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Aim: To investigate the real-world utilization and comparative clinical outcomes of injectable and oral semaglutide in individuals with type 2 diabetes (T2D) with the aim of enhancing understanding of the practical implications associated with choosing between these formulations., Methods: New users of oral or injectable semaglutide were selected from a cohort of 14 079 initiators of glucagon-like peptide-1 receptor agonists. Propensity-score matching (PSM) was employed to create balanced groups, ensuring comparability. The analysis encompassed dose exposure, drug persistence, and clinical outcomes, including changes in glycated haemoglobin (HbA1c) and body weight, with up to 18 months' follow-up., Results: We analysed two matched groups of 107 participants each, who comprised on average 63.6% men, aged 64 years, with diabetes duration of approximately 10 years, body mass index of 29 kg/m 2 and HbA1c level of 7.7-7.8% (61-62 mmol/mol). The proportion of low, intermediate and high doses were similar with the oral and the injectable formulation. The change in HbA1c was similar between groups (-0.9% / -10 mmol/mol at 18 months) as was the proportion of individuals reaching HbA1c <6.5% (48 mmol/mol). The average change in body weight was similar in the two groups (-3.7 kg with injectable and -3.3 kg with oral at 18 months) but more new users of injectable semaglutide lost ≥5% body weight. Persistence on drug was longer with injectable than with oral semaglutide., Conclusion: In a real-world setting, improvements in HbA1c and body weight were similar after initiation of oral or injectable semaglutide. These results may be specific to the features of the matched cohorts under investigation, with limited generalizability to populations with different characteristics., (© 2024 John Wiley & Sons Ltd.)

Objectives: To retrospectively analyze real-world treatment patterns in patients with relapsed/refractory multiple myeloma (RRMM) who initiated third-line treatment in Europe., Methods: German and Italian administrative claims data were sourced from the German AOK PLUS health insurance fund and Italian local health units (2016-2020). Data for the United Kingdom (UK), France, and Spain were sourced from medical chart reviews (MCRs) from 2016 to 2018 (historical) and 2019 to 2021 (new) using electronic case report forms., Results: Across all countries, immunomodulatory imide drug (IMiD)-based regimens were prominent in the third-line setting. From 2016 to 2020, lenalidomide-dexamethasone was most common in Italy (18.0%) and Germany (12.7%). From 2019 to 2021, the most common regimen was ixazomib-lenalidomide-dexamethasone (67.5%) in the UK, pomalidomide-dexamethasone (17.1%) in France, and daratumumab-bortezomib-dexamethasone (15.0%) in Spain. In the historical data (2016-2018), third-line lenalidomide- and pomalidomide-dexamethasone doublet use across the UK (>47%), France (>46%), and Spain (>33%) was high. From historical to new, triplet use increased in Spain (>19% to >60%) as did anti-CD38 agent use in France (15.1% to 51.9%) and Spain (19.7% to 42.1%)., Conclusions: From 2016 to 2021, third-line regimens were mostly IMiD based. The MCR data demonstrated evolving treatment choices from 2016 to 2018 and 2019 to 2021, providing insights into uptake of novel agents and current RRMM European clinical practice., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: The Expanded Disability Status Scale (EDSS) quantifies disability and measures disease progression in multiple sclerosis (MS), however is not available in administrative claims databases., Objectives: To develop a claims-based algorithm for deriving EDSS and validate it against a clinical dataset capturing true EDSS values from medical records., Methods: We built a unique linked dataset combining claims data from the German AOK PLUS sickness fund and medical records from the Multiple Sclerosis Management System 3D (MSDS 3D ). Data were deterministically linked based on insurance numbers. We used 69 MS-related diagnostic indicators recorded with ICD-10-GM codes within 3 months before and after recorded true EDSS measures to estimate a claims-based EDSS proxy (pEDSS). Predictive performance of the pEDSS was assessed as an eight-fold (EDSS 1.0-7.0, ≥8.0), three-fold (EDSS 1.0-3.0, 4.0-5.0, ≥6.0), and binary classifier (EDSS <6.0, ≥6.0). For each classifier, predictive performance measures were determined, and overall performance was summarized using a macro F1-score. Finally, we implemented the algorithm to determine pEDSS among an overall cohort of patients with MS in AOK PLUS, who were alive and insured 12 months prior to and after index diagnosis., Results: We recruited 100 people with MS insured by AOK PLUS who had ≥1 EDSS measure in MSDS 3D between 01/10/2015 and 30/06/2019 (620 measurements overall). Patients had a mean rescaled EDSS of 3.2 and pEDSS of 3.0. The pEDSS deviated from the true EDSS by 1.2 points, resulting in a mean squared error of prediction of 2.6. For the eight-fold classifier, the macro F1-score of 0.25 indicated low overall predictive performance. Broader severity groupings were better performing, with the three-fold and binary classifiers for severe disability achieving a F1-score of 0.68 and 0.84, respectively. In the overall AOK PLUS cohort (3,756 patients, 71.9% female, mean 51.9 years), older patients, patients with progressive forms of MS and those with higher comorbidity burden showed higher pEDSS., Conclusion: Generally, EDSS was underestimated by the algorithm as mild-to-moderate symptoms were poorly captured in claims across all functional systems. While the proxy-based approach using claims data may not allow for granular description of MS disability, broader severity groupings show good predictive performance., Competing Interests: EM-L and LC were employees of F. Hoffmann La Roche Ltd. MG and TW were employees of IPAM. EZ was an employee of Cytel Inc. AD has received personal compensation and travel grants from Biogen, Celgene, Janssen, Roche and Sanofi for speaker activity. TZ has received consulting fees, grants, and research support from various pharmaceutical companies e.g., Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Roche, Sanofi, and Teva. TW has received honoraria from several pharmaceutical/consultancy firms e.g. Novo Nordisk, Roche, Abbvie, Merck, GSK, BMS, Bayer, and Boehringer Ingelheim. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that can be construed as a potential conflict of interest. The authors declare that this study received funding from F. Hoffmann La Roche Ltd. The funder had the following involvement in the study: conception of the study, design, interpretation of the results and writing and revision of the manuscript., (Copyright © 2023 Muros-Le Rouzic, Ghiani, Zhuleku, Dillenseger, Maywald, Wilke, Ziemssen and Craveiro.)

Background: ENCORE, an observational, prospective, open-label study, investigated real-world treatment practices and outcomes with cetuximab plus platinum-based therapy (PBT) in first-line (1L) recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN)., Aims: This multinational study aimed to investigate the long-term use of cetuximab plus PBT for 1L R/M SCCHN in a clinical setting. In particular, this study aimed to explore clinical considerations such as the decision to prescribe cetuximab plus PBT in R/M SCCHN, the mode and duration of treatment, and patient outcomes., Methods and Results: Previously untreated patients with R/M SCCHN whose planned treatment was cetuximab plus PBT were enrolled from 6 countries. Among 221 evaluable patients, planned treatments included cetuximab plus carboplatin (31.2%), cisplatin plus 5-fluorouracil (31.7%), or carboplatin plus 5-fluorouracil (23.1%); 3.2% included a taxane, and 45.2% did not include 5-fluorouracil. Cetuximab treatment was planned for a fixed duration (≤24 weeks) in 15 patients (6.8%) and until disease progression in 206 (93.2%). Median progression-free survival and overall survival were 6.5 and 10.8 months, respectively. Grade ≥3 adverse events occurred in 39.8% of patients. Serious adverse events occurred in 25.8% of patients; 5.4% were cetuximab-related., Conclusion: In patients with R/M SCCHN, first-line cetuximab plus PBT was feasible and modifiable in a real-world setting with similar toxicity and efficacy as in the pivotal phase III EXTREME trial., Clinical Trial Registration Number: EMR 062202-566., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Purpose: The aim of this study was to investigate the burden of disease among a real-world cohort of patients with prevalent Crohn's disease (CD) in Germany., Methods: We conducted a retrospective cohort analysis using administrative claims data from the German AOK PLUS health insurance fund. Continuously insured patients with a CD diagnosis between 01 October 2014 and 31 December 2018 were selected and followed for at least 12 months or longer until death or end of data availability on 31 December 2019. Medication use (biologics, immunosuppressants (IMS), steroids, 5-aminosalicylic acid) was assessed sequentially in the follow-up period. Among patients with no IMS or biologics (advanced therapy), we investigated indicators of active disease and corticosteroid use., Results: Overall, 9284 prevalent CD patients were identified. Within the study period, 14.7% of CD patients were treated with biologics and 11.6% received IMS. Approximately 47% of all prevalent CD patients had mild disease, defined as no advanced therapy and signs of disease activity. Of 6836 (73.6%) patients who did not receive advanced therapy in the follow-up period, 36.3% showed signs of active disease; 40.1% used corticosteroids (including oral budesonide), with 9.9% exhibiting steroid dependency (≥ 1 prescription every 3 months for at least 12 months) in the available follow-up., Conclusions: This study suggests that there remains a large burden of disease among patients who do not receive IMS or biologics in the real world in Germany. A revision of treatment algorithms of patients in this setting according to the latest guidelines may improve patient outcomes., (© 2023. The Author(s).)

Real-world evidence in multiple sclerosis (MS) is limited by the availability of data elements in individual real-world datasets. We introduce a novel, growing database which links administrative claims and medical records from an MS patient management system, allowing for the complete capture of patient profiles. Using the AOK PLUS sickness fund and the Multiple Sclerosis Documentation System MSDS 3D from the Center of Clinical Neuroscience (ZKN) in Germany, a linked MS-specific database was developed (MSDS-AOK PLUS). Patients treated at ZKN and insured by AOK PLUS were recruited and asked for informed consent. For linkage, insurance IDs were mapped to registry IDs. After the deletion of insurance IDs, an anonymized dataset was provided to a university-affiliate, IPAM e.V., for further research applications. The dataset combines a complete record of patient diagnoses, treatment, healthcare resource use, and costs (AOK PLUS), with detailed clinical parameters including functional performance and patient-reported outcomes (MSDS 3D ). The dataset currently captures 500 patients; however, is actively expanding. To demonstrate its potential, we present a use case describing characteristics, treatment, resource use, and costs of a patient subsample. By linking administrative claims to clinical information in medical charts, the novel MSDS-AOK PLUS database can increase the quality and scope of real-world studies in MS.

Background and Objectives: Although vaccine preventable, the incidence of tick-borne encephalitis (TBE) increased in Germany from 2001 to 2021 by on average 2% each year, with a peak of more than 700 TBE infections documented in 2020. TBE-risk areas, as designated by district based on incidence of human cases, expanded north- and northeastward, present in 11 of the 16 Federal States as of 2022. Using claims data from a German statutory health insurance in the Federal States of Saxony and Thuringia (AOK PLUS), we aimed to assess whether official assignment of a district to a risk area had an impact on vaccination rates in Germany., Methods: The data covered the period from 01/01/2010 to 31/12/2018 and included information on vaccine administrations from outpatient physicians. Yearly incident vaccination rates were reported overall and by district. To investigate the association between a new designation of an incident TBE-risk area and vaccination rates, a difference-in-difference analysis was conducted., Results: Overall, the incident vaccination rates increased from 6.2 to 9.5 per 1,000 person-years between 2012 and 2018, with a peak of 12.2 in 2015. While districts that had been risk-areas for the whole study period had always a higher vaccination rate compared to districts that were never categorized as risk areas, the increase between 2012 and 2018 was comparable in the two groups (3.0 and 3.2 per 1,000 person-years, respectively). In contrast, districts that were newly designated risk districts during the study period experienced a significantly larger increase in vaccination rates, going from 5.8 to 14.7 per 1,000 person-years between 2012 and 2018, with a peak of 19.6 in 2015., Conclusion: The results suggest that the new designation of a district as risk area has a significant positive impact on vaccination rates, which is strongest immediately after designation of risk area., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [All authors had complete autonomy for the process of designing the study, carrying out the analyses, interpreting the results and writing the manuscript. This also includes the full right to publish the results without limitation. MG is a staff member of IPAM. UM is an employee of AOK PLUS. TW received honoraria from several pharmaceutical/consultancy firms (e.g. GSK, Novo Nordisk, Abbvie, Merck, BMS, LEOPharma, Bayer, Boehringer Ingelheim). CH, JF, CvE and CM are employees of Pfizer Pharma GmbH]., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The positioning of new biologic agents for the treatment of Crohn's disease (CD) following failure of initial anti-tumor necrosis factor (anti-TNF) therapy remains a challenge in the real world., Objectives: This study aims to investigate the real-world outcomes associated with the sequential use of biologics in CD patients that newly initiate anti-TNFs, specifically comparing those that switch to another anti-TNF versus biologics with other modes of action., Design: Retrospective cohort study., Methods: We identified CD patients who newly began anti-TNF therapy between 1 October 2014 and 31 December 2018 using two German claims databases. Patients were classified as within-class switchers (WCS) if they switched to another anti-TNF or outside-class switchers (OCS) if they switched to vedolizumab (VDZ) or ustekinumab (UST). To compare WCS and OCS, baseline covariates were adjusted through inverse probability of treatment weighting (IPTW), and time-to-event analyses were performed using Cox Proportional Hazard regressions. Results from both databases were meta-analyzed using an inverse variance model., Results: Overall, 376 prevalent adult CD patients who initiated anti-TNFs and switched to another biologic were identified. After IPTW, there were 152 and 177 patients in the WCS and OCS group, respectively. WCS were more likely to receive prolonged corticosteroid therapy [hazard ratio (HR): 1.63, 95% confidence interval (CI): 1.17-2.27, p  = 0.004], switch a second time to a different biologic (HR: 2.44, 95% CI: 1.63-3.66, p  < 0.001), and discontinue treatment (HR: 1.71, 95% CI: 1.25-2.34, p  = 0.001) than OCS., Conclusion: This study suggests that CD patients exhibit more favorable outcomes when switching outside the anti-TNF class to VDZ or UST after initial anti-TNF failure than switching to a second anti-TNF. With loss of response to anti-TNFs as a concern in the real world, comparative evidence from claims data assessing sequential use of biologics can help optimize treatment algorithms of patients after anti-TNF failure., Competing Interests: EZ and BAF are employees of Cytel. The work of Cytel was sponsored by Janssen-Cilag. AB, RN, IB, JNB, MLB, JL, and AP are employees of Janssen-Cilag. UM is an employee of AOK PLUS and declares no conflicts of interest. BD is an employee of GWQ ServicePlus AG and declares no conflicts of interest. BB has received consulting fees from Abbvie, MSD, Shire, Ferring, UCB, Hospira, Takeda, Movetis, Shield Therapeutics, Pfizer, Biogen, Janssen, Hexal, Cellgene, Boehringer, Allergan, Galapagos, and Arena; provided speeches/lectures for Abbvie, Ferring, MSD, Merckle, Falk, HLR, UCB, Shield Therapeutics, Pfizer, Celltrion, Takeda, Janssen, Mundipharma, and Arena; and received research grants from Abbvie, Ferring, UCB, Given Imaging, Janssen, Takeda, Pfizer, and Galapagos. TW has received honoraria from several pharmaceutical/consultancy firms, for example, Novo Nordisk, Abbvie, Merck, GSK, BMS, LEOPharma, Bayer, Boehringer Ingelheim. MG is an employee of Cytel and staff member of IPAM e.V., (© The Author(s), 2022.)

Background and Purpose: Comorbidity between diabetes and depression, and diabetes and eating disorders (ED) conveys significant diagnostic, clinical and therapeutic implications. The present study was conducted on a sample of adult outpatients affected by Type 1 Diabetes (T1DM) to assess lifetime prevalence of ED; current prevalence of depression and Disturbed Eating Behaviors (DEB) and their impact on glycemic control. We hypothesized that patients with depression would have higher rates of lifetime ED and current DEB. We hypothesized a significant and independent association between DEB and the prevalence of depression., Materials and Methods: The study was carried out using a cross-sectional design in a sample of 172 diabetic patients with T1DM aged from 17 to 55 years. Lifetime prevalence of ED according to DSM-5 criteria was assessed by means of the Module H modified of the Structured Clinical Interview for DSM-IV Axis I Disorder (SCID-I). The following questionnaires were used: Beck Depression Inventory-IA version (BDI-IA) and Diabetes Eating Problems Survey-Revised (DEPS-R), to assess respectively the current presence of depression and DEB. Socio-demographic, clinical, and laboratory data were also collected., Results: High rates of depression (35.5%) and DEB (19.2%) were observed in our sample of 172 adult outpatients with T1DM. Lifetime history of ED was present in 20.9% of the sample and was more frequently diagnosed in patients with current depression (34.4% vs. 13.9%, p = 0.002). Higher levels of DEB at DEPS-R significantly increased the odds of depression (adjOR: 1.09; 95% CI: 1.03-1.15; p = 0.003). The presence of DEB was associated with poor glycemic control. On the other hand, no association was found between depression and metabolic compensation., Conclusion: Adult patients with T1DM and depression should be screened for ED and DEB. Treating DEB could positively impact both mood and glycemic control in this population. Further studies should be carried out on a larger patient population using a longitudinal design and an accurate method of evaluation to explore the complex relationship between diabetes, depression, ED, and DEB. Future research should investigate treatment strategies for DEB in T1DM patients and their impact on both psychopathological and metabolic outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pinna, Suprani, Deiana, Lai, Manchia, Paribello, Somaini, Diana, Nicotra, Farci, Ghiani, Cau, Tuveri, Cossu, Loy, Crapanzano, Grassi, Loviselli, Velluzzi and Carpiniello.)

Aims: Using German claims, the authors replicated the CHAARTED trial in metastatic hormone-sensitive prostate cancer. Methods: The authors identified metastatic hormone-sensitive prostate cancer patients replicating the inclusion/exclusion criteria of CHAARTED. Patients treated with docetaxel in combination with androgen deprivation therapy (ADT) at first line (docetaxel group) were compared with patients treated with ADT monotherapy (ADT mono group). After propensity score matching, overall survival was compared between the matched cohorts. Results: The authors included 441 patients. After propensity score matching, two equally sized matched cohorts of 74 patients each were compared in terms of overall survival. The hazard ratio (HR) was 0.71 (95% CI: 0.42-1.19), comparable to the HR in CHAARTED (HR: 0.72; 95% CI: 0.59-0.89). Conclusions: Using early comparative evidence from real-world data for regulatory and health technology assessment decisions is useful.

Objectives: Previous studies have shown that weekend hospitalizations are associated with poorer health outcomes and higher mortality ("weekend effect"). However, few of these studies have adjusted for disease severity and little is known about the effect on costs. This work investigates the weekend effect and its costs for patients with cerebral infarction in Germany, adjusting for patient characteristics and proxies of stroke severity., Methods: Adult patients with a cerebral infarction hospitalization 10th revision of the International statistical classification of diseases and related health problems (ICD-10: I63) between 01 January 2014 and 30 June 2017 were included from German health claims (AOK PLUS dataset). Propensity score matching was used to match patients hospitalized on weekends or on public holidays (weekend group) with patients hospitalized during the working week (workday group), based on baseline characteristics and proxies for disease severity such as concomitant diagnoses of aphasia, ataxia, and coma, or peg tube at index hospitalization. Matched cohorts were compared in terms of in-hospital, 7-day, and 30-day mortality, as well as risk and costs of stroke and rehabilitation stays in the year after first stroke., Results: Of 32,311 patients hospitalized with cerebral infarction between 01 January 2014 and 30 June 2017, 8409 were in the weekend group and 23,902 in the workday group. After propensity score matching, 16,730 patients were included in our study (8365 per group). Matched cohorts did not differ in baseline characteristics or stroke severity. In the weekend group, the risk of in-hospital death (11.2%) and the seven-day mortality rate (6.8%) were 13.1% and 17.2% higher than in the workday group, respectively (both p  < 0.01). The hazard ratio for death in the weekend group was 1.1 ( p  = 0.043). The risks of subsequent stroke hospitalization and rehabilitation stays for a stroke were 8.4% higher and 5.5% higher in the weekend group (both p  = 0.02). As a result, the stroke-related hospitalization and rehabilitation costs per patient year were, respectively, 5.6% and 8.0% higher in the weekend group (both p  = 0.01)., Conclusions: A significant weekend effect emerged after controlling for observable patient characteristics and proxies of stroke severity. This effect also resulted in higher costs for patients admitted on weekends.

Purpose: Given the rapid expansion of recreational marijuana legalization (RML) polices, it is essential to assess whether such policies are associated with shifts in the use of marijuana and other substances, particularly for adolescents, who are uniquely susceptible to negative repercussions of marijuana use. This analysis seeks to provide greater generalizability, specificity, and methodological rigor than limited prior evidence., Methods: Youth Risk Behavior Survey data from 47 states from 1999 to 2017 assessed marijuana, alcohol, cigarette, and e-cigarette use among adolescents (14-18+ years; N = 1,077,938). Associations between RML and adolescent past-month substance use were analyzed using quasi-experimental difference-in-differences zero-inflated negative binomial models., Results: Controlling for other state substance policies, year and state fixed effects, and adolescent demographic characteristics, models found that RML was not associated with a significant shift in the likelihood of marijuana use but predicted a small significant decline in the level of marijuana use among users (incidence rate ratio = .844, 95% confidence interval [.720-.989]) and a small increase in the likelihood of any e-cigarette use (odds ratio of zero use = .647, 95% confidence interval [.515-.812]). Patterns did not vary over adolescent age or sex, with minimal differences across racial/ethnic groups., Conclusions: Results suggest minimal short-term effects of RML on adolescent substance use, with small declines in marijuana use and increase in the likelihood of any e-cigarette use. Given the delayed rollout of commercial marijuana sales in RML states and rapid expansion of RML policies, ongoing assessment of the consequences for adolescent substance use and related health and behavioral repercussions is essential., (Copyright © 2020 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: Use claims data to assess healthcare resource utilization (HCRU) and cost for patients with ulcerative colitis (UC) who had surgery and patients who did not., Methods: UC patients from a German health insurance were included between 01/01/2010-31/12/2017. Patients with proctocolectomy or colectomy between 01/07/2010 and 31/12/2014 were identified, and surgery date was set as index. For patients with IPAA, the last surgery in the 6 months was taken as index. Non-surgery patients received random index. After propensity score matching, UC-related HCRU and cost were observed for three years post-index., Results: Of 21,392 UC patients, 85 underwent surgery and 2655 did not. After matching, 76 were included in the surgery group and 114 in the non-surgery group. Matched cohorts did not differ in baseline characteristics and mortality rates where high in both groups (21.1% and 29.0%, respectively). The percentage of patients with at least one hospitalization in the follow-up period was higher in the surgery (53.9%) compared to the non-surgery group (25.4%, p<0.001). In contrast, the number of outpatient prescriptions of UC-related drugs in the non-surgery group (11.2) was almost twice as large as in the surgery group (5.8, p<0.001). Hospitalization cost was 4.6 times higher in the surgery (1955.5€) than in the non-surgery group (419.6€, p<0.001). Medication cost was three times higher in the non-surgery group (6519€) compared to the surgery group (2151.7€, p<0.001)., Conclusions: Based on hospitalizations, outpatient visits, and medical treatment, results show a considerable patient burden in UC from surgery complications or disease exacerbation in case of colectomy.

Background: This study analyzes the impact of skeletal-related events (SRE) on healthcare resource utilization (HCRU) and costs incurred by patients with bone metastases (BM) from solid tumors (ST), who are therapy-naïve to bone targeting agents (BTAs)., Methods: German claims data from 01/01/2010 to 30/06/2018 were used to conduct a retrospective comparative cohort analysis of BTA-naive patients with a BM diagnosis and preceding ST diagnosis. HCRU and treatment-related costs were compared in two matched cohorts of patients with and without a history of SREs, defined as pathological fracture, spinal cord compression, surgery to bone and radiation to bone. The first SRE was defined as the patient-individual index date. Conversely, for the non-SRE patients, index dates were assigned randomly., Results: In total, 45.20% of 9,832 patients reported experiencing at least one SRE (n = 4444) while 54.80% experienced none (n = 5388); 2,434 pairs of SRE and non-SRE patients were finally matched (mean age: 70.87/71.07 years; females: 39.07%/38.58%). Between SRE and non-SRE cohorts, significant differences in the average number of hospitalization days per patient-year (35.80/30.80) and associated inpatient-care costs (14,199.27€/10,787.31€) were observed. The total cost ratio was 1.16 (p < 0.001) with an average cost breakdown of 23,689.54€ and 20,403.27€ per patient-year in SRE and non-SRE patients., Conclusion: The underutilization of BTAs within a clinical setting poses an ongoing challenge in the real-world treatment of BM patients throughout Germany. Ultimately, the economic burden of treating SREs in patients with BM from ST was found to be considerable, resulting in higher direct healthcare costs and increased utilization of inpatient care facilities.

Summary: A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted., Learning Points: A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists. In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.

Background and Aims: While a minority of inflammatory bowel disease (IBD) patients receives biologics in Germany, little is known about therapeutic needs of patients receiving non-biologic therapies. This study aimed to identify indicators of active disease/steroid dependency in patients with moderate to severe Crohn's disease (CD) and ulcerative colitis (UC) treated with conventional therapies and to describe health care resource use (HCRU)/cost., Methods: CD/UC patients treated with immunosuppressants (IS) and/or systemic or locally acting oral corticosteroids (CS) were identified in German claims data (2013-2017) and followed for 12 months post-therapy start. Indicators of active disease/steroid dependency during follow-up period were (i) ≥ 2 prescriptions of CS (sensitivity ≥ 4) or (ii) ≥ 1 IBD-related surgery or (iii) > 7 days IBD-related hospitalization(s)., Results: Of 9871 included IBD patients (5170 CD, 4701 UC), 25.7%/19.9% (CD/UC) received ≥ 2 prescriptions of CS (sensitivity, 17.4%/15.7%) (i), 3.2% experienced IBD-related surgeries (ii), and 2.5% > 7 days of hospitalizations (iii). Altogether, 44.4% had indicators of active disease/steroid dependency (sensitivity, 23.9%). Among patients with active disease/steroid dependency, 78.0% received CS monotherapy at baseline. Of these, 89.6% received a CS monotherapy in the follow-up period, too. Proportionally, fewer patients with CS monotherapy (57.4%) than IS therapy (91.0%) visited a specialist. HCRU/cost per patient year was significantly higher in patients with than without active disease/steroid dependency., Conclusions: A substantial percentage of biologic-naïve IBD patients suffers from active disease/steroid dependency. The majority receives a monotherapy with systemic CS. Referral to gastroenterologists for treatment optimization is recommended, also because active disease/steroid dependency is associated with increased HCRU/cost.

Background: Triple Negative breast cancer (TNBC) includes a heterogeneous group of tumors with different clinico-pathological features, molecular alterations and treatment responsivity. Our aim was to evaluate the clinico-pathological heterogeneity and prognostic significance of TNBC histologic variants, comparing "special types" to high-grade invasive breast carcinomas of no special type (IBC-NST)., Methods: This study was performed on data obtained from TNBC Database, including pathological features and clinical records of 1009 TNBCs patients diagnosed between 1994 and 2015 in the four most important Oncology Units located in different hospitals in Sardinia, Italy. Kaplan-Meier analysis, log-rank test and multivariate Cox proportional-hazards regression were applied for overall survival (OS) and disease free survival (DFS) according to TNBC histologic types., Results: TNBC "special types" showed significant differences for several clinico-pathological features when compared to IBC-NST. We observed that in apocrine carcinomas as tumor size increased, the number of metastatic lymph nodes manifestly increased. Adenoid cystic carcinoma showed the smallest tumor size relative to IBC-NST. At five-year follow-up, OS was 92.1, 100.0, and 94.5% for patients with apocrine, adenoid cystic and medullary carcinoma, respectively; patients with lobular and metaplastic carcinoma showed the worst OS, with 79.7 and 84.3%, respectively. At ten-years, patients with adenoid cystic (100.0%) and medullary (94.5%) carcinoma showed a favourable prognosis, whereas patients with lobular carcinoma showed the worst prognosis (73.8%). TNBC medullary type was an independent prognostic factor for DFS compared to IBC-NST., Conclusions: Our study confirms that an accurate and reliable histopathologic definition of TNBC subtypes has a significant clinical utility and is effective in the therapeutic decision-making process, with the aim to develop innovative and personalized treatments.

Head and neck cancers (HNC) represent 5% of all malignancies worldwide with about 180,000 cancer deaths per year. Patients with HNC are characterized by a systemic inflammatory state, generally associated with worse outcomes. Treatment-related toxicity is common among HNC patients and causes systemic consequences such as fatigue or cognitive dysfunction. The therapeutic treatments of HNC involve the release in circulation of inflammatory systemic mediators, whose effects trigger a vicious circle that may lead to functional and behavioral alterations. The areas of the head and neck are highly sensitive to pain. Literature data confirm that in HNC patients, pain is one of the most distressing symptoms across all the phases of treatment. Pain is associated with worse general conditions, depression, fatigue, impaired cognitive functions, and lower survival rate. The treatment of advanced HNC cases is multimodal and requires a multidisciplinary psycho-socio-pharmacological approach mediated by a team of experts. The pharmacological approach in management of HNC patients with pain is fundamental and involves the use of opioids, NSAIDs, steroids, or other drugs. Opioids in pain management therapy in patients with HNC could allow the pain level to be adequately monitored, thus improving quality of life. The integration of opioid and non-opioid therapy as well as non-pharmacological interventions is essential for the rehabilitation of physical, social, and psychological functions and to achieve pain control in patients with HNC. Opioid treatment is the mainstay for pain control, being used both for background and breakthrough cancer pain (BTcP) episodes. Fentanyl, easily absorbed and generally well tolerated, appears to be a possible choice due to its versatility. Non-pharmacological interventions, such as tailored yoga, physical exercise, and acupuncture, may have a role in pain management in patients with HNC.

Introduction: Recent increases in maternal mortality and persistent disparities have led to speculation about why the U.S. has higher rates than most high-income countries. The aim was to examine the impact of changes in state-level factors plausibly linked to maternal mortality on overall rates and by race/ethnicity., Methods: This quasi-experimental, population-based, difference-in-differences study used 2007-2015 National Vital Statistics System microdata mortality files from 38 states and DC. The primary exposures were 5 state-level sexual and reproductive health indicators and 6 health and economic conditions. Maternal mortality rate was defined as number of deaths of women while pregnant or within 42 days of termination of pregnancy per 100,000 live births. A difference-in-differences zero-inflated negative binomial regression model was estimated using the race/ethnicity-age-state-year population as the denominator and adjusting for race/ethnicity, age, state, and year. Data were analyzed in 2017-2018., Results: There were 4,767 deaths among women up to age 44 years, resulting in a maternal mortality rate of 17.9. Reducing the proportion of Planned Parenthood clinics by 20% from the state-year mean increased the maternal mortality rate by 8% (incidence rate ratio, 1.08; 95% CI=1.04, 1.12). States that enacted legislation to restrict abortions based on gestational age increased the maternal mortality rate by 38% (incidence rate ratio, 1.38; 95% CI=1.03, 1.84). Planned Parenthood clinic closures negatively impacted all women, increasing mortality by 6%-15% across racial/ethnic groups, whereas gestational limits primarily increased mortality among white women., Conclusions: Recent fiscal and legislative changes reducing women's access to family planning and reproductive health services have contributed to rising maternal mortality rates., (Copyright © 2019 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Despite an increase in adolescent use of electronic nicotine delivery systems (ENDS), little is known about the role of tobacco control policies on ENDS use., Objective: For aim 1, we examined how trends in adolescent use of cigarettes were affected by the introduction of ENDS; for aim 2, we examined the associations between ENDS age restrictions, cigarette taxes, and smoke-free legislation and adolescent use of ENDS and cigarettes., Design and Setting: Repeated cross-sections of the 1999-2015 Youth Risk Behavior Surveys linked to state-level tobacco control policies., Participants: 938 486 adolescents aged 14 to 18 years from 45 states., Main Outcome Measures: For aim 1, we examined adolescent use of cigarettes. For aim 2, we examined adolescent use of ENDS, only ENDS, and cigarettes., Results: We found there was an overall decreasing trend in adolescent use of cigarettes, but the actual decline was greater than the predicted decline for 17- and 18-year-olds. While we found no associations between ENDS use and ENDS age restrictions or cigarette taxes, ENDS use was 3.8 percentage points higher in those states with smoke-free legislation for combustible tobacco products., Conclusions: Our findings highlight that ENDS age restrictions may not be adequate to curb ENDS use and additional local- and state-level policies governing ENDS are needed.

We examined the impact of a state gun law environment on suicides overall and within demographic subgroups. We linked 211,766 firearm suicides and 204,625 nonfirearm suicides in the 50 states of the United States for 2005-2015 to the population in each state, year, race/ethnicity, sex, and age, as well as to an index of state-level gun control. Difference-in-differences, zero-inflated, negative-binomial models were used to evaluate the impact of strengthening gun control on firearm and nonfirearm suicides. We subsequently stratified by sex and tested for interactions with race/ethnicity and age. We found 25 states strengthened gun control by an average of 6 points. Such an increase may result in a 3.3% (incidence rate ratio = 0.967; 95% confidence interval: 0.938, 0.996) decrease in firearm suicides. Although no impact on nonfirearm suicides was found overall, interaction models showed an increase in nonfirearm suicides among black men, white women, black women, and older individuals. Strengthening gun control may reduce firearm suicides overall but may increase nonfirearm suicides in some populations. The results indicate stricter gun laws should be advocated for and that additional policies are needed for populations who shifted to nonfirearm suicides., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This paper examines the associations between state-level gun control and adolescent school safety overall and by student sex, age, and race., Methods: We used data on 926 639 adolescents from 45 states in the 1999-2015 Youth Risk Behavior Surveys. Students self-reported on weapon carrying at school, the number of times they experienced weapon threats or injuries at school, the number of school days missed due to feeling unsafe, and weapon carrying at any location. For each state and year, 133 gun laws were combined into an index of gun control strength. Difference-in-differences logistic regression models were used to evaluate the associations of stricter gun laws with binary measures of students' weapon carrying and perception of school safety, controlling for individual and state characteristics, as well as year and state fixed effects., Results: An IQR increase in the index (ie, a 15-point increase corresponding to a strengthening of gun control) was associated with a 0.8-percentage point decrease in the probability of weapon threats at school (p=0.029), a 1.1-percentage point decrease in the probability of missing school due to feeling unsafe (p=0.002) and a 1.9-percentage point decrease in the probability of carrying weapons at any location (p=0.001). Stricter gun laws had a stronger negative association with weapon carrying among males compared with females. Stricter gun laws were also differentially associated with weapon carrying by race/ethnicity., Conclusions: The adoption of stricter state gun laws was associated with improvements in school climate and subjective perceptions of safety., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Marijuana use carries risks for adolescents' well-being, making it essential to evaluate effects of recent marijuana policies., Objectives: This study sought to delineate associations between state-level shifts in decriminalization and medical marijuana laws (MML) and adolescent marijuana use., Methods: Using data on 861,082 adolescents (14 to 18+ years; 51% female) drawn from 1999 to 2015 state Youth Risk Behavior Surveys (YRBS), difference-in-differences models assessed how decriminalization and MML policy enactment were associated with adolescent marijuana use, controlling for tobacco and alcohol policy shifts, adolescent characteristics, and state and year trends., Results: MML enactment was associated with small significant reductions (OR = 0.911, 95% CI [0.850, 0.975]) of 1.1 percentage points in current marijuana use, with larger significant declines for male, Black, and Hispanic (2.7-3.9 percentage points) adolescents. Effects of MML increased significantly with each year of exposure (OR = 0.980, 95% CI [0.968, 0.992]). In contrast, decriminalization was not associated with significant shifts in use for the sample as a whole, but predicted significant declines in marijuana use among 14-year olds and those of Hispanic and other ancestry (1.7-4.4 percentage points), and significant increases among white adolescents (1.6 percentage points). Neither policy was significantly associated with heavy marijuana use or the frequency of use, suggesting that heavy users may be impervious to such policy signals., Conclusion: As the first study to concurrently assess unique effects of multiple marijuana policies, results assuage concerns over potential detrimental effects of more liberal marijuana policies on youth use.

Background: To provide further information on the clinical and pathological prognostic factors in triple-negative breast cancer (TNBC), for which limited and inconsistent data are available., Methods: Pathological characteristics and clinical records of 841 TNBCs diagnosed between 1994 and 2015 in four major oncologic centers from Sardinia, Italy, were reviewed. Multivariate hazard ratios (HRs) for mortality and recurrence according to various clinicopathological factors were estimated using Cox proportional hazards models., Results: After a mean follow-up of 4.3 years, 275 (33.3%) TNBC patients had a progression of the disease and 170 (20.2%) died. After allowance for study center, age at diagnosis, and various clinicopathological factors, all components of the TNM staging system were identified as significant independent prognostic factors for TNBC mortality. The HRs were 3.13, 9.65, and 29.0, for stage II, III and IV, respectively, vs stage I. Necrosis and Ki-67 > 16% were also associated with increased mortality (HR: 1.61 and 1.99, respectively). Patients with tumor histotypes other than ductal invasive/lobular carcinomas had a more favorable prognosis (HR: 0.40 vs ductal invasive carcinoma). No significant associations with mortality were found for histologic grade, tumor infiltrating lymphocytes, and lymphovascular invasion. Among lymph node positive TNBCs, lymph node ratio appeared to be a stronger predictor of mortality than pathological lymph nodes stage (HR: 0.80 for pN3 vs pN1, and 3.05 for >0.65 vs <0.21 lymph node ratio), respectively. Consistent results were observed for cancer recurrence, except for Ki-67 and necrosis that were not found to be significant predictors for recurrence., Conclusions: This uniquely large study of TNBC patients provides further evidence that, besides tumor stage at diagnosis, lymph node ratio among lymph node positive tumors is an additional relevant predictor of survival and tumor recurrence, while Ki-67 seems to be predictive of mortality, but not of recurrence.

Background: The purpose of the study was to evaluate in a sample of insulin-treated diabetic patients, with type 1 or type 2 diabetes, the psychometric characteristics of the Italian version of the DEPS-R scale, a diabetes-specific self-report questionnaire used to analyze disordered eating behaviors., Methods: The study was performed on 211 consecutive insulin-treated diabetic patients attending two specialist centers. Lifetime prevalence of eating disorders (EDs) according to DSM-IV and DSM-5 criteria were assessed by means of the Module H of the Structured Clinical Interview for DSM IV Axis I Disorder and the Module H modified, according to DSM-5 criteria. The following questionnaires were administered: DEPS-R and the Eating Disorder Inventory - 3 (EDI-3). Test/retest reproducibility was assessed on a subgroup of 70 patients. The factorial structure, internal consistency, test-retest reliability and concurrent validity of DEPS-R were assessed., Results: Overall, 21.8% of the sample met criteria for at least one DSM-5 diagnosis of ED. A "clinical risk" of ED was observed in 13.3% of the sample. Females displayed higher scores at DEPS-R, a higher percentage of at least one diagnosis of ED and a higher clinical risk for ED. A high level of reproducibility and homogeneity of the scale were revealed. A significant correlation was detected between DEPS-R and the 3 ED risk scales of EDI-3., Conclusions: The data confirmed the overall reliability and validity of the scale. In view of the significance and implications of EDs in diabetic patients, it should be conducted a more extensive investigation of the phenomenon by means of evaluation instruments of demonstrated validity and reliability.

In the year 2010, effluents from 90 European wastewater treatment plants (WWTPs) were analyzed for 156 polar organic chemical contaminants. The analyses were complemented by effect-based monitoring approaches aiming at estrogenicity and dioxin-like toxicity analyzed by in vitro reporter gene bioassays, and yeast and diatom culture acute toxicity optical bioassays. Analyses of organic substances were performed by solid-phase extraction (SPE) or liquid-liquid extraction (LLE) followed by liquid chromatography tandem mass spectrometry (LC-MS-MS) or gas chromatography high-resolution mass spectrometry (GC-HRMS). Target microcontaminants were pharmaceuticals and personal care products (PPCPs), veterinary (antibiotic) drugs, perfluoroalkyl substances (PFASs), organophosphate ester flame retardants, pesticides (and some metabolites), industrial chemicals such as benzotriazoles (corrosion inhibitors), iodinated x-ray contrast agents, and gadolinium magnetic resonance imaging agents; in addition biological endpoints were measured. The obtained results show the presence of 125 substances (80% of the target compounds) in European wastewater effluents, in concentrations ranging from low nanograms to milligrams per liter. These results allow for an estimation to be made of a European median level for the chemicals investigated in WWTP effluents. The most relevant compounds in the effluent waters with the highest median concentration levels were the artificial sweeteners acesulfame and sucralose, benzotriazoles (corrosion inhibitors), several organophosphate ester flame retardants and plasticizers (e.g. tris(2-chloroisopropyl)phosphate; TCPP), pharmaceutical compounds such as carbamazepine, tramadol, telmisartan, venlafaxine, irbesartan, fluconazole, oxazepam, fexofenadine, diclofenac, citalopram, codeine, bisoprolol, eprosartan, the antibiotics trimethoprim, ciprofloxacine, sulfamethoxazole, and clindamycine, the insect repellent N,N'-diethyltoluamide (DEET), the pesticides MCPA and mecoprop, perfluoroalkyl substances (such as PFOS and PFOA), caffeine, and gadolinium., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Intake of dairy fat has long been considered as a risk factor for CVD. Pasture and dietary lipid supplementation have been reported to be reliable strategies in ruminant nutrition, in order to increase the content of α-linolenic acid (ALA), conjugated linoleic acid (CLA) and vaccenic acid (VA), and decrease SFA in milk fat. In the present study, we aimed at verifying whether consumption of a sheep cheese, naturally enriched in ALA, CLA and VA, would modify the plasma lipid and endocannabinoid profiles in mildly hypercholesterolaemic subjects. A total of forty-two adult volunteers (nineteen males and twenty-three females) with diagnosed mildly hypercholesterolaemia (total cholesterol 5·68-7·49 mmol/l) were randomly assigned to eat 90 g/d of a control or enriched cheese for 3 weeks, with a cross-over after 3 weeks of washout. Plasma lipids, endocannabinoids, adipokines and inflammatory markers were measured. The intake of enriched cheese significantly increased the plasma concentrations of CLA, VA, the n-3 fatty acids ALA and EPA, and more remarkably decreased that of the endocannabinoid anandamide. LDL-cholesterol decreased significantly (7%). No changes were detected in the levels of inflammatory markers; however, a significant correlation was found between the plasma levels of anandamide and leptin. The control cheese modified none of the parameters measured. The results obtained do not support the view that intake of dairy fat is detrimental to hypercholesterolaemic subjects. Indeed, they show that a naturally enriched cheese possesses beneficial properties, since it ameliorates the plasma lipid profile, and more remarkably reduces endocannabinoid biosynthesis.

Background: Using recombinant human monoclonal thyroglobulin antibodies expressed as Fab molecules (TgAb-Fab), we have recently confirmed the restriction of Tg epitopes in Hashimoto's thyroiditis (HT)., Objective: To investigate Tg epitopes of serum TgAb in HT adults and HT juveniles from a geographically isolated area (Sardinia)., Design and Patients: Serum TgAb of 39 Sardinian HT adults, 53 Sardinian HT juveniles and 45 non-Sardinian HT adults were evaluated. The binding of serum TgAb to Tg in ELISA was inhibited by four recombinant human TgAb-Fab, identifying Tg epitopic regions A-D. The percentage of Tg binding inhibition was calculated comparing the binding of serum TgAb in presence of each TgAb-Fab with that in its absence., Results: In the whole cohort of 137 patients, A region TgAb-Fab induced the highest levels of inhibition (55.3 +/- 17.8%) (mean +/- SD). Lower levels of inhibition were induced by TgAb-Fab of regions B (27.8 +/- 25.8%), C (26.8 +/- 24.6%) and D (17.5 +/- 18.4%). In Sardinian HT adults inhibition by TgAb-Fab of regions A, B and C were comparable to Sardinian HT juveniles; the marginal D region TgAb-Fab induced a slightly higher inhibition (22.1 vs. 13.8%; P = 0.034) in the former than in the latter group. In Sardinian and non-Sardinian HT adults inhibitions by the four TgAb-Fab were similar., Conclusions: In HT, the Tg epitope pattern of serum TgAb was similar in juveniles and adults from a geographically restricted area and in two adult populations from different geographical areas. Thus, in HT, neither age nor genetic background appear to influence B-cell epitopes.

The orphan Leucine-rich repeat G protein-coupled receptor 5 (LGR5/GPR49), a target of Wnt signaling, is a marker of adult intestinal stem cells (SC). However, neither its function in the adults, nor during development of the intestine have been addressed yet. In this report, we investigated the role of LGR5 during ileal development by using LGR5 null/LacZ-NeoR knock-in mice. X-gal staining experiments showed that, after villus morphogenesis, Lgr5 expression becomes restricted to dividing cells clustered in the intervillus region and is more pronounced in the distal small intestine. At day E18.5, LGR5 deficiency leads to premature Paneth cell differentiation in the small intestine without detectable effects on differentiation of other cell lineages, nor on epithelial cell proliferation or migration. Quantitative RT-PCR experiments showed that expression from the LGR5 promoter was upregulated in LGR5-null mice, pointing to the existence of an autoregulatory negative feedback loop in intact animals. This deregulation was associated with overexpression of Wnt target genes in the intervillus epithelium. Transcriptional profiling of mutant mice ileums revealed that LGR5 function is associated with expression of SC and SC niche markers. Together, our data identify LGR5 as a negative regulator of the Wnt pathway in the developing intestine.

Background: Chronic autoimmune thyroiditis (CAT) displays a strong female predominance with female-to-male (F:M) ratios of 4-20:1 in adults and 2-9:1 in children and adolescents. Both genetic and hormonal factors are involved in this phenomenon. The relation between puberty and F:M ratio in CAT has never been evaluated., Methods: The F:M ratio of 133 children with CAT (group A, age at diagnosis 2.4-17.7 years) was compared with that of 113 adult CAT patients (group B, age at diagnosis 21-79 years). Group A included 64 prepubertal (aged 2.4-13.2 years, group A1) and 69 pubertal (aged 9.2-17.4, group A2) children., Results: The F:M ratio in group A was 3.0, which is significantly (p < 0.001) lower than that (10.3) found in group B patients. The F:M ratio of group A1 prepubertal children was lower (1.6) and significantly different from that of pubertal (6.7, p < 0.01) and adult patients (10.3, p < 0.0001). This phenomenon was more evident in hypothyroid as compared to euthyroid CAT., Conclusions: This study provides the first evidence that female predominance of CAT strongly increases during puberty, suggesting a major role for sex hormones in this phenomenon. Further studies are needed to clarify this point., (Copyright 2009 S. Karger AG, Basel.)

In this study we analyzed allele and genotype distributions of 24 bp duplication of the CHIT1 gene in a sample of patients (N=300) with coronary artery disease (CAD) and in a control group (N=300) from central Corsica (France), with the aim to investigate the possible association between CHIT1 genotypes and CAD in Corsican population. Serum chitotriosidase activity is increased in individuals experiencing an ischemic stroke of atherothrombotic etiology and in subjects with ischemic heart disease. Our results suggest that 24 bp duplication of CHIT1 gene is not correlated with CAD in Corsican population, according to a previous study carried out on a Spanish sample. Gene prevalence and perhaps gene-disease associations vary according to ethnicity. Further studies, based on different ethnic groups, could be suitable to determine the implication of this polymorphism with respect to CAD.

Objective: Genetic screening of RET proto-oncogene is a powerful tool for the early identification of familial cases of medullary thyroid carcinoma (MTC), comprising isolated familial thyroid medullary carcinoma (FMTC) and multiple endocrine neoplasia syndromes 2A (MEN-2A) and 2B (MEN-2B). We report the results obtained by RET mutation analysis of subjects living in Sardinia, an Italian island whose inhabitants display a peculiar genetic background due to geographic isolation and low immigration rate for several centuries., Design: Retrospective study reporting data on 67 patients referred during the last 5 years for RET analysis because affected by MTC or first degree relatives of MTC patients., Main Outcome: Only three mutations were identified affecting codons 620 (exon 10), 634 (exon 11), and 804 (exon 14); surprisingly, the most prevalent mutation found was V804M (overall prevalence: 59%). This finding is quite different from previous studies carried out in other Caucasian and non-Caucasian populations, in which the frequency of the V804M mutation is consistently reported less than 5%. The phenotype associated to V804M mutation was mostly FMTC (16/17 cases = 94.1%), but in one case (5.9%) primary hyperparathyroidism was found, suggesting a MEN-2A., Conclusions: These results underline the importance of the genetic background in the distribution of RET mutations and should be taken into consideration when performing genetic evaluation of MTC patients.

Background: Triplet regimens were occasionally reported to produce a higher response rate (RR) than doublets in locally advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was conducted to assess (i) whether the addition of cisplatin (CDDP) to either gemcitabine (GEM) and vinorelbine (VNR) or GEM and paclitaxel (PTX) significantly prolongs overall survival (OS) and (ii) to compare the toxicity of PTX-containing and VNR-containing combinations., Patients and Methods: Stage III or IV NSCLC patients were randomly assigned to (i) GEM 1000 mg/m(2) and VNR 25 mg/m(2) on days 1 and 8 (GV arm); (ii) GEM 1000 mg/m(2) and PTX 125 mg/m(2) on days 1 and 8 (GT arm); (iii) GV plus CDDP 50 mg/m(2) on days 1 and 8 (PGV arm); and (iv) GT plus CDDP 50 mg/m(2) on days 1 and 8 (PGT arm). Treatments were repeated every 3 weeks for a maximum of six cycles., Results: A total of 433 (stage III, 160; stage IV, 273) patients were randomly allocated to the study. RR was 48% [95% confidence interval (CI), 42% to 54%] for triplets and 35% (95% CI, 32% to 38%) for doublets (P = 0.004). Median progression-free survival (6.1 versus 5.5 months, P = 0.706) and median OS (10.7 versus 10.5 months, P = 0.379) were similar. CDDP significantly increased the occurrence of severe neutropenia (35% versus 13%), thrombocytopenia (14% versus 4%), anaemia (9% versus 3%), vomiting (6% versus 0.5%), and diarrhoea (6% versus 2%). Conversely, frequency of severe neutropenia (30% versus 17%) and thrombocytopenia (11% versus 6%) was significantly higher with VNR-containing regimens., Conclusions: Adding CDDP to GV or GT significantly increased RR, but did not prolong the OS of patients. Among doublets, the GT regimen should be preferred in view of its better safety profile.

The paper presents the results of a laboratory investigation conducted for assessing the feasibility of immobilising the heavy metals (As, Cd, Cu, Pb and Zn) contained in a disused mine tailings dam. Samples of tailings were mixed with relatively small proportions of bauxite red mud and power station fly ash. The sorption capacity of these two materials, already determined for Cd, Cu, Pb and Zn, has been determined here for arsenic by means of batch experiments on purposely prepared solutions. The results of this preliminary investigation show that sorption capacity is strongly influenced by pH. While the red mud performs better at low pH, the ability of fly ash to adsorb As increases with increasing pH. Tests carried out in leach columns containing tailings alone and tailings mixed with 15% by weight neutralized red mud or fly ash demonstrate the heavy metal sorption potential of the two materials, the red mud proving to be the more effective.