bluuebunny/crossref_metadata_2025 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.
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]