On the basis of previous studies supporting that glutathione (GSH) reduced cisplatin nephrotoxicity we have designed a new regimen in the treatment of advanced colorectal cancer, which included GSH as a modulator of cisplatin-induced toxicity. Eleven untreated patients with measurable metastatic colorectal cancer received 5-fluorouracil (750 mg/m2, daily continuous infusion for days 1-5) and cisplatin (40 mg/m2 1 hour-infusion for days 6-8) given every 4 weeks. Reduced glutathione (2.5 g) was delivered i.v. prior to each cisplatin infusion. Toxicity was minimal and reversible and included nausea/vomiting (11 cases), mild neurotoxicity (4 cases) and leukopenia (2 cases); only 2 patients showed moderate and transient increases of serum creatinine (less than 2 mg/dl) and BUN. Renal function impairment was also monitored by magnesemia levels and urinary marker enzymes indicating minimal cumulative nephrotoxicity. Out of 10 evaluable patients, only 2 partial responses were observed. The median survival was 9 months (range 5-26). The study was closed, since the preliminary results do not suggest any therapeutic advantage in adding cisplatin to 5-fluorouracil in the present schedule, even using an intensive regimen. Indirect evidence suggests that these disappointing results are not the consequence of interference of GSH on the cytotoxic efficacy of cisplatin. The lack of incidence of severe toxicity of this regimen supports the role of reduced glutathione as a potential protective against cisplatin nephrotoxicity. Although these preliminary results suggest that further studies with the present regimen in this disease are not warranted, in view of its safety this program deserves evaluation in the treatment of neoplastic diseases responsive to 5-fluorouracil/cisplatin.
The glomic tumours of the stomach are exceedingly unfrequent, occur in the middle age, have a slow or very slow evolution and are small in size. Histologically, they must be distinguished from the more frequent haemangiopericytomas. Clinically, they are characterized by gastralgiae of ulcerous and haemorrhagic type. A personal case, which adds to the 7 ones referred to in the literature, is exposed. It concerns a woman aged 45, who has been suffering for 4 months from anorexia, vomit and postprandial pain. She was operated upon 2 years ago, and at present she is well.
Abstract. The S‐phase cell fraction was prospectively defined as the [ 3 H]‐thymidine labeling index ([ 3 H]dT LI) and flow cytometric S‐phase (FCM‐S) on 52 Dukes' D colorectal cancers. FCM‐S estimates obtained by using different modeling systems were superimposible but they were weakly related to [ 3 H]dT LI detected on the same tumour. Moreover, FCM‐S values were higher in aneuploid than in diploid tumours, whereas [ 3 H]dT LI values were independent of DNA‐ploidy status. [ 3 H]dT LI and FCM‐S were also related differently to some clinical and pathological features such as tumour site and histology. [ 3 H]dT LI and FCM‐S were indicative of prognosis in terms of 2–year freedom from progression and overall survival. However, product‐limit survival analysis showed an unexpectedly better freedom from progression and overall survival for patients with high S‐phase tumours than for those with low S‐phase tumours as defined by both cell kinetic variables.
Since 1980 120 patients with hepatic metastases from colorectal cancer underwent surgery at the Istituto Nazionale Tumori of Milan. Of these, 34 developed recurrence in the liver only and 11 underwent repeat surgery. The median interval between the two resections was 10 months and operative morbidity and mortality rates were 40 per cent and 9 per cent respectively. Nine patients with adequate follow-up were evaluated and after a median follow-up of 17 months four were alive and disease-free, two were alive with lung metastases and hepatic relapse and three had died. The overall median survival of these patients was 23 months.
This study was done to define the prognostic role of some clinical and pathologic variables in patients with carcinoma of the stomach who underwent a curative subtotal gastrectomy for cancer located at the lower two-thirds of the stomach. An univariate and multivariate analysis, according to Cox's regression model, was retrospectively performed upon 361 patients operated upon at the Istituto Nazionale Tumori of Milan from 1965 to 1979 by a curative subtotal gastrectomy. Data were stored by an IBM 4331 computer. Several factors were taken into consideration: age, sex, site and size of tumor, gross appearance, histologic type, invasion of the gastric wall, nodal status and symptoms. Of six variables selected by the univariate analysis, only four (sex, age, lymph node status and degree of invasion in the gastric wall) were validated by the multivariate evaluation, whereas tumor size and symptoms lost their prognostic relevance. The most important variables were nodal status and the degree of invasion in the gastric wall. The influence of age had a different impact on survival time, depending upon nodal status. In fact, patients with positive nodes who were less than 60 years old had the worst prognosis; the same age group with negative nodes had the best prognosis. Multifactorial analysis, according to the automatic interaction detection procedure, showed that prognosis worsened progressively beginning with female patients with negative nodes at pT1 or pT2 (91.6 per cent five year survival rate), male patients with negative nodes at pT1 or pT2 (76.3 per cent five year survival rate), female patients with negative nodes at pT3 or pT4 (62.4 per cent), male patients with negative nodes at pT3 or pT4 (40.0 per cent), patients more than 60 years old with negative nodes (36.8 per cent) and patients less than 60 years old with positive nodes (20.8 per cent). In our opinion, these parameters should be taken into consideration when stratification of patients as candidates to undergo adjuvant treatment after surgical treatment is planned.
The outcome of patients with colorectal cancer is more favorable when the tumor exhibits high-frequency microsatellite instability (MSI). Although associated with earlier-stage tumors, MSI has been proposed as an independent predictor of survival. We tested the prognostic value of MSI in a large series of patients diagnosed with colorectal cancer in the last decade.The survival of 893 consecutive patients with colorectal cancer characterized by microsatellite status was analyzed. The 89 (10%) patients with MSI cancer were classified according to tumor mismatch repair (MMR) defect, MMR germ-line mutation, hMLH1 and p16 promoter methylation, BRAF and K-ras mutations, and frameshifts of target genes.The colorectal cancer-specific survival was significantly (P = 0.02) better in patients with MSI cancer than in those with stable tumor (MSS). MSI did not predict a significantly lower risk of cancer-related death if tumor stage was included in the multivariate analysis [hazard ratio, 0.72; 95% confidence interval (95% CI), 0.40-1.29; P = 0.27]. Instead, MSI was strongly associated with a decreased likelihood of lymph node (odds ratio, 0.31; 95% CI, 0.17-0.56; P < 0.001) and distant organ (odds ratio, 0.13; 95% CI, 0.05-0.33; P < 0.001) metastases at diagnosis, independently of tumor pathologic features. Molecular predictors of reduced metastatic risk, and then of more favorable prognosis, included TGFbetaRII mutation for all MSI tumors, hMSH2 deficiency for hereditary non-polyposis colorectal cancer, and absence of p16 methylation for sporadic hMLH1-deficient cancers.Tumor MSI is a stage-dependent predictor of survival in patients with colorectal cancer. The decreased likelihood of metastases in patients with MSI cancer is associated with specific genetic and epigenetic changes of the primary tumor.
