Down-regulation of µ-protocadherin expression is a common event in colorectal carcinogenesis.

We have previously reported that treatment of colorectal cancer cells with mesalazine results in the up-regulated expression of a novel member of the cadherin protein superfamily, named µ-protocadherin, which is able to sequester ß-catenin on plasmatic membrane of treated cells inhibiting its proliferation signalling pathway. This finding suggests that µ-protocadherin could exert an oncosuppressive effect on colorectal epithelium. The purpose of our study was to assess whether µ-protocadherin expression is down-regulated during colorectal carcinogenesis. This issue was addressed by analyzing the messenger RNA and protein expression of µ-protocadherin in normal and tumor colorectal cell samples using a combination of quantitative real-time polymerase chain reaction, microarray analysis, and immunohistochemical examination. To better contextualize the role played by µ-protocadherin in the pathogenesis of colorectal cancer, this last assay was also extended to ß-catenin, E-cadherin, and Ki-67 proteins. The results obtained evidenced that (1) levels of µ-protocadherin transcript were down-regulated in all the analyzed colorectal cancer samples as compared with normal mucosa; (2) expression of µ-protocadherin protein was completely lost in most analyzed colorectal cancer samples (71%); (3) µ-protocadherin retains ß-catenin on the plasmatic membrane of normal colon enterocytes, which implies that ß-catenin is released from this site and translocated to the nucleus in colorectal cancer cells. Our data consequently suggest that down-regulation of µ-protocadherin expression is a common event in colorectal carcinogenesis and might therefore play an important role in this pathologic process.

Water-soluble contrast medium (gastrografin) value in adhesive small intestine obstruction (ASIO): a prospective, randomized, controlled, clinical trial.

BACKGROUND: Patients with adhesive small intestine obstruction (ASIO) are difficult to evaluate and to manage and their treatment is still controversial. The diagnostic and therapeutic role of water-soluble contrast medium (Gastrografin) in ASIO is still debated. This study was designed to determine the therapeutic role of Gastrografin in patients with ASIO. METHODS: The study was a multicenter, prospective, randomized, controlled investigation. The primary end points were the evaluation of the operative rate reduction and shortening the hospital stay after the use of Gastrografin. A total of 76 patients were randomized into two groups: the control group received traditional treatment (TT), whereas the study group (GG) received in addition a Gastrografin meal and follow-through study immediately. Patients with Gastrografin in the colon within 36 hours were considered to be partially obstructed and submitted to nonoperative management. If after 36 hours, the Gastrografin had not entered the colon, the subjects were submitted to laparotomy. RESULTS: No significant differences were found in age, sex, intravenous administration of prokinetics, incidence and characteristics of the previous procedures in surgical history of the patients, previous episodes of ASIO and surgery for adhesiolysis, or duration of symptoms before admission. In the GG group obstruction resolved subsequently in 31 of 38 cases (81.5%) after a mean time of 6.4 hours. The remaining seven patients were submitted to surgery, and one of them needed bowel resection for strangulation. In the control group, 21 patients were not submitted to surgery (55%), whereas 17 showed persistent untreatable obstruction and required laparotomy: 2 of them underwent bowel resection for strangulation. The difference in the operative rate between the two treatment groups reached statistical significance (p = 0.013). The time from the hospital admission for obstruction to resolution of symptoms was significantly lower in the GG group (6.4 vs. 43 hours; p < 0.01). The length of hospital stay revealed a significant reduction in the GG group (4.7 vs. 7.8 days; p < 0.05). This reduction was more evident in the subset of patients who did not require surgery (3 vs. 5.1 days; p < 0.01). No GG-related complications or significant differences in major complications and the relapse rate were found (relapse rate, 34.2% after a mean time to relapse of 6.3 months in the GG group vs. 42.1% after 7.6 months in the TT; p = not significant). CONCLUSIONS: Data showed that the use of Gastrografin in ASIO is safe and reduces the operative rate and the time to resolution of obstruction, as well as the hospital stay.

Preoperative therapy for lower rectal cancer and modifications in distance from anal sphincter.

PURPOSE: To assess the frequency and magnitude of changes in lower rectal cancer resulting from preoperative therapy and its impact on sphincter-saving surgery. Preoperative therapy can increase the rate of preserving surgery by shrinking the tumor and enhancing its distance from the anal sphincter. However, reliable data concerning these modifications are not yet available in published reports. METHODS AND MATERIALS: A total of 98 cases of locally advanced cancer of the lower rectum (90 Stage uT3-T4N0-N+ and 8 uT2N+M0) that had undergone preoperative therapy were studied by endorectal ultrasonography. The maximal size of the tumor and its distance from the anal sphincter were measured in millimeters before and after preoperative therapy. Surgery was performed 6-8 weeks after therapy, and the histopathologic margins were compared with the endorectal ultrasound data. RESULTS: Of the 90 cases, 82.5% showed tumor downsizing, varying from one-third to two-thirds or more of the original tumor mass. The distance between the tumor and the anal sphincter increased in 60.2% of cases. The median increase was 0.73 cm (range, 0.2-2.5). Downsizing was not always associated with an increase in distance. Preserving surgery was performed in 60.6% of cases. It was possible in nearly 30% of patients in whom the cancer had reached the anal sphincter before the preoperative therapy. The distal margin was tumor free in these cases. CONCLUSION: The results of our study have shown that in very low rectal cancer, preoperative therapy causes tumor downsizing in >80% of cases and in more than one-half enhances the distance between the tumor and anal sphincter. These modifications affect the primary surgical options, facilitating or making sphincter-saving surgery possible.

Prognostic value of Dworak grade of regression (GR) in patients with rectal carcinoma treated with preoperative radiochemotherapy.

BACKGROUND AND AIM: Preoperative radiochemotherapy improves local control in locally advanced rectal cancer; however, its role in prolonging survival is still controversial. In order to better define the subset in patients who might benefit from this multimodal treatment, we have evaluated the correlation between grade of regression (GR) to preoperative treatment and disease-free survival (DFS). METHODS: We reviewed retrospectively the surgical specimens of 106 patients with locally advanced T3/T4 N0/ M0 rectal cancer. All patients were treated preoperatively with radiotherapy and 5-fluorouracil-based regimen chemotherapy. We evaluated ypTNM stage, and tumor regression was graded using the Dworak system that varies from GR 0 (absence of regression) to GR 4 (complete regression). RESULTS: GR was as follows: GR 4, 16 patients (15%); GR 3, 25 patients (23.6%), GR 2, 30 patients (28.4%), GR 1, 32 patients (30.2%) and GR 0, 3 patients (2.8%). A significant correlation was found between GR and DFS. Three-year DFS was 100, 85, 82, 66 and 33% in GR 4, 3, 2, 1 and 0, respectively (p=0.01). DFS was significantly lower in patients with advanced stages at diagnosis and in patients without down-staging. Moreover, in postoperative stage II and III cases, GR 3 correlated with a better DFS than GR 2-0 (p=0.2 and p=0.4, respectively). CONCLUSIONS: The GR was a significant prognostic factor in locally advanced rectal carcinoma treated with preoperative chemoradiotherapy. The pathological stage and down-staging also have prognostic value. The use of a standardized system to evaluate GR in rectal cancer can allow for comparisons between different institutions and can identify patients at worse prognosis to be treated with adjuvant therapy.

Incidence and clinical impact of sterilized disease and minimal residual disease after preoperative radiochemotherapy for rectal cancer.

PURPOSE: In advanced rectal cancer, chemoradiation can induce downstaging until complete disappearance of the tumor or its persistence in minimal form. The complete sterilized and the minimal residual disease often are considered similar. We evaluated the specific incidence of these two conditions and analyzed their impact in terms of local recurrence, distant metastasis, and survival. METHODS: We studied 139 uT3/T4 N0/N+ rectal cancers, treated with preoperative chemoradiation and curative surgery after six to eight weeks. We evaluated ypTNM stage and tumoral regression, according to the five degrees proposed by Dworak, with special attention to 4 and 3 (sterilized and minimal residual disease). RESULTS: Tumor downstaging occurred in 65 patients (46.7 percent), including 25 sterilized lesions (17.9 percent) and 24 minimal residual disease (17.2 percent). In median follow-up of 30 months, none of the patients with sterilized disease developed local or distant recurrence. Among patients with minimal residual disease, none developed local recurrence, whereas two (8.3 percent) developed distant metastasis, and one died from disease. In patients with gross residual disease (Grade 2, 1, 0) the percentage of local recurrence was 8.8 percent, distant recurrence 26.6 percent, and 13.3 percent died from disease. The difference between three groups is statistically significant as regards local and distant recurrence. CONCLUSIONS: After preoperative therapy, the sterilized disease shows an excellent prognosis. The minimal residual disease has an important numeric incidence. Its outcome is different, with a not-negligible risk of distant recurrence. The minimal residual disease has a much better prognosis in comparison with the gross residual disease.

Preoperative concomitant radiotherapy and chemotherapy in ultrasound-staged T3 and T4 rectal cancer.

BACKGROUND: To analyze early results of a single institution's experience using neo-adjuvant chemoradiotherapy in locally advanced, ultrasound-staged rectal cancer. PATIENTS AND METHODS: Since 1998, 67 consecutive patients (36 males and 31 females; mean age, 59.5) have received preoperative combined treatment for T3 or T4 rectal cancer. All patients were staged by endorectal ultrasound and computed tomography, and all had a pathology-demonstrated invasive adenocarcinoma of the rectum. Patients were treated preoperatively with concomitant radiochemotherapy: pelvic irradiation (50 Gy in 25 fractions) and protracted-venous-infusion 5-fluorouracil (225 mg/m2/d, 7 days per week). Patients were restaged within 4 weeks, then submitted to surgery within 6-7 weeks after the end of therapy. Adjuvant postoperative chemotherapy with 5-fluorouracil plus folinic acid--the "de Gramont" schedule--for 24 weeks was purposed to all patients. RESULTS: Radiotherapy was completed in all cases; only one patient required suspension of the treatment for grade 4 toxicity (diarrhea). Instead, chemotherapy was interrupted in 3 cases (2 for central venous catheter thrombosis and 1 for grade IV diarrhea). Sixty-six patients underwent surgical resection (1 patient died before surgical treatment). Radical surgery was performed in 94%, and 46% of the 26 patients with distal rectal cancer had a conservative sphincter-sparing surgery. A complete pathologic response (defined as no evidence of viable tumor cells) was obtained in 22%. At a median follow-up of 17 months, distant metastases have been observed in 10 patients, and 3 of them developed a local recurrence. The actuarial estimations of 4-year overall survival, disease-free survival, local and distant control are 79%, 61%, 94% and 61%, respectively. CONCLUSIONS: Preoperative chemoradiotherapy seems to be an effective and well-tolerated treatment with a low complication rate. The high percentage of down-staging and sphincter sparing, also in distal rectal cancer, shows the efficacy of the treatment, which could significantly influence the incidence of relapses and quality of life.