Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for V600-Mutant Unresectable or Metastatic Melanoma.

Purpose: Preclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with V600-mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti-programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with V600-mutant unresectable or metastatic melanoma.

Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy: Analysis from phase 2 and 3 clinical trials.

Background: Previous analyses of BREAK-2 and BREAK-3 showed that durable outcomes lasting ≥3 years are achievable with dabrafenib in some patients with BRAF V600-mutant metastatic melanoma (MM); however, additional follow-up is needed to fully characterise the long-term impact of dabrafenib in these patients.

Methods: BREAK-2 was a single-arm phase 2 study evaluating dabrafenib in treatment-naive or previously treated BRAF V600E/K-mutant MM. BREAK-3, a randomised (3:1) phase 3 study, assessed dabrafenib versus dacarbazine in previously untreated unresectable or metastatic BRAF V600E-mutant melanoma.

Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected V600-Mutant Stage III Melanoma.

Purpose: Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47; < .001) in patients with resected V600-mutant stage III melanoma (BRF115532; COMBI-AD; ClinicalTrials.

Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis.

Background: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy.

Methods: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy.

Everolimus and sunitinib for advanced pancreatic neuroendocrine tumors: a matching-adjusted indirect comparison.

Background: Everolimus and sunitinib have been approved for the treatment advanced pancreatic neuroendocrine tumors, but have not been compared to each other in a randomized trial and have not demonstrated prolonged overall survival compared to placebo. This study aimed to indirectly compare overall and progression-free among everolimus, sunitinib and placebo across separate randomized trials.

Methods: A matching adjusted indirect comparison was conducted in which individual patient data from the pivotal trial of everolimus (n = 410) were adjusted to match the inclusion criteria and average baseline characteristics reported for the pivotal trial of sunitinib (n = 171).

Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases.

Everolimus is a potent, oral inhibitor of the mammalian target of rapamycin (mTOR) that has been investigated in multiple clinical development programs since 1996. A unique collaboration between academic and pharmaceutical experts fostered research that progressed rapidly, with simultaneous indication findings across numerous tumor types. Initially developed for the prophylaxis of organ transplant rejection, everolimus has demonstrated efficacy and safety for the treatment of patients with various types of cancer (renal cell carcinoma, neuroendocrine tumors of pancreatic origin, and breast cancer) and for adult and pediatric patients with tuberous sclerosis complex.

Patient-reported outcomes in a phase iii study of everolimus versus placebo in patients with metastatic carcinoma of the kidney that has progressed on vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy.

Purpose: A phase III, randomized, double-blind, placebo-controlled trial was conducted in patients with metastatic renal cell carcinoma. The focus of this paper is to evaluate the patient-reported outcomes.

Methods: Patients were randomly assigned (2:1) to receive oral everolimus 10 mg once daily or placebo.

Everolimus for advanced pancreatic neuroendocrine tumors.

Background: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.

Methods: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care.

Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial.

PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy.

Standard surgical versus percutaneous dilatational tracheostomy in intensive care patients.

Objective: The present prospective randomized trial compared surgical tracheostomy (ST) and percutaneous dilatational tracheostomy (PDT) in intensive care unit (ICU) patients in terms of outcomes and complications.

Methods: Between January 2003 and December 2005 tracheostomies were performed on critically ill ICU patients in Medical Faculty Hospital in Prague, with a random allocation of 105 patients for ST and 100 for PDT.

Results: The 2 groups did not differ significantly in terms of basic demographic characteristics or length of endotracheal intubation prior to the procedure.

12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients.

The proliferation signal inhibitor everolimus (Certican), has demonstrated efficacy with full-dose cyclosporine (CsA) (Neoral). Two multicenter randomized controlled studies were performed to compare 12-month efficacy and safety of everolimus 1.5 and 3.

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

Background: Fingolimod (FTY720) is a new oral immunomodulating agent under evaluation for the treatment of relapsing multiple sclerosis.

Methods: We randomly assigned 281 patients to receive oral fingolimod, at a dose of 1.25 mg or 5.

Analysis of 645 patients with primary hyperparathyroidism with special references to cholelithiasis.

Unlabelled: OBJECTIVE The clinical picture of primary hyperparathyroidism (PHPT) has changed during the past 50 years. It is currently unknown whether or not PHPT is associated with an increased risk of cholelithiasis.

Patients: To determine the frequency of cholelithiasis in PHPT we analyzed 645 consecutive patients seen at Prague University Hospital from 1992 through 2002 and compared them with a of normocalcaemic control group.

Everolimus and reduced-exposure cyclosporine in de novo renal-transplant recipients: a three-year phase II, randomized, multicenter, open-label study.

Background: Everolimus and cyclosporine (CsA) exhibit synergistic immunosuppressive activity when used in combination. We explored the use of everolimus with a CsA-sparing strategy in de novo renal-transplant recipients.

Methods: A phase II, randomized, open-label 3-year study was performed in 111 patients to compare the efficacy and tolerability of everolimus (3 mg/day) in combination with basiliximab, steroids, and either full-dose Neoral (FDN) or reduced-dose Neoral (RDN) (CsA trough levels 125-250 ng/mL and 50-100 ng/mL, respectively).

Effect of atorvastatin on non-cholesterol sterols in patients with type 2 diabetes mellitus and cardiovascular disease.

An increased risk of cardiovascular morbidity and mortality in diabetes mellitus type 2 has been associated with disturbances of lipid homeostasis. Recently, decreased intestinal absorption of cholesterol and increased liver cholesterol production have been reported. To investigate the influence of cholesterol lowering therapy using statin on cholesterol turnover in diabetes mellitus type 2, the levels of non-cholesterol based sterols were studied.

Repeatability of noninvasive surrogates of endothelial function.

We compared the repeatability of 2 ultrasonographic methods for endothelial function assessment at brachial artery-flow-mediated dilation (FMD) and post-ischemic peak blood flow (PBF). Twenty healthy volunteers were examined twice within 10 days; coefficients of variation were 13.8% for PBF and 41.

Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies.

Two prospective, randomized studies evaluated everolimus 1.5 vs. 3 mg/day with steroids and low-exposure cyclosporine (CsA) (C2 monitoring) in de novo renal transplant patients.

Effect of atorvastatin and fenofibrate on autonomic tone in subjects with combined hyperlipidemia.

This randomized open-label trial investigated whether autonomic cardiovascular control is altered in middle-aged men with combined hyperlipidemia and whether such alterations are affected by short-term, lipid-lowering therapy with atorvastatin and/or fenofibrate. Compared with normolipidemic subjects, untreated subjects with combined hyperlipidemia had several abnormalities of autonomic tone, indicating increased sympathetic tone and decreased baroreflex sensitivity. The alterations in autonomic cardiovascular control were partially reversible by each of the lipid-lowering drugs.

Effect of folic acid on fenofibrate-induced elevation of homocysteine and cysteine.

Background: An elevated total plasma homocysteine (tHcy) level is considered to be an independent risk factor for atherosclerosis. It has been reported that lipid-lowering therapy with fibric acid derivatives (fibrates) increases tHcy and total plasma cysteine (tCys) levels. The aim of this study was to determine whether therapy with folic acid, a potent tHcy-lowering agent, could modify the fenofibrate-induced elevation of plasma aminothiols.

Intima-media thickness of the common carotid artery is the significant predictor of angiographically proven coronary artery disease.

Background: Previous studies have shown a relationship between intima-media thickness (IMT) of the common carotid artery and coronary artery disease (CAD). The role of IMT in the prediction of significant CAD has not been established.

Objectives: To investigate the diagnostic accuracy of IMT measurement and the detection of carotid plaques in relation to cardiovascular risk factors in the prediction of significant CAD.

Soluble leptin receptor levels in patients with anorexia nervosa.

Objective: To examine whether changes of serum soluble leptin receptor levels (S-LEPR) can modify leptin half-life and its tissue effects. The aim of our study was to measure S-LEPR levels in patients with anorexia nervosa (AN) before and 6 weeks after partial refeeding.

Methods: Anthropometric variables, serum leptin, S-LEPR, insulin, cortisol and TNF-alpha were measured in 15 AN patients before and after partial refeeding and 15 healthy control women.