-CTP-A with a median OS of 16.09 months (95% CI = 13.06 to 23.29 months) (p <0.0001), whereas 37 patients were reclassified as intermediate risk (IGF-CTP-B) and had significantly shorter OS of 10.66 months (95% CI = 5.49 to 26.51) (p <0.0001). Conclusions: The results of this study support our biologically-driven hypothesis that IGF-CTP score is predictive of overall survival to therapy in advanced HCC treated with local and/or systemic therapy. Among HCC pts with CTP-A class, some are reclassified as IGF-CP-B/C and were found to have significantly poorer prognosis in terms of shorter OS. Future validation of the predictive ability of our IGF-1 score may lead to adopting it as a stratification tool in clinical trials as well as to predict HCC outcome and guide therapy decision in routine practice.

[Table: see text]
Impact of population center (PC) size on access to care in advanced hepatocellular carcinoma (HCC).
Authors: Yu Irene S. , Liu Shiru Lucy , Zaborska Valeriya O. , Raycraft Tyler , Davies Janine Marie
Published: February 2020

489

Background: To evaluate access to subspecialists, local therapies, treatment at a specialized HCC center, and survival in advanced HCC patients (pts) based on geographical distribution. Methods: Retrospective chart review was performed on HCC pts who received sorafenib in British Columbia from 2008 to 2016. Pts were stratified by Statistics Canada PC size criteria: large urban PC (LUPC), medium urban PC (MUPC), and small urban PC (SUPC). Chi-square tests and Kaplan Meier were used to analyze the groups. Results: Of 288 pts, geographical distribution was: LUPC 75%, MUPC 16%, SUPC 8%, and rural 0.3%. Age, gender, and ECOG performance status were similar; a higher proportion of Asians (50 vs 9 vs 4%), Child Pugh A (93 vs 83 vs 83%), and hepatitis B (37 vs 15 vs 4%) was observed in LUPC vs MUPC and SUPC, respectively. SUPC pts were less likely to see a hepatologist (p=0.04, Table); access to other subspecialists was similar. Pts from LUPC were more likely to have transarterial chemoembolization compared to MUPC and SUPC (38 vs 20 vs 21%; p=0.04); receipt of other local therapies was similar. Sixty percent were treated at a specialized HCC center and were more likely to see a hepatologist (83 vs 19%), hepatobiliary surgeon (57 vs 42%), and/or interventional radiologist (32 vs 13%) (all p<0.01). Median OS was higher for pts treated at a HCC center (24.7 vs 13.2 mo, p<0.01), but similar when stratified by PC size (overall mOS 19.3 mo, p=0.59). Conclusions: Geography did not significantly impact access to care or survival, but pts treated at a specialized HCC center have improved survival. Further research is needed to better understand social and clinical factors that influence these findings. [Table: see text]
Efficacy and safety of lenvatinib (LEN) in Korean patients (pts) with advanced hepatocellular carcinoma (aHCC): Multicenter retrospective analysis.
Authors: Cheon Jaekyung , Yoo Changhoon , Bang Yeonghak , Chon Hong Jae , Ryoo Baek-Yeol
Published: February 2020

490

Background: LEN has demonstrated the efficacy and safety in pts with aHCC as first-line treatment in the pivotal REFLECT trial. Further evaluation in real-world setting is necessary to measure the clinical outcomes of LEN in daily practice. Methods: This is a multicenter retrospective analysis from 3 Korean referral cancer institutions. Between September 2018 and August 2019, a total of 74 pts received LEN for the management of BCLC B or C aHCC, and 66 pts who had at least one follow-up visit after the start of LEN were included in this analysis. Results: Median age was 58 years (range, 19-81), and 46 pts (69.7%) were male. Baseline characteristics were as follows; Child-Pugh class A/B/C in 46 (69.7%)/14 (21.2%)/6 (9.1%), BCLC B/C/D in 1 (1.5%)/63 (95.5%)/2 (3.0%), prior systemic therapy in 25 (37.9%) including 14 (21.2%) with prior immune checkpoint inhibitors (ICIs). LEN was used as first/second/third to fourth lines of therapy in 41 (62.1%)/13 (19.7%)/12 (18.2%) pts, and 27 (40.9%) had extensive disease extent excluded in the REFLECT trial. With a median follow-up duration of 4.8 months (95% CI, 3.4–6.1), the median PFS and OS were 4.6 (95% CI, 3.2-6.0) and 7.5 months (mo) (95% CI, 3.7–11.2), respectively, in overall pts: first-line setting, 4.2 (95% CI, 3.2-5.2) and 6.5 mo (95% CI, 5.0-8.1), respectively; ≥ second-line setting, 6.1 mo (95% CI, 3.6–8.5) and not reached, respectively. In pts with prior ICIs, median PFS was 6.1 mo (95% CI, 1.8-8.4) and median OS was not reached. According to the RECIST v 1.1, response rates and disease control rate were 12.1% and 71.2%, respectively, in overall pts. The most common grade 3-4 toxicities were hyperbilirubinemia (n=9, 13.6%), AST elevation (n=5, 7.6%), diarrhea (n=4, 6.1%) and fatigue (n=4, 6.1%). Conclusions: LEN was effective and well tolerated in pts with aHCC in Korean real-life setting.
The impact of skeletal muscle loss for hepatocellular carcinoma treated with lenvatinib.
Authors: Okada Mao , Nakanishi Hiroyuki , Kurosaki Masayuki , Inada Kento , Kirino Sakura , Yamashita Koji , Sekiguchi Shuhei , Hayakawa Yuka , Osawa Leona , Wang Wan , Higuchi Mayu , Takaura Kenta , Maeyashiki Chiaki , Kaneko Shun , Tamaki Nobuharu , Yasui Yutaka , Tsuchiya Kaoru , Itakura Jun , Takahashi Yuka , Izumi Namiki
Published: February 2020

493

Background: Many previous reports have shown that skeletal muscle loss (SML) is one of the prognostic factors for hepatocellular carcinoma (HCC) patients treated with sorafenib. However, there are few reports about the impact of SML for the HCC patients treated with lenvatinib. Therefore, we evaluated the relation between SML and overall survival (OS) of HCC patients treated with lenvatinib (LEN). Methods: We retrospectively analyzed 50 HCC patients treated with LEN from April 2018 to February 2019. We included 36 patients who continued LEN more than 8 weeks and evaluated CT scans before treatment and after 8 weeks. Skeletal muscle area was measured on axial image at the level of the third lumber vertebra (L3) using sliceOmatic. Skeletal Mass Index (SMI) was calculated by dividing the muscle area (㎠) with square of height (㎡). The definition of myopenia is based on the guideline described by the Japan Society of Hepatology (42㎠/㎡ in men and 38 ㎠/㎡ in women). ΔSMI is a chronological change of SMI for 8 weeks. We calculated decreasing rate of ΔSMI. We evaluated the relation between chronological change of SMI and OS. Results: The patients with myopenia at baseline were 12 (33.3 %). The decreasing rate of ΔSMI at 8 weeks was -2.57 % [-5.9, 0.2]. SMI had decreased in 27 patients (75 %) for 8 weeks. There was no significant difference between OS and baseline myopenia (p = 0.2), ALBI grade (p = 0.2), BCLC stage (p = 0.5), up to 7 in or out (p = 0.35), previous TKI treatment (p = 0.15), metastasis (p = 0.91), or vascular invasion (p = 0.12). However, the patients who had decreased SMI had significantly poor prognosis (p = 0.028). In backgrounds, there was no significant difference between patients with or without decreasing of ΔSMI, such as baseline myopenia (p = 0.7), ALBI grade (p = 0.4), BCLC stage (p = 1.0), Child Pugh score (p = 0.8), age (p = 0.6), sex (p = 0.3), up to7 in or out (p = 1.0), previous TKI treatment (p = 0.3), and relative dose intensity at 4 weeks (p = 0.9). Conclusions: There was no significant correlation between baseline myopenia and OS. However, chronological decreasing of SMI for 8 weeks was a prognostic factor of HCC patients treated with LEN. Therefore, monitoring and preventing of decreasing of skeletal muscle mass may be important.