bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between sarcopenia and gastric carcinogenesis: A health check-up cohort study.
Authors: Kim Young Min , Kim Jie-Hyun , Baik Su Jung , Jung Da Hyun , Park Jae Jun , Youn Young Hoon , Park Hyojin
Published: January 2019

46

Background: Insulin resistance which is a mechanism of metabolic syndrome has been known to promote carcinogenesis of various malignancies. In addition, metabolic syndrome is associated with sarcopenia. Thus, the aim was to investigate the association between sarcopenia and gastric carcinogenesis including precancerous conditions: atrophic gastritis (AG), intestinal metaplasia (IM), and gastric adenoma. Methods: The study subjects were an adult population who underwent gastroduodenoscopy at Gangnam Severance Check-up Center. AG and IM were evaluated by endoscopic findings. Sarcopenia based on muscle mass was defined as appendicular skeletal muscle (ASM) as a percentage of body weight that was less than 1 standard deviation below the sex-specific mean for healthy adults aged 20 to 39 years (cutoff point: 29.3% in male and 26.7% in female). Obesity was defined as body mass index (BMI) ≥ 25 kg/m2 according to the Asia-Pacific criteria. Sarcopenic obesity was a condition of combined sarcopenia and obesity. The association between sarcopenia and gastric lesions was evaluated. Results: 8,356 patients were enrolled this study. Among them, 12 (0.14%) and 3,552 (42.5%) patients were diagnosed as gastric cancer and precancerous conditions, respectively. 5 (41.7%) of 12 gastric cancer patients and 594 (16.9%) of 3.552 patients with gastric precancerous conditions were diagnosed with sarcopenia. Both diabetes mellitus (DM) (OR = 5.152, P = 0.005) and sarcopenic obesity (OR = 4.139, P = 0.016) were independent predictive factors for gastric cancer. And smoking, alcohol, DM, hypertension, dyslipidemia, Helicobacter pylori, and sarcopenia were significantly associated with gastric precancerous conditions. Conclusions: Sarcopenia and sarcopenic obesity were significantly associated with gastric carcinogenesis. Thus, sarcopenia may be one of the risk factors for gastric carcinogenesis.
Difference of colorectal cancer microbial community by metagenomics and culture-based methods.
Authors: Lee Dong Ho , Seol Mijin , Lee Yu Ra , Park Young Soo , Shin Cheol Min , Yoon Hyuk , Kim Nayoung , Cho Jae Ho , Song Dong Jin , Kim Kyung Mi
Published: January 2019

489

Background: Dysbiosis of intestinal microbiota is promoting the development of colorectal cancer (CRC). We confirmed the intestinal microbiota composition from fecal sample of Korean CRC patients. Metagenomic analysis was performed and we isolated single microbes through culture-based method. Methods: CRC fecal samples were collected from 12 individuals. Metagenome Sequencing was based on the 16S rRNA gene amplicon on the Illumina MiSeq platform. The bacteria strains were subcultivated on the agar plate medium in aerobic and anaerobic and further identified by using the 16s rRNA gene sequencing. Results: Bacteria diversity by metagenome analysis was decreased in CRC group compared to control group. In CRC group, relative abundance of Firmicutes and Bacteroidetes were increased while the prevalence of Proteobacteria was decreased. The difference of microbial composition between control and CRC group was found at the genus level. Bacteroides, Parabacteroides of Bacteroidetes have increased and Acinetobacter, Pseudomonas of Proteobacteria have significantly decreased in CRC compared to control group. Using culture method, we isolated diverse bacteria of species level including five strains of Bacteroides; B. ovatus, B. uniformis, B. salyersiae, B. vulgatus and B. xylanisolvens and two strains of Fusobacterium; F. gonidiaformans and F. necrophorum from CRC patients. Conclusions: Metagenome analysis showed the genus Bacteroides, Parabacteroides of the phylum Bacteroidetes has increased and the genus Acinetobacter, Pseudomonas of Proteobacteria decreased in CRC group compared to control group. In addition to, we have isolated various strains associated with CRC by culture-based method.
Expression patterns of PD-L1 and other immune checkpoint molecules in gastric cancer.
Authors: Nakamura Kenichi , Hatakeyama Keiichi , Toriumi Tetsuro , Koseki Yusuke , Waki Yuhei , Fujiya Keiichi , Kamiya Satoshi , Makuuchi Rie , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Yamaguchi Ken , Terashima Masanori
Published: January 2019

49

Background: Immune checkpoint inhibitors (ICPIs) have provided clinical benefit for various malignancies. A new attempt was recently made to combine PD-1/PD-L1 inhibitors and other ICPIs. In order to establish a new strategy for ICPI combination therapy, we must first understand the expression patterns of PD-L1 and other ICP molecules. To identify possible candidate agents for application in combination therapy with PD-1/PD-L1, we analyzed the expression patterns of ICP molecules in gastric cancer. Methods: Tumor samples were obtained from 278 patients who underwent gastrectomy for gastric cancer from 2014 to 2016, and a comprehensive gene expression analysis using a DNA microarray. We analyzed the TCGA dataset to identify the candidate ICP molecules in relation to PD-L1. The immune landscape was evaluated according to the expression patterns of known immune cell markers reported by Bindea et al. Results: Seven ICP molecules ( PD-L2, IDO1, CD80, ICOS, CTLA4, LAG3 and TIM3) were coexpressed with PD-L1 in the TCGA dataset. In our cohort, all of these molecules were also coexpressed (R > 0.5, P < 0.0001). Using a cluster analysis based on these gene expression profiles, patients were divided into Group A, characterized by the co-overexpression of PD-L1 and other ICP molecules, and Group B, characterized by the underexpression of PD-L1. In Group A, PD-L2 (R = 0.67) and IDO1 (R = 0.61) were particularly strongly associated with the PD-L1 expression. In Group B, elevated expressions of CTLA4 and ICOS were predominantly observed, and these expressions were strongly correlated with each other (R = 0.90). The tumor stage was significantly more advanced in Group B than in Group A (P = 0.02). Accordingly, Group A exhibited a better survival outcome than Group B. The immune landscape of Group A was particularly enriched for Th1, NK CD56dim and activated dendritic cells. Conclusions: PD-L1 and several immune checkpoint molecules tend to be coexpressed in gastric cancer. The combination of PD-L1/-L2 and IDO1 target agents may be a new strategy for treating gastric cancer with PD-L1 overexpression. In contrast, the underexpression of PD-L1 might be an indication for the use of CTLA4- and/or ICOS-directed therapies.
Relation between the size of nonmetastatic and metastatic lymph nodes and outcomes in patients with stage III colon cancer.
Authors: Okada Kazutake , Sadahiro Sotaro , Kamei Yutaro , Ogimi Takashi , Miyakita Hiroshi , Saito Gota , Tanaka Akira , Suzuki Toshiyuki , Chan Lin Fung
Published: January 2019

494

Background: In colon cancer, retrieval of less than 12 lymph nodes is a risk factor for recurrence. We previously reported that the long-axis diameter of the largest LNs (maximum LNs) is associated with a higher number of retrieved LNs and better outcomes in stage II disease (Int J Colorectal Dis 2015). Furthermore, the number of natural killer cells in the maximum LNs is associated with the number of retrieved LNs and lymph node size, and is an independent prognostic factor (Oncology 2018). We examined whether the long-axis diameter of maximum LNs with and without metastasis is a prognostic factor in stage III colon cancer. Methods: The study group comprised 190 patients with stage III colon cancer from 2005 to 2014. For each patient, one negative LN and one positive LN with the greatest long-axis diameter were selected, and the diameter was measured on H-E stained specimens. The endpoint of survival analysis was relapse free survival (RFS). The cut-off value (COV) was determined by using receiver operating characteristic curves. Results: The mean long-axis diameter of maximum negative and positive LNs were 8.5 ± 3.7 and 9.9 ± 4.9 mm, respectively. Factors related to the number of retrieved LNs were the tumor size (less than 4.3 cm, 13.5 ± 6.4; 4.3 cm or more, 16.6 ± 7.3; p = 0.004) and the long axis diameter of maximum negative LNs (< 8.1 mm, 13.4 ± 6.9; ≥ 8.1 mm, 17.6 ± 6.6; p < 0.001). Maximum negative LNs with a diameter of ≥ 8.1 mm was associated with significantly better RFS than maximum negative LNs with a diameter of < 8.1 mm (p = 0.020). The diameter of maximum positive LNs was not a prognostic factor. On multivariate analysis, the tumor size (≥ 4.3 cm/< 4.3 cm, HR 3.02; p < 0.001), venous invasion (absent/present, HR 0.41; p = 0.017), the number of LNs (≥ 12/< 12, HR 0.56; p = 0.043), and the diameter of maximum negative LNs (≥ 8.1 mm/< 8.1 mm, HR 0.45; p = 0.008) were independent prognostic factors. Conclusions: In stage III colon cancer, the long-axis diameter of negative maximum LNs was a prognostic factor. Enlarged negative LNs are caused by hyperplasia of cell components in LNs. The size of negative maximum LNs might reflect the tumor immunity of the host.
Utility of restaging patients with stage II/III rectal cancer following neoadjuvant chemo/XRT: A systematic review.
Authors: Hendrick Leah E. , Levesque Renee L , Shibata David , Hinkle Nathan M , Monroe Justin J , Glazer Evan Scott , Deneve Jeremiah Lee , Dickson Paxton Vandiver
Published: January 2019

495

Background: In the US, patients with clinical stage II/III rectal cancer typically receive neoadjuvant chemoradiation (chemo/XRT) over 5-6 weeks followed by a 6-10 week break before proctectomy. As this chemotherapy is delivered at radio-sensitizing doses, there is essentially a 3-month window during which potential systemic disease is untreated. Evidence regarding the utility of restaging patients prior to proctectomy is limited. Methods: PubMed, Scopus, Web of Science, and the Cochrane Library were searched for studies evaluating the utility of restaging patients with locally advanced rectal cancer after completion of long course chemo/XRT, and reporting changes in management after restaging. Studies that were non-English, included < 50 patients, or examining the diagnostic accuracy of specific imaging modalities were excluded. Study quality was evaluated using the modified Newcastle Ottawa Scale. Results: Eight studies were identified including a total of 1251 patients restaged between completion of chemo/XRT and proctectomy. All studies were retrospective (6 single institution, 2 multi-institution). Restaging identified new metastatic disease in 72 (6.0%) patients, with 4 studies reporting specific sites: liver (n = 28), lung (n = 8), adrenal (n = 1), bone (n = 1), and multiple sites (n = 7). Overall, progression (distant or local) was detected in 85 (6.8%) patients and resulted in a reported change in management in 71 (5.7%) patients. One study identified an association of high-grade tumors with progression (p ≤ 0.05), however, this was not reported in any other study. Moreover, tumor-related prognostic characteristics were inconsistently reported among studies, precluding meta-analysis. Conclusions: Although restaging between completion of neoadjuvant chemo/XRT and proctectomy detects disease progression in only a small percentage of patients, findings may alter the treatment plan. A multi-institutional collaboration with analysis of well-defined prognostic variables may better identify a group of patients most likely to benefit from restaging.
Sidedness in metastatic colorectal carcinoma: Which are the factors which influence the prognosis?
Authors: Kogay Maria , Evesque Ludovic , Falcoz Antoine , Saint Angelique , Cavaglione Gerard , Schiappa Renaud , Baudin Guillaume , Milano Gerard A. , Chamorey Emmanuel , Francois Eric
Published: January 2019

497

Background: Recent reports demonstrate prognostic and predictive impacts of the location of the primary tumor in metastatic colorectal cancer (mCRC). Our retrospective analysis aimed to determine the influence of primary site on metastatic distribution and disease evolution. Methods: From our database all patients (pts) with mCRC (except transverse carcinoma) treated from 1/12/2007 to 1/12/2016 in our institution were collected. Univariate and multivariate analyses were performed to identify predictors of overall survival (OS). Results: A total of 284 pts with available data were analyzed: 83 with Right-sided Colon Cancer (RCC) (29%), 123 with Left-sided Colon Cancer (LCC) (43%) and 78pts with Rectal Cancer (RC) (28%). Hepatic, lung, lymph nodes and peritoneal metastases were respectively found in 63%, 36%, 23% and 20% of the population. The incidence or number of liver metastases were not influenced by sidedness (p = 0.06), LCC presented more bilobar involvement compared to RCC and RC (p = 0.017). Peritoneal carcinomatosis was significantly correlated to colon cancer (p = 0.002), whereas lung metastases were more common in RC (p < 0.001). Patients with RCC more often presented distal lymph node involvement (p = 0.008). RAS mutation status was known for 241pts (80%), of those 110 (37%) were RAS mutated with no significant differences between RCC, LCC and RC (p = 0.4), BRAF mutation (p = 0.007) was more common in RCC. On a multivariable analysis, primary tumor resection (PTR) and complete response after first line therapy were associated with a better OS but only a trend was observed for LCC and RC. Lung, lymph and peritoneal metastasis were associated with worse OS (Table). Conclusions: These results suggests that mCRC had different clinical presentation at diagnosis, the association with molecular features may explain the independent prognostic factor for OS of the sidedness. [Table: see text]
Prognostic immune markers for recurrence and survival in locally advanced esophageal adenocarcinoma.
Authors: Babar Laila , Zaidi Ali Hussainy , Omstead Ashten N. , Zheng Ping , Kelly Ronan Joseph , Jobe Blair Anderson
Published: January 2019

50

Background: Treatment options and risk stratification for esophageal adenocarcinomas (EAC) primarily rely on clinical and pathological criteria, such as tumor stage and pathological response (PR) evaluation. However, with immunotherapy showing hints of activity in EAC there is an emerging need to develop new predictive biomarkers that will not only identify high-risk patients but also unlock novel therapeutic strategies. The aim of this study was to evaluate if LAG3, TIM3, IDO and CXCL9 gene expression along with pathological classifiers correlate with recurrence and/or death in EAC. Methods: Clinical and histopathology data on 49 resectable EAC patients was captured. Mean age at diagnosis was 64.2 years with a median follow up of 21.2 months. Laser capture microdissection followed by qRT-PCR was performed on pretreatment FFPE samples to quantify LAG3, TIM3, IDO and CXCL9 gene levels. Statistical tools established individual biomarker cutoffs and these were correlated with clinical outcomes. Results: For disease free survival, a best fit Cox model was generated consisting of PR (HR=9.54, 95% CI = 2.13 ~ 42.62, p = .003), LAG3 (HR = 2.86, 95% CI = 1.03 ~ 7.94, p = .044), and CXCL9 (HR = 0.40, 95% CI = 0.16 ~ 0.99, p = .049). Moreover, the classification performance of the 3 predictor Cox model was deemed superior to PR alone; P = 0.0001 (Likelihood Ratio Test (LRT)) indicated strong significance in predictability with the recurrence model. For overall survival, a best fit Cox model was generated consisting of TIM3 (HR = 4.43, 95% CI= 1.70 ~ 11.5, p = .002) PR (HR = 3.09, 95% CI= 1.00 ~ 9.56, p = .051) and IDO (HR = 0.31, 95% CI = 0.11 ~ 0.82, p = .019). Likewise, the classification performance of the 3 predictor Cox model was deemed superior to PR alone; P = 0.0004 (LRT) indicated strong significance in predictability with the survival model. Conclusions: LAG3, TIM3, IDO and CXCL9 expression in conjunction with PR to neoadjuvant therapy provide superior tools to predict recurrence and death in locally advanced EAC patients. Additionally, given the paucity of treatment options for esophageal cancer we must check for these markers early on in the disease course to better risk stratify patients and provide newer targets for novel treatments.
Gene-specific features (MLH1, MSH2, MSH6, PMS2) of mismatch repair (MMR) protein expression and somatic mutations (muts), microsatellite instability (MSI) and tumor mutational burden (TMB) in MSI-H and MMR-mutated tumor genomic profiles (TGPs).
Authors: Hall Michael J. , Bodor Joseph Nicholas , Xiu Joanne , Feldman Rebecca , Grothey Axel , Goldberg Richard M. , Worrilow William Mills , Hwang Jimmy J. , Kim Edward S. , Lenz Heinz-Josef , Raghavan Derek , Shields Anthony Frank , Marshall John , Korn W. Michael , Salem Mohamed E.
Published: January 2019

505

Background: MSI is a tumor biomarker for immunotherapy efficacy that is closely associated w/deficient MMR, and is also variably associated w/somatic muts of the MMR genes, loss of MMR protein expression by immunohistochemistry (IHC), and high TMB. Germ-line muts (Lynch syndrome/LS) in the 4 MMR genes are recognized to have distinct cancer spectrums/penetrance in LS, yet across all tumors, gene-specific variability in MMR IHC, MMR muts, and TMB is understudied. Methods: Results of TGPs performed by Caris Lifesciences (2015-17) were analyzed in colorectal (CRC), endometrial (EC) and all other cancers/tumors (OT) as: 1) all MSI-H tumors (n = 1057) and 2) all tumors w/ ≥1 mut in an MMR gene (n = 470). A subset of cases had IHC for MMR protein and PD-L1 expression. MSI and TMB were determined by NGS. Results: Characteristics of MSI-H tumors and tumors w/ ≥1 MMR mut are seen in the Table. A single MSH6 mut [F1088fs] in a coding microsatellite represented 31% of all MMR muts detected. F1088fs was found in 58% tumors w/MLH1/PMS2 loss (IHC) but only 25% w/MSH2/MSH6 loss (p < 0.001), was more commonly seen in EC vs CRC/OT (p < 0.001), and was negatively associated w/somatic POLE mut (p = 0.002). Distinct mut signatures in the MMR genes (e.g. GLUàSTOP) were seen in tumors w/POLE muts and DNA repair genes. Conclusions: MSI-H and MMR mutated tumors demonstrate marked gene-specific heterogeneity in IHC patterns, TMBs, and somatic muts that may be relevant to treatment selection, resistance, and response. [Table: see text]
Colorectal cancer (CRC) among very elderly ( > 80 yo) patients (pts): A Brazilian single institution cohort.
Authors: Crosara Alves Texeira Marcela , Moura Kelsen , Cabral Pedro , Silva Suelen Medeiros , Pereira Allan Andresson Lima , Costa Frederico , Sabagga Jorge , Hoff Paulo Marcelo , Fernandes Gustavo Dos Santos
Published: January 2019

507

Background: Approximately 60% of all cancers and 70% of the mortality occurs in pts aged 65 years and over. Despite that, there is a significant lack of evidence regarding the safety and efficacy of treatments for this part of the population. Our goal is to profile very elderly (VE) pts with gastrintestinal malignancies to highlight research opportunities and improve cancer care among this growing population. Methods: We retrospectively analyzed very elderly pts that attended at Sírio Libanês Hospital in Brazil in a 3 year period and had colorrectal cancer (CRC) diagnosed. We collected information from electronic medical charts on age, gender, ECOG-PS, staging, and surgery. We also gathered information about the type of treatment and survival from diagnosis. Results: Of 88 consecutive VE GI cancer pts, 40 (45,4%) were found to have CRC being 29 colon and 11 rectum. 14 patients were considered to have right sided tumors and 26 left sided. Among CRC pts, the median age was 82, 5 yo and 21 (52.5%) were men. ECOG-PS at diagnosis was 0/1 in 29pts, 19 (47.5%) presented as stage IV disease and 27 pts had surgery of the primary site. As treatment 23(57.5%) received chemotherapy, being 4 adjuvant and 19 palliative. Single agent fluoropyrimidine was the first line therapy in 47%, chemotherapy doublet in 42%, 26% pts received anti-VEGF. Six patients with rectal cancer received chemoRT. The median survival among the stage IV CRC pts was 27.5ms. Conclusions: This cohort is one of the few reported data on VE population cancer, the incidence of cancer in this age group is high and deserve to be more characterized in both trials and retrospective data. Interestingly, those patients seem to benefit from treatments likewise historic data from average age patients. Treatment details, tumor location, pathology, and survival curves will be presented.
Retrospective multicenter study for assessment of association between imaging change and outcome after treatment of regorafenib: KSCC1603.
Authors: Esaki Taito , Kawahira Masahiro , Kusumoto Tetsuya , Yuki Satoshi , Hatanaka Kazuteru , Kobayashi Yoshimitsu , Nishie Akihiro , Kawanami Satoshi , Makiyama Akitaka , Saeki Hiroshi , Shimokawa Mototsugu , Oki Eiji , Maehara Yoshihiko
Published: January 2019

509

Background: Molecular-targeted drugs are known to have angiogenesis-inhibiting properties, and thus can inhibit angiogenesis inside the tumor tissue to cause necrosis, even if the tumor diameter is unchanged. We retrospectively investigated relationship between imaging change associated with regorafenib (REGO) treatment and the treatment outcome in Japanese mCRC. Methods: Eligibility included ECOG-PS 0 or 1, treated with REGO with lung or liver metastasis, started dose with 120 or 160mg/day of regorafenib and duration of treatment (DOT) must be 35 days or more (excluding interruption). Patients (Pts) were performed baseline CT within 28 days before and first CT assessment were between eight and 12 weeks after start of regorafenib. The main objective of this analysis is to investigate the correlation between the imaging change and outcome. As imaging change, onset or increase of Cavitation of lung lesion (CLL), morphologic response of liver lesion (MRL), Change of liver metastasis density (CLD) were evaluated. In all cases, independent two radiologists are evaluating radiological change after regorafenib treatment. Results: We finally screened 671 cases and 231 cases were eligible. The pts background was male/female 147/84, median age　64.0 (range: 32-83), median DOT of REGO　86 days (range: 35-818). The pts with lung metastasis were 153, and with liver metastasis were 166. CLL were positive in 69 (40.0%) pts. The median progression free survival (PFS) of the pts with/without CLL were 3.2/2.4 months (HR 0.794; 95% CI 0.584-1.080). Median overall survival (OS) of the pts with/without CLL were 10.5/9.0 months (HR 1.058; 95% CI 0.751-1.489). Median OS of pts with/without CLL in female were 11.4/7.9 months (HR 0.630; 95% CI 0.352-1.127). The MRL and CLD of liver metastasis were analyzed in 147 / 91 pt. Median OS of pts with/without MRL were 9.9/8.2 months (HR 1.015; 95% CI 0.581-1.774) and Median OS with/ without CLD were 11.6/7.0 months (HR 0.604; 95% CI 0.353-1.031). Conclusions: Cavitation of lung metastasis may predict PFS of the pts but not OS. Change of Liver metastasis density were predictor of favorable outcome to regorafenib. (UMIN000023329).
Early detection of lower GI tract tumors by dedicated assessment of the colon on routine computed tomography (CT) imaging: An observational study.
Authors: Chang John , Pluhm Russell , Lutrick Ashley , Guerra Jessica , Koo Phillip , Kundranda Madappa N.
Published: January 2019

510

Background: We have previously reported that up to 48% of the early features of colorectal cancer (subtle wall thickening, pericolonic stranding, and small lymph nodes in the draining nodal station) were not identified on the original CT abdomen and pelvis (CTAP) reports. This resulted in a 36% decrease in five-year survival based on historical data. In this report, we assessed whether dedicated assessment of the colon on routine CT scans could lead to early detection of colorectal cancer. Methods: 210 CTAPs over a three-month period were screened from the emergency room records at a tertiary care hospital. 194 scans met eligibility. Exclusion criteria included: cases known to the evaluating radiologist and age ≤ 19 or > 89 years. No study was excluded for suboptimal image quality. The original report was reviewed for abnormalities involving the colon, mesentery and bowel and was recorded. A blinded evaluation of the eligible case was then performed by a board-certified radiologist with attention specifically to the colon and the mesentery for the suspicious early features of CRC. The concordance and discordance was then tabulated. Discordant findings were re-evaluated to determine if the discordance was true. Results: 72/194 patients were male, median age 44.5 years (range 20 - 89). 55/194 patients (29.1%) included in the study were noted to have suspicious features. 26 had abnormal lymph nodes, 24 had abnormal colonic wall thickening and 16 had pericolonic stranding and/or wall edema. 45/55 studies were truly discordant from the original interpretation. These included one missed colorectal cancer (confirmed), one likely small bowel neuroendocrine tumor (no follow up), and one likely transitional cell carcinoma of the right renal pelvis (no follow up). Conclusions: Dedicated search of the colon and mesentery on CTAP can identify subtle findings, although their true relevance is being evaluated in a larger future study. Our observational data does indicate that there maybe a potential role for a focused evaluation of the colon and mesentery on routine CTAP in an attempt to potentially increase the rate of cancer detection especially in younger low-average risk patients.
The strategy of zero-mortality due to postoperative VTE in patients with colorectal cancer.
Authors: Iwahashi Shoko , Nishi Masaaki , Tetsuya Ikemoto , Yoshikawa Kozo , Higashijima Jun , Miyatani Tomohiko , Tokunaga Takuya , Takasu Chie , Kashihara Hideya , Shimada Mitsuo
Published: January 2019

511

Background: The best method of venous thromboembolism (VTE) prevention after surgery for colorectal cancer remains unclear. It is reported that about 20-40% of high-risk patients were diagnosed as DVT and 2-4% was diagnosed as PE and its mortality rate is 0.5-1.0%. The aim of this study is to evaluate the incidence of postoperative VTE patients with colorectal adenocarcinoma and to evaluate the efficacy of VTE preventive strategy. Methods: A total of 264 patients who had undergone curative surgical resection for colorectal cancer at Tokushima University Hospital were included in this study (n = 264 colon: rectum = 1:0.57). All patients were measured D-dimer preoperatively. When D-dimer was ≥ 1.1, lower extremities ultrasonography (US) was performed. All patients were treated with Heparin (10,000U/24h) continuously intravenous injection from the day of surgery, and administered Enoxaparin (2,000U/24h) subcutaneous injection after 24h of the operation. Results: In all 264 patients, 74 (28%) were D-dimer ≥ 1.1 and 16 (6%) diagnosed VTE in US (proximal:distal type n = 6:1). 239 (91%) were treated with postoperative anticoagulant therapy. 2 developed perioperative VTE (symptomatic: asymptomatic = 1:1) and after discharge 12 developed postoperative VTE and mortality rate of VTE was 0%. Univariate analysis indicated that obesity (BMI ≥ 25), hyperlipidemia and preoperative PE were risk factors for deep venous thrombosis (DVT) (p < 0.0001, 0.014, 0.0135, respectively) and multivariate analysis revealed that obesity was an independent risk factor for postoperative DVT (p < 0.0001). Conclusions: Obesity (BMI ≥ 25) was independent risk factor for postoperative VTE. Our preventive protocol including screening using D-dimer and lower extremities US and treatment with Enoxaparin is considered as effective for prevention of postoperative VTE.
DNA damage response pathway mutations contribute to a high proportion of hereditary colorectal cancer in patients from the Republic of Macedonia.
Authors: Staninova Marija , Matevska Geshkovska Nadica , Angelovska Biljana , Nenad Mitrevski , Panovski Milco , Dimovski Aleksandar J
Published: January 2019

512

Background: Hereditary factors are assumed to play а role in 35-45% of all colorectal cancers with 5%-10% associated with high penetrant disease-causing mutations in genes correlating to hereditary polyposis (HP) or hereditary nonpolyposis syndromes (HNPCC). Although inherited germline mismatch repair and APC gene mutations contribute significantly to CRC, still a genetic diagnosis cannot be obtained in > 50% of familial cases. Methods: We performed a targeted NGS sequencing of 103 probands with clinically diagnosed HP (39) or HNPCC (64) using a multigene panel on two different platforms (Illumina Cancer Panel and Ion Torrent custom panel) covering coding and exon/intron sequences of 100 genes implicated in hereditary cancers. Results: Overall, the molecular defect was identified in 60 (58%) index patients. As expected, a large percentage (82%) of these patients exhibited the presence of clearly pathogenic mutations in well-known genes associated with hCRC (APC, MUTYH, BMPR1A, NTHL1 in HP, MLH1, MSH2, PMS6, MSH6 in HNPCC). Surprisingly, all except one (FLCN c.1285dupC, detected in a family with classical FAP), of the remaining mutations were located in genes involved in the DNA damage response pathway, of which 3 in CHEK2 (c.1031delT; c.1229delC; c.599T>G), 2 in BRIP1 (c.2392C>T) and 1 in each of BLM (c.1642C>T), BRCA2 (c.4446_4451dupAACAGA), FANCM (c.2953delG), FH (c.1431_1433dupAAA) and ERCC2 (c.1403C>T). Clinically, six of these cases exhibited the HNPCC type X phenotype (mutations in BRCA2, BRIP1, FANCM and CHEK2) while the other four were classified as oligopolyposis (mutations in BLM, FH and CHEK2). Conclusions: Our data indicate a significant association of DNA damage response pathway deficiencies and carcinogenesis in patients with hCRC syndromes exhibiting either the HNPCC type X or oligopolyposis phenotype. No genetic defect was detected within the analyzed gene panel in 44 (42%) families, indicating the need of extended exome/whole genome analyses in a substantial portion of patients with this disease.
Are quantitative measures of visceral adiposity obtained after neoadjuvant chemoradiation associated with postoperative morbidity in patients with locally advanced rectal cancer?
Authors: Hendrick Leah E. , Lippuner Veronica , Speaks Tyler , Scharr Travis S , Fleming Andrew M , Guerrero Whitney M , Glazer Evan Scott , Dyer Andrew W , Shibata David
Published: January 2019

514

Background: Body mass index (BMI) is an inconsistent predictor of surgical morbidity in cancer patients. Increased visceral obesity measured before neoadjuvant chemoradiation (NCR) has been associated with post-operative morbidity in rectal cancer (RC). We sought to evaluate whether visceral obesity/BMI measured immediately after NCR correlates with postoperative complications in a heterogenous, largely underserved cohort of RC patients. Methods: 116 patients (64% white, 34% black, 2% other) underwent proctectomy for stage II/III RC after NCR. Automated CT segmentation software was used to determine body fat distribution at the L4/L5 level. Patients were classified as obese by BMI (≥ 30 kg/m2) and post-NCR CT measures of adiposity including visceral fat area (VFA; > 100cm2), visceral to subcutaneous fat area ratio (V/S; > 0.4), and perinephric fat thickness (PNF; > median) were obtained. Complications were classified (Clavien-Dindo) into low (1-2) or high (3-4) grade. Associations between measures of adiposity, short-term surgical outcomes and clinicopathologic factors were evaluated with one-way ANOVA, Chi-square, and Fischer’s exact test as appropriate for overall, white, and non-white cohorts. Results: Obese patients by adiposity measures (but not BMI) were more likely to be male by V/S (91.4% vs. 54.3%, p ≤ 0.001) and PNF (62.9% vs. 26.1%, p ≤ 0.001), Caucasian by VFA (mean 135.2 cm2vs. 93.8 cm2, p = 0.002), and have preexisting metabolic comorbidities by VFA and PNF ( p < 0.01). V/S was associated with the presence of key metabolic comorbidities in both white and non-white groups ( p < 0.05). Obesity by V/S but not BMI was associated with development of postoperative complications in the non-white group (65.5% vs. 30.8%, p = 0.049), but not in the overall or white cohorts. Conclusions: V/S as measured after NCR is associated with presence of key metabolic comorbidities in the entire cohort but with postoperative complications only in non-white patients. Given these observations, further evaluation of the impact of socioeconomic factors and change in adiposity between pre- and post-NCR time periods is warranted.
Microsatellite instability detection from plasma of colorectal cancer patients.
Authors: Sun Jing , Cai Zhenghao , He Songbing , Liu Chengliu , Zheng Minhua , Zhu Xinguo , Zhou Jian , Yao Yizhou , Han-Zhang Han , Liu Hao
Published: January 2019

515

Background: MSI, detected in 15% of colorectal cancer (CRC) patients, is a hypermutable phenotype caused by deficiency in DNA mismatch repair system. Currently, MSI detection is limited to tissue samples. Detection of MSI from blood samples has been explored but confounded by low sensitivity due to the trace amount of ctDNA present. In this study, we developed a NGS read-count based algorithm-bMSISEA (blood MSI signature enriched analysis) to detect MSI from blood samples. Methods: Matched tumor and adjacent normal tissues were obtained from 50 MSI-H CRC patients to establish a microsatellite pattern for MSI-H tumors. White blood cells (WBCs) from 100 CRC patients were used to establish a microsatellite pattern for MSS. Plasma samples were obtained from 75 CRC patients with known MSI status assessed by IHC (38 MSI-H and 37 MSS) to validate the algorithm. Results: To establish features for MSI-H and MSS tumors, 51 microsatellite loci covered by ColonCore panel with mononucleotide repeats longer than 10bp were scanned using paired tumor and adjacent normal tissues and 8 loci with significant differential read length distribution were identified. MSI signature enrichment analysis was performed using WBCs to establish a microsatellite signature for MSS tumors. For each locus, the numbers of total reads supporting either MSI-H (denoted as K in the equation) or MSS (N-K, where N refers to the total number of reads supporting either MSI-H or MSS at a specific locus) were counted. The MSI signature enrichment analysis was performed using hypergeometric test. The log-transformed p values were used to calculate z scores. The final microsatellite status was reflected by MS score, which was the sum of z scores of all loci. A MS score of 15 was derived to differentiate MSS and MSI-H tumors. Both simulation data and data generated using clinical samples revealed more than 98% sensitivity and 100% specificity with ctDNA percentage greater than 1%. This method is still reliable if the ctDNA percentage drops to 0.4%, yielding sensitivity of 93.3% and specificity of 100%. Conclusions: We developed a sensitive algorithm which can reliably detect MSI status with ctDNA fraction greater than 0.4% with sensitivity of 93.3% and specificity of 100%.
Association between primary tumor site, perioperative CEA ratio, and overall survival in patients with colorectal cancer.
Authors: Odeny Thomas A , Farha Nicole , Vazquez Wilfred , Batool Amna , Saeed Anwaar , Paluri Ravi Kumar , Kasi Anup
Published: January 2019

518

Background: There are differences in the incidence, clinical presentation, molecular pathogenesis and outcome of colorectal cancer (CRC) based on the tumor location. Emerging research suggests that the perioperative carcinoembryonic antigen (CEA) ratio is a prognostic factor for CRC patients. We aimed to determine the association between tumor location, perioperative CEA ratio, and 5-year survival among patients with CRC. Methods: We analyzed 111 patients who underwent resection for CRC at KUMC. After excluding patients without pre- or post-operative CEA data, 62 patients for whom we could calculate a CEA ratio (post-op/pre-op CEA) were classified as either high ( ≥ 0.5) or low ( < 0.5) ratio. The primary outcomes were: 1) overall survival (OS) stratified by tumor location; 2) OS stratified by CEA ratio; and 3) whether there was effect modification by tumor location, of the association between perioperative CEA ratio and OS, after adjusting for tumor stage and smoking status. Kaplan-Meier method was used to estimate survival rates, and Cox proportional hazards models for multivariate analysis. Results: The median age was 61 years, 54% male, 31% smokers, 74% left-sided tumors, median pre-operative CEA was 3.3, and 60% had CEA ratio ≥ 0.5. The OS rates were 89.1% and 81.3% in patients with left-sided versus right-sided tumors respectively (p-value = 0.4). The OS rates were 83.8% and 92.0% in patients with high versus low CEA ratios respectively (p-value = 0.3). There was effect modification by tumor location on association between CEA ratio and OS, after adjusting for smoking status and tumor stage (p-value < 0.001). However, in the stratified analysis, the n was too small to permit inferential analysis. In multivariate analysis, both tumor location (HR 0.4; p = 0.3) and perioperative CEA ratio (HR 2.7; p = 0.3) were not significantly associated with OS after adjusting for smoking status and tumor stage. Conclusions: There was no difference in OS between left versus right-sided tumors. The association between perioperative CEA ratio and OS was significantly modified by tumor location. However, to attribute this modification to left versus right warrants validation in a larger cohort as our sample size was limited.
Clinical and functional analysis of SOX9 in colorectal cancer.
Authors: Lizarraga Erik , Ruiz Garcia Erika , Lopez-Camarillo Cesar , Meneses Abelardo , Astudillo Horacio , Fernandez Figueroa Edith Araceli , Lino-Silva Leonardo , Avendaño-Félix Mariana Melisa , Parra-Niebla Maryelv , Bermúdez-Cortés Mercedes , Ramos-Payán Rosalío , Silva-Benítez Erik , Romero-Quintana José Geovanni , Aguilar-Medina Elsa Maribel
Published: January 2019

519

Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. CRC develops within the intestinal epithelium, which is constantly self-renewing, developmental genes could promote the initiation and progression of cancer. SOX9 transcription factor is expressed especially in intestinal stem cells and in Paneth cells, thus alterations in expression could greatly promote neoplasia. However, the clinical significance and functional role of SOX9 in CRC remains unclear. The aim of this study is to investigate the association of SOX9 expression with relapse in CRC patients and initiate functional studies by evaluating the effects of silencing SOX9 in stem cells properties such as colonospheres formation in HCT116 CRC cells. Methods: 97 FFPE biopsies from CRC patients in stage I (N = 34) and stage II (N = 63) were analyzed. Immunoreactivity of SOX9 was classified as low and high expression groups based on the percentage of positive nucleus and tissue staining intensity. SOX9 silencing was achieved using a specific siRNA and Lipofectamine-RNAiMax and confirmed by qPCR 24 h postransfection. 40,000 HCT116 and HCT116-siSOX9 cells were seeded under adherent and ultra-low attachment conditions for tumorigenesis assays. After 72 h colonospheres were seeded and quantified. ROC analysis was used to assess the clinical correlation of SOX9 with relapse. Experimental data were expressed as means and differences tested by t-Student. Results: Data showed that 12.3% of patients relapsed. Interestingly, all of them showed lower SOX9 expression (p ≤ 0.05), regardless of their relapse free survival. In functional analysis, SOX9-deficient HCT116 cells formed smaller and less-compacted spheroid when compared to non-transfected HCT116 (p ≤ 0.05). Nonetheless, cell proliferation and migration under adherent condition were similar between the groups. Conclusions: This study did not find association between SOX9 expression and relapse. So far, in vitro assays results suggest that silencing of SOX9 inhibits colonospheres formation in HCT116 cells. Further investigation will be performed in order to evaluate the functional importance of SOX9 in chemotherapy response.
Prediction of peritoneal recurrences of gastric cancer by qPCR analysis of peritoneal lavage fluids.
Authors: Nakanishi Koki , Kanda Mitsuro , Umeda Shinichi , Tanaka Chie , Kobayashi Daisuke , Hayashi Masamichi , Yamada Suguru , Nakayama Goro , Koike Masahiko , Fujiwara Michitaka , Kodera Yasuhiro
Published: January 2019

52

Background: Peritoneal lavage cytology has been regarded as the only reliable method detect free cancer cells in the abdominal cavity. However, there certainly are patients who experience peritoneal recurrences despite negative cytology. Methods: Using qRT-PCR analysis, mRNA levels of 9 candidate molecular markers were quantified in peritoneal lavage fluids of from 187 patients with gastric cancer and 30 benign disease controls. ROC curve analysis was conducted to compare accuracies of the candidate markers. The cut-off points were set at the highest values of the benign disease controls. We evaluated predictive values of molecular markers in peritoneal lavage fluids for peritoneal recurrence. Results: From the result of ROC curve analysis, synaptotagmin XIII ( SYT13) and carcinoembryonic antigen ( CEA) mRNA levels were identified as predictive markers for peritoneal recurrences (The AUC value, 0.771, 0.775, respectively). 162 patients who had no concomitant peritoneal metastasis and were negative for lavage cytology (P0CY0), 13 patients (8.2%) had peritoneal recurrences. Those with either positive SYT13 or CEA mRNA level in peritoneal lavage fluids had significantly shorter peritoneal recurrence-free survival times compared to those with negative (3-years peritoneal recurrence-free survival rates, 69.5% vs 95.6%; P = 0.0069 and 79.3% vs. 93.4%; P = 0.0211, respectively). By combination of SYT13 and CEA, patients with both markers-positive had the greatest prevalence of peritoneal recurrences. Moreover, the peritoneal recurrence free survival curves of the both markers-positive group approached to that of the positive for lavage cytology group. Univariate analysis revealed that both SYT13-positive and CEA-positive were prognostic factors for peritoneal recurrence (hazard ratio: 4.21 and 3.53, respectively). In the multivariable analysis, SYT13-positive was found to be statistically significant independent prognostic factors (hazard ratio: 3.84, 95% confidence interval 1.24-13.2, P = 0.0202). Conclusions: SYT13 and CEA levels in peritoneal lavage fluids accurately predict peritoneal recurrences in patients with P0CY0.
Validation of the NCI Colorectal Cancer Risk Assessment Tool for baseline advanced neoplasia in a veterans cohort.
Authors: Musselwhite Laura W. , Redding Thomas S. , Hauser Elizabeth R. , Lieberman David A. , Provenzale Dawn T.
Published: January 2019

521

Background: Tailoring screening strategy to colorectal cancer (CRC) risk may improve efficiency for all stakeholders. We applied the National Cancer Institute (NCI) CRC Risk Assessment Tool, which calculates 5-10-year, and 20-year absolute risk of colorectal cancer to determine whether it could be used to predict baseline risk of colorectal cancer precursors in a Veterans cohort undergoing first screening colonoscopy. Methods: This was a prospective evaluation of whether the NCI CRC Risk Assessment Tool which offers an absolute risk over time, could be used to estimate baseline cancerous precursors (advanced neoplasia) in Veterans undergoing first screening colonoscopy. Family, medical, dietary and physical activity histories were collected at the time of screening colonoscopy and used to calculate absolute 5, 10, and 20-year CRC risk, and to compare estimated CRC risk to observed AN. Sensitivity analyses were performed. Results: Of 3,121 Veterans undergoing screening colonoscopy, 94% had complete data available to calculate risk (N = 2,934, median age 63 years, 100% men, and 15% minorities). 11% (N = 313) were diagnosed with AN on baseline screening colonoscopy. The area under the curve for predicting AN was 0.60 (95% CI; 0.57-0.63, p < 0.0001) at 5 years, 0.60 (95% CI, 0.57-0.63, p < 0.0001) at 10 years and 0.58 (95% CI, 0.54-0.61, p < 0.0001) at 20 years. At 5 years, we calculated the sensitivity (0.18, 95% CI; 0.14-0.22), specificity (0.91, 95% CI; 0.90-0.92) positive predictive value (0.19, 95% CI; 0.15-0.24) and negative predictive value (0.90, 95% CI; 0.89-0.91) considering the top 10th percentile of risk tool scores as a positive result. Conclusions: The NCI CRC Risk Assessment Tool had modest discriminatory function for predicting AN risk at 5, 10 and 20 years. The Tool’s specificity and negative predictive value were quite good, highlighting its usefulness in risk prediction. This tool may beused to inform the benefit-risk assessment of screening colonoscopy for patients with competing comorbidities.
Characteristics and survival among early onset and standard onset colorectal cancer by race.
Authors: Acuna Villaorduna Ana , Goel Sanjay
Published: January 2019

522

Background: The incidence of early-onset colorectal cancer (EO) is increasing. Guidelines recommend to start screening colonoscopy at 45 yo in Non-Hispanic Black (NHB). We compare the clinical features and outcomes between EO and standard-onset (SO) colorectal cancer (CRC) among racial groups. Methods: Patients with CRC adenocarcinoma; available race/ethnicity and stage were identified using the SEER registry. Clinical features and 5 year-overall survival (OS) is described by racial and age groups. Results: 190 670 patients were identified. EO rates were higher for minorities than NHW. Median age at diagnosis in EO was 44 and was similar among racial groups; while it was 71 in SO, being lower among minorities compared to NHW (67 vs. 72 years, p < 0.01). Left-sided tumors accounted for 77.4% of tumors in EO while it was 60.8% in SO for minorities versus NHW. The most common CRC location for EO was the rectum and sigmoid colon for SO. EO was most commonly diagnosed as stage III. Surgery and radiation rates were higher for EO for all stages. OS was higher in all stages of EO compared to SO. Conclusions: EO frequency is higher in all minority groups and most commonly located in the rectum. Despite higher stage and grade, OS is higher for EO which might be due to higher treatment rates. Early screening should be extended to all minority groups. [Table: see text]
Prevalence of KRAS, NRAS, and BRAF gene mutations in metastatic colorectal cancer patients: A systematic literature review and meta-analysis.
Authors: Lowe Kimberly , Bylsma Lauren C , Levin-Sparenberg Elizabeth D , Sangaré Laura , Fryzek Jon , Alexander Dominik D
Published: January 2019

523

Background: A systematic literature review and meta-analysis was conducted to summarize the prevalence of KRAS, NRAS, and BRAF mutations in mCRC patients. These mutations have substantial implications for treatment decisions among mCRC patients. Methods: Multiple databases were searched to identify observational studies and clinical trials (standard of care arms only) that reported mutation status among mCRC patients. Random effects meta-analysis models were used to estimate summary prevalence estimates for each of the mutations. Subgroup and sensitivity analyses were conducted to identify potential sources of heterogeneity in mutation prevalence. Results: The meta-analyses included 275 studies comprising over 77,000 mCRC patients. The summary prevalence estimate was 35.9% for KRAS mutations, 7.1% for BRAF mutations, and 4.1% for NRAS mutations. Female patients had significantly more KRAS and BRAF mutations than males ( KRAS: 42.2% vs. 37.3%, p = 0.011; BRAF: 11.0% vs. 7.9%, p = 0.018), and significant variation by study location was observed for both KRAS (p = 0.025) and BRAF (p = 0.002) mutation prevalence. Conclusions: The prevalence of KRAS, BRAF, or NRAS mutations in mCRC patients varies significantly by gender and study location. compared to patients with wild-type tumors. The results of these analyses are informative for clinicians, patients, and researchers.