bluuebunny/crossref_metadata_2025_split huggingface dataset:
On the road again: Travel patterns and outcomes in rectal cancer.
Authors: Kledzik Mary , Scholer Anthony Joseph , Khader Adam , Santamaria-Barria Juan , Fischer Trevan D , Goldfarb Melanie 
Published: January 2019

530 Background: Associations between high volume centers and outcomes have many advocating for centralization of cancer care, which can lead to increased travel, patient burden, and cost. There is, however, some conflicting data regarding outcomes for patients with more advanced disease. This study aims to explore factors associated with travel and the impact on survival for patients receiving surgery for rectal adenocarcinoma. Methods: All patients >18 years of age with rectal adenocarcinoma that had a surgical resection were identified using the National Cancer Database from 2004-2014. Univariate and multivariate (MV) regression analyses determined factors associated with increased travel distance (<50 miles, 50-100 miles, >100 miles) as well as the impact of travel on overall survival (OS). Results: Of 83,933 patients, those that traveled the furthest were more commonly younger, white non-Hispanic, insured, and with less comorbidities (all p<0.05 on MV analysis). Cancer stage, surgical approach, and type of surgery were not associated with travel distance (p=NS). Increased travel distance improved 5-year OS for stage IV disease (10%, p=0.002), and trended toward significance for stage II (4.0%, p=0.06) and stage 1 (4.3%, p=0.09) disease. After controlling for other factors, travel distance did not impact OS for stage II/III disease, but stage I and IV patients traveling 50-100 miles had an increased risk of death (stage I HR 1.16, CI 1.04-1.30; stage IV HR 1.19, CI 1.07-1.32). This was similar in the entire cohort where traveling 50-100 miles had an increased risk of death (HR 1.09; CI 1.03-1.14). Patients treated at non-low volume centers did have improved outcomes across all stages (p<0.01). Patients treated in academic hospitals had improved outcomes in stages I and IV (p=0.02). Conclusions: Younger, white, non-Hispanic patients are most likely to travel longer distances for rectal cancer treatment, regardless of stage. Increased hospital volume improves OS while travel and use of academic centers may impact patients with stage I/IV disease. Educating patients and providers regarding the influence of travel and hospital volume could help reallocate some resources, decrease financial toxicity, and ease the travel burden for patients.
The role of Parvimonas micra in intestinal tumorigenesis in germ-free and conventional APCmin/+ mice.
Authors: Yu Jun , Zhao Liuyang , Zhao Risheng , Long Xiaohang , Coker Olabisi Oluwabukola , Sung Joseph J.Y. 
Published: January 2019

531 Background: Our in-house meta-analysis of fecal shotgun metagenomic sequences from colorectal cancer (CRC) and control subjects from four cohorts of various ethnicities identified a higher abundance of Parvimonas micra in CRC. We aimed to investigate the effect of P. micra in colon tumor formation and development. Methods: We collected 309 fecal samples and 259 colon biopsies from patients with CRC, advanced adenoma and healthy subjects. P. micra strain was isolated from the feces of a CRC patient. APC min/+ mice and germ-free (GF) mice were orally gavaged with P. micra, or Esherichia coli. Colon epithelial cell line NCM460 and cancer cell lines HT-29 and Caco-2 were exposed to P. micra or E. coli conditional medium. Results: P. micra was significantly enriched both in the feces (n = 207, p < 0.01) and tissue biopsies (n = 99, p < 0.01) of CRC patients compared with controls (n = 102 for fecal samples, n = 160 for tissues biopsies). APCmin/+ mice gavaged with P. micra exibited significantly higher tumor burden ( p < 0.01) and tumor load ( p < 0.01), compared to mice gavaged with either E. coli or non-bacterial control. Consistently, cell proliferation was significantly higher in the colon tissues of P. micra gavaged GF mice relative to control mice evidenced by increased Ki-67 positive cells ( p < 0.05) and PCNA protein expression ( p < 0.01) at weeks 20 and 32. In line with this, colon cell lines NCM460, HT-29 and Caco-2 exposed to P. micra conditional medium significantly increased proliferation than control group (all p < 0.05). Flow cytometry analyses showed that Th2 and Th17 cells were markedly increased, while Th1 were reduced in the lamina propria of the colon tissues of P. micra gavaged mice compared to control mice (all p < 0.01) . Consistently, P. micra colonization in GF mice was associated with increased expression of pro-inflammatory cytokines, including TNF-α, IL-6 and IL-12 (all p < 0.01). Conclusions: The abundance of P. micra was significantly increased in the feces and tissue biopsies of CRC patients. P. micra promotes intestinal carcinogenesis in APC min/+ mice and increase cell proliferation in GF mice. The tumor promoting effect of P. micra is associated with altered immune responses and enhanced inflammation in the gut.
Mismatch repair/microsatellite instability (MMR/MSI) testing practices among United States physicians treating patients (pts) with advanced/metastatic colorectal cancer (mCRC).
Authors: Eriksson Jennifer , Amonkar Mayur , Thomson Gemma , Lambert Jeremy , Malmenas Mia , Chase Monica , Sun Lucy , Kollmar Linda Grossman , Vichnin Michelle 
Published: January 2019

533 Background: Approximately 12-15% of all CRCs are associated with defects in the DNA MMR pathway. NCCN 2017 guidelines endorsed universal MMR/MSI testing for all pts with a personal history of CRC. The study objective was to assess US physicians’ MMR/MSI genetic testing practices for mCRC pts. Methods: A non-interventional, cross-sectional online survey was conducted among 151 physicians (91 oncologists, 15 surgeons and 45 pathologists) treating mCRC pts in the US. A draft survey was first developed based on a targeted literature review and exploratory interviews with 15 physicians, and then pilot tested with a new series of 10 physicians. Physicians were eligible if they were US based with at least 5 years of experience treating CRC pts, had at least one mCRC pt in their routine care in the past 6 months of practice, and experienced with MMR/MSI testing including having ordered at least 1 MMR/MSI test for CRC in the past 6 months. Physicians were invited to participate through a market research panel. Descriptive and logistic regression analyses were performed. Results: Awareness of specific MMR/MSI testing guidelines was high (N = 127, 84.1%). Of those, 93.7% (119/127) physicians had awareness of specific published guidelines with majority 67.2% (80/119) being aware of NCCN guidelines. Universal testing for all CRC pts was performed by 68.9% (104/151) physicians, while 29.8% (45/151) selectively orders the test for some CRC pts. Key barriers for testing included insufficient tissue sample to enable running the test (48.3%, 73/151), patient refusal to have the test done (35.8%, 54/151) and insurance cost concerns for the pts (31.1%, 47/151), while 27.2% (41/151) reported no barriers. There were no statistically significant differences based on physician specialty, practice type and years of practice. Conclusions: The survey demonstrated high awareness and compliance with MMR/MSI testing guidelines although universal testing rates seem to be suboptimal. Addressing the key physician barriers to testing along with increased communication and education on the benefits of testing may help to enhance testing rates.
The safety assessment of robotic versus laparoscopic gastrectomy for gastric cancer using a propensity score matching method.
Authors: Makuuchi Rie , Toriumi Tetsuro , Waki Yuhei , Nakamura Kenichi , Kamiya Satoshi , Tanizawa Yutaka , Bando Etsuro , Terashima Masanori 
Published: January 2019

55 Background: We have previously reported the safety of robotic gastrectomy (RG) for clinical Stage IA or IB gastric cancer in single arm phase II studies. To date, a number of retrospective case control studies comparing RG and laparoscopic gastrectomy (LG) have been performed. However, since randomized controlled trials have never been conducted, no definitive conclusion demonstrating benefits of RG over LG has been demonstrated. In this study, we aimed to evaluate the safety of RG compared to LG using propensity score matching (PSM) methods. Methods: We retrospectively reviewed 766 consecutive patients who underwent either RG (n = 231) or LG (n = 535) for gastric cancer between January 2012 and December 2017. A 1:1 PSM was performed with the matched variables of age, sex, body mass index, performance status, clinical Stage, type of gastrectomy, and extent of lymphadenectomy. We compared short-term outcomes between the patients who underwent RG (RG group) and LG (LG group). Results: After PSM analysis, 231 patients were included in the RG group and 230 in the LG group. Intraoperative blood loss was similar between the groups. Operation time was significantly longer in the RG group (326 min vs. 281 min, P < 0.001). Significantly more lymph nodes were retrieved in the RG group (42 vs. 38.5, P = 0.031). Serum CRP level were significantly lower in the RG group in postoperative day 3 (9.0 mg/dL vs. 9.8 mg/dL, P = 0.049) and 6 (3.1 mg/dL vs. 3.7 mg/dL, P = 0.034), and drain amylase level in postoperative day 3 was also significantly lower in the RG group (612 U/L vs. 856 U/L, P < 0.001). Overall postoperative complication (Clavien–Dindo classification grade IIIA or greater) was similar between the groups (RG: 3.9% vs. LG: 5.6%, P = 0.656). However, pancreatic fistula tended to be less frequent in the RG group than in the LG group (0.4% vs. 2.2%, P = 0.122), although it did not reach statistically significant difference. Conclusions: Although RG takes longer operation time, it appears to be less invasive than LG with the possibility of decreased postoperative complications. To validate the results, randomized controlled trial should be performed.
Genetic variations within the CD40L immune stimulating gene predict outcome for mCRC patients treated with first-line FOLFIRI/bevacizumab: Data from FIRE-3 and TRIBE.
Authors: Berger Martin D. , Stintzing Sebastian , Heinemann Volker , Cao Shu , Miyamoto Yuji , Suenaga Mitsukuni , Hanna Diana L. , Soni Shivani , Puccini Alberto , Tokunaga Ryuma , Naseem Madiha , Battaglin Francesca , Zhang Wu , Cremolini Chiara , Falcone Alfredo , Loupakis Fotios , Lenz Heinz-Josef 
Published: January 2019

558 Background: The introduction of immunotherapy has significantly improved outcome in various tumors. Immune stimulating proteins exert an anti-tumor effect mainly through enhancing T-cell mediated immune response. Additionally, preliminary data suggest a major role of immune stimulating proteins in modulating angiogenesis. We therefore hypothesize that variations in genes involved in the immune activation pathway may predict outcome in pts with mCRC treated with first-line FOLFIRI/ bevacizumab (bev). Methods: The impact of 4 functional SNPs within the CD40L, Light, OX40L and ICOS genes on outcome was evaluated in 322 pts with mCRC treated with first-line FOLFIRI/bev in two randomized phase III trials. We used TRIBE as a discovery (n = 215) and FIRE-3 as a validation set (n = 107). One hundred twenty-nine pts treated with FOLFIRI/cetuximab (cet) served as a control cohort (FIRE-3). OncoArray, a custom array manufactured by Illumina was used for data extraction. Genomic DNA was extracted from blood. Results: Baseline characteristics: FOLFIRI/bev, discovery set (TRIBE), median PFS/OS/FU 9.7/26.2/48.9 mo; FOLFIRI/bev, validation set (FIRE-3), PFS/OS/FU 11.5/32.4/71.1 mo; FOLFIRI/cet, control set (FIRE-3) PFS/OS/FU 12.8//23.9/70.7 mo. The CD40L rs1126535 SNP showed significant association with OS. Pts in the discovery cohort harboring any T allele and treated with FOLFIRI/bev had a longer median OS compared to C/C carriers (27.9 vs. 20.0 mo) in both univariate (HR 1.83, 95% CI 1.19-2.81, p = 0.005) and multivariate analyses (HR 1.62, 95% CI 1.03-2.56, p = 0.038). Similarly, any T allele carriers in the validation cohort had a significantly longer median OS than those harboring a C/C genotype (40 vs. 19.0 mo) in the multivariate analysis (HR 2.80, 95% CI 1.05-7.50, p = 0.040). However, this association could not be shown in pts receiving FOLFIRI/cet (HR 0.60, 95% CI, 0.18-1.94, p = 0.38). Conclusions: We show for the first time that the CD40L polymorphism rs1126535 might serve as a predictive marker in pts with mCRC treated with FOLFIRI/bev. Targeting CD40L might be promising to further improve treatment against mCRC and to overcome resistance to anti-angiogenic therapy.
Genetic variants in the lipopolysaccharide (LPS) receptor complex and TLR4 expression levels to predict efficacy of cetuximab (cet) in patients (pts) with metastatic colorectal cancer (mCRC): Data from the FIRE-3 phase III trial.
Authors: Battaglin Francesca , Puccini Alberto , Cao Shu , Millstein Joshua , Tokunaga Ryuma , Naseem Madiha , Soni Shivani , Lo Jae Ho , Ning Tricia , Arai Hiroyuki , Berger Martin D. , Barzi Afsaneh , Zhang Wu , Heinemann Volker , Stintzing Sebastian , Lenz Heinz-Josef 
Published: January 2019

564 Background: Large metagenomic studies associate disrupted gut microbiome signatures, comprising more prevalently gram-negative bacteria, with CRC carcinogenesis. TLR4, the LPS receptor, has been involved in microbiota-mediated tumorigenesis. High TLR4 expression is associated with poor prognosis in CRC and TLR4 can activate EGFR through ligands epiregulin and amphiregulin. Hence, we hypothesized that genetic variants in the LPS receptor complex and TLR4 expression levels may predict cetuximab efficacy in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in the randomized FIRE-3 trial was genotyped through the OncoArray, a custom array manufactured by Illumina. The impact on outcome of 5 functional SNPs within TLR4, MD2 and CD14 was analyzed in 129 pts treated with first-line FOLFIRI/cet (discovery, mPFS/OS: 12.8/49.8 mo) and 107 pts treated with FOLFIRI/bevacizumab (bev) (mPFS/OS: 11.5/31.4 mo). Gene expression levels were measured from 102 tumor samples of pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. Results: In the discovery cohort, pts carrying the C/T variant of TLR4 rs4986791 had significantly shorter mPFS and OS compared to the C/C genotype in both uni- and multivariable analysis (PFS: 5.4 vs 13.3 mo, adjusted P[ Padj] = .01; OS: 21.7 vs 40.7 mo, Padj= .03). Conversely, C/C carriers of rs12377632 had a longer mPFS compared to any T in uni- and multivariable analysis (15.8 vs 12.2 mo, Padj< .001). Any A allele carriers of MD2 rs12546552 and any G allele carriers of CD14 rs2569190 showed shorter mPFS in multivariable analyses. These associations were not observed in bev arm. Significant interaction was found between TLR4 rs12377632 and RAS status ( P= .015). High TLR4 expression (log2 > 10.93) was associated with worse mPFS (7.2 vs 11 mo, P= .003) and OS (19.1 vs 29.8 mo, P< .001) in FIRE-3 cet arm. Conclusions: Our results provide the first evidence that polymorphisms in the LPS receptor complex and TLR4 expression levels may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment and, overall, contribute to resistance to anti-EGFRs.
Polymorphisms in the telomerase complex to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from TRIBE and FIRE-3 phase III trials.
Authors: Battaglin Francesca , Loupakis Fotios , Stintzing Sebastian , Cao Shu , Puccini Alberto , Tokunaga Ryuma , Naseem Madiha , Berger Martin D. , Soni Shivani , Lo Jae Ho , Bergamo Francesca , Lonardi Sara , Millstein Joshua , Zhang Wu , Zagonel Vittorina , Cremolini Chiara , Falcone Alfredo , Heinemann Volker , Lenz Heinz-Josef 
Published: January 2019

566 Background: Telomere/telomerase interplay is involved in the regulation of genomic stability and cellular replicative potential. In CRC, shortening of telomeres promotes early steps of carcinogenesis but the prognostic role of telomere length is debated. High circulating levels of telomerase reverse transcriptase (TERT) appear to be a negative prognostic biomarker and polymorphisms in the telomerase RNA component (TERC) are associated with increased cancer risk. We hypothesized that genetic variants in the telomerase/telomere capping complex may predict first-line treatment outcome in mCRC pts. Methods: The impact on outcome of 21 selected SNPs within 13 genes ( TERT, TERC, CLPTM1L, TERF1/2, POT1, ACD, NOP10, NHP2, GAR1, STN1, CTC1) was analyzed through the OncoArray, a custom array manufactured by Illumina, on genomic DNA from blood samples of 451 pts enrolled in two independent randomized trials. TRIBE FOLFIRI/bevacizumab (bev) arm (n=215, mPFS/OS: 9.7/26.2 mo) served as discovery cohort, FIRE-3 FOLFIRI/bev arm (n=107, mPFS/OS: 11.5/31.4 mo) as validation and FOLFIRI/cetuximab (cet) arm (n=129, mPFS/OS: 12.8/49.8 mo) as control. Results: In the discovery cohort, pts carrying any A allele of TERT rs2075786 showed longer mPFS (11.1 vs 9.3 mo, P= .021) and OS (33.5 vs 25 mo, P= .005) compared to the G/G genotype in multivariable analysis. Same results were observed for pts carrying any T allele of CLPTM1L rs401681 compared to the C/C genotype ( P= .022). Any C allele carriers of TERC rs2293607 also showed longer mOS in multivariable analysis ( P= .041) and the A/A genotype of ACD rs6979 was associated with longer mPFS in both uni- and multivariable analysis. Interestingly, the T/T genotype of CLPTM1L rs401681 was associated with shorter mPFS (7.8 vs 13.5 mo) in the cet cohort in uni- ( P= .003) and multivariable analysis ( P= .041). In subgroup analyses based on RAS mutational status several SNPs in additional genes were associated with PFS and/or OS in different cohorts. Conclusions: Our results suggest that SNPs in core telomerase/telomere capping complex genes may have a predictive and prognostic value in mCRC pts receiving targeted first-line treatments.
Evaluating and manipulating the immune landscape in hepatic verses peritoneal metastases arising from colorectal primary tumors.
Authors: Ramsay Robert George , Millen Rosemary , Narasimhan Vignesh , Roth Sara , Pham Toan , Kong Joseph , Guerra Glen , Phillips Wayne A , Heriot Alexander Graham 
Published: January 2019

568 Background: Colorectal metastases arise predominantly in the liver, lung and peritoneum. It is becoming increasingly clear that these locations might be distinct in terms of tumor cell tropism and genetics. We explored the immunological landscape in primary colorectal tumors along with hepatic and peritoneal metastases. The ultimate intent is to identify opportunities to implore immunomodulatory strategies to improve patient outcomes. Methods: Cancer biopsies were processed to generate tumor-derived organoids and TILs from patients with primary and/or metastatic tumors. These were co-cultured with patient matched TILs to assess immune competency and opportunities to employ checkpoint blockade using an in vitro platform we recently developed to explore TIL activity in patients with rectal cancer prior to standard of care therapy. Results: We found substantively different levels of TILs, their sub-set composition and most importantly their capacity to kill tumor cells. The nature of the metastatic peritoneal and hepatic tumor TILs were distinct. Where high programmed cell death 1 (PD-1) expression was high on TILs there was an opportunity to test PD-1 receptor function with blocking antibodies whereby some TILs showed enhanced cytotoxicity while others did not. Conclusions: Using our immune function assay we have demonstrated the distinct activities of patient-matched TILs in terms of killing at different organ sites of metastases. We also found differences in response to checkpoint inhibition blockade and de novo immune resistance.
KRAS mutation is associated with upregulation of integrin beta-4 expression leading to tumor invasion in colorectal cancer.
Authors: Choi Seo-Hyun , Marco Michael , Chen Ching-Tung , Pelossof Raphael , O'Rourke Kevin Patrick , Smith Jesse Joshua , Garcia-Aguilar Julio 
Published: January 2019

576 Background: KRAS mutation ( KRASmut) is associated with aggressive biological behavior and resistance to chemoradiotherapy in colorectal cancer (CRC). The tumor microenvironment is a critical component framing the biological behavior of cancers. We have recently shown that a KRASmut modulates the tumor microenvironment by reducing the expression of extracellular matrix (ECM) genes in CRC. The effect of a KRASmut on integrins, the epithelial cell receptors for ECM proteins, remains largely unknown. Here, we investigated the impact of KRASmut on integrin expression in CRC and the effect of integrin beta 4 (ITGB4) expression on CRC phenotype. Methods: The genomic profile of 79 locally advanced rectal cancers (LARC) was characterized by the MSK-IMPACT DNA assay and RNA sequencing by Hi-Seq platform. The transcriptomic changes associated with KRAS in the LARC cohort was validated in the TCGA colon cancer dataset. Expression of ITGB4 was investigated by immunofluorescence (IF) in 39 colon cancer specimens by counting ITGB4-positive cells in an E-cadherin positive epithelial population. The relationship between KRAS and ITGB4 was also explored by manipulating KRAS expression in human cell lines and genetically engineered mouse models (GEMMs). ITGB4 knockout in HCT116 CRC cell lines and organoids from GEMMs were generated with CRISPR/Cas9. ITGB4 expression was confirmed using qRT-PCR and western blotting. Cell proliferation was assessed with the MTT assay. Cell invasion and migration were assessed in a trans-well system. Results: ITGB4 gene expression was increased in KRASmut compared to KRASwildtype in LARC and TCGA. Increased ITGB4 expression in KRASmut colon cancers was also validated by IF (p = 0.0029). Introduction of KRASmut in HCT116 CRCs and GEMMs increased ITGB4 expression by 1.5 to 2 fold. Knockout of ITGB4 reduced the migration and invasion of HCT116 CRC cells but did not alter proliferation. Conclusions: KRASmutincreases the expression of ITGB4 in CRC. Increased ITGB4 expression is associated with CRC cell invasion and migration. These results inform the biology of tumor progression in KRASmut CRC tumors.