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Obesity and hypertension independently promote pathological left ventricular remodelling (LVR) and left ventricular hypertrophy (LVH), but to what extent they do so when they do not coexist is unclear. We used data from the Cardiovision Brno 2030 study to assess—for the first time in a region where no investigations have been previously carried out—the independent association of obesity and hypertension with LV geometry, and to evaluate the effects of hypertension in normal weight patients and the effects of obesity in normotensive patients. Overall, 433 individuals, aged 25–65 years, with no history of cardiovascular disease and/or antihypertensive treatment, were stratified into four groups according to BMI and hypertension: normal weight non-hypertensive (NWNH), normal weight hypertensive (NWH), overweight/obese non-hypertensive (ONH) and overweight/obese hypertensive (OH). LVR was classified as normal, concentric LVR (cLVR), concentric LVH (cLVH) or eccentric LVH (eLVH). Linear regression analysis demonstrated that body mass index (BMI) and systolic blood pressure (SBP) are the main predictors of LV mass and that they interact: SBP had a stronger effect in overweight/obese (β = 0.195; p = 0.033) compared to normal weight patients (β = 0.134; p = 0.048). Hypertension increased the odds of cLVR (OR = 1.78; 95%CI = 1.04–3.06; p = 0.037) and cLVH (OR = 8.20; 95% CI = 2.35–28.66; p = 0.001), independent of age, sex and BMI. Stratified analyses showed that NWH had a greater odd of cLVH (OR = 7.96; 95%CI = 1.70–37.08; p = 0.008) and cLVR (OR = 1.62; 95%CI = 1.02–3.34; p = 0.047) than NWNH. In the absence of hypertension, obesity was not associated with LVM and abnormal LV geometry, suggesting that it is not per se a determinant of LVR. Thus, antihypertensive therapy still remains the first-line approach against LVH in hypertensive patients, though weight loss interventions might be helpful in those who are obese.

Head and neck cancer is the sixth leading cancer by incidence worldwide. Unfortunately, drug resistance and relapse are the principal limitations of clinical oncology for many patients, and the failure of conventional treatments is an extremely demoralizing experience. It is therefore crucial to find new therapeutic targets and drugs to enhance the cytotoxic effects of conventional treatments without potentiating or offsetting the adverse effects. Melatonin has oncostatic effects, although the mechanisms involved and doses required remain unclear. The purpose of this study is to determine the precise underlying mitochondrial mechanisms of melatonin, which increase the cytotoxicity of oncological treatments, and also to propose new melatonin treatments in order to alleviate and reverse radio- and chemoresistant processes. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 0.1, 0.5, 1, and 1.5 mM melatonin combined with 8 Gy irradiation or 10 μM cisplatin. Clonogenic and MTT assays, as well as autophagy and apoptosis, involving flow cytometry and western blot, were performed in order to determine the cytotoxic effects of the treatments. Mitochondrial function was evaluated by measuring mitochondrial respiration, mtDNA content (RT-PCR), and mitochondrial mass (NAO). ROS production, antioxidant enzyme activity, and GSH/GSSG levels were analyzed using a fluorometric method. We show that high concentrations of melatonin potentiate the cytotoxic effects of radiotherapy and CDDP in HNSCC, which are associated with increased mitochondrial function in these cells. In HNSCC, melatonin induces intracellular ROS, whose accumulation plays an upstream role in mitochondria-mediated apoptosis and autophagy. Our findings indicate that melatonin, at high concentrations, combined with cisplatin and radiotherapy to improve its effectiveness, is a potential adjuvant agent.

Background Optimal management of patients with severe mitral stenosis ( MS ) and low transmitral gradient is incompletely understood. Methods and Results We examined 101 consecutive patients with severe rheumatic MS (mitral valve area ≤1.5 cm 2 ) who underwent balloon valvuloplasty. Low gradient was defined as mean transmitral gradient <10 mm Hg and low flow as stroke volume index ≤35 mL/m 2 by echocardiography. Symptoms and mortality data were collected. Systolic, diastolic, and arterial function were characterized by measuring left ventricular (LV) end‐systolic elastance, LV stiffness constant (β), diastolic capacitance (predicted LV end‐diastolic volume at a common LV filling pressure of 30 mm Hg), and effective arterial elastance. Low gradient (<10 mm Hg) was present in 55 patients, including low flow/low gradient in 11 and normal flow/low gradient in 44 patients, and high gradient was present in 46 patients. Participants with low‐flow/low‐gradient (LG) MS were older with higher rates of atrial fibrillation (64%) and subvalvular thickening, higher afterload, and decreased LV compliance with lower ejection fraction (57±10% versus 65±4% versus 63±6%, P =0.002) but similar end‐systolic elastance compared with patients with normal‐flow/ LG and high‐gradient MS . The normal‐flow/ LG group had larger mitral valve area and lower left atrial pressure by catheterization, as well as favorable long‐term outcomes compared with the low‐flow/ LG and high‐gradient MS group. A total of 40% of patients with LG MS had no symptomatic benefit from valvuloplasty compared with 18% of patients with high‐gradient MS ( P =0.02). Conclusions Presence of low gradient in patients with severe MS was associated with lesser symptomatic benefit from valvuloplasty. In the subset with low stroke volume index, this may be related to independent ventricular‐vascular uncoupling, decreased LV compliance, and high prevalence of atrial fibrillation in addition to intrinsic MS .

Primary mucosal desmoplastic melanoma is an exceedingly rare, potentially devastating disease that is often initially misdiagnosed because of its deceptively benign presentation. We report what we believe is only the second case of mucosal desmoplastic melanoma arising from the nasal vestibule. The patient, a 62-year-old woman, presented with an obstructive, enlarging mass in the nasal cavity. The tumor, which was initially believed to be benign, was excised, but it recurred 12 months postoperatively. The recurrence was excised, but 4 years later, the patient experienced a second recurrence; in this case, the tumor had invaded the cribriform plate and extended to the anterior cranial fossa. The tumor subsequently metastasized to the dura mater, which led to the patient's death. We review the distinction between conventional mucosal melanoma and mucosal desmoplastic melanoma, and we discuss the ways in which the behavior of a desmoplastic melanoma can point to the diagnosis. Because a diagnosis can be difficult to establish, we stress the importance of maintaining a high index of suspicion when evaluating pathologic and immunohistochemical findings in a patient with a recurrent mucosal nasal mass.

As the treatment of hematopoietic cancers evolves, otolaryngologists will see a higher incidence of opportunistic infections. We discuss a case of invasive fungal disease that invaded the larynx, pharynx, trachea, and pulmonary parenchyma after chemotherapy. The patient, a 46-year-old woman, presented 1 week after undergoing induction chemotherapy. Her initial symptoms were odynophagia and dysphagia. Despite encouraging findings on physical examination, her health rapidly declined and she required an urgent tracheotomy and multiple operations to address spreading necrosis. Because of her inability to heal, she was not a candidate for laryngectomy, so she was treated with conservative management. The patient was then lost to follow-up, but she returned 5 months later with laryngeal destruction and a complete laryngotracheal separation. While noninvasive fungal laryngitis is routinely encountered, its invasive counterpart is rare. The literature demonstrates that some cases completely resolve with medical therapy alone but that surgery is necessary in others. We recommend surgical debridement of all necrotic tissue.

AbstractAimsMechanisms of chronic ischaemic mitral regurgitation (IMR) are well-characterized by apically tethered leaflet caused by papillary muscles (PMs) displacement and adynamic mitral apparatus. We investigated the unique geometry and dynamics of the mitral apparatus in first acute myocardial infarction (MI) by using quantified 3D echocardiography.Methods and resultsWe prospectively performed 3D echocardiography 2.3 ± 1.8 days after first MI, in 174 matched patients with (n = 87) and without IMR (n = 87). 3D echocardiography of left ventricular (LV) volumes and of mitral apparatus dynamics throughout cardiac cycle was quantified. Similar mitral quantification was obtained at chronic post-MI stage (n = 44). Mechanistically, acute IMR was associated with larger and flatter annulus (area 9.29 ± 1.74 cm2 vs. 8.57 ± 1.94 cm2, P = 0.002, saddle shape 12.7 ± 4.5% vs. 15.0 ± 4.6%, P = 0.001), and larger tenting (length 6.36 ± 1.78 mm vs. 5.60 ± 1.55 mm, P = 0.003) but vs. chronic MI, mitral apparatus displayed smaller alterations (all P < 0.01) and annular size, PM movement remained dynamic (all P < 0.01). Specific to acute IMR, without PM apical displacement (P > 0.70), greater separation (21.7 ± 4.9 mm vs. 20.0 ± 3.4 mm, P = 0.01), and widest angulation of PM (38.4 ± 6.2° for moderate vs. 33.5 ± 7.3° for mild vs. 31.4 ± 6.3° for no-IMR, P = 0.0009) wider vs. chronic MI (P < 0.01).Conclusions3D echocardiography of patients with first MI provides insights into unique 4D dynamics of the mitral apparatus in acute IMR. Mitral apparatus remained dynamic in acute MI and distinct IMR mechanism in acute MI is not PM displacement seen in chronic IMR but separation and excess angulation of PM deforming the mitral valve, probably because of sudden-onset regional wall motion abnormality without apparent global LV remodelling. This specific mechanism should be considered in novel therapeutic strategies for IMR complicating acute MI.

Multiple myeloma is a plasma cell malignancy that occurs among older adults and accounts for 15% of all hematologic malignancies in the United States. Thirty-five percent of patients are diagnosed at age 75 or older. Novel therapeutics and routine use of autologous stem cell transplantation (ASCT) have led to substantial improvements in patient survival, although improvements have been more impressive among patients younger than age 65. Finding the balance between under- and overtreating elderly patients is one of the biggest challenges specific to them as a subgroup of patients with MM. Decision making about which therapies and their dose intensity and duration should be influenced by a patient’s functional status, personal preferences, disease characteristics, and ability to tolerate therapy. ASCT should be considered for all patients younger than age 80, assuming that they are not frail. The attainment of a stringent complete response and minimal residual disease negativity is associated with improved progression-free and overall survival. Again, consideration of quality of life for these patients is paramount. Although there is a growing list of tools to sort through these issues, a fully integrated approach has not yet been finely tuned, leaving additional work to be done for the treatment of elderly patients with MM.

4505 Background: While inhibiting VEGF improves outcomes in mRCC pts, most develop resistance, often within a year. Here, we report results from a Ph II study of atezo (anti–PD-L1) and bev (anti-VEGF) vs and following atezo or sun (TKI) in mRCC pts. Methods: Pts with untreated mRCC were enrolled in the hypothesis generating IMmotion150 study (NCT01984242) and randomized to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w, atezo alone or sun 50 mg PO QD 4 wk on/2 wk off. After progression on atezo or sun, crossover to atezo + bev was allowed. PD-L1 status was scored on tumor-infiltrating immune cells (IC, SP142 IHC assay). The primary analysis was modified prior to final analysis to reflect the coprimary endpoints of IRF-assessed PFS (RECIST v1.1) in ITT pts and pts with PD-L1 expression on ≥ 1% of IC (PD-L1+). Results: 54% of pts were PD-L1+. In PD-L1+ pts 1L treatment resulted in a PFS hazard ratio (HR) of 0.64 for atezo + bev vs sun (table). After 1L treatment, 78% of sun and 60% of atezo pts who progressed subsequently received atezo + bev and achieved ORRs of 28% and 24%, respectively (table). Safety was comparable to the known individual profiles of atezo and bev. Additional clinical, safety and biomarker data will be presented. Conclusions: Atezo + bev resulted in encouraging antitumor activity in 1L pts with PD-L1+ mRCC. Preliminary activity in the 2L setting was demonstrated in pts who crossed over to atezo + bev, regardless of prior therapy. 1L atezo + bev vs sun is being evaluated in the ongoing Ph III study IMmotion151 (NCT02420821). Clinical trial information: NCT01984242. [Table: see text]