Hirotoshi Kobayashi

Understanding Optimal Colonic Cancer Surgery: Comparison of Japanese D3 Resection and European Complete Mesocolic Excision With Central Vascular Ligation

PURPOSE Over recent years, patient outcomes after colon cancer resection have not improved to the same degree as for rectal cancer. Japanese D3 resection and European complete mesocolic excision (CME) with central vascular ligation (CVL) are both based on sound oncologic principles. Expert surgeons using both techniques report impressive outcomes as compared with standard surgery. We aimed to independently compare the physical appearances and quality of specimens resected using both techniques in major institutions in Japan and Germany. METHODS A series of resections for primary colon cancer from one European and two Japanese centers were independently assessed in terms of the plane of surgery, physical characteristics, and lymph node yields. RESULTS Mesocolic plane resection rates from both series were high; however, Japanese D3 specimens were significantly shorter (162 v 324 mm, P < .001), resulting in a smaller amount of mesentery (8,309 v 17,957 mm(2), P < .001) and nodal yield (median, 18 v 32, P < .001). The distance from the high vascular tie to the bowel wall (100 v 99 mm, P = .605) was equivalent. CONCLUSION Both techniques showed high mesocolic plane resection rates and long distances between the high tie and the bowel wall. The extended longitudinal resection after CME with CVL increased the nodal yield but did not increase the number of tumor involved nodes. Both series were oncologically superior to recently reported series from other countries and confirm the wide variation in colonic cancer surgery and the need for further standardization and optimization following the approach undertaken in improving rectal cancer outcomes.

Outcomes of surgery alone for lower rectal cancer with and without pelvic sidewall dissection.

PURPOSE: The goal of this retrospective multicenter study was to investigate the efficacy of pelvic sidewall dissection for lower rectal cancer. METHODS: Data from 1,272 consecutive patients who underwent total mesorectal excision for lower rectal cancer in 12 institutions from 1991 through 1998 were reviewed. The rates of local recurrence and survival in patients with pelvic sidewall dissection were compared with those without pelvic sidewall dissection. Logistic regression analysis was used to determine independent risk factors for lymph node metastasis and local recurrence, and the Cox proportional hazards model was used to determine independent prognostic factors. RESULTS: Of the 1,272 patients, 784 underwent pelvic sidewall dissection. Among them, 117 patients (14.9 percent) had lateral pelvic lymph node metastasis. Risk factors for lateral pelvic lymph node metastasis included female gender, tumor not well-differentiated adenocarcinoma, and perirectal lymph node metastasis. Lateral pelvic and perirectal lymph node metastases were independent risk factors for local recurrence. The Cox proportional hazard model showed age, grade of histology, invasion depth of the tumor, perirectal lymph node metastasis, and lateral pelvic lymph node metastasis to be independent prognostic factors. No significant differences between patients with and those without pelvic sidewall dissection were seen regarding rates of local recurrence (10.5 percent vs. 7.4 percent) or five-year overall survival (75.8 percent vs. 79.5 percent). Although the proportion of patients with advanced stages of disease was greater in patients who had pelvic sidewall dissection, no differences between the two groups were seen in local recurrence even when tumor category was taken into account. However, lack of pelvic sidewall dissection was a predictor of poor prognosis. CONCLUSIONS: Although pelvic sidewall dissection does not appear to confer overall benefits regarding local recurrence or survival, the effectiveness of pelvic sidewall dissection in specific patient groups remains uncertain. A randomized controlled study is necessary to clarify this issue.

The rationale behind complete mesocolic excision (CME) and a central vascular ligation for colon cancer in open and laparoscopic surgery: Proceedings of a consensus conference

BackgroundIt has been evident for a while that the result after resection for colon cancer may not have been optimal. Several years ago, this was showed by some leading surgeons in the USA but a concept of improving results was not consistently pursued. Later, surgeons in Europe and Japan have increasingly adopted the more radical principle of complete mesocolic excision (CME) as the optimal approach for colon cancer. The concept of CME is a similar philosophy to that of total mesorectal excision for rectal cancer and precise terminology and optimal surgery are key factors.MethodThere are three essential components to CME. The main component involves a dissection between the mesenteric plane and the parietal fascia and removal of the mesentery within a complete envelope of mesenteric fascia and visceral peritoneum that contains all lymph nodes draining the tumour area (Hohenberger et al., Colorectal Disease 11:354–365, 2009; West et al., J Clin Oncol 28:272–278, 2009). The second component is a central vascular tie to completely remove all lymph nodes in the central (vertical) direction. The third component is resection of an adequate length of bowel to remove involved pericolic lymph nodes in the longitudinal direction.ResultThe oncological rationale for CME and various technical aspects of the surgical management will be explored.ConclusionThe consensus conference agreed that there are sound oncological hypotheses for a more radical approach than has been common up to now. However, this may not necessarily apply in early stages of the tumour stage. Laparoscopic resection appears to be equally well suited for resection as open surgery.

Effect of classification based on combination of mutation and methylation in colorectal cancer prognosis

Colorectal cancer (CRC) is caused by an accumulation of genetic alterations and epigenetic alterations. The molecular classification of CRCs based on genetic alterations and epigenetic alterations is evolving. Here, we examined mutations and methylation status in CRCs to determine if the combination of genetic and epigenetic alterations predicts prognosis. We examined 134 sporadic CRCs. We used the direct sequencing method to identify mutations in BRAF and AKT1, which are downstream of KRAS and PIK3CA, respectively, in the EGFR pathway. We used the Methylight method to determine the methylation status of hMLH1, p16, MINT1, MINT2 and MINT31. Both BRAF and AKT1 mutations were found in only one case (0.75%). Aberrant methylation of hMLH1, p16, MINT1, MINT2 and MINT31 was detected in 22.4, 35.1, 32.8, 59.7 and 41.0% of cases, respectively. The clinicopathological factors were not significantly correlated to mutation or methylation. Among the patients who had no mutation in the EGFR pathway, the overall survival was significantly shorter in the patients with methylation compared to the patients with no methylation in hMLH1 and p16 (p=0.0318). Methylation could play a key role in the prognosis of patients without mutations in the EGFR pathway. The combination of genetic and epigenetic alterations may be a good marker for the prognosis of CRC patients.

Lymph node ratio is a powerful prognostic index in patients with stage III distal rectal cancer: a Japanese multicenter study

PurposeThe present study aims to define the prognostic impact of the lymph node ratio (LNR) in patients with stage III distal rectal cancer.MethodsWe analyzed data from 501 patients who underwent curative resection (total mesorectal excision, TME) for stage III distal rectal cancer at 12 institutions between 1991 and 1998. Patients were divided into four groups according to quartiles based on LNR.ResultsAmong the 501 patients, 381 underwent TME with pelvic sidewall dissection (PSD). The median numbers of lymph nodes retrieved with and without PSD were 45 and 17, respectively (P < 0.0001). Forty-nine patients with lymph node retrieved less than 12 were excluded from further analyses. Among various clinicopathological parameters, univariate analysis identified age (P = 0.0059), histological grade (P < 0.0001), depth of tumor invasion (P = 0.0003), and number of positive nodes (P < 0.0001) and LNR (P < 0.0001) as prognostic factors. The Cox proportional hazards model revealed that age (P = 0.014), histological grade (P < 0.0001), depth of tumor invasion (P = 0.0002), and LNR (group 3, P = 0.0012; group 4, P < 0.0001) were independent prognostic factors. When the American Joint Committee on Cancer (AJCC) seventh staging system was added as a covariate, both AJCC stage (P < 0.0001) and LNR (P < 0.0001) were independent prognostic factors.ConclusionsAdding the LNR concept to the AJCC cancer staging system will improve accuracy in evaluating the nodal status of distal rectal cancer.

Validation and Clinical Use of the Japanese Classification of Colorectal Carcinomatosis: Benefit of Surgical Cytoreduction Even without Hyperthermic Intraperitoneal Chemotherapy

Background: This study aimed to validate an easy to use practical classification of peritoneal metastasis arising from colorectal cancer. Patients and Methods: Data from 2,134 consecutive patients who underwent resection for colorectal cancer at a single institution were reviewed. Peritoneal metastasis was classified depending on extent into three groups (P1–P3). The macroscopic radical resection rates and survival of patients with colorectal cancer complicated with peritoneal metastasis were analyzed. Results: Of the 2,134 patients, 116 (5.4%) had peritoneal metastasis. Among them, 20 (17.2%) underwent macroscopic radical resection. Tumor location on the right side was associated with more extensive peritoneal metastasis (p = 0.010). Male gender (p = 0.0027), liver metastasis (p = 0.0021), and P3 peritoneal metastasis were independent risk factors for noncurative resection. The Cox proportional hazards model showed that gender (p = 0.031), operation period (p = 0.031), and macroscopic radical resection for colorectal cancer and peritoneal metastasis (p = 0.031) were independent prognostic factors. Conclusions: Being female with left colon cancer complicated with P1 or P2 peritoneal metastasis is a good indicator for macroscopic radical resection if liver metastasis is absent. The present classification helped to determine surgical indication for patients with colorectal cancer complicated with synchronous peritoneal metastasis in routine clinical practice.

Clinical Significance of Lymph Node Ratio and Location of Nodal Involvement in Patients with Right Colon Cancer

Background/Aims: Increasing negative lymph node count has been reported to be associated with better outcomes in patients with colon cancer. The present study aimed to clarify the clinical significance of the lymph node ratio (LNR) and location of lymph node metastasis (LNM) in patients with stage III right colon cancer. Methods: We enrolled 820 patients who had undergone curative resection due to colon cancer at a single institution between 1991 and 2005. Among them, 197 underwent curative resection for T2–T4 right colon cancer. We evaluated the oncological outcomes according to LNR (quartiles) and distribution of LNM (n1 = LNM adjacent to the colon or along the vascular arcades of the marginal arteries; n2 = LNM along the major vessels; n3 = LNM near the roots of the major vessels). Results: The rates of LNM in T2, T3 and T4 right colon cancer were 11.1, 38.6 and 58.0%, respectively (p < 0.0001). Recurrence rates were 27.3, 37.5 and 57.1% in patients with n1, n2 and n3 LNM, respectively (p < 0.0001). LNR (p < 0.0001) and distribution of LNM (p = 0.046) were independent risk factors for recurrence in patients with stage III right colon cancer. Conclusions: Some patients with extensive LNM benefited from lymph node dissection with high ligation. Those with T3–T4 right colon cancer are suitable candidates for lymph node dissection with high ligation. Adding the concept of LNR and location of LNM to conventional TNM staging could improve the accuracy of evaluating nodal status.

Is Total Mesorectal Excision Always Necessary for T1–T2 Lower Rectal Cancer?

BackgroundThe goal of this multicenter study was to clarify the determinants of local excision for patients with T1–T2 lower rectal cancer.MethodsData from 567 consecutive patients who underwent radical resection for T1–T2 lower rectal cancer at 12 institutions between 1991 and 1998 were reviewed. Rates of lymph node metastasis were investigated using a tree analysis, which was hierarchized using independent risk factors for nodal involvement.ResultsThe independent risk factors for lymph node metastasis were female gender, depth of tumor invasion, histology other than well-differentiated adenocarcinoma, and lymphatic invasion. According to the first three parameters that can be obtained preoperatively, only 0.99% of the patients without risk factors had lymph node metastasis. On the other hand, even if the lower rectal cancer was at stage T1, women with histological types other than well-differentiated adenocarcinoma had an approximately 30% probability of having lymph node metastasis. Lymphatic invasion was most useful to predict nodal involvement among patients with T2 lower rectal cancer. The rates of lymph node metastasis in T2 patients with and without lymphatic invasion were 32.9% and 9.1%, respectively.ConclusionsGender is one of the most important predictors for lymph node metastasis in patients with early distal rectal cancer. Three parameters, including depth of tumor invasion, histology, and gender, are useful determinants for local excision. Additional studies are required to establish the minimum optimal treatment for T2 lower rectal cancer.

Clinical significance of UNC5B expression in colorectal cancer

The purpose of this study was to find a methylation-related gene that could become a biomarker or therapeutic target in colorectal carcinoma (CRC). We screened candidate genes suspected to be silenced by DNA methylation using cDNA microarray analysis. To investigate the clinical significance of one candidate gene (UNC5B), we analyzed the correlation between mRNA expression and clinicopathological features using clinical tissue samples. Moreover, methylation specific PCR analysis was performed to reveal whether the promoter region was methylated in CRC cell lines. We found 75 candidate genes that were potentially suppressed by DNA methylation in CRC. We focused on UNC5B, a possible tumor suppressor gene and regulator of apoptosis known to be inactivated in CRC. The mRNA expression analysis using tissue samples revealed that UNC5B mRNA was down-expressed in about 20% of CRC patients, and the patients with low-UNC5B-expression tumors showed a significantly higher recurrence rate after curative surgery. According to the univariate and multivariate analysis, low UNC5B expression was an independent risk factor for postoperative recurrence in stage I, II and III CRC patients. Furthermore, patients with low expression of UNC5B in tumors had significantly poorer prognosis than those with high expression of UNC5B. Although UNC5B mRNA expression was restored by the demethylation treatment in CRC cell lines, the promoter region of UNC5B was not methylated. UNC5B is a potential biomarker for the selection of patients with high risk of postoperative recurrence and worse prognosis in CRC.

Timing of Relapse and Outcome after Curative Resection for Colorectal Cancer: A Japanese Multicenter Study

Background: The aim of this multicenter study was to clarify the influence of timing of relapse after curative resection for colorectal cancer on prognosis. Methods: We enrolled 5,230 consecutive patients who underwent curative resection for colorectal cancer at 14 hospitals from 1991 to 1996. All patients were intensively followed up. Time to relapse (TR) was classified into three groups as follows: group A, TR ≤1 year; group B, TR >1 year and ≤3 years, and group C, TR >3 years. The prognoses after relapse were compared among the three groups. Results: Of the 5,230 patients, 906 experienced relapse (17.3%). The curative resection rates for recurrent tumors were 35.2% in group A, 46.6% in group B, and 45.1% in group C (p = 0.0045). There were significant differences in the prognoses after relapse among the three TR groups in patients with relapse to the liver (p = 0.0175) and in those with local relapses (p = 0.0021), but not in those with pulmonary or anastomotic recurrence. There were no differences in prognoses after relapse in any recurrence site among the three groups in patients who underwent curative resection for relapse. Conclusion: If patients can undergo curative resection for relapse, they receive a survival benefit regardless of the timing of relapse.