bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of anti-PD-1 antibody dostarlimab in patients (pts) with mismatch repair deficient (dMMR) GI cancers.
Authors: Andre Thierry , Berton Dominique , De Braud Filippo G. , Curigliano Giuseppe , Guo Wei , Danaee Hadi , Lu Sharon , Im Ellie , Starling Naureen 
Published: February 2020

218 Background: Dostarlimab (TSR-042) is an investigational humanized anti-PD-1 monoclonal antibody that binds the PD-1 receptor, blocking the interaction with ligands PD-L1 and PD-L2. The ongoing GARNET trial (NCT02715284) is evaluating dostarlimab in pts with advanced solid tumors. Here we present safety and efficacy data from cohort F. Methods: Cohort F in the GARNET trial enrolled pts with dMMR or microsatellite instability high (MSI-H) non-endometrial solid tumors, the majority of which were GI in origin. Pts must have progressed following prior systemic therapy for advanced disease, assessed by independent central review (ICR). Pts received 500 mg dostarlimab Q3W for 4 cycles and 1000 mg Q6W thereafter. Objective response rate (ORR) and duration of response (DOR) were assessed by ICR per RECIST v1.1. Pts were included in the efficacy analysis if they received ≥1 dose of dostarlimab, had measurable disease at baseline, and ≥24 weeks of follow up. All pts who received ≥1 dose were included in the safety analysis. Results: 109 pts were included in the safety analysis, with 48 dMMR pts in the efficacy analysis. Of the 48 pts, 42 (88%) had GI tumors. Confirmed ORR in dMMR pts was 43.8% (95% CI: 29.5, 58.8), with a complete response rate of 8.3%. ORR was consistent across tumor type (Table). Median DOR was not reached. The probability of maintaining response at 12 months was 85.9%. Treatment-related adverse events (TRAEs) were reported in 55% of pts; 7.3% of pts experienced grade ≥3 TRAEs, including 1 each of adrenal insufficiency, rash, diarrhea, and fatigue. Treatment-related serious AEs (SAEs) were reported in 6 (5.5%) pts, and 2 pts (1.8%) discontinued dostarlimab due to a TRAE. No treatment-related deaths were reported. Conclusions: Dostarlimab demonstrated robust, durable antitumor activity in a cohort of dMMR solid tumor pts, the majority of whom had GI cancers, with an acceptable safety profile. Clinical trial information: NCT02715284. [Table: see text]
Minimally invasive colorectal resection: Association with elevated levels of plasma TIM-3 post surgery and effect on immune tolerance and the growth of residual metastases.
Authors: Shantha Kumara Hmc , Mitra Neil , Niyagama Gamage Dasuni , Yan Xiaohong , Cekic Vesna , Baxter Kathy , Whelan Richard L. 
Published: February 2020

219 Background: TIM-3 (T cell immunoglobulin and mucin domain-3) is a type I transmembrane glycoprotein expressed on CD4+ T helper 1 (Th1) and CD8+ T cytotoxic 1 (Tc1) T cells and endothelial cells. TIM-3, after binding to its ligand, Galectin-9, inhibits anti-tumor immune function. Co-expression of TIM-3 and PD-1 together is associated with enhanced dysfunctionality of tumor toxic CD8+ T cells. The combination of TIM-3 blockade with anti-PD-1 /PDL1 intervening therapy may enhance response. Tim-3 over expression has been associated with oncogenic activity in colorectal cancer(CRC). Persistently elevated plasma PDL1 levels after CRC resection have been reported. This study’s purpose was to measure plasma TIM3 levels before and during the first month after minimally invasive colorectal resection (MICR) for CRC. Methods: CRC patients (pts) in an IRB approved data/plasma bank who underwent MICR for whom plasma samples were available were studied. Clinical/pathologic data were reviewed. Blood samples were collected preoperatively (PreOp) and at 6 post-operative (Postop) time points (POD 1, 3, 7-13, 14-20, 21-27, 28-41) and processed. TIM3 levels were analyzed in duplicate using ELISA. Wilcoxon paired t-test was used for analysis. Results: A total of 96 CRC pts who had MICR met the study criteria (colon 72%; rectal 28%; mean age 64.8± 13.3). Compared to the mean PreOp plasma TIM3 levels (2619 ± 1410,n = 96;pg/ml ), significantly higher levels (p < 0.001)were noted on (POD)1(2823±1504,n = 95), POD3 (3469±1755,n = 89), POD7-13 (4317±1957,n = 79),POD14-20 (4779±3111,n = 26), POD 21-27(4553± 1846,n = 18) and on POD 28-41 (3621±1859,n = 21). Conclusions: Plasma TIM3 levels were significantly elevated over baseline for 1 month after MICR (% change range, 8-70; peak value weeks 2-4). The acute inflammatory response might account for the early increases but late elevations are more likely associated with wound healing/tissue remodeling. Elevated plasma TIM-3 levels may exhaust tumor infiltrating T-cells which may facilitate the growth of residual tumor. Further investigation is warranted.
Clinical and molecular markers of immune checkpoint inhibitor (ICI) response in dMMR colorectal cancer (CRC) patients (pts).
Authors: Sahin Ibrahim Halil , Goyal Subir , Pumpalova Yoanna S , Sonbol Mohamad Bassam , Das Satya , Haraldsdottir Sigurdis , Chen Zhengjia , Akce Mehmet , Alese Olatunji B. , Shaib Walid Labib , Ahn Daniel H. , Ciombor Kristen Keon , Berlin Jordan , Bekaii-Saab Tanios S. , Draper Amber , Lesinski Gregory B. , El-Rayes Bassel F. , Wu Christina 
Published: February 2020

225 Background: ICIs induce durable responses in dMMR CRC patients. However, clinical and molecular biomarkers of response to ICIs have not been well-established. In this study, we investigated impact of specific MMR gene loss, BRAF V600E mutation and clinical characteristics of pts on clinical outcomes of ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or MSI-H by PCR and received ICIs between 01/01/2012 and 05/01/2019 at Winship Cancer Institute of Emory University, Mayo Clinic, Vanderbilt or Stanford University. Due to the functional dependency, the groups were categorized as protein loss of MLH1+PMS2 vs MSH2+MSH6. Log-rank test, Cox hazard model and Fisher’s exact test were used for survival outcomes, the best response and the distribution of variables among the subgroups. Results: A total of 66 pts with dMMR CRC were identified and BRAF status was available for 41 pts. ORRs in MLH1+PMS2 and MSH2+MSH6 groups were 72.9% and 56.5% respectively (P = 0.189). At 2 years, PFS rates were 55.6% and 78.2% for MLH1+PMS2 and MSH2+MSH6 groups respectively (P < 0.001). Pts with BRAF V600E mutations had significantly worse outcomes as compared to pts with wild-type BRAF (2-year PFS rate of 35.0% and 73.3% respectively; P < 0.001). Notably pts < 65 had better 2-year disease control rates when compared to > 65 (71.1% and 41.5% respectively; P < 0.001). We also observed worse 2-year PFS rates in pts with liver metastases (P = 0.014). CRC side and tumor volume did not impact 2-year PFS rates in our cohort. Conclusions: Our data suggest that pts with loss of function in MSH2+MSH6 may have better 2 year-PFS rates compared pts with MLH1+PMS2 even though ORR favored MLH1+PMS2 group suggesting that ORR may not reflect the durability of ICI response in dMMR CRC patients. Consistently, pts with BRAF V600E mutation which is associated with MLH1 promoter methylation had significantly worse 2-year PFS rates. Overall, our findings suggest that BRAFV600E mutation, the affected MMR proteins, pt age, and site of metastasis may impact durability of ICI response in dMMR CRC patients.
Genetic variants involved in bromodomain-containing protein 4 (BRD4) regulating pathway to predict outcomes in patients with metastatic colorectal cancer: Results from FIRE3 and MAVERICC trials.
Authors: Wang Jingyuan , Xiao Yi , Loupakis Fotios , Stintzing Sebastian , Arai Hiroyuki , Battaglin Francesca , Soni Shivani , Zhang Wu , Mancao Christoph , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Millstein Joshua , Lenz Heinz-Josef 
Published: February 2020

232 Background: BRD4 plays an important role in transcription, DNA repair and drug resistance. High expression and polymorphisms of BRD4 regulating pathways were reported to be related to worse prognosis in colorectal cancer. Therefore, we hypothesized that genetic variants in BRD4 regulating pathway may predict first-line treatment outcome in mCRC pts. Methods: The impact on outcome of 22 SNPs in 7 genes involved in BRD4 regulating pathway (BRD4, SIPA1, MYC, 53BP1, H2AX, BATF, CD47) was analyzed through the OncoArray, a customized array manufactured by Illumina, on genomic DNA from blood samples of pts enrolled in 2 randomized trials. MAVERICC FOLFIRI/bevacizumab (bev) arm served as discovery cohort (N = 107), FIRE3 FOLFIRI/bev arm as validation (N = 107) and FOLFIRI/cetuximab (cet) arm as control (N = 129). Results: In the discovery cohort, right(R)-sided pts with BRD4 rs4808272 any G allele (N = 46) showed significantly shorter PFS (9.5 vs 18 m) compared to carriers of A/A (N = 21) in both uni- and multi-variable analysis ( p < .01); R-sided pts carrying any T allele of BATF rs7161377 (N = 50) showed longer PFS (12.3 vs 6.8 m) compared to carriers of C/C (N = 14) in univariate analysis ( p < .05) and had a strong trend in multivariable analysis ( p = .06). These findings were all validated in R-sided pts in FIRE3 bev arm (BRD4 rs4808272, PFS 9.8 vs 18.7 m; BATF rs7161377, PFS 15.1 vs 4.2 m) in uni- (both p < .01) and multi-variable ( p = .08 and p < .05 respectively) analysis. No significant association was observed in the control arm. Interestingly, pts carrying CD47 rs3206652 any C allele (N = 13) only showed significant longer PFS (9.0 vs 3.0 m, univariable p < .01 and multivariable p = .07) in the R-sided pts of FIRE3 cet cohort, but no association was observed in the bev-based treatment. Conclusions: Our study demonstrates for the first time that BRD4 and BATF polymorphisms may predict outcomes of bev-based treatment in R-sided mCRC pts; Meanwhile CD47 polymorphism could predict outcomes of cet-based treatment in R-sided mCRC pts. This finding supports a possible role of BRD4 regulating pathway in contributing to resistance to anti-VEGF/EGFR treatment.
Stage-specific conditional survival among young versus older adults with colorectal cancer in the United States, 2004-2010.
Authors: Sanford Nina Niu , Ahn Chul , Folkert Michael Ryan , Aguilera Todd Anthony , Sher David J. 
Published: February 2020

257 Background: Conditional survival (CS) is a relevant prognostic measure for cancer survivors and physicians and may be particularly important for young adult patients with CRC (colorectal cancer), whose incidence is rising. We sought to compare CS among young versus older adults with CRC. Methods: Patients diagnosed with colon or rectal adenocarcinoma between 2004-2010 were identified from the Surveillance, Epidemiology and End Results (SEER) registry. Overall survival (OS) and cancer-specific survival (CSS) were estimated, along with smoothed yearly hazards of death due to CRC, other causes and any cause, stratified by age at diagnosis ( < 50 vs. >50 years). Stage-specific conditional 5-year OS and 5-year CSS given that patients had already survived 1, 2, 3, 4 or 5 years after diagnosis was calculated, also stratified by age. Results: Among 161,859 patients with median follow-up of 54 months, 35,411 (21.9%) were aged < 50 years. Both OS and CSS were superior among younger adult as compared to older adult patients (p < 0.001). For older adults with rectal cancer, hazards of death due to non-cancer causes exceeded that of rectal and colon cancer approximately 6 and 4.5 years after diagnosis, respectively. Among younger adults, hazard of death from cancer remained greater than death from other causes throughout the entire study interval. Patients experienced improved conditional survival over time with greater improvement seen for more advanced stages. However, young adults had less CS improvement over time than older adults. For example, the 5-year overall and CSS for Stage IV colon cancer improved from 7.4% to 52.4%% (OS) and 15.1% to 78.5% (CSS) 0 to 5 years after diagnosis for older adults. In contrast, for younger adults, the 5-year overall and CSS for Stage IV colon cancer improved from 15.6% to 57% (OS) and 19.3% to 68.4% (CSS). Conclusions: Prognosis for CRC improves over time for all patients, although the increase in survival appears to be less for younger than older adults. Up to 10 years after diagnosis, the primary cause of death in younger adults with CRC remains their incident cancer.
An assessment of dose intensity of the TNT approach on outcomes in locally advanced rectal cancer.
Authors: Glode Ashley Elizabeth , Friedrich Tyler , Sandhu Gurprataap Singh , Herter Whitney , McCarter Martin , Gleisner Ana Luiza , Birnbaum Elisa , Ahrendt Steven Arthur , Vogel Jon , Goodman Karyn A. , Schefter Tracey E. , Purcell William T. , Leal Alexis Diane , King Gentry Teng , Davis S. Lindsey , Leong Stephen , Messersmith Wells A. , Lieu Christopher Hanyoung 
Published: February 2020

258 Background: Patients with clinical stage II or III locally advanced rectal cancer may be treated with the total neoadjuvant therapy (TNT) approach; chemotherapy with 4 mths of FOLFOX followed by chemoradiation (chemo/XRT) with capecitabine for 5 wks administered before surgery. We hypothesized that full dose intensity is not necessary for treatment benefit. Methods: A retrospective chart review was conducted on patients with newly diagnosed rectal cancer recommended to receive TNT by the multidisciplinary (multiD) colorectal cancer tumor board at the University of Colorado Cancer Center (UCCC). The primary objective was to evaluate dose intensity of TNT and its impact on response assessed by biopsy and/or imaging (MRI). Results: Between January 31, 2016 and January 31, 2019, 80 patients were recommended the TNT approach for cancer management by the multiD team. Of those, 48 completed their neoadjuvant treatment at UCCC and were included in the analysis. The average age was 55 years (range 23-80) and 61% were male. Thirty-one patients had an ECOG of 0 and 17 had an ECOG of 1. Overall responses were 44% complete response (CR, n = 21), 15% near complete response (nCR, n = 7), 35% partial response (PR, n = 17), and 6% no response (NR, n = 3). See Table for responses seen by dose intensity for chemotherapy. Two patients did not receive their full planned XRT course, and 9 patients had their capecitabine doses held/decreased during chemoradiation. Conclusions: This single center retrospective analysis of patients receiving the TNT approach for rectal cancer provides data supporting that achieving full dose intensity is not necessary to achieve treatment benefit. [Table: see text]
Trastuzumab + fluoropyrimidine maintenance in the frontline setting for non-progressing advanced HER-2 positive gastroesophageal adenocarcinoma.
Authors: Abdelhakeem Ahmed , Rogers Jane Elizabeth , Wang Xuemei , Thomas Irene , Blum-Murphy Mariela A. , Trail Allison , Zhao Meina , Ajani Jaffer A. 
Published: February 2020

291 Background: In untreated patients with HER2 positive advanced gastroesophageal adenocarcinoma (AGEA), trastuzumab plus active cytotoxic combination is the standard of care. Our objective was to assess the role of maintenance therapy (trastuzumab + fluoropyrimidine) in the absence of cancer progression. Methods: We retrospectively analyzed HER2 positive AGEA patients (between August 2008 and October 2018) who received first-line trastuzumab-based therapy followed by maintenance therapy. The primary objectives were to assess the time to maintenance failure (TTMF), the first progression-free survival (PFS), and overall survival (OS). Results: Of 70 patients analyzed, 80% were men with a median age of 60.5 years. Primary tumor commonly involved the gastroesophageal junction (65.7%). More than 1 sites of metastases were frequent (88.6%). The best response was complete in 17%, partial in 70%, and stable in 11.4%. The median follow-up time for survivors was 2.1 years (range, 0.6 to 9.2). The median TTMF was 0.7 years (95% CI; 0.4 to 1.1 years). One-year TTMF-free rate was 41%. The median PFS was 1.3 years (95% CI, 0.8-1.6). The median OS was 3.2 years (95% CI, 2.3 years–4.5 years), with a 3-year survival rate of 55% (95% CI, 40%-67%). Conclusions: Our results showed that the OS of this unique population of HER2 positive AGEA patients who qualify for maintenance therapy is excellent. The contribution of the maintenance therapy can be clarified only by prospective investigations.
Propensity-score-matched analysis of a multi-institutional dataset to compare the postoperative complications after distal gastrectomy between Billroth I and Roux-en-Y.
Authors: Nakanishi Koki , Kanda Mitsuro , Ito Seiji , Mochizuki Yoshinari , Teramoto Hitoshi , Ishigure Kiyoshi , Mmurai Toshifumi , Asada Takahiro , Ishiyama Akiharu , Matsushita Hidenobu , Shimizu Dai , Tanaka Chie , Kobayashi Daisuke , Fujiwara Michitaka , Kodera Yasuhiro 
Published: February 2020

292 Background: Billroth I (B-I) or Roux-en-Y (R-Y) are common reconstruction technique after distal gastrectomy, each with advantages and disadvantages and which is the most successful remains unclear. The aim of the present study was to clarify the difference of postoperative complications between the two techniques. Methods: A multi‐institutional retrospective database comprising clinical information of 3484 patients who received resection of gastric cancer from 2010 to 2014 at nine institutions. Using propensity scores to strictly balance the significant variables, and we compared the overall and severity postoperative complications. We considered Clavien–Dindo grade ≥ II postoperative complications clinically relevant, and grade ≥ III severe postoperative complications. Results: After matching, we enrolled 1086 patients (n=543 in each group). The incidence of postoperative complications in the R-Y group was significantly higher vs the B-I group (28% vs 17%, respectively; P<0.0001). The incidence of intra-abdominal abscess (4.2% vs 1.7%, P=0.0120), pancreatic fluid leakage (3.1% vs 1.1%, P=0.0204), bowel obstruction (2.8% vs 0.7%, P=0.0109), and delayed gastric emptying (5.0%s 0.9%, P<0.0001) in the R-Y group was significantly higher vs the B-Ⅰ group, respectively; but not significant difference in leakage (3.2% vs 3.3%, respectively; P=0.8636). The incidence of severe postoperative complications in the R-Y group was also significantly higher vs the B-I group (15% vs 6.3%, respectively; P<0.0001). Multivariable analysis for severe postoperative complications found that R-Y reconstruction was an independent risk factor (odds ratio, 2.20, P=0.0005). Subgroup analysis found that R-Y reconstruction was associated with a greater risk of severe postoperative complications in most subgroups, but not the subgroup of patients receiving intraoperative transfusions. Conclusions: R-Y reconstruction was associated with increasing overall postoperative complications, as well as grade ≥ III severe postoperative complications.
Prognostic value of modified Glasgow Prognostic Score (mGPS) and neutrophil-lymphocyte ration (NLR) after curative resection for gastric cancer.
Authors: Shimodaira Yusuke , Koike Sachie , Takahashi Yusuke , Okada Masao , Hayashibara Kaori , Sekino Yasushi , Sakon Masahiro , Takata Manabu , Seki Hitoshi , Munakata Yasuhiro 
Published: February 2020

295 Background: Several biomarkers based on serum chemistry have been reported to be associated with the prognosis of several types of cancers. This retrospective study aimed to investigate the prognostic value of preoperative mGPS and NLR after curative resection for gastric cancer. Methods: A total of 295 patients who underwent curative gastrectomy for primary gastric cancer at our institution from January 2013 to December 2017 were enrolled in this study. The mGPS was calculated by CRP and Alb using standard thresholds ( > 0.5 mg/dL for CRP and < 3.5 g/dL for Alb). The NLR was defined as absolute neutrophil count divided by absolute lymphocyte count. The survival curves of patients stratified by each parameter were plotted by the Kaplan-Meier method and compared by log-rank test. Multivariate Cox proportional hazards regression models were used to select parameters independently correlated with prognosis. Results: The median follow-up time was 36.7 months, and 29 patients died during follow-up. The estimated 5-year survival rate was 83.1%. Results from the univariate analyses showed mGPS2 (CRP > 0.5 mg/dL and Alb < 3.5 g/dL) was associated with poor survival while NLR and NLRc was not (P < 0.001, P = 0.506, and P = 0.423, respectively). In the multivariate analyses, the mGPS2 was identified as an independent predictive factor for OS in gastric cancer patients after curative resection (HR: 2.624; 95% CI: 1.058-6.505; P = 0.037). Conclusions: Preoperative mGPS2 was associated with worse survival after curative resection of gastric cancer patients. Based on our study, those with mPGS2 may be warranted to receive additional therapy or nutritional support to acquire better survival.
Chemoradiation-related lymphopenia and its association with survival in patients with anal cancer.
Authors: Lee Grace , Kim Daniel W. , Muralidhar Vinayak , Mitra Devarati , Horick Nora , Eyler Christine Elissa , Hong Theodore S. , Drapek Lorraine C. , Allen Jill N. , Blaszkowsky Lawrence Scott , Giantonio Bruce J. , Parikh Aparna Raj , Ryan David P. , Clark Jeffrey William , Wo Jennifer Yon-Li 
Published: February 2020

3 Background: While treatment-related lymphopenia (TRL) is common and associated with poorer survival in multiple solid malignancies, little data exists for anal cancer. We evaluated TRL and its association with survival in anal cancer patients treated with chemoradiation (CRT). Methods: A retrospective analysis of 140 patients with non-metastatic anal squamous cell carcinoma (SCC) treated with definitive CRT was performed. Total lymphocyte counts (TLC) at baseline and monthly intervals up to 12 months after initiating CRT were analyzed. Multivariable Cox regression analysis was performed to evaluate the association between overall survival (OS) and TRL, dichotomized by G4 TRL ( < 0.2k/μl) two months after initiating CRT. Kaplan-Meier and log-rank tests were used to compare OS between patients with versus without G4 TRL. Results: Median time of follow-up was 55 months. Prior to CRT, 95% of patients had a normal TLC ( > 1k/μl). Two months after initiating CRT, there was a median of 71% reduction in TLC from baseline and 84% of patients had TRL: 11% G1, 31% G2, 34% G3, and 8% G4. On multivariable Cox model, G4 TRL at two months was associated with a 3.7-fold increased risk of death (p = 0.013). On log-rank test, the 5-year OS rate was shorter in the cohort with versus without G4 TRL at two months (32% vs. 86%, p < 0.001). Conclusions: TRL is common and may be another prognostic marker of OS in anal cancer patients treated with CRT. The association between TRL and OS supports the hypothesis that host immunity plays an important role in survival among patients with anal cancer. These results support ongoing efforts of randomized trials underway to evaluate the potential role of immunotherapy in localized anal cancer.