Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders

Background: In recent years, more awareness is raised about sex-specific dilemmas in inherited bleeding disorders. However, no large studies have been performed to assess differences in diagnosis, bleeding phenotype and management of men and women with bleeding disorders. Therefore, we investigated sex differences in a large cohort of well-defined patients with autosomal inherited bleeding disorders (von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs)). Methods: We included patients from three nationwide cross-sectional studies on VWD, RBDs and CPDs in the Netherlands, respectively the WiN, RBiN and TiN study. In all studies a bleeding score (BS) was obtained, and patients filled in an extensive questionnaire on the management and burden of their disorder. Findings: We included 1092 patients (834 VWD; 196 RBD; 62 CPD), of whom 665 (60.9%) were women. Women were more often referred because of a bleeding diathesis than men (47.9% vs 36.6%, p = 0.002). Age of first bleeding was similar between men and women, respectively 8.9 ± 13.6 (mean ±sd) years and 10.6 ± 11.3 years (p = 0.075). However, the diagnostic delay, which was defined as time from first bleeding to diagnosis, was longer in women (11.6 ± 16.4 years) than men (7.7 ± 16.6 years, p = 0.002). Similar results were found when patients referred for bleeding were analyzed separately. Of women aging 12 years or older, 469 (77.1%) had received treatment because of sex-specific bleeding. Interpretation: Women with autosomal inherited bleeding disorders are more often referred for bleeding, have a longer diagnostic delay, and often require treatment because of sex-specific bleeding. Funding: The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda), and CSL Behring (unrestricted grant)

Effects of prophylactic swallowing exercises on dysphagia and quality of life in patients with head and neck cancer receiving (chemo) radiotherapy: the Redyor study, a protocol for a randomized clinical trial

Background: Radiation-induced dysphagia is common in patients with head and neck cancer (HNC). Available evidence suggests that exercise therapy prior to oncological treatment could potentially improve deglutition and quality of life; however, a randomized clinical trial is needed to confirm this observation. Methods/design: The Redyor study is a single-blind randomized clinical trial designed to compare the effect of prophylactic oropharyngeal exercises on quality of life and dysphagia of 52 patients with HNC referred to the Radiotherapy Department. The intervention will consist of respiratory muscle training (3 times/day, 5 days/week, 21 weeks) added to the standard swallow therapy. All patients will perform the same exercise intervention, but at different times: before chemoradiotherapy (CRT; early intervention group) or immediately after completing CRT (late intervention group). The main outcome will be change in dysphagia severity assessed with the Penetration-Aspiration Scale in videofluoroscopy study; quality of life will be assessed with the EORTC-QLQ-C30 and its Head and Neck Cancer Module (QLQ-H&N35) at 3, 6, and 12 months after completing CRT. Discussion: This ongoing clinical trial, registered in 2016, is based on the hypothesis that undergoing a pre-radiotherapy rehabilitation (pre-habilitation) program will have greater benefits (less decrease in quality of life, less delay in swallowing parameters, and less severe dysphagia) compared to post-CRT rehabilitation. The main objective is to assess dysphagia severity in HNC patients; and secondly, to evaluate changes in dysphagia-related quality of life, and to determine the correlation between a clinical variable and instrumental parameters during this period

Anti-inflammatory and vasculogenic conditioning of peripheral blood mononuclear cells reinforces their therapeutic potential for radiation-injured salivary glands

Background: There are currently no effective treatments available for patients with irreversible loss of salivary gland (SG) function caused by radiation therapy for head and neck cancer. In this study, we have developed an effective culture method to enhance the anti-inflammatory and vasculogenic phenotypes of peripheral blood mononuclear cells (PBMNCs) and investigated whether such effectively conditioned PBMNCs (E-MNCs) could regenerate radiation-injured SGs and ameliorate salivary secretory function in mice. Methods: Mouse PBMNCs were expanded in primary serum-free culture with five vasculogenic proteins for 5 days, and then the resulting cells (E-MNCs) were analyzed for their characteristics. Subsequently, 5 104 E-MNCs (labeled with EGFP in some experiments) were injected intra-glandularly into a mouse model of radiation-injured atrophic submandibular glands. After 2-3 weeks, the submandibular glands were harvested, and then the injected E-MNCs were tracked. Four, 8, and 12 weeks after irradiation (IR), salivary outputs were measured to evaluate the recovery of secretory function, and the gland tissues were harvested for histological and gene expression analyses to clarify the effects of cell transplantation. Results: The resulting E-MNCs contained an enriched population of definitive CD11b/CD206-positive (M2 macrophage-like) cells and showed anti-inflammatory and vasculogenic characteristics. Salivary secretory function in E-MNC-transplanted mice gradually recovered after 4 weeks post-irradiation (post-IR) and reached 3.8-fold higher than that of non-transplanted mice at 12 weeks. EGFP-expressing E-MNCs were detected in a portion of the vascular endothelium and perivascular gland tissues at 2 weeks post-IR, but mainly in some microvessels at 3 weeks. Between 4 and 12 weeks post-IR, mRNA expression and histological analyses revealed that E-MNC transplantation reduced the expression of inflammatory genes and increased the level of tissue-regenerative activities such as stem cell markers, cell proliferation, and blood vessel formation. At 12 weeks post-IR, the areas of acinar and ductal cells regenerated, and the glands had less fibrosis. Conclusions: This effective conditioning of PBMNCs is a simple, rapid, and efficient method that provides a non-invasive source of therapeutic cells for regenerating radiation-injured atrophic SGs