bluuebunny/crossref_metadata_2025_split huggingface dataset:
The immune milieu of anal squamous cell carcinoma and implications of IDO expression on outcome.
Authors: Mitra Devarati , Brackett Diane , Horrick Nora , Hong Theodore Sunki , Parikh Aparna , Clark Jeffrey W. , Ryan David P. , Deshpande Vikram , Wo Jennifer Y 
Published: January 2019

659 Background: Recent studies have examined the immune microenvironment in anal squamous cell carcinoma (ASCC) with focus on T-cell infiltrate and PD-1/-L1 expression. This study examines a variety of immune markers in our institution’s pre-treatment localized ASCC cohort including indoleamine-2,3-dioxygenase 1 (IDO1) and class I HLA (hc10) which have not been previously studied in ASCC. Methods: Retrospective review identified 48 patients with localized ASCC treated at our institution with definitive chemoradiation between 2006-2016 with ≥6 months of follow-up in survivors and tissue locally available. Immunohistochemistry (IHC) for the immune markers CD8, PD1, PDL1, HLA class I (hc10) and IDO1 was performed and scored by two pathologists. Univariate and multivariate analyses were performed using a Cox proportional hazards model. Results: Of the 48 patients studied, distribution by stage was: I-14.5%, II-33%, IIIA-14.5%, IIIB-35%, unknown-2% with 27% having HIV or being on immunosuppressive medication. The distribution of immune marker staining was: median (med) CD8 72/hpf (0-319/hpf), med PD1 16/hpf (0-178/hpf), med PDL1 1% (0-40%), and med IDO1 3% (0-100%). Hc10 staining showed > 50% loss of HLA class I in 12.5% of patients. Spearman correlation calculations suggested that patients with high CD8 tended to have higher PD1 (R = 0.47, p = 0.0006) and tumor PDL1 (R = 0.36, p = 0.04) though hc10 and IDO1 expression were not correlated. Median follow-up for surviving patients was 35 months (6-102 months). CD8, PD1, PDL1 and hc10 expression did not correlate with clinical outcomes. However, IDO1 staining in > 50% of tumor cells was associated with worse outcomes, even when adjusted in a multivariable model for higher T-stage and nodal positivity: HR for progression 5.7 (95% CI 1.5-20.7, p = 0.008) and HR for death 5.6 (95% CI 1.5-21.5, p = 0.01). No other clinical variables were associated with outcome. Conclusions: ASCC has a diverse immune milieu. While patients generally do well with standard therapy, IDO1 may serve as a prognostic indicator of poor outcome and suggest a patient population in which IDO-directed therapies may prove particularly valuable.
Prognostic value of neutrophil-to-lymphocyte ratio (NLR) in intestinal neuroendocrine tumors: An analysis of the U.S. Neuroendocrine Tumor Study Group.
Authors: Krasnick Bradley A. , Davidson Jesse T , Panni Roheena Z. , McGilvray Martha , Zarate Rodriguez Jorge , Lopez-Aguiar Alexandra G , Dillhoff Mary , Beal Eliza W , Poultsides George A. , Makris Eleftherios , Rocha Flavio G. , Crown Angelena , Idrees Kamran , Hawkins William G. , Strasberg Steven M. , Hammill Chet , Chapman William C. , Doyle Maria Majella , Maithel Shishir , Fields Ryan ,   Members of the U.S. NET Study Group
Published: January 2019

694 Background: Intestinal neuroendocrine tumors (NETs) can often be indolent, with survival commonly exceeding 10 years. However, a subset can be more aggressive. The search for a prognostic test based on preoperative lab results would be of benefit. An elevated NLR has been found to be predictive of diminished overall survival (OS) in several cancers, and we hypothesized that this same trend would hold true for intestinal NETs. Methods: Utilizing the 8 member institutions of the retrospective U.S. NET Study Group, patients undergoing resection of intestinal NETs were included. After excluding patients undergoing emergent surgery, those with preoperative sepsis or distant mets, and those with missing neutrophil/lymphocyte lab values, 281 patients were included for analysis. The cutoff values for NLR were determined using receiver operator curve (ROC) analysis. Univariate analysis was performed based on these groups. A Kaplan-Meier survival curve was created based off optimal NLR from ROC analysis. OS was calculated as date of surgery to date of death/ last follow-up. SPSS 23.0 was used for analysis. Results: Of the 281 patients identified, 9% were appendiceal, 9% colonic, 21% duodenal, 5% rectal, and 56% jejunal/ileal. Using a NLR of >2.47, the ROC area under the curve was 0.609 ( p=0.002). Median survival for the 130 patients in the <2.47 group was 159.8 months, versus 115.63 months in the ≥2.47 group (p =0.009). When comparing the NLR <2.47 and ≥2.47 groups, mean age (57.5 vs. 59.0 years, respectively, p=0.642), ASA status (89% ASA 2 /3 in both groups, p=0.314), tumor Ki-67 status (Ki-67>3% in 30% vs. 26%, respectively, p=0.57), and post-op complications (36 vs. 42%, respectively, p=0.310) were similar between groups. A significantly greater number of patients in the NLR high group had positive lymph nodes (60 vs. 47%, p =0.002). Conclusions: For patients undergoing curative resection of intestinal NETs with no distant mets, a preoperative NLR of ≥2.47 was significantly predictive of decreased OS, with those in the elevated NLR group having an OS 3.7 years less than those in the <2.47 group. Future prospective data is warranted to further validate these findings.
Expression of B7-H3 (CD276) in surgically resected esophageal squamous cell carcinoma.
Authors: Maruki Yuta , Takashima Atsuo , Miyamoto Takahiro , Hirano Hidekazu , Shoji Hirokazu , Honma Yoshitaka , Iwasa Satoru , Okita Natsuko , Kato Ken , Sekine Shigeki , Koyanagi Kazuo , Daiko Hiroyuki , Kitano Shigehisa , Aoki Kazunori , Boku Narikazu 
Published: January 2019

70 Background: B7-H3 (also known as CD276) belongs to a family of immune modulators that includes PD-1 and PD-L1 (also known as B7-H1 or CD274), which has been reported to be expressed in many carcinomas and associated with poor prognosis. In this study, we explored the relationship between B7-H3 expression and clinical background and prognosis of esophageal squamous cell carcinoma (ESCC) patients treated with surgery alone. Methods: The subjects of this study was the ESCC patients who received curative surgery between January 2009 and December 2014 without prior treatment, excluding T4 and M1 disease. We evaluated tumor B7-H3 expression by immunohistochemistry, which was scored to 0 (absent) if < 10% of cancer cells were stained, and 1 (weak), 2 (moderate), or 3 (strong) according to the intensity in stained cancer cells (> 10%). The B7-H3 expression of score 2 and 3 was regarded as positive. We compared the clinical characteristics and prognosis between B7-H3 positive and negative patients using log rank test and Cox proportional hazards regression analysis for adjusting the backgrounds. Results: 33 (45%) of 74 patients were positive for expression of B7-H3. Between H7-H3 (+) and (-) groups, there were difference in pathological T stage (pT1/pT2/pT3: 9/0/24 vs. 23/4/14, p < 0.01) and lymph vessel invasion (+/-: 7/26 vs. 17/24, p=0.08). There was no association between sex, age, N factor, and vascular invasion. B7-H3 (+) patients showed trend of poor recurrence free survival (RFS) and overall survival, not significant, (HR=1.41[95%CI:0.63-3.14] p=0.41 for RFS, HR=1.34[ 95%CI:0.52-3.48] p=0.55 for OS). However B7-H3 status was not a prognostic factor in multivariate analysis (HR=0.78[95% CI: 0.33-1.85] for RFS, HR=0.73 [ 95%CI:0.26-2.02] for OS). Conclusions: The expression ratio of B7-H3 was observed in 45% of the esophageal cancer, which was related with T stage and lymphatic vessel invasion but not with clinical outcomes such as RFS and OS.
Mutant allele-specific imbalance in patients with metastatic colorectal cancer.
Authors: Yarom Nirit , Birenboim Miriam , Binder-Gallimidi Adi , Hanovich Ekaterina , Sella Avishay 
Published: January 2019

706 Background: Patients with colorectal cancer(CRC) harboring RAS mutations do not respond to antiepidermal growth factor receptor (anti-EGFR) therapy. Next generation sequencing (NGS) identifies and quantifies mutant and wild type alleles as seen on the sequencing electropherograms. RAS mutant allele-specific imbalance (MASI) occurs when the mutant allele peak is higher than the wild type one. The aims of this study were to verify the rate and tissue distribution of RAS MASI as well as its clinical relevance. Methods: Results of NGS study of patients with metastatic colorectal cancer were collected retrospectively. The clinical charts of patients with RAS mutations were reviewed by the investigators who were blinded to the MASI results. Results: Between August 2014 and Jan 2016, 26 out of 52 (50%)patients tested, were found to harbor RAS mutations. Among them, 11 patients were detected with KRAS MASI(42.3%) Table 1 shows the different characteristics. 6 out of 11 patients presented with synchronous metastatic disease. This correlated with a statistically significant difference in the mean disease free survival that was 9 months in the KRAS MASI group compared with 27.5 months in the non MASI group. A few patients had more than one mutation. ie KRAS Ex2- G12D, 62.3%, PKI3CA Ex9-E545K, 24.6%, Ex20-H1047Y, 0.6% in the MASI group and KRAS Ex2-G12C+G12V - 10.85%, KRAS Ex4-A146T - 10.3%, NRAS gene Ex2-G12D - 1.1%, in non MASI group. Patients in the MASI group had a different clinical profile. (See Table 1) The overall survival of patients was calculated from diagnosis of metastatic disease, till death, 24 months-this was not significantly nor statistically different amongst groups. Conclusions: With the caveat of a small study and a retrospective analysis we showed that patients with MASI have worse characteristics that were translated to a significant shorter disease free survival. OS was not different amongst the groups. [Table: see text]
Serial monitoring of circulating tumor DNA in patients with metastatic colorectal cancer to predict the therapeutic response.
Authors: Zhou Jianfeng , Jia Ning , Sun Zhao , Gao Xin , Cheng Yuejuan , Chen Wei , Shen Chunying , Bai Chunmei 
Published: January 2019

713 Background: Early biomarkers of therapeutic responses could help optimize the treatment of metastatic colorectal cancer (mCRC). This prospective study was designed to explore the serial changes in plasma-circulating tumor DNA (ctDNA) as an early marker of therapeutic response to systemic treatment in mCRC. Methods: Twenty-six mCRC patients receiving standard first-line therapy once every two weeks were enrolled. Plasma ctDNA, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were assessed serially before each of the first four cycles. Somatic mutations in plasma ctDNA were detected via next-generation sequencing using a panel of 50 cancer-related genes, and the mutation of maximal frequency in pretreatment ctDNA was selected as the candidate mutation for analysis. Radiologic responses were assessed after the fourth cycle. Results: Mutations in pretreatment ctDNA could be detected in 25 (96.2%) of the 26 initially enrolled patients. Among the 20 patients monitored serially, changes in ctDNA could differentiate patients with progressive disease two cycles (approximately four weeks) earlier than the changes in CEA and CA19-9 levels could, and changes in ctDNA levels as early as prior to cycle 2 predicted the radiologic responses after cycle 4. A log2 value of fold-change in ctDNA after cycle 1 (log2 (C1/C0)) > 0.044 predicted progressive disease, with a sensitivity and specificity of 100.0% (95%CI: 47.8-100.0%) and 86.7% (95%CI: 59.5-98.3%), respectively, and an accuracy of 90.0% (95%CI: 68.3-98.8%). Patients with log2 (C1/C0) > 0.044 showed worse progression-free survival than did those with log2 (C1/C0) ≤0.044 (median 2.0 versus 17.0 months; P = 0.092). Conclusions: Early changes in ctDNA that are detected via targeted sequencing could predict later radiologic responses in mCRC.
Association of COX-2 expression with lymphocyte infiltration in colorectal cancer.
Authors: Wu Zehua , Zhang Jianwei , Cai Yue , Yang Liu , Deng Yanhong 
Published: January 2019

716 Background: It is proved that in colorectal cancer, Tumor infiltrating lymphocytes is associated with good prognosis. Someone pointed out that COX inhibitors act with anti-PD-1 antibody in pre-clinical models. This study aims to investigate whether COX-2 expression is associated with lymphocyte infiltration, and to know how they affect the survival. Methods: We collected specimens of resected tumor from patients who received surgery and pathological staging II and III from May 2007 to Jan 2012. These patients received surgery and adjuvant therapy with FOLFOX regimen. Tissue microarrays were made by resected tumor. Immunohistochemical staining was performed with COX-2, CD3 and CD8, PD-1 and PD-L1 antibody. Staining result of COX-2 was measured by two degrees of high and low. For CD3 and CD8, stained lymphocytes in and around tumor tissue were defined stained positive. For PD-1 and PD-L1, more 1% cells stained were defined positive stained. Results: COX-2 expression was correlated with CD3 and CD8.There were more CD3 (63.0% vs. 48.5% p=0.028) and CD8 (95.5% vs. 83.5% p=0.002) expression in the COX-2 high expression group. However, there was no significant difference in PD-1 and PD-L1 expression between COX-2 high and low expression group. As for CD3, PD-1 expression was higher in CD3 positive group than in the negative group (27.6% vs. 10.3% p=0.001). similarly, PD-L1 expression was higher in the CD3 positive group (47.3% vs. 15.2% p < 0.001). but PD-1 and PD-L1 expression was not significantly different between in the CD8 positive and negative group. Three years DFS for the whole group patient was 77.6%. There was a better tendency for 3 years DFS in the CD3 positive group (80.6% vs. 73.7%), but it was not significantly different (p=0.216). Conclusions: CD3 and CD8 expression were more in the COX-2 high expression group, which indicated COX-2 inhibitor use may act with tumor infiltrating lymphocytes. But neither PD-1 nor PD-L1 expression was correlated with COX-2 expression. Infiltrating CD3 lymphocytes may be associated with better DFS for adjuvant chemotherapy colorectal cancer patients. [Table: see text]
The prognostic role of inflammatory markers in patients with metastatic colorectal cancer treated with bevacizumab.
Authors: Clarke Stephen John , Burge Matthew E. , Feeney Kynan , Jones Kristian , Gibbs Peter , Molloy Mark P. , Marx Gavin M. , Price Timothy Jay , Reece William , Segelov Eva , Tebbutt Niall C. 
Published: January 2019

719 Background: Bevacizumab (BEV) with fluoropyrimidine-containing chemotherapy is well-established for patients (pts) with mCRC. There is a need for reproducible, validated, inexpensive and accessible prognostic markers to aid in treatment selection. Pre-treatment levels of systemic inflammatory markers including the neutrophil to lymphocyte ratio (NLR) have been shown retrospectively to be prognostic in many tumors. This study aimed to prospectively evaluate the relationship between NLR and treatment outcomes in previously untreated mCRC pts receiving BEV-based therapy. Methods: ASCENT (NCT01588990) is an open-label, single arm, phase-IV, multi-center study. Pts received 1st-line BEV+XELOX or mFOLFOX6 in phase A (PhA) with planned continuation of BEV+FOLFIRI beyond 1st progression in phase B (PhB). Primary analysis: association of NLR with progression free survival (PFS). Secondary analyses: overall survival (OS) and safety. Sub-study: safety in pts with intact primary in situ (PIS) and resected primary tumor (RPT). Results: 128 pts started PhA; median age 63.5 years (range: 26-84), 70(55%) females, 51(40%) PIS, 71(56%) and 56(44%) were PS 0 and ≥ 1; respectively. 53(41%) pts entered PhB. The median baseline (b) NLR was 3.2 (range: 1.5-20.4) with 32(25%) pts having a baseline level > 5. The hazard ratio (HR) for PFS by NLR > 5 vs ≤5 was 1.4 (95% CI: 0.9-2.2; p = 1.01). Median PFS was 9.2 months (mo; 95% CI: 7.9-10.8) for PhA and 6.7 mo (95% CI: 3.0-8.2) for PhB. HR for OS based on baseline NLR > 5 vs ≤5 was 1.6 (95% CI: 1.0-2.7; p = 0.052). Based on a multivariate model, the 12-month predicted OS probability for pts with PS 0, no metastatic liver disease and ≤ 3 sites of other metastatic disease, was 87% in pts with bNLR ≤ 5 and 79% in pts with bNLR > 5. Median OS was 25 mo (95% CI: 19.2-29.7) for the full analysis set and 14.9 mo for PhB. Treatment related toxicities were numerically and qualitatively consistent with prior experience. There were 4(3%) instances of GI perforation, of which, 3(6%) occurred in the PIS group. Conclusions: Consistent with previous studies, the trend was towards worse PFS and OS in pts with higher bNLR, but the association was not proven. Clinical trial information: NCT01588990.
Small leucine-rich proteoglycans expression in colorectal cancer: Differences by primary tumor location.
Authors: Solis Hernandez Maria Del Pilar , Perez Lopez Natalia , Garcia Mesa Yolanda , Fernandez-Vega Ivan , García-Suárez Olivia , Lozano Iturbe Victor , García Beatriz , Quirós Luis M ,   Department of Functional Biology, University of Oviedo
Published: January 2019

721 Background: SLRP are present in normal and tumor colorectal tissue, with different patterns of expression, being predominant in L CRC. However, due to the small sample the differences observed in survival were no statistically significative. These alterations could be related to interactions at the extracellular matrix level. Further prospective and larger analysis are needed for a better comprehension of tumor microenvironment. Aims: To describe SLRP expression pattern by PTL and survival rate. Methods: 32 tumor specimens and their respective healthy tissue (fresh frozen tissue) from primary tumor surgery from the local biobank: 12 right-sided (R) & 20 left-sided (L) CRC. Transcriptomic approach to analyze SLRP core protein transcriptions using RT-PCR in Those with significative differences were confirmed by immunohistochemistry. Survival analysis was performed using Kaplan-Meier curves and log rank test. Results: Both sides showed BGN 2-fold overexpression (R p = 0.015, L p = 0.001) and OGN decreased 4-3-fold (R p = 0.038, L p < 0.001). PODNL was only expressed in tumor tissue. Additionally, alterations in other 4 genes in L CRC: PODN 2-fold p = 0.003, CHAD 4-fold p = 0.017, DCN 2fold p = 0.047 and PRELP 3-fold p = 0.003. EPYC was only expressed in 50% of L CRC. No difference in ASPN, FMOD, LUM, ECM2, KERA, OMD, TSK. Neither it was in PRELP for L CRC nor EPYC and DCN in R CRC. No expression of OPTC was found. No significative differences in survival were found. Median relapse-free survival (RFS) was 25 months (mo), 10.75 mo R CRC and 19.47mo L CRC. BGN overexpression (44%) was related with worse RFS (14 vs 19mo), better in L CRC (12 vs 19mo). OGN decrease (17%) showed better RFS (40 vs 16mo) favoring L CRC (21 vs 17mo). Overall survival displayed a similar behavior. Conclusions: SLRP are present in normal and tumor colorectal tissue, with different patterns of expression, being predominant in L CRC. However, due to the small sample the differences observed in survival were no statistically significative. These alterations could be related to interactions at the ECM level. Further prospective and larger studies are needed for a better comprehension of tumor microenvironment.
Association of proteinuria, hypertension, and hand-foot-skin reaction with efficacy of apatinib in gastric cancer: Results from the post-marketing study (Ahead-G201).
Authors: Li Jin , Deng Wenying , Wen Lu , Wang Junsheng , Zhang Guifang , Zhong Haijun , Jia Tongfu , Yang Jianwei , Ba Yi , Bai Yuxian , Lin Xiaoyan , Wang Mei , Wang Lin , Liu Likun , He Yifu , Tao Min , Xie Congying , Ye Feng , Wu Xiang-yuan , Qin Shukui 
Published: January 2019

73 Background: Ahead-G201 is an ongoing open-label, multicenter, post-marketing Phase IV trial assessing safety and efficacy of apatinib in 2000+ patients (pts) with chemotherapy-refractory advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction. Proteinuria (PTN), hypertension (HTN) and hand-foot-skin reaction (HFSR) are common adverse events (AEs) related to anti-angiogenesis drugs. Methods: As of 2017/7/10, 1037 and 820 pts were evaluable for safety and survival. Clinical outcomes were compared between pts with and without PTN / PTN / HFSR using Kaplan–Meier methods and multivariate Cox regression model. Results: 200 (19.3%), 194 (18.8%) and 115 (11.1%) pts had PTN, HTN and HFSR, respectively. Similar mean daily dosage was found between pts with and without PTN, HTN or HFSR (from 520.6 to 551.0 mg/day). Pts developed PTN / HTN / HFSR had longer median medication durations (57 vs. 33 / 55 vs. 35 / 65 vs. 36 days; p<0.001). However, there was no significant difference in tumor response and progression free survival (PFS) between pts with and without PTN/HTN/HFSR (Table). Only pts had HFSR showed significantly longer overall survival (OS) (8.38 vs. 5.95 months; p=0.0003). After adjusted for baseline and treatment characteristics, presence of HFSR was found to be independently associated with prolonged OS (HR: 1.82 [95%CI, 1.25–2.66]). Conclusions: Occurrence of HFSR is an independent predictor of better OS. Prior analysis based on Phase II and III indicated the relationship between HTN and prolonged OS, which needs to be further analyzed. Clinical trial information: NCT02426034. [Table: see text]
A randomized phase II study of mFOLFOX6 plus bevacizumab versus mFOLFOX6 plus cetuximab for previously untreated, liver-limited metastatic colorectal cancer that is unsuitable for resection (ATOM trial).
Authors: Uetake Hiroyuki , Emi Yasunori , Yamanaka Takeharu , Muro Kei , Oki Eiji , Takahashi Takao , Nagasaka Takeshi , Hatano Etsuro , Ojima Hitoshi , Manaka Dai , Kusumoto Tetsuya , Katayose Yu , Fujiwara Toshiyoshi , Yoshida Kazuhiro , Unno Michiaki , Hyodo Ichinosuke , Tomita Naohiro , Sugihara Kenichi , Maehara Yoshihiko 
Published: January 2019

734 Background: It is still a topic of ongoing debate as to which of the two agents, anti-VEGF antibody or anti-EGFR antibody, is more effective in patients with KRAS Exon 2 or RAS wild-type metastatic colorectal cancer (mCRC) in the first-line setting. ATOM is a multicenter, randomized trial comparing mFOLFOX6 plus bevacizumab (Bmab arm) with mFOLFOX6 plus cetuximab (Cmab arm) in patients with liver-limited metastases unsuitable for upfront resection. Methods: Patients with previously untreated mCRC were eligible if they had ≥5 liver-limited metastatic lesions and/or had liver-limited metastases with the maximum lesion diameter of > 5cm. Patients with KRAS Exon2-wild were registered but after Jan 2015 limited to those with all RAS-wild. Primary endpoint was progression-free survival (PFS), which was defined as the time from randomization to disease progression, recurrence after resection by surgery, or death from any cause (Central review). Key secondary endpoints included overall response rate (ORR), liver resection rate, and overall survival (OS). Results: A total of 122 pts were enrolled between May 2013 and April 2016. Of 116 eligible (59 in the Cmab arm and 57 in the Bmab arm), median age was 65/64 in the Cmab/Bmab arm; ECOG PS 0, 86/89%; all RAS wt, 98/95%; left-sided primary tumor, 76/84%. Efficacy results were summarized in the table. With a median follow-up of 24.3 months, the median PFS was 15.0 months in Cmab arm and 11.6 months in the Bmab arm with a hazard ratio of 0.803 (95%CI, 0.513–1.256), whereas ORR was 86% in the Cmab arm and 68% in the Bmab arm. Liver resection rate was 49% and 56% in the Cmab arm and the Bmab arm, respectively. Conclusions: In patients considered unsuitable for upfront resection of liver-limited metastasis, the two agents showed a similar efficacy. OS result will be presented elsewhere. Clinical trial information: NCT01836653. [Table: see text]