The role of immune checkpoint inhibitor therapy in advanced adrenocortical carcinoma revisited: review of literature.

PURPOSE: Adrenocortical carcinoma (ACC) is a rare disease with few therapeutic options. There is an urgency of new effective therapeutic options for these patients. The role of immune checkpoint inhibitors (ICI) in advanced ACC patients is still unclear. METHODS: We conducted a MEDLINE search using the following string: adrenocortical carcinoma and immunotherapy or checkpoint inhibitors. RESULTS: We found four case series comprising 10 patients, and four prospective studies totaling 115 patients. The response rate (RR) in the group of 10 patients was 1 complete response, 3 partial response (PR), 4 stable disease (SD), and 2 progressive disease (PD). The median progression-free survival (mPFS) ranged from 2 to 31 months and the median overall survival (mOS) ranged from 4.3 to 31 months. The results in the 115 patients from prospective trials was variable, the PR ranged from 6 to 23%, the SD ranged from 18 to 50% and overall disease control rate ranged from 30 to 64%. The mPFS reported varied from 1.8 to 2.6 months while the mOS varied from 10.6 to 24.9 months. There were five patients with sustained response for more than 24 months. The most common treatment-related adverse event (TRAE) was the increase in liver enzymes. No treatment-related deaths were reported. Better results in terms of RR and survival were observed in studies that used pembrolizumab. No predictive biomarker of response was found up to now. CONCLUSION: ICI, mainly pembrolizumab, is a potential therapeutic option, which is safe and associated with prolonged OS benefit, in selected patients with advanced ACC.

Vancomycin-resistant enterococci isolates colonizing and infecting haematology patients: clonality, and virulence and resistance profile.

BACKGROUND: Vancomycin-resistant enterococci (VRE) are an important agent of colonization and infection in haematology patients. However, the role of virulence on VRE colonization and infection is controversial. AIM: To characterize the lineage, virulence and resistance profile of VRE infection and colonization isolates; as well as their impact on outcome of haematology patients using a regression logistic model. METHODS: Eighty-six isolates (80 Enterococcus faecium and six E. faecalis) from 76 patients were evaluated. Polymerase chain reaction for resistance and virulence genes, and pulsed-field gel electrophoresis and whole genome sequencing of the major clusters, were performed. Bivariate and multivariate analyses were carried out to evaluate the role of virulence genes on outcome. FINDINGS: All isolates harboured the vanA gene. Regarding the virulence genes, 96.5% of isolates were positive for esp, 69.8% for gelE and asa1 genes. VRE infection isolates were more virulent than colonization isolates and harboured more often the gelE gene (P = 0.008). Infections caused by VRE carrying asa1 gene resulted more frequently in death (P = 0.004), but only the predominant clone remained as protector in the multivariate model. The E. faecium strains were assigned to seven STs (ST78, ST412, ST478, ST792, ST896, ST987, ST963) that belonged to CC17. The E. faecalis sequenced belonged to ST9 (CC9). CONCLUSION: E. faecium was predominant, and infection isolates were more virulent than colonization isolates and harboured more often the gene gelE. Infections caused by VRE carrying the asa1 gene appeared to be associated with a fatal outcome.

Urinary Tract Infections and Surgical Site Infections due to Carbapenem-Resistant Enterobacteriaceae in Renal Transplant.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) are emerging pathogens. Recent publications have shown that renal transplant recipients are a population at risk for CRE infections. Management of these infections in this population is complex, requiring frequent use of nephrotoxic antimicrobial agents. Differentiating between urinary tract infection (UTI) and surgical site infection (SSI) in renal transplant recipients is sometimes difficult. The aim of this study was to describe CRE UTIs and SSIs in renal transplant recipients and to evaluate the impact of these infections on renal graft and patient survival. RESULTS: Between January 2010 and October 2015, a total of 428 renal transplants were performed; 25 UTIs and 9 SSIs were identified. Median time between transplantation and diagnosis of CRE infection was 26 days; 29 cases (85.29%) were considered early infections. Of the 34 CRE isolates, 100% were sensitive to amikacin and colistin. Polymyxins were the most commonly used antimicrobial agent (27 cases [79.41%]). Nephrotoxicity was found in 4 (15.38%) of 26 cases. Combination therapy was used in 19 cases (55.88%), with a cure rate of 74%; monotherapy was used in 15 cases (44.11%), with a cure rate of 86%. Among the 25 cases of UTI, the cure rate was 100%, and recurrence occurred in 4 cases (16%). Among the 9 cases of SSI, 7 (77.7%) had negative outcomes (nephrectomy or death). CONCLUSIONS: We observed that CRE UTIs had a high therapeutic success rate, low recurrence, and low mortality. However, CRE SSIs were associated with high morbidity and mortality, with high graft loss. Polymyxins and aminoglycosides, despite the risk of nephrotoxicity, had little impact on renal graft function, and are thus a safe therapeutic alternative to treat these infections.

A novel approach for the automated segmentation and volume quantification of cardiac fats on computed tomography.

The deposits of fat on the surroundings of the heart are correlated to several health risk factors such as atherosclerosis, carotid stiffness, coronary artery calcification, atrial fibrillation and many others. These deposits vary unrelated to obesity, which reinforces its direct segmentation for further quantification. However, manual segmentation of these fats has not been widely deployed in clinical practice due to the required human workload and consequential high cost of physicians and technicians. In this work, we propose a unified method for an autonomous segmentation and quantification of two types of cardiac fats. The segmented fats are termed epicardial and mediastinal, and stand apart from each other by the pericardium. Much effort was devoted to achieve minimal user intervention. The proposed methodology mainly comprises registration and classification algorithms to perform the desired segmentation. We compare the performance of several classification algorithms on this task, including neural networks, probabilistic models and decision tree algorithms. Experimental results of the proposed methodology have shown that the mean accuracy regarding both epicardial and mediastinal fats is 98.5% (99.5% if the features are normalized), with a mean true positive rate of 98.0%. In average, the Dice similarity index was equal to 97.6%.

Improving plant transformation using Agrobacterium tumefaciens.

Here, we report a quick and low-cost method to improve plant transformation using Agrobacterium tumefaciens. This method involves the use of physical wounding, ultrasound, and an increase in exposure time to the bacteria. We show how the transformation rate increased from 0 to 14% when an ultrasound pulse of 10 s was used in conjunction with 96 h of bacterial exposure in Eclipta alba explants.

Ipilimumab-induced hypophysitis: review of the literature.

PURPOSE: Ipilimumab is a human monoclonal antibody against cytotoxic T-lymphocyte antigen 4 available as an immunotherapy mainly for advanced melanoma. It induces an activation of T cells, resulting in an immune-mediated anti-tumor response and also immune-related adverse events, including hypophysitis. The aim of this review is to identify and discuss features concerning ipilimumab-induced hypophysitis (IIH). DESIGN: A MEDLINE research of all years of publication of IIH was conducted. We gathered information regarding clinical, radiologic and laboratory features of 71 cases recorded in the literature. RESULTS: In our review, IIH was more frequent among older and male patients. Fatigue and headache were the most frequent initial clinical manifestations of IIH and enlargement of the pituitary gland at MRI was present in the majority of patients. Those who received more than 3 cycles of ipilimumab had more fatigue (p = 0.04) and arthritis (p = 0.04). Adrenal insufficiency was more prevalent in men (p = 0.007). Glucocorticoid therapy and hormone replacement were required in most patients and pituitary function recovery was uncommon. Low prolactin at diagnosis tended to predict permanent pituitary dysfunction (p = 0.07). CONCLUSION: Hypopituitarism as a consequence of IIH, if not promptly recognized, can lead to potentially fatal events, such as adrenal insufficiency. IIH can be easily managed with glucocorticoids and hormonal replacement; therefore, physicians should be familiar with the key aspects of this condition. More studies to develop screening protocols and therapeutic intervention algorithms should be performed to decrease morbidity related to IIH.

Pre-task music improves swimming performance.

AIM: The purpose of this study was to investigate the effects of pre-task music on swimming performance and other psychological variables. METHODS: A randomized counterbalanced within-subjects (experimental and control condition) design was employed. Eighteen regional level male swimmers performed two 200-m freestyle swimming time trials. Participants were exposed to either 5 minutes of self-selected music (pre-task music condition) or 5 minutes of silence (control condition) and, after 1 minute, performed the swimming task. RESULTS: Swimming time was significantly shorter (-1.44%) in the pre-task music condition. Listening to pre-task music increased motivation to perform the swimming task, while arousal remained unchanged. While fatigue increased after the swimming task in both conditions, vigor, ratings of perceived exertion and affective valence were unaltered. CONCLUSION: It is concluded, for the first time, that pre-task music improves swimming performance.

Susceptibility of multiresistant gram-negative bacteria to fosfomycin and performance of different susceptibility testing methods.

Fosfomycin may be a treatment option for multiresistant Gram-negative bacteria. This study compared susceptibility methods using 94 multiresistant clinical isolates. With agar dilution (AD), susceptibilities were 81%, 7%, 96%, and 100% (CLSI) and 0%, 0%, 96%, and 30% (EUCAST), respectively, for Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter spp. Categorical agreement between Etest and AD for Enterobacteriaceae and A. baumannii was ≥80%. Disk diffusion was adequate only for Enterobacter. CLSI criteria for urine may be adequate for systemic infections.

Low somatostatin receptor subtype 2, but not dopamine receptor subtype 2 expression predicts the lack of biochemical response of somatotropinomas to treatment with somatostatin analogs.

OBJECTIVES: To evaluate somatostatin receptor 2A (SSTR2A) and dopamine receptor 2 (DR2) protein expression in somatotropinomas and to relate it to response to somatostatin analogues (SA). DESIGN AND PATIENTS: SSTR2A and DR2 expression was analyzed by immunohistochemistry in 88 somatotropinomas from patients submitted to either pre-surgical or adjuvant SA treatment. Tumors were scored according to percentage of immunostained cells: 0 (< 25%), 1 (25-50%), and 2 (> 50%). Relation between protein expression and response to SA was performed in 66 patients. Response to SA was assessed by percent IGF-I reduction, being considered as an IGF-I per cent reduction higher than 50%. Disease control was also assessed (GH < 1.0 ng/ml and normal IGF-I). RESULTS: SSTR2A and DR2 were expressed in 100% and 98% of tumors, respectively. Biochemical response and disease control rates were 48% and 32%, respectively. Median IGF-I percent reduction after 3 months of SA treatment was lower in the SSTR2A score 0 than in the scores 1 and 2 (p < 0.001, both), and after 6 months in the score 0 than in the score 1 (p = 0.001) and 2 (p < 0.001). Biochemical response and disease control were associated with SSTR2 expression (p < 0.001 and p = 0.004, respectively). A negative predictive value for biochemical response of 100% was found when a SSTR2A expression < 25%of immunostained cells cut-off point was considered. No relation was found between DR2 expression and biochemical response and disease control. CONCLUSION: SSTR2A and DR2 are highly expressed in somatotropinomas. Low SSTR2A, but not DR2, expression is a negative predictive factor to response to SA.

Antifolates inhibit Cryptococcus biofilms and enhance susceptibility of planktonic cells to amphotericin B.

The Cryptococcus neoformans species complex contains the most important agents of fungal meningoencephalitis. Therapeutic choices are limited and issues related to toxicity and resistance to antifungals have been described. The present study evaluated the inhibitory effect of the antifolate combinations sulfamethoxazole-trimethoprim (SMX/TMP) and sulfadiazine-pyrimethamine (SDZ/PYR) against planktonic cells and biofilms of C. neoformans and C. gattii. The influence of the antifolate combinations on the amphotericin minimum inhibitory concentration (MIC) of planktonic cells was also investigated. In addition, the effect of these combinations on the cellular ergosterol content of planktonic cells was studied. Strains of C. neoformans (n = 15) and C. gattii (n = 15) obtained from environmental or clinical sources were evaluated by the broth microdilution method. SMX/TMP and SDZ/PYR showed antifungal activity against free living cells and sessile cells of Cryptococcus spp. Moreover, planktonic cells showed increased susceptibility to amphotericin B after pre-incubation with sub-inhibitory concentrations of SMX/TMP or SDZ/PYR. The drug combinations SMX/TMP and SDZ/PYR were able to prevent the biofilm formation and showed inhibitory effect against mature biofilms of both species. Additionally, the study showed that antifolate drugs reduced the ergosterol content in C. neoformans and C. gattii planktonic cells. Our results highlight the antifungal potential of antifolate drugs.

Viral protease inhibitors affect the production of virulence factors in Cryptococcus neoformans.

The effects of the protease inhibitors saquinavir, darunavir, ritonavir, and indinavir on growth inhibition, protease and phospholipase activities, as well as capsule thickness of Cryptococcus neoformans were investigated. Viral protease inhibitors did not reduce fungal growth when tested in concentrations ranging from 0.001 to 1.000 mg/L. A tendency toward increasing phospholipase activity was observed with the highest tested drug concentration in a strain-specific pattern. However, these drugs reduced protease activity as well as capsule production. Our results confirm a previous finding that antiretroviral drugs affect the production of important virulence factors of C. neoformans.

Candida parapsilosis meningitis as the first manifestation of AIDS: case report.

Candida meningitis is a rare condition that occurs more frequently in premature infants, immunocompromised patients or patients after neurosurgery. We describe a case of a previously healthy 41-year-old man with Candida parapsilosis meningitis associated with oropharyngeal candidiasis as the first manifestation of AIDS.

Orthopaedic evaluation in children with severe haemophilia A or B submitted to primary prophylaxis therapy in a coagulopathy treatment centre.

There is a lack of publications concerning the use of primary prophylaxis in developing countries. The aim of this study was to evaluate the effectiveness of primary prophylaxis therapy in preventing the development of arthropathy in children with severe haemophilia A or B. From January 1999 to April 2009, a prospective study was carried out involving 39 patients with severe haemophilia A or B. These haemophilia A and haemophilia B patients received 20-40 UI kg(-1) of factors VIII and IX, three and two times per week, respectively. The patients were followed up by a multidisciplinary team. The analysis was carried out in 23 patients who had been on prophylaxis therapy for at least 12 months. The orthopaedic evaluation was performed according to the recommendations of the Orthopedic Advisory Committee of the World Federation of Hemophilia, by evaluating pain and bleeding, and by conducting physical examination and radiological assessment (Pettersson's Joint Score and magnetic resonance): 82.6% of patients who had used the factor regularly did not present any clinical or radiographic changes in the studied joints; 17.4% used the factor irregularly at the beginning of the treatment and of those, most patients presented mild changes in the joints; and 4.3% presented transient knee and ankle pain in spite of regular factor use. The preliminary results of primary prophylaxis confirm its effectiveness in preventing haemophilic arthropathy. Socioeconomic factors did not play a significant role.

Effects of GH-IGF-I excess and gonadal status on bone mineral density and body composition in patients with acromegaly.

SUMMARY: Studies on body composition and bone mineral density in acromegaly have conflicting results. Our data point to an increase in lean mass, a decrease in adipose tissue, and that the anabolic effect of GH on bone is partially dependent on modifications in body composition. INTRODUCTION: The effects of growth hormone (GH) and insulin-like growth factor I (IGF-I) excess and gonadal status on bone mineral density (BMD) and body composition (BC) in acromegalic patients are uncertain. METHODS: Bone mineral density and BC were evaluated by dual-energy X-ray absorptiometry (Prodigy-GE) in 75 patients (22 men and 53 women) with acromegaly, mean age 48.9 ± 14.5 years. Acromegaly was considered "controlled" when serum IGF-I was within the specific age-adjusted reference range, and serum GH was lower than 2.5 ng/mL. Comparisons between groups were performed using unpaired t test or Mann-Whitney U test. Categorical variables were analyzed by chi-square (x (2)) test. In order to compare data of different subgroups stratified by disease activity and gonadal status, one-way analysis of variance (ANOVA) and Bonferroni post hoc analysis were performed. To evaluate the correlation between GH and IGF-I and densitometric parameters, Pearson and Spearman rank order correlation were performed, as appropriate. RESULTS: There were no differences in BMD when considering disease activity and gonadal status. Active disease and eugonadism were positively correlated to an increase in lean mass and a decrease in fat mass. After multiple linear regression, there were positive correlations between GH and Z-score at lumbar spine and between lean mass and BMD at proximal femur. CONCLUSION: Our data support that GH-IGF-I excess and eugonadism have great influence on BC modifications and that the anabolic effects of GH-IGF-I on bone are, at least in part, dependent on these alterations in body composition.

Herpes simplex virus ophthalmic disease induced using two different methods of mice inoculation.

Two different procedures for inoculation of HSV on corneas of BALB/c mice were evaluated. The first was by the use of HSV suspensions directly on the corneas and the other was after corneal scarification. Animals by this later method presented greater morbidity and mortality than those of first group, suggesting that inoculation of HSV without scarification of the cornea should be the method of choice for the study of HSV ophthalmic infection. This model showed also be an efficient experimental system to testing antiviral drugs.