bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient-derived colorectal cancer spheroids for single cell characterization of intratumor heterogenity in response to EGFR inhibition.
Authors: Kratz Jeremy D. , Sprackling Carley M. , Favreau Peter F. , Karim Mohammad R. , Pasch Cheri , Clipson Linda , Skala Melissa C , Deming Dustin A. 
Published: January 2019

569 Background: Epidermal growth factor receptor inhibitors (EGFRi) have improved clinical outcomes in patients (pts) with metastatic colorectal cancer (mCRC). Molecular profiling and primary tumor sidedness are used to predict population benefit. Our group has recently demonstrated that patient-derived organotypic cancer spheroids (PDOCS) and optical metabolic imaging (OMI) can predict in vivo chemotherapy response. Translational tools are needed to characterize targeted therapeutic response to predict clinical outcomes. Methods: PDOCS were generated from patients with mCRC at time of molecular profiling. Following culture maturation, PDOCS were treated with physiologic doses of EGFRi panitumumab. Response was evaluated by change in sphere diameter and OMI to exploit intrinsic autofluorescence of NAD(P)H and FAD at spheroid and single-cell level. Effect size was calculated using Glass’s delta (GΔ) defined as differences in means between treatment groups normalized to control standard deviation with comparison to predetermined sensitivity thresholds. Results: PDOCS from pts with mCRC were generated from tissue biopsies, surgical specimens, and malignant effusions (n = 38). Mutational profiles were stratified by RAS status from next-generation sequencing. Six PDOCS were evaluable for experimental and clinical response. KRAS mutation predicted primary resistance to EGFRi with no difference in diameter (GΔ = -0.01) or single cell response by OMI (GΔ = 0.02). RAS wild-type PDOCS had significant response with decreased diameter with EGFRi (P < 0.001). Gaussian fit of single-cell analyses revealed heterogeneity in EGFRi sensitivity. Differential sensitivity to EGFRi in RAS wild-type population correlated with clinical response. Conclusions: PDOCS predict response to panitumumab in these preliminary investigations. Diameter and OMI analyses provide complementary information of line-specific sensitivity. Further studies are warranted to characterize the molecular profiles underlying intratumor heterogenity. Prospective investigations are needed to understand the predictive role of this technique in targeted therapeutic response.
Comprehensive profiling of immune landscape in gastrointestinal (GI) and head and neck (HN) cancers via computational deconvolution.
Authors: Szeto Christopher , Veerapaneni Saihitha , Kazmierczak Kevin , Benz Stephen Charles , Reddy Sandeep K. , Yan Dongyao 
Published: January 2019

579 Background: Immune contexture shapes oncogenesis, tumor progression and response to therapy. Traditional techniques for studying the microenvironment, such as flow cytometry, are limited by low throughput. Recently, computational methods using transcriptomic data have enabled deconvolution of tumor immune landscape, particularly in colorectal cancer (CRC). However, the immune profiles of other GI and HN cancers remain unclear. We proposed that elucidating the immune compositions in those cancers would reveal biological insights and potentially therapeutic targets. Methods: 464 GI tumors with RNA-Seq data (∼200x106reads per tumor) from a commercial database were available for analysis. Tumors were categorized into CRC, gastroesophageal (GE), HN, and biliary cancer. A curated panel of 122 genes that discriminate between 28 immune subsets was identified. For each of these immune signatures, a database containing 1880 unselected tumors was used to define a distribution of expression. The study samples were then scored for their deviances within such distributions.In addition to immune deconvolution, each of the 464 tumors were assigned to one of the colorectal Consensus Molecular subtypes (CMS). Significant enrichment for immune subsets between locations and CMS was analyzed. Results: Unsupervised clustering revealed 2 clusters with distinct immune profiles, which largely separated CRC from HN/GE tumors (silhouette coefficient = 0.14). Eosinophils are more abundant in GI cancers than others. HN/GE tumors were characterized by abundant NK and Tregs (adj. p < 0.001), and were predominantly classified as the immune-active CMS1 (adj. p < 0.001). CRC was significantly associated with high eosinophils and fibroblasts (adj. p < 0.0001). Biliary tumors spanned both immune-type clusters, and were frequently classified as the stromal-rich CMS4 (adj. p < 0.0001). Immature dendritic cells were sparse in GI tumors, especially GE. Conclusions: Upper and lower GI tumors have distinct immune contextures, which may differentially impact the efficacy of immunotherapy. Comprehensive immune profiling may facilitate the identification of targetable immune subsets.
Liquid biopsy for optimizing the rechallenge of cetuximab in metastatic colorectal cancer: Additional study of E-Rechallenge Trial.
Authors: Ohhara Yoshihito , Shinozaki Eiji , Osawa Hiroshi , Nakamura Masato , Shindo Yoshiaki , Shiozawa Manabu , Uetake Hiroyuki , Matsumoto Hiroshi , Ureshino Norio , Satake Hironaga , Kobayashi Takaaki , Suto Takeshi , Kitano Shiro , Ohashi Yasuo , Uemura Kohei , Yamaguchi Kensei 
Published: January 2019

585 Background: Several previous reports indicated that cetuximab (Cmab) rechallenge may be efficacious in some patients for whom Cmab was previously effective. Liquid biopsy can detect the some emerging mutations for resistance with Cmab. Considering the plasticity and elasticity of sensitive clone, we assumed we could identify the patients with benefit from Cmab rechallenge by liquid biopsy. This current study investigates the predictability of efficacy for Cmab rechallenge by liquid biopsy in the E-Rechallenge Trial. Methods: The E-Rechallenge Trial is a multicenter phase II study in mCRC patients who have become refractory to fluoropyrimidines, L-OHP, CPT-11, Cmab, and bevacizumab, and in whom previous treatment with Cmab was effective in any earlier line (achieving CR, PR, or SD that persisted for ≥ 6 months). The other main eligibility criteria are; RAS wild type, measurable disease, aEFI ≥ 16 weeks between the last dose of Cmab during previous treatment and the start of Cmab rechallenge. Protocol treatment is the combination of weekly Cmab with biweekly CPT-11. Additional research of ctDNA was conducted optionally. Baseline plasma samples were analyzed for KRAS, NRAS, BRAF and EGFR S492R mutations using digital PCR (LBx probe, RIKEN GENESIS). A cut-off of the mutation allele frequency was > 0.1%. Results: Between Dec. 2014 and Oct. 2017, 33 patients were enrolled. The primary endpoint; the rates of PR/SD/PD were PR 15.6%/SD 40.6%/PD 43.8%. Twenty-four of 33 patients participated in the additional research. In the additional cohort, the rates of PR/SD/PD were PR 12.5%/SD 50.0%/PD 37.5%. The mutations were detected at the baseline of Cmab rechallenge as followings; KRAS exon 2 29.2%, exon 3,4 33.3%, BRAF V600E 12.5%, EGFR S492R 12.5%. In wild type of these genes the PR and SD rate increased to 25% and 50%, respectively. Conclusions: Cmab rechallenge showed some activity in the salvage setting, in patients for whom Cmab was previously effective. KRAS, BRAF, and EGFR S492R screening by liquid biopsy may contribute to identify patients with benefit from Cmab rechallenge. The additional data of ctDNA may be provided in the conference. Clinical trial information: UMIN 000016439.
Activity of EGFR inhibition in atypical (non-V600E) BRAF-mutated metastatic colorectal cancer.
Authors: Johnson Benny , Loree Jonathan M. , Morris Van K. , Dasari Arvind , Pant Shubham , Raghav Kanwal Pratap Singh , Kopetz Scott 
Published: January 2019

596 Background: Atypical BRAF mutations (a BRAF) represent a rare molecular subtype of metastatic colorectal cancer (mCRC), distinct from BRAFV600E (class I). Preclinical data categorizes a BRAF into class II (intermediate-high kinase activity without RAS dependency) and III (low kinase activity, RAS dependent), however the clinical impact regarding these functional classes is unknown. Methods: We retrospectively analyzed 2,084 mCRC patients (pts) at MD Anderson Cancer Center (MDACC) to identify a BRAF and BRAFV600E. Clinicopathologic features were compared by chi-square or fisher’s exact test. Overall survival (OS) calculated utilizing Kaplan-Meier method and log-rank test. Statistical tests were two-sided. Results: a BRAF occurred in 36 mCRC pts (1.7%; 95% CI 1.2-2.4): 22 class III, 10 class II, 4 unclassified. The most common class II and class III BRAF codons were 469 (60%) and 594 (59%), respectively . Median OS (mOS) for a BRAF mCRC was 39.4 months (mo), without difference between class III and II. 19/36 (53%) were left sided primary tumors and 24/36 (67%) were microsatellite stable. BRAFV600E occurred in 221 mCRC pts (10.6%; 95% CI 9.3-12.0) with a mOS of 21.0 mo. In contrast to BRAFV600E which is mutually exclusive with RAS mutations, 12 pts with a BRAF were RAS mutants (class III, 7/21 [33%], class II 5/10 [50%]). Among a BRAF RAS wt pts, 11 (50%) received anti-EGFR monoclonal antibodies (mAb) (class III 7/14 [50%], class II 3/5 [60%]). There were no responses, and only three pts (all class III) achieved stable disease as best response. Median time on therapy was 4 months. Class II RAS wt pts treated with anti-EGFR mAb had mOS of 31.7 mo versus 46.8 mo for those not exposed (HR 2.0; 95% CI 0.3-15.9). Class III RAS wt pts treated with anti-EGFR mAB had mOS of 44.2 mo versus 45.7 mo for those not treated (HR 0.80; 95% CI 0.2-2.6). Conclusions: a BRAF mCRC appear to manifest improved clinical outcomes as previously reported. Despite this, the efficacy of anti-EGFR therapy appears limited in class II and III patients. Future efforts are needed to establish the predictive impact of functional classes on anti-EGFR efficacy and to design novel therapeutic strategies for a BRAF mCRC.
FOLFOX versus POF (paclitaxel plus FOLFOX) versus IP PAC (intraperitoneal paclitaxel plus FOLFOX) as a first-line treatment in advanced gastric cancer (AGC): A multicenter, randomized phase II trial, FNF-004 trial.
Authors: Lin Rongbo , Li Hui , Chen Yigui , Zhu Jinfeng , Lin Peicheng , Chen Wujin , Fang Wenzheng , Liu Jie , Zhao Shen , Fan Nanfeng 
Published: January 2019

6 Background: Double regimens are commonly accepted for AGC in East Asia. However, triple regimens are recommended in west countries. POF regimen (reported in 2007, 2008, 2009, 2010 ASCO) appeared to be of good efficacy and was well tolerated in patients with AGC. Intraperitoneal paclitaxel showed high local concentration in abdominal cavity and low systemic toxicity. The aims of this study were to find out if the POF and IP PAC was more effective with manageable side effects than FOLFOX in AGC (reported in 2017 ASCO-GI for feasibility analysis). Methods: The patients with AGC were randomized to three groups. The POF consisted of a 3-hour infusion of paclitaxel 135 mg/m2, followed by FOLFOX omitted 5-Fu bolus. The IP PAC consisted of paclitaxel 80 mg/m2 intraperitoneally plus FOLFOX. Every 14 days repeated for all three regimens. Up to 9 cycles of treatment were administered, followed by S-1 until disease progression. The primary endpoint was PFS. Results: Between Nov 2015 and May 2018, 89 pts (30 POF, 29 IP PAC, 30 FOLFOX) were randomly allocated. PFS, OS and RR were seen in the table below. POF was better in PFS and RR than FOLFOX, although no statistically significant difference in RR. IP PAC was trend to be better in PFS than FOLFOX, but not in RR. OS was unmatured. The most common adverse events of grade 3 or 4 were neutropenia and neuropathy, but no significant difference among three groups. Conclusions: Both POF and IP PAC improved survival compared to FOLFOX. Only POF, not IP PAC, improved response rate compared to FOLFOX. Clinical trial information: NCT02845908. [Table: see text]
Microsatellite instability (MSI) as an independent predictor of pathologic complete response (PCR) in locally advanced rectal cancer: A National Cancer Database (NCDB) analysis.
Authors: Hasan Shaakir , Renz Paul , Wegner Rodney E , Finley Gene Grant , Raj Moses S. , Monga Dulabh K. , McCormick James , Kirichenko Alexander V. 
Published: January 2019

616 Background: The relationship between microsatellite instability (MSI) and response to neoadjuvant chemoradiation in rectal cancer is not well understood. We therefore utilized the national cancer database (NCDB) to investigate the association between MSI and pathologic complete response (pCR) in this patient population. Methods: We analyzed 5,086 patients between 2010-2015 with locally advanced rectal cancer who were tested for MSI and treated definitively with chemoradiation followed by surgery. Primary comparison groups were between 4,450 MSI-negative(-) and 636 MSI-positive(+) patients. Multivariable regression analysis was conducted to identify demographic, therapeutic, and clinical characteristics predictive of pCR. Cox proportional hazard ratios were used for survival. Results: All patients were treated with definitive chemoradiation (median dose 50.4 Gy) followed by resection within 4 months. MSI(+) patients were associated with earlier year of diagnosis and higher grade tumors (P < 0.05). The overall pCR rate was 8.6%, including 8.9% for MSI(-) and 5.9% for MSI(+) tumors (P = 0.01). Along with lower T stage, MSI(+) cases were significantly associated with a reduced pCR rate (OR = 0.65, 95% CI 0.43 – 0.96) with multivariable analysis. The 5-year survival for patients with pCR was 93% compared to 73% without it (< 0.001). Conclusions: Microsatellite instability was independently associated with a reduction in pathologic complete response for locally advanced rectal cancer following neoadjuvant chemoradiation in this NCDB-based analysis.[Table: see text]
Distribution of neuroendocrine marker-positive cells in colorectal cancer tissue and adjacent mucosa.
Authors: Ogimi Takashi , Sadahiro Sotaro , Miyakita Hiroshi , Saito Gota , Chan Lin Fung , Okada Kazutake , Tanaka Akira , Suzuki Toshiyuki , Kajiwara Hiroshi 
Published: January 2019

617 Background: Neuroendocrine carcinoma (NEC) is a rare disease and has been reported to most frequently arise in the right side of the colon. In the 2010 WHO classification, mixed adenoneuroendocrine carcinoma (MANEC) was defined as a neoplasm consisting of NEC and adenocarcinoma components. To clarify the histogenesis of NEC, we attempted to detect neuroendocrine marker-positive cells in cancer tissue and in the adjacent mucosa in patients with adenocarcinoma. Methods: The study group comprised 390 patients with Stage II or III colorectal adenocarcinoma between 2007 and 2012. Immunostaining was performed with anti chromogranin A, synaptophysin, and CD56 antibodies. Cases with positively stained cells in cancer tissue were defined as positive. In the adjacent mucosa, at least 5 cm from the tumor, the numbers of positive cells per 15 HPF were measured. Results: Tumor location was right side in 181 patients, left side in 173, and the rectum in 36 patients. Positive rates of Chromogranin A in cancer tissues were 23.7% in the right colon, 13.2% in the left colon, and 19.4% in the rectum. Those of synaptopysin were 35.3%, 21.9%, and 30.6%, respectively. Those of CD56 were 22.6%, 8.0%, and 16.7%, respectively. Positive rates of these three markers in right colon were significantly higher than those in left colon and rectum. (p = 0.0115, p = 0.0054, p = 0.0062). In the adjacent mucosa, the mean numbers of positive cells for chromogranin A were 62.2 ± 20.5 in the right colon, 131.9 ± 44.7 in the left colon, and 243.7 ± 60.2 in the rectum (p < 0.001). Those for synaptophysin were 47.7 ± 23.5, 95.3 ± 35.1, and 156.9 ± 56.8, respectively. (p < 0.001). There were no significant differences in the number of positive cells for CD56 among the sites (p = 0.295). Conclusions: In cancer tissue, the rate of positive staining for neuroendocrine marker-positive cells was higher in the right side of the colon, whereas in normal mucosa the rates of positive staining for these cells were higher in the sigmoid colon and the rectum. These results suggest that neuroendocrine marker-positive cells are an acquired characteristic of cancer tissue.
The prognostic value of systemic inflammatory factors in BRAF (V600E) mutant metastatic colorectal cancer (mCRC).
Authors: Martinez Lago Nieves , Covela Rúa Marta , Brozos Vazquez Elena , Fernandez Montes Ana Fernandez , de la Cámara Gómez Juan Cruz , Méndez Méndez Carlos , Jorge Fernández Mónica , Cousillas Castiñeira Antia , Suárez Begoña Graña , Quintero Aldana Guillermo Alfonso , Candamio Folgar Sonia , Salgado Fernandez Mercedes , Pellon Augusto Maria Luz , Gonzalez Villarroel Paula , Gallardo Martin Elena , Carmona Campos Marta , Vazquez Rivera Francisca , Grande Ventura Carlos , Carral Maseda Alberto , Reboredo Lopez Margarita 
Published: January 2019

622 Background: Multiple studies have reported prognostic association of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLT) and albumin levels including patients with early and advanced metastatic colorectal cancer. However, it is unknown the prognostic impact in patients with BRAF (V600E) mutant metastatic colorectal cancer (mCRC). Methods: We conducted an observational, retrospective, multicentric study of patients with BRAF V600E-mt mCRC treated at nine university Spanish hospitals belonging to GITuD (Galician Research Group on Digestive Tumors). Demographic, clinic, pathological characteristics, overall survival (OS) and progression free survival (PFS) data were retrospectively analyzed. Results: Data from 65 pts. treated between November 2010 to June 2018 were recorded. Median age was 62.8 years (range 30-83), 55.4 % female, 75.4% ECOG PS0-1, 49.2% right-sided, 35.2% high grade, 69.2% synchronous presentation, 66.2% primary tumor resection and median metastatic locations was 2 (range 1-5). With a median follow up of 64.6 months, median OS was 12.9 months (95% CI, 9.8-16.0) and first line PFS was 4.1 months (95% CI, 2.7-5.5). NLR (HR 2.294; p = 0.004), PLR (HR 6.329; p = 0.028) and albumin levels (HR 2.575, p = 0.011) were independent prognostic factors for OS. Patients with higher NLR (> 3 vs. < 3): had a significantly lower OS 6.8 versus 17.5 months (HR 2.294; 95% CI 1.3-4.1, p = 0.004), which was also true for patients with higher PLR (> 200 vs. < 200): with OS 6.3 versus 14.5 months (HR 1.879; 95% CI 1.1-3.3, p = 0.028), while patients with low albumin had lower OS 6.8 versus 13.4 months (HR 2.575; 95% CI 1.2-5.5, p = 0.011). NLR was positively associated with PLR (p < 0.001). Neither NLR (p = 0.190) or PLR (p = 0.327) were associated with low albumin levels. A Systemic Inflammation Score (assigning one point for each factor) was predictive of survival: OS 0/1/2/3 factors were 17.7 versus 8.7 versus 9.7 versus 5.0 months (p < 0.001). Patients with Systemic Inflamation Score = 0 had significantly higher OS: 17.7 versus 8.2 months (HR 0.357; 95% CI 0.2-0.7, p = 0.001). Conclusions: NLR, PLR and albumin levels are significant prognostic factors in patients with BRAF V600E-mt mCRC.
Comprehensive molecular profiling of signet-ring-cell carcinoma (SRCC) from the stomach and colon.
Authors: Puccini Alberto , Poorman Kelsey , Salem Mohamed E. , Goldberg Richard M. , Shields Anthony Frank , Berger Martin D , Battaglin Francesca , Tokunaga Ryuma , Naseem Madiha , Zhang Wu , Soni Shivani , Korn W. Michael , Philip Philip Agop , Marshall John , Lenz Heinz-Josef 
Published: January 2019

63 Background: Signet ring cell carcinoma (SRCC) is a rare variant of adenocarcinoma, accounting for about 10% of gastric cancer (GC) and 1% of colorectal cancer (CRC). SRCC is associated with poor prognosis, however little is known about the underlying molecular characteristics. Herein, we aimed to characterize the molecular features of SRCCs, and to compare the molecular profile of SRCC to adenocarcinoma; further, we assessed the impact of tumor location on the molecular profile of SRCC. Methods: SRCCs were analyzed using NGS (MiSeq on 47 genes, NextSeq on 592 genes), immunohistochemistry, and in-situ hybridization. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Chi-square and t-tests were used for comparative analyses. Results: A total of 8,500 CRC and 1,100 GC were screened for SRCC histology. Seventy-six SRCC were identified from the CRC cohort (<1%) and 98 from the GC cohort (9%). The most frequently mutated genes in CRC-SRCC were TP53 (47%), ARID1A (26%), APC (25%), KRAS (22%), RFN43 (16%), KMT2D (12%), KMT2C (11%), SMAD4 (10%) and BRAF (10%), while in GC-SRCC were TP53 (42%), ARID1A (27%), CDH1 (11%), BAP1 (7%), PIK3CA (7%), ERBB2 (5%). When compared to non-SRCC histology (N=3522), CRC-SRCC (N=37) showed more frequently mutation in BRCA1 (11% vs 1%, P < .001) and less mutation in APC (19% vs 78%, P < .001), KRAS (22% vs 51%, P = .001) and TP53 (47% vs 73%, P = .001). Among GC cohort, SRCC (N=54) had a higher frequency of mutations in CDH1, BAP1, and ERBB2, and higher rate of amplification MYB compared to non-SRCC (N=540), although none of these differences were statistically significance. When we compared GC-SRCC vs. CRC-SRCC, only the mutation rate in APC (0% vs 25%) and KRAS (2% vs 22%) genes were significantly different (P < .001). Conclusions: Our research is the first to comprehensively characterize the molecular features of SRCC. Our data suggest that SRCCs harbor similar molecular profile, regardless the tumor location. On the other hand, significant differences were observed between SRCCs and non-SRCC tumors, therefore tailored therapy should be provided to these patients.
A phase I study of TAS-102 in combination with oxaliplatin (TAS-OX) for refractory metastatic colorectal cancer (mCRC).
Authors: Cecchini Michael , Kortmansky Jeremy S. , Lacy Jill , Fischbach Neal A. , Thumar Jaykumar Ranchodbhai , Sabbath Kert D. , Gomez Christina M. , Sporn Jonathan , Stein Stacey , Hochster Howard S. 
Published: January 2019

630 Background: TAS-102 is an oral combination of the anti-metabolite 5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI), preventing the degradation of FTD. It is approved as mCRC monotherapy with improved survival. Oxaliplatin is often reintroduced in mCRC after progressive disease (PD) on maintenance 5-FU although response is poor. The decreased efficacy may be related to acquired 5-FU resistance. We therefore explored the safety and efficacy of oxaliplatin in combination with an alternative and non cross-resistant anti-metabolite, TAS-102. Methods: Phase 1 of TAS-OX is a 3+3 dose-escalating study at a starting dose of TAS-102 25 mg/m2 and oxaliplatin 85 mg/m2 with three dose levels (table). TAS-102 is administered days 1-5 and oxaliplatin day 1, every 2 weeks. Eligible patients previously received 5FU, oxaliplatin, irinotecan, appropriate biologics, had measurable disease, usual laboratory parameters, and ECOG PS 0-1. The primary objective was to determine the recommended phase II dose (RP2D). Results: Twelve patients were evaluable for dose limiting toxicity (DLT). No DLTs were observed. Treatment related grade ≥ 3 AEs were neutropenia (n = 4) and thrombocytopenia (n = 1). No AEs resulted in treatment discontinuation. Two patients (dose levels 2 and 3) required dose reductions for prolonged neutropenia. Median number of cycles for all treated patients was 6 ± 4. The disease control rate (DCR) at 8 weeks was 67%. Best response in all evaluable patients was 1 PR (8%) 7 (59%) SD and 4 (33%) PD. Conclusions: The RP2D of TAS-102 is 35 mg/m2 in combination with oxaliplatin 85 mg/m2. No DLTs were observed and no unexpected AEs were seen. The DCR in this heavily pretreated patient population is encouraging. Phase II is now enrolling at this dose (NCT 02848079). Clinical trial information: NCT02848079. [Table: see text]