Yojiro Hashiguchi

Tumor Budding at the Invasive Margin Can Predict Patients at High Risk of Recurrence After Curative Surgery for Stage II, T3 Colon Cancer

AbstractPURPOSE: The aim of this study was to identify indicators that can predict patients at high risk of tumor recurrence in Stage II, T3 colon cancer. METHODS: A total of 138 patients classified as Stage II, T3 underwent curative resection of colon cancer between 1981 and 1993. Clinical variables included age, gender, bowel obstruction, tumor location, and emergency presentation. For each colon tumor specimen, the following histopathological variables were assessed: maximum tumor diameter (<5 vs. ≥5 cm), depth, tumor grade (well and moderate vs. other), lymphatic and venous invasion (absent vs. present), perineural invasion, tumor necrosis, and tumor margin (expanding vs. infiltrating). We also categorized tumor budding, defined as a single cancer cell or small clusters of undifferentiated cancer cells in the invasive frontal lesion, into two categories: none or minimal (BD-1), and moderate or severe (BD-2). Univariate analysis for factors regarding recurrence and disease-specific survival were performed with the logistic regression model and the log-rank test. RESULTS: Among the factors analyzed, tumor budding was the only factor that was significantly associated with recurrence and survival. The numbers of patients with BD-1 and BD-2 tumors were 111 and 27, respectively. Forty-eight percent of BD-2 tumor patients developed recurrence, compared with 4.5 percent of BD-1 tumor patients (P < 0.0001). The cumulative disease-specific survival rates at five years for patients with BD-1 and BD-2 tumors were 98 and 74 percent, respectively (P < 0.0001). CONCLUSION: The presence of moderate or severe budding at the invasive margin in Stage II, T3 colon cancer indicated a high risk of tumor recurrence after curative surgery, providing useful information for the decision regarding postoperative adjuvant chemotherapy.

Prognostic Determinants of Patients With Lateral Nodal Involvement by Rectal Cancer

ObjectiveTo clarify the characteristics related to long-term survival in patients with lateral nodal involvement. Summary Background DataFew reports have addressed the prognostic determinants in patients with actual lateral nodal involvement, which are important in determining treatment. MethodsReview of a prospective colorectal database at a single institution for a 10-year period (1987–1996) identified 53 patients with lateral nodal involvement. ResultsAll nine patients who underwent resection of synchronous distant metastases developed recurrence and died within 3 years. Of the 44 patients without distant metastases, 25 (57%) developed locoregional recurrence, and the overall 5-year survival rate was 32%. Multivariate analysis showed that age, total number of involved nodes (mesorectal and lateral), and circumferential surgical margin involvement had independently predicted postoperative survival. Patients with three or fewer nodes involved accounted for one third of lateral-positive patients, with a 5-year survival rate of 75%, whereas the 18 patients with four or more involved nodes had a 5-year survival rate of 4%. All eight patients with circumferential margin involvement died of carcinoma, and seven developed locoregional recurrences. Involvement of other pelvic organs had no effect on prognosis, nor were adverse prognostic outcomes noted by the region of lateral involvement. ConclusionsFor patients with lateral involvement, the most important prognostic variables are distant metastases, the total number of nodes involved, circumferential margin involvement, and age. Selection of patients based on these variables may lead to the identification of a subgroup for whom lateral nodal dissection could be the first treatment choice.

New criteria for histologic grading of colorectal cancer.

Conventional tumor grading systems based on the degree of tumor differentiation may not always be optimal because of difficulty in objective assessment and insufficient prognostic value for decision making in colorectal cancer (CRC) treatment. This study aimed to determine the importance of assessing the number of poorly differentiated clusters as the primary criterion for histologic grading of CRC. Five hundred consecutive patients with curatively resected stage II and III CRCs (2000 to 2005) were pathologically reviewed. Cancer clusters of ≥5 cancer cells and lacking a gland-like structure were counted under a ×20 objective lens in a field containing the highest number of clusters. Tumors with <5, 5 to 9, and ≥10 clusters were classified as grade (G)1, G2, and G3, respectively (n=156, 198, and 146 tumors, respectively). Five-year disease-free survival rates were 96%, 85%, and 59% for G1, G2, and G3, respectively (P<0.0001). Poorly differentiated clusters affected survival outcome independent of T and N stages and could help in more effective stratification of patients by survival outcome compared with tumor staging (Akaike information criterion, 1086.7 vs. 1117.0; Harrell concordance index, 0.73 vs. 0.67). The poorly differentiated cluster-based grading system showed a higher weighted &kgr; coefficient for interobserver variability (5 observers) compared with conventional grading systems (mean, 0.66 vs. 0.52; range, 0.55 to 0.73 vs. 0.39 to 0.68). Our novel histologic grading system is expected to be less subjective and more informative for prognostic prediction compared with conventional tumor grading systems and TNM staging. It could be valuable in determining individualized postoperative CRC treatment.

Preoperative Parameters Expanding the Indication of Sphincter Preserving Surgery in Patients With Advanced Low Rectal Cancer

Objective:To clarify the preoperative parameters of the required distal margin that can be applied to the criteria of sphincter-preserving surgery in rectal cancer. Summary Background Data:Although aggressive sphincter-preserving surgery, including intersphincteric resection, is beginning to be applied to low rectal tumors, unexpected distal cancer spread might undermine local control in patients undergoing such a procedure. The ‘two-centimeter rule’ of distal clearance is predominant at present, whereas preoperative criteria to determine the individual required distal margin have not yet been established. Methods:First, by reviewing 556 rectal cancers, promising risk parameters of intramural distal spread (IM) were selected and, subsequently, such parameters were examined in regard to whether they could be evaluated preoperatively. Furthermore, 80 patients with lower rectal cancers located above the anal canal who were undergoing abdominoperineal resection were reviewed as to whether IM risk factors could be used as criteria to identify the low rectal cancer with or without anal canal involvement. Results:IM was observed in 10.6% (IM ≥ 10 mm: 2.3%) of the patients examined, and the incidence was higher in tumors with certain unfavorable histologic characteristics, including tumor “budding,” in their submucosal region at the distal edge (24.4%) than in those with no such histology (5.3%). Regarding such unfavorable histology as IM risk factor, together with 3/4 or more annularity and type 3 gross appearance, IM rates were 3.3% (IM ≥ 10 mm: 0.5%) in the no-risk group, 9.1% (IM ≥ 10 mm: 1.7%) in the one-risk group, and 29.1% (IM ≥ 10mm: 7.8%) in the multiple-risks group. These results were reproduced well even if such risk factors were evaluated endoscopically or histologically on preoperative biopsy specimens. Furthermore, no anal canal involvement was observed in 32 tumors without IM risk; however, microscopic cancer spread down to the anal canal, including that into outside of the internal sphincter muscle, was observed in 9.1% of tumors with one IM risk and in 26.7% of multiple-risk tumors. Conclusions:The preoperative evaluation of particular parameters related to IM enabled the accurate selection of rectal cancer to which the one-centimeter rule of distal clearance can be applied. This could allow us to expand the indication of sphincter preservation for very low rectal cancer patients.

Potential Prognostic Benefit of Lateral Pelvic Node Dissection for Rectal Cancer Located Below the Peritoneal Reflection

Objective:To identify the parameters related to the effective selection of patients who could receive prognostic benefit from lateral pelvic node dissection. Background:Accurate preoperative diagnosis of lateral nodal involvement (LNI) remains difficult, and the indications for lateral lymph node dissection have been controversial. Patients and Methods:A total of 244 consecutive patients who underwent potentially curative surgery with lateral dissection for advanced lower rectal cancer (1985–2000) were reviewed. Patients were stratified into groups based on various parameters, and the therapeutic value index for survival benefit was compared among groups. The therapeutic index of lateral dissection was calculated by multiplying the frequency of metastasis to the lateral area and the cancer-related 5-year survival rate of patients with metastasis to the lateral area, irrespective of metastasis to other areas (mesorectal, superior rectal artery [SRA], and inferior mesenteric artery [IMA] areas). Results:LNI was observed in 41 patients (17%); and 88% of them had nodal involvement in the region along the internal iliac/pudendal artery or in the obturator region (“vulnerable field”). The cancer-related 5-year survival rate among the patients with LNI was 42%; the therapeutic index for lateral dissection was calculated as 7.0 patients, which was much higher than that of lymphadenectomy of the SRA area (1.6 patients) and the IMA area (0.4 patients), and almost comparable to that of lymphadenectomy of the upward mesorectal area (6.9 patients). Although it was possible to select groups at high and low risk for LNI based on several parameters related to tumor aggressiveness, such as tumor differentiation in biopsy specimens, the therapeutic value index was not significantly different between these groups. Unlike these parameters, the diameter of the largest lymph node in the “vulnerable field,” which was positively correlated with the rate of LNI but irrelevant to the prognosis, was able to successfully stratify patients by therapeutic index. Conclusions:Advanced lower rectal cancer patients having LNI in the lateral pelvic area are likely to receive prognostic benefit from lymphadenectomy. The most efficient means of determining the effectiveness of lateral dissection preoperatively is to estimate the nodal diameter in the “vulnerable” lateral regions by diagnostic imaging.

Predictors of extrahepatic recurrence after resection of colorectal liver metastases.

It is important to identify patients at high risk of extrahepatic recurrence after surgery for liver metastases, in order to maximize the survival benefit obtained by prophylactic regional chemotherapy.

Intraoperative irradiation after surgery for locally recurrent rectal cancer

PURPOSE: This study retrospectively evaluated the effects of intraoperative electron beam irradiation on patients with locally recurrent (pelvic) rectal cancer. METHODS: From November 1, 1975, to December 31, 1997, 51 patients underwent surgery for locally recurrent rectal or rectosigmoid cancer, and 27 patients received intraoperative electron beam irradiation. The intraoperative electron beam irradiation dose was 15 to 30 Gy. Kaplan-Meier survival estimates at three and five years were analyzed for the 47 patients who recovered postoperatively. RESULTS: Statistically significant factors related to survival included intraoperative electron beam irradiationvs. no intraoperative electron beam irradiation (P=0.0007), amount of residual tumor (slightvs. gross;P=0.0022), and symptom status (P=0.0024). Factors not associated with survival included distant metastases at reoperation, type of surgery for the recurrent tumor, external beam irradiation, pathologic grade, age, and gender. Surgical resection without intraoperative electron beam irradiation resulted in three-year and five-year survival rates of 5 and 0 percent, respectively. For patients who received intraoperative electron beam irradiation, the three-year survival rate was 43 percent and five-year survival rate was 21 percent. Intraoperative electron beam irradiation was a statistically significant factor related to survival in patients with and without distant metastasis (P=0.04 andP=0.0035, respectively), with slight residual tumor (P=0.0003), or with palliative surgery (P=0.0276). CONCLUSION: The trends seen in resection with intraoperative electron beam irradiation are encouraging with regard to improvements in survival as compared with studies not using intraoperative electron beam irradiation treatment.

Down-regulation of miR-125a-3p in human gastric cancer and its clinicopathological significance

Recent reports have demonstrated that another strand of mature microRNA (miRNA), called microRNA* or 3p (5p) strand, which is generated from the same precursor miRNA (Pre-miR), has a crucial role in cellular function. We previously reported the tumor suppressive effect of miR-125a-5p in gastric cancer. The current study was designed to examine the function and clinical significance of miR-125a-3p, a partner strand of miR-125a-5p, in human gastric cancer. Quantitative RT-PCR was used to evaluate miR-125a-3p expression in 70 gastric cancer cases to determine the clinicopathologic significance of miR-125a-3p expression. In addition, the effect of miR-125a-3p on the proliferation of gastric cancer cells was investigated. Low expression levels of miR-125a-3p were associated with indicators of enhanced malignant potential such as tumor size (p=0.0002), tumor invasion (p=0.0149), lymph node metastasis (p=0.018), liver metastasis (p=0.016), peritoneal dissemination (p=0.03), advanced clinical stage (p=0.0037) and poor prognosis (p=0.0083). Multivariate analysis indicated that low miR-125a-3p expression was an independent prognostic factor for survival, while in vitro assays demonstrated that miR‑125a-3p suppressed the proliferation of gastric cancer cells. MiR-125a-3p is a potent prognostic marker in gastric cancer. The clinical significance and tumor suppressive effect of miR‑125a-3p, as well as previously reported miR-125a-5p, suggest that the functional role of another strand of the mature form miRNA cannot be ignored, at least in miR-125a biogenesis.

Alanyl-glutamine-supplemented total parenteral nutrition improves survival and protein metabolism in rat protracted bacterial peritonitis model

BACKGROUND The effects of glutamine-enriched total parenteral nutrition (TPN) solution on survival, and protein turnover in the whole body and in individual organs were investigated in a rat protracted peritonitis model. METHODS Twenty-three rats underwent venous catheter insertion. Osmotic pumps were implanted in the peritoneal cavity to allow continuous delivery of Escherichia coli (4 x 10(8) CFU/d). The conventional TPN group received a conventional amino acid solution. The Ala-Gln TPN group received an alanyl-glutamine-enriched TPN solution. The two TPN solutions were isocaloric and isonitrogenous. RESULTS Over the 5 days of TPN treatment, the survival rate of the Ala-Gln group was significantly higher than that of the conventional group. The Ala-Gln group tended to have increased whole-body protein turnover compared with the conventional group. Fractional protein synthetic rates (FSR) in the liver and gastrocnemius muscle of the Ala-Gln group were significantly higher than those of the conventional group. The serum glutamine concentration correlated positively with the FSR of both liver and muscle. The Ala-Gln group showed significantly greater mucosal height and mitoses per crypt, in the small intestine, than did the conventional group. CONCLUSIONS Our results suggested that, in comparison with standard glutamine-free TPN, Ala-Gln-supplemented TPN increases protein synthesis in the liver and skeletal muscle, protects the morphology of the intestinal mucosa, and improves survival in protracted bacterial peritonitis. Ala-Gln supplementation may be useful in septic patients.

Extent of Mesorectal Tumor Invasion as a Prognostic Factor After Curative Surgery for T3 Rectal Cancer Patients

Objective:To determine the significance of the extent of mesorectal tumor invasion as a prognostic factor for T3 rectal cancer patients. Summary Background Data:There is controversy as to which primary lesion characteristics, other than regional lymph node involvement, in T3 rectal cancer are reliable prognostic factors. Patients and Methods:The extent of mesorectal tumor invasion was evaluated using 2 data sets comprising 196 and 247 patients undergoing curative surgery at separate institutes. When the outer aspect of the muscular layer was not identifiable, an estimate was obtained by drawing a straight line between the 2 break points of the muscular layer. Results:We selected 6 mm as the optimal value for subclassification of T3 rectal patients into 2 groups, based on the extent of mesorectal invasion, using the first data set. The overall 5-year survival rate was significantly higher in patients with <6 mm than in those with ≥6 mm of mesorectal invasion (72% versus 50%; P< 0.01). Similarly, in the second data set, the overall 5-year survival rates of patients with mesorectal invasion <6 mm and ≥6 mm were 59% and 37%, respectively (P < 0.01). In both data sets, multivariate analyses verified the extent of mesorectal invasion to be an independent prognostic factor, together with nodal involvement. Regarding positive nodal involvement and mesorectal invasion ≥6 mm as risk factors, the overall 5-year survival rates with none, one, and both of these factors were 84%, 61%, and 38%, respectively, in the first data set (P < 0.01). Prognostic results were similar for the second data set. Conclusion:Extent of mesorectal invasion, based on a 6-mm cutoff value, is useful for subclassification of T3 rectal cancer patients.