Amsterdam criteria II and endometrial cancer index cases for an accurate selection of HNPCC families

Endometrial carcinoma (EC) is the second most common tumor in hereditary nonpolyposis colorectal cancer (HNPCC), with an incidence rate of 60% by the age of 70 in mutation carriers. The International Collaborative Group on HNPCC revised the Amsterdam criteria and proposed a new, wider definition including extracolonic cancers. The aim of our study was to evaluate the accuracy of a new definition called Amsterdam criteria II. We updated, reclassified and compared the pedigrees of 29 women, already reported as being affected by EC and having a colorectal cancer familial background, according to the two clinical diagnostic criteria for HNPCC (Amsterdam criteria I, ACI, and Amsterdam criteria II, ACII) after two periods of observation (1990-1995 and 1995-2000). According to ACII the frequency of HNPCC in the population under study increased from 0.9% to 3.7% in the period 1990-1995 and from 3.2% to 3.7% in the period 1995-2000. ACII allowed early detection of HNPCC families and thus made it possible to provide them with a suitable surveillance program and genetic testing.     

High-dose cytarabine as consolidation treatment for patients with acute myeloid leukemia with t(8;21)

Seventeen patients affected by acute myeloid leukemia (AML) with t(8;21) were prospectively programmed to receive three courses of high-dose cytarabine (HDARA-C) as post-remission therapy. The median age was 39 years and in all cases t(8;21) was the only karyotypic abnormality. Complete remission (CR) was achieved in 14 out of 17 cases (82%) and, after first consolidation with NOVIA regimen (intermediate dose ARA-C plus mitoxantrone), all patients received the three planned courses of HDARA-C (3g/m(2) q12h on days 1, 3, 5). There were two documented infections, while all patients experienced fever of unknown origin (FUO). Nonhematological toxicity was mild. Thirteen out of 14 patients are in continuous CR after a median follow-up of 44 months. One patient relapsed at 16 months and, following CR2 achievement, underwent allogeneic transplantation; he died 3 months later while in CR from acute graft versus host disease (GVHD). Survival at 5 years is projected at 79%. Our data confirm the efficacy of repeated courses of HDARAC for patients with t(8;21) AML.     

Anti-heparan sulfate antibodies in neurological disease

Antibodies to heparan sulfate (HS) have previously been found in association with peripheral neuropathy. We tested sera from patients with neuropathies and with other neurological diseases for antibodies to HS using an avidin-biotin enzyme-linked immunosorbent assay (ELISA) system. Increased titers of anti-HS antibodies were found in 3.4% of patients with neuropathy, and in 3% of patients with other neurological diseases. In all cases, however, an inflammatory disease was present, including chronic inflammatory neuropathy, cerebral vasculitis, or multiple sclerosis. Antibodies to HS appear not to be specific for neuropathy, as they occur in several inflammatory diseases. They might contribute to the associated breakdown of the blood-brain or blood-nerve barrier.     

Use of lipid-lowering drugs and blood pressure control in patients with arterial hypertension

A large proportion of patients have both hypertension and hypercholesterolemia, two of the most important risk factors for cardiovascular diseases. Statins are the most widely used drugs for the treatment of plasma lipid abnormalities and have been reported to interact with elevated blood pressure. A reduction in blood pressure associated with the use of these agents has been reported in patients with untreated hypertension and in patients treated with antihypertensive drugs, particularly angiotensin-converting enzyme inhibitors and calcium channel blockers. This effect on blood pressure control has also been observed in diabetic patients. The mechanism responsible for the hypotensive effect seems to be largely independent of the effect of statins on plasma cholesterol, and probably is related to the interaction of the medications with endothelial function or angiotensin II receptors. The capacity of statins to improve blood pressure control may represent a useful tool for improvement in the prevention of cardiovascular diseases.     

Changes of topoisomerase IIalpha expression in breast tumors after neoadjuvant chemotherapy predicts relapse-free survival.

PURPOSE: To assess the value of changes in the expression of topoisomerase IIalpha (TopoII) and the proto-oncogene erbB-2 (HER-2) as predictors of relapse-free survival in women with operable breast cancer treated with anthracycline-based neoadjuvant chemotherapy. PATIENTS AND METHODS: Seventy-seven patients with primary breast cancer who had undergone neoadjuvant anthracycline-based chemotherapy were included in the present study. TopoII and HER-2 were measured by immunohistochemistry in prechemotherapy and postchemotherapy (at the time of surgery) tumor specimens, and the value of their changes as predictors of relapse-free survival were evaluated by Kaplan-Meier and Cox proportional hazard regression analyses. RESULTS: Neoadjuvant chemotherapy resulted in a significant reduction in the percentage of cells expressing TopoII (P < 0.0001). No significant change was observed for HER-2. TopoII and HER-2 expression before chemotherapy predicted tumor response to treatment. Changes in TopoII expression after chemotherapy were strongly associated with a poor relapse-free survival (P < 0.0001) in a Cox multivariate analysis adjusted for other clinicopathologic prognostic factors. CONCLUSION: Changes in TopoII expression after anthracycline-based neoadjuvant chemotherapy is an independent predictor of a poor relapse-free survival in patients with breast cancer. Tumor cells displaying an increased TopoII expression after treatment may be responsible for relapses, and may, therefore, define a group of patients with anthracycline-resistant breast cancer.     

Chemotherapy regimen GOLF induces apoptosis in colon cancer cells through multi-chaperone complex inactivation and increased Raf-1 ubiquitin-dependent degradation

The multi-drug combination of oxaliplatin (OXA), 5-Fluorouracil (5-FU) and leucovorin (LF) is currently considered as the gold standard treatment for metastatic colorectal carcinoma. In previous studies, we have studied a chemotherapy regimen containing gemcitabine (GEM), OXA, LF, and 5-FU (named GOLF regimen) that has shown a good safety profile and highly significant anti-tumor activity. In the present study, we have investigated on the anti-tumour mechanisms of GOLF in human colon cancer HT-29 and WiDr cell lines. We have found that GOLF induced growth inhibition that was largely caused by apoptosis differently from other combinations. Moreover, the different drugs composing GOLF were highly synergistic in inducing growth inhibition. Apoptosis induced by GOLF combination was paralleled by PARP cleavage and caspase 9 and 3 activation that were not recorded in the other combinations. An about 85% decrease of the activity of Erk and Akt was found in GOLF-treated cells. These effects were likely due to decreased expression of the upstream activator Raf-1 and of Akt itself, respectively. The intracellular levels of these signalling components can be post-translationally regulated by ubiquitin-dependent degradation through proteasome. Therefore, we have evaluated the expression of some chaperone components and we have found that GOLF did not affect the expression of both heat shock protein (HSP) 90 and 27 but induced an about 90% increase of HSP70 levels suggesting the inactivation of the multi-chaperone complex. Moreover, an about 4-fold increase of the ubiquitination of Raf-1 was also found and the addition for 12 h of 10 microM proteasome inhibitor lactacystin caused an accumulation of the ubiquitinated isoforms of Raf-1. In conclusions, GOLF was a combination highly synergistic in inducing both growth inhibition and apoptosis of colon cancer cells. These effects likely occurred through the disruption of critical survival pathways and the inactivation of multi-chaperone complex.     

Uterus preservation in surgical correction of urogenital prolapse

OBJECTIVE: This study aimed to evaluate the efficacy of colposacropexy with uterine preservation as therapy for uterovaginal prolapse. Surgical techniques, efficacy and overall results are described. METHODS: In this prospective, controlled study, 34 of the 72 consecutive patients with symptomatic uterovaginal prolapse were treated with colposacropexy with uterus conservation (hysterocolposacropexy, HSP) and the other 38 with hysterectomy followed by sacropexy (CSP). Anchorage was achieved with two rectangular meshes in CSP and with one posterior rectangular and one anterior Y-shaped mesh in HSP. Check-ups were scheduled at 3, 6 and 12 months and then yearly. Pre-operative patient characteristics, operative and post-operative events and follow-up results were recorded. Mean follow-up was 51 months (range 12-115). RESULTS: No significant differences emerged in demographic and clinical characteristics between the HSP and CSP groups. Mean operating times, intra-operative blood loss and hospital stay were significantly less after HSP (p<0.001). At follow-up success rates were similar in the two groups in terms of uterine and upper vaginal support (100%). Recurrent low-grade cystoceles developed in 1/38 (2.6%) in the CSP group and in 5/34 (14.7%) in the HSP group (p=NS), recurrent low-grade rectocele developed in 6/38 (15.8%) and in 3/34 (8.8%) patients respectively (p=NS). No patient required surgery for recurrent vault or uterus prolapse. Urodynamic results showed that pressure/flow parameters improved significantly (p<0.001) in both groups. Thirty-one of the 34 patients (91%) in the HSP group and 33/38 (86.8%) in the CSP group were satisfied and would repeat surgery again. CONCLUSIONS: Colposacropexy provides a secure anchorage, restoring an anatomical vaginal axis and a good vaginal length. HSP can be safely offered to women who request uterine preservation. Whether the uterus was preserved or not, patients had similar results in terms of prolapse resolution, urodynamic outcomes, improvements in voiding and sexual dysfunctions. HSP has shorter operating times and less blood loss.