Optimization of the schedule of gemcitabine-cisplatin combination as induction regimen for patients with biopsy-proven stage IIIa N2 - stage IIIb non-small-cell lung cancer: a prospective phase-II study

Aim of this study was to define the optimal schedule of gemcitabine (GCB)\cisplatin (CDDP) combination as induction chemotherapy (CHT) in patients with stage IIIa pN2-IIIb non - small-cell lung cancer (NSCLC). Fifty patients with mediastinoscopically-proven stage-IIIa pN2 -IIIb NSCLC were treated with 3 cycles of induction CHT followed by surgery (if staged IIIa) and three-time-daily accelerated radiotherapy. Chemotherapy initially consisted of 3 courses of CDDP 100 mg\m(2) d1 plus GCB 1000 mg\m(2) dd 1,8,15 repeated every 4 weeks, than was modified in CDDP 80 mg\m(2) d1 plus GCB 1250 mg\m(2) dd 1,8 repeated every 3 weeks. Twenty-nine four-week scheduled treatment cycles were firstly administered to 10 patients (pts): treatment-related toxicity, mainly hematological, caused a dose-reduction or treatment omission on day 15 in 65% of cycles. After the protocol was amended, 119 three-week scheduled treatment cycles were administered to 40 pts. Treatment-related toxicity of the new schedule caused a dose-reduction or treatment omission in only 10% of cycles, no patients requiring chemotherapy discontinuation. Thirty-seven out of fifty patients (74%, 95% CI: 60-85%) achieved a partial response, 7 had stable disease and 6 had disease progression. Similar activity was seen with both schedules. One nodal pathological complete remission was observed among the 24 pts who underwent surgery. At present, with a median follow-up of 13 months (mos), 2-year (y) survival of all the 50 pts and of the 24 pts staged IIIa who underwent surgery is estimated as 37% (95% CI: 24-58%) and 47% (95%CI: 27-80%), respectively. When given as induction chemotherapy, a three-week schedule of CDDP plus GCB combination appeared to be effective, with lower toxicity and better compliance than a four-week schedule.     

Ultrasound (US) guided central venous catheterization of internal jugular vein on over 65-year-old patients versus blind technique

BACKGROUND AND OBJECTIVES: Performing a central venous catheterization (CVC) on older patients for long-term central intravenous therapy could be a very important procedure. It could be associated with a high incidence of related complications, especially on over 65-year-old, high risk, selected patients. METHODS: The authors analyzed the results of 72 central venous CVC of internal jugular vein performed on over 65-year-old patients with ultrasound (US) guide from January 1998 to April 2003. RESULTS: The average performing time was 4 min, with 98.7% of success, 0% of major complications, and 4.1% of minor complications (one mild vagal hypotension and two catheter dislocation). CONCLUSIONS: The US guided technique is a safer procedure especially in older patients; it affords an easier and more rapid cannulation of a central vein, drastically reducing major and minor complications.     

Cine-MR in a patient with suspected normal pressure hydrocephalus

The case of a patient with predominant short-term memory and CT pattern suggestive of of normal pressure hydrocephalus, is discussed. Clinical and CT findings did not allow to predict the clinical response to a possible ventriculoperitoneal shunt. On MRI more accurate morphological evaluation with cine-MR functional assessment was obtained. Calculated CSF flow indexes evidenced hyperdynamia usually associated with a good outcome after ventriculoperitoneal shunting.     

Safety and tolerability of oral erectile dysfunction treatments in the elderly

Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men worldwide. It is generally accepted that sexual function tends to decline with aging, which is often associated with a higher prevalence of sexual problems, including ED and loss of libido. As the mean age of men seeking medical help for sexual dysfunction continues to increase, it is important to assess the safety and tolerability of currently available medical treatments in elderly men, who often share other co-morbidities that should be carefully evaluated when any type of ED therapy is considered. With this aim in mind, a MEDLINE search was conducted from 1 January 1998 to 31 May 2004 to identify studies assessing the efficacy, safety and tolerability of treatments for ED in the elderly. Particular care was taken to assess the cardiovascular safety of oral drugs for ED in this subset of patients, who often have multiple cardiovascular risk factors which contribute to a complicated clinical scenario. The most important conclusion of the paper is that the high efficacy, reliability, safety and tolerability of oral ED treatments makes them appropriate first-line therapies for elderly patients with ED.     

Multiinstitutional European validation of the 2002 TNM staging system in conventional and papillary localized renal cell carcinoma

BACKGROUND: The current study validated the 2002 edition of the TNM staging system in a multicenter, multinational European series of localized renal cell carcinoma (RCC). METHODS: The authors analyzed the clinical data of 2217 patients who had undergone radical or partial nephrectomy for localized RCC in 7 urologic centers. RESULTS: In the current study, 1065 patients (48%) were classified as having pT1a disease, 771 (34.8%) were classified as having pT1b disease, and 381 (17.2%) were classified as having pT2 disease. Tumor histotype was conventional RCC in 1886 patients (85%), papillary in 182 (8.2%) patients, chromophobe in 64 (2.9%) patients, and unclassified in 85 (3.8%) patients. The mean follow-up time was 65.36 +/- 52.09 months. The 5 and 10-year disease-specific survival probabilities were 95.3% and 91.4% in patients with pT1a disease, 91.4% and 83.4% in patients with pT1b disease, and 81.6% and 75.2% in patients with pT2 disease (log-rank test P value = 0.0000). The disease-specific survival rates of patients with pT1a RCC were significantly higher than those recorded in patients with pT1b and pT2 RCC. Similarly, the disease-specific survival probabilities of patients with pT1b RCC were significantly better than those of patients with pT2 RCC. Analyzing the seven series individually, the 2002 TNM staging system provided appropriate stratification for only one series. The 2002 TNM staging system allowed significant stratification of the cancer-related outcomes in the subgroup of patients with conventional RCC but not in those with papillary carcinomas. CONCLUSIONS: The application of the 2002 TNM staging system in the current multicenter series enabled the authors to demonstrate optimal stratification of patients with localized RCC. Stratifying by tumor histotype, the data coming from the whole group analysis were reconfirmed for clear cell RCC only.     

Mammary carcinoma provides highly tumourigenic and invasive reactive stromal cells

The progression of a lesion to a carcinoma is dependent on theengagement of ‘reactive stroma’ that provides structuraland vascular support for tumour growth and also leads to tissuereorganization and invasiveness. The composition of reactivestroma closely resembles that of granulation tissue, and myofibroblastsare thought to play a critical role in driving the stromal reactionof invasive tumours as well as of physiological wound repair.In the present work, we established a myofibroblast-like cellline, named A17, from a mouse mammary carcinoma model in whichtumourigenesis is triggered in a single step by the overexpressionof HER-2/neu transgene in the epithelial compartment of mammaryglands. We showed that although they derived from a tumour ofepithelial origin and did not express HER-2/neu transgene, theirsubcutaneous injection into the backs of syngeneic mice gaverise to sarcomatoid tumours which expressed alpha-smooth muscleactin at the invasive edge. The expression of cytokeratin 14suggested a myoepithelial origin but immunophenotypical profile,invasive and neoangiogenic potential of A17 cells and tumoursshowed many similarities with the reactive stroma that occursin wound repair and in cancerogenesis. Our results suggest thatepithelial tumours have the potential to develop highly tumourigenicand invasive reactive stromal cells and our cell line representsa novel, effective model for studying epithelial-stromal interactionand the role of myofibroblasts in tumour development.     

The Fanconi anemia group A protein modulates homologous repair of DNA double-strand breaks in mammalian cells

Fanconi anemia (FA) cells exhibit hypersensitivity to DNA interstrand cross-links (ICLs) and high levels of chromosome instability. FA gene products have been shown to functionally or physically interact with BRCA1, RAD51 and the MRE11/RAD50/NBS1 complex, suggesting that the FA complex may be involved in the repair of DNA double-strand breaks (DSBs). Here, we have investigated specifically the function of the FA group A protein (FANCA) in the repair of DSBs in mammalian cells. We show that the targeted deletion of Fanca exons 37-39 generates a null for Fanca in mice and abolishes ubiquitination of Fancd2, the downstream effector of the FA complex. Cells lacking Fanca exhibit increased chromosomal aberrations and attenuated accumulation of Brca1 and Rad51 foci in response to DNA damage. The absence of Fanca greatly reduces gene-targeting efficiency in mouse embryonic stem (ES) cells and compromises the survival of fibroblast cells in response to ICL agent treatment. Fanca-null cells exhibit compromised homology-directed repair (HDR) of DSBs, particularly affecting the single-strand annealing pathway. These data identify the Fanca protein as an integral component in the early step of HDR of DSBs and thereby minimizing the genomic instability.     

Correlation between fatigue and hemoglobin level in multiple myeloma patients: results of a cross-sectional study

This cross-sectional study showed a positive correlation between fatigue-related quality of life, evaluated with the FACT-An questionnaire, and hemoglobin level in 1071 patients with multiple myeloma. Multiple regression analysis adjusting for several covariates was used. Improved FACT-An scores in women and men were associated with hemoglobin increase up to sex-specific normal values.     

Interaction of Tau with Fe65 links tau to APP

The beta-amyloid precursor protein APP and the microtubule-associated protein Tau play a crucial role in the pathogenesis of Alzheimer's disease (AD). However, the possible molecular events linking these two proteins are still unknown. Here, we show that Fe65, one of the ligands of the APP cytodomain, is associated with Tau in vivo and in vitro, as demonstrated by co-immunoprecipitation, co-localization, and FRET experiments. Deletion studies indicated that the N-terminal domain of Tau and the PTB1 domain of Fe65 are required for this association. This interaction is regulated by the phosphorylation of Tau at selected sites, by glycogen synthase kinase-3beta (GSK3beta) and cyclin-dependent kinase 5 (Cdk5), and requires an intact microtubule network. Furthermore, laser scanner microscopy and co-immunoprecipitation experiments provide preliminary evidence of possible complex(es) involving Tau, Fe65, APP. These findings open new perspectives for the study of the possible crosstalk between these proteins in the pathogenesis of AD.