Tomomichi Kiyomatsu

Prediction of sensitivity of rectal cancer cells in response to preoperative radiotherapy by DNA microarray analysis of gene expression profiles.

Preoperative radiotherapy has been widely used to improve local control of disease and to improve survival in the treatment of rectal cancer. However, the response to radiotherapy differs among individual tumors. Our objective here was to identify a set of discriminating genes that can be used for characterization and prediction of response to radiotherapy in rectal cancer. Fifty-two rectal cancer patients who underwent preoperative radiotherapy were studied. Biopsy specimens were obtained from rectal cancer before preoperative radiotherapy. Response to radiotherapy was determined by histopathologic examination of surgically resected specimens and classified as responders or nonresponders. By determining gene expression profiles using human U95Av2 Gene Chip, we identified 33 novel discriminating genes of which the expression differed significantly between responders and nonresponders. Using this gene set, we were able to establish a new model to predict response to radiotherapy in rectal cancer with an accuracy of 82.4%. The list of discriminating genes included growth factor, apoptosis, cell proliferation, signal transduction, or cell adhesion-related genes. Among 33 discriminating genes, apoptosis inducers (lumican, thrombospondin 2, and galectin-1) showed higher expression in responders whereas apoptosis inhibitors (cyclophilin 40 and glutathione peroxidase) showed higher expression in nonresponders. The present study suggested the possibility that gene expression profiling may be useful in predicting response to radiotherapy to establish an individualized tailored therapy for rectal cancer. Global expression profiles of responders and nonresponders may provide insights into the development of novel therapeutic targets.

Laparoscopic surgery for ulcerative colitis: a review of the literature

Despite the development of new therapies, including anti-TNF alpha antibodies and immunosuppressants, a substantial proportion of patients with ulcerative colitis (UC) still require surgery. Restorative proctocolectomy with ileal-pouch anal anastomosis is the standard surgical treatment of choice for UC. With the advent of laparoscopic techniques for colorectal surgery, ileal-pouch anal anastomosis has also been performed laparoscopically. This paper reviews the history and current trends in laparoscopic surgery for UC. The accumulation of experience and improvement of laparoscopic devices have shifted the paradigm of UC surgery towards laparoscopic surgery over the past decade. Although laparoscopic surgery requires a longer operation, it provides significantly better short and long-term outcomes. The short-term benefits of laparoscopic surgery over open surgery include shorter hospital stays and fasting times, as well as better cosmesis. The long-term benefits of laparoscopy include better fecundity in young females. Some surgeons favor laparoscopic surgery even for severe acute colitis. More efforts are being made to develop newer laparoscopic methods, such as reduced port surgery, including single incision laparoscopic surgery and robotic surgery.

Level of arterial ligation in sigmoid colon and rectal cancer surgery.

BackgroundCurative resection of sigmoid colon and rectal cancer includes “high tie” of the inferior mesenteric artery (IMA). However, IMA ligation compromises blood flow to the anastomosis, which may increase the leakage rate, and it is unclear whether this confers a survival advantage. Accordingly, the IMA may be ligated at a point just below the origin of the left colic artery (LCA) “low tie” combined with lymph node dissection (LND) around the origin of the IMA (low tie with LND). However, no study has investigated the detailed prognostic results between “high tie” and “low tie with LND.” The aim of this study was to assess the utility of “low tie with LND” on survival in patients with sigmoid colon or rectal cancer.MethodsA total of 189 sigmoid colon or rectal cancer patients who underwent curative operation from 1997 to 2007 were enrolled in this study. The patient’s medical records were reviewed to obtain clinicopathological information. Overall survival (OS) and relapse-free survival (RFS) rates were calculated using the Kaplan-Meier method, with differences assessed using log-rank test.ResultsForty-two and 147 patients were ligated at the origin of the IMA (high tie) and just below the origin of the LCA combined with LND around the origin of the IMA (low tie with LND), respectively. No significant differences were observed in the complication rate and OS and RFS rates in the two groups. Further, no significant difference was observed in the OS and RFS rates in the lymph node-positive cases in the two groups.Conclusions“Low tie with LND” is anatomically less invasive and is not inferior to “high tie” with prognostic point of view.

Prognostic impact of tumor location in stage IV colon cancer: A propensity score analysis in a multicenter study

BACKGROUND Right-sided colon cancer is considered to be biologically different from left-sided colon cancer; however, conflicting results have been reported regarding differences in prognosis. We aimed to clarify the prognostic impact of tumor location in stage IV colon cancer. METHODS Stage IV colon cancer treated from January 1997 to December 2007 (n = 2208) were retrospectively studied. Clinical and pathological features were compared between right-sided colon cancer (cecum, ascending, and transverse colon) and left-sided colon cancer (descending, sigmoid, and rectosigmoid colon). The impact of tumor location on cancer-specific survival (CSS) was analyzed in a multivariate analysis and propensity score analysis to mitigate the differences in background features. RESULTS Right-sided colon cancer was associated with older age, female sex, larger tumor size, poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet-ring cell carcinoma, a more advanced state within stage IV disease, and a worse CSS. In the cohort matched by propensity scores for background clinicopathological features, tumor location in the right-sided colon was associated with a significantly worse CSS (hazard ratio 1.2, 95% confidence interval 1.1-1.4, p = 0.008) in patients treated with palliative primary tumor resection, but not in those treated with R0 resection or no resection. CONCLUSION Right-sided colon cancer were diagnosed at a more advanced state within stage IV disease and showed a significantly worse prognosis than left-sided colon cancer, suggesting that stage IV right-sided colon cancer is oncologically more aggressive than left-sided colon cancer.

LINE-1 hypomethylation status of circulating cell-free DNA in plasma as a biomarker for colorectal cancer

Colorectal cancer (CRC) is a serious public health problem and non-invasive biomarkers improving diagnosis or therapy are strongly required. Circulating cell-free DNA (cfDNA) has been a promising target for this purpose. In this study, we evaluated the potential of long interspersed nuclear element-1 (LINE-1) hypomethylation as a blood biomarker for CRC. LINE-1 hypomethylation level in plasma cfDNA in 114 CRC patients was retrospectively examined by absolute quantitative analysis of methylated alleles real-time PCR, and was expressed using LINE-1 hypomethylation index (LHI) [unmethylated copy number/ (methylated copy number + unmethylated copy number)]. Greater LHI values indicated enhanced hypomethylation. In our clinicopathological analysis, CRC patients with large tumors (≥6.0 cm), advanced N stage (≥2), and distant metastasis (M1) had statistically significantly higher cfDNA LHI than other CRC patients, suggesting cfDNA LHI as a disease progression biomarker for CRC. Furthermore, early stage I/II (n = 57) as well as advanced stage III/IV (n =57) CRC patients had significantly higher cfDNA LHI than healthy donors (n=53) [stage I/II: median 0.369 (95% confidence interval, 0.360–0.380) vs. 0.332 (0.325–0.339), P < 0.0001; stage III/IV: 0.372 (0.365–0.388) vs. 0.332 (0.325–0.339), P < 0.0001]. The receiver operating characteristic analysis showed that cfDNA LHI had the detection capacity of CRC with area under the curve(AUC) of 0.79 and 0.83 in stage I/II and stage III/IV CRC patients, respectively. The present study demonstrated for the first time the potential of plasma cfDNA LHI as a novel biomarker for CRC, particularly for early stage detection.

Oncological Outcomes of Lateral Pelvic Lymph Node Metastasis in Rectal Cancer Treated With Preoperative Chemoradiotherapy

BACKGROUND: Oncological outcomes of lateral pelvic lymph node metastasis in rectal cancer treated with preoperative chemoradiotherapy remain to be elucidated. OBJECTIVE: The purpose of this study was to clarify the therapeutic effect of chemoradiotherapy on lateral pelvic lymph node metastasis, the risk factors of lateral pelvic lymph node metastasis, and oncological outcomes of lateral pelvic lymph node dissection after chemoradiotherapy. DESIGN: This was a nonrandomized, retrospective study. SETTINGS: The study was conducted at a tertiary referral university hospital. PATIENTS: Patients with rectal cancer treated with chemoradiotherapy and radical surgery from 2003 to 2015 (N = 222) were included. INTERVENTIONS: Radiation (total, 50.4 Gy in 28 fractions) with concomitant fluorouracil-based chemotherapy was administered. Lateral pelvic lymph nodes with a diameter of ≥8 mm before chemoradiotherapy were selectively dissected. MAIN OUTCOME MEASURES: Frequency and risk factors of lateral pelvic lymph node metastasis were examined. RESULTS: Lateral pelvic lymph node dissection was performed in 31 patients (14.0%), and 16 (51.6%) of these patients were pathologically diagnosed as positive for metastasis. Among the patients treated with total mesorectal excision alone (n = 191), 2 (0.9%) had recurrence in the lateral pelvic lymph node area, which was pathologically confirmed after salvage R0 resection. T category downstaging (73.3% vs 12.5%; p < 0.01) and high histological regression of the primary lesion (73.3% vs 18.8%; p < 0.01) were more frequent in patients with pathologically negative lateral pelvic lymph nodes than in those with positive lateral pelvic lymph nodes. Young age, short distance from the anal verge, and enlarged lateral pelvic lymph node before chemoradiotherapy were associated with lateral pelvic lymph node metastasis. LIMITATIONS: The study was limited by its retrospective nature and small study population. CONCLUSIONS: The incidence of lateral pelvic lymph node metastasis after chemoradiotherapy was estimated to be 8.1% (18/222). Young age, short distance from the anal verge, and enlarged lateral pelvic lymph node before chemoradiotherapy were risk factors of lateral pelvic lymph node metastasis after chemoradiotherapy.

Nomograms for colorectal cancer: A systematic review

AIM To assist in the selection of suitable nomograms for obtaining desired predictions in daily clinical practice. METHODS We conducted electronic searches for journal articles on colorectal cancer (CRC)-associated nomograms using the search terms colon/rectal/colorectal/nomogram. Of 174 articles initially found, we retrieved 28 studies in which a nomogram for CRC was developed. RESULTS We discuss the currently available CRC-associated nomograms, including those that predict the oncological prognosis, the short-term outcome of treatments, such as surgery or neoadjuvant chemoradiotherapy, and the future development of CRC. Developing nomograms always presents a dilemma. On the one hand, the desire to cover as wide a patient range as possible tends to produce nomograms that are too complex and yet have C-indexes that are not sufficiently high. Conversely, confining the target patients might impair the clinical applicability of constructed nomograms. CONCLUSION The information provided in this review should be of use in selecting a nomogram suitable for obtaining desired predictions in daily clinical practice.

Pouchitis after ileal pouch-anal anastomosis in ulcerative colitis: diagnosis, management, risk factors, and incidence

Restorative proctocolectomy with ileal pouch‐anal anastomosis has been the surgical treatment of choice for patients with ulcerative colitis who require surgery. Quality of life after this procedure is satisfactory in most cases; however, pouchitis is a troublesome condition involving inflammation of the ileal pouch. When a patient presents with symptoms of pouchitis, such as increased bowel movements, mucous and/or bloody exudates, abdominal cramps, and fever, endoscopy is essential for a precise diagnosis. The proximal ileum and rectal cuff, as well as the ileal pouch, should be endoscopically observed. The reported incidence of pouchitis ranges from 14% to 59%, and antibiotic therapy is the primary treatment for acute pouchitis. Chronic pouchitis includes antibiotic‐dependent and refractory pouchitis. Intensive therapy including antitumor necrosis factor antibodies and steroids may be necessary for antibiotic‐refractory pouchitis, and pouch failure may occur despite such intensive treatment. Reported risk factors for the development of pouchitis include presence of extraintestinal manifestations, primary sclerosing cholangitis, non‐smoking, and postoperative non‐steroidal anti‐inflammatory drug usage. In the present review, we focus on the diagnosis, endoscopic features, management, incidence, and risk factors of pouchitis in patients with ulcerative colitis who underwent ileal pouch‐anal anastomosis.

Hereditary gastrointestinal cancer

Gastrointestinal (GI) cancer, including gastric and colorectal cancer, is a major cause of death worldwide. A substantial proportion of patients with GI cancer have a familial history, and several causative genes have been identified. Gene carriers with these hereditary GI syndromes often harbor several kinds of cancer at an early age, and genetic testing and specific surveillance may save their lives through early detection. Gastroenterologists and GI surgeons should be familiar with these syndromes, even though they are not always associated with a high penetrance of GI cancer. In this review, we provide an overview and discuss the diagnosis, genetic testing, and management of four major hereditary GI cancers: familial adenomatous polyposis, Lynch syndrome, hereditary diffuse gastric cancer, and Li–Fraumeni syndrome.

Surveillance colonoscopy for colitis-associated dysplasia and cancer in ulcerative colitis patients

Long‐standing ulcerative colitis patients are known to be at high risk for the development of colorectal cancer. Therefore, surveillance colonoscopy has been recommended for these patients. Because colitis‐associated colorectal cancer may be difficult to identify even by colonoscopy, a random biopsy method has been recommended. However, the procedure of carrying out a random biopsy is tedious and its effectiveness has also not yet been demonstrated. Instead, targeted biopsy with chromoendoscopy has gained popularity in European and Asian countries. Chromoendoscopy is generally considered to be an effective tool for ulcerative colitis surveillance and is recommended in the guidelines of the British Society of Gastroenterology and the European Crohns and Colitis Organisation. Although image‐enhanced endoscopy, such as narrow‐band imaging and autofluorescence imaging, has been investigated as a potential ulcerative colitis surveillance tool, it is not routinely applied for ulcerative colitis surveillance in its present form. The appropriate intervals of surveillance colonoscopy have yet to be determined. Although the Japanese and American guidelines recommend annual or biannual colonoscopy, the British Society of Gastroenterology and the European Crohns and Colitis Organisation stratified their guidelines according to the risks of colorectal cancer. A randomized controlled trial comparing random and targeted biopsy methods has been conducted in Japan and although the final analysis is still ongoing, the results of this study should address this issue. In the present review, we focus on the current detection methods and characterization of dysplasia/cancer and discuss the appropriate intervals of colonoscopy according to the stratified risks.