Yoshifumi Shimada

Intramural and mesorectal distal spread detected by whole-mount sections in the determination of optimal distal resection margin in patients undergoing surgery for rectosigmoid or rectal cancer without preoperative therapy.

BACKGROUND: The current Japanese general rules for clinical and pathologic studies on cancer of the colon, rectum, and anus state that a 3-cm distal resection margin is needed in resecting rectosigmoid cancer and rectal cancer with a distal edge above the peritoneal reflection, and 2 cm is needed for rectal cancer with a distal edge below the peritoneal reflection. The appropriateness of these rules has not been proved. OBJECTIVE: Our aim was to evaluate the appropriateness of the Japanese rules. DESIGN AND SETTING: We retrospectively analyzed surgical and pathology records of patients who underwent surgery at a tertiary care cancer center in Japan. PATIENTS: The study included 381 consecutive patients with stage I to IV rectosigmoid or rectal cancer without preoperative chemotherapy or radiotherapy. MAIN OUTCOME MEASURES: We investigated both intramural and mesorectal distal spread, using whole-mount sections to measure the maximum length of distal spread. Long distal spread was defined as distal spread longer than the distal resection margin stated in the Japanese general rules. Risk factors for both distal spread and long distal spread were evaluated. RESULTS: Of 381 patients, 325 (85.3%) had no distal spread and a total of 56 (14.7%) had distal spread. Distal spread was within the limits specified by the Japanese general rules in 48 of the 381 patients (12.6%) and beyond the Japanese limits (long distal spread) in 8 patients (2.1%). The prevalence of distal spread increased with TNM stage (stage I, 2.7%; stage II, 5.3%; stage III, 17.4%; stage IV, 46.2%). Long distal spread was not observed in stage I or II, was found in only 1.4% of patients with stage III disease and in 11.5% of patients with stage IV. The maximum extent of distal spread in patients with rectosigmoid cancer or rectal cancer with the distal edge above the peritoneal reflection was 38 mm; in patients with rectal cancer with the distal edge below the peritoneal reflection, 35 mm. Multivariable analyses showed that nodal involvement and distant metastasis were independent risk factors for distal spread; distant metastasis was the only independent risk factor for long distal spread. CONCLUSIONS: The Japanese general rules specifying the distal resection margin are appropriate for most patients who undergo surgery for rectosigmoid and rectal cancer without preoperative chemotherapy or radiotherapy. A further increase of 1 to 2 cm beyond the recommended distal resection margin may contribute to improved local control for patients with distant metastasis.

Clinical impact of mesorectal extranodal cancer tissue in rectal cancer: detailed pathological assessment using whole-mount sections.

PURPOSE: Mesorectal cancer deposits showing no histological evidence of lymph node structure (extranodal cancer tissue) are a common feature in rectal cancer. However, optimal categorization of extranodal cancer tissue using TNM grading is not yet established. We reviewed extranodal cancer tissue in detail using whole-mount sections to clarify its clinical impact. METHODS: This retrospective study involved 214 consecutive patients with stage I-III rectal cancer. After fixation, the whole tumor mass including the mesorectum was sliced into longitudinal sections and stained. Mesorectal involvement was classified as direct tumor infiltration, lymph node involvement, or extranodal cancer tissue. Extranodal cancer tissue was classified morphologically, and its maximum size and distance from the primary tumor were measured. The clinical impact of extranodal cancer tissue was evaluated by univariate and multivariate analyses. RESULTS: A total of 498 extranodal cancer deposits were detected in 88 patients (41.1%). Multivariate Cox proportional hazards model analysis indicated that the presence of extranodal cancer tissue was an independent prognostic factor for relapse-free (P < .001) and overall survival (P = .003). The hazard ratio for extranodal cancer tissue was higher than for nodal involvement, irrespective of morphological classification. The clinical impact differed significantly with the number of histological types of extranodal cancer tissue, the number of deposits, their maximum size, and their distance from the primary tumor. CONCLUSIONS: In the present study, we have shown that extranodal cancer tissue detected by whole-mount sections has a clinical impact that is more severe than nodal involvement.

Genomic landscape of colorectal cancer in Japan: Clinical implications of comprehensive genomic sequencing for precision medicine

BackgroundComprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC).MethodsUsing next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC.ResultsThe 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double-strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy.ConclusionsUse of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities.

Toxic megacolon associated with cytomegalovirus infection in ulcerative colitis

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Comprehensive genomic sequencing detects important genetic differences between right-sided and left-sided colorectal cancer

Objectives Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than right-sided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing. Materials and methods A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as “all wild-type”, while remaining patients were defined as “mutant-type”. Results Fifty-six patients (28%) and 145 patients (72%) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) with RCRC were “all wild-type” compared with 41 of 145 patients (28%) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and “mutant-type” RCRC showed significantly worse PFS compared with “all wild-type” LCRC (P = 0.004). Conclusions RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC.

Actionable gene-based classification toward precision medicine in gastric cancer

BackgroundIntertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed.MethodsA total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were obtained from surgical or biopsy specimens and were subjected to DNA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired with US Food and Drug Administration-approved targeted therapies, and the evaluation of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status.ResultsComprehensive genomic sequencing detected at least one alteration of 435 cancer-related genes in 194 GCs (93.7%) and of 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N = 9), MSI (N = 17), chromosomal instability (N = 119), and genomically stable subtype (N = 62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N = 32), while the others (N = 175) were sub-divided into six clusters including five with actionable gene alterations: ERBB2 (N = 25), CDKN2A, and CDKN2B (N = 10), KRAS (N = 10), BRCA2 (N = 9), and ATM cluster (N = 12). The clinical utility of this classification was demonstrated by a case of unresectable GC with a remarkable response to anti-HER2 therapy in the ERBB2 cluster.ConclusionsThis actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC.

Tumor Budding Detection by Immunohistochemical Staining is Not Superior to Hematoxylin and Eosin Staining for Predicting Lymph Node Metastasis in pt1 Colorectal Cancer

BACKGROUND: Tumor budding is recognized as an important risk factor for lymph node metastasis in pT1 colorectal cancer. Immunohistochemical staining for cytokeratin has the potential to improve the objective diagnosis of tumor budding over detection based on hematoxylin and eosin staining. However, it remains unclear whether tumor budding detected by immunohistochemical staining is a significant predictor of lymph node metastasis in pT1 colorectal cancer. OBJECTIVE: The purpose of this study was to clarify the clinical significance of tumor budding detected by immunohistochemical staining in comparison with that detected by hematoxylin and eosin staining. DESIGN: This was a retrospective study. SETTINGS: The study was conducted at Niigata University Medical & Dental Hospital. PATIENTS: We enrolled 265 patients with pT1 colorectal cancer who underwent surgery with lymph node dissection. MAIN OUTCOME MEASURES: Tumor budding was evaluated by both hematoxylin and eosin and immunohistochemical staining with the use of CAM5.2 antibody. Receiver operating characteristic curve analyses were conducted to determine the optimal cutoff values for tumor budding detected by hematoxylin and eosin and CAM5.2 staining. Univariate and multivariate analyses were performed to identify the significant factors for predicting lymph node metastasis. RESULTS: Receiver operating characteristic curve analyses revealed that the cutoff values for tumor budding detected by hematoxylin and eosin and CAM5.2 staining for predicting lymph node metastases were 5 and 8. On multivariate analysis, histopathological differentiation (OR, 6.21; 95% CI, 1.16–33.33; p = 0.03) and tumor budding detected by hematoxylin and eosin staining (OR, 4.91; 95% CI, 1.64–14.66; p = 0.004) were significant predictors for lymph node metastasis; however, tumor budding detected by CAM5.2 staining was not a significant predictor. LIMITATIONS: This study was limited by potential selection bias because surgically resected specimens were collected instead of endoscopically resected specimens. CONCLUSIONS: Tumor budding detected by CAM5.2 staining was not superior to hematoxylin and eosin staining for predicting lymph node metastasis in pT1 colorectal cancer.

Utility of comprehensive genomic sequencing for detecting HER2-positive colorectal cancer

HER2-targeted therapy is considered effective for KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (CRC). In general, HER2 status is determined by the use of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Comprehensive genomic sequencing (CGS) enables the detection of gene mutations and copy number alterations including KRAS mutation and HER2 amplification; however, little is known about the utility of CGS for detecting HER2-positive CRC. To assess its utility, we retrospectively investigated 201 patients with stage I-IV CRC. The HER2 status of the primary site was assessed using IHC and FISH, and HER2 amplification of the primary site was also assessed using CGS, and the findings of these approaches were compared in each patient. CGS successfully detected alterations in 415 genes including KRAS codon 12/13 mutation and HER2 amplification. Fifty-nine (29%) patients had a KRAS codon 12/13 mutation. Ten (5%) patients were diagnosed as HER2 positive because of HER2 IHC 3+, and the same 10 (5%) patients had HER2 amplification evaluated using CGS. The results of HER2 status and HER2 amplification were completely identical in all 201 patients (P < .001). Nine of the 10 HER2-positive patients were KRAS 12/13 wild-type and were considered possible candidates for HER2-targeted therapy. CGS has the same utility as IHC and FISH for detecting HER2-positive patients who are candidates for HER2-targeted therapy, and facilitates precision medicine and tailor-made treatment.

Prognostic analysis of submucosa-invasive gastric cancer with lymph node metastasis

BACKGROUND The aims of this study were to identify prognostic factors of patients with submucosa-invasive (T1b) gastric cancer and to verify the validity of adjuvant chemotherapy for this disease. METHODS We retrospectively examined the cases of 1,236 consecutive patients in our prospectively maintained database with T1b gastric cancer who underwent gastrectomy in 1995-2012. We used 11 clinicopathologic characteristics to identify prognostic factors by univariate and multivariate analyses. We compared the survival of the 160 node-positive T1b gastric cancer patients with that of 133 patients in the same database who had node-positive muscularis propria-invasive (T2) gastric cancer and had undergone gastrectomy without adjuvant chemotherapy during the same period, as a reference cohort. RESULTS The 5-year overall survival rate was 91.4% for all 1,236 patients. Advanced age (hazard ratio [HR] 4.51; 95% confidence interval [CI] 3.26-6.24; P < .01), male sex (HR 2.26; 95% CI 1.56-3.26; P < .01), and the presence of lymph node metastasis (HR 1.89; 95% CI 1.33-2.70; P < .01) were independent prognostic factors. The 5-year overall survival rates were 92.5% in node-negative patients, 84.5% in patients with 1 or 2 metastatic nodes, and 80.1% in patients with 3 or more metastatic nodes (P < .01). The 5-year overall survival rates of the node-positive T1b and T2 gastric cancer patients were 83.6% and 81.2%, respectively (P = .73). CONCLUSION The prognosis of node-positive T1b gastric cancer patients after curative gastrectomy was unsatisfactory. Adjuvant chemotherapy should be considered for these patients, especially those with 3 or more metastatic nodes.

Small Bowel Obstruction After Ileal Pouch-Anal Anastomosis With a Loop Ileostomy in Patients With Ulcerative Colitis

Purpose Small bowel obstruction (SBO) remains a common complication after pelvic or abdominal surgery. However, the risk factors for SBO in ulcerative colitis (UC) surgery are not well known. The aim of the present study was to clarify the risk factors associated with SBO after ileal pouch-anal anastomosis (IPAA) with a loop ileostomy for patients with UC. Methods The medical records of 96 patients who underwent IPAA for UC between 1999 and 2011 were reviewed. SBO was confirmed based on the presence of clinical symptoms and radiographic findings. The patients were divided into 2 groups: the SBO group and the non-SBO group. We also analyzed the relationship between SBO and computed tomography (CT) scan image parameters. Results The study included 49 male and 47 female patients. The median age was 35.5 years (range, 14–72 years). We performed a 2- or 3-stage procedure as a total proctocolectomy and IPAA for patients with UC. SBO in the pretakedown of the loop ileostomy after IPAA occurred in 22 patients (22.9%). Moreover, surgical intervention for SBO was required for 11 patients. In brief, closure of the loop ileostomy was performed earlier than expected. A multivariate logistic regression analysis revealed that the 2-stage procedure (odds ratio, 2.850; 95% confidence interval, 1.009–8.044; P = 0.048) was a significant independent risk factor associated with SBO. CT scan image parameters were not significant risk factors of SBO. Conclusion The present study suggests that a 2-stage procedure is a significant risk factor associated with SBO after IPAA in patients with UC.