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We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.

Increased mobilization of circulating endothelial progenitor cells may represent a new biological hallmark of myeloproliferative neoplasms. We measured circulating endothelial colony forming cells (ECFCs) in 106 patients with primary myelofibrosis, fibrotic stage, 49 with prefibrotic myelofibrosis, 59 with essential thrombocythemia or polycythemia vera, and 43 normal controls. Levels of ECFC frequency for patient's characteristics were estimated by using logistic regression in univariate and multivariate setting. The sensitivity, specificity, likelihood ratios, and positive predictive value of increased ECFC frequency were calculated for the significantly associated characteristics. Increased frequency of ECFCs resulted independently associated with history of splanchnic vein thrombosis (adjusted odds ratio = 6.61, 95% CI = 2.54-17.16), and a summary measure of non-active disease, i.e. hemoglobin of 13.8 g/dL or lower, white blood cells count of 7.8×10(9)/L or lower, and platelet count of 400×10(9)/L or lower (adjusted odds ratio = 4.43, 95% CI = 1.45-13.49) Thirteen patients with splanchnic vein thrombosis non associated with myeloproliferative neoplasms were recruited as controls. We excluded a causal role of splanchnic vein thrombosis in ECFCs increase, since no control had elevated ECFCs. We concluded that increased frequency of ECFCs represents the biological hallmark of a non-active myeloproliferative neoplasm with high risk of splanchnic vein thrombosis. The recognition of this disease category copes with the phenotypic mimicry of myeloproliferative neoplasms. Due to inherent performance limitations of ECFCs assay, there is an urgent need to arrive to an acceptable standardization of ECFC assessment.

We analysed determinants of hysterectomy and oophorectomy using data from hospital control subjects, interviewed in a large case-control study on risk factors for breast cancer, conducted since 1983 in the Greater Milan area, Italy. Out of the 2916 women interviewed 355 (12.2%) were hysterectomized. Mean age at hysterectomy was 52. The cumulative probability of hysterectomy was similar in women born during the periods from 1900 to 1909 and 1910 to 1919. It rose steadily in each subsequent cohort for all ages till the cohort born between 1930 and 1939, then decreased in the cohort born between 1940 and 1949. The cumulative probability of hysterectomy by 60 years of age was 12.8% in women born between 1900 and 1909, and of 9.8%, 16.7% and 22.0% respectively in subsequent cohorts. Concerning determinants of hysterectomy, we found no relation with education and parity. Among the 355 hysterectomized women, 178 (50.1%) underwent unilateral (40 women) or bilateral (138 women) oophorectomy. The probability of oophorectomy was higher in more educated women. Compared with women who had had hysterectomy before the age of 45, those aged between 45 and 54 reported more frequently oophorectomy (odds ratio (OR): 1.5, 95% confidence interval (CI) from 0.9 to 2.3), but the OR was only 0.8 in those aged 55 or more (95% CI from 0.3 to 2.2). We found no relation between menopausal status or cohort of birth and oophorectomy.

The objective of this study was to assess the association between alcohol drinking before and during pregnancy and the risk of spontaneous abortion using data from a case-control study conducted in Milan, Italy. A total of 462 women (median age 30 years) were admitted for spontaneous abortion (within the 12th week of gestation) to a network of obstetrics departments in the greater Milan area. Of these, 148 (32%) were between the fourth and the eighth week of gestation and 314 (68%) between the ninth and the 12th week. A control group was made up of 814 women (median age 29 years) who gave birth at term (37 weeks gestation) to healthy infants (Apgar 5th minuteor = 8, weightor = 3000 g) on randomly selected days at the same hospitals where cases had been identified. A total of 212 cases (46%) and 355 controls (47%) reported alcohol drinking before conception. Considering non-drinkers as the reference category, the relative risks (RR) of spontaneous abortion were 1.2 [95% confidence interval (CI), 0.9-1.6] and 0.8 (95% CI, 0.6-1.1), respectively, in drinkers of one to seven and more than seven drinks per week before conception. No association emerged between the duration of alcohol drinking and the risk of spontaneous abortion. A total of 166 cases (35.9%) and 263 (32.3%) controls reported any alcohol drinking during the first trimester of pregnancy. The corresponding relative risk was 1.1 (95% CI, 0.9-1.4) and no relationship emerged between the number of drinks per week and the risk of abortion.(ABSTRACT TRUNCATED AT 250 WORDS)

To analyze risk factors for ectopic pregnancy in a population at low risk for the disease.Between September 1989 and February 1991 in Milan, we conducted a case-control study on 120 cases of ectopic pregnancy and 209 controls. The control subjects gave birth at term (more than 37 weeks' gestation) to healthy infants on randomly selected days at the same hospitals where the cases had been identified.The risk of ectopic gestation was about 40% higher in smokers than in controls, and the risk estimates increased with the number of cigarettes smoked per day (chi 2(1) trend 4.21, P = .04) and the duration of smoking (chi 2(1) trend 7.31, P.01). However, smoking was not associated with the risk of ectopic pregnancy after adjustment for potential confounding factors (including history of pelvic inflammatory disease) in a multivariate analysis (relative risks [RRs] for ten or fewer and more than ten cigarettes per day versus no smoking were 0.8 and 1.1, respectively; chi 2(1) trend 0.10, P = not significant). Infertility problems or difficulty in conception were reported by 32% of the cases and 10% of the controls; the corresponding multivariate RR was 4.7 (95% confidence interval [CI] 2.3-9.5). A history of abdominal surgery was associated with about double the risk of ectopic pregnancy (multivariate RR 2.4, 95% CI 1.4-4.2). Similar estimates were found when the analysis was performed considering various types of surgery separately such as appendectomy, cesarean delivery, and other abdominal surgery. Finally, the risk of ectopic pregnancy was higher in women reporting a history of pelvic inflammatory disease (RR 2.7, 95% CI 0.9-8.7) and increased with the number of sexual partners (chi 2(1) trend 4.51, P = .03).Problems of infertility or difficulties in conception, history of pelvic inflammatory disease/salpingitis, and abdominal surgery are the main risk factors for ectopic pregnancy in this Italian study. Sexual habits also appear to have some independent effect.

Purpose: Many different treatments are suggested by guidelines to treat grade 1−2 (G1−G2) neuroendocrine tumors (NET). However, a precise therapeutic algorithm has not yet been established. This study aims at identifying and comparing the main therapeutic sequences in G1−G2 NET. Methods: A retrospective observational Italian multicenter study was designed to collect data on therapeutic sequences in NET. Median progression-free survival (PFS) was compared between therapeutic sequences, as well as the number and grade of side effects and the rate of dose reduction/treatment discontinuation. Results: Among 1182 patients with neuroendocrine neoplasia included in the ELIOS database, 131 G1–G2 gastroenteropancreatic, lung and unknown primary NET, unresectable or persistent/relapsing after surgery, treated with ≥2 systemic treatments, were included. Four main therapeutic sequences were identified in 99 patients: (A) somatostatin analogs (SSA) standard dose to SSA high dose (n = 36), (B) SSA to everolimus (n = 31), (C) SSA to chemotherapy (n = 17), (D) SSA to peptide receptor radionuclide therapy (PRRT) (n = 15). Median PFS of the second-line treatment was not reached in sequence A, 33 months in sequence B, 20 months in sequence C, 30 months in sequence D (p = 0.16). Both total number and severity of side effects were significantly higher in sequences B and C than A and D (p = 0.04), as well as the rate of dose reduction/discontinuation (p = 0.03). Conclusions: SSA followed by SSA high dose, everolimus, chemotherapy or PRRT represent the main therapeutic sequences in G1−G2 NET. Median PFS was not significantly different between sequences. However, the sequences with SSA high dose or PRRT seem to be better tolerated than sequences with everolimus or chemotherapy.

We assessed the activity and toxicity of the XELBEVOCT regimen in patients with metastatic well-to-moderately differentiated neuroendocrine neoplasms (WMD-NEN). Ancillary studies evaluated hypertension, proteinuria, and vascular endothelial growth factor (VEGF) polymorphisms in predicting progression-free survival (PFS) and the predictive role of serum vitamin D in progression-free survival and proteinuria onset. This prospective phase 2 study included 45 patients with WMD-NEN arising from various primary sites. The treatment regimen was octreotide long-acting release (LAR), 20 mg monthly, metronomic capecitabine, 2000 mg/daily, and intravenous bevacizumab, 5 mg/kg every 2 weeks, without interruption for 9 months. Bevacizumab was continued until disease progression. Partial response was obtained in 8 patients (17.8%, 95% confidence interval [CI], 6.4%-28.2%); tumor response was more frequent in pancreatic than in non-pancreatic malignancies. The median PFS was 14.9 months; median overall survival was not attained. Biochemical and symptomatic responses were observed in 52.9% and 82.3% of cases, respectively. The treatment was well tolerated. Grade 3 toxicities included hand and foot syndrome (11.1%), proteinuria (4.4%), and renal toxicity (2.2%). Proteinuria (all grades) was correlated with longer PFS (p = 0.017). There was an inverse relationship between proteinuria and vitamin D levels. VEGF polymorphisms were not associated with patient outcome. The XELBEVOCT regimen is active and well tolerated in patients with metastatic WMD-NEN. Proteinuria correlated with hypovitaminosis D status and was the best predictive factor of treatment efficacy. Trial registration number NCT01203306 .

Objectives: We analysed the association between coffee drinking before and during the three trimesters of pregnancy and the risk of preterm birth of babies normal for gestational age (NGA) or small for gestational age (SGA). Methods: Case-control study conducted in University clinics of North Italy. Cases were 502 women who delivered at < weeks of gestation. The controls included 1966 women who gave birth at term (≥37 weeks of gestation) to healthy infants on randomly selected days at the hospitals where cases had been identified. Results: There was inverse association for coffee consumption in the third trimester of pregnancy in SGA cases compared to NGA (heterogeneity test between OR: χ12 P≤0.05). In comparison with not drinkers, all the ORs of overall intake of caffeine were closed near the unity for both SGA and NGA preterm birth. Conclusion: Compared with no consumption, a low consumption of coffee during pregnancy may not have significant effects on preterm birth. © 2006 Nature Publishing Group. All rights reserved.

Objective: We have analysed the association between coffee drinking before and during the three trimesters of pregnancy and risk of small for gestational age (SGA) birth. Methods: Cases were 555 women who delivered SGA births (ie

The relationship between family history of breast, ovarian and endometrial cancer and risk of breast cancer was analysed using data from a case-control study of breast cancer conducted in the greater Milan area, Northern Italy. The cases studied were 3415 women (median age 52 years, range 23-74) who had histologically confirmed breast cancer diagnosed within the year preceding the interview. The controls were 2916 women (median age 54 years; range 21-74) in hospital for a spectrum of acute illnesses excluding gynaecological, hormonal or neoplastic conditions. A total of 375 cases (11.0%) and 128 controls (4.4%) reported a history of breast cancer in first degree relatives. Compared with women with no family history of breast cancer, the RR was 2.7 (95% confidence interval [Cl] : 2.2-3.3) in those with one first degree relative affected and 2.8 (95% Cl : 1.3-5.7) in those with two or more affected relatives. In comparison with women without family history of ovarian cancer the RR of breast cancer was 1.4 195% Cl : 0.9-2.3) for those reporting one or more first degree relatives with ovarian cancer. However, the multivariate estimate for family history of ovarian cancer, including a term for familial breast cancer, decreased to 0.8 (95% Cl : 0.5-1.4). The risk of breast cancer was similar in women reporting a family history of breast cancer (RR = 2.2) and in those reporting a family history of both breast and ovarian cancer (RR = 2.5), in comparison with women reporting no family history of breast and/or ovarian cancer. When the relation with family history of breast cancer was analysed in strata of women with and without family history of ovarian cancer, no difference was found in the RR estimates: the RR for family history of breast cancer was 2.8 in women with family history of ovarian cancer and 2.7 in those without history of ovarian cancer. No relation was found between history of endometrial cancer in first degree relatives and risk of breast cancer.