Reduced Handgrip Strength Is Associated with 1 Year-Mortality in Brazilian Frail Nonagenarians and Centenarians.

The aim of the present study was to investigate the association between handgrip strength and mortality in Brazilian frail nonagenarians and centenarians. Eighty-one oldest old were included (mean age [SD]: 94.2 [3.8] years). Data on strength was assessed by handgrip strength. Mortality rate of the participants was evaluated at 1-year follow-up after the functional assessment. A logistic regression analysis was used to assess differences in categories of handgrip strength between groups regarding the mortality rate. Forty-six participants (56.8%) had reduced handgrip strength. After 1 year, there were 16 deaths. Those older adults with a low handgrip strength had higher prevalence (28.3% vs. 8.6%) and increased risk of mortality than those with preserved handgrip strength (Odds ratio=4.4, confidence interval 95% 1.1, 18.4) (p=0.042). Reduced handgrip strength is associated with higher mortality rate at 1-year follow-up in Brazilian frail nonagenarians and centenarians.

Everolimus pharmacokinetics and its exposure-toxicity relationship in patients with thyroid cancer.

BACKGROUND: Everolimus is a mTOR inhibitor used for the treatment of different solid malignancies. Many patients treated with the registered fixed 10 mg dose once daily are in need of dose interruptions, reductions or treatment discontinuation due to severe adverse events. This study determined the correlation between systemic everolimus exposure and toxicity. Additionally, the effect of different covariates on everolimus pharmacokinetics (PK) was explored. METHODS: Forty-two patients with advanced thyroid carcinoma were treated with 10 mg everolimus once daily. Serial pharmacokinetic sampling was performed on days 1 and 15. Subsequently, a population PK model was developed using NONMEM to estimate individual PK values used for analysis of an exposure-toxicity relationship. Furthermore, this model was used to investigate the influence of patient characteristics and genetic polymorphisms in genes coding for enzymes relevant in everolimus PK. RESULTS: Patients who required a dose reduction (n = 18) due to toxicity at any time during treatment had significant higher everolimus exposures [mean AUC0-24 (SD) 600 (274) vs. 395 (129) µg h/L, P = 0.008] than patients without a dose reduction (n = 22). A significant association between everolimus exposure and stomatitis was found in the four-level ordered logistic regression analysis (P = 0.047). The presence of at least one TTT haplotype in the ABCB1 gene was associated with a 21 % decrease in everolimus exposure. CONCLUSION: The current study showed that dose reductions and everolimus-induced stomatitis were strongly associated with systemic everolimus drug exposure in patients with cancer. Our findings confirm observations from another study in patients with cancer and show us that everolimus is a good candidate for individualized dosing in patients with cancer. CLINICALTRIAL. GOV NUMBER: NCT01118065.

Beneficial Effects of the mTOR Inhibitor Everolimus in Patients with Advanced Medullary Thyroid Carcinoma: Subgroup Results of a Phase II Trial.

Objective. Until recently, advanced medullary thyroid cancer (MTC) had few treatment options except surgery. The mTOR inhibitor everolimus has shown encouraging results in neuroendocrine tumors. As part of a prospective phase II study, we analyzed the safety and efficacy of everolimus in advanced MTC. Methods. Seven patients with per RECIST 1.1 documented advanced MTC were included and received everolimus 10 mg daily. The primary objective was determining treatment efficacy. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and pharmacokinetics (PK). Results. Median follow-up duration was 28 weeks (17-147). Five patients (71%) showed SD, of which 4 (57%) showed SD >24 weeks. Median PFS and OS were 33 (95%CI: 8-56) and 30 (95%CI: 15-45) weeks, respectively. Toxicity was predominantly grade 1/2 and included mucositis (43%), fatigue (43%), and hypertriglyceridemia (43%). Four MTCs harbored the somatic RET mutation c.2753T>C, p.Met918Thr. The best clinical response was seen in a MEN2A patient. PK characteristics were consistent with phase I data. One patient exhibited extensive toxicity accompanying elevated everolimus plasma concentrations. Conclusions. This study suggests that everolimus exerts clinically relevant antitumor activity in patients with advanced MTC. Given the high level of clinical benefit and the relatively low toxicity profile, further investigation of everolimus in these patients is warranted.

To treat or not to treat: developments in the field of advanced differentiated thyroid cancer.

BACKGROUND: Thyroid cancer is the most prevalent endocrine malignancy. Based on the increased understanding of thyroid tumourigenesis, novel therapeutic agents have been identified. However, given the low incidence, the good prognosis of the majority of these tumours and the limited evidence of different treatment modalities, a wide variety of treatment strategies are available. These are mostly based on small studies, data from retrospective analyses and the particular experiences of treating physicians. We discuss the recent developments in the treatment of advanced differentiated thyroid cancer. CASE DESCRIPTION: Three cases demonstrate the considerations involved in treatment decisions for patients with advanced thyroid cancer. The first patient achieved stable disease for over five years with different targeted therapies. The second patient shows the potential (severe) toxicity of these drugs and the third patient illustrates the indolent nature of this disease. CONCLUSION: The treatment of patients with extensively metastasised thyroid cancer is very complicated. The timing of initiation of therapy and the potential toxicity of targeted therapies are important in the clinical decision to treat or not to treat because of the slowly progressive course of differentiated thyroid cancer. When targeted therapy is considered, it remains of great importance to enrol patients in clinical studies in order to further determine the position of these therapies, to develop more effective (combination) treatment schemes, and above all, to identify those patients that truly benefit.

Long-term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: final results of a phase II trial.

OBJECTIVE: We conducted a prospective phase II clinical trial to determine the efficacy of sorafenib in patients with advanced radio-iodine refractory differentiated thyroid cancer. In this article, the long-term results are presented. PATIENTS AND METHODS: Thirty-one patients with progressive metastatic or locally advanced radioactive iodine refractory differentiated thyroid cancer received sorafenib 400 mg orally twice daily. The study end points included response rate, progression-free survival (PFS), overall survival (OS), best response by Response Evaluation Criteria in Solid Tumors criteria 1.0, and toxicity. RESULTS: Median PFS was 18 months (95% confidence interval (95% CI): 7-29 months) and median OS was 34.5 months (95% CI: 19-50 months). Eight patients (31%) achieved a partial response and 11 patients (42%) showed stable disease after a median follow-up of 25 months (range 3.5-39 months). Toxicity mostly included hand foot syndrome, weight loss, diarrhea, and rash. CONCLUSION: Sorafenib has clinically relevant antitumor activity in patients with progressive metastatic or locally advanced radio-iodine refractory differentiated thyroid cancer. Sorafenib can nowadays be considered as the standard option in these patients.

New treatment modalities in advanced thyroid cancer.

BACKGROUND: Thyroid cancer is a heterogeneous disease that is classified into differentiated thyroid carcinoma (DTC), undifferentiated/anaplastic thyroid carcinoma (ATC) and medullary thyroid carcinoma. Results of conventional treatment modalities in advanced thyroid cancer have been disappointing and therefore, new therapies are needed. METHODS: We searched PubMed, The Cochrane Library, Medline and EMBASE databases and abstracts published in annual proceedings for new treatment modalities in advanced thyroid cancer. We also searched for ongoing trials in www.clinicaltrials.gov. RESULTS: Six phase I, 17 phase II and 1 phase III trials with tyrosine kinase inhibitors were carried out. We found 2 pilot studies and 11 phase II trials with redifferentiation therapies, mainly in DTC. For antiproliferative approaches, three phase I and four phase II trials were found. Immunomodulatory gene therapy was tested in a pilot study in ATC patients. Two phase II trials were carried out with immunotherapy. One phase I and nine phase II trials were found with radionucleotide therapy in patients with DTC. CONCLUSION: The developments in the treatment of advanced thyroid cancer are intriguing. Future trials should aim at combinations of targeted agents with or without other treatment modalities, and will hopefully contribute to further improvement of outcomes.

The malfunctioning silastic catheter--radiologic assessment and treatment.

Occlusion of silastic catheters is attributed to several documented causes. One factor not yet adequately documented is fibrin sleeve formation. In this instance, the catheter functions for infusion purposes, but blood withdrawal is no longer feasible. This is a troublesome occurrence when encountered in the clinical setting. This report reviews the assessment of fibrin sleeve formation, the use of catheter phlebography and treatment with low-dose streptokinase. Seventeen instances of the inability to aspirate blood from silastic catheters are evaluated with restoration of full catheter function in all cases after streptokinase administration.

The relationship of the level of training and area of medical specialization with registrant performance in an advanced trauma life-support course.

Approved advanced trauma life-support (ATLS) programs were given to 160 residents and practitioners of various specialties, utilizing a standardized 50-item, multiple-choice posttest. Level of training (practitioner v resident) and area of medical specialization with registrant performance on total score and in specific subcontent areas of ATLS were evaluated by subjecting total and subcontent percent scores to a two-way analysis of variance and Newman-Keuls pairwise comparisons. Practitioners outperformed the residents in the subcontent area of abdominal injuries, P less than .05. In specialization, emergency medicine outperformed internal medicine specialists, P less than .05. Pairwise differences among specialists were not statistically significant. In airway problems, surgeons and internists were outperformed by emergency medicine, whereas in burns, emergency medicine and family practitioners significantly outperformed the surgeons. Emergency medicine outperformed internal medicine, P less than .05, in subcontent area of extremity injuries. We conclude that registrants are likely to benefit from an ATLS course, but preliminary evidence would seem to justify some "tailoring" of the ATLS curriculum for different registrant specialty groups.

A re-evaluation of energy expenditure during parenteral nutrition.

Nutritional support regimens are currently based on estimates of energy expenditure, and these estimates are then increased substantially in patients with severe trauma or sepsis because of a presumed hypermetabolic state. Forty-four patients on parenteral nutrition were evaluated using indirect calorimetry to measure actual energy expenditure, and an attempt was made to correlate metabolic rate with clinical diagnosis. We found no statistical difference in metabolic rates between groups of patients classified as malnourished, stressed, or catabolic, If high levels of nonprotein energy substrates are to be administered to a catabolic or "hypermetabolic" patient group, the justification must be on a basis other than a significant increase in actual rate of energy expenditure.

Management of carcinoma of anal canal.

The application of various treatment modalities in the management of carcinoma of the anal canal remains controversial. Forty-nine patients were reviewed from the affiliated hospitals of the Medical College of Wisconsin. Exclusions for postoperative deaths, associated vulvar carcinoma, and lack of follow-up left 35 patients for determinate study. The overall 5-year survival rate was 28.6% (10 of 35). When reviewed by stage of disease, a direct relationship between advanced stage and decreased survival (i.e., 60% five-year survival rate with stage I, 25% with stage II, and 14.3% with stage III) was noted. Further reclassification of stage III, nodal involvement, showed the same survival for perirectal nodal involvement as for synchronous inguinal node involvement. Seven of ten 5-year survivors received a combined surgery-radiotherapy approach. In addition, in those patients receiving tumoricidal radiation pre- or postoperatively, no local recurrence was demonstrated. A treatment protocol of abdominal perineal resection, with combined radiation therapy for locally advanced lesions, is proposed.