Immune checkpoint inhibitors in endometrial cancer.

The incidence of endometrial cancer (EC) is increasing worldwide. The prognosis for patients diagnosed with early-stage remains good, whereas for patients with recurrent or metastatic disease, the prognosis is poor and treatment options, until recently, were limited. In 2017, pembrolizumab was approved by the US Food and Drug Administration (FDA) for those patients with mistmach repair deficiency (MMRd) or high microsatellite instability (MSI-H) tumors. However, only 20-30 % of EC have MSI, and just over half of these patients benefit from treatment. In 2019, the FDA granted breakthrough therapy designation to lenvatinib in combination with pembrolizumab for the potential treatment of patients with advanced microsatellite stable EC that has progressed after treatment with at least one previous systemic therapy. It appears clear that immune check-point inhibitors will have a definite place in the management of EC, both as single agent or in combination with other targeted agents. In this review, we summarize the current evidence of immune check point blockade and the identification of potential biomarkers, beyond MSI-H or MMRd, that could help to predict response to this agents in correlation with the genomic EC subtypes.

Toxicity of cyanobacterial blooms from the reservoir Valle de Bravo (Mexico): A case study on the rotifer Brachionus calyciflorus.

Proliferating cyanobacterial blooms due eutrophication in reservoirs is a major global problem. The production of cyanotoxins often increases with grazing pressure and temperature while the sensitivity of zooplankton to cyanotoxins is directly related to temperature. Here we evaluate the effect of different concentrations of the crude extract of cyanobacteria from Valle de Bravo reservoir during dry (January) and rainy (September) seasons at 20 and 25 °C on the rotifer Brachionus calyciflorus based on acute and chronic toxicity tests. We filtered 20 or 150 l of lake water, depending on the intensity of the bloom, and estimated the density and diversity of the cyanobacteria. The crude extracts, after 5 cycles of freezing, thawing and sonication at 14 MHz, were filtered and the microcystin concentration quantified based on ELISA. The extracts were used to conduct the acute and chronic toxicity tests, all in quadruplicate. Acute toxicity tests were based on 24 h mortality. Chronic toxicity tests (population growth and life table experiments) were conducted at 5 and 10% of the median lethal concentration. The field samples were dominated by Microcystis sp. (January) or Woronichinia naegeliana (September). The microcystin concentration in lake water was 9.57 µg/l and 0.097 µg/l and the median lethal concentration was 5.34 µg microcystin/L and 0.35 µg microcystin/L in January and September, respectively. Survival and reproduction of B. calyciflorus were lower in the presence of the cyanobacteria crude extract, more so at 20° than at 25 °C. Our results highlight the urgency of regular monitoring based on zooplankton assays for reservoirs in tropical and temperate regions, subject to frequent and dominant cyanobacterial blooms, often as a result of climate change.

Engorgement of Deep Medullary Veins in Neurosarcoidosis: A Common-Yet-Underrecognized Cerebrovascular Finding on SWI.

We describe the prevalence and potential significance of deep medullary vein engorgement on SWI in patients with neurosarcoidosis, a finding that has not been described previously. Engorgement was evaluated for possible associations with meningeal or perivascular disease, intracranial hemorrhage, and venous thrombosis, as well as with modified Rankin Scale scores at the time of MR imaging and at follow-up. Deep medullary vein engorgement was seen in 7 of 21 patients and was more common in men. Patients with venous engorgement had a significantly increased incidence of microhemorrhages, perivascular disease, and hydrocephalus. There was no association with the degree of leptomeningeal disease, venous dural sinus thrombosis, or modified Rankin Scale scores. In conclusion, deep medullary vein engorgement was common in our patients with neurosarcoidosis. Although its pathophysiology remains uncertain, it could be related to venous or perivenous abnormalities and may represent a useful secondary finding of cerebrovascular disease.

Fístula hepatopulmonar: Una complicación rara del absceso hepático / Hepatopulmonary fistula: a rare complication of hepatic abscess

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Cavitary Plaques in Otospongiosis: CT Findings and Clinical Implications.

BACKGROUND AND PURPOSE: Cavitary plaques have been reported as a manifestation of otospongiosis. They have been related to third window manifestations, complications during cochlear implantation, and sensorineural hearing loss. However, their etiology and clinical implications are not entirely understood. Our purpose was to determine the prevalence, imaging findings, and clinical implications of cavitary plaques in otospongiosis. MATERIALS AND METHODS: We identified patients with otospongiosis at a tertiary care academic medical center from January 2012 to April 2017. Cross-sectional CT images and clinical records of 47 patients (89 temporal bones) were evaluated for the presence, location, and imaging features of cavitary and noncavitary otospongiotic plaques, as well as clinical symptoms and complications in those who underwent cochlear implantation. RESULTS: Noncavitary otospongiotic plaques were present in 86 (97%) temporal bones and cavitary plaques in 30 (35%). Cavitary plaques predominated with increasing age (mean age, 59 years; P = .058), mostly involving the anteroinferior wall of the internal auditory canal (P = .003), and their presence was not associated with a higher grade of otospongiosis by imaging (P = .664) or with a specific type of hearing loss (P = .365). No patients with cavitary plaques had third window manifestations, and those with a history of cochlear implantation (n = 6) did not have complications during the procedure. CONCLUSIONS: Cavitary plaques occurred in one-third of patients with otospongiosis. Typically, they occurred in the anteroinferior wall of the internal auditory canal. There was no correlation with the degree of otospongiosis, type of hearing loss, or surgical complications. Cavitary plaques tended to present in older patients.

Transplantation of Human Amniotic Membrane over the Liver Surface Reduces Hepatic Fibrosis in a Cholestatic Model in Young Rats.

PURPOSE: Biliary atresia precedes liver cirrhosis and liver transplantation. Amniotic membrane (AM) promotes tissue regeneration, inhibits fibrosis, and reduces inflammation. Here, we test amniotic membrane potential as a therapeutic tool against cholestatic liver fibrosis. METHODS: Three groups of rats were used: sham surgery (SS), bile duct ligature (BDL), and bile duct ligature plus human amniotic membrane (BDL + AM). After surgery, animals were sacrificed at different weeks. Biochemical and histopathological analyses of liver tissue were performed. Collagen was expressed as a percentage of total liver tissue area. qPCR was performed to analyse gene expression levels of transforming growth factor-ß1 (Tgfb1) and apelin (Apln). Statistical analysis performed considered p < 0.05 was significant. RESULTS: Groups undergoing BDL developed cholestasis. Biochemical markers from BDL + AM group improved compared to BDL group. Ductular reaction, portal fibrosis, and bile plugs were markedly reduced in the BDL + AM group compared to BDL group. Collagen area in BDL + AM group was statistically decreased compared to BDL group. Finally, expression levels of both Apln and Tgfb1 mRNA were statistically downregulated in BDL + AM group versus BDL group. CONCLUSION: AM significantly reduces liver fibrosis in a surgical animal model of cholestasis. Our results suggest that AM may be useful as a therapeutic tool in liver cirrhosis.

Comparación de ceftazidima-amikacina contra imipenem en el tratamiento de fiebre neutropénica / Comparison of ceftazidime/amikacin vs imipenem in the treatment of neutropenic fever

Resumen: ANTECEDENTES: la fiebre neutropénica es una de las principales complicaciones del tratamiento oncológico y es causa importante de morbilidad y mortalidad; afecta a más de 80% de los pacientes con neoplasias hematológicas durante el primer ciclo de quimioterapia. El tratamiento consiste en antibióticos de amplio espectro con respuestas terapéuticas heterogéneas. OBJETIVO: determinar el tiempo promedio de la desaparición de la fiebre después de la administración de la primera dosis del antibiótico. MATERIAL Y MÉTODO: estudio prospectivo, aleatorizado, doble ciego, efectuado del 1 de mayo al 24 de septiembre de 2014, en el que los pacientes se distribuyeron al azar para recibir tratamiento con ceftazidima-amikacina o imipenem durante 10 días. Se registraron la temperatura y fiebre. Se tomaron hemocultivos previo al tratamiento y a las 48 horas en caso de persistencia de fiebre. Se registraron todos los hemocultivos con crecimiento bacteriano. RESULTADOS: se evaluaron 31 pacientes, de 17 a 61 años de edad (promedio de 33.6 ± 13.9); 15 pacientes recibieron ceftazidima-amikacina (48.4%) y 16 pacientes imipenem (51.6%). El tiempo promedio de remisión de la fiebre fue de 11.2 ± 16.3 vs 9.6 ± 14.8 horas (p = 0.6) en el grupo de ceftazidima-amikacina e imipenem, respectivamente. CONCLUSIONES: no hubo diferencia en el tiempo de mejoría clínica entre los pacientes tratados con imipenem o ceftazidima-amikacina. Ambos esquemas antimicrobianos fueron igual de eficaces para el tratamiento de la fiebre neutropénica secundaria a quimioterapia.

Abstract: BACKGROUND: Neutropenic fever is one of the major complications of cancer treatment and it is an important cause of morbidity and mortality. It occurs in more than 80% of patients with hematologic malignancies during the first cycle of chemotherapy. Treatment consists on broad-spectrum antibiotics with heterogeneous therapeutic responses. OBJECTIVE: To determine the average time for disappearance of fever after the administration of the first dose of antibiotics. MATERIAL AND METHOD: A prospective, randomized, double blind study was conducted. Patients were randomized to receive treatment with ceftazidime/amikacin or imipenem for 10 days. A record of temperature and fever was kept. Blood cultures prior to treatment and at 48 hours were taken in case of persistent fever. All blood cultures were recorded for bacterial growth. RESULTS: Were evaluated 31 patients with ages between 17 and 61 years (mean 33.6 ± 13.9). Fifteen patients received ceftazidime/amikacin (48.4%) and 16 patients imipenem (51.6%). The average time of remission of fever was 11.2±16.3 vs 14.8 ± 9.6 hours (p = 0.6) for the ceftazidime/amikacin and imipenem group, respectively. CONCLUSIONS: There was no difference about the time of clinical improvement among patients treated with imipenem or ceftazidime/amikacin. Both antimicrobials schemes were equally effective for the treatment of secondary neutropenic fever chemotherapy.

[Characterising people who demanded the rapid HIV test in Andalusia between 2013 and 2014]. / Caracterización de las personas que demandaron la prueba de detección rápida del VIH en Andalucía entre 2013 y 2014.

BACKGROUND: The aim of the study was to describe people who demanded the HIV screening test in Andalusia (Spain). DESIGN: Cross-sectional study carried out by social organisation collaborating with the Program for early diagnosis of HIV in Andalusia. Participants underwent an oral HIV test and answered a survey beforehand, from September 2013 to August 2014. The study included a descriptive analysis of data and a logistic regression in order to determine the risk factors associated with a reactive test result. We analysed variables related to: social organisation, sociodemographic characteristics, risk exposure that caused the test, previous test history, history of sexually transmitted infections (predictive variables) and test result (dependent variable). RESULTS: It was possible to characterise 1,844 people (48%). They were mostly men (70%) who had sex with men (MSM) in the last 12 months (59%). The 53% had a previous HIV test and came to social organisations after an exposure to risk, especially unprotected oral sex (75%), vaginal (50%) and/or anal (38%). Twenty-three percent was foreigners. A positive result was associated to: HIV work area, male sex, MSM, unprotected sex (anal, with HIV+ person or with sex worker) and test antecedent (p<0.05). These unprotected practices and male sex were also significant in the multivariate analysis. CONCLUSIONS: This approach of the study made it possible to characterise a great number of people (around 50%). These results will guide improvements in the Program's data collection and future community interventions.

Imaging Manifestations of Pseudoprogression in Metastatic Melanoma Nodes Injected with Talimogene Laherparepvec: Initial Experience.

Talimogene laherparepvec is an oncolytic virus recently approved for targeted treatment of advanced melanoma. Because of an inflammatory reaction, treated lesions may increase in size and develop infiltrative margins that can be construed as disease progression or extracapsular spread. In this report, we describe our initial experience imaging the response of metastatic nodes injected with talimogene laherparepvec. Six of 12 nodes (50%) showed growth from baseline followed by decreased size, 5 of 12 nodes (42%) showed a downward size trend, and 1 node showed continued increase in size. Seven of 9 nodes (78%) developed infiltrative margins at a median of 79 days, and 6 of 9 (67%) nodes became necrotic at a median of 76 days after injection, all showing decreased size at final follow-up. An increase in the size of nodes injected with talimogene laherparepvec does not necessarily indicate progression. Infiltrative margins are also frequently seen and may be confused with extracapsular disease.

Th17 cells and neutrophils: Close collaborators in chronic Leishmania mexicana infections leading to disease severity.

Cutaneous leishmaniasis caused by Leishmania mexicana is associated with an important inflammatory response. We here analysed the kinetics of Th17 cells and neutrophils in ear lobe lesions caused by Leishmania mexicana throughout 90 days of disease progression in susceptible BALB/c and semi-resistant C57BL/6 mice infected with 1 × 105 Leishmania mexicana promastigotes. Cells in the lesions were extracted and quantified by flow cytometry, whereas their distribution in the tissues in relation to the parasites was analysed by immunohistochemistry. Our results show that in BALB/c mice, both Th17 cells and neutrophils increase concomitantly and to significantly higher levels on day 90 post-infection, as compared to C57BL/6 mice. Our results provide novel evidence on the cells causing chronic inflammation throughout Leishmania mexicana infections, resulting as a consequence of neutrophil recruitment together with Th17 cell differentiation and recruitment, both of which remain in the infection site throughout the late phase of the infection. We conclude that the more enhanced levels of Th17 cells and neutrophils during chronic inflammatory lesions in BALB/c mice participate in their enhanced susceptibility towards a progressive disease evolution, whereas the more controlled response of these cells in C57BL/6 mice possibly relates to the more resistant profile of this mouse strain.

A first-in-human study of DS-1040, an inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor, in healthy subjects.

Essentials DS-1040 inhibits the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa). Infusion of DS-1040 was safe and well tolerated in healthy young and elderly subjects. DS-1040 substantially decreased TAFIa activity but had no impact on bleeding time. DS-1040 may provide an option of safer thrombolytic therapy. SUMMARY: Background Current treatments for acute ischemic stroke and venous thromboembolism, such as recombinant tissue-type plasminogen activator and thrombectomy, are limited by a narrow time window and the risk of bleeding. DS-1040 is a novel low molecular weight compound that inhibits the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa), and was developed as a fibrinolysis enhancer for the treatment of thromboembolic diseases. Objectives This first-in-human, randomized, placebo-controlled, three-part, phase 1 study was conducted to evaluate the safety, pharmacokinetics and pharmacodynamics of DS-1040 in healthy subjects. Subjects/Methods Young (18-45 years) or elderly (65-75 years) subjects (N = 103) were randomized to receive single ascending doses of DS-1040 ranging from 0.1 mg to 40 mg, or placebo, administered either as a 0.5-h intravenous infusion or as a 24-h continuous infusion. Results All doses of DS-1040 were tolerated, and no serious adverse events (AEs) or discontinuations resulting from AEs occurred during the study. Bleeding time remained within the normal range for all doses tested in all subjects. Plasma exposure of DS-1040 increased proportionally with increase in dose. Elderly subjects had higher exposures to DS-1040 and prolonged elimination times, probably because of decreased renal clearance. DS-1040 caused a substantial dose-dependent and time-dependent decrease in TAFIa activity and in 50% clot lysis time. The levels of D-dimer, indicative of endogenous fibrinolysis, increased in some individuals following DS-1040 treatment. No effects of DS-1040 on coagulation parameters or platelet aggregation were observed. Conclusions The novel fibrinolysis-enhancing agent DS-1040 has favorable pharmacokinetic/pharmacodynamic properties and a favorable safety profile, warranting further clinical development.

Evaluation and management of longitudinally extensive transverse myelitis: a guide for radiologists.

Longitudinal extensive transverse myelitis (LETM) is defined as an intramedullary spinal cord T2 signal abnormality extending craniocaudally over at least three vertebral bodies on an MRI study. Timely and appropriate diagnosis greatly facilitates patient management. The radiologist should review the relevant clinical information and determine the patient demographics and acuity of symptoms. Herein, we review the spectrum of diseases causing LETM and propose interpretation to guide the radiologist when presented with the MRI finding of LETM.

Clinical Significance of Contamination of the Preservation Solution in Liver Transplantation.

INTRODUCTION: The aim of the present study was to describe the incidence and microbiological profiles of positive cultures obtained from preservation solution (PS) and correlate these findings with infectious complications detected in the liver transplant (LT) recipient. PATIENTS: We conducted a single-center, retrospective study between December 2010 and August 2014 among 178 LT. In all grafts, a PS culture was carried out. All the infections in the receipt until hospital discharge were collected. In patients with >1, infection was considered the most severe according to Clavien-Dindo classification. RESULTS: PS culture was positive for bacterial or fungal agents in 79 of 178 LT recipients (44%). The most commonly cultured organisms were coagulase-negative staphylococci (64%), Enterobacteriaceae (17%), and Staphylococcus aureus (4.7%). In the 79 patients with positive PS, 49 blood cultures were requested in the period after LT. Twenty-five postoperative infections (31.7%) were diagnosed. Only 4 of 79 patients (5%) with PS contamination had a postoperative infections related with isolated microorganism. CONCLUSIONS: Contamination of PS appears in a high percentage of liver grafts before LT, although there is a poor correlation with postoperative infections in LT recipient. In these patients, a standardized process including fungal and bacterial cultures could be useful.

The prognostic value of the neoadjuvant response index in triple-negative breast cancer: validation and comparison with pathological complete response as outcome measure.

The Neoadjuvant response index (NRI) has been proposed as a simple measure of downstaging by neoadjuvant treatment in breast cancer. It was previously found to predict recurrence-free survival (RFS) in triple-negative (TN) breast cancer. It was at least as accurate as the standard binary system, the absence or presence of a pathological complete remission (pCR), which is the commonly employed outcome measure. The NRI was evaluated in an independent consecutive series of patients to validate the previous findings. Univariable and multivariable analyses were done to assess the predictive value of clinical parameters and of the NRI for RFS. We combined the original and validation series of patients to build a multivariable predictive model for RFS after neoadjuvant chemotherapy in TN breast cancer. The validation set (N = 108) confirmed that patients with a higher-than-median NRI (>0.7) had excellent RFS (P = 0.002), similar to that of patients who had achieved a pCR. Multivariable analysis in 191 patients showed that the NRI was a strong independent predictor of RFS (P = 0.0002), with N-stage (P = 0.001) and T-stage (P = 0.014) ranking second and third, respectively. Importantly, among patients who did not achieve a pCR (NRI values below 1), higher NRI values were still associated with better RFS. The NRI is a simple method and a practical tool to predict RFS in TN breast cancer patients treated with neoadjuvant chemotherapy. It adds prognostic information to the presence or absence of pCR and could be useful to compare the efficacies of different chemotherapy regimens.

IL-6 blockade reverses the abnormal STAT activation of peripheral blood leukocytes from rheumatoid arthritis patients.

Considering the interplay of multiple STATs in response to cytokines, we investigated how IL-6 and its blocking affect STAT signaling in rheumatoid arthritis (RA). Leukocytes obtained from RA patients before and after tocilizumab treatment and healthy donors (HDs) were cytokine-stimulated and STAT phosphorylation was analyzed by cytometry. RA patients had significantly fewer pSTAT1+, pSTAT3+, and pSTAT6+ monocytes and pSTAT5+ lymphocytes than HDs. After 24weeks of treatment, percentages of IFNγ-induced pSTAT1+ and IL-10-induced pSTAT3+ monocytes in RA patients increased, reaching levels comparable to HDs. pSTAT1+ and pSTAT3+ cells correlated inversely with RA disease activity index and levels of pSTAT+ cells at baseline were higher in patients with good EULAR response to tocilizumab. IFNγ-induced pSTAT1+ cells correlated inversely with memory T cells and anti-CCP levels. IL-10-induced pSTAT3+ cells correlated with Treg/Teff ratio. Our findings suggest that IL-6 blocking reduces the inflammatory mechanisms through the correction of STAT1 and STAT3 activation status.