Association between age at disease onset of anti-neutrophil cytoplasmic antibody-associated vasculitis and clinical presentation and short-term outcomes

Objectives: ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- A nd older-onset patients are still incompletely understood. Methods: We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: <65 years or ≥65 years. We adjusted associations for the type of AAV and the type of ANCA (anti-MPO, anti-PR3 or negative). Results: A total of 1338 patients with AAV were included: 66% had disease onset at <65 years of age [female 50%; mean age 48.4 years (s.d. 12.6)] and 34% had disease onset at ≥65 years [female 54%; mean age 73.6 years (s.d. 6)]. ANCA (MPO) positivity was more frequent in the older group (48% vs 27%; P = 0.001). Younger patients had higher rates of musculoskeletal, cutaneous and ENT manifestations compared with older patients. Systemic, neurologic,cardiovascular involvement and worsening renal function were more frequent in the older-onset group. Damage accrual, measured with the Vasculitis Damage Index (VDI), was significantly higher in older patients, 12% of whom had a 6 month VDI ≥5, compared with 7% of younger patients (P = 0.01). Older age was an independent risk factor for early death within 6 months from diagnosis [hazard ratio 2.06 (95% CI 1.07, 3.97); P = 0.03]. Conclusion: Within 6 months of diagnosis of AAV, patients >65 years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients

New insights into the functions of Cox-2 in skin and esophageal malignancies

Understanding the cellular and molecular mechanisms of tumor initiation and progression for each cancer type is central to making improvements in both prevention and therapy. Identifying the cancer cells of origin and the necessary and sufficient mechanisms of transformation and progression provide opportunities for improved specific clinical interventions. In the last few decades, advanced genetic manipulation techniques have facilitated rapid progress in defining the etiologies of cancers and their cells of origin. Recent studies driven by various groups have provided experimental evidence indicating the cellular origins for each type of skin and esophageal cancer and have identified underlying mechanisms that stem/progenitor cells use to initiate tumor development. Specifically, cyclooxygenase-2 (Cox-2) is associated with tumor initiation and progression in many cancer types. Recent studies provide data demonstrating the roles of Cox-2 in skin and esophageal malignancies, especially in squamous cell carcinomas (SCCs) occurring in both sites. Here, we review experimental evidence aiming to define the origins of skin and esophageal cancers and discuss how Cox-2 contributes to tumorigenesis and differentiation

Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1P29S) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit

Need for deprescribing in hospital elderly patients discharged with a limited life expectancy: The REPOSI study

Objective: Older people approaching the end of life are at a high risk for adverse drug reactions. Approaching the end of life should change the therapeutic aims, triggering a reduction in the number of drugs. The main aim of this study is to describe the preventive and symptomatic drug treatments prescribed to patients discharged with a limited life expectancy from internal medicine and geriatric wards. The secondary aim was to describe the potentially severe drug-drug interactions (DDI). Materials and Methods: We analyzed Registry of Polytherapies Societa Italiana di Medicina Interna (REPOSI), a network of internal medicine and geriatric wards, to describe the drug therapy of patients discharged with a limited life expectancy. Results: The study sample comprised 55 patients discharged with a limited life expectancy. Patients with at least 1 preventive medication that could be considered for deprescription at the end of life were significantly fewer from admission to discharge (n = 30; 54.5% vs. n = 21; 38.2%; p = 0.02). Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, lipid-lowering drugs, and clonidine were the most frequent potentially avoidable medications prescribed at discharge, followed by xanthine oxidase inhibitors and drugs to prevent fractures. Thirty-seven (67.3%) patients were also exposed to at least 1 potentially severe DDI at discharge. Conclusion: Hospital discharge is associated with a small reduction in the use of commonly prescribed preventive medications in patients discharged with a limited life expectancy. Cardiovascular drugs are the most frequent potentially avoidable preventive medications. A consensus framework or shared criteria for potentially inappropriate medication in elderly patients with limited life expectancy could be useful to further improve drug prescription

Use of non-steroidal anti-inflammatory drugs and analgesics in a cohort of hospitalized elderly patients: Results from the REPOSI study.

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Changing pathology with changing drugs: skin cancer

Today skin cancer is mainly treated by surgical interventions. New findings concerning molecular biology and the signaling pathways in epithelial skin cancers such as basal cell carcinoma, squamous cell carcinoma or melanoma, and mesenchymal skin cancers such as angiosarcoma and dermatofibrosarcoma protuberans (DFSP) have identified new molecular targets for a systemic or local treatment approach. For DFSP there is an opportunity already today to reduce the intensity of surgical procedures by pretreatment with targeted therapy. This article highlights important aspects in several skin cancer types