Shinichi Yamauchi

Morphologic change of the psoas muscle as a surrogate marker of sarcopenia and predictor of complications after colorectal cancer surgery

PurposeSarcopenia is reported to be associated with complications after surgery. However, there is no established optimal parameter to determine sarcopenia affecting surgical outcome. This study investigated whether morphologic change of the psoas muscle (MPM) reflects sarcopenia and could be a predictor of complications after colorectal cancer surgery.MethodsColorectal cancer patients who underwent primary tumor resection with anastomosis between 2015 and 2016 were analyzed. MPM score was evaluated as the ratio of the short-to-long axis of the psoas muscle in CT images at the L3 vertebrae and classified into five MPM grades. Then, the impact of MPM grade on development of postoperative complications was investigated.ResultsA total of 133 patients were studied. MPM score was significantly correlated to the sectional areas of the psoas muscle at the L3 vertebrae which was evaluated by manual tracing. 21.1% of the subjects were classified into severe MPM (defined as MPM grade 3–4). Overall and infectious complications were noted in 37 (27.8%) and 16 (12.0%) patients. Severe MPM (odds ratio [OR] 2.71, 95% confidence interval [CI] 1.09–6.73), longer operative time (OR 1.01, 95%CI 1.001–1.01), and open surgery (OR 2.73, 95%CI 1.17–6.35) were identified as independent risk factors of overall complications. Severe MPM (OR 4.26,95%CI 1.38–13.10) and open surgery (OR 3.42, 95%CI 1.11–10.48) were identified as independent factors associated with infectious complications.ConclusionsMPM grade may be used as a simple and convenient marker of sarcopenia and to identify patients at increased risk of complications after colorectal cancer surgery.

Variations in genes involved in immune response checkpoints and association with outcomes in patients with resected colorectal liver metastases

In patients with colorectal liver metastases (CLM), liver resection offers the possibility of cure and long-term survival. The liver is a highly immunogenic organ harboring ~80% of the body’s tissue macrophages. Emerging data demonstrate a critical role of the immune response for cancer treatment. We investigated variations within genes involved in immune response checkpoints and their association with outcomes in patients with CLM who underwent neoadjuvant chemotherapy including bevacizumab and liver resection. Single-nucleotide polymorphisms (SNPs) in nine genes (CCL2, CCR2, LAG3, NT5E, PDCD1, CD274, IDO1, CTLA4 and CD24) were analyzed in genomic DNA from 149 patients with resected bevacizumab-pretreated CLM by direct Sanger DNA sequencing, and correlated with response, recurrence-free survival (RFS), overall survival (OS), probability of cure and recurrence patterns. IDO1 (indoleamine 2, 3-dioxygenase) rs3739319 G>A and CD24 rs8734 G>A showed a significant difference in 3-year OS rates. In addition, IDO1 rs3739319 G>A was significantly associated with extrahepatic recurrence. Recursive partitioning analyses revealed that IDO1 rs3739319 G>A was the dominant SNP predicting RFS and OS. Our data suggest that variants within genes involved in immune response checkpoints are associated with outcomes in patients with resected CLM and might lead to improved treatment strategies modulating anti-tumor immune response by targeting novel immune checkpoints.

Germline polymorphisms in genes involved in the Hippo pathway as recurrence biomarkers in stages II/III colon cancer

The Hippo pathway regulates tissue growth and cell fate. In colon cancer, Hippo pathway deregulation promotes cellular quiescence and resistance to 5-Fluorouracil (5-Fu). In this study, 14 polymorphisms in 8 genes involved in the Hippo pathway (MST1, MST2, LATS1, LATS2, YAP, TAZ, FAT4 and RASSF1A) were evaluated as recurrence predictors in 194 patients with stages II/III colon cancer treated with 5-Fu-based adjuvant chemotherapy. Patients with a RASSF1A rs2236947 AA genotype had higher 3-year recurrence rate than patients with CA/CC genotypes (56 vs 33%, hazard ratio (HR): 1.87; P=0.017). Patients with TAZ rs3811715 CT or TT genotypes had lower 3-year recurrence rate than patients with a CC genotype (28 vs 40%; HR: 0.66; P=0.07). In left-sided tumors, this association was stronger (HR: 0.29; P=0.011) and a similar trend was found in an independent Japanese cohort. These promising results reveal polymorphisms in the Hippo pathway as biomarkers for stages II and III colon cancer.The Pharmacogenomics Journal advance online publication, 15 September 2015; doi:10.1038/tpj.2015.64

Colorectal carcinoma: Ex vivo evaluation using 3-T high-spatial-resolution quantitative T2 mapping and its correlation with histopathologic findings ☆

PURPOSE In this study, we aimed to evaluate the feasibility of determining the mural invasion depths of colorectal carcinomas using high-spatial-resolution (HSR) quantitative T2 mapping on a 3-T magnetic resonance (MR) scanner. MATERIALS AND METHODS Twenty colorectal specimens containing adenocarcinomas were imaged on a 3-T MR system equipped with a 4-channel phased-array surface coil. HSR quantitative T2 maps were acquired using a spin-echo sequence with a repetition time/echo time of 7650/22.6-361.6ms (16 echoes), 87×43.5-mm field of view, 2-mm section thickness, 448×224 matrix, and average of 1. HSR fast-spin-echo T2-weighted images were also acquired. Differences between the T2 values (ms) of the tumor tissue, colorectal wall layers, and fibrosis were measured, and the MR images and histopathologic findings were compared. RESULTS In all specimens (20/20, 100%), the HSR quantitative T2 maps clearly depicted an 8-layer normal colorectal wall in which the T2 values of each layer differed from those of the adjacent layer(s) (P<0.001). Using this technique, fibrosis (73.6±9.4ms) and tumor tissue (104.2±6.4ms) could also be clearly differentiated (P<0.001). In 19 samples (95%), the HSR quantitative T2 maps and histopathologic data yielded the same findings regarding the tumor invasion depth. CONCLUSIONS Our results indicate that 3-T HSR quantitative T2 mapping is useful for distinguishing colorectal wall layers and differentiating tumor and fibrotic tissues. Accordingly, this technique could be used to determine mural invasion by colorectal carcinomas with a high level of accuracy.

Evaluation of appropriate follow-up after curative surgery for patients with colorectal cancer using time to recurrence and survival after recurrence: a retrospective multicenter study

Introduction The follow-up schedule for colorectal cancer patients after curative surgery is inconsistent among the guidelines. Evaluation of time to recurrence (TTR) and survival after recurrence (SAR) may provide evidence for appropriate follow-up. Methods We assessed 3039 colon cancer (CC) and 1953 rectal cancer (RC) patients who underwent curative surgery between 2007 and 2008. We evaluated the pre- and post-recurrent clinicopathological factors associated with TTR and SAR in each stage of CC and RC. Results The recurrence rates of stages I, II, and III were 1.2%, 13.1%, and 26.3%, respectively, for CC, and 8.4%, 20.0%, and 30.4%, respectively, for RC. In CC patients, high carcinoembryonic antigen (CEA) level and lymphovascular invasion were independent predictors of short TTR. In RC patients, metastatic factors (liver metastasis in stage III) and venous invasion (stage III) were independent predictors of short TTR. The prognostic factors of SAR were age (stage II CC and stage III RC), female gender (stage III RC), high CEA level (stage II RC), histological type (stage III CRC), nodal status (stage III CC), recurrence within 1 year (stage III RC), M1b recurrence (stage II CRC), local recurrence (stage II CC), and no surgical resection after recurrence (stage II and III CRC). Conclusions The follow-up schedule for stage I should be different from that for the other stages. We recommend that intensive follow-up is appropriate in stage III CC patients with undifferentiated adenocarcinoma or N2 nodal status, stage II RC patients with high preoperative CEA level, and stage III RC patients.

The Role of Systemic Chemotherapy in Colorectal Cancer

In recent decades, treatment for metastatic colorectal cancer (mCRC) has remarkably progressed with the advent of biological agents. Under such circumstances, it becomes a key issue which biological agent is a preferred treatment, especially for first-line treatment of mCRC patients with RAS wild-type tumor. For unresectable diseases, preferred treatment depends on the treatment goal; patients should be treated to seek for maximum shrinkage or treatment duration. If the former, anti-EGFR mab might be a preferred option in terms of depth of response. If the latter, bevacizumab might be preferred in terms of maintenance therapy. For potentially resectable diseases, such as liver-limited diseases, a similar strategy for treatment can be recommended. There are several types of liver metastases (LM). If LM is bulky and unresectable, a tumor shrinkage is needed so that LM can be converted to be resectable. If LM is disseminated and unresectable, a pathological effect is needed to prevent recurrence after liver resection. If the former, anti-EGFR mab might be preferred, and if the latter, bevacizumab might be better, considering the characteristics of biological agents.

Colorectal carcinoma: Ex vivo evaluation using q-space imaging; Correlation with histopathologic findings: q-Space Imaging of Colorectal Carcinoma

Although the prognosis of colorectal carcinoma (CRC) patients depends on the histologic grade (HG) and lymph node metastasis (LNM), accurate preoperative assessment of these prognostic factors is often difficult.

The impact of tumor location on the biological and oncological differences of colon cancer: multi-institutional propensity score-matched study

BACKGROUND Several studies have reported some differences between right-sided and left-sided colon cancer. The aim was to analyze the differences in clinical and pathological features, recurrence, and prognostic impact of tumor location in patients with tumors truly located in the right and left side of the colon. PATIENTS The study included 6790 stage I-III colon cancer patients who underwent curative resection. Patient characteristics were balanced using propensity score matching. RESULTS Recurrence rates of stage I and II patients with left-sided colon cancer were higher than those in the right-sided group, indicating that recurrence free survival of left-sided colon cancer patients was significantly shorter than that of the right-sided patients. In stage III patients that experienced recurrence, cancer specific survival after recurrence of the right-sided colon cancer patients was significantly shorter than that of the left-sided patients (P = 0.003). CONCLUSIONS In stage I-II patients, left-sided colon cancer was a significant risk factor for recurrence free survival, however, in stage III patients, right-sided colon cancer was a significant risk factor for after recurrence cancer specific survival.

Association between single nucleotide polymorphisms (SNPs) of genes involved in spindle assembly checkpoint (SAC) and clinical outcomes in advanced gastric cancer (AGC) patients (pts) treated with taxane-based chemotherapy.

79 Background: Taxanes which disrupt the microtubule function and inhibit the process of cell division have shown encouraging activity in the treatment of AGC. Resistance to these agents often becomes a problem in clinical settings and its mechanism hasn’t been dissolved conclusively. SAC is a safety device ensures the proper chromosome segregation in mitosis and is required for taxane-induced cell death. We hypothesized genetic variants in SAC genes may be associated with clinical outcomes in pts with AGC treated with taxane. Methods: Genomic DNA was isolated from blood or tissue samples of 39 U.S. pts (median age 57; median follow-up 6.4 months) for evaluation set and 39 Japanese (JPN) pts (median age 63; median follow-up 9.4 months) for validation set, with AGC treated with taxane. Twenty-five functionally significant SNPs in SAC genes (MAD1, MAD2, BUB3, BUBR1, RAN, TPX2, CDC20, AURKA, AURKB, RCC1, ANAPC10, ANAPC13) were analyzed by PCR-based direct sequencing and evaluated for association with outcome...

Polymorphism of the chemokine CXCR4 to predict treatment benefit of first-line bevacizumab-based chemotherapy in patients with metastatic colorectal cancer.

635 Background: The chemokine receptor CXCR4 and its ligand CXCL12 promote angiogenesis and the migration of tumor cells into the metastatic sites in many cancers. CXCR4 expression on tumor cells is upregulated by hypoxia and angiogenic factors, such as vascular endothelial growth factor. Therefore, we analyzed the association between CXCR4/CXCL12 polymorphisms and prognosis in metastatic colorectal cancer (mCRC) patients underwent bevacizumab-based chemotherapy. Methods: This study included 144 Japanese patients (pts) for evaluation set and 424 patients from two clinical trials (204 of TRIBE arm A and 220 of PROVETTA) for validation set, with mCRC treated with bevacizumab-based chemotherapy as first line. A total of 144 Japanese pts with (male/female; 81/63, median age 61 years, median follow-up 4.2 years) and 424 pts (male/female; 252/172, median age 62 years; median follow-up time; 2.8 years) were enrolled in a pharmacogenomics translational study. Genomic DNA was extracted from the pts’ blood or tissu...