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Aim: Pregnancies of women with pregestational diabetes are at risk of after-meal glucose peaks and late after-meal hypoglycemia, particularly at breakfast. We aimed to explore the effectiveness of a specific feature of insulin pump therapy called superbolus in preventing these glucose swings., Methods: In this retrospective observational study, we analyzed continuous glucose monitoring data of patients with type 1 diabetes in pregnancy who were advised to use superbolus to manage their breakfast. Some of the postprandial basal insulin delivery was partially reduced and delivered instead as additional insulin bolus on top of a normal bolus. Outcomes of interest were one hour after breakfast glucose levels, the time in glucose range for after breakfast period, the number of late hypoglycemic episodes., Results: Overall, 21 consecutive pregnant women with type 1 diabetes (mean age 34.3 ± 5.5 years, mean pregestational body mass index 23.7 ± 4.7 kg/m 2 , HbA1c levels during pregnancy 6.1 ± 0.6%) were studied. Superbolus reduced after breakfast glucose peaks (one hour after breakfast glucose levels 130 ± 17 mg/dL vs 123 ± 10 mg/dL before and after superbolus use, respectively, P = .01), improved the time in glucose range for after breakfast period (70.4% vs 50.8%, P = .001), and reduced the number of late hypoglycemic episodes (3 [1-5] vs 1 [0-2], P < .0001)., Conclusion: Superbolus was effective in avoiding after-meal glucose peaks, increased postprandial glucose time in target, without late hypoglycemia occurrence. It represents a valid option for the treatment of pregnant women with type 1 diabetes using insulin pump., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Intermittently Scanned Continuous Glucose Monitoring (isCGM) devices are increasingly being used in patients with type 2 diabetes mellitus (T2DM) on insulin therapy for their benefits regarding disease management. Evidence of isCGM use in patients with T2DM on basal or non-insulin therapy is lacking. This study aimed at assessing the efficacy and safety of isCGM in this population. This was an observational, retrospective, real-world study enrolling patients with T2DM who were starting the use of isCGM. Data from medical records (i.e., demographics, clinical characteristics, laboratory assessments, and isCGM metrics) were collected over three time periods (baseline, 3 and 6 months). The endpoints were glycated haemoglobin (HbA1c) changes and changes in isCGM metrics as defined by the International Consensus from baseline to 3 months and 6 months. Overall, 132 patients were included (69.5% male; mean age 68.2 ± 11.0 years; mean disease duration 19.0 ± 9.4 years; 79.7% on basal insulin ±non-insulin therapy; mean baseline HbA1c 8.1% ± 1.3%). The estimated mean change in HbA1c was statistically significant at three (-0.4 ± 1.0%; p = 0.003) and six months (-0.6 ± 1.3%; p < 0.0001). In conclusion, isCGM proved to be effective and safe in improving glycaemic control in patients with T2DM on basal insulin or non-insulin therapy.

Type 2 diabetes mellitus (T2DM) is characterized by high blood glucose levels and lipid alterations. Besides pharmacological treatment, lifestyle modifications and nutraceuticals can be used to manage glucose and lipid profiles, which is crucial for preventing, or avoiding, serious consequences associated with the condition. This randomized controlled clinical trial on 75 patients with T2DM evaluated the effects of a combination of myo-inositol and d-chiro-inositol (40:1), α-lactalbumin, Gymnema sylvestre, and zinc on glucose and lipid profile. The intention-to-treat analysis displayed no significant differences in glucose parameters between the groups; however, the study group displayed reduced levels of total cholesterol ( p = 0.01) and LDL ( p = 0.03) after 3 months of supplementation. A subgroup analysis involving patients who did not modify their antidiabetic therapy, after 6 months displayed improved levels of total cholesterol ( p = 0.03) and LDL ( p = 0.04) in the study group versus placebo, along with a greater body weight reduction ( p = 0.03) after 3 months. Furthermore, within the study group, levels of HDL ( p = 0.03) and triglycerides ( p = 0.04) improved after 3 months. These findings support supplementation with myo-inositol and d-chiro-inositol (40:1), α-lactalbumin, Gymnema sylvestre, and zinc as an adjuvant and safe strategy to manage the lipid profiles of patients with T2DM.

Background: Highly cross-linked polyethylene with vitamin E (VE-HXLPE) has shown superior tribological properties and has been rapidly adopted in total hip arthroplasty. However, the majority of studies compare VE-HXLPE to conventional or moderately cross-linked polyethylene using standard femoral head sizes. This study's purpose was 2-fold: (1) compare radiographic femoral head penetration (FHP) between VE-HXLPE and HXLPE and (2) evaluate FHP in large femoral heads ≥40 mm., Methods: One hundred forty-two consecutive primary total hip arthroplasties using ceramic femoral heads (n = 84 VE-HXLPE; n = 58 HXLPE) in a single implant system were retrospectively reviewed. FHP was measured radiographically utilizing Martell method at 4-week, 1-year, and latest radiographs. FHP, cup position, and demographic variables were compared between VE-HXLPE and HXLPE liners., Results: Median linear FHP was lower for VE-HXLPE compared to HXLPE during the initial "bedding-in" period between 4-week and 1-year (0.383 vs 0.551 mm, P = .650) and between 1-year and latest follow-up (0.131 vs 0.270 mm/y, P = .636) although without statistical significance. Acetabular cup inclination and anteversion did not influence linear or volumetric FHP (P ≥ .204). Large femoral heads (≥40 mm) were predictive of higher FHP during the early bedding-in period (P ≤ .025) but did not have an effect beyond 1 year in multivariate regression with numbers available. No radiographic osteolysis was observed in any case., Conclusion: These findings support others that VE-HXLPE is the optimal polyethylene bearing surface to minimize FHP during the bedding-in period and beyond. Surprisingly, large ceramic femoral heads appear to influence FHP during the initial bedding-in period but do not increase FHP beyond 1 year. Further longer term follow-up remains warranted., Level of Evidence: III., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: The new advanced hybrid closed loop insulin infusion systems have the potential to significantly improve glycaemic control. The aim of this study was to evaluate the effectiveness of the Minimed 780G system in 59 patients with type 1 diabetes., Methods and Results: Glucose control obtained by using the system in automatic mode at 1-2 months of activation, at 2-4 months, at 4-6 months, and beyond 6 month was compared with those obtained with the system in manual mode. A significant improvement in time-in-range and in time-above-range throughout the follow-up was observed, as well as a significant reduction in time-below-range (<54 mg/dl) after 6 months, a significant reduction of the glucose variability and of HbA1c. After switching the mode, all target percentages lied on the average within the recommended ranges by literature consensus and no severe hypoglycemia nor ketoacidosis episodes were recorded., Conclusion: The Minimed 780G allowed a rapid and progressive improvement of the overall glucose control., Competing Interests: Declaration of competing interest The Authors declare that there is no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The use of a televisit service complying with efficiency and safety regulatory parameters was effective in significantly improving HbA1c levels of people with T1D after a one-year follow-up period. No acute diabetes-related complications occurred. Patients were highly satisfied with the service. Televisit is a valid option for diabetes management., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Health risks at population level may be investigated with different types of environmental studies depending on access to data and funds. Options include ecological studies, case-control studies with individual interviews and human sample analysis, risk assessment or cohort studies. Most public health projects use data and methodologies already available due to the cost of ad-hoc data collection. The aim of the article is to perform a literature review of environmental exposure and health outcomes with main focus on methodologies for assessing an association between water and/or soil pollutants and cancer. A systematic literature search was performed in May 2019 using PubMed. Articles were assessed by four independent reviewers. Forty articles were identified and divided into four groups, according to the data and methods they used, i.e.: (1) regression models with data by geographical area; (2) regression models with data at individual level; (3) exposure intensity threshold values for evaluating health outcome trends; (4) analyses of distance between source of pollutant and health outcome clusters. The issue of exposure assessment has been investigated for over 40 years and the most important innovations regard technologies developed to measure pollutants, statistical methodologies to assess exposure, and software development. Thanks to these changes, it has been possible to develop and apply geo-coding and statistical methods to reduce the ecological bias when considering the relationship between humans, geographic areas, pollutants, and health outcomes. The results of the present review may contribute to optimize the use of public health resources., (© 2020. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Purpose: Endocrine therapy (ET) is the mainstream adjuvant treatment for ER-positive breast cancer (BC). We analysed 9293 ER-positive BC patients diagnosed in nine European countries in 2009-2013 to investigate how comorbidities at diagnosis, age, stage and subtype affected ET use over time, and relapse., Methods: Adjusted odds ratios (ORs) and 95% confidence intervals (95%CIs) of receiving ET were estimated according to Charlson comorbidity, age, stage and subtype using logistic regression. The 2-year cumulative incidence and adjusted sub-hazard ratios (SHRs) of relapse were estimated using competing risk analysis, with all-cause death as the competing event. The z-test was used to assess differences in the proportion of patients receiving ET in 1996-1998 and 2009-2013., Results: Ninety percent of the patients started adjuvant ET, range 96% (Belgium, Estonia, Slovenia, Spain)-75% (Switzerland). ORs of starting ET were lower for women aged > 75 years, with severe comorbidities, or luminal B HER2-positive cancer. The factors independently increasing the risk of relapse were: not receiving ET (SHR 2.26, 95%CI 1.02-5.03); severe comorbidity (SHR 1.94, 95%CI 1.06-3.55); luminal B, either HER2 negative (SHR 3.06, 95%CI 1.61-5.79) or positive (SHR 3.10, 95%CI 1.36-7.07); stage II (SHR 3.20, 95%CI 1.56-6.57) or stage III (SHR 7.41, 95%CI 3.48-15.73). ET use increased significantly but differently across countries from 51-85% in 1996-1998 to 86-96% in 2009-2013., Conclusions: ER-positive BC patients in Europe are increasingly prescribed ET but between-country disparities persist. Older women and women with severe comorbidity less frequently receive ET. ET omission and severe comorbidity independently predict early disease relapse.

Aim: To assess the impact of age, comorbidities and endocrine therapy (ET) in older breast cancer (BC) patients treated with hypofractionated radiotherapy (Hypo-RT)., Methods: From June 2009 to December 2017, we enrolled in this study 735 ER-positive BC patients (stage pT1-T2, pNx-1, M0 and age ≥ 65 years) receiving hypo-RT and followed them until September 2019. Baseline comorbidities included in the hypertension-augmented Charlson Comorbidity Index were retrospectively retrieved. Logistic regression model estimated adjusted-odds ratios (ORs) of ET prescription in relation to baseline patient and tumor characteristics. Competing risk analysis estimated 5-year cumulative incidence function (CIF) of ET discontinuation due to side effects (with BC progression or death as competing events), and its effect on locoregional recurrence (LRR) and distant metastasis (DM) (with death as competing event)., Results: ET has been prescribed in 89% patients. In multivariable analysis, the odds of ET prescription was significantly reduced in older patients (≥ 80 years, OR 0.08, 95% CI 0.03-0.20) and significantly increased in patients with moderate comorbidity. Patients ≥ 80 years discontinued the prescribed therapy earlier and more frequently than younger (65-69 years) patients (p = 0.060). Five-year CIF of LLR, DM and death from causes other that BC were 1.7%, 2.2% and 7.5%, respectively. Patients who discontinued ET had higher chance of LRR (p = 0.004). ET use did not impact on OS in any of the analyzed groups., Conclusions: In older patients, ET did not show a benefit in terms of overall survival. Further studies focusing on tailored treatment approaches are warranted to offer the best care in terms of adjuvant treatment to these patients.

Background: Primary tumor characteristics, which are readily available to all clinicians, may aid in selecting the optimal adjuvant therapy for patients with breast cancer (BC). Herein, we investigated the relationship between tumor size, hormone receptor and HER2 status, Ki67 and age with axillary lymph node metastases (ALNM) in early-BC patients., Methods: We analyzed data on consecutive 2600 early-BC cases collected in the registry of Fondazione IRCC Istituto Nazionale dei Tumori, Milano, Italy. Correlation between Ki67 and primary tumor size (T-size) was calculated by Spearman's rank correlation coefficient. Association of ALNM with Ki67 and other tumor characteristics was investigated by logistic regression. Adjusted odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated in all cases, and separately analyzed according to age, T-size and BC subtype., Results: Large tumor size strongly associated to ALNM, with an adjusted odds ratio (OR) for each 5-mm increase of 1.32 (95% CI 1.24-1.41), except for triple-negative BC (TNBC) cases. In tumors =10 mm, without lymphovascular invasion, representing the strongest predictor of ALNM (OR 6.09, 95% CI 4.93-7.53), Ki67 resulted particularly informative, with a fourfold increased odds of ALNM for values > 30%., Conclusions: These results raise the question whether axillary node status is redundant in cases with exceptionally good features, i.e., small tumors with low Ki67, or in those candidate to adjuvant systemic treatment/radiotherapy anyway including TNBC, and support the incorporation of primary BC tumor characteristics as stratification factors in ongoing trials aiming at de-escalating axillary surgical procedures.

Background: Ductal carcinoma in situ (DCIS) is considered a morphologic precursor of invasive cancer and is often treated with adjuvant whole-breast irradiation and endocrine therapy, as if it were an invasive cancer. Our aim was to provide further support for treatment de-escalation or enrollment of such patients in active surveillance trials., Methods: We retrospectively analyzed data on patients with conservatively treated primary DCIS subsequently diagnosed with ipsilateral invasive breast cancer (IBC) at 2 comprehensive breast cancer centers. From their merged databases, we identified 50 cases with full details on tumor grade, hormone receptor expression, and HER2 amplification, for both the primary DCIS and the corresponding IBC, and we assessed the similarities and differences between the two., Results: Distributions of hormone receptors were similar in primary DCIS and IBC, while high-grade and HER2-positive status was less common in IBC than in primary DCIS. The positivity for estrogen receptors (ER) and well-differentiated or moderately differentiated morphology in the primary DCIS persisted in 90% of the matching IBC. Changes in progesterone receptor expression were slightly more common than those in ER expression. Overall consistency for the luminal-like receptors subtype was found in 90% of cases., Conclusion: The high consistency between the features of primary DCIS and those of subsequent IBC (in the rare but not negligible cases of local failure) should be borne in mind when considering the therapeutic options. Treatment de-escalation and accrual of patients for active surveillance trials could be appropriate for luminal-like precursors.

To assess the efficacy, and the acute and late toxicity of hypofractionated radiotherapy (Hypo-RT), and the impact of age and comorbidities on disease progression and death in elderly breast cancer (BC) patients. Women aged ≥65 years who received Hypo-RT (42.4 Gy in 16 fractions, plus a boost for high-risk patients) were considered for the present analysis. Competing risk analysis was used to estimate the 5-year cumulative incidence of BC progression and BC-related death, calculating the adjusted subhazard ratios (SHR) with 95% confidence intervals (95%CI) in relation to age, hypertension-augmented Charlson Comorbidity Index (hCCI), tumor characteristics, and chemotherapy. The sample included 794 patients with a median age of 74 years (range 65-91 years). At the baseline, 70% of these patients had at least one comorbidity. With a median follow-up of 48.3 months, the 5-year cumulative incidence of BC progression and BC-related death was 6.7% (95%CI 4.8%-9.2%) and 2.3% (95%CI 1.2%-3.9%), respectively. Old age (≥80 years) and a high burden of comorbidity (hCCI ≥ 2) were independently associated with BC progression. Hypo-RT is safe in elderly BC patients, but age and comorbidities influence BC progression. Further studies are warranted., (© 2019 Wiley Periodicals, Inc.)

Triple negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options. New opportunities are emerging from current comprehensive characterization of tumor immune infiltration and fitness. Therefore, effectiveness of current chemotherapies and novel immunotherapies are partially dictated by host inflammatory and immune profiles. However, further progress in breast cancer immuno-oncology is required to reach a detailed awareness of the immune infiltrate landscape and to determine additional reliable and easily detectable biomarkers. In this study, by analyzing gene expression profiles of 54 TNBC cases we identified three TNBC clusters displaying unique immune features. Deep molecular characterization of immune cells cytolytic-activity and tumor-inflammation status reveled variability in the local composition of the immune infiltrate in the TNBC clusters, reconciled by tumor-infiltrating lymphocytes counts. Platelet-to-lymphocyte ratio (PLR), a blood systemic parameter of inflammation evaluated using pre-surgical blood test data, resulted negatively correlated with local tumoral cytolytic activity and T cell-inflamed microenvironment, whereas tumor aggressiveness score signature positively correlated with PLR values. These data highlighted that systemic inflammation parameters may represent reliable and informative markers of the local immune tumor microenvironment in TNBC patients and could be exploited to decipher tumor infiltrate properties and consequently to select the most appropriate therapies.

Background: The objective is to show variations in the number of non-tenured personnel (NTP) in a public health research centre (IRCCS) between 30th June 2016 and 31st December 2017. In this time interval, the issue of NTP was at the centre of governmental discussions., Methods: Data collection was performed from CVs and scientific publications of NTP working at the Fondazione IRCCS Istituto Nazionale dei Tumori (INT). We compared the characteristics of NTP entering or leaving INT and those of NTP who remained in the considered time interval., Results: NTP in INT counted 465 members of staff at 30th June 2016 and 472 at 31st December 2017. 75% of these works in the research. 26% of NTP left INT and their position resulted entirely substituted by other NTP. NTP staff who left are mainly aged under 40 and show fewer publications than those who stayed. Newly acquired NTP are younger and show a fewer number of publications compared to the personnel who left., Conclusions: 1 out of 4 NTP members of staff moved to a new job during a period in which the uncertain future of NTP research staff was under the spotlight. It appears that IRCCS are progressively being identified as suitable for hands-on, post university internships from which researchers would then choose to move, in search of a new job in public or private centres, with a consequent decline of IRCCS' role in health research.

The purpose of the study was to examine adherence to hormone therapy (HT) in elderly breast cancer patients (≥ 65 years old) treated with hypofractionated radiotherapy. We analyzed data on 550 ER-positive breast cancer patients given hypofractionated whole-breast radiotherapy from June 2009 to September 2016. Baseline comorbidities considered in the hypertension-augmented Charlson Comorbidity Index (hCCI) were retrospectively retrieved. Total hCCI scores were classified as no comorbidity (hCCI = 0), low burden of comorbidity (hCCI = 1), and high burden of comorbidity (hCCI ≥ 2). Competing risk analysis was used to estimate the 5-year cumulative incidence of HT discontinuation. Fine and Gray models were used to estimate the adjusted subhazard ratio (SHR) of HT discontinuation by hCCI score. HT was initially prescribed for 85.6% of patients and almost all of them (468/471) took it for at least one month. It was subsequently discontinued by 45 patients (9.6%), for an overall 5-year cumulative incidence of 11.7%. The 5-year cumulative incidence of HT discontinuation rose from 3.9% in the youngest age group (65-69 years) to 23.3% in the oldest (≥ 80 years) (p = 0.005). Baseline comorbidity had some effect on the likelihood of discontinuing HT, but only among patients with a low burden of comorbidity (hCCI = 1, SHR 2.00, 95%CI 0.95-4.20). Adherence to HT was better in our sample than in the literature, probably because patients were selected and motivated to continue HT. This confirms the importance of communication with patients to improve adherence to HT. We confirmed the association between HT discontinuation and older age, while comorbidity had a limited influence.

Aims: The growing incidence of diabetes and the need to contain healthcare costs empower the necessity to identify new models of care. Telemedicine offers an acknowledged instrument to provide clinical health care at a distance, increasing patient compliance and the achievement of therapeutical goals. The objective was to test the feasibility and the efficacy in the improvement of the glycemic control of the teleconsultation for patients with type 1 diabetes mellitus., Methods: A randomized open-label, parallel arms, controlled trial was conducted in two diabetes centers in Italy. Participants affected by type 1 diabetes mellitus have been randomly (1:1) assigned to receive their visits as standard or a web-based care. Patients in the teleconsultation group can arrange their appointments on a Web site and can also have access to web educational courses or to nutritional and psychological counseling. The primary outcome was the assessment of glycemic control by HbA1c measurement after a 12-month follow-up., Results: Overall 74 participants were followed for 1 year. HbA1c changes were not statistically different within (p = 0.56 for standard care group; p = 0.45 for telemedicine group) and between (p = 0.60) groups when considering differences from baseline to the end of the study. Patients randomized to teleconsultation reported reduced severe hypoglycemic episodes (p = 0.03). In addition, they were largely satisfied with the activities, perceived a good improvement in the self-management of the diabetes, and reported to have a time saving and a cost reduction., Conclusions: In conclusion, TELEDIABE proposes a new system for the management of patients with type 1 diabetes mellitus.

Five years of adjuvant therapy with anti-estrogens reduce the incidence of disease progression by about 50% in estrogen receptor-positive breast cancer patients, but late relapse can still occur after anti-estrogens have been discontinued. In these patients, excessive androgen production may account for renewed excessive estrogen formation and increased risks of late relapse. In the 50% of patients who do not benefit with anti-estrogens, the effect of therapy is limited by de novo or acquired resistance to treatment. Androgen receptor and epidermal growth factor receptor overexpression are recognized mechanisms of endocrine resistance suggesting the involvement of androgens as activators of the androgen receptor pathway and as stimulators of epidermal growth factor synthesis and function. Data from a series of prospective studies on operable breast cancer patients, showing high serum testosterone levels are associated to increased risk of recurrence, provide further support to a role for androgens in breast cancer progression. According to the above reported evidence, we proposed to counteract excessive androgen production in the adjuvant setting of estrogen receptor-positive patients and suggested selecting postmenopausal patients with elevated levels of serum testosterone, marker of ovarian hyperandrogenemia, for adjuvant treatment with a gonadotropins-releasing hormone analogue (medical oophorectomy) in addition to standard therapy with anti-estrogens. The proposed approach provides an attempt of personalized medicine that needs to be further investigated in clinical trials., (© 2017 Society for Endocrinology.)

Objective: Subcutaneous insulin absorption is one of the key factors affecting glycemic control in patients with diabetes mellitus under insulin therapy. Insulin-induced subcutaneous lipohypertrophy has been reported to impair insulin regular absorption and hence glycemic control. So far, lipohypertrophy diagnosis has only been clinical. This study aims at evaluating the possible role of ultrasound scan in the assessment of subcutaneous lipohypertrophy in patients affected by type 1 diabetes mellitus., Methods: A pilot observational retrospective study was performed in 20 patients affected by type 1 diabetes mellitus. In these patients the areas with clinical evidence of lipohypertrophy dependent on the insulin injections were characterized by the presence of tissues that at the ultrasound scan resulted similar to fibrotic tissues (hyperechogenic) or to an interstitial edema or to fat tissues (hypoechogenic). It was utilized a multi frequency linear probe (6-18 MHz). The patients were advised to avoid insulin injections on the areas with lipohypertrophy scanned by the ultrasound and the HbA1c changes were evaluated 3 months later., Results: The lipohypertrophic areas presented at least three different aspects upon ultrasound assessment: the iso-hyperechogenic one, with a predominant fibrotic component; the isoechogenic one, with "large tangles" fibrotic elements and the iso-hypoechogenic aspect with no fibrotic elements. When patients were advised to avoid insulin injections on areas with lipohypertrophy defined by ultrasound scan, 3 months after the first evaluation HbA1c had significantly improved (basal HbA1c 7.87 ± 0.56 versus 7.67 ± 0.52 3 months later, p = 0.029). No significant improvements of the HbA1c were found in the control matched group in which lipohypertrophy was only clinically valued through inspection and palpation., Conclusions: Ultrasound scan can help identify and characterize the lipohypertrophic areas and this might be useful to improve glycemic control.

Minimizing endogenous estrogen production and activity in women at high risk for breast cancer is a prominent approach to prevention of the disease. A number of clinical trials have shown that the administration of selective-estrogen receptor modulators or aromatase inhibitors significantly reduces the incidence of breast cancer in healthy women. Unfortunately, these drugs often produce adverse effects on the quality of life and are, therefore, poorly accepted by many women, even those who are at high risk for breast cancer. We propose a novel alternative approach to decreasing estrogen production: suppression of ovarian synthesis of the androgen precursors of estrogens by administration of long-acting gonadotropin-releasing hormone analogs to women with ovarian stromal hyperplasia. The specific target population would be elderly postmenopausal women, at increased risk of breast cancer, and with high blood levels of testosterone, marker of ovarian hyperandrogenemia, and recognized factor of risk for breast cancer. Testosterone levels are measured at baseline to identify women at risk and during the follow-up to evaluate the effectiveness of therapy. The postmenopausal ovary is an important source of excessive androgen production which originates from the ovarian interstitial cell hyperplasia frequently present in breast cancer patients. We propose to counter the source of androgen excess in women with ovarian stromal hyperplasia, thus reducing the substrate for estrogen formation without completely inhibiting estrogen synthesis. Available evidence indicates that gonadotropin-releasing hormone analogs can be safely used for breast cancer prevention in postmenopausal women.

Purpose: To illustrate the out-of-pocket (OOP) costs incurred by a population-based group of patients from 5 to 10 years since their cancer diagnosis in a country with a nationwide public health system., Methods: Interviews on OOP costs to a sample of 5-10 year prevalent cases randomly extracted from four population-based cancer registries (CRs), two in the north and two in the south of Italy. The patients' general practitioners (GPs) gave assurance about the patient's physical and psychological condition for the interview. A zero-inflated negative binomial model was used to analyze OOP cost determinants., Results: Two hundred six cancer patients were interviewed (48 % of the original sample). On average, a patient in the north spent €69 monthly, against €244 in the south. The main differences are for transport, room, and board (TRB) to reach the hospital and/or the cancer specialist (north €0; south €119). Everywhere, OOP costs without TRB costs were higher for patients with a low quality of life., Conclusions: Despite the limited participation, our study sample's characteristics are similar to those of the Italian cancer prevalence population, allowing us to generalize the results. The higher OOP costs in the south may be due to the scarcity of oncologic structures, obliging patients to seek assistance far from their residence. Implications for cancer survivors Cancer survivors need descriptive studies to show realistic data about their status. Future Italian and European descriptive studies on cancer survivorship should be based on population CRs and involve GPs in order to approach the patient at best.

Obesity and metabolic syndrome are risk and prognostic factors for breast cancer (BC) and are associated with chronic inflammation. We investigated the association between distinct BC subtypes and markers of adiposity, dysmetabolisms, and inflammation. We analyzed 1779 patients with primary invasive BC treated at a single institution, for whom anthropometric and clinical-pathological data were archived. BC subtypes were classified by immunohistochemical staining of ER, PR, HER2, and Ki67, and their relations with the study markers were assessed by multinomial logistic regression. Adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated taking luminal A as reference. All subtypes more aggressive than luminal A were significantly more frequent in younger (<45 years) than older women. Before menopause, luminal B HER2-negative tumors were positively associated with large waist (OR 2.55, 95 % CI 1.53-4.24) and insulin resistance (OR 1.90, 95 % CI 1.05-3.41); luminal B HER2-positive tumors with large waist (OR 2.11, 95 % CI 1.03-4.35) and triple-negative tumors with overweight (OR 3.04, 95 % CI 1.43-6.43) and high C-reactive protein (p trend = 0.026). In postmenopausal women aged <65, luminal B HER2-negative (OR 1.94, 95 % CI 1.16-3.24) and luminal B HER2-positive tumors (OR 2.48, 95 % CI 1.16-5.27) were positively related with metabolic syndrome. Dysmetabolisms and inflammation may be related to different BC subtypes. Before menopause, triple-negative cancers were related to obesity and chronic inflammation, and aggressive luminal subtypes to abdominal adiposity. After menopause, in women aged <65 these latter subtypes were related to metabolic syndrome. Control of adiposity and dysmetabolism can reduce the risk of aggressive BC subtypes, improving the prognosis.

Background: Significant advances in the management of patients with lymphoid and myeloid malignancies entered clinical practice in the early 2000's. The EUROCARE-5 study database provides an opportunity to assess the impact of these changes at the population level by country in Europe. We provide survival estimates for clinically relevant haematological malignancies (HM), using the International Classification of Diseases for Oncology 3, by country, gender and age in Europe., Methods: We estimated age-standardised relative survival using the complete cohort approach for 625,000 adult patients diagnosed in 2000-2007 and followed up to 2008. Survival information was provided by 89 participating cancer registries from 29 European countries. Mean survival in Europe was calculated as the population weighted average of country-specific estimates., Results: On average in Europe, 5-year relative survival was highest for Hodgkin lymphoma (81%; 40,625 cases), poorest for acute myeloid leukaemia (17%; 57,026 cases), and intermediate for non-Hodgkin lymphoma (59%; 329,204 cases), chronic myeloid leukaemia (53%; 17,713 cases) and plasma cell neoplasms (39%; 94,024 cases). Survival was generally lower in Eastern Europe and highest in Central and Northern Europe. Wider between country differences (>10%) were observed for malignancies that benefited from therapeutic advances, such as chronic myeloid leukaemia, chronic lymphocytic leukaemia, follicular lymphoma, diffuse large B-cell lymphoma and multiple myeloma. Lower differences (<10%) were observed for Hodgkin lymphoma., Conclusions: Delayed or reduced access to innovative and appropriate therapies could plausibly have contributed to the observed geographical disparities between European regions and countries. Population based survival by morphological sub-type is important for measuring outcomes of HM management. To better inform quality of care research, the collection of detailed clinical information at the population level should be prioritised., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: The study investigated the geographic variation of mortality risk for hematological malignancies (HMs) in order to identify potential high-risk areas near an Italian petrochemical refinery., Material and Methods: A population-based case-control study was conducted and residential histories for 171 cases and 338 sex- and age-matched controls were collected. Confounding factors were obtained from interviews with consenting relatives for 109 HM deaths and 267 controls. To produce risk mortality maps, two different approaches were applied and compared. We mapped (1) adaptive kernel density relative risk estimation for case-control studies which estimates a spatial relative risk function using the ratio between cases and controls' densities, and (2) estimated odds ratios for case-control study data using Generalized Additive Models (GAMs) to smooth the effect of location, a proxy for exposure, while adjusting for confounding variables., Results: No high-risk areas for HM mortality were identified among all subjects (men and women combined), by applying both approaches. Using the adaptive KDE approach, we found a significant increase in death risk only among women in a large area 2-6 km southeast of the refinery and the application of GAMs also identified a similarly-located significant high-risk area among women only (global p-value<0.025). Potential confounding risk factors we considered in the GAM did not alter the results., Conclusion: Both approaches identified a high-risk area close to the refinery among women only. Those spatial methods are useful tools for public policy management to determine priority areas for intervention. Our findings suggest several directions for further research in order to identify other potential environmental exposures that may be assessed in forthcoming studies based on detailed exposure modeling., (Copyright © 2015 Elsevier Inc. All rights reserved.)

In clinical research, many potentially useful variables are available via the routine activity of cancer center-based clinical registries (CCCR). We present the experience of the breast cancer clinical registry at Fondazione IRCCS "Istituto Nazionale dei Tumori" to give an example of how a CCCR can be planned, implemented, and used. Five criteria were taken into consideration while planning our CCCR: (a) available clinical and administrative databases ought to be exploited to the maximum extent; (b) open source software should be used; (c) a Web-based interface must be designed; (d) CCCR data must be compatible with population-based cancer registry data; (e) CCCR must be an open system, able to be connected with other data repositories. The amount of work needed for the implementation of a CCCR is inversely linked with the amount of available coded data: the fewer data are available in the input databases as coded variables, the more work will be necessary, for information technology staff, text mining analysis, and registrars (for collecting data from clinical records). A cancer registry in a comprehensive cancer center can be used for several research aspects, such as estimate of the number of cases needed for clinical studies, assessment of biobank specimens with specific characteristics, evaluation of clinical practice and adhesion to clinical guidelines, comparative studies between clinical and population sets of patients, studies on cancer prognosis, and studies on cancer survivorship.

Purpose: We investigated the risk of death for hematological malignancies (HMs) in the area surrounding an Italian petrochemical refinery, where atmospheric concentrations of benzene (known carcinogen) had not been adequately monitored in the past., Methods: We performed a population-based case-control study, using conditional logistic regression to estimate odds ratios (ORs) of HM death, with 95 % confidence intervals (CIs), and p trends, in relation to tertiles of time-weighted average residential proximity to the refinery. We identified 177 HM deaths and 349 sex- and age-matched controls from municipal files. Confounding factors were investigated from interviews with consenting relatives for 109 HM deaths and 178 matched controls., Results: For males and females combined, risk of HM death was unrelated to residential proximity. For females, ORs of HM death by increasing tertiles of proximity were 1, 2.74 (95 % CI 1.48-5.09, significant) and 1.49 (95 % CI 0.76-2.92) (p trend 0.184). For the subgroup of persons who plausibly spent most of their time at home (long-term retired, homemakers or unemployed, 53 cases, 79 controls), the ORs of leukemia plus non-Hodgkin lymphoma death (38 cases, 56 controls) by increasing tertiles of proximity were 1, 3.44 (95 % CI 1.04-11.37, significant) and 3.25 (95 % CI 0.82-12.87) (p trend 0.083)., Conclusions: No increased risk of HM death for males and females combined living close to the refinery was found. However, the findings for females and a subgroup plausibly spending most of their time at home suggest a relation between increased risk of HM death and residential proximity to the refinery.

Background: Androgen receptors (AR) are frequently expressed in breast cancers, but their implication in cancer growth is still controversial. In the present study, we further investigated the role of the androgen/AR pathway in breast cancer development., Methods: AR expression was evaluated by immunochemistry in a cohort of 528 postmenopausal breast cancer patients previously examined for the association of serum testosterone levels with patient and tumor characteristics. AR expression was classified according to the percentage of stained cells: AR-absent (0%) and AR-poorly (1%-30%), AR-moderately (>30%-60%), and AR-highly (>60%) positive., Results: Statistical analysis was performed in 451 patients who experienced natural menopause. AR-high expression was significantly related with low histologic grade and estrogen receptor (ER)- and progesterone receptor (PR)-positive status (P trend<0.001). Mean testosterone levels were significantly higher in the AR-high category than in the other categories combined (P=0.022), although a trend across the AR expression categories was not present. When women defined by ER status were analyzed separately, regression analysis in the ER-positive group showed a significant association of high testosterone levels with AR-highly-positive expression (OR 1.86; 95% CI, 1.10-3.16), but the association was essentially due to patients greater than or equal to 65 years (OR 2.42; 95% CI, 1.22-4.82). In ER-positive group, elevated testosterone levels appeared also associated with AR-absent expression, although the small number of patients in this category limited the appearance of significant effects (OR 1.92; 95% CI, 0.73-5.02): the association was present in both age groups (<65 and ≥65 years). In the ER-negative group, elevated testosterone levels were found associated (borderline significance) with AR-absent expression (OR 2.82, 95% CI, 0.98-8.06). In this ER-negative/AR-absent subset of tumors, elevated testosterone levels cannot stimulate cancer growth either directly or after conversion into estrogens, but they probably induce increased synthesis of some other substance that is responsible for cancer growth through binding to its specific receptor., Conclusions: The findings in the present study confirm that testosterone levels are a marker of hormone-dependent breast cancer and suggest that the contemporary evaluation of ER status, AR expression, and circulating testosterone levels may identify different subsets of cancers whose growth may be influenced by androgens.

Background: To further investigate the role of sex hormones in breast cancer, we assessed the relations of circulating estradiol and testosterone to tumor size and estrogen receptor (ER) status., Method: This was a cross-sectional study including 492 postmenopausal breast cancer patients. The relation of circulating hormones to patient and tumor characteristics was assessed using the Fisher or Cuzick tests. Multivariable logistic regression was used to estimate the odds ratios (ORs) of having tumors =2 cm (vs and <2 cm) and having ER-positive tumors (vs ER-negative) with increasing quartiles of estradiol and testosterone., Results: Mean estradiol and testosterone levels increased significantly with increasing tumor size. The ORs of tumors =2 cm increased significantly with increasing quartiles of estradiol (Ptrend and <0.001) and testosterone (Ptrend=0.005). When adjusted for estradiol, the association between testosterone and tumor size was no longer significant. Mean testosterone levels were higher in ER-positive than ER-negative patients (p and <0.001), while mean estradiol levels did not differ significantly between the two ER categories (p=0.192). The ORs of having an ER-positive tumor increased significantly with increasing quartiles of testosterone (Ptrend=0.002), whereas the increase with increasing estradiol quartiles was not significant (Ptrend=0.07)., Conclusion: The association of both hormones with tumor size implies that both are involved in tumor growth, testosterone mainly by conversion to estradiol. The strong association of testosterone with ER contrasts with the weak association of estradiol with ER and confirms testosterone as a marker of hormone-dependent tumors. These findings suggest that testosterone evaluation might be useful to better identify patients with hormone-dependent disease.

Androgens are involved in the development of breast cancer, although the mechanisms remain unclear. To further investigate androgens in breast cancer, we examined the relations between serum testosterone and age, body mass index (BMI), tumor size, histologic type, grade, axillary node involvement, estrogen receptor status, progesterone receptor status, and HER2 overexpression in a cross-sectional study of 592 postmenopausal breast cancer patients. Mean testosterone differences according to categories of patient and tumor characteristics were assayed by Fisher's or Kruskall-Wallis test as appropriate; adjusted odds ratios (OR) of having a tumor characteristic by testosterone tertiles were estimated by logistic regression. Testosterone concentrations were significantly higher in women with BMI >or=30 versus BMI <25. ORs of having a tumor >or=2 cm increased significantly with increasing testosterone tertiles, and the association was stronger in women >/=65 years. The OR of having infiltrating ductal carcinoma was significantly higher in the highest compared with the lowest testosterone tertile. ORs of having estrogen receptor- and progesterone receptor-negative versus estrogen receptor- and progesterone receptor-positive tumors decreased significantly with increasing testosterone tertiles. In women >or=70 years, those with high testosterone had a significantly greater OR of HER2-negative cancer than those with low testosterone. These results support previous findings that high-circulating testosterone is a marker of hormone-dependent breast cancer. The age-related differences in the association of testosterone with other disease and patient characteristics suggest that breast cancers in older postmenopausal women differ markedly from those in younger postmenopausal women. The relationship between testosterone and HER2 status in the oldest patients merits further investigation.

Aims: To compare the effect of continuous subcutaneous insulin infusion (CSII) and multiple daily insulin injections (MDI) on albumin excretion rate (AER) in Type 1 diabetic patients., Methods: In a 3-year multicentre retrospective observational study, 110 Type 1 diabetic patients treated with CSII were compared with 110 patients treated with MDI matched at baseline for age, sex, diabetes duration and HbA(1c). At entry, 90 patients in each group had normal AER and 20 persistent microalbuminuria. AER, estimated glomerular filtration rate (eGFR), HbA(1c,) lipids and blood pressure were assessed., Results: HbA(1c) was lower in the CSII than in the MDI group (8.1 +/- 0.9 vs. 8.4 +/- 1.3%; P < 0.005 after 3 years). Blood pressure and eGFR were similar during the study. AER [median (95% confidence interval)], similar at baseline [6.0 microg/min (9, 21) in the CSII group vs. 4.4 (8, 16) in the MDI group, NS] was significantly lower in the patients treated with CSII both at year 2 and at year 3 of follow-up [4.7 microg/min (6, 12) vs. 6.4 (13, 29), P < 0.002]. This difference was observed even when normo- and microalbuminuric patients were analysed separately. Nine patients progressed to microalbuminuria in the MDI group and only one in the CSII group. Nine patients regressed to normoalbuminuria in the CSII group, whereas only two regressed to normoalbuminuria in the MDI group., Conclusions: Despite a small benefit in terms of improved glycaemic control, CSII therapy may be useful in decreasing the progressive increase in AER in Type 1 diabetic patients.

Aim: To verify whether, with thorough practical and theoretical training, well-controlled, non-complicated diabetic patients can safely go diving underwater with no additional medical or metabolic risks., Methods: Twelve diabetic patients participated in the study after undergoing training focused on their diabetic status. Two dives per day were scheduled during two five-day stays on the island of Ventotene (Italy). Capillary blood glucose (BG) was checked at 60, 30 and 10 minutes before diving, and corrective measures adopted if necessary, based on BG absolute levels and dynamics. A device for continuous subcutaneous glucose monitoring (CGM), expressly modified for the purpose, was worn during dives., Results: Data were gathered from 90 dives; mean BG at 60, 30 and 10 minutes before diving was 205.8+/-69.6 mg/dL, 200.0+/-66.4 mg/dL and 200.5+/-61.0mg/dL, respectively. In 56 of the 90 dives, supplementary carbohydrates or insulin were necessary, but only one dive was interrupted on account of hypoglycaemic symptoms. Mean post-dive BG was 158.9+/-80.8 mg/dL. CGM recordings showed that glucose levels gradually decreased during the dives (nadir: -19.9%)., Conclusion: Experienced, well-controlled, complication-free young diabetic patients can safely go scuba diving, provided that they apply a rigorous protocol based on serial pre-dive BG measurements. The specific variables of underwater diving do not appear to involve significant additional risks of hypoglycaemia.

Background: The role of retinol (vitamin A) in breast cancer prognosis has never been investigated in postmenopausal women. We prospectively assessed the long-term prognostic role of retinol plasma levels in a cohort of postmenopausal breast cancer patients., Patients and Methods: We investigated 208 women self-reported as postmenopausal operated on for T(1-2)N(0)M(0) breast cancer who participated in a chemoprevention trial as controls and never received chemotherapy or hormone therapy. Plasma samples were collected 3 months (median) after surgery and assayed within 3 weeks for retinol. Minimum and median potential follow-up were 12 and 15 years, respectively. The main analyses were on all women and on a subgroup ages >or=55 years, assumed too old to be in perimenopause. The main end point was breast cancer death. Breast cancer survival was estimated by the Kaplan-Meier method. The hazard ratios of breast cancer death by retinol level were estimated by Cox models stratified for age, where relevant, and recruitment period, and adjusted for tumor size and histology., Results: At 12 years, patients with low retinol (<2.08 micromol/L, median of distribution) had lower breast cancer survival than those with high retinol (log-rank P = 0.052); the difference was significant for women >or=55 years (log-rank P = 0.006). The adjusted hazard ratios for low versus high retinol were 2.11 (95% confidence interval, 1.08-4.14) for all women and 3.58 (95% confidence interval, 1.50-8.57) for those >or=55 years., Conclusions: Low plasma retinol strongly predicts poorer prognosis in postmenopausal breast cancer patients. Retinol levels should be determined as part of the prognostic workup.

Purpose: High endogenous testosterone is associated with increased breast cancer (BC) risk. We designed this study specifically to assess the long-term prognostic role of testosterone in a cohort of postmenopausal BC patients., Patients and Methods: We considered 194 postmenopausal women, operated on for early BC (T1-2N0M0), who never received chemotherapy or hormonal therapy, and who participated in a fenretinide BC prevention trial as untreated controls. Blood samples were collected 3 months (median) after surgery; plasma samples, stored at -80 degrees C, were radioimmunoassayed for testosterone. Median follow-up was 14 years. The main end point was any cancer event. Event-free survival was estimated by the Kaplan-Meier method. Hazard ratios (HRs) of events by testosterone level were estimated by the Cox model, adjusting for age, tumor size, and histology., Results: Patients with high testosterone (> or = 0.40 ng/mL, median of distribution) had significantly lower event-free survival than those with low testosterone (log-rank P = .004). The adjusted HR of patients with high versus low testosterone was 2.05 (95% CI, 1.28 to 3.27). High testosterone was also associated with a significantly higher risk of BC events (relapse and second primary) with an adjusted HR of 1.77 (95% CI, 1.06 to 2.96). Eleven second primaries (non-BC) occurred in the high-testosterone group, four in the low-testosterone group., Conclusion: High plasma testosterone strongly predicts poorer prognosis in postmenopausal BC patients not administered adjuvant therapy. Testosterone levels should be determined as part of the prognostic work-up.

Aims and Background: Cancer burden estimates in Italian regions are available for the period 1970-2010 as a result of the project "I TUMORI IN ITALIA" connected with EUROCHIP, the European project on cancer control. The Italian health-care system is organized at a regional level, so regional estimates of cancer indicators are useful to identify priorities for cancer plans. We compared cancer site-specific epidemiological estimates by 3 macro-areas (obtained by grouping regions) to suggest priorities for Italian cancer control plans, both at national and regional levels., Methods: Mortality and incidence estimates for all cancers combined and for stomach, colorectal, lung, breast and prostate cancers were downloaded from the website www.tumori.net and aggregated in broad age classes (0-54, 55-74 and 75-84 years) and macro-areas (northern, central and southern Italy)., Results: Historically, Southern Italy had a lower cancer risk than the Center and North. After 2000 this epidemiological picture disappeared and the incidence and mortality rates in the Center are reaching those of the North. Also the weight of various cancer sites on all cancers has changed in Italy in the last decades. Lung cancer is still the most frequent cancer in the male population in the South, while in the Center-North it has been surpassed by prostate cancer and colorectal cancer. The lung cancer weight on all cancer deaths is increasing in women. Prostate cancer has become the most frequent male cancer in the Center-North in the age class 55-84. Breast cancer is the most frequent cancer in the female population and its incidence rates in the North are higher than those in the Center-South for all age classes. Colorectal cancer incidence rates have dramatically increased in men and colorectal cancer is nowadays the second cancer diagnosed in women in all age classes and macro-areas., Discussion: From the epidemiological data here presented we derived the following suggestions and observations for cancer control plans: (a) tobacco prevention should focus on the male population in the South, and on female populations in the country as a whole; (b) prevention concerning diet and physical activity (risk factors for colorectal cancer) should be considered mainly for men at a national level; (c) the coverage of breast cancer screening programs should be increased in the Center-South; (d) colorectal cancer screening should be promoted at a national level; (e) PSA testing (that is not actually included among the screening programs recommended) for prostate cancer is probably more widespread in the Center-North, resulting in an increased incidence without any evident decline in mortality as yet.

Aims and Background: The growing number of cancer survivors in Italy is expected to continue to increase as a consequence of population aging and survival improvements, but few estimates are currently available, particularly on the national and regional scale. The purpose of this work is to present detailed and updated prevalence estimates in Italy over the period 1970-2010 by cancer site (all cancers combined, stomach, colon and rectum, lung, breast and prostate) and gender., Methods: Prevalence was derived with the MIAMOD statistical method, using cancer-specific mortality and relative survival as input data. Survival data from the Italian cancer registries were modeled to derive a national estimate for each cancer site and sex. To estimate prevalence trends, survival was assumed to improve in the future with the same rate observed in the period 1978-1994. A double scenario for survival--increasing or stationary--was considered to decompose the prevalence growth from 1995 to 2005 by its determinants: demographic changes, incidence and survival dynamics. The prevalence estimates were also decomposed by disease duration (2, 5 and 10 years) and by age (0-44, 45-59, 60-74 and 75-99)., Results: The proportion of cancer survivors in 2010 is expected to be about 4% in women and 3% in men, about twice the values attained in 1990. The highest dynamics was observed for prostate cancer, with a three-fold increase just in the 1995-2005 period (from 212 to 623 per 100,000), whereas in absolute terms breast cancer presented the highest levels (1700 per 100,000 in 2010). The overall number of cancer prevalent cases is expected to rise by about 48% in the decennium 1995-2005 (from 1,152,000 to 1,709,000), and this growth is mainly attributable to incidence dynamics (+21%), then to survival improvements (+14%) and population aging (13%). In 2005, the 2-year prevalent cases were estimated to be 20% of all cancer survivors, 21% between 2 and 5 years from the diagnosis, 23% between 5 and 10 years, with 36% surviving for more than 10 years. Prevalence proportion was very high in the elderly (12.6% for 75-84 years and 8% for 60-74 years)., Conclusions: Updated prevalence data with appropriate coverage of the national territory are essential to define priorities in health care management and to develop cancer control programs. Prevalence by disease duration and by age should be the basis for planning research on the quality of life of cancer survivors, as long as cancer continues to become an even more chronic disease.

Objective: HIV lipodystrophy is a common complication of highly active anti-retroviral therapy, characterized by both metabolic and morphological features. The most feared morphological feature is body fat redistribution leading to HIV lipodystrophy. GH is known to induce reduction of visceral obesity and body fat redistribution in adults., Design: A crossover, double-blind protocol of GH treatment (6 months of recombinant human GH (rhGH) at 0.2 IU/kg per week) vs placebo (6 months of placebo with a 2 month wash-out between periods) was performed., Subjects and Setting: Thirty HIV-infected patients with lipodystrophy were recruited in the Outpatient Clinic of the Division of Infectious Diseases of San Raffaele Scientific Institute in Milan, Italy., Main Outcome and Results: Our data demonstrate an effect of low-dose rhGH administration in reducing trunk adiposity in HIV patients with lipodystrophy (Delta from basal: -394 +/- 814 g, P = 0.048 with respect to placebo. Data are given as mean +/- standard deviation). A trend to an increase of arm depots was also shown (Delta from basal: +43 +/- 384 g, P = NS with respect to placebo). Interestingly, no detrimental metabolic effects on glucose tolerance and lipid levels were found following the administration of 0.2 IU/kg per week of rhGH for 6 months., Conclusions: Low-dose GH administration is an effective treatment in reducing trunk obesity in HIV-infected patients with lipodystrophy.

There is evidence that abnormal glucose metabolism may contribute to the risk of breast cancer. The measurement of markers of glucose metabolism could help to identify women at risk for breast cancer. Serum fructosamine is one such marker. In this study, we investigated whether prediagnostic serum fructosamine was associated with breast cancer. Between 1987 and 1992, 10,786 women ages 35 to 69 were recruited in Italy for a prospective study. Women with a history of cancer or on hormone therapy were excluded at baseline. Blood samples were collected after 12 hours fasting from all participants at recruitment. After 5.5 years of follow-up, 144 breast cancer cases were identified and four matched controls were selected from the cohort; serum fructosamine levels were measured in both groups at baseline. Adjusted odds ratios (OR) for the highest tertile of serum fructosamine compared to the lowest was 1.60 [95% confidence interval (CI), 0.95-2.73]. In premenopausal women, the OR was 1.58 (95% CI, 0.76-3.40) and in postmenopausal women, the OR was 1.60 (95% CI, 0.76-3.48). Serum fructosamine levels tended to be positively associated with breast cancer risk independent of menopausal status.

Because of large intra-individual variation in hormone levels, few studies have investigated the relation of serum sex hormones to breast cancer (BC) in premenopausal women. We prospectively studied this relation, adjusting for timing of blood sampling within menstrual cycle. Premenopausal women (5,963), recruited to the Hormones and Diet in the Etiology of Breast Tumors (ORDET) cohort study, provided a blood sample in the 20-24th day of their menstrual cycle. After 5.2 years of follow-up, 65 histologically confirmed BC cases were identified and matched individually to 4 randomly selected controls. Sera, stored at -80 degrees C, were assayed blindly for dehydroepiandrosterone sulfate, total and free testosterone (FT), androstenedione, androstanediol-glucoronide, progesterone, 17-OH-progesterone, sex hormone-binding globulin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fifty-five cases had information for multivariate analyses. Compared to controls, BC cases had shorter cycles and intervals between blood sampling and bleeding, and lower LH and FSH. FT was significantly associated with BC risk: relative risk (RR; adjusted for age, body mass index and ovarian cycle variables) of highest vs. lowest tertile was 2.85 [95% confidence interval (CI) = 1.11-7.33, p for trend = 0.030]. Progesterone was inversely associated with adjusted RR for highest vs. lowest tertile of 0.40 (95% CI = 0.15-1.08, p for trend = 0.077), significantly so in women with regular menses, where adjusted RR was 0.12 (95% CI = 0.03-0.52, p for trend = 0.005). These findings support the hypothesis that ovarian hyperandrogenism associated with luteal insufficiency increases the risk of BC in premenopausal women., (Copyright 2004 Wiley-Liss, Inc.)

Diabetes mellitus was diagnosed in 16 out of 1011 HIV-positive patients over a median follow-up of 289 days (person-year incidence 2.06, 95% confidence interval 1.18-3.33). Significant risk factors for the onset of diabetes were older age and antiretroviral therapy with stavudine or indinavir. Older men with HIV infection should be considered at higher risk of diabetes, and caution maybe warranted in the use of both indinavir and stavudine in these patients.

Adipose tissue alterations (ATAs) were clinically assessed in 2258 HIV-1-infected outpatients consecutively observed in 6 Italian clinical centers and were found to be present in 29.5% of the men and 41.9% of the women. A logistic regression model including age, HIV disease Centers for Disease Control stage, CD4 cell counts, HIV RNA load, the duration of antiretroviral therapy, the number of drugs taken, and the use of d4T showed that men had a 0.47 adjusted risk of presenting with ATAs (95% CI: 0.38-0.58, P < 0.0001). The risks of having ATAs (except circumscribed lipomas) in any body region, presenting with fat accumulation, or being affected by combined forms of ATA were also lower in men, whereas the risk of developing pure lipoatrophy was similar in the 2 genders. Our results indicate that women are at higher risk of developing antiretroviral treatment-related ATAs and show a particular and complex ATA pattern.

Antiretroviral therapy in human immunodeficiency virus (HIV)-positive patients can induce a lipodystrophy syndrome of peripheral fat wasting and central adiposity, dyslipidemia, and insulin resistance. To test whether in this syndrome insulin resistance is associated with abnormal muscle handling of fatty acids, 12 HIV-1 patients (8 females/4 males, age = 26 +/- 2 yr, HIV duration = 8 +/- 1 yr, body mass index = 22.0 +/- 1.0 kg/m(2), on protease inhibitors and nucleoside analog RT inhibitors) and 12 healthy subjects were studied. HIV-1 patients had a total body fat content (assessed by dual-energy X-ray absorptiometry) similar to that of controls (22 +/- 1 vs. 23 +/- 2%; P = 0.56), with a topographic fat redistribution characterized by reduced fat content in the legs (18 +/- 2 vs. 32 +/- 3%; P < 0.01) and increased fat content in the trunk (25 +/- 2 vs. 19 +/- 2%; P = 0.03). In HIV-positive patients, insulin sensitivity (assessed by QUICKI) was markedly impaired (0.341 +/- 0.011 vs. 0.376 +/- 0.007; P = 0.012). HIV-positive patients also had increased total plasma cholesterol (216 +/- 20 vs. 174 +/- 9 mg/dl; P = 0.05) and triglyceride (298 +/- 96 vs. 87 +/- 11 mg/dl; P = 0.03) concentrations. Muscular triglyceride content assessed by means of (1)H NMR spectroscopy was higher in HIV patients in soleus [92 +/- 12 vs. 42 +/- 5 arbitrary units (AU); P < 0.01] and tibialis anterior (26 +/- 6 vs. 11 +/- 3 AU; P = 0.04) muscles; in a stepwise regression analysis, it was strongly associated with QUICKI (R(2) = 0.27; P < 0.0093). Even if the basal metabolic rate (assessed by indirect calorimetry) was comparable to that of normal subjects, postabsorptive lipid oxidation was significantly impaired (0.30 +/- 0.07 vs. 0.88 +/- 0.09 mg x kg(-1) x min(-1); P < 0.01). In conclusion, lipodystrophy in HIV-1 patients in antiretroviral treatment is associated with intramuscular fat accumulation, which may mediate the development of the insulin resistance syndrome.

Intramyocellular lipid (IMCL) storage is considered a local marker of whole body insulin resistance; because increments of body weight are supposed to impair insulin sensitivity, this study was designed to assess IMCL content, lipid oxidation, and insulin action in individuals with a moderate increment of body fat mass and no family history of diabetes. We studied 14 young, nonobese women with body fat <30% (n = 7) or >30% (n = 7) and 14 young, nonobese men with body fat <25% (n = 7) or >25% (n = 7) by means of the euglycemic-insulin clamp to assess whole body glucose metabolism, with indirect calorimetry to assess lipid oxidation, by localized (1)H NMR spectroscopy of the calf muscles to assess IMCL content, and with dual-energy X-ray absorptiometry to assess body composition. Subjects with higher body fat had normal insulin-stimulated glucose disposal (P = 0.80), IMCL content in both soleus (P = 0.22) and tibialis anterior (P = 0.75) muscles, and plasma free fatty acid levels (P = 0.075) compared with leaner subjects in association with increased lipid oxidation (P < 0.05), resting energy expenditure (P = 0.046), resting oxygen consumption (P = 0.049), and plasma leptin levels (P < 0.01) in the postabsorptive condition. In conclusion, in overweight subjects, preservation of insulin sensitivity was combined with increased lipid oxidation and maintenance of normal IMCL content, suggesting that abnormalities of these factors may mutually determine the development of insulin resistance associated with weight gain.

Artificial phospholipid vesicles (liposomes) containing in their membrane about eight Na,K-ATPase (sodium pump) molecules per vesicle were incubated in the presence of [110mAg]silver nitrate to label the membrane protein; silver binds specifically to the Na,K-ATPase protein. When such silver-labelled liposomes were incubated with freshly isolated human peripheral blood mononuclear cells, a large number of liposomes was found in cells as evidenced by their 110mAg content after washing them with powerful silver chelators. Thus, liposomes containing an integral membrane protein can be transferred to human peripheral blood mononuclear cells rapidly and without toxicity.

The Na,K-ATPase (EC 3.6.1.37) is the receptor for cardioactive steroids, the only specific inhibitors known at the present time for this unique membrane bound transport system. We report here that silver is the most rapid and potent inhibitor of isolated Na,K-ATPase ever described. Inhibition of Na,K-ATPase activity by silver is immediate and strikingly distinct from other inhibitors: addition of 1 mM of cysteine or DMPS reactivates the silver blocked-enzyme immediately. The results reveal that silver interacts with Na,K-ATPase and inhibits differently by an on-off mechanism involving most likely a few critical sulfhydryl groups. Inhibition of Na-K transport by silver has been demonstrated also in an artificial membrane, e.g., in liposomes reconstituted with pure Na,K-ATPase performing active transport. Silver inhibits the active 86Rb transport mediated by the pure Na,K-ATPase molecule. The Na,K-ATPase contained in the liposomes was labeled specifically with 110mAg and appeared to bind two silver ions. Taken together, the results show that the mechanism of silver interaction with Na,K-ATPase might be different from other metals, for instance, mercury. The unique action mechanism of silver suggests a fundamental role of a few critical sulfhydryl groups for Na,K-transport.