Melanoma brain metastases: Biological basis and novel therapeutic strategies

The development of brain metastases is the deadliest complication of advanced melanoma and has long been associated with a dismal prognosis. The recent years have seen incredible progress in the development of therapies for melanoma brain metastases (MBM), with both targeted therapies (the BRAF-MEK inhibitor combination) and immune checkpoint inhibitors (the anti-CTLA-4, anti-PD-1 combination) showing impressive levels of activity. Despite this, durations of response for these therapies remain lower at intracranial sites of metastasis compared to extracranial metastases and it has been suggested that there are unique features of the brain microenvironment that contribute to therapeutic escape. In this review, we outline the latest research into the biology and pathophysiology of melanoma brain metastasis development and progression. We then discuss the current status of clinical trial that are open to patients with MBM and end by describing the ongoing challenges for the field.     

Social Stigma Towards People with Medically Unexplained Symptoms: the Somatic Symptom Disorder

Psychiatric Quarterly - The majority of previous studies on mental health stigma have focused on medically explained symptoms and the studies on medically unexplained symptoms (MUS) have only...     

Clinical and Ultrasonographic Evaluation of Lower-extremity Vein Thrombosis in Behcet Syndrome: An Observational Study

Vascular involvement can be seen in up to 40% of patients with Behcet syndrome (BS), the lower-extremity vein thrombosis (LEVT) being the most common type. The aim of the current study was to compare venous Doppler findings and clinical features between BS patients with LEVT and control patients diagnosed as having LEVT due to other causes.All consecutive 78 patients (71 men, 7 women; mean age 38.6 ± 10.3 years) with LEVT due to BS and 50 control patients (29 men, 21 women; mean age 42.0 ± 12.5 years) who had LEVT due to other causes, or idiopathic, were studied with the help of a Doppler ultrasonography after a detailed clinical examination. Patterns of venous disease were identified by cluster analyses. Clinical features of chronic venous disease were assessed using 2 classification systems. Venous claudication was also assessed.Patients with BS were more likely to be men, had significantly earlier age of onset of thrombosis, and were treated mainly with immunosuppressives and less frequently with anticoagulants. Furthermore, they had significantly more bilateral involvement, less complete recanalization, and more frequent collateral formation. While control patients had a disorganized pattern of venous involvement, BS patients had a contiguous and symmetric pattern, involving all deep and superficial veins of the lower extremities, with less affinity for crural veins. Clinical assessment, as measured by the 2 classification systems, also indicated a more severe disease among the BS patients. In line, 51% of the BS patients suffered from severe post-thrombotic syndrome (PTS) and 32% from venous claudication, whereas these were present in 8% and 12%, respectively, among the controls. Among BS patients, a longer duration of thrombosis, bilateral femoral vein involvement, and using no anticoagulation along with immunosuppressive treatment when first diagnosed were found to be associated independently with severe PTS.Lower-extremity vein thrombosis associated with BS, when compared to LEVT due to other causes, had distinctive demographic and ultrasonographic characteristics, and had clinically a more severe disease course.     

Comparison of Shoulder-Arm Complex Pain,Function, and Scapular Dyskinesia in Women With and Without Unilateral Lymphedema After Breast Cancer Surgery

IntroductionLymphedema is the most important complication seen after breast cancer surgery. The study aimed to evaluate pain, shoulder-arm complex function, and scapular function in women who developed lymphedema after breast cancer surgery and to compare these with women without lymphedema.Materials and MethodsFifty women with lymphedema (age, 54.34 ± 9.08 years; body mass index, 30.10 ± 4.03 kg/cm²) and 57 women without lymphedema (age, 53.68 ± 9.41 years; body mass index, 29.0 ± 5.44 kg/cm²) after unilateral surgery for breast cancer were included. Clinical and demographic information was noted. The severity of lymphedema with perimeter measurements (Frustum model), level of heaviness discomfort sensation with a visual analog scale, pain threshold with a digital algometer, shoulder-arm complex functionality with the Disabilities of the Arm, Shoulder, Hand Problems Survey (DASH), and scapular function with observational scapular dyskinesia and lateral scapular sliding tests were assessed. The t test, χ² test, and Mann-Whitney U test were used for analyses.ResultsThe follow-up duration after the surgery was 4.24 ± 2.97 years and 3.19 ± 1.76 years, and the upper extremity volume was 2106.65 ± 510.82 cm³ and 1725.92 ± 342.49 cm³ in the lymphedema group and in the no-lymphedema group, respectively. In the lymphedema group, arm-heaviness discomfort, pain threshold levels in the trapezius and deltoid muscles, and DASH scores were worse (P < .05). The rate of scapular dyskinesia (70.0%) and type 2 scapula (32%) in the surgical side was higher in patients with lymphedema.ConclusionThe pain pressure threshold in the trapezius and deltoid muscles, heaviness sensation level, and inadequate upper extremity function are significantly higher in patients with lymphedema, and the scapular dyskinesia rate was higher.     

Development of Orally Applicable,Combinatorial Drug–Loaded Nanoparticles for the Treatment of Fibrosarcoma

Nanoparticulate systems have been receiving a significant attention especially for the treatment of cancer but one of the main hurdles is to produce these developed and high-tech nanosystems in large quantities. Anticancer drug formulations are generally designed for parenteral administrations but oral administration is still the most convenient route. In this study, orally applicable nano-sized chitosan nanoparticles (NPs) were successfully prepared using Nano Spray Dryer. It is possible to produce these NPs in large quantities by simply increasing the processing time using the machine without changing any parameter. A chemotherapeutic agent (imatinib mesylate; IMA) and nonsteroidal anti-inflammatory drug (dexketoprofen trometamol) were loaded together in these NPs. NPs were also functionalized with polyethylene glycol and folic acid to obtain long circulating NPs and tumor targeting. The antitumoral activities of formulations showed that these developed NPs can enhance the effectiveness. Animal experiments were performed on fibrosarcoma-bearing mice model, and the treatment with 0.8 mg/μL/kg IMA-loaded chitosan NPs was found to be successful to slow down the growth of tumors. The tumor tissues were removed from the animals and enzymatic activities were evaluated. The inhibitory effect of tyrosine kinase was found to be enhanced from 36.4% to 68.4% when IMA was used in combination with dexketoprofen trometamol. Furthermore, all dried NPs were found to be stable for more than a year at 25°C. Presented results show that these developed combinatorial drug–loaded NPs can be used for the treatment of fibrosarcoma, and these data can provide an insight, new strategies for productions or alternatives in cancer treatment.     

β‐adrenergic Receptor Blocker ICI 118,551 Selectively Increases Intermediate‐Conductance Calcium‐Activated Potassium Channel (IKCa)‐Mediated Relaxations in Rat Main Mesenteric Artery

Endothelial IK_Ca and/or SK_Ca channels play an important role in the control of vascular tone by participating in endothelium‐dependent relaxation. Whether β‐AR antagonists, mainly used in hypertension, affect endothelial K_Ca channel function is unknown. In this study, we examined the effect of the β2‐AR antagonist and inverse agonist ICI 118,551 on the IK_Ca/SK_Ca channel activity by assessing functional relaxation responses to several agonists that stimulate these channels. Mesenteric arterial rings isolated from male Sprague Dawley mounted to organ baths. Acetylcholine elicited IK_Ca‐ and SK_Ca‐mediated relaxations that were abolished by TRAM‐34 and apamin, respectively. ICI 118,551, which did not dilate the arteries per se, increased the IK_Ca‐mediated relaxations, whereas SK_Ca‐mediated relaxations remained unaltered. Same potentiating effect was also detected on the IK_Ca‐mediated relaxations to carbachol and A23187, but not to NS309. Neither acetylcholine‐induced nitric oxide‐mediated relaxations nor SNP relaxations changed with ICI 118,551. The PKA inhibitor KT‐5720, the selective β2‐AR agonist salbutamol, the selective β2‐AR antagonist butoxamine, the non‐selective β‐AR antagonist propranolol, and the inverse agonists carvedilol or nadolol failed to affect the IK_Ca‐mediated relaxations. ICI 118,551‐induced increase was not reversed by salbutamol or propranolol as well. Besides, low potassium‐induced relaxations in endothelium‐removed arteries remained the same in the presence of ICI 118,551. These data demonstrate a previously unrecognized action of ICI 118,551, the ability to potentiate endothelial IK_Ca channel‐mediated vasodilation, through a mechanism independent of β2‐AR antagonistic or inverse agonistic action. Instead, the enhancement of acetylcholine relaxation seems likely to occur by a mechanism secondary to endothelial calcium increase.