Caveolin-1 expression in lung carcinoma varies according to tumour histotype and is acquired de novo in brain metastases

Aims:  To study caveolin-1 (Cav-1) expression in metastatic lung carcinomas.
Methods and results:  Cav-1 expression was investigated in a series of 121 lung carcinomas and it was shown that 18/121 tumours (14.9%) were Cav-1+. None of the pure bronchioloalveolar carcinomas proved to be positive, vs. 42.8% of the large cell carcinomas (neuroendocrine subtype excluded). Adenocarcinomas (8.5%), large cell neuroendocrine carcinomas (20%) and squamous cell carcinomas (29.6%) displayed an intermediate percentage of positive cases, suggesting a gradient of Cav-1 expression according to tumour histotype-related aggressiveness. Moreover, the percentage of Cav-1+ tumours with distant metastases was almost double that of non-metastatic tumours (17.8% vs. 8.1%), irrespective of the histotype. In 34 tumours metastatic to the brain, primary and secondary lesions were compared and 53% of brain metastases were Cav-1+ vs. 20.6% of primaries, indicating a de novo acquisition of Cav-1 expression. This pattern was exclusive to the brain, as it was not acquired in adrenal metastases. In our series, the presence of epidermal growth factor receptor amplification, determined by fluorescence in situ hybridization, was not related to Cav-1 reactivity.
Conclusions:  Cav-1 immunoreactivity in lung carcinoma is histotype-dependent and acquired de novo in brain metastases, suggesting a site-specific phenotypic shift in secondary lesions.     

Cycle-ergometry stress testing and use of chronotropic reserve adjustment of ST depression for identification of significant coronary artery disease in clinical practice

Diagnostic reliability of indexations of peak exercise ST segment depression (DeltaST) for heart rate reserve (HRi) or chronotropic reserve (CR) to identify significant coronary artery disease (CAD) by cycle-ergometer exercise testing has not been evaluated previously. Exercise testing by upright cycle-ergometer (25 W/3 min) were performed in consecutive patients in primary prevention with history of exercise-related chest discomfort and cardiovascular risk factors, or with overt peripheral artery disease, with or type-2 diabetes associated with two or more additional cardiovascular risk factors. Coronary angiography was performed after the test to assess significant CAD. Three different criteria for definition of inducible myocardial ischemia were tested versus significant CAD: peak DeltaST>or=100 microV, ST/HRi>1.69 microV/bpm or ST/CR>1.76 microV/%. Diagnostic accuracy vs. CAD of DeltaST>or=100 microV, of ST/HRi>1.69 microV/bpm, and of ST/CR>1.76 microV/% were 78%, 72%, and 89% respectively; sensitivity and specificity of the three criteria were 91% and 50%, 84% and 43%, 88% and 93%, respectively. Abnormal ST/CR predicted CAD independent of risk factors, pre-test probability, and more strongly than DeltaST. Combination of ST/HRi and ST/CR criteria did not improve CAD prediction. In conclusions, in clinical setting in patients in primary prevention but with moderate-to-high pre-test probability of CAD, exercise testing by cycle-ergometry and use of ST/CR>1.76 microV/% showed elevated sensitivity and specificity, and the best accuracy for diagnosis of significant CAD.     

Myofiberbreak-up: a marker of ventricular fibrillation in sudden cardiac death

BACKGROUND: Electrophysiologically, ventricular fibrillation is defined as a "chaotic, random, asynchronous electrical activity of the ventricles due to repetitive re-entrant excitation and/or rapid focal discharge". To this point its morphological equivalent has not been defined. MATERIAL AND METHOD: Several groups of different diseases and types of accidental death in normal subjects were studied. A complete autopsy was performed and the hearts were examined in 432 cases. A total of 16 myocardial samples per heart were processed for histological examination and sections were stained by haematoxylin and eosin or by specific stains. The frequency, location and extent of myocellular segmentation (stretching and/or rupture) of intercalated discs and associated changes of myocardial bundles and single myocells were investigated. A quantitative analysis was performed and the data were processed for statistical evaluation. RESULTS: The frequency of MFB was maximal in coronary (88%) and Chagas (76%) groups followed by the intracranial brain haemorrhage group (52%). The extent of myofiberbreak-up was maximal in coronary/Chagas groups followed by intracranial haemorrhage and transplant groups. CONCLUSIONS: No correlation was seen between gender, age, heart weight, degree of coronary atherosclerosis, myocardial fibrosis, survival and MFB. If our postulate is correct, finding MFB in the myocardium might allow the diagnosis of a malignant arrhythmia followed by cardiac arrest due to ventricular fibrillation even in the absence of clinical information (sudden death out-of-hospital).     

Combination chemotherapy with mitomycin C,vindesine and melphalan for refractory metastatic breast cancer

Summary A combination of mitomycin C, vindesine and melphalan was administered to 33 patients with heavily pretreated refractory breast cancer. The overall response rate was 27% with a mean duration of more than 10.2 months. A stabilization with a mean duration of 5.1 months was seen in 56% of cases, while 20% of patients progressed. Gastrointestinal toxicity, mostly grade 1 or 2 nausea/vomiting was seen in 85% of cases, grade 1 or 2 leukopenia in 60% of patients, and grade 1 or 2 thrombocytopenia in 42%. Considering the good compliance of this regimen and the poor prognosis of patients with refractory advanced breast cancer, this combination can be useful as a palliative treatment of breast carcinoma.Abbreviations MMC mitomycin C - VDS vindesine - L-PAM melphalan     

Unbalanced X-chromosome inactivation in haemopoietic cells from normal women

We studied X-chromosome inactivation patterns in blood cells from normal females in three age groups: neonates (umbilical cord blood), 25–32 years old (young women group) and >75 years old (elderly women). Using PCR, the differential allele methylation status was evaluated on active and inactive X chromosomes at the human androgen receptor (HUMARA) and phosphoglycerate kinase (PGK) loci. A cleavage ratio (CR)  3.0 was adopted as a cut-off to discriminate between balanced and unbalanced X-chromosome inactivation. In adult women this analysis was also performed on hair bulbs. The frequency of skewed X-inactivation in polymorphonuclear (PMN) cells increased with age: CR  3.0 was found in 3/36 cord blood samples, 5/30 young women and 14/31 elderly women. Mathematical analysis of patterns found in neonates indicated that X-chromosome inactivation probably occurs when the total number of haemopoietic stem cell precursors is 14–16. The inactivation patterns found in T lymphocytes were significantly related to those observed in PMNs in both young ( P  < 0.001) and elderly women ( P  < 0.01). However, the use of T lymphocytes as a control tissue for distinguishing between skewed inactivation and clonal proliferation proved to be reliable in young females, but not in elderly women, where overestimation of the frequency of clonal myelopoiesis may appear.     

Improved patient survival after acute variceal bleeding: a multicenter,cohort study

OBJECTIVE: Existing literature indicates that the mortality rate with each variceal bleeding episode is 30-50%. Over the past 2 decades, there have been significant developments in the management of variceal bleeding. The effect of these developments on the natural history of variceal bleeding is unclear. Therefore, a retrospective, multicenter study was conducted to define the outcomes of variceal bleeding and to describe the patterns of current practice in the management of variceal bleeding. METHODS: All patients with documented variceal bleeding hospitalized at four large county hospitals from January 1, 1997, to June 30, 2000, were included. Study outcomes were in-hospital, 6-wk, and overall mortality, rate of rebleeding, transfusion requirement, and length of stay. After discharge, patients were followed until death or study closure date, on June 30, 2000. RESULTS: A total of 231 subjects were included, and their in-hospital, 6-wk, and overall mortality rates were 14.2%, 17.5%, and 33.5%, respectively. The frequency of rebleeding during follow-up was 29%. Median length of total hospital stay was 8 days (0-34 days). Median number of packed red cell units transfused was 4 U (0-60 U). Upper endoscopy was performed in 95% of patients within 24 h, and endoscopic therapy was done in all but eight patients (ligation 64%, sclerotherapy 33%). Octreotide was administered in 74% of the patients. Portasystemic shunts were performed in 7.5% of the patients for controlling acute variceal bleeding. CONCLUSIONS: The mortality rate after variceal bleeding in this study was substantially lower than previously reported. This suggests that advances made in the management of variceal bleeding have improved outcomes after variceal bleeding.     

Colorectal cancer screening in HIV-infected patients 50 years of age and older: missed opportunities for prevention

OBJECTIVES: Although human immunodeficiency virus (HIV)-infected patients are now living longer, there are no published data on colorectal cancer (CRC) screening in this population. We hypothesized that HIV-infected patients were less likely to be screened for CRC compared to patients without HIV. METHODS: Consecutive HIV-infected patients > or =50 yr old seen in our outpatient clinic from 1/1/01 to 6/30/02 were identified. For each HIV-infected patient, we selected one age- and gender-matched control subject without HIV infection who was seen during the same time period. The electronic medical records were reviewed to determine the proportion of patients that had a fecal occult blood test (FOBT), flexible sigmoidoscopy, air-contrast barium enema (ACBE), or colonoscopy. RESULTS: During the 18-month study period, 538 HIV-infected outpatients were seen and 302 (56.1%) were > or =50 yr old. Despite significantly more visits with their primary care provider, HIV-infected patients were less likely to have ever had at least one CRC screening test (55.6%vs 77.8%, p < 0.001). The proportion of HIV-infected patients who ever had a FOBT (43.0%vs 66.6%, p < 0.001), flexible sigmoidoscopy (5.3%vs 17.5%, p < 0.001), ACBE (2.6%vs 7.9%, p= 0.004), or colonoscopy (17.2%vs 27.5%, p= 0.002) was significantly lower than in control subjects. In addition, HIV-infected patients were significantly less likely to be up-to-date with at least one CRC screening test according to current guidelines (49.3%vs 65.6%, p < 0.001). CONCLUSIONS: A substantial number of HIV-infected patients are > or =50 yr of age and CRC screening is underutilized in this population. Public health strategies to improve CRC screening in HIV-infected patients are needed.     

Sex incidence of diabetes. An epidemiological study in the la spezia area

Summary The authors studied the relationship between age, year of onset of the disease and sex in 1,428 diabetic subjects. The whole population of the province of La Spezia was used for comparison. As for the M/F ratio, differences of homogeneousness were not observed between the diabetics examined and the population of the province. When the series was subdivided according to the year in which diabetes was diagnosed, it was found that from the five-year period 1950–1954 to the five-year period 1965–1969 the M/F ratio had changed from 0.47 to 0.96. Statistically, this is equivalent to an exponential function.     

Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa

OBJECTIVE: The aim of this study was to determine the efficacy of epoetin alfa in alleviating anemia and minimizing ribavirin (RBV) dose reductions in patients with chronic hepatitis C virus (HCV) infection receiving combination RBV/interferon alfa (IFN) therapy. METHODS: HCV-infected patients who had Hb levels of 12 g/dl or less during the first 24 wk of combination RBV/IFN therapy (n=64) were randomized to treatment with epoetin alfa (40,000 units) s.c. q.w. or to standard of care (SOC) for anemia management (RBV dose reduction or discontinuation, transfusions). Primary and secondary efficacy endpoints were changes in Hb level and RBV dosage, respectively, from baseline to week 16 of epoetin alfa therapy.Based on intent-to-treat analysis, the mean changes from baseline Hb levels at week 16 were +2.8 g/dl for epoetin alfa versus +0.4 g/dl for SOC (p<0.0001), and the mean changes in RBV dosage were -34 mg/day for epoetin alfa versus -146 mg/day (p=0.060) for SOC. The mean Hb level at week 16 in the epoetin alfa group (13.8 g/dl) was significantly (p<0.0001) higher than that of the SOC group (11.4 g/dl). At week 4 and subsequently, significantly more patients in the epoetin alfa group did not have RBV dosage reductions (p<0.011). At study end, 83% of epoetin alfa-treated patients maintained RBV dosages of at least 800 mg/day, compared with 54% of patients receiving SOC (p=0.022). Epoetin alfa was well tolerated. CONCLUSIONS: In anemic HCV-infected patients treated with RBV/IFN, epoetin alfa increases Hb levels and maintains RBV dosing. Based on these results, epoetin alfa seems to be promising in the treatment of HCV treatment-related anemia. Further research is warranted to determine the potential impact on outcomes, including quality of life and sustained viral response rate.