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.

Extramural cancer deposits without nodal structure in colorectal cancer: optimal categorization for prognostic staging.

To establish an optimal categorization of cancer deposits without lymph node structure (extranodal cancer deposits [EX]) in a prognostic staging system, we analyzed 1,027 cases in which patients underwent potentially curative surgery for advanced colorectal adenocarcinoma. EX was classified as vascular invasion-type (VAS) or non-VAS.A total of 512 foci of EX were identified in 205 patients (20.0%), with VAS and non-VAS found in 68 and 182 patients, respectively. The hazard ratio for patients with nodal involvement was 3.6 and for patients with VAS and non-VAS, 2.5 and 4.7, respectively. Based on multivariate analysis of these 3 parameters, only nodal involvement and non-VAS were significant prognosticators. By using the Akaike information criterion, N staging was capable of predicting survival outcome with the highest accuracy when both nodal involvement and non-VAS were treated together as an N factor and VAS was treated as a T factor ("new categorization"). The clinical significance of the TNM grading system for colorectal cancer would be enhanced if we treat EX as a new categorization.

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 > or =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 > or =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 > or =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.

Regulation of fibroblast growth factor-23 signaling by klotho.

The aging suppressor gene Klotho encodes a single-pass transmembrane protein. Klotho-deficient mice exhibit a variety of aging-like phenotypes, many of which are similar to those observed in fibroblast growth factor-23 (FGF23)-deficient mice. To test the possibility that Klotho and FGF23 may function in a common signal transduction pathway(s), we investigated whether Klotho is involved in FGF signaling. Here we show that Klotho protein directly binds to multiple FGF receptors (FGFRs). The Klotho-FGFR complex binds to FGF23 with higher affinity than FGFR or Klotho alone. In addition, Klotho significantly enhanced the ability of FGF23 to induce phosphorylation of FGF receptor substrate and ERK in various types of cells. Thus, Klotho functions as a cofactor essential for activation of FGF signaling by FGF23.

Regulation of oxidative stress by the anti-aging hormone klotho.

klotho is an aging suppressor gene and extends life span when overexpressed in mice. Klotho protein was recently demonstrated to function as a hormone that inhibits insulin/insulin-like growth factor-1 (IGF-1) signaling. Here we show that Klotho protein increases resistance to oxidative stress at the cellular and organismal level in mammals. Klotho protein activates the FoxO forkhead transcription factors that are negatively regulated by insulin/IGF-1 signaling, thereby inducing expression of manganese superoxide dismutase. This in turn facilitates removal of reactive oxygen species and confers oxidative stress resistance. Thus, Klotho-induced inhibition of insulin/IGF-1 signaling is associated with increased resistance to oxidative stress, which potentially contributes to the anti-aging properties of klotho.