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The aim of this double-blind, randomized, placebo-controlled, 12-week study was to assess the efficacyof rifabutin (450 or 600 mgld) in the treatment of disseminated nontuberculous mycobacterial infection in patients with AIDS. Companion drugs in both arms of the study were ethambutol, clofazimine, and isoniazid. Because of low accrual, the study was prematurely terminated when a total of 382 patients had been enrolled, of which 200 were eligible (i.e., their specimens were culturepositive for Mycobacterium avium complex [MAC] or Mycobacterium xenopi at baseline) and 102 were evaluable (i.e., they were eligible, were treated for a minimum of 6 weeks, and had at least one culture assessment after baseline). The original protocol called for a total of 220 evaluable patients. At week 12, rifabutin treatment was associated with higher, although nonsignificant, rates of bacteriologic conversion than was the placebo arm, with regard to both the eligible patients (25% vs. 18%)and the evaluable patients (45%vs. 38%).Corresponding median times to culture conversion were 42 vs. 63 days (eligible patients) and 43 vs. 69 days (evaluable patients). No significant difference was observed in clinical improvement, mortality, or toxicity between the two treatment arms. The addition of rifabutin to a triple-drug regimen may contribute to the clearance of disseminated MAC infection in patients with AIDS, without causing additional toxicity. [ABSTRACT FROM PUBLISHER]

Purpose: Fibroblast growth factor (FGF) signaling regulates tumor growth and vascularization and partly mediates antiangiogenic escape from VEGF receptor (VEGFR) inhibitors. Dovitinib (TKI258) is a tyrosine kinase inhibitor (TKI) that inhibits FGF receptor (FGFR), VEGFR, and platelet-derived growth factor receptor, which are known drivers of antiangiogenic escape, angiogenesis, and tumor growth in renal cell carcinoma (RCC)., Experimental Design: Patients with advanced or metastatic RCC were treated with oral dovitinib 500 mg/day (5-days-on/2-days-off schedule). The study population was enriched for patients previously treated with a VEGFR TKI and an mTOR inhibitor., Results: Of 67 patients enrolled, 55 patients (82.1%) were previously treated with ≥1 VEGFR TKI and ≥1 mTOR inhibitor (per-protocol efficacy set). The 8-week overall response rate and disease control rate in this population were 1.8% and 52.7%, respectively. Disease control rate during the entire study period was 56.4% (50.9% ≥4 months). Median progression-free survival and overall survival in the entire population were 3.7 and 11.8 months, respectively. Pharmacodynamic analyses demonstrated dovitinib-induced inhibition of VEGFR (as determined by increased levels of placental growth factor and decreased levels of soluble VEGFR2) and FGFR (as determined by increased FGF23 serum measures). The most frequently reported treatment-related adverse events of all grades included nausea (65.7%), diarrhea (62.7%), vomiting (61.2%), decreased appetite (47.8%), and fatigue (32.8%)., Conclusion: Dovitinib was shown to be an effective and tolerable therapy for patients with metastatic RCC who had progressed following treatment with VEGFR TKIs and mTOR inhibitors. Clin Cancer Res; 20(11); 3012-22. ©2014 AACR., (©2014 American Association for Cancer Research.)

Background: In China, there are currently no approved therapies for the treatment of metastatic renal cell carcinoma (mRCC) following progression with vascular endothelial growth factor (VEGF)-targeted agents. In the phase 3 RECORD-1 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus afforded clinical benefit with good tolerability in Western patients with mRCC whose disease had progressed despite VEGF receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. This phase 1b study was designed to further evaluate the safety and efficacy of everolimus in VEGFr-TKI-refractory Chinese patients with mRCC., Methods: An open-label, multicenter phase 1b study enrolled Chinese patients with mRCC who were intolerant to, or progressed on, previous VEGFr-TKI therapy (N = 64). Patients received everolimus 10 mg daily until objective tumor progression (according to RECIST, version 1.0), unacceptable toxicity, death, or study discontinuation for any other reason. The final data analysis cut-off date was November 30, 2011., Results: A total of 64 patients were included in the study. Median age was 52 years (range, 19-75 years) and 69% of patients were male. Median duration of everolimus therapy was 4.1 months (range, 0.0-16.1 months). Expected known class-effect toxicities related to mTOR inhibitor therapy were observed, including anemia (64%), hypertriglyceridemia (55%), mouth ulceration (53%), hyperglycemia (52%), hypercholesterolemia (50%), and pulmonary events (31%). Common grade 3/4 adverse events were anemia (20%), hyperglycemia (13%), increased gamma-glutamyltransferase (11%), hyponatremia (8%), dyspnea (8%), hypertriglyceridemia (6%), and lymphopenia (6%). Median PFS was 6.9 months (95% CI, 3.7-12.5 months) and the overall tumor response rate was 5% (95% CI, 1-13%). The majority of patients (61%) had stable disease as their best overall tumor response., Conclusions: Safety and efficacy results were comparable to those of the RECORD-1 trial. Everolimus is generally well tolerated and provides clinical benefit to Chinese patients with anti-VEGF-refractory mRCC., Trial Registration: clinicaltrials.gov, NCT01152801.

Background and Objectives: The RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to address an unmet medical need by providing everolimus prior to commercial availability, and also to further assess the safety and efficacy of everolimus in patients with VEGFr-TKI-refractory mRCC., Patients and Methods: REACT (Clinicaltrials.gov: NCT00655252) was a global, open-label, expanded-access programme in patients with mRCC who were intolerant of, or who had progressed on or after stopping treatment with, any available VEGFr-TKI therapy. Patients received everolimus 10mg once daily, with dose and schedule modifications allowed for toxicity. Patients were closely monitored for the development of serious and grades 3/4 adverse events (AEs). Response was assessed by RECIST every 3months for the first year and every 6months thereafter., Results: A total of 1367 patients were enroled. Safety findings and tumour responses were consistent with those observed in RECORD-1, with no new safety issues identified. The most commonly reported serious AEs were dyspnoea (5.0%), pneumonia (4.7%) and anaemia (4.1%), and the most commonly reported grades 3/4 AEs were anaemia (13.4%), fatigue (6.7%) and dyspnoea (6.5%). Best overall response was stable disease in 51.6% and partial response in 1.7% of patients. Median everolimus treatment duration was 14weeks., Conclusion: Everolimus is well tolerated in patients with mRCC and demonstrates a favourable risk-benefit ratio., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: Luteinizing hormone-releasing hormone (LHRH) agonists (e.g., triptorelin) reduce ovarian estrogen production in premenopausal women with hormone-sensitive breast cancer. Aromatase inhibitors (e.g., exemestane) inhibit extraovarian production of estrogen and may further reduce circulating estrogens when combined with an LHRH agonist., Methods: Healthy premenopausal women were randomized to receive 3.75 mg triptorelin (T) on days 1 and 29 with 25 mg exemestane (EX) or matched placebo once daily for 8 weeks, from day 1 to day 56. The primary objective was to evaluate the effect of T +/- EX on estradiol (E(2)) suppression by comparing the AUC(day 36-57 )for the 2 treatments. Secondary objectives included evaluation of estrone (E(1)), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) suppression; effects of EX on the T-induced gonadotrophin and estrogen flare; pharmacokinetics (PK); and safety., Results: Twenty-eight (14 in each arm) were evaluable for efficacy and PK. Mean plasma estrogen levels (AUC(day 36-57)) were significantly lower for subjects who received T + EX than for subjects who received T alone (20.6 vs. 54.0 pg d/ml [-62%; P < 0.05], and 38.9 vs. 198.0 pg d/ml [-80%; P < 0.01] for E(2) and E(1), respectively). Coadministration of EX did not affect the initial flare or subsequent suppression of LH and FSH following the first dose of T, or the PK of T. Both treatments were well tolerated., Conclusions: Coadministration of T and EX resulted in greater estrogen suppression than when T was given alone. These findings could translate into improved clinical outcomes for premenopausal breast cancer patients receiving LHRH agonists.

Purpose: To determine the recommended starting doses and pharmacokinetics of irinotecan in cancer patients with impaired liver function treated on a weekly schedule., Experimental Design: Patients with solid tumors who had impaired liver function were enrolled into four groups based on baseline serum total bilirubin and aspartate aminotransferase (AST)/alanine aminotransferase (ALT): Group 1 (n = 19): total bilirubin 1.5 to 3.0 x institutional upper limit of normal (IULN) and ALT/AST

The objectives of this phase I/II trial were to determine the maximum tolerated dose, toxicities, and the dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non small-cell lung cancer (NSCLC). Seventy-three patients with stage IIIB/IV NSCLC were enrolled in this multicenter, phase I/II study. The initial regimen was paclitaxel 225 mg/m2 over 3 hours, followed by carboplatin at an area under the curve (AUC) of 6 over 30 minutes on day 1 and CPT-11 starting at 40 mg/m2 over 90 minutes on days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of the original seven patients. The regimen was amended with doses reduced to paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 at 40 mg/m2, all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m2 and 125 mg/m2 before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m2. Doses suitable for phase II study were determined to be paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 100 mg/m2. The pri-mary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia. On the phase I portion of the study, objective tumor response was observed in 39% (12 of 31, 95% confidence interval: 22%-58%). The median time to tumor progression was 6.8 months, median survival was 11.0 months, and 1-year survival probability was 0.46. These data were confirmed in the phase II portion with a 30% objective response rate, median time to progression of 5.6 months, median survival of 12.5 months, and a 1-year survival probability of 0.50. In conclusion, CPT-11 100 mg/m2, paclitaxel 175 mg/m2, and carboplatin AUC = 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable, warranting further study of this regimen. A review of other irinotecan-containing triplet combinations is presented.

Purpose: To determine the maximum-tolerated dose, toxicities, and dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with stage IIIB/IV NSCLC were enrolled to this multicenter, phase I study. The initial regimen was paclitaxel 225 mg/m(2)/3 h, followed by carboplatin area under the curve (AUC) 6 over 30 minutes on day 1, and CPT-11 starting at 40 mg/m(2) over 90 minutes, days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of seven patients. The regimen was amended, with doses reduced to paclitaxel 175 mg/m(2)/3 h, carboplatin AUC 5 and CPT-11 at 40 mg/m(2), all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m(2) then 125 mg/m(2) before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m(2)., Results: Thirty-three patients were enrolled; 32 patients were assessable for safety, and 31 were assessable for tumor response. The primary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia (16 patients [50%], with six [19%] developing neutropenic fever). Objective tumor response was observed in 39% (12/31, 95% confidence interval, 22% to 58%). The median time to tumor progression was 6.8 months, median survival 11.0 months, and 1-year survival probability 0.46., Conclusion: CPT-11 100 mg/m(2), paclitaxel 175 mg/m(2), and carboplatin AUC 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable.

Background: Irinotecan is a topoisomerase I inhibitor that prolongs survival in patients with colorectal cancer refractory to fluorouracil (5-FU) and leucovorin (LV). This demonstrated activity of irinotecan as effective second-line therapy for colorectal cancer led to evaluation of combination irinotecan/5-FU/LV as first-line therapy for patients with metastatic disease. The results of two prospective phase III randomized, controlled, multicenter, multinational clinical trials in patients with previously untreated metastatic colorectal cancer served as the basis for U.S. and European approval of irinotecan/5-FU/LV for this indication. An overview of the findings of these two pivotal studies provides insights regarding the application of this new combination in clinical practice., Methods: Patients were randomly assigned to receive 5-FU/LV, either alone, or with concurrent irinotecan. The study conducted primarily in North America (study 1), employed bolus 5-FU/LV schedules, while the study performed primarily in Europe (study 2), employed infusional 5-FU/LV regimens. Major endpoints included tumor response rate, time to tumor progression (TTP), overall survival, quality of life, and safety., Results: In study 1, the respective confirmed response rates for irinotecan/5-FU/LV versus 5-FU/LV were 39% and 21% (p <.001); median TTPs were 7.0 months and 4.3 months, respectively (p =.004). In study 2, response rates for irinotecan/5-FU/LV versus 5-FU/LV alone were 35% and 22% (p =.005); median TTPs were 6.7 months and 4.4 months, respectively (p <.001). Survival time increased significantly with irinotecan/5-FU/LV versus 5-FU/LV alone in both studies (study 1: median 14.8 months versus 12.6 months, p =.042; study 2: median 17.4 months versus 14.1 months, p =.032). The combined analysis of the data from the two studies showed median survivals of 15.9 months versus 13.3 months, favoring the irinotecan-containing combinations (stratified-by-study p =.003). Patients in study 1 had a 36% lower risk of tumor progression and a 20% lower risk of death with the irinotecan combination than with 5-FU/LV alone; comparable risk reduction values in study 2 were 42% and 23%. While grade 3 diarrhea and vomiting were more common with irinotecan/5-FU/LV, grade 4 neutropenia, neutropenic fever, and mucositis were less common with irinotecan/5-FU/LV than with the Mayo Clinic 5-FU/LV regimen., Conclusion: The combination of irinotecan/5-FU/LV is superior to 5-FU/LV alone as first-line therapy for patients with metastatic colorectal cancer, offering consistently improved tumor control and prolonged survival. Irinotecan-based combination therapy sets a new survival standard for the treatment of this life-threatening disease.

Background: The combination of fluorouracil and leucovorin has until recently been standard therapy for metastatic colorectal cancer. Irinotecan prolongs survival in patients with colorectal cancer that is refractory to treatment with fluorouracil and leucovorin. In a multicenter trial, we compared a combination of irinotecan, fluorouracil and leucovorin with bolus doses of fluorouracil and leucovorin as first-line therapy for metastatic colorectal cancer. A third group of patients received irinotecan alone., Methods: Patients were randomly assigned to receive irinotecan (125 mg per square meter of body-surface area intravenously), fluorouracil (500 mg per square meter as an intravenous bolus), and leucovorin (20 mg per square meter as an intravenous bolus) weekly for four weeks every six weeks; fluorouracil (425 mg per square meter as an intravenous bolus) and leucovorin (20 mg per square meter as an intravenous bolus) daily for five consecutive days every four weeks; or irinotecan alone (125 mg per square meter intravenously) weekly for four weeks every six weeks. End points included progression-free survival and overall survival., Results: Of 683 patients, 231 were assigned to receive irinotecan, fluorouracil, and leucovorin; 226 to receive fluorouracil and leucovorin; and 226 to receive irinotecan alone. In an intention-to-treat analysis, as compared with treatment with fluorouracil and leucovorin, treatment with irinotecan, fluorouracil, and leucovorin resulted in significantly longer progression-free survival (median, 7.0 vs. 4.3 months; P=0.004), a higher rate of confirmed response (39 percent vs. 21 percent, P<0.001), and longer overall survival (median, 14.8 vs. 12.6 months; P=0.04). Results for irinotecan alone were similar to those for fluorouracil and leucovorin. Grade 3 (severe) diarrhea was more common during treatment with irinotecan, fluorouracil, and leucovorin than during treatment with fluorouracil and leucovorin, but the incidence of grade 4 (life-threatening) diarrhea was similar in the two groups (<8 percent). Grade 3 or 4 mucositis, grade 4 neutropenia, and neutropenic fever were less frequent during treatment with irinotecan, fluorouracil, and leucovorin. Adding irinotecan to the regimen of fluorouracil and leucovorin did not compromise the quality of life., Conclusions: Weekly treatment with irinotecan plus fluorouracil and leucovorin is superior to a widely used regimen of fluorouracil and leucovorin for metastatic colorectal cancer in terms of progression-free survival and overall survival.

Background: To evaluate the possible influence of a series of clinical angiographic and surgical variables on the 1-year patency of saphenous vein (SV) coronary graft, data collected prospectively in a multicenter randomized clinical trial were analyzed., Methods and Results: The study group included 349 patients--847 SV distal anastomoses--who underwent angiography at a median time of 374 days after surgery. By logistic binomial regression analysis, age, sex, smoking habits, hypertension, high cholesterol, previous myocardial infarction, and angina were not found to be significant factors leading to graft occlusion. Among the angiographic and surgical variables, the following were retained as predictive of higher occlusion risk: (1) vessel diameter (< or = 1.5 mm versus > 1.5 mm, odds ratio (OR) = 2.46); (2) the location of the grafted vessel, namely, the right coronary artery versus the left anterior descending (OR = 2.15); and (3) the wall motion of the vessel-dependent myocardial region (altered versus normal: OR = 2.12). The presence of two or three risk factors multiplied the occlusion risk up to 11-fold., Conclusions: The study suggests that vessel diameter, wall motion of the vessel-dependent myocardial region, and location of the grafted vessel are the main determinants of SV coronary graft patency during the first postoperative year. Knowledge of these artery-specific factors may provide a basis for estimating the risk of graft occlusion, thereby modifying surgical strategy and postoperative surveillance.

In clinical trials aimed at assessing the efficacy of drugs after coronary artery grafting, statistical analysis is usually carried out on a per-patient basis and on a per-graft basis. Owing to the independence of responses among patients, the former outcome is analyzed by assuming a binomial model. However, this model cannot be directly adopted in analyzing the latter outcome because multiple vein grafts in the same patient do not act independently. It has been suggested that patients be considered as clusters of distal anastomoses, subsequently comparing the frequencies of occlusion under different treatments after adjusting the variance of each frequency for the size of the cluster. Alternatively, one can measure the intraclass (intrapatient) correlation coefficient and adopt distribution functions that include this quantity as one of the parameters. This approach has been adopted by many authors although the studies differed in the statistical model used to represent this kind of data. Two probability functions, Altham's and beta-binomial, have found wide application in different biomedical fields. Both are able to model the extrabinomial variability since their tails tend to zero more slowly than those of the binomial distribution. An alternative to adopting a specific probabilistic model consists of specifying a mixed model or a Markov-like susceptibility model. These models follow the same rationale since they assume the existence of two processes, one that causes an individual to become susceptible to occlusion, the other that determines the subsequent probability of occlusion in the individual. After presenting these models in a unified framework, this paper compares the estimates obtained by fitting the models to data gathered at coronary angiography 1 year after surgery by the SINBA group on a total of 847 saphenous vein anastomoses in 349 patients. Finally, the issue concerning the contribution of each patient to the effective sample size is discussed.

Objective: To analyse the determinants of caesarean section rates in Italy., Design: Analysis of information using a standard form on all the deliveries after the 28th week of gestation routinely collected by the Italian Central Institute of Statistics., Setting: National data of all Italian deliveries in the periods 1980-1983., Subjects: A total of more than 2,400,000 deliveries occurred in Italy in the period and are considered in this analysis., Results: The frequency of caesarean section rose from 11.2/100 deliveries in 1980 to 14.5/100 in 1983. Caesarean section rates were lower in the Southern (less rich) areas, and rose steadily with maternal age, being about three times higher in women aged greater than or equal to 40 years than in teenagers. Maternal education was directly associated with caesarean section rates: compared with women with only primary school education, those with a college education reported an about 40% higher rate of caesarean section, but this difference dropped markedly after allowance for maternal age and birthweight. The section rate was 13.3/100 deliveries in public hospitals and 11.8/100 in private ones, but this reflected the different utilization of public and private services in various geographical areas. Birthweight and gestational age at delivery were important determinants of caesarean section rates; lowest values were observed for very-low-birthweight and very preterm deliveries and babies weighing 3000-3999 g and term deliveries. Caesarean section rates were about 20% higher in nulliparous than in parous women and the rates increased with number of stillbirths or miscarriages; further, the rate ratio was about double in multiple than in single births., Conclusion: Caesarean section rates in Italy in the early 1980s were still lower than in North America, but their determinants share several similarities with those reported in other areas.

Determinants of stillbirths, perinatal and infant mortality in Italy have been analyzed using information collected routinely by the Italian Central Institute of Statistics on more than 2,400,000 births and 33,000 infant deaths in the period 1980-1983. Individual records included data on maternal (i.e. age, education, obstetric history) and fetal characteristics (sex, birth weight, gestational week at birth). The Italian stillbirth, perinatal and infant (1st-365th day of life) mortality rates in the period considered were respectively 7.7/1000 births, 16.4/1000 births and 13.5/1000 livebirths. Perinatal and infant mortality was extremely elevated in the very-low-birth-weight category. About 90% of liverbirths weighing less than 1000 g died within the first year of life, but this fell to about 45% in babies weighing 1000-1499 g. Among other factors, stillbirth, perinatal and infant mortality rates were elevated among males, born to older women and in higher birth rank and multiple pregnancies. These findings persisted, although less markedly, after adjustment for weight. Mortality rates were about 50-70% higher in less educated women. This finding was not markedly changed after adjustment for birth weight and maternal age, suggesting that socio-economic factors are per se important determinants of perinatal and infant mortality in Italy.

The frequency and determinants of cesarean section rates in Italy were analyzed using data collected routinely by the Italian Central Institute of Statistics on more than 2,400,000 deliveries in 1980-83. The rate of cesarean section in Italy rose from 11.2/100 deliveries in 1980 to 14.5 in 1983. This increase was comparable with other European countries, although the rate of abdominal deliveries was still about 30-40% lower than in the United States and Canada. In the southern (and less rich) areas, the rate of cesarean section was about 40% lower than in the North or Centre of Italy. The rate of cesarean birth rose constantly with maternal age; being in comparison with teen-agers, about three times higher in women aged 45 years or more. Compared with women with primary or intermediate degree, those with university education reported about 40% higher rate of cesarean section, but this differences was markedly reduced after taking into account maternal age and birth weight. In southern areas of the country the frequency of cesarean birth was about 40% higher in public hospital than in private ones (11.5 and 8.1/100 deliveries, respectively), while in northern and central areas the frequency of cesarean birth was higher in private hospital than public ones (18.5 vs 14.7/100 deliveries in the North, and 19.6 vs 14.6/100 deliveries in the Centre). There were relationships between cesarean rates and birth weight or gestational weeks. The lowest values were observed in very low birth weight (less than or equal to 999 gr) as in babies weighing 3000-3999 gr and in deliveries occurred between the 25th and 27th gestational weeks and in term deliveries. About 55% of deliveries with breech presentation were delivered by cesarean section.

Determinants of stillbirth, perinatal and infant mortality in Italy have been analyzed using information collected routinely by the Italian Central Institute of Statistics on more than 2,400,000 births and 33,000 infant deaths in the period 1980-1983. Individual records include data on maternal (for example age, education, obstetric history) and fetal (sex, birth weight, gestational week at birth) characteristics. The Italian stillbirth, perinatal and infant (1st-365th day of life) mortality rates were respectively 7.7/1000 births, 16.4/1000 births and 13.5/1000 livebirths for the considered period. Perinatal and infant mortality was impressive in very low birth weight. About 90% of livebirths weighing less than 1000g died within the first year of life, but this percentage decreased to about 45% in babies weighing 1000-1499g. As a whole, low birth weight explained more than 70% of deaths. Further, stillbirth, perinatal and infant mortality rates were higher in male babies, in older women and in higher birth rank. These findings persist, although less markedly, after adjustment for weight. Mortality rates were about 60-70% higher in less educated women. Stillbirth, perinatal and infant mortality rates were 20 to 30% higher in Southern Italy, as compared to the North of the country. This finding was not markedly changed after adjustment for birth weight and maternal age and education, suggesting that socio-economic factors are per se important determinants of perinatal and infant mortality in Italy, and explain in terms of population attributable risk, about 15% of stillbirths or deaths within the first year of life.