Takashi Akiyoshi

Factors affecting the difficulty of laparoscopic total mesorectal excision with double stapling technique anastomosis for low rectal cancer

BACKGROUND Although the laparoscopic approach is accepted for the treatment of colon cancer, its value for low rectal cancer is unknown. The purpose of this study was to evaluate the influence of patient and tumor factors, particularly pelvic dimensions, on the difficulties in laparoscopic total mesorectal excision (TME) for low rectal cancer. METHODS Seventy-nine consecutive patients underwent laparoscopic TME with intracorporeal rectal transection and double stapling technique (DST) anastomosis for low rectal cancer. Gender, body mass index (BMI), tumor diameter, tumor depth, tumor distance from the anal verge, preoperative chemoradiotherapy, and 5 pelvic dimensions (pelvic inlet, pelvic outlet, length of sacrum, interspinous distance, and intertuberous distance) were analyzed as variables affecting the difficulties of laparoscopic TME. The dependent variables were pelvic operative time, which was defined as the time required for dissection of the rectum from the pelvis, intracorporeal transaction, and anastomosis. Other dependent variables were intraoperative blood loss, overall postoperative morbidity, and anastomotic leakage. Univariate and multivariate analyses were performed to determine the predictive significance of variables. RESULTS Multivariate analysis showed that BMI (P < .0001), tumor distance from the anal verge (P = .0003), tumor depth (P = .0021), and pelvic outlet (P = .0362) were independently predictive of pelvic operative time. Pelvic operative time was related to intraoperative blood loss (P < .0001). The tumor distance from the anal verge (P = .0333, odds ratio [OR]: 1.06) was related to postoperative morbidity, and pelvic outlet was related to anastomotic leakage (P = .0305, OR: 1.13). CONCLUSION BMI, tumor distance from the anal verge, tumor depth, and pelvic outlet were independent predictors for operative time and morbidity. These factors should be taken into account when planning laparoscopic TME.

Chromosomal Instability (CIN) Phenotype, CIN High or CIN Low, Predicts Survival for Colorectal Cancer

PURPOSE To examine whether chromosomal instability (CIN) phenotype, determined by the severity of CIN, can predict survival for stages II and III colorectal cancer (CRC). PATIENTS AND METHODS We determined microsatellite instability (MSI) and loss of heterozygosity (LOH) status in 1,103 patients (training [n = 845] and validation [n = 258] sets with stages II and III CRC). The LOH ratio was defined as the frequency of LOH in chromosomes 2p, 5q, 17p, and 18q. According to the LOH ratio, non-MSI high tumors were classified as CIN high (LOH ratio ≥ 33%) or CIN low (LOH ratio < 33%). CIN-high tumors were subclassified as CIN high (mild type; LOH ratio < 75%) or CIN high (severe type; LOH ratio ≥ 75%). We used microarrays to identify a gene signature that could classify the CIN phenotype and evaluated its ability to predict prognosis. RESULTS CIN high showed the worst survival (P < .001), whereas there was no significant difference between CIN low and MSI high. CIN high (severe type) showed poorer survival than CIN high (mild type; P < .001). Multivariate analysis revealed that CIN phenotype was an independent risk factor for disease-free and overall survival, respectively, in both the training (P < .001 and P = .0155) and validation sets (P < .001 and P = .0076). Microarray analysis also revealed that survival was significantly poorer in those with the CIN-high than in the CIN-low gene signature (P = .0203). In a validation of 290 independent CRCs (GSE14333), the CIN-high gene signature showed significantly poorer survival than the CIN-low signature (P = .0047). CONCLUSION The CIN phenotype is a predictive marker for survival and may be used to select high-risk patients with stages II and III CRC.

Incidence of and risk factors for anastomotic leakage after laparoscopic anterior resection with intracorporeal rectal transection and double-stapling technique anastomosis for rectal cancer

BACKGROUND Laparoscopic rectal cancer surgery involving rectal division with intracorporeal stapling devices is technically difficult. This study aimed to identify risk factors for anastomotic leakage associated with laparoscopic anterior resection for rectal cancer. METHODS We studied 363 patients who underwent laparoscopic anterior resection with intracorporeal rectal transection and double-stapling technique (DST) anastomosis for rectal cancer between July 2005 and February 2010. Twenty-two independent clinical variables were examined by univariate and multivariate analyses. The outcome of interest was clinical anastomotic leakage. RESULTS Anastomotic leakage was identified in 13 (3.6%) patients. Multivariate analysis identified middle/lower rectal cancer (odds ratio, 9.446) and lack of pelvic drain (odds ratio, 3.814) as independent predictive factors for anastomotic leakage. The number of cartridges used for rectal division had no significant impact on anastomotic leakage. CONCLUSIONS Laparoscopic anterior resection involving intracorporeal rectal transection and DST anastomosis is safe if performed using an appropriate technique.

Results of a Japanese nationwide multi-institutional study on lateral pelvic lymph node metastasis in low rectal cancer: is it regional or distant disease?

Objective:To evaluate whether lateral pelvic lymph nodes (LNs) in low rectal cancer are metastatic disease or part of regional LNs that are amenable to curative resection. Background:It is highly controversial whether lateral pelvic LNs should be considered as regional or distant disease, although the American Joint Committee on Cancer (AJCC) defines internal iliac LNs as regional LNs of rectal cancer. Methods:Data of patients with stage I to III low rectal cancer who underwent curative resection from 1978 to 1998 were extracted from the multi-institutional registry of large bowel cancer in Japan. Patients with only mesorectal LN metastasis were classified as the mesorectal-LN group. Patients with lateral pelvic LN metastasis localized to or extending beyond the internal iliac area were classified as the internal lateral pelvic lymph nodes (LPLN) group and external-LPLN group, respectively. Overall survival (OS) and cancer-specific survival (CSS) were compared between the groups. Results:Lateral pelvic LN dissection was performed in 5789 (50%) of 11,567 patients. Overall, 3905 (34%), 411 (3.6%), and 244 (2.1%) patients were classified as the mesorectal-LN, internal-LPLN, and external-LPLN groups, respectively. When the mesorectal LN group was subdivided as defined by the AJCC, both 5-year OS and CSS were not significantly different between the N2a and internal-LPLN groups (OS: 45% vs 45%, P = 0.9585; CSS: 51% vs 49%, P = 0.5742), and the N2b and external-LPLN groups (OS: 32% vs 29%, P = 0.3342; CSS: 37% vs 34%, P = 0.4347). OS and CSS were significantly better in the external-LPLN group than in stage IV patients who underwent curative resection (OS: 29% vs 24%, P = 0.0240; CSS: 34% vs 27%, P = 0.0117). Conclusions:Lateral pelvic LNs can be considered as regional LNs in low rectal cancer, although metastasis extending beyond the internal iliac area is associated with poorer survival.

Altered Bile Acid Metabolism in Nonobese, Spontaneously Diabetic (NOD) Mice

Cholesterol and bile acid metabolism was examined in nonobese, spontaneously diabetic (NOD) female mice before and after the development of diabetes. After the development of glucosuria, the plasma and liver cholesterol levels, gallbladder bile weight after 5-h fasting, biliary cholesterol, phospholipid and bile acid concentrations, the lithogenic index, the pool size of bile acids, and fecal sterol excretion markedly increased, but fecal bile acid excretion and fractional turnover rates for the cholic acid and chenodeoxycholic acid groups decreased. The distribution percentage of bile acids in the small intestine did not change, but it increased in the gallbladder and decreased in the large intestine. One striking finding was a change in the bile acid composition: increases were recorded in cholic and deoxycholic acids while decreases occurred in bile acids derived from chenodeoxycholic acid, such as β-muricholic and ursodeoxycholic acids in the bile and α-muricholic, β-muricholic, ω-muricholic, and hyodeoxychollc acids in the feces. Therefore, the cholic acid group/chenodeoxycholic acid group (CA/CDCA) ratio increased in the bile, feces, and small and large intestines after the development of diabetes. These changes were very similar to those observed in alloxan-treated mice, suggesting that the changes found in NOD mice are caused by insulin deficiency.

Predicting the response to preoperative radiation or chemoradiation by a microarray analysis of the gene expression profiles in rectal cancer

Preoperative radiotherapy or chemoradiotherapy (CRT) has become a standard treatment for patients with locally advanced rectal cancer. However, there is a wide spectrum of responses to preoperative CRT, ranging from none to complete. There has been intense interest in the identification of molecular biomarkers to predict the response to preoperative CRT, in order to spare potentially non-responsive patients from unnecessary treatment. However, no specific molecular biomarkers have yet been definitively proven to be predictive of the response to CRT. Instead of focusing on specific factors, microarray-based gene expression profiling technology enables the simultaneous analysis of large numbers of genes, and might therefore have immense potential for predicting the response to preoperative CRT. We herein review published studies using a microarray-based analysis to identify gene expression profiles associated with the response of rectal cancer to radiation or CRT. Although some studies have reported gene expression signatures capable of high predictive accuracy, the compositions of these signatures have differed considerably, with little gene overlap. However, considering the promising data regarding gene profiling in breast cancer, the microarray analysis could still have potential to improve the management of locally advanced rectal cancer. Increasing the number of patients analyzed for more accurate prediction and the extensive validation of predictive classifiers in prospective clinical trials are necessary before such profiling can be incorporated into future clinical practice.

Effect of body mass index on short-term outcomes of patients undergoing laparoscopic resection for colorectal cancer: a single institution experience in Japan.

Background: The impact of body mass index (BMI) on laparoscopic surgery for colorectal cancer in Asian countries is unclear, partly because obesity is less common in Asia than in western countries. The purpose of this study was to evaluate the association between BMI and short-term outcomes after laparoscopic resection for colorectal cancer in Japanese patients. Methods: A cohort of 1194 patients who underwent laparoscopic resection for colorectal cancer at Cancer Institute Hospital between July 2005 and February 2010 were enrolled in this prospective study. Outcomes were analyzed according to BMI category: nonobese (BMI<25), obese I (25⩽BMI<30), and obese II (BMI≥30). Results: A total of 926 patients (78%) were classified as nonobese, 243 (20%) were obese I, and 25 (2%) were obese II. Mean operating time (214 min vs. 244 min vs. 293 min) and mean estimated blood loss (23 mL vs. 42 mL vs. 88 mL) increased significantly with increasing BMI (P<0.0001, respectively). The rate of postoperative complications was significantly higher in obese II patients than in nonobese and obese I patients (24% vs. 9.2% vs. 9.1%, P=0.0428). Multivariate analysis showed that a BMI in the obese II range was an independent predictive factor for developing anastomotic leakage (odds ratio: 10.27, 95% confidence interval, 1.98-53.44). Conclusions: Laparoscopic surgery for colorectal cancer is technically more demanding in Japanese obese II patients than in nonobese or obese I patients. Special care is required because of the increased risk of developing postoperative complications.

Recent approaches to identifying biomarkers for high-risk stage II colon cancer

The use of adjuvant chemotherapy for stage II colon cancer remains controversial. The accurate assessment of the risk factors associated with recurrence in patients with stage II disease is the key to identifying the patients that are most likely to benefit from adjuvant chemotherapy. Recent guidelines advocate that adjuvant chemotherapy for high-risk stage II colon cancer should take into account factors such as the T stage, number of lymph nodes examined, tumor differentiation, and tumor perforation. In addition to these clinicopathological factors, there has also been intense interest in the identification of new prognostic or predictive biomarkers that can improve outcomes through better patient classification and selection for adjuvant chemotherapy. Recent advances in the field of molecular genetics have led to the identification of specific biomarkers involved in colorectal cancer progression, whereas gene expression microarray technology has led to the identification of molecular profiles able to predict recurrence or benefit from adjuvant chemotherapy. However, none of these has yet been validated in large prospective clinical trials. In this article, we review the current status of prognostic and predictive biomarkers for stage II colon cancer and provide an update on the most recent developments.

Prediction of response to preoperative chemoradiotherapy in rectal cancer by using reverse transcriptase polymerase chain reaction analysis of four genes.

BACKGROUND: Patients with rectal cancer exhibit a wide spectrum of responses to chemoradiotherapy. Several gene expression signatures have been reported to predict the response to chemoradiotherapy in rectal cancer, but the lack of practical assays has restricted the clinical use of this technique. OBJECTIVE: We aimed to identify a set of discriminating genes that can be used for the clinical prediction of response to chemoradiotherapy in rectal cancer. DESIGN AND SETTINGS: This study is a retrospective analysis of tumor samples in a single institute. PATIENTS: Sixty-two patients who underwent preoperative chemoradiotherapy were studied. MAIN OUTCOME MEASURES: Gene expression was initially studied in 46 training samples by microarray analysis, and the association between gene expression and response to chemoradiotherapy was evaluated. Quantitative reverse transcriptase polymerase chain reaction was performed to validate the microarray expression levels of the discriminating genes. We developed a gene expression model for the prediction of response to chemoradiotherapy based on the reverse transcriptase polymerase chain reaction findings and validated it by using 16 independent test samples. RESULTS: We identified 24 discriminating probes with expression levels that differed significantly between responders and nonresponders. Among 18 genes identified by Gene Symbol, real-time reverse transcriptase polymerase chain reaction showed significant differences in the expression of 16 genes between responders and nonresponders. We constructed a predictive model by using different sets of these 16 genes, and the highest accuracy rate (89.1%) was obtained by using LRRIQ3, FRMD3, SAMD5, and TMC7. The predictive accuracy rate of this 4-gene signature in the independent set of 16 patients was 81.3%. LIMITATIONS: Validation in a different and large cohort of patients is necessary. CONCLUSIONS: The 4-gene signature identified in this study is closely associated with response to chemoradiotherapy in rectal cancer.

Simultaneous Resection of Colorectal Cancer and Synchronous Liver Metastases: Initial Experience of Laparoscopy for Colorectal Cancer Resection

Background/Aims:Although laparoscopy is accepted for treatment of colorectal cancer, there is no established consensus for its use when resection of synchronous liver metastases is performed simultaneously. The purpose of this study was to evaluate whether laparoscopic colorectal resection with simultaneous resection of synchronous liver metastases was technically feasible and whether it may be a therapeutic option. Methods: Ten patients underwent laparoscopic resection for primary colorectal cancer, combined with synchronous resection of liver metastases. Results: The primary tumor location was in the sigmoid colon in 3 patients and the rectum in 7. All laparoscopic colorectal resections were successful, with no conversion to open surgery. Simultaneously, there were 7 conventional open and 3 laparoscopy-assisted liver resections. The median total operating time was 446 (range 300–745) min, including 222 (range 152–313) min for colorectal resection. The median total estimated blood loss was 175 (range 30–1,200) ml, including 10 (range 0–550) ml for colorectal resection. There was no major morbidity, except 1 patient who developed decubitus. Conclusion: This preliminary report suggests that laparoscopic resection for sigmoid colon and rectal cancer, combined with synchronous resection of liver metastases, is a safe and feasible procedure in selected patients.