Incidence and risk factors for respiratory tract bacterial colonization and infection in lung transplant recipients.

To evaluate incidence of and risk factors for respiratory bacterial colonization and infections within 30 days from lung transplantation (LT). We retrospectively analyzed microbiological and clinical data from 94 patients transplanted for indications other than cystic fibrosis, focusing on the occurrence of bacterial respiratory colonization or infection during 1 month of follow-up after LT. Thirty-three percent of patients developed lower respiratory bacterial colonization. Bilateral LT and chronic heart diseases were independently associated to a higher risk of overall bacterial colonization. Peptic diseases conferred a higher risk of multi-drug resistant (MDR) colonization, while longer duration of aerosol prophylaxis was associated with a lower risk. Overall, 35% of lung recipients developed bacterial pneumonia. COPD (when compared to idiopathic pulmonary fibrosis, IPF) and higher BMI were associated to a lower risk of bacterial infection. A higher risk of MDR infection was observed in IPF and in patients with pre-transplant colonization and infections. The risk of post-LT respiratory infections could be stratified by considering several factors (indication for LT, type of LT, presence of certain comorbidities, and microbiologic assessment before LT). A wider use of early nebulized therapies could be useful to prevent MDR colonization, thus potentially lowering infectious risk.

Predictors of incomplete viral response and virologic failure in patients with acute and early HIV infection. Results of Italian Network of ACuTe HIV InfectiON (INACTION) cohort.

OBJECTIVES: The aim of this study was to evaluate the factors that can influence an incomplete viral response (IVR) after acute and early HIV infection (AEHI). METHODS: This was a retrospective, observational study including patients with AEHI (Fiebig stages I-V) diagnosed between January 2008 and December 2014 at 20 Italian centres. IVR was defined by: (1) viral blip (51-1000 HIV-1 RNA copies/mL after achievement of < 50 HIV-1 RNA copies/mL); (2) virologic failure [> 1000 copies/mL after achievement of < 200 copies/mL, or ≥ 200 copies/mL after 24 weeks on an antiretroviral therapy (ART)]; (3) suboptimal viral response (> 50 copies/mL after 48 weeks on ART or two consecutive HIV-1 RNA levels with ascending trend during ART). Cox regression analysis was used to calculate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for IVR. RESULTS: In all, 263 patients were studied, 227 (86%) males, with a median [interquartile range (IQR)] age of 38 (30-46) years. During a median follow-up of 13.0 (5.7-31.1) months, 38 (14.4%) had IVR. The presence of central nervous system (CNS) symptoms was linked to a higher risk of IVR (HR = 4.70, 95% CI: 1.56-14.17), while a higher CD4/CD8 cell count ratio (HR = 0.13, 95% CI: 0.03-0.51 for each point increase) and first-line ART with three-drug regimens recommended by current guidelines (HR = 0.40, 95% CI: 0.18-0.91 compared with other regimens including four or five drugs, older drugs or non-standard backbones) were protective against IVR. CONCLUSIONS: Patients with lower CD4/CD8 ratio and CNS symptoms could be at a higher risk of IVR after AEHI. The use of recommended ART may be relevant for improving short-term viral efficacy in this group of patients.

Reduced risk of Efavirenz Discontinuation in Naïve Patients Starting First-Line Antiretroviral Therapy with Single Tablet versus dual Tablet Regimen.

OBJECTIVES: Despite not being approved in Europe as first-line therapy, the efavirenz (EFV)-containing single tablet regimen (STR) is frequently used in clinical practice in naïve patients but few data are available on this strategy. In our study, we aimed to assess the risk of EFV discontinuation in patients starting antiretroviral therapy with STR vs. nonSTR. METHODS: This was a multicentre study retrospectively enrolling naïve patients starting EFV+TDF+FTC. Patients were followed from the time of treatment initiation to the discontinuation of the EFV-containing regimen, comparing STR vs. nonSTR. Two different analyses were performed: (A) nonSTR patients censored at the last observation (switch to STR not considered as the end of observation); (B) nonSTR patients censored at the time of switch to STR. RESULTS: The study included 235 patients, of whom 74 (31.5%) directly started STR. Among patients starting nonSTR, 108 (67.1%) switched to STR after a median period of 6 months. Forty-four EFV discontinuations were observed (13 among STR vs. 31 among nonSTR patients). The overall estimated probability of discontinuation was 30% at 5 years, about half (14.8%) of these occurring during the first year. Analysis A did not show significant differences between STR and nonSTR regarding the probability of efavirenz discontinuation (19.9% vs. 24.7% at 5 years, P = 0.630). In contrast, Analysis B showed that the probability of EFV discontinuation was similar (8.3%) between STR and nonSTR patients up to 8 months. Thereafter, a significantly higher rate of discontinuation was observed in nonSTR patients (47.5% vs. 19.9% at 5 years, P = 0.034). CONCLUSIONS: Our data suggest that an early switch to STR during the first months of treatment could reduce the risk of EFV discontinuation.

Initial antifungal strategy does not correlate with mortality in patients with candidemia.

The incidence of Candida bloodstream infections (BSIs) has increased over time, especially in medical wards. The objective of this study was to evaluate the impact of different antifungal treatment strategies on 30-day mortality in patients with Candida BSI not admitted to intensive care units (ICUs) at disease onset. This prospective, monocentric, cohort study was conducted at an 1100-bed university hospital in Rome, Italy, where an infectious disease consultation team was implemented. All cases of Candida BSIs observed in adult patients from November 2012 to April 2014 were included. Patients were grouped according to the initial antifungal strategy: fluconazole, echinocandin, or liposomal amphotericin B. Cox regression analysis was used to identify risk factors significantly associated with 15-day and 30-day mortality. During the study period, 130 patients with candidemia were observed (58 % with C. albicans, 7 % with C. glabrata, and 23 % with C. parapsilosis). The first antifungal drug was fluconazole for 40 % of patients, echinocandin for 57.0 %, and liposomal amphotericin B for 4 %. During follow-up, 33 % of patients died. The cumulative mortality 30 days after the candidemia episode was 30.8 % and was similar among groups. In the Cox regression analysis, clinical presentation was the only independent factor associated with 15-day mortality, and Acute Physiology and Chronic Health Evaluation (APACHE) II score and clinical presentation were the independent factors associated with 30-day mortality. No differences in 15-day and 30-day mortality were observed between patients with and without C. albicans candidemia. In patients with candidemia admitted to medical or surgical wards, clinical severity but not the initial antifungal strategy were significantly correlated with mortality.

Efficacy and safety of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients with virological suppression: 144 week follow-up of the AtLaS pilot study.

OBJECTIVES: AtLaS was a single-arm pilot study that demonstrated promising efficacy and safety of treatment simplification to a dual regimen with atazanavir/ritonavir + lamivudine in virologically suppressed HIV-positive patients. Here, we report data from the 144 week follow-up. METHODS: At baseline, patients treated with a three-drug atazanavir/ritonavir-based regimen were switched to 300/100 mg of atazanavir/ritonavir plus 300 mg of lamivudine once daily. Major clinical events, laboratory parameters, neurocognitive performance, bone composition and body fat distribution were monitored. Treatment failure was defined as a discontinuation/switch of the regimen or virological failure (HIV-RNA >50 copies/mL in two consecutive determinations or a single level above 1000 copies/mL). RESULTS: After 144 weeks, 9/40 (22.5%) treatment failures occurred, including two virological failures (Weeks 48 and 53, without resistance). A significant increase in the CD4 count was observed at Week 96 (+124 cells/mm(3); P = 0.002) and Week 144 (+94 cells/mm(3); P = 0.008). After 144 weeks, a significant increase in total cholesterol (+25 mg/dL; P = 0.001), HDL cholesterol (+6 mg/dL; P = 0.024) and LDL cholesterol (+12 mg/dL; P = 0.008) was observed, without any change in triglyceride levels, total cholesterol/HDL ratio or LDL/HDL ratio. A significant increase in the estimated glomerular filtration rate (+25 mL/min/1.73 m(2); P < 0.001) and lumbar spine T-score and Z-score (+0.2, P = 0.011; and +0.35, P = 0.001, respectively) and a decrease in trunk fat (-1.898 g; P = 0.005) were also observed. Neurocognitive function did not decline over time. Concerning safety, 10 moderate to severe adverse events were recorded in eight patients; overall seven cases of renal colic (possibly treatment related) were observed, leading to a discontinuation of treatment in two patients. CONCLUSIONS: Data from the 144 week follow-up suggested good long-term efficacy of the simplification strategy that was investigated, with rare virological failure and a potential for improvement of the CD4 count, renal function and bone mineral density. This strategy warrants further investigation in a randomized trial.

Pharmacokinetics of etravirine in HIV-infected patients concomitantly treated with rifampin for tuberculosis.

Etravirine is metabolized by three cytochrome P450 enzymes that are in turn induced by rifampin. Consequently, co-administration of etravirine and rifampin is not recommended. To date, however, no clinical studies exploring the drug-drug interaction of this combination have been conducted. Here we report two cases of off-label etravirine use concurrently with antitubercular treatment, dictated by the unavailability of other treatments. Plasma drug concentrations were monitored by regular measurements. Our results appear to confirm the increased metabolism of etravirine through the induction of cytochrome P450 enzymes, but the adequacy of drug levels in all of the measurements and subsequent virological suppression suggest that this drug interaction may not be clinically relevant.

Comparison of cognitive performance in HIV or HCV mono-infected and HIV-HCV co-infected patients.

PURPOSE: Our aim was to explore the interplay between human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections in the expression of cognitive disorders. METHODS: We performed a multi-centre cross-sectional study, enrolling three groups of asymptomatic outpatients matched for age and education: (1) HIV mono-infected; (2) HCV mono-infected; (3) HIV-HCV co-infected. All subjects were subjected to the Zung depression scale and a comprehensive neuropsychological battery. RESULTS: A total of 50 patients for each group were enrolled. Patients in the three groups did not significantly differ in the main common demographic and clinical characteristics, except for a lower proportion of past injecting drug use (IDU) in group 1 (4 %) in comparison to groups 2 (38 %, p < 0.001) and 3 (78 %, p < 0.001), a longer duration of HIV infection in group 3 in comparison to group 1 (p < 0.001) and a longer duration of HCV infection in group 3 in comparison to group 2 (p = 0.028). Overall, 39.3 % of patients showed minor cognitive impairment, with a higher proportion in group 3 (54 %) when compared to groups 1 (28 %, p = 0.015) or 2 (36 %, p = 0.108). Patients in group 3 [odds ratio (OR) 3.35, p = 0.038 when compared to group 1] and those with higher depression scores (OR 1.05, p = 0.017) showed an increased risk of cognitive impairment after adjusting for education and past injection drug use. In particular, group 3 showed worse performance in psychomotor speed tasks when compared to group 1 (p = 0.033). CONCLUSIONS: A worse cognitive performance in HIV-HCV co-infected patients was observed, suggesting an additive role of the two viruses in the pathogenesis of cognitive disorders.

Cardiovascular risk factors and carotid intima-media thickness are associated with lower cognitive performance in HIV-infected patients.

OBJECTIVES: The aim of the study was to investigate the relationship between metabolic comorbidities, cardiovascular risk factors or common carotid intima-media thickness (cIMT) and cognitive performance in HIV-infected patients. METHODS: Asymptomatic HIV-infected subjects were consecutively enrolled during routine out-patient visits at two clinical centres. All patients underwent an extensive neuropsychological battery and assessment of metabolic comorbidities and cardiovascular risk factors. Moreover, cIMT was assessed by ultrasonography. Cognitive performance was evaluated by calculating a global cognitive impairment (GCI) score obtained by summing scores assigned to each test (0 if normal and 1 if pathological). RESULTS: A total of 245 patients (median age 46 years; 84.1% with HIV RNA < 50 copies/mL; median CD4 count 527 cells/µL) were enrolled in the study. Cardiovascular risk factors were highly prevalent in our population: the most frequent were dyslipidaemia (61.2%), cigarette smoking (54.3%) and hypertension (15.1%). cIMT was abnormal (≥ 0.9mm) in 31.8% of patients. Overall, the median GCI score was 2 [interquartile range (IQR) 1-4]; it was higher in patients with diabetes (P = 0.004), hypertension (P = 0.030) or cIMT ≥ 0.9 mm (P < 0.001). In multivariate analysis, it was confirmed that diabetes (P = 0.007) and cIMT ≥ 0.9 mm (P = 0.044) had an independent association with lower cognitive performance. In an analysis of patients on combination antiretroviral therapy (cART), abacavir use was independently associated with a better cognitive performance (P = 0.011), while no association was observed for other drugs or neuroeffectiveness score. CONCLUSIONS: Diabetes, cardiovascular risk factors and cIMT showed a strong association with lower cognitive performance, suggesting that metabolic comorbidities could play a relevant role in the pathogenesis of HIV-associated neurocognitive disorders in the recent cART era.

Factors influencing the normalization of CD4+ T-cell count, percentage and CD4+/CD8+ T-cell ratio in HIV-infected patients on long-term suppressive antiretroviral therapy.

We evaluated factors associated with normalization of the absolute CD4+ T-cell counts, per cent CD4+ T cells and CD4+/CD8+ T-cell ratio. A multicentre observational study was carried out in patients with sustained HIV-RNA <50 copies/mL. Outcomes were: CD4-count >500/mm(3) and multiple T-cell marker recovery (MTMR), defined as CD4+ T cells >500/mm(3) plus%CD4 T cells >29%plus CD4+/CD8+ T-cell ratio >1. Kaplan-Meier survival analysis and Cox regression analyses to predict odds for achieving outcomes were performed. Three hundred and fifty-two patients were included and followed-up for a median of 4.1 (IQR 2.1-5.9) years, 270 (76.7%) achieving a CD4+ T-cell count >500 cells/mm(3) and 197 (56%) achieving MTMR. Using three separate Cox models for both outcomes we demonstrated that independent predictors were: both absolute CD4+ and CD8+ T-cell counts, %CD4+ T cells, a higher CD4+/CD8+ T-cell ratio, and age. A likelihood-ratio test showed significant improvements in fitness for the prediction of either CD4+ >500/mm(3) or MTMR by multivariable analysis when the other immune markers at baseline, besides the absolute CD4+ count alone, were considered. In addition to baseline absolute CD4+ T-cell counts, pretreatment %CD4+ T cells and the CD4+/CD8+ T-cell ratio influence recovery of T-cell markers, and their consideration should influence the decision to start antiretroviral therapy. However, owing to the small sample size, further studies are needed to confirm these results in relation to clinical endpoints.

Relationship between antiretroviral plasma concentration and emergence of HIV-1 resistance mutations at treatment failure.

PURPOSE: The relationship between antiretroviral pharmacokinetic exposure and acquisition of human immunodeficency virus-1 (HIV-1) drug resistance mutations (DRM) is not fully understood. The aim of this study was to investigate whether antiretroviral plasma concentration could predict the emergence of DRM at treatment failure. METHODS: The study cohort comprised retrospectively selected patients with failing antiretroviral regimens for whom a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) trough concentration measurement (TDM) had been obtained before failure, a genotypic resistance test (GRT1) had been performed before the TDM, and a genotypic resistance test (GRT2) had been performed at therapeutic failure. Drug levels were classified as undetectable/detectable or subtherapeutic/therapeutic according to limits of quantification of a high-performance liquid chromatography-ultraviolet assay or pre-defined efficacy thresholds, respectively. The number of DRM acquired at treatment failure was evaluated by comparing the results of the GRT2 and GRT1. RESULTS: A total of ten and 57 failure episodes occurred among our patients on NNRTI-based and PI-based regimens, respectively, and included in the evaluation. PI concentration was subtherapeutic in 28.1% of patients, among which the levels were undetectable in 21.1%. Twenty-five (43.9%) patients acquired at least one new PI-DRM according to the GRT2. Patients with undetectable PI levels showed a lower emergence of PI-DRM (minor + major) than those with detectable levels (8.3 vs. 53.3%, p = 0.007). Multivariate analysis confirmed that undetectable PI levels were independent negative predictors of DRM selection. NNRTI measurements were subtherapeutic in 2/10 (20%) patients. NNRTI-DRM were acquired by all patients regardless of NNRTI levels. CONCLUSIONS: A PI measurement showing undetectable drug levels prior to treatment failure predicted the lack of emergence of PI-DRM at failure. These results suggest that PI levels can help clinicians interpret the reasons for treatment failure and guide the type of interventions needed.

Update on emergence of HIV-1 resistance to antiretroviral drug classes in an Italian national database: 2007-2009.

We analysed trends of human immunodeficiency virus type 1 (HIV-1) drug resistance during 2007-2009 in the Italian national HIV drug resistance database 'ARCA'. Prevalence of resistance in each year was examined on the basis of the presence of major International AIDS Society-2009 mutations. Predictors of resistance were analysed by multivariable logistic regression. Nine hundred and sixty-six patients were selected. Resistance to nucleoside reverse transcriptase inhibitors and protease inhibitors showed a significant decline with respect to previous surveys. Resistance to any class of drug and three drug classes remained stable. Independent predictors of three-class resistance were the number of treatment regimens experienced, prior suboptimal nucleoside reverse transcriptase inhibitor therapy and the current use of ritonavir-boosted protease inhibitors.

Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients.

BACKGROUND: Despite the availability of potent antiretroviral regimens (combination antiretroviral therapy [cART]), HIV-associated neurocognitive disorders (HAND) are increasingly recognized. Our aim was to investigate the prevalence and treatment-related correlates of HAND, exploring the potential neurotoxicity of antiretrovirals on cognitive functions. METHODS: We performed a cross-sectional single cohort study by consecutively enrolling asymptomatic HIV+ subjects during routine outpatient visits. Each patient was submitted to a comprehensive neuropsychological battery and was considered cognitively impaired on the basis of results obtained in matched healthy HIV-negative subjects. CNS penetration effectiveness (CPE) rank was calculated for cART regimens according to 2010 CHARTER criteria. Factors associated with cognitive impairment were investigated by linear or logistic regression analysis. RESULTS: A total of 146 patients were enrolled. Of these, 129 (88.4%) were on cART and 59.6% of them were on current regimen from ≥1 year. Sixty-nine patients (47%) were classified as cognitively impaired (35.6% asymptomatic and 11.6% mild neurocognitive impairment). In the multivariate analysis, efavirenz use (odds ratio [OR] = 4.00; p = 0.008) and non-Italian nationality (OR = 3.46; p = 0.035) were associated with increased risk of cognitive impairment, whereas higher education was associated with a lower risk (OR = 0.85; p = 0.002). Furthermore, efavirenz use and age ≥65 years independently predicted worse performance on the double barrage and the Stroop test (time). No association between CPE rank and cognitive impairment was observed. CONCLUSIONS: A high prevalence of HAND was observed in apparently asymptomatic HIV+ individuals. HAND was associated with efavirenz use, suggesting the potential neurotoxicity of this drug. Routine neuropsychological examinations could help clinicians make correct diagnoses and manage mild, but clinically relevant, forms of HAND.

Clinical presentation, microbiological features and correlates of disease severity of 2009 pandemic influenza A (H1N1) infection.

The purpose of this study was to describe epidemiological, clinical and microbiological characteristics of confirmed novel influenza A (H1N1) infection, investigating factors associated with disease severity. We retrospectively selected patients seeking care for respiratory symptoms in two periods (May-August and September-November 2009) with different epidemiological characteristics. Only patients with confirmed pandemic influenza A (H1N1) were enrolled in this study. A total of 104 patients with H1N1 infection were evaluated, mostly referring classic influenza symptoms; in addition, diarrhea and vomiting were often referred. Clinical signs, symptoms and respiratory complications were different in the two periods. Of all patients, 18 (17%) had pneumonia. Patients older than 50 years showed a lower probability of pneumonia diagnosis when compared to children aged 0-13 (p = 0.049); a longer duration of symptoms before medical care was associated with a higher probability of pneumonia (p = 0.026). Phylogenetic analysis showed a low variability both in hemagglutinin and neuraminidase genes. In addition, no neuraminidase mutation associated with antiviral resistance was detected. A detailed description of respiratory diseases associated with H1N1 infection was provided and factors associated with its severity were investigated, thus contributing to the insight into epidemiological, clinical and microbiological knowledge of the disease.

Mid-dosing interval concentration of atazanavir and virological outcome in patients treated for HIV-1 infection.

OBJECTIVES: We investigated the clinical significance of monitoring the mid-dosing interval atazanavir (ATV) concentration (measured 12 +/- 2 h after intake; C(12 h)) in patients taking this drug once daily in the evening. METHODS: We retrospectively selected HIV-infected patients harbouring ATV-susceptible virus who underwent therapeutic drug monitoring (TDM) of ATV C(12 h) during routine out-patient visits, and we correlated C(12 h) to the 24-week virological response and toxicity. RESULTS: A total of 115 plasma samples from 86 patients (76.7% with baseline HIV RNA<50 HIV-1 RNA copies/mL) were analysed. ATV plasma concentrations showed high inter-individual variability. ATV plasma levels were higher in samples obtained from patients taking boosted regimens (P<0.001) and not concomitantly receiving acid-reducing agents (P=0.007). In a multivariate model, ritonavir boosting, use of acid-reducing agents and liver cirrhosis showed an independent association with ATV level. Virological response at 24 weeks was observed for 94 of the 115 samples (81.7%). We identified a concentration cut-off of 0.23 mg/L which predicted virological response at 24 weeks: samples with a C(12 h)< or =0.23 mg/L showed virological failure in 41.2% of cases, whereas samples with a C(12 h)>0.23 mg/L showed virological failure in 14.3% of cases (P=0.021). In multivariate analysis, C(12 h)>0.23 mg/L was an independent predictor of virological response [odds ratio (OR) 4.23, P=0.031]. ATV levels correlated with concomitant unconjugated bilirubin levels (r=0.223, P=0.037), but a concentration cut-off predictive of moderate/severe hyperbilirubinaemia could not be identified. CONCLUSIONS: We identified a C(12 h) efficacy threshold that predicted virological response; this could be useful for morning TDM in selected subjects receiving ATV in the evening. Results must be interpreted with caution given the retrospective design of the study.

Impact of hepatitis B vaccination in children born to HBsAg-positive mothers: a 20-year retrospective study.

BACKGROUND: Preventive measures remain the best approach to control the spread of hepatitis B virus (HBV) infection. PATIENTS AND METHODS: To evaluate the effectiveness of vaccination against HBV, we conducted a 20-year retrospective study on 100 subjects, born to hepatitis B surface antigen (HBsAg)-positive mothers, who had received postexposure prophylaxis at the Clinic of Infectious Diseases (Siena University, Italy) during 1984-2004. All patients were tested for the presence of HBsAg, anti-HBs and anti-HB core antigen (anti-HBc). RESULTS: Two subjects (2%) acquired the infection as shown by the presence of anti-HBc. Of the 98 patients who did not acquire the infection, 62 of these (63.3%) had an anti-HBs concentration considered protective (> or =10 mIU/ml). The percentage of protected subjects decreased in relation to time from vaccination with a significant reduction (p = 0.009) of anti-HBs geometric mean titre (GMT) after 5 years, which reached the level of 10 mIU/ml after about 15 years. No patients without protective concentration have acquired the infection as of today. Only 12% of the HBsAg-positive mothers were followed in specialized structures after pregnancy, reflecting the scarce knowledge of the problem in the general population. CONCLUSION: Our data, while confirming the effectiveness of anti hepatitis B vaccination, highlight the need for postvaccination follow-up, particularly in high-risk categories, to prolong protection, through booster doses if necessary. We show, moreover, the importance of maintaining active surveillance in the territory to improve follow-up to chronic carriers and to sensitize families.

[Retrospective study of tuberculosis in the Province of Siena]. / Studio retrospettivo sui ricoveri per tubercolosi nella Provincia di Siena.

We report here the results of a retrospective study carried out on 200 tuberculosis cases admitted to the Hospital of Siena during the period 1994-2003. For each case, epidemiological, clinical and microbiological data were collected in order to analyze the trend of tuberculosis over the years and to compare our experience with similar studies. Indigenous patients were significantly older than immigrants (60.1 vs 34.2 yrs) more frequently affected by underlying chronic diseases. Overcrowding and HIV infection were predisposing conditions in 30 subjects (15% of cases) recently arrived from high endemicity countries. Pulmonary tuberculosis (TB) was diagnosed in 71% of cases, irrespective of origin. The death rate was 5%. Microbiological investigation was positive in 74.4% of examined subjects; 9.8% of isolates were resistant to one or more antituberculous drugs. The number of cases admitted to the Hospital seems to have slowly decreased in the last few years; factors that may influence this trend are discussed. Our results confirm a distinct epidemiological pattern of the disease between indigenous patients and immigrants, which is typical of low-endemicity countries. The delay in the diagnosis and management of the disease observed in this case-series report underlines the need to improve information on TB and skill in treatment, and to maintain specialized centres.

Can laparoscopic cholecystectomy be a day surgery procedure?

BACKGROUND/AIMS: Gallbladder surgery by videolaparoscopy (VL) is now able to obtain the same goals as traditional surgery, and is associated with comparable or better results both in terms of positive surgical outcome and patient satisfaction. With public health spending under growing social and administrative pressure, and continuous efforts focusing on enhancing the efficiency of both surgical instruments and operating procedures, it is a most attractive, albeit initially challenging, prospect to regard video-laparoscopic surgery as day-case surgery. Herein, the authors assess the outpatient treatment option, due to recent technical developments and relevant major organizational and professional implications, and consider the feasibility of day-case surgery projects which should soon be implemented. METHODOLOGY: From January 1994 to December 1996, 1,334 patients underwent videolaparoscopic cholecystectomy. Of these, 898 were women and 436 men. In 1,034 of the laparoscopies gas was used and 300 were performed without gas. Out of the total 1,334 patients who were submitted to the videolaparoscopic cholecystectomy procedure with or without the use of gas, 72 (5.4%) were treated on an outpatient basis. RESULTS: In our series, 93.5% of patients reported normal post-operative functions within 24 hours; 90.2% of patients were able to take oral fluid on the same day of the operation and had normal bowel peristalsis within the first post-operative day. CONCLUSIONS: The authors assess the outpatient option treatment, due to recent technical developments and relevant major organizational and professional implications, and consider the feasibility of a day-case surgery project which should soon be implemented.

Severe hypoxia enhances the formation of erythroid bursts from human cord blood cells and the maintenance of BFU-E in vitro.

Incubation in severe hypoxia (1% oxygen) increased the number of erythroid bursts generated from full-term CD34+, or premature mononucleated, human cord blood (CB) cells, in semisolid cultures containing stem cell factor (SCF), interleukin (IL)-3 and erythropoietin (EPO). Severe hypoxia also enhanced the maintenance of erythroid burst-forming units (BFU-E) in CB cell liquid cultures. These positive effects of hypoxia on the maintenance and cloning efficiency of BFU-E did not extend to the other progenitors assayed. Hypoxia, on the other hand, markedly reduced the size and level of hemoglobinization of bursts and, in liquid cultures, suppressed the growth factor-stimulated numerical increase in BFU-E and inhibited the expression of CD36, a marker of erythroid colony-forming units and maturing erythroid precursors. However, when transferred to clonal assays incubated in air, cells from liquid cultures incubated in hypoxia or in air generated fully expanded and hemoglobinized bursts, suggesting that in hypoxia the clonogenic potential of BFU-E was maintained and the development of erythroid clones reversibly inhibited. These results indicate that hypoxia inversely regulates two subsequent phases of erythropoiesis, i.e., it enhances the maintenance of BFU-E and the early development of erythroid clones but inhibits the terminal expansion and maturation of these clones. The cloning of CB cells selected for CD34 positivity, when compared with that of the total population of mononucleated CB cells, revealed that the early development of erythroid bursts was either hypoxia-enhanced or hypoxia-insensitive, reflecting the existence of two different types of BFU-E. Hypoxia-enhanced BFU-E are relatively immature, are maintained in hypoxia but not in air, and account for a large part of CD34+ BFU-E and for a high percentage of the BFU-E in premature CB. Hypoxia-insensitive BFU-E are mostly CD34- and are largely predominant in full-term CB, and most probably correspond to a more mature type of BFU-E.

An I.T.M.O. group study on second-line treatment in advanced epithelial ovarian cancer: an attempt to identify clinical and biological factors determining prognosis.

The aim of the present study was to determine the activity of a combined regimen of mitoxantrone (DHAD) and ifosfamide (IFO) and identify clinical and biological factors with prognostic importance for the second-line treatment of ovarian cancer. The following factors were investigated for their prognostic importance: age, disease sites, platinum responsiveness, histological grade, the presence of clinically/radiologically detectable versus not detectable disease, residual disease volume after first surgery, p53 protein, c-erbB-2 oncoprotein and laminin receptor. 72 patients entered the trial. DHAD and IFO therapy led to a 15% response rate among the 47 cases with clinically/radiologically detectable disease (1 complete and 6 partial responses), with a median response duration of 4 months. The response rate was significantly different according to platinum responsiveness (4% objective responses in platinum-resistant versus 27% in platinum-sensitive disease). The time to treatment failure (TTF) and overall survival (OS) were affected by the presence of clinically detectable disease at study entry (median TTF 4 months in the presence of clinically/radiologically detectable disease versus 9 months if the disease was not similarly detectable, P = 0.02; median OS 10 months versus 21 months, P = 0.01). Initially overexpressed in only a few tumours, the c-erbB-2 oncoprotein became overexpressed in 36% of platinum-resistant tumours; this modulation did not occur in platinum-sensitive tumours. Furthermore, laminin receptor was expressed in 77% of platinum-sensitive versus 39% of platinum-resistant patients. There were no differences in p53 protein expression according to drug responsiveness.