Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation?

Now is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on-going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.g. PD1 and CTLA-4), in R/M NPC. All randomized and nonrandomized controlled trials involving immune checkpoint inhibitor interventions for treatment of NPC were included in the study. We utilized a validated “risk of bias” tool to assess study quality. Four separate Phase I–II trials report the potential of PD1 inhibitor treatment for patients with NPC. Within the observed groups, camrelizumab combined with chemotherapy achieved an objective response in 91% of patients as first-line treatment for metastatic NPC (PFS 68% at 1-year) but this was associated with a high rate of grade >3 adverse events (87%; CTCAE version 4.03). The remaining three studies focused on recurrent NPC disease in patients who had received at least one line of prior chemotherapy. Within this group, camrelizumab monotherapy achieved an objective response in 34% of patients (PFS 27% at 1-year; range across all three studies 20.5–34%). No NPC trial has yet reported on specific outcomes for non-PD1 checkpoint inhibitors but 11 on-going studies include alternative targets (e.g. PD-L1/CTLA-4) as combination or monotherapy treatments. In considering checkpoint immunotherapies for NPC, initial results show promise for anti-PD1 interventions. Further phase I–III trials are in progress to clarify clinical outcomes, fully determine safety profiles, and optimize drug combinations and administration schedules.     

Utilization of muscle flaps in the treatment of bronchopleural fistulas

This paper reports the results of a series of 5 patients who underwent closure of persistent bronchopleural fistula using extrathoracic muscle flaps over a 6-year period. All patients had failed more conservative treatment. The surgeries were one- or two-stage procedures performed with the collaboration of cardiovascular and reconstructive surgical staffs. There were no associated mortalities. The muscle flaps utilized were the latissimus dorsi, serratus anterior, pectoralis major, pectoralis minor, and trapezius. The results have been encouraging and allowed the complete closure of the bronchopleural fistula in the majority of patients. The authors present the best management of this serious disease, as well as its pathophysiology and clinical aspects.     

Time-lapse variables and embryo gender: a retrospective analysis of 81 live births obtained following minimal stimulation and single embryo transfer

Purpose

The purpose of this study was to determine which morphokinetic variables are related to embryo gender in a cohort of consecutive live births obtained through single blastocyst transfer following mild ovarian stimulation.

Methods

Eighty-one live births (49 % of them females) from successfully treated, consecutive infertile patients (maternal age 36.9?±?3.8 years, range 28–46) who underwent minimal ovarian stimulation, prolonged embryo culture in a time-lapse monitoring (TLM) incubator and elective single blastocyst transfers during 2012–2014. Early (PNf, t2–t9, cc2a, b, s2, s3) and late (tM, tSB, tfullB, texpB₁, and texpB₂) morphokinetic variables were scored according to published consensus criteria and were normalized to the time of pronuclear fading. For each variable, the ranges with the highest proportion of female embryos (optimal range) were determined by detailed examination of histograms.

Results

Female embryo gender was associated both with late cleavage (t8), morula (tM), and blastocyst stage morphokinetic variables. The strongest associations (adjusted ORs, 7.0–7.8) were found for late, expanded stage blastocyst parameters; tfullB, texpB₁, and texpB₂. The proportion of female embryos was 69–71 and 25–26 % inside and outside of the optimal ranges, respectively. This allowed to predict 74–78 % of them, increasing their proportion by 57 % compared to the average.

Conclusions

Although the sample size of our cohort was limited, our findings suggest that several expanded blastocyst stage morphokinetic parameters are associated with female embryo gender. If confirmed on a larger sample these could be potentially used to increase the proportion of female embryos among non-invasively selected blastocysts following single embryo transfer.

     

Oxidative stress as a novel target in pediatric sepsis management

Sepsis with secondary multisystem organ dysfunction syndrome is the leading cause of death in the pediatric intensive care unit. Increased reactive oxygen species may influence circulating and endothelial cells, contributing to inflammatory tissue injury and explaining the tissue hypoxia paradigm based on microvascular dysfunction. An impaired mitochondrial cellular oxygen utilization, rather than inadequate oxygen delivery, was claimed to play a more important role in the development of multisystem organ dysfunction syndrome. Anyway, it seems plausible that reactive oxygen species can mediate the pathophysiologic processes occurring in sepsis. However, the consensus guidelines for the management of patients with these conditions do not include the enhancement of antioxidant potential. Therefore, further investigation is needed to support interventions aimed to attenuate the severity of the systemic compromise by abrogating the mechanism of oxidative damage. Antioxidant supplementation currently in use lacks a mechanistic support. Specific pharmacologic targets, such as mitochondria or Nicotinamide Adenine Dinucleotide Phospate-Oxidase (NADPH) oxidase system, need to be explored. Furthermore, the early recognition of oxidative damage in these seriously ill patients and the usefulness of oxidative stress biomarkers to define a cut point for more successful therapeutic antioxidant interventions to be instituted would offer a new strategy to improve the outcome of critically ill children.     

Role of RNA chaperones in virus replication

RNA molecules are functionally diverse in part due to their extreme structural flexibility that allows rapid regulation by refolding. RNA folding could be a difficult process as often molecules adopt a spatial conformation that is very stable but not biologically functional, named a kinetic trap. RNA chaperones are non-specific RNA binding proteins that help RNA folding by resolving misfolded structures or preventing their formation. There is a large number of viruses whose genome is RNA that allows some evolutionary advantages, such as rapid genome mutation. On the other hand, regions of the viral RNA genomes can adopt different structural conformations, some of them lacking functional relevance and acting as misfolded intermediates. In fact, for an efficient replication, they often require RNA chaperone activities. There is a growing list of RNA chaperones encoded by viruses involved in different steps of the viral cycle. Also, cellular RNA chaperones have been involved in replication of RNA viruses. This review briefly describes RNA chaperone activities and is focused in the roles that viral or cellular nucleic acid chaperones have in RNA virus replication, particularly in those viruses that require discontinuous RNA synthesis.     

Salud Para Su Corazon-NCLR: a comprehensive Promotora outreach program to promote heart-healthy behaviors among hispanics

This article describes results of year-1 implementation of the Salud Para Su Corazón (Health For Your Heart)-National Council of la Raza (NCLR) promotora (lay health worker) program for promoting heart-healthy behaviors among Latinos. Findings of this community outreach initiative include data from promotora pledges and self-skill behaviors, cardiovascular disease risk factors of Latino families, family heart-health education delivery, and program costs associated with promotora time. Participation included 29 trained promotoras serving 188 families from three NCLR affiliates in Escondido, California; Chicago, Illinois; and Ojo Caliente, New Mexico. Using several evaluation tools, the results showed that the promotora approach worked based on evidence obtained from the following indicators: changes in promotora's pre-post knowledge and performance skills, progress toward their pledge goals following training, recruiting and teaching families, providing follow-up, and organizing or participating in community events. Strengths and limitations of the promotora model approach are also discussed.