Trends in postoperative radiotherapy delay and the effect on survival in breast cancer patients treated with conservation surgery

The adequate timing of adjuvant radiotherapy (RT) in breast cancer has become a subject of increasing interest in recent years. A population-based study was undertaken to determine the influence of demographic and clinical factors on the postoperative RT delay in patients treated with breast-conserving surgery (BCS) and to assess the impact of delay on survival. In total, 7800 breast cancer patients treated with BCS and adjuvant RT between 1986 and 1998 in Yorkshire were included in the study. The median interval between surgery and the start of RT (S-RT interval) was 8 weeks (7 weeks for chemotherapy negative and 11 for chemotherapy positive patients). This interval increased substantially over time from 5 weeks during 1986-1988, irrespective of patients' chemotherapy status, to 10 and 17 weeks among chemotherapy negative and chemotherapy positive patients, respectively, in 1997-1998. The S-RT interval was also significantly influenced by travel time to RT centre, year and at which RT centre patient had the treatment (

Sequencing chemotherapy and radiotherapy in locoregional advanced breast cancer patients after mastectomy – a retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Combined chemo- and radiotherapy are established in breast cancer treatment. Chemotherapy is recommended prior to radiotherapy but decisive data on the optimal sequence are rare. This retrospective analysis aimed to assess the role of sequencing in patients after mastectomy because of advanced locoregional disease.</p> <p>Methods</p> <p>A total of 212 eligible patients had a stage III breast cancer and had adjuvant chemotherapy and radiotherapy after mastectomy and axillary dissection between 1996 and 2004. According to concerted multi-modality treatment strategies 86 patients were treated sequentially (chemotherapy followed by radiotherapy) (SEQgroup), 70 patients had a sandwich treatment (SW-group) and 56 patients had simultaneous chemoradiation (SIM-group) during that time period. Radiotherapy comprised the thoracic wall and/or regional lymph nodes. The total dose was 45–50.4 Gray. As simultaneous chemoradiation CMF was given in 95.4% of patients while in sequential or sandwich application in 86% and 87.1% of patients an anthracycline-based chemotherapy was given.</p> <p>Results</p> <p>Concerning the parameters nodal involvement, lymphovascular invasion, extracapsular spread and extension of the irradiated region the three treatment groups were significantly imbalanced. The other parameters, e.g. age, pathological tumor stage, grading and receptor status were homogeneously distributed. Looking on those two groups with an equally effective chemotherapy (EC, FEC), the SEQ- and SW-group, the sole imbalance was the extension of LVI (57.1 vs. 25.6%, p < 0.0001).</p> <p>5-year overall- and disease free survival were 53.2%/56%, 38.1%/32% and 64.2%/50%, for the sequential, sandwich and simultaneous regime, respectively, which differed significantly in the univariate analysis (p = 0.04 and p = 0.03, log-rank test). Also the 5-year locoregional or distant recurrence free survival showed no significant differences according to the sequence of chemo- and radiotherapy. In the multivariate analyses the sequence had no independent impact on overall survival (p = 0.2) or disease free survival (p = 0.4). The toxicity, whether acute nor late, showed no significant differences in the three groups. The grade III/IV acute side effects were 3.6%, 0% and 3.5% for the SIM-, SW- and SEQ-group. By tendency the SIM regime had more late side effects.</p> <p>Conclusion</p> <p>No clear advantage can be stated for any radio- and chemotherapy sequence in breast cancer therapy so far. This could be confirmed in our retrospective analysis in high-risk patients after mastectomy. The sequential approach is recommended according to current guidelines considering a lower toxicity.</p

Long-Term Follow-Up of Transsexual Persons Undergoing Sex Reassignment Surgery: Cohort Study in Sweden

CONTEXT: The treatment for transsexualism is sex reassignment, including hormonal treatment and surgery aimed at making the person's body as congruent with the opposite sex as possible. There is a dearth of long term, follow-up studies after sex reassignment. OBJECTIVE: To estimate mortality, morbidity, and criminal rate after surgical sex reassignment of transsexual persons. DESIGN: A population-based matched cohort study. SETTING: Sweden, 1973-2003. PARTICIPANTS: All 324 sex-reassigned persons (191 male-to-females, 133 female-to-males) in Sweden, 1973-2003. Random population controls (10:1) were matched by birth year and birth sex or reassigned (final) sex, respectively. MAIN OUTCOME MEASURES: Hazard ratios (HR) with 95% confidence intervals (CI) for mortality and psychiatric morbidity were obtained with Cox regression models, which were adjusted for immigrant status and psychiatric morbidity prior to sex reassignment (adjusted HR [aHR]). RESULTS: The overall mortality for sex-reassigned persons was higher during follow-up (aHR 2.8; 95% CI 1.8-4.3) than for controls of the same birth sex, particularly death from suicide (aHR 19.1; 95% CI 5.8-62.9). Sex-reassigned persons also had an increased risk for suicide attempts (aHR 4.9; 95% CI 2.9-8.5) and psychiatric inpatient care (aHR 2.8; 95% CI 2.0-3.9). Comparisons with controls matched on reassigned sex yielded similar results. Female-to-males, but not male-to-females, had a higher risk for criminal convictions than their respective birth sex controls. CONCLUSIONS: Persons with transsexualism, after sex reassignment, have considerably higher risks for mortality, suicidal behaviour, and psychiatric morbidity than the general population. Our findings suggest that sex reassignment, although alleviating gender dysphoria, may not suffice as treatment for transsexualism, and should inspire improved psychiatric and somatic care after sex reassignment for this patient group

Assessing non-Mendelian inheritance in inherited axonopathies

PURPOSE: Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot–Marie–Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cause IA; however, about 50% of IA cases do not receive a genetic diagnosis. A more comprehensive spectrum of causative genes and alleles is warranted, including causative and risk alleles, as well as oligogenic multilocus inheritance. METHODS: Through international collaboration, IA exome studies are beginning to be sufficiently powered to perform a pilot rare variant burden analysis. After extensive quality control, our cohort contained 343 CMT cases, 515 HSP cases, and 935 non-neurological controls. We assessed the cumulative mutational burden across disease genes, explored the evidence for multilocus inheritance, and performed an exome-wide rare variant burden analysis. RESULTS: We replicated the previously described mutational burden in a much larger cohort of CMT cases, and observed the same effect in HSP cases. We identified a preliminary risk allele for CMT in the EXOC4 gene (p value= 6.9 × 10-6, odds ratio [OR] = 2.1) and explored the possibility of multilocus inheritance in IA. CONCLUSION: Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders

Guidelines for histopathological specimen examination and diagnostic reporting of primary bone tumours

This review is intended to provide histopathologists with guidelines for clinical assessment, specimen handling and diagnostic reporting of benign and malignant primary bone tumours. Information from radiology, surgical, oncology and other clinical colleagues involved in the diagnosis and treatment of primary bone tumours should be properly assessed before undertaking a structured approach to specimen handling and histological reporting. This ensures that the information needed for planning appropriate treatment of these complex tumours is provided. Consistency in diagnostic evaluation with respect to both terminology and report content facilitates liaison at multidisciplinary bone tumour meetings and collaboration between cancer units and networks, as well as providing a common database for audit of the clinical, radiological and pathological aspects of bone tumours

Risk of hospitalization for heart failure in patients with type 2 diabetes newly treated with DPP-4 inhibitors or other oral glucose-lowering medications: A retrospective registry study on 127,555 patients from the Nationwide OsMed Health-DB Database

Aims Oral glucose-lowering medications are associated with excess risk of heart failure (HF). Given the absence of comparative data among drug classes, we performed a retrospective study in 32 Health Services of 16 Italian regions accounting for a population of 18 million individuals, to assess the association between HF risk and use of sulphonylureas, DPP-4i, and glitazones. Methods and results We extracted data on patients with type 2 diabetes who initiated treatment with DPP-4i, thiazolidinediones, or sulphonylureas alone or in combination with metformin during an accrual time of 2 years. The endpoint was hospitalization for HF (HHF) occurring after the first 6 months of therapy, and the observation was extended for up to 4 years. A total of 127 555 patients were included, of whom 14.3% were on DPP-4i, 72.5% on sulphonylurea, 13.2% on thiazolidinediones, with average 70.7% being on metformin as combination therapy. Patients in the three groups differed significantly for baseline characteristics: age, sex, Charlson index, concurrent medications, and previous cardiovascular events. During an average 2.6-year follow-up, after adjusting for measured confounders, use of DPP-4i was associated with a reduced risk of HHF compared with sulphonylureas [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.62-0.97; P = 0.026]. After propensity matching, the analysis was restricted to 39 465 patients, and the use of DPP-4i was still associated with a lower risk of HHF (HR 0.70; 95% CI 0.52-0.94; P = 0.018). Conclusion In a very large observational study, the use of DPP-4i was associated with a reduced risk of HHF when compared with sulphonylureas

Proceedings of the 24th Paediatric Rheumatology European Society Congress: Part three

From Springer Nature via Jisc Publications Router.Publication status: PublishedHistory: collection 2017-09, epub 2017-09-0

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease