LASSO-Based Machine Learning Algorithm for Prediction of Lymph Node Metastasis in T1 Colorectal Cancer.

PURPOSE: The role of tumor-infiltrating lymphocytes (TILs) in predicting lymph node metastasis (LNM) in patients with T1 colorectal cancer (CRC) remains unclear. Furthermore, clinical utility of a machine learning-based approach has not been widely studied. MATERIALS AND METHODS: Immunohistochemistry for TILs against CD3, CD8, and forkhead box P3 in both center and invasive margin of the tumor were performed using surgically resected T1 CRC slides. Three hundred and sixteen patients were enrolled and categorized into training (n=221) and validation (n=95) sets via random sampling. Using clinicopathologic variables including TILs, the least absolute shrinkage and selection operator (LASSO) regression model was applied for variable selection and predictive signature building in the training set. The predictive accuracy of our model and the Japanese criteria were compared using area under the receiver operating characteristic (AUROC), net reclassification improvement (NRI)/integrated discrimination improvement (IDI), and decision curve analysis (DCA) in the validation set. RESULTS: LNM was detected in 29 (13.1%) and 12 (12.6%) patients in training and validation sets, respectively. Nine variables were selected and used to generate the LASSO model. Its performance was similar in training and validation sets (AUROC, 0.795 vs. 0.765; p=0.747). In the validation set, the LASSO model showed better outcomes in predicting LNM than Japanese criteria, as measured by AUROC (0.765 vs. 0.518, p=0.003) and NRI (0.447, p=0.039)/IDI (0.121, p=0.034). DCA showed positive net benefits in using our model. CONCLUSION: Our LASSO model incorporating histopathologic parameters and TILs showed superior performance compared to conventional Japanese criteria in predicting LNM in patients with T1 CRC.

High-Definition Chromoendoscopy Versus High-Definition White Light Colonoscopy for Neoplasia Surveillance in Ulcerative Colitis: A Randomized Controlled Trial.

OBJECTIVES: Although chromoendoscopy is currently the recommended mode of surveillance in patients with long-standing ulcerative colitis, it is technically challenging and requires a long procedure time. The aim of this study was to compare the dysplasia detection rate of high-definition white light endoscopy with random biopsy (HDWL-R) vs high-definition chromoendoscopy with targeted biopsy (HDCE-T). METHODS: This was a multicenter, prospective randomized controlled trial involving 9 tertiary teaching hospitals in South Korea. A total of 210 patients with long-standing ulcerative colitis were randomized to undergo either the HDWL-R group (n = 102) or HDCE-T group (n = 108). The detection rates of colitis-associated dysplasia (CAD) or all colorectal neoplasia from each trial arm were compared. RESULTS: There was no significant difference in the CAD detection rate between HDCE-T and HDWL-R groups (4/102, 3.9% vs 6/108, 5.6%, P = 0.749). However, HDCE-T showed a trend toward improved colorectal neoplasia detection compared with HDWL-R (21/102, 20.6% vs 13/108, 12.0%, P = 0.093). The median (range) time for colonoscopy withdrawal between the 2 groups was similar (17.6 [7.0-43.3] minutes vs 16.5 [6.3-38.1] minutes; P=0.212; for HDWL-R and HDCE-T, respectively). The total number of biopsies was significantly larger in the HDWL-R group (34 [12-72]) compared with the HDCE-T group (9 [1-20]; P < 0.001). DISCUSSION: On the basis of our prospective randomized controlled trial, HDCE-T was not superior to HDWL-R for detecting CADs.

Aberrant expression of OATP1B3 in colorectal cancer liver metastases and its clinical implication on gadoxetic acid-enhanced MRI.

PURPOSE: To investigate the factors associated with hepatobiliary phase (HBP) enhancement at gadoxetic acid-enhanced magnetic resonance imaging (MRI) and to determine whether HBP images could be used to predict prognosis in patients with colorectal cancer liver metastasis (CRLM). RESULTS: Of the 96 total nodules, 65 and 31 nodules were in the mixed and clearly hypointense groups, respectively. In the 55 nodules without preoperative chemotherapy, organic anionic transporting polypeptide 1B3 (OATP1B3) expression was a significant factor regarding the HBP enhancement (P=0.042). In this subgroup, nodules with OATP1B3 expression displayed a significantly higher relative intensity ratio on the HBP image (RIRpost) and relative enhancement ratio (RER) than those lacking this marker (P=0.024, 0.003, respectively). No significant factor was associated with the enhancement pattern in the chemotherapy group. The mixed hypointense group displayed worse survival rates (P=0.002). MATERIALS AND METHODS: Ninety-six patients who underwent pre-operative liver MRI and surgical resection for CRLM from January 2010 to June 2012 were retrospectively analyzed. We qualitatively evaluated the HBP enhancement pattern of CRLMs and classified them into mixed and clearly hypointense groups. For quantitative measurement, the RIRpost and RER were analyzed. To investigate factors associated with HBP enhancement, tumor components (fibrosis, necrosis, and cellularity) and OATP1B3 expression were scored on a 4-point scale. Univariate and multivariate analyses were done to determine significant factors for visual enhancement and quantitative parameters. CONCLUSIONS: OATP1B3 expression is associated with mixed hypointense CRLMs without chemotherapy. Signal intensity on HBP has potential usefulness to predict prognosis in CRLMs.

Promoter methylation of PCDH10 by HOTAIR regulates the progression of gastrointestinal stromal tumors.

HOTAIR, a long non-coding RNA (lncRNA), plays a crucial role in tumor initiation and metastasis by interacting with the PRC2 complex and the modulation of its target genes. The role of HOTAIR in gastrointestinal stromal tumors (GISTs) is remains unclear. Herein we investigate the mechanism of HOTAIR in the genesis and promotion of GISTs. The expression of HOTAIR was found to be higher in surgically resected high-risk GISTs than that in low- and intermediate-risk GISTs. Using GIST-T1 and GIST882 cells, we demonstrated that HOTAIR repressed apoptosis, was associated with cell cycle progression, and controlled the invasion and migration of GIST cells. Using a gene expression microarray and lists of HOTAIR-associated candidate genes, we suggested that protocadherin 10 (PCDH10) is a key molecule. PCDH10 expression was significantly decreased in GIST-T1 and GIST882 cells, possibly as a consequence of hypermethylation. We observed that HOTAIR induced PCDH10 methylation in a SUZ12-dependent manner. In this study, we found that the malignant character of GISTs was initiated and amplified by PCDH10 in a process regulated by HOTAIR. In summary, our findings imply that PCDH10 and HOTAIR may be useful markers of disease progression and therapeutic targets.

Pathological Complete Remission of Pancreatic Cancer Following Neoadjuvant Chemoradiation Therapy; Not the End of Battles.

In spite of controversial issues, pancreatectomy following neoadjuvant chemoradiation therapy (NeoCRT) has been applied in treating advanced pancreatic cancer. Cases of pathological complete remission (pCR) following NeoCRT is rare, and its long-term follow-up data are still lacking.From January 2000 to December 2012, medical records of the patients who underwent pancreatectomy for pancreatic ductal adenocarcinoma were retrospectively reviewed. Characteristics of the patients with pCR were summarized and their long-term follow-up data were analyzed.Among 86 patients with pancreatic cancer who underwent radical pancreatectomy following NeoCRT, 10 patients (11.6%) were reported to pCR. Nine out of 10 patients received gemcitabine-based chemoradiation therapy. Median pre-NeoCRT serum CA 19-9 was 313.5 U/ml, and post-NeoCRT serum CA 19-9 was 9.9 U/ml, which was shown to be significant difference between 2 serum CA 19-9 level (P = 0.005). Pylorus-preserving pancreaticoduodenectomy was done in 8 patients, and the others received distal pancreatosplenectomy. Postoperative chemotherapy was received in 6 patients. Disease-free survival was statistically superior in patients with pCR than patients without pCR (P < 0.05). However, 5 patients experienced cancer recurrence and no clinicopathologic variables including preoperative resectability could not predict the potential recurrence of tumor in patients with pCR (P > 0.05).pCR is rarely reported following NeoCRT, but this condition is not telling the cure of the disease. Early recurrence in the pattern of liver metastasis and peritoneal seeding can be expected. However, long-term survival could be maintained in patients without recurrence. Further investigation is necessary for predicting failure of treatment.

Overestimated Oncologic Significance of Lymph Node Metastasis in G1 Nonfunctioning Neuroendocrine Tumor in the Left Side of the Pancreas.

Recent studies have expounded on the oncologic significance of lymph node metastasis in nonfunctioning (NF) neuroendocrine tumors (NETs) of the pancreas and suggest regional lymph node dissection for treating pancreatic NET. We tested this recommendation in NF pancreatic NET-G1, as these tumors are generally small and suitable for function-preserving minimally invasive pancreatectomy.From January 2005 to December 2014, medical records of patients who underwent pancreatectomy for pathologically confirmed NF NET-G1 of the left side of the pancreas were retrospectively reviewed. Oncologic outcomes were compared between limited pancreatectomy and distal pancreatosplenectomy.Thirty-five patients (14 males and 21 females) with a mean age of 55.9 ±â€Š11.4 years were enrolled in this study. Six patients (17.1%) underwent distal pancreatosplenectomy. Limited pancreatectomies comprised 15 spleen-preserving distal pancreatectomies (42.8%), 10 enucleations (28.6%), and 4 central pancreatectomies (11.4%). Lymph node metastasis was not found in 6 patients who underwent distal pancreatectomy with a splenectomy; meanwhile, the others were regarded as pNx since no lymph node retrieval was attempted during the limited pancreatectomy. Overall disease-free survival was 36.5 months (95% confidence interval [CI]: 25.9-47.1) and no tumor-related mortality was noted. Minimally invasive pancreatectomy (P = 0.557) and limited pancreatectomy (P = 0.758) showed no adverse impact in treating NF NET-G1 of the left side of the pancreas.The oncologic significance of lymph node metastasis is overestimated in NF NET-G1 of the left side of the pancreas. Routine conventional distal pancreatosplenectomy to retrieve regional lymph nodes may be too excessive in treating NF NET-G1 of the distal pancreas.

Endoscopic and clinicopathologic characteristics of early gastric cancer with high microsatellite instability.

AIM: To investigate endoscopic and clinicopathologic characteristics of early gastric cancer (EGC) according to microsatellite instability phenotype. METHODS: Data were retrospectively collected from a single tertiary referral center. Of 981 EGC patients surgically treated between December 2003 and October 2007, 73 consecutive EGC patients with two or more microsatellite instability (MSI) mutation [high MSI (MSI-H)] and 146 consecutive EGC patients with one or no MSI mutation (non-MSI-H) were selected. The endoscopic and clinicopathologic features were compared between the MSI-H and non-MSI-H EGC groups. RESULTS: In terms of endoscopic characteristics, MSI-H EGCs more frequently presented with elevated pattern (OR 4.38, 95% CI: 2.40-8.01, P < 0.001), moderate-to-severe atrophy in the surrounding mucosa (OR 1.91, 95% CI: 1.05-3.47, P = 0.033), antral location (OR 3.99, 95% CI: 2.12-7.52, P < 0.001) and synchronous lesions, compared to non-MSI-H EGCs (OR 2.65, 95% CI: 1.16-6.07, P = 0.021). Other significant clinicopathologic characteristics of MSI-H EGC included predominance of female sex (OR 2.77, 95% CI: 1.53-4.99, P < 0.001), older age (> 70 years) (OR 3.30, 95% CI: 1.57-6.92, P = 0.002), better histologic differentiation (OR 2.35, 95% CI: 1.27-4.34, P = 0.007), intestinal type by Lauren classification (OR 2.34, 95% CI: 1.15-4.76, P = 0.019), absence of a signet ring cell component (OR 2.44, 95% CI: 1.02-5.86, P = 0.046), presence of mucinous component (OR 5.06, 95% CI: 1.27-20.17, P = 0.022), moderate-to-severe lymphoid stromal reaction (OR 3.95, 95% CI: 1.59-9.80, P = 0.003), and co-existing underlying adenoma (OR 2.66, 95% CI: 1.43-4.95, P = 0.002). CONCLUSION: MSI-H EGC is associated with unique endoscopic and clinicopathologic characteristics including frequent presentation in protruded type, co-existing underlying adenoma, and synchronous lesions.

Signet ring cell carcinoma of the extrahepatic bile duct.

Most tumors affecting the extrahepatic bile duct are adenocarcinomas; the other histologic types occur only rarely. We herein report the extremely rare case of signet ring cell carcinoma (SRCC) originating from the extrahepatic bile duct. A 55-year-old man was hospitalized for jaundice and pruritus. Computed tomography and positron emission tomography suggested the presence of distal extrahepatic bile-duct cancer. He underwent a pylorus preserving pancreaticoduodenectomy. A histologic study confirmed a signet ring cell neoplasm of the distal common bile duct. Because the upper resection margin was invaded by the tumor, he received postoperative concurrent chemoradiotherapy and four cycles of chemotherapy. The patient has survived with no evidence of recurrence for 2 years. This is the second case of primary SRCC of the distal extrahepatic bile duct reported in the literature; further reports of cases are warranted to determine the nature of SRCC in the extrahepatic bile duct.

Current trends in the epidemiological and pathological characteristics of gastrointestinal stromal tumors in Korea, 2003-2004.

Despite remarkable progress in understanding and treating gastrointestinal stromal tumors (GISTs) during the past two decades, the pathological characteristics of GISTs have not been made clear yet. Furthermore, concrete diagnostic criteria of malignant GISTs are still uncertain. We collected pathology reports of 1,227 GISTs from 38 hospitals in Korea between 2003 and 2004 and evaluated the efficacy of the NIH and AFIP classification schemes as well as the prognostic factors among pathologic findings. The incidence of GISTs in Korea is about 1.6 to 2.2 patients per 100,000. Extra-gastrointestinal GISTs (10.1%) are more common in Korea than in Western countries. In univariate analysis, gender, age, tumor location, size, mitosis, tumor necrosis, vascular and mucosal invasions, histologic type, CD34 and s-100 protein expression, and classifications by the NIH and AFIP criteria were found to be significantly correlated with patient's survival. However, the primary tumor location, stage and classification of the AFIP criteria were prognostically significant in predicting patient's survival in multivariate analysis. The GIST classification based on original tumor location, size, and mitosis is more efficient than the NIH criteria in predicting patient's survival, but the mechanism still needs to be clarified through future studies.

RORalpha attenuates Wnt/beta-catenin signaling by PKCalpha-dependent phosphorylation in colon cancer.

Wnt family members play diverse roles in development and disease. Noncanonical Wnt ligands can inhibit canonical Wnt signaling depending on the cellular context; however, the underlying mechanism of this antagonism remains poorly understood. Here we identify a specific mechanism of orphan nuclear receptor RORalpha-mediated inhibition of canonical Wnt signaling in colon cancer. Wnt5a/PKCalpha-dependent phosphorylation on serine residue 35 of RORalpha is crucial to link RORalpha to Wnt/beta-catenin signaling, which exerts inhibitory function of the expression of Wnt/beta-catenin target genes. Intriguingly, there is a significant correlation of reduction of RORalpha phosphorylation in colorectal tumor cases compared to their normal counterpart, providing the clinical relevance of the findings. Our data provide evidence for a role of RORalpha, functioning at the crossroads between the canonical and the noncanonical Wnt signaling pathways, in mediating transrepression of the Wnt/beta-catenin target genes, thereby providing new approaches for the development of therapeutic agents for human cancers.

In vitro adenosine triphosphate based chemotherapy response assay in gastric cancer.

PURPOSE: The purpose of this study was to investigate the reliability and the clinical applicability of the adenosine-triphosphate-based chemotherapy response assay (ATP-CRA) as a method of determining in vitro chemosensitivity in patients with gastric cancer. MATERIALS AND METHODS: A total of 243 gastric cancer tissue samples were obtained from gastrectomies performed between February 2007 and January 2010. We evaluated the effectiveness of the ATP-CRA assay in determining the chemosensitivity of gastric cancer specimens using eleven chemotherapeutic agents - etoposide, doxorubicin, epirubicin, mytomicin, 5-fluorouracil, oxaliplatin, irinotecan, docetaxel, paclitaxel, methotraxate, and cisplatin - for chemosensitivity studies using ATP-CRA. We assessed the failure rate, the cell death rate, and the chemosensitivity index. RESULTS: The failure rate of ATP-CRA was 1.6% (4/243). The mean coefficient of variation for triplicate ATP measurements was 6.5%. Etoposide showed the highest cell death rate (35.9%) while methotrexate showed the lowest (16.6%). The most active chemotherapeutic agent was etoposide, which most frequently ranked highest in the chemosensitivity test: 31.9% (51/160). Oxaliplatin was more active against early gastric cancers than advanced gastric cancers, whereas docetaxel was more active against advanced cancers. The lymph node negative group showed a significantly higher cell death rate than the lymph node positive group when treated with doxorubicin, epirubicin, and mitomycin. CONCLUSIONS: ATP-CRA is a stable and clinically applicable in vitro chemosensitivity test with a low failure rate. The clinical usefulness of ATP-CRA should be evaluated by prospective studies comparing the regimen guided by ATP-CRA with an empirical regimen.

Tumor volume changes assessed by three-dimensional magnetic resonance volumetry in rectal cancer patients after preoperative chemoradiation: the impact of the volume reduction ratio on the prediction of pathologic complete response.

PURPOSE: The aim of this study was to determine the correlation between tumor volume changes assessed by three-dimensional (3D) magnetic resonance (MR) volumetry and the histopathologic tumor response in rectal cancer patients undergoing preoperative chemoradiation therapy (CRT). METHODS AND MATERIALS: A total of 84 patients who underwent preoperative CRT followed by radical surgery were prospectively enrolled in the study. The post-treatment tumor volume and tumor volume reduction ratio (% decrease ratio), as shown by 3D MR volumetry, were compared with the histopathologic response, as shown by T and N downstaging and the tumor regression grade (TRG). RESULTS: There were no significant differences in the post-treatment tumor volume and the volume reduction ratio shown by 3D MR volumetry with respect to T and N downstaging and the tumor regression grade. In a multivariate analysis, the tumor volume reduction ratio was not significantly associated with T and N downstaging. The volume reduction ratio (>75%, p = 0.01) and the pretreatment carcinoembryonic antigen level (< or =3 ng/ml, p = 0.01), but not the post-treatment volume shown by 3D MR (< or = 5 ml), were, however, significantly associated with an increased pathologic complete response rate. CONCLUSION: More than 75% of the tumor volume reduction ratios were significantly associated with a high pathologic complete response rate. Therefore, limited treatment options such as local excision or simple observation might be considered after preoperative CRT in this patient population.

Obstructive colitis proximal to obstructive colorectal carcinoma.

The term "obstructive colitis" refers to ulceroinflammatory lesions occurring in the colon proximal to a completely or partially obstructing lesion. It has been referred to by various terms in the literature. This entity differs from the carcinoma of the colon that complicates true ulcerative colitis where there is involvement distal to the neoplasm as well as proximal to it. Although it has appeared in the literature over several decades, it remains an uncommon and troublesome disease. In Yonsei University Medical Center, for 11 years from January 1996 to December 2006 we encountered seven patients with obstructing colorectal carcinoma complicated by obstructive colitis. Here we report our cases to share our experience and to review the literature to facilitate the recognition and proper management of this rare disease entity.

Cyclooxygenase-2 expression in pretreatment biopsy as a predictor of tumor responses after preoperative chemoradiation in rectal cancer.

OBJECTIVE: To determine whether cyclooxygenase-2 (COX-2) expression in pretreatment biopsy specimens is a useful predictive marker of tumor response to preoperative chemoradiation (CRT) in rectal cancer. DESIGN: Case series. SETTING: Colorectal cancer clinic. PATIENTS: Thirty patients with locally advanced rectal cancer were given preoperative CRT of 5040 cGy for 6 weeks with concurrent administration of 5-fluorouracil and leucovorin. MAIN OUTCOME MEASURES: Immunohistochemical staining for COX-2 and angiogenesis markers (vascular endothelial growth factor, thymidine phosphorylase, and CD34) were performed on biopsy specimens obtained before preoperative CRT. The responses to preoperative CRT were assessed by radiologic downsizing (measured using magnetic resonance imaging volumetry), histopathologic downstaging, and a 3-point tumor regression grade (TRG) evaluation, based on the ratio of residual cancer to fibrosis. RESULTS: Tumor downstaging was seen in 15 patients (50.0%) and nodal downstaging was noted in 14 patients (46.7%). Tumor regression grade 1 (good response) was shown by 7 patients (23.3%); TRG2 (moderate response) in 15 patients (50.0%); and TRG3 (poor response) in 8 patients (26.7%). Patients with COX-2 overexpression were more likely to show a poor TRG (P = .003) and were less likely to achieve histopathologic nodal downstaging (P = .03) than those with normal COX-2 expression. Vascular endothelial growth factor overexpression was found to be associated with COX-2 overexpression (P = .02). CONCLUSIONS: Overexpression of COX-2 in pretreatment biopsies might be predictive of poor tumor regression after preoperative CRT. Administration of COX-2 inhibitors to patients with COX-2 overexpression, in an attempt to improve response rate to preoperative CRT, warrants assessment in clinical trials.

Factors influencing pathologic results after total mesorectal excision for rectal cancer: analysis of consecutive 100 cases.

BACKGROUND: The aim of this study was to analyze clinical and anatomical factors affecting the pathologic quality of the resected specimen after total mesorectal excision (TME) for rectal cancer. METHODS: A total of 100 patients who underwent TME for mid or low rectal cancer were evaluated prospectively. MRI pelvimetry data (transverse diameter, obstetric conjugate, interspinous distance, sacrum length, and sacrum depth) were analyzed as anatomically affecting factors to postoperative specimen quality. Sex, body mass index (BMI), type of surgery, tumor size, and tumor distance from the anal verge were analyzed as clinically affecting factors. The gross judgment of resected specimen, circumferential resection margin and the number of harvested lymph nodes were used to access postoperative specimen quality. RESULTS: The univariate and multivariate analysis showed that narrow obstetric conjugate and shorter interspinous distance were related to the inadequate quality of the mesorectum in the specimen (P = 0.022, P = 0.030). Interspinous distance was a predicting factor of a positive circumferential resection margin (P = 0.007). There were no clinical factors affecting the inadequate quality of the mesorectum or positive circumferential resection margin. Moreover, there were no clinico-anatomical factors affecting the number of harvested lymph nodes after TME. CONCLUSION: Narrow obstetric conjugate and shorter interspinous distance were factors leading to poor postoperative specimen quality. Rectal cancer patients with narrow obstetric conjugate or shorter interspinous distance should be considered as high-risk patients with regard to specimen quality, which is in turn related to oncological outcome.

Cetuximab in combination with 5-fluorouracil, leucovorin and irinotecan as a neoadjuvant chemotherapy in patients with initially unresectable colorectal liver metastases.

BACKGROUND: The efficacy and safety of a combination of cetuximab, irinotecan, and 5-fluorouracil/leucovorin (FOLFIRI) in downsizing unresectable colorectal liver metastases was investigated. PATIENTS AND METHODS: Patients with unresectable colorectal liver metastases with or without resectable extrahepatic metastasis were enrolled. 23 patients initially received 400 mg/m2 of cetuximab, followed by a weekly infusion of 250 mg/m2 and a biweekly dose of irinotecan (180 mg/m2), with 5-fluorouracil both by bolus (400 mg/m2) and by a 46-h infusion (total of 2,400 mg/m2) with leucovorin (400 mg/m2). RESULTS: The overall response rate was 39.1% (n = 9; 95% confidence interval (CI): 17.6-60.7%). The most common grade 3-4 toxicities were skin reactions (30.4%) and diarrhea (26.1%). The rate of conversion to resectable liver metastases was 30.4% (n = 7; 95% CI: 10.1-50.8%). The factors found to be significantly associated with R0 resection were lower serum carcinoembryonic antigen levels after chemotherapy (p = 0.039), being chemonaive (p = 0.002), and showing a higher incidence of grade 3-4 skin toxicity (p = 0.011). CONCLUSIONS: Cetuximab with FOLFIRI may be an effective and safe treatment option for downsizing unresectable colorectal liver metastases.

A comparative study of volumetric analysis, histopathologic downstaging, and tumor regression grade in evaluating tumor response in locally advanced rectal cancer following preoperative chemoradiation.

PURPOSE: To compare tumor volume reduction rate, histopathologic downstaging, and tumor regression grade (TRG) among tumor responses in rectal cancer after preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS: Between 2002 and 2004, 30 patients with locally advanced rectal cancer underwent preoperative CRT, followed by surgical resection. Magnetic resonance volumetry was performed before and after CRT. Histopathologic tumor staging and tumor regression were reviewed. We compared pre- and post-CRT tumor volume and percent of volume reduction, according to histopathologic downstaging and TRG. RESULTS: The tumor volume reduction rates ranged from 14.6% to 100%. Mean pre- and post-CRT tumor volumes were significantly smaller in patients who showed T downstaging than in those who did not (p = 0.040, 0.014). The mean tumor volume reduction was 66.4% vs. 55.2% (p = 0.361). However, the mean pre- and post-CRT tumor volume and mean tumor volume reduction rate between patients who showed N downstaging and those who did not were not statistically different (p = 0.176, 0.767, and 0.899). With respect to TRG, the mean pre- and post-CRT tumor volumes were not statistically significant (p = 0.108, 0.708, and 0.120). CONCLUSION: Tumor volume reduction rate does not correlate with histopathologic downstaging and TRG. It might be hazardous to evaluate tumor response with respect to volume reduction and to select the surgical method on this basis.

RASSF1A hypermethylation and its inverse correlation with BRAF and/or KRAS mutations in MSI-associated endometrial carcinoma.

Both hypermethylation of the tumor suppressor gene RASSF1A and activating mutations of the KRAS and/or BRAF gene have been reported in a variety of human cancers. To investigate these epigenetic and genetic alterations in endometrial carcinoma (EC), we examined their frequency in 4 uterine EC cell lines and in 75 sporadic primary ECs. Using methylation specific PCR, we found RASSF1A methylation in 25 of 75 (33.3%) ECs. RASSF1A methylation was significantly associated with microsatellite instability (MSI, p < 0.001) and also with hMLH1 methylation (p < 0.001). KRAS mutations were detected in 14 of 75 (18.7%) ECs. BRAF mutations were identified in only 3 of 75 (4.0%) ECs and were not found in ECs with KRAS mutations or RASSF1A methylation. RASSF1A methylation was more frequent in KRAS mutation-negative ECs than in KRAS mutation-positive ECs (37.7% vs 14.3%), but this inverse correlation is not statistically significant (p = 0.122). However, we observed that RASSF1A methylation was inversely correlated with KRAS and/or BRAF mutations (p = 0.028) in MSI-negative ECs, while this inverse correlation disappeared in MSI-positive ECs. Furthermore, in MSI-positive ECs, 2 cases of concomitant RASSF1A methylation and KRAS mutation were found. Taken together, these results provide strong evidence that, in EC tumorigenesis, RASSF1A promoter hypermethylation is as important as KRAS mutations in activating the RAS pathway.