bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of tumor infiltrating CD8 positive T cells and PDL-1 expression with survival after conversion surgery for unresectable gastric cancer.
Authors: Tanaka Hiroaki , Nishimura Junya , Miki Yuichiro , Tamura Tatsuro , Muguruma Kazuya , Shibutani Masatsune , Ohira Go , Yamazoe Sadaaki , Nagahara Hisashi , Kimura Kenjiro , Toyokawa Takahiro , Amano Ryosuke , Maeda Kiyoshi , Hirakawa Kosei , Ohira Masaichi 
Published: January 2019

62 Background: Conversion surgery after chemotherapy responds to unresectable gastric cancer has long-term prognosis, however, chemotherapy after surgery should also be considered to improve treatment outcome. The effectiveness of immune checkpoint inhibitors for gastric cancer has been proved. In this study, we investigated the association between PDL-1 expression and CD8+ T cell infiltration in the primary tumor and prognosis of patients who underwent conversion surgery after S-1-based multidrug chemotherapy in unresectable gastric cancer. Methods: We evaluated PDL-1 expression and CD8 T cell infiltration by immunohistochemical staining and examined the relationship with prognosis in 90 patients with Stage IV gastric cancer who underwent gastrectomy in our department from 2007 to 2015. Results: 90 cases included 47 cases of palliative resection, 26 cases of CY1P 0cases and 17 cases of conversion surgery. Among Conversion Surgery cases, 11 (65%) patients underwent R0 surgery, and the 5-year survival rate was 66%. The 5-year survival rate of non-curative resected cases was 16%. In immunohistochemical examination, PDL-1 high expression was a poor prognostic factor in palliative surgery and CY1P0 cases. Meanwhile, in the case of Conversion Surgery, the 5-year survival rate was 58%, 32%, 61%, and 30% in the order of PDL-1 high expression group, low expression group, CD8 T cell high infiltration, and low infiltration group, respectively. Prognosis of PDL-1 high expression group and CD8 T cell infiltration group was good. There was no association between curative resection and neither of CD8 T cell infiltration or PDL-1 expression. Conclusions: We found that the prognosis was relatively good in patients where local immune response was enhanced, regardless of R0 excision. Our results suggested that infiltration of CD8 T cells in the primary tumor may be a prognostic predictor, and it is expected to use an immune check point inhibitor after conversion surgery for unresectable gastric cancer.
Are BRAF mutated metastatic colorectal cancer (mCRC) tumors more responsive to VEGFR-2 blockage? Analysis of patient outcomes by RAS/RAF mutation status in the RAISE study—A global, randomized, double-blind, phase III study.
Authors: Yoshino Takayuki , Obermannova Radka , Bodoky Gyorgy , Prausová Jana , Garcia-Carbonero Rocio , Ciuleanu Tudor-Eliade , Garcia Alfonso Pilar , Portnoy David Craig , Cohn Allen Lee , Van Cutsem Eric , Yamazaki Kentaro , Clingan Philip , Muro Kei , Kim Tae Won , Wijayawardana Sameera R. , Hozak Rebecca , Nasroulah Federico , Tabernero Josep 
Published: January 2019

622 Background: The RAISE trial (NCT01183780) demonstrated that ramucirumab (RAM) plus leucovorin, fluorouracil, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo (PBO) plus FOLFIRI as second-line mCRC treatment. RAS/RAF mutations are associated with resistance to anti-EGFR therapies and poor prognosis, particularly BRAF mutations. The extensive RAISE biomarker program assessed the association of multiple candidate markers with efficacy outcomes. Here we present the results for RAS/ RAF mutations. Methods: Plasma and tumor tissue collection were mandatory. KRAS mutation status was determined locally before randomization. Further RAS and RAF mutations were assessed centrally by multiplex qPCR using the Modaplex system (Qiagen) only in samples that were initially reported as KRAS wild type. Thus, patients were classified into one of the 3 categories in the table. OS and PFS by RAS and RAF subgroups were evaluated by Kaplan-Meier and Cox proportional hazards analyses. Results: As with previously reported KRAS analyses, the favorable RAM treatment effect was similar between patients with expanded RAS mutations compared with patients with RAS/ RAF wild-type tumors. However, in the 41 patients with BRAF mutated tumors, the RAM benefit was even more notable for both OS (hazard ratio [HR] 0.54; 95% CI 0.25–1.13) and PFS (HR 0.55; 95% CI 0.28–1.08). Conclusions: RAISE demonstrated that the addition of RAM to FOLFIRI improved patient outcomes regardless of RAS mutation status. The noteworthy signal for patients with BRAF mutant tumors is encouraging due to their poor prognosis but requires further validation in other clinical trials. Clinical trial information: NCT01183780. [Table: see text]
Clinical and molecular characteristics of younger versus older patients with colorectal cancer.
Authors: Iyer Pritish , Wong Kit , Lieu Christopher Hanyoung , Henry Jason , Davis Sarah Lindsey , Goodman Karyn A. , Davies Kurtis , Aisner Dara , Messersmith Wells A. , Leong Stephen 
Published: January 2019

630 Background: Although overall incidence of colorectal cancer is declining, the incidence for young patients (age < 50) with colon cancer is increasing. Reasons for this rise are unclear. Understanding clinical and molecular differences between younger and older cohorts can help guide both patient education strategies and future research into the mechanisms of this phenomenon. Methods: A retrospective analysis of patients diagnosed with colon cancer between 2008 and 2015 who underwent molecular tumor profiling via next-gen sequencing of 26 commonly mutated genes at the University of Colorado. Data collected by chart review includes demographic, pathologic, treatment course, and outcomes. Age group cutoffs for data analysis were set at < 50, 50-65, and > 65 based on screening guidelines and average age of diagnosis Results: We evaluated a total of 242 patients, stage I (n = 1), stage II (n = 65), stage III (n = 68), stage IV (n = 105). Mean age was 59.5 (range 27 to 89). A higher percentage of younger patients were non-smokers (77% of youngest cohort vs 46% of oldest cohort, p < 0.001) and had a non-significant trend towards male gender (youngest cohort 63.8% male, oldest cohort 43.4% male, p = 0.065). Younger patients had similar body mass index (BMI) compared to older patients (BMI 27 vs 25.7, p = 0.35). Younger patients had higher rates of rectal cancer (42% vs 21%, p = 0.01) and lower rates of proximal/right sided colon cancer (20% vs 46.5%, p = 0.014). Younger patients also had lower rates of MSI-H tumors (8% vs 14%, p = 0.01). Finally, younger patients had significantly lower rates of APC (43.1% vs 69.3%, p = 0.009) and BRAF (3.5% vs 19.7%, p = 0.004) mutations. Conclusions: Younger patients ( < 50 years old) with colorectal cancer had lower rates of tobacco use and no difference in obesity rates compared to older patients. In addition, although APC and BRAF mutations were lower in younger patients, there were no mutations that were more prevalent in the young cohort. Therefore, further research into lifestyle factors (specific diet/exercise patterns) or alternative molecular mechanisms are needed.
Tumour infiltrating lymphocyte expression of PD-1 as a favourable prognostic factor in patients with mismatch repair competent colorectal cancer.
Authors: Park James Hugh , Grant Lauren , Quinn Jean A , Roxburgh Campbell SD , McMillan Donald C , Edwards Joanne 
Published: January 2019

631 Background: Immune checkpoint activation is recognised in mismatch repair (MMR) deficient colorectal cancer (CRC), and Programmed Cell Death Protein-1 (PD-1) inhibitors have been shown to have therapeutic benefit in this patient group. However, the role of PD-1 and PD Ligand-1 (PDL-1) in patients with MMR competent CRC remains unclear. The present study examined the relationship between tumor infiltrating lymphocyte (TIL) PD-1 and tumour PDL-1 expression, tumour microenvironment (TME) characteristics and cancer-specific survival (CSS) of patients with MMR competent CRC. Methods: The presence of TIL PD-1 and tumour cell PDL-1 expression was examined in patients who had undergone resection of TNM I-III CRC using a tissue microarray. Relationship with clinicopathological characteristics and the TME (Klintrup-Makinen (KM) grade, Immunoscore, tumour stroma percentage (TSP) and Glasgow Microenvironment Score (GMS)) and CSS was examined. Results: 189 patients were included; 64% were older than 65 and 52% were male. PDL-1 expression was not associated with clinicopathological or TME characteristics. Lymphocyte PD-1 expression was not associated with clinicopathological characteristics, but was associated with a high KM grade ( P< 0.001), high Immunoscore ( P< 0.001), low TSP ( P= 0.068) and a low GMS ( P< 0.001). On multivariate survival analysis, high TIL PD-1 expression was associated with improved CSS (HR 0.60, P= 0.016) independent of Immunoscore (HR 0.74, P= 0.03) and TSP (HR 1.91, P= 0.027). PDL1 expression was not associated with CSS on univariate or multivariate analysis. Pre-operative aspirin use was known for 131 patients. Aspirin use showed a trend towards improved 5-year CSS in patients with low PDL-1 expression (100% vs. 77%, P= 0.103) but worse 5-year CSS in those with high expression (55% vs. 82%, P= 0.045). Conclusions: The presence of PD-1 expressing TILs is a favourable prognostic factor in MMR competent CRC independent of other TME characteristics. Furthermore, the relationship between aspirin and CSS may be dependent on PDL-1 expression. Both PD-1 and PDL-1 may be potential prognostic and predictive markers in patients with MMR competent CRC.
Predictors for detecting circulating tumor DNA (ctDNA) in metastatic colorectal cancer (mCRC).
Authors: Pereira Allan Andresson Lima , Loree Jonathan M. , Davis Jennifer S , Lam Michael , Morris Van Karlyle , Overman Michael J. , Raghav Kanwal Pratap Singh , Kee Bryan K. , Fogelman David R. , Vilar Sanchez Eduardo , Shureiqi Imad , Eng Cathy , Manuel Shanequa , Crosby Shadarra , Wolff Robert A. , Lanman Richard B. , Talasaz AmirAli , Janku Filip , Kopetz Scott 
Published: January 2019

634 Background: Utilization of ctDNA has been rapidly adopted as a predictive diagnostic in advanced NSCLC and indications in GI cancers may be emerging. While tissue-based assays have yields above 90%, there is less known about factors that influence the sensitivity of ctDNA for detecting mutations. Methods: We retrospectively evaluated mCRC patients (pts) who had plasma-derived NGS utilizing a highly-sensitive 68-73-gene assay. Tissue from prior resections or biopsies underwent concurrent 46-gene sequencing. In a case-control design, pts with a known mutation on tissue and radiologic evidence of metastatic disease but no detectable ctDNA mutation were matched 1:3 with randomly selected pts with detectable mutations and compared according to clinical, laboratory, and radiologic characteristics. A binary logistic regression was performed and Kaplan-Meier and Cox-proportional hazards models were used to compare overall (OS) and progression-free (PFS) survivals. Results: Of 427 mCRC pts who underwent ctDNA testing, 416 pts met inclusion criteria. Plasma-derived NGS did not find tumor mutations in 66 cases (15.9%); 198 pts with detectable alterations were selected as controls. After multivariate analysis, the lack of detection of ctDNA was associated with decreasing age (OR 0.94; 95%CI 0.91-0.98; p = 0.004), absence of liver (OR 0.19; 95%CI 0.08-0.45; p < 0.001) and lymph node metastases (OR 0.28; 95%CI 0.12-0.70; p = 0.006). A key determinant was timing of collection relative to disease status: plasma collected after evidence of progression was substantially more likely to have detectable alterations (OR 10.95; 95%CI 4.23-28.33; p < .001); in these pts, the modeled rate of detection was 98%, which increased to > 99% if the pts also had either liver or nodal disease. Pts with no detectable ctDNA had better OS (HR 0.38; 95%CI 0.21-0.69, p = 0.002) and PFS (HR 0.52; 95%CI 0.32-0.85; p = 0.009). Conclusions: When limited to ctDNA collected in newly diagnosed or recently progressing pts, the yield of ctDNA is 98%, which equals or exceeds the yield of tissue based testing. Our findings support the notion that ctDNA testing, when appropriately utilized, can replace tissue based testing and may provide prognostic information.
The impact of preoperative dexamethasone on long-term survival following surgery for colorectal cancer.
Authors: McSorley Stephen Thomas , Khor Bo , Roxburgh Campbell SD , Horgan Paul G. , McMillan Donald C 
Published: January 2019

644 Background: Steroids given at the induction of anaesthesia are associated with a reduction in the magnitude of the postoperative systemic inflammatory response and fewer complications following elective surgery for colorectal cancer (McSorley et al. Ann Surg Oncol 2017;24(8):2104-2112). The present study examined their impact on survival. Methods: Patients who underwent elective surgery, with curative intent, for stage I-III colorectal cancer at a single centre between 2008 and 2016 were included. Data on preoperative dexamethasone was obtained from anaesthetic records, and its impact on cancer specific (CSS) and overall survival (OS) assessed using Cox regression in an unmatched (n=556) and a propensity score matched cohort (n=276) (Table 1). Results: After excluding postoperative mortalities (n=3), there were 98 deaths (18%), with 57 (10%) due to cancer. Of those alive at censoring, the median follow up was 47 months (range 16-110). In the unmatched cohort, there was no significant association between dexamethasone and CSS (HR 0.90, 95% CI 0.52-1.53, p=0.688) or OS (HR 0.95, 95% CI 0.63-1.43, p=0.804). In the propensity score matched cohort, there was no significant association between dexamethasone and CSS (HR 1.18, 95% CI 0.55-2.53, p=0.668) or OS (HR 1.21, 95% CI 0.67-2.17), p=0.532). Conclusions: These results suggest that whilst preoperative steroids are associated with improved short term outcomes following surgery for colorectal cancer, they have no negative effect on long term outcomes. [Table: see text]
Appraisal of prognostic interaction between sidedness and histology in colon cancer: A population-based study.
Authors: Yang Lu-Ping , Wang Zi-Xian , Wang Ying-Nan , Wang Feng , Xu Rui-hua 
Published: January 2019

649 Background: It is reported that sidedness (right vs. left) and histology (mucinous vs. non-mucinous) of CC is predictive of survival. We investigated whether the prognostic values of sidedness and histology were affected by each other. Methods: We identified 81342 patients with stage II–IV CC between 2004 and 2012 from the Surveillance, Epidemiology, and End Results database. Inverse probability propensity score weighting was used to balance the clinical features (i.e., age, sex, race, marital status, year of diagnosis, registry, tumor grade, and T and N stage) between the non-mucinous right-sided, non-mucinous left-sided, mucinous right-sided, and mucinous left-sided subgroups with stratification for tumor stage. Afterwards, overall survival (OS) was compared between these subgroups using univariable Cox proportional hazards models. Results: In stage III/IV CC, the prognosis for non-mucinous left-sided tumors was significantly better than that for non-mucinous right-sided tumors and that for mucinous left-sided tumors, whereas the survival was similar between left-sided and right-sided tumors with the mucinous subtype and between mucinous and non-mucinous tumors in the right-sided colon (Table; test for interaction between sidedness and histology, P < 0.001 in both stages). In stage II CC, the weighted 5-year OS rates were comparable among the four sidedness-histology subgroups (range, 70.3%–72.6%; P= 0.159 and Pinteraction= 0.466). Conclusions: In stage III/IV CC, the prognostic impact of sidedness differed according to histology, and vice versa. By contrast, neither should be considered in risk stratification for stage II CC. [Table: see text]
Malignant peritoneal mesothelioma: Clinicopathological features, prognostic factors, and survival outcomes.
Authors: Patel Meera , Loree Jonathan M. , Taggart Melissa W. , Malpica Anais , Matamoros Aurelio , Kopetz Scott , Varadhachary Gauri R. , Fournier Keith F. , Royal Richard Eldon , Raghav Kanwal Pratap Singh 
Published: January 2019

650 Background: Peritoneal mesothelioma (PeM) is an orphan disease with approximately 300-400 cases diagnosed in the United States each year. Due to its rarity, data on its presentation and prognostic factors is limited. The purpose of this study was to investigate the clinicopathological profile and outcome of Malignant PeM (MPeM). Methods: We retrospectively reviewed 128 PeM patients (pts) seen at UTMDACC (2011 - 2017) comprised of 111 MPeM and 17 variants (VPeM) [9 well-differentiated papillary and 8 multicystic]. Kaplan-Meier method was used to estimate median overall survival (mOS) and compared with log-rank tests. Results: Median age at diagnosis was 57 yrs. with a higher proportion of women (61%). The mOS for MPeM was significantly shorter than VPeM (HR 3.7, 95% CI: 1.6 – 8.4, P = 0.002). Among pts with MPeM, median age at diagnosis was 56 yrs. and 58% were women. Only 22% had prior exposure to asbestos. Epithelioid subtype was seen in 94 (85%) pts. Calretinin and WT-1 IHC were positive in 98% and 96% of cases. BerEP4 and MOC-31 IHC were negative in 90% and 84% of cases. After median follow-up of 31 months (m), the mOS for MPeM cohort was 78 m. In univariate analysis, age, prior asbestos exposure, ECOG PS, histologic subtype, CA125, neutrophil-lymphocyte ratio (NLR) and cytoreductive surgery (CRS) were found to be associated with OS. In multivariate analyses, age ≥ 65 years (HR 4.5, 95% CI: 1.3 - 15.2, P = 0.02), prior asbestos exposure (HR 4.1, 95% CI: 1.1 – 15.6, P = 0.04), poor PS (ECOG 2/3) (HR 8.9, 95% CI: 1.7 – 47.7, P = 0.01), elevated CA125 ( > 3X upper limit of normal) (HR 4.5, 95% CI: 1.3 – 15.5, P = 0.02), and high NLR (HR 3.8, 95% CI: 1.1 – 12.6, P = 0.03) were found to be independently associated with poor OS. A total of 50 (45%) pts underwent CRS and among these the completion of cytoreduction score (CCS) was strongly associated with OS (mOS: 201 m, 53 m and 36 m for CCS 0, 1, 2/3, respectively, P = 0.005). Conclusions: MPeM is associated with poor survival outcomes. Prognostic factors include age, history of asbestos exposure, CA-125 level, NLR, and PS. CRS with CCS 0 results in favorable survival. Further understanding of molecular genetics is warranted to improve prognostication and outcomes.
The impact of Tfh cell/ B cell pathway-related genetic variants in metastatic colorectal cancer patients with bevacizumab-based chemotherapy.
Authors: Tokunaga Ryuma , Cao Shu , Zhang Wu , Puccini Alberto , Berger Martin D , Naseem Madiha , BATTAGLIN FRANCESCA , Soni Shivani , McSkane Michelle , Stintzing Sebastian , Loupakis Fotios , Heinemann Volker , Falcone Alfredo , Millstein Joshua , Lenz Heinz Josef 
Published: January 2019

651 Background: B cells are recognized for their immune activation and lymph-angiogenesis, which attract us to clarify the correlation between B cells and the effect of bevacizumab in cancer patients. We thus investigated whether genetic polymorphisms in Tfh cell/ B cell pathway could predict clinical outcomes in metastatic colorectal cancer (mCRC) patients with bevacizumab-based chemotherapy in first-line treatment. Methods: Genomic DNA was extracted from 451 samples of three independent cohorts: a discovery cohort of 215 patients with bevacizumab plus FOLFIRI in TRIBE (NCT00719797); a validation cohort of 107 patients with bevacizumab plus FOLFIRI in FIRE-3 (NCT00433927); a control cohort of 129 patients with cetuximab plus FOLFIRI in FIRE-3. The OncoArray including 530K single nucleotide polymorphisms (SNPs) from Illumina was used in this study. The correlation between selected SNPs in Tfh cell/ B cell pathway ( CCL19, CCL21, CCR7, CXCL13, CXCR5, and S1PR2) and clinical outcomes were analyzed. Results: In the discovery cohort, patients with any CXCL13 rs355687 C allele had shorter OS than those with T/T variant (22.9 vs. 30.8 months, HR 1.36, 95%CI: 1.00–2.86, P = 0.050), which remained significant in multivariable analysis (HR 1.51, P = 0.013); they also showed a trend of lower response rate (51 vs. 63%, P = 0.093); patients with any CCL21 rs11574915 C allele had shorter OS than those with A/A variant (25.6 vs. 27.9 months) in both univariate (HR 1.43, 95%CI: 1.01–2.02, P = 0.043) and multivariable analyses (HR 1.50, P = 0.030). In the validation cohort, patients with any CXCL13 rs355687 C allele had a trend which showed lower response rate than those with T/T variant (56 vs. 71%, P = 0.099). The findings were not detected in the control cohort. Conclusions: Genetic polymorphisms of CXCL13 and CCL21 may impact the angiogenic environment and patients survivals. They are impacting efficacy of bevacizumab-based chemotherapy in first-line treatment.
Combined analysis of tumor budding and tumor microenvironment in patients with stage III colorectal cancer.
Authors: Nakajima Hiromichi , Inoshita Naoko , Kondoh Chihiro , Ozaki Yukinori , Tomizawa Kenji , Hanaoka Yutaka , Toda Shigeo , Tanabe Yuko , Miura Yuji , Moriyama Jin , Matoba Shuichiro , Kuroyanagi Hiroya , Takano Toshimi 
Published: January 2019

652 Background: Tumor budding (TB) represents the epithelial-mesenchymal transition (EMT) and is a novel marker that predicts metastasis and poor survival in patients with colorectal cancer. Although recent preclinical studies have elucidated the interaction between the EMT process and tumor microenvironment (TME), the clinicopathological correlation between TB and TME remains unclear. Methods: Formalin-fixed paraffin-embedded blocks of specimens were obtained from patients with stage III colorectal cancer who underwent surgical resection and adjuvant chemotherapy at our institution between January 2009 and July 2012. TB, tumor stroma percentage (TSP), and inflammatory reaction (IR) graded using the Klintrup-Mäkinen method were evaluated on hematoxylin and eosin sections. The densities of CD8+ T-cells at the tumor centers and invasive margins were analyzed using immunohistochemistry and digital image analysis. Cox proportional hazards models were used to assess the effect of clinicopathological variables on relapse-free survival (RFS). Results: One hundred and ninety-five patients were included in this analysis. The median age was 62 years (range 32–84 years). The median follow-up duration of this study was 5.8 years. High TB ( > 5 buds/0.785 mm2) was observed in 106 patients (54.4%) and was associated with high TSP (P < 0.01), but not with IR and CD8 expression. Multivariate analysis, including clinicopathological factors such as histology, TB, TSP, and IR revealed that high TB was an independent poor prognostic factor (hazard ratio, 1.89; 95% confidence interval, 1.04–3.45; P = 0.04). Patients with high TB and low IR (21.0%) exhibited a shorter survival than others; the 5-year RFS rates were 82.7%, 81.1%, 78.4%, and 40.8% in patients with low TB and high IR, low TB and IR, high TB and high IR, and high TB and low IR, respectively. Conclusions: Our study demonstrated that high TB was an adverse prognostic factor, regardless of TME status. The combined analysis of TB plus IR could improve prognostic value in patients with stage III colorectal cancer. Patients with high TB and low IR may need novel therapeutic approaches.