Hazard function analysis of prognosis after recurrent colorectal cancer.

BACKGROUND AND OBJECTIVES: Mean survival time (MST) is used as the indicator of prognosis in patients with a colorectal cancer (CRC) recurrence. The present study aimed to visualize the changes in death risk after a CRC recurrence using hazard function analysis (HFA) to provide an alternative prognostic indicator to MST. METHODS: The medical records of 725 consecutive patients with a recurrence following R0 radical surgery for CRC were retrospectively reviewed. RESULTS: The five-year, post-recurrence survival rate was 37.8%, and the MST was 3.5 years while the risk of death peaked at 2.9 years post-recurrence. Seven variables were found to predict short-term survival, including the number of metastatic organs ≥ 2, non-surgical treatment for the recurrence, and a short interval before recurrence. In patients with a recurrence in one organ, the MST was four years, the peak time of death predicted by HFA was 2.9 years, and the five-year survival rate was 45.8%. In patients with a surgical resection of the recurrence, the MST was 8 years, the peak time of death was 3.3 years, and the five-year survival rate was 62%. CONCLUSIONS: The present study established a novel method of assessing changes in mortality risk over time using HFA in patients with a CRC recurrence.

Modified neoadjuvant rectal score as a novel prognostic model for rectal cancer patients who underwent chemoradiotherapy.

BACKGROUND: The neoadjuvant rectal score (NAR score) has recently been proposed as a better prognostic model than the conventional TNM classification for rectal cancer patients that have undergone neoadjuvant chemoradiotherapy. We recently developed an apoptosis-detection technique for assessing the viability of residual tumors in resected specimens after chemoradiotherapy. This study aimed to establish an improved prognostic classification by combining the NAR score and the assessment of the apoptosis of residual cancer cells. METHODS: We retrospectively enrolled 319 rectal cancer patients who underwent chemoradiotherapy followed by radical surgery. The recurrence-free survival and overall survival of the four models were compared: TNM stage, NAR score, modified TNM stage by re-staging according to cancer cell viability, and modified NAR score also by re-staging. RESULTS: Downstaging of the ypT stage was observed in 15.5% of cases, whereas only 4.5% showed downstaging of ypN stage. C-index was highest for the modified NAR score (0.715), followed by the modified TNM, TNM, and NAR score. Similarly, Akaike's information criterion was smallest in the modified NAR score (926.2), followed by modified TNM, TNM, and NAR score, suggesting that the modified NAR score was the best among these four models. The overall survival results were similar: C-index was the highest (0.767) and Akaike's information criterion was the smallest (383.9) for the modified NAR score among the four models tested. CONCLUSION: We established a novel prognostic model, for rectal cancer patients that have undergone neoadjuvant chemoradiotherapy, using a combination of apoptosis-detecting immunohistochemistry and neoadjuvant rectal scores.

Clinicopathological characteristics of Lynch-like syndrome.

BACKGROUND: Lynch-like syndrome (LLS) has recently been proposed as a third type of microsatellite instability (MSI) tumor after Lynch syndrome (LS) and sporadic MSI colorectal cancer (CRC) without either a germline variant of mismatch repair (MMR) genes or hypermethylation of the MLH1 gene. The present study aimed to clarify and compare the clinicopathological characteristics of LLS with those of the other MSI CRC subtypes. METHODS: In total, 2634 consecutive patients with CRC who underwent surgical resection and subsequently received universal tumor screening (UTS), including MSI analysis were enrolled between January 2008 and November 2019. Genetic testing was performed in patients suspected of having Lynch syndrome. RESULTS: UTS of the cohort found 146 patients with MSI CRC (5.5%). Of these, excluding sporadic MSI CRC, 30 (1.1%) had a diagnosis of LS, and 19 (0.7%) had no germline pathogenic variants of the MMR gene. The CRC type in the latter group was identified as LLS. LLS occurred significantly more often in young patients, was left-sided, involved a KRAS variant and BRAF wild-type, and had a higher concordance rate with the Revised Bethesda Guidelines than sporadic MSI CRC. No significant differences were observed in terms of the clinicopathological factors between LLS and LS-associated MSI CRC; however, LLS had a lower frequency of LS-related neoplasms compared with LS. CONCLUSIONS: Distinguishing clinically between LS and LLS was challenging, but the incidence of neoplasms was higher in LS than in LLS, suggesting the need for different screening and surveillance methods for the two subtypes.

Risk of gastric adenoma and adenocarcinoma in patients with familial adenomatous polyposis in Japan: a nationwide multicenter study.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) have an increased risk of developing gastric neoplasms. However, the clinical course of FAP with these gastric lesions has not yet been fully clarified. The present study aimed to clarify the changes in the incidence risk of developing gastric adenoma or gastric cancer during the lifespan of patients with FAP. METHODS: Four hundred forty-three patients with data regarding gastric adenoma and gastric cancer retrospectively registered in a nationwide Japanese multicenter study were enrolled. The cumulative incidences and hazard rates (HRs) of gastric neoplasms were evaluated. RESULTS: The cumulative incidence rates in 50-year-old patients with FAP were 22.8% for gastric adenoma and 7.6% for gastric cancer, respectively. No significant association was found between gastric neoplasms and the colonic phenotype. The peak age for the HR of gastric adenoma was 65 years, with the highest HR (0.043). Regarding the incidence of gastric cancer, the HR increased moderately up to the age of 40 years, but the increase accelerated from the age of 50 years (HR = 0.0067). CONCLUSION: Careful surveillance of the upper gastrointestinal tract in elderly patients with FAP, such as shortening the interval of follow-up according to age, may be helpful for early diagnosis of gastric cancer.

Clinical features and distribution of the APC variant in duodenal and ampullary polyps in patients with familial adenomatous polyposis: a multicenter retrospective cohort study in Japan.

BACKGROUND: Management of duodenal or ampullary adenomas in patients with familial adenomatous polyposis (FAP) is a major challenge for clinicians. Insufficient data are available to evaluate the clinical manifestations and distribution of adenomatous polyposis coli (APC) variants in these patients. METHODS: We enrolled 451 patients with data regarding duodenal or ampullary polyps from 632 patients with FAP retrospectively registered in a nationwide Japanese multicenter study. Clinicopathological features and distribution of APC variants were compared between patients with and without duodenal or ampullary polyps. RESULTS: Duodenal and ampullary polyps were found in 59% and 18% of patients with FAP, respectively. The incidence of duodenal cancer was 4.7% in patients with duodenal polyps, and that of ampullary cancer was 18% in patients with ampullary polyps. Duodenal polyps were significantly associated with the presence of ampullary polyps and jejunal/ileal polyps. Duodenal polyps progressed in 35% of patients with a median follow-up of 776 days, mostly in those with early Spigelman stage lesions. Ampullary polyps progressed in 50% of patients with a follow-up of 1484 days. However, only one patient developed a malignancy. The proportion of patients with duodenal polyps was significantly higher among those with intermediate- or profuse-type APC variants than attenuated-type APC variants. The presence of duodenal polyps was significantly associated with ampullary and jejunal/ileal polyps in patients with intermediate- or profuse-type APC variants. CONCLUSIONS: Periodic endoscopic surveillance of the papilla of Vater and small intestine should be planned for patients with FAP with duodenal polyps.

A rare case of localized peliosis hepatis during adjuvant chemotherapy including oxaliplatin mimicking a liver metastasis of colon cancer.

BACKGROUND: Oxaliplatin-based regimens are commonly used as adjuvant chemotherapy following surgery for colorectal cancer. Adverse events associated with oxaliplatin include blue liver, which is caused by sinusoidal dilation and diffuse peliosis hepatis. We report herein a case of localized peliosis hepatis closely resembling a metastatic liver tumor. CASE PRESENTATION: The patient, a 50-year-old male, underwent a robotically assisted colectomy for rectosigmoid colon cancer, which was discovered when hematochezia occurred. The patient received a diagnosis of pStage IIIb and was treated with four courses of CAPOX as adjuvant chemotherapy starting at postoperative month 1. At postoperative month 4, contrast-enhanced computed tomography (CT) of the abdomen revealed a 20-mm, low-density area with heterogeneous internal structure in S6/7 of the liver. Abdominal ultrasound and gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) findings led to a diagnosis of metastatic liver tumor, for which a laparoscopic partial hepatectomy was performed. The resected lesion was a dark reddish-brown nodule with indistinct margins that appeared to be continuous with the surrounding area. Histopathological analysis revealed severe, localized dilatation of the sinusoids and congestion consistent with the gross nodule. Based on these findings, localized peliosis hepatis associated with oxaliplatin-induced sinusoidal damage was diagnosed. CONCLUSIONS: Localized peliosis hepatis associated with oxaliplatin use can be difficult to distinguish from a metastatic liver tumor on imaging studies.

Usefulness of genotyping APC gene for individualizing management of patients with familial adenomatous polyposis.

BACKGROUND: Colorectal polyp burden is crucial for the management of patients with familial adenomatous polyposis (FAP). However, accurate evaluation of polyp burden is difficult to standardize. This study aimed to examine the possible utility of genotype-oriented management of colorectal neoplasms in patients with FAP. METHODS: Clinicopathological data from genetically proven patients with FAP was analyzed using the database of a nationwide retrospective Japanese multicenter study. The cumulative incidence of CRC was evaluated between different genotype groups. Genotype-1 were defined as germline variants on attenuated FAP-associated regions (codons 1-177, alternative splice site of exon 10 (codon 312), 1581-2843) and Genotype-2 as the other variants. Weibull and Joinpoint analyses were performed to determine the annual percentage changes in CRC risk. RESULTS: Overall, 69 men and 102 women were included. Forty-eight patients underwent colorectal resection for the first CRC, and five patients underwent resection for first cancer in the remnant anorectal segment after prophylactic surgery. The 70-year cumulative incidence of CRC in all patients was 59.3%. Patients with Genotype-1 (n = 23) demonstrated a lower risk of CRC stages II-IV than those with Genotype-2 (n = 148, P = 0.04). The risk of stage II-IV CRC was estimated to increase markedly at the age of 49 years in the Genotype-1 patients and 34 years in the Genotype-2 patients, respectively. CONCLUSIONS: Different interventional strategies based on genotypes may be proposed for the clinical management of patients with FAP. This policy needs to be validated in further prospective studies focusing on long-term endoscopic intervention and optimal age at prophylactic (procto)colectomy.

Fusobacterium nucleatum load in MSI colorectal cancer subtypes.

BACKGROUND: Fusobacterium nucleatum (F. nucleatum) infection may lead to colorectal cancer (CRC) development in the context of microsatellite instability (MSI). To date, however, the relationship between F. nucleatum load and MSI CRC subtypes has not been clarified. METHODS: One hundred seventy-nine consecutive patients with CRC were enrolled in the present study. In 94 patients with MSI CRC, 32 had hereditary MSI CRC from Lynch syndrome, 62 had sporadic MSI CRC, while the remaining 85 had microsatellite stable (MSS) CRC. The association of the F. nucleatum load with each CRC subtype and the patients' clinicopathological characteristics was examined. RESULTS: Of the 179 patients with CRC, 158 (88.3%) were F. nucleatum-positive. A high F. nucleatum load was found in 84.4% (27/32), 96.8% (60/62), and 83.5% (71/85) of the patients with hereditary MSI CRC, sporadic MSI CRC, and MSS CRC, respectively (P = 0.024). In terms of clinicopathological features, a high F. nucleatum load was significantly associated with female, right-sided CRC, BRAF V600E, CpG island methylator phenotype-positive CRC, and MSI CRC (P = 0.008, P = 0.015, P = 0.007, P = 0.006, and P < 0.001, respectively). However, the clinicopathological characteristics did not differ significantly by F. nucleatum load between hereditary and sporadic MSI CRCs without tumor depth. CONCLUSIONS: The F. nucleatum load was higher in hereditary MSI CRC than in MSS CRC as well as sporadic MSI CRC. These findings may contribute to preventing CRC in hereditary MSI CRC through appropriate intervention.

Upper gastrointestinal tumors are unrelated to the APC genotype in APC-associated polyposis.

BACKGROUND: In patients with APC-associated polyposis, the prevalence of upper gastrointestinal tumors and the relationship between these and Helicobacter pylori infection have not been clarified in detail. The present study aimed to clarify the features of upper gastrointestinal lesions in patients with APC-associated polyposis. METHODS: Consecutive patients with APC-associated polyposis who underwent esophagogastroduodenoscopy between 2004 and 2018 were recruited. RESULTS: In total, 36 patients were enrolled. The types of gastrointestinal tumor observed were fundic gland polyposis in 28 patients (77.8%), gastric adenoma in 15 patients (41.7%), duodenal adenoma in 27 patients (75.0%) and periampullary adenoma in 20 patients (55.6%). The phenotype of these upper gastrointestinal tumors was not necessarily the same in patients belonging to the same family. Germline variants in the APC gene were distributed across various sites, regardless of the presence or absence of upper gastrointestinal lesions, and none of the tumors correlated with the genotype or phenotype of upper gastrointestinal tumors. Fundic gland polyposis was observed in 28 of 31 patients without a H. pylori infection and in none of the patients with a H. pylori infection (P = 0.00015). After eradication therapy for H. pylori, fundic gland polyposis developed in one, previously infected patient. CONCLUSION: The upper gastrointestinal tumor phenotype was not associated with the genotype in patients with APC-associated polyposis. Ascertaining the H. pylori infection status is helpful for endoscopic surveillance of upper gastrointestinal tumors in patients with APC-associated polyposis.

APC germline variant analysis in the adenomatous polyposis phenotype in Japanese patients.

BACKGROUND: Familial adenomatous polyposis (FAP), an autosomal dominant disorder characterized by multiple colonic polyps, is caused by a germline pathogenic variant of the APC gene. However, this variant is not detected in up to 30% of patients with the adenomatous polyposis phenotype. METHODS: We performed next-generation sequencing (NGS) to identify the causative genes in FAP patients with 10 or more polyps. For patients in whom the APC germline variant was not able to be identified, we screened for APC mosaicism using high-coverage NGS of APC with DNA from leucocytes and/or frozen tissue. RESULTS: The pathogenic APC germline variant was found in 93.3%, 71.6%, and 17.1% of patients with profuse-type polyposis, sparse-type polyposis, and oligo-polyposis, respectively. The APC germline variant detection rate in patients with FAP-related diseases was 69.7% for fundic gland polyposis, 79.7% for duodenal adenoma, 94.7% for desmoid tumor, and 71.4% for thyroid cancer, with increasing numbers of extracolonic lesions associated with an increasing APC germline variant detection rate. A mosaic test detected nine patients with APC mosaicism. A comparison of APC-associated polyposis with APC mosaicism showed that patients with APC mosaicism had a low frequency of duodenal adenoma and a family history of colonic polyposis. CONCLUSIONS: We determined the detection rate of the APC germline variant by phenotype and identified APC mosaicism. Genetic testing of FAP patients is important because it can help with surgical decision-making, monitoring, and genetic counseling. Furthermore, genetic testing by NGS proved to be an effective method of detecting APC germline variants.

Clinicopathological features of sporadic MSI colorectal cancer and Lynch syndrome: a single-center retrospective cohort study.

BACKGROUND: The clinical and pathological features of sporadic microsatellite instability-high (MSI) colorectal cancer (CRC) are still unclear. The present study aimed to clarify the clinicopathological features of sporadic MSI CRC in comparison with those of Lynch syndrome (LS) exploratorily. METHODS: The present study was a single-center, retrospective cohort study. Sporadic MSI CRC was defined as MSI CRC with aberrant promoter hypermethylation of the MLH1 gene, while hereditary MSI CRC was defined colorectal cancer in patients with LS. RESULTS: In total, 2653 patients were enrolled; of these, 120 (4.5%) had MSI CRC, 98 had sporadic MSI CRC, and 22 had LS. Patients with sporadic MSI CRC were significantly older (p < 0.001) than those with LS and had a right-sided colonic tumor (p < 0.001) which was pathologically poorly differentiated or mucinous (p = 0.025). The overall survival rate was significantly lower in patients with stage I, II or III MSI CRC than in those with LS (p = 0.024). However, the recurrence-free survival rate did not differ significantly (p = 0.85). CONCLUSIONS: We concluded that patients with sporadic MSI are significantly older, tumors more likely to locate in the right-sided colon, pathologically poorly differentiated or mucinous, and worse overall survival than in those with LS.

[A Case of Transverse Colon Cancer Undergoing Laparoscopic Right Hemicolectomy after Distal Gastrectomy with Billroth â ¡ Reconstruction].

A 79-year-old man was diagnosed with transverse colon cancer who had a history of distal gastrectomy and antecolic Billroth Ⅱ(B-Ⅱ)reconstruction for duodenal ulcer. We performed laparoscopic right hemicolectomy. Surgical findings indicated that the tumor was located in the center of the transverse colon. After we performed mobilization of right colon and lymph node dissection, we performed mobilization of left colon and we peeled off those adhesions with the jejunal limb and transverse colon mesentery. Then, we resected transverse colon and removed right hemicolon. We reconstructed a functional end-to-end anastomosis on the ventral side of the jejunal limb. The patient was discharged without complications on the 10th postoperative day. In post B-Ⅱ reconstruction cases, we can perform laparoscopic colectomy safely with preoperative CT confirmation and adequate colon mobilization.

Clinicopathological and molecular differences between right-sided and left-sided colorectal cancer in Japanese patients.

BACKGROUND: The aim of this study was to clarify clinicopathological features, frequencies of molecular biomarkers, and prognoses in Japanese colorectal cancer patients and compare them with right-sided colon cancer (RCC) and left-sided colorectal cancer (LCRC). METHODS: We consecutively selected 575 colorectal cancer patients who underwent surgical resection from 2008 to 2011. RCC was located from the cecum to the transverse colon, and LCRC was located from the splenic flexure to the rectum. Frequencies of KRAS gene mutation, BRAF gene mutation, microsatellite instability (MSI), l18qLOH and CpG island methylator phenotype (CIMP) were statistically analyzed between groups. RESULTS: Tumors were located in the RCC in 26.3% of patients and in the LCRC in 73.7%. Elderly patients, females and advanced diseases were significantly more frequent in the RCC group than in the LCRC group. However, venous invasion was significantly more frequent in LCRC than in RCC. Between groups, BRAF mutant type, KRAS mutant type, MSI and CIMP+ were significantly more frequent in RCC, whereas 18qLOH was significantly more frequent in LCRC. In overall survival, RCC demonstrated poor prognosis compared with LCRC; however, age, gender, stage, lymphatic invasion, KRAS status and BRAF status rather than tumor location were independent prognostic factors. In addition, the independent prognostic factors in RCC were different from those in LCRC in each stage. However, the consistency between OS and DFS was not observed in this study, excluding lymphatic invasion in LCRC. CONCLUSION: Comparing RCC with LCRC, RCC is different from LCRC in clinicopathological features, molecular biomarkers and prognostic factors in Japanese colorectal cancer patients. Since the proportions of molecular biomarkers of CRC in this study are different from Western CRCs, further studies are required to clarify the clinicopathological differences between Japanese CRCs and Western CRCs.

Tumor development in Japanese patients with Lynch syndrome.

BACKGROUND: Lynch syndrome (LS) patients have a high risk of developing various tumors. This study aimed to clarify the characteristics of tumors developing in LS patients. METHODS: This is a retrospective review of 55 LS patients treated at Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital. RESULTS: The median age at the diagnosis of the first malignant tumor and first LS-related tumor was 44 (range, 19-65) and 44 (range, 24-66) years, respectively. Of the 55 LS patients with developing malignant tumors, 45 (93.8%) developed an LS-related tumor as the first malignant tumor. Colorectal cancer (CRC) developed in 47 patients (85.4%), followed by endometrial cancer (n = 13, 56.5%) in females and gastric cancer (n = 10, 18.1%). In 6 gastric cancer patients, Helicobacter pylori was detected in resected specimens. Twenty-nine patients (52.7%) developed CRC and extra-colonic tumors; of these, 15 patients (48.3%) had mutations in MLH1, 10 (58.8%) in MSH2, and 4 (57.1%) in MSH6. At the age of 50, the cumulative incidence was 50.9% [95% confidence interval (CI), 36.9-63.3%] for CRC, 17.4% (95% CI, 5.2-35.6%) for endometrial cancer, and 5.5% (95% CI, 1.4-13.8%) for gastric cancer. Eight gastric cancer, one breast cancer patient, five bladder cancer patients, and one prostate cancer patient demonstrated loss of expression of the mismatch repair (MMR) protein; patients with thyroid cancer, spindle cell sarcoma, and giant cell tumors did not demonstrate this. CONCLUSION: Gastric cancer incidence was high in Japanese patients with LS and associated with H. pylori infection. MMR protein deficiency caused the development of malignant tumors in LS patients.

Characteristics of MUTYH variants in Japanese colorectal polyposis patients.

BACKGROUND: The base excision repair gene MUTYH is the causative gene of colorectal polyposis syndrome, which is an autosomal recessive disorder associated with a high risk of colorectal cancer. Since few studies have investigated the genotype-phenotype association in Japanese patients with MUTYH variants, the aim of this study was to clarify the clinicopathological findings in Japanese patients with MUTYH gene variants who were detected by screening causative genes associated with hereditary colorectal polyposis. METHODS: After obtaining informed consent, genetic testing was performed using target enrichment sequencing of 26 genes, including MUTYH. RESULTS: Of the 31 Japanese patients with suspected hereditary colorectal polyposis, eight MUTYH variants were detected in five patients. MUTYH hotspot variants known for Caucasians, namely p.G396D and p.Y179D, were not among the detected variants.Of five patients, two with biallelic MUTYH variants were diagnosed with MUTYH-associated polyposis, while two others had monoallelic MUTYH variants. One patient had the p.P18L and p.G25D variants on the same allele; however, supportive data for considering these two variants 'pathogenic' were lacking. CONCLUSIONS: Two patients with biallelic MUTYH variants and two others with monoallelic MUTYH variants were identified among Japanese colorectal polyposis patients. Hotspot variants of the MUTYH gene for Caucasians were not hotspots for Japanese patients.

Differences in histological features and PD-L1 expression between sporadic microsatellite instability and Lynch-syndrome-associated disease in Japanese patients with colorectal cancer.

BACKGROUND: The field of immunotherapy has recently focused on cancers with microsatellite instability (MSI). These cancers include both Lynch-syndrome-associated tumors, which are caused by mismatch repair (MMR) germline mutations, and sporadic MSI tumors, which are mainly attributed to MLH1 promoter methylation. The present study aimed to clarify differences in the histological and PD-L1 expression profiles between these two types of MSI cancers in Japanese patients. METHODS: Among 908 cases of colorectal cancer treated via surgical resection from 2008 to 2014, we identified 64 MSI cancers, including 36 sporadic MSI and 28 Lynch-syndrome-associated cancers, using a BRAF V600E mutation analysis and MLH1 methylation analysis. Of the latter subgroup, 21 (75%) harbored MMR germline mutations. RESULTS: The following were more frequent with sporadic MSI than with Lynch syndrome associated cancers: poor differentiation (50.0 vs. 7.1%, P = 0.0002), especially solid type (30.6 vs. 3.6%, P = 0.0061); medullary morphology (19.4 and 0%, P = 0.015), Crohn-like lymphoid reaction (50.0 vs. 25.0%, P = 0.042), and PD-L1 expression (25.0 vs. 3.6%, P = 0.034). However, the groups did not differ in terms of the mean invasive front and intratumoral CD8-positive cell densities. In a logistic regression analysis, PD-L1 expression correlated with poor differentiation (odds ratio: 7.65, 95% confidence interval: 1.55-37.7, P = 0.012), but not with the difference between sporadic MSI cancer and Lynch-syndrome-associated cancer (odds ratio: 4.74, 95% confidence interval: 0.50-45.0, P = 0.176). CONCLUSIONS: Therefore, compared with Lynch-syndrome-associated cancers, sporadic MSI cancers are more frequently solid, poorly differentiated medullary cancers that express PD-L1.

Predictive model for high-frequency microsatellite instability in colorectal cancer patients over 50 years of age.

Microsatellite instability (MSI) is an important biomarker for screening for Lynch syndrome, and also of response to immune checkpoint inhibitors. The aim of this study is to create a predictive model to determine which elderly patients with colorectal cancer (CRC) should undergo MSI and/or immunohistochemistry testing on the basis of clinicopathological data. We analyzed a test cohort of CRC patients aged ≥50 years (n = 2219) by multivariate logistic regression analyses to identify predictors of high-frequency MSI (MSI-H). The created prediction model was validated in an external cohort (n = 992). The frequency of MSI-H was 5.5% among CRC patients aged ≥ 50 years. The following five predictors of MSI-H were identified in the test cohort: female (1 point), mucinous component (2 points), tumor size ≥ 60 mm (2 points), location in proximal colon (3 points), and BRAF mutation (6 points). The area under curve (AUC) in the receiver-operating characteristic (ROC) analysis of this prediction model was 0.832 (95% confidence interval: 0.790-0.874). The sensitivity and specificity were 74.4% and 77.7%, respectively, for a cut-off score of 4 points. The receiver-operating characteristic curve of the validation cohort also showed an AUC of 0.856 (95% CI: 0.806-0.905). This prediction model is useful to select elderly CRC patients who should undergo MSI testing, and who may benefit from treatment with 5-FU-based adjuvant chemotherapy and cancer immunotherapy.

Colorectal Cancer with BRAF D594G Mutation Is Not Associated with Microsatellite Instability or Poor Prognosis.

OBJECTIVE: BRAF D594G mutations in colorectal cancer patients are not clearly understood. We retrospectively investigated the clinicopathological features of colorectal cancers with BRAF D594G mutations. METHODS: We selected 908 colorectal cancer patients who underwent surgical resection from January 2008 to January 2013, and assessed BRAF, KRAS, microsatellite instability, and CpG island methylator phenotype (CIMP). RESULTS: We detected BRAF D594G in 7 patients and BRAF V600E in 45 patients. The clinicopathological features of cancers with BRAF D594G mutation were similar to those with BRAF wild-type, but differed from those with BRAF V600E mutations. Regarding microsatellite instability status, 44.4% of cases with BRAF V600E mutations exhibited high microsatellite instability, compared to 14.3% of those with BRAF D594G mutations and 4.4% of those with BRAF wild-type. There were no CIMP-positive tumors in cancers with BRAF D594G mutations, whereas 67.8% of tumors with BRAF V600E mutations were CIMP-positive. In stage IV cancers, the survival rates of patients at 2 years were 8.5, 50.0, and 68.2% in the BRAF V600E mutation, BRAF D594G mutation, and BRAF wild-type groups, respectively. CONCLUSION: Colorectal cancers with BRAF D594G mutations exhibit similar clinicopathological features, microsatellite instability status, and prognosis as those with BRAF wild-type.