Table of Contents

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Editorial Board

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Masthead

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In this Issue

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Acknowledgment of Reviewers

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Surgical Treatment with Locoregional Flap for the Nose

Nonmelanotic skin cancers (NMSCs) are the most frequent of all neoplasms and nasal pyramid represents the most common site for the presentation of such cutaneous malignancies, particularly in sun-exposed areas: ala, dorsum, and tip. Multiple options exist to restore functional and aesthetic integrity after skin loss for oncological reasons; nevertheless, the management of nasal defects can be often challenging and the best "reconstruction" is still to be found. In this study, we retrospectively reviewed a total of 310 patients who presented to our Department of Plastic and Reconstructive Surgery for postoncological nasal reconstruction between January 2011 and January 2016. Nasal region was classified into 3 groups according to the anatomical zones affected by the lesion: proximal, middle, and distal third. We included an additional fourth group for complex defects involving more than one subunit. Reconstruction with loco regional flaps was performed in all cases. Radical tumor control and a satisfactory aesthetic and functional result are the primary goals for the reconstructive surgeon. Despite tremendous technical enhancements in nasal reconstruction techniques, optimal results are usually obtained when "like is used to repair like." Accurate evaluation of the patients clinical condition and local defect should be always considered in order to select the best surgical option.

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Evaluation of afferent pain pathways in adrenomyeloneuropathic patients

X-linked adrenoleukodystrophy (ALD) is an inherited disorder of peroxisomal metabolism characterized by the accumulation of saturated very long chain fatty acids (VLCFA) in the brain, adrenal cortex and plasma. It is caused by mutations in the ABCD1 gene, which encodes an adenosine triphosphate-binding cassette peroxisomal transporter, involved in the import of VLCFA into the peroxisome for degradation (Moser et al., 2004). There is an evident wide range of phenotypic variability: childhood, adolescent and adult cerebral forms of ALD, adrenomyeloneuropathy (AMN), Addison's disease only and presymptomatic or asymptotic phenotype (Moser, 1997).

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Sleep patterns associated with the severity of impairment in a large cohort of patients with chronic disorders of consciousness

Brain injury due to severe anoxic, hemorrhagic or traumatic events often lead to chronic disorders of consciousness (DOCs), which have recently received increasing attention because of growing medical and ethical concerns relating to patient management. A considerable proportion of survivors of severe brain damage enter an unresponsive wakefulness syndrome/vegetative state (UWS/VS) or minimally conscious state (MCS) (Laureys et al., 2010) and a number of studies have assessed more or less extensive series of DOC patients using imaging procedures or neurophysiological evaluations designed to provide information supporting the clinical assessment of different degrees of DOCs or to identify prognostic markers (see reviews by Bender et al., 2015; Kondziella et al., 2015).

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Automatic bad channel detection in intracranial electroencephalographic recordings using ensemble machine learning

Intracranial electroencephalographic (iEEG) recordings, either from depth electrodes (stereoelectroencephalography, SEEG) (Kahane and Dubeau 2014) or from subdural grids and strips (electrocorticography, ECoG) (Fernández and Loddenkemper 2013), are used to localize the epileptogenic zone in some patients with drug-resistant focal epilepsy where other non-invasive measures are limited. These techniques permit to collect prominent data for assessing brain dynamics in pathological and physiological conditions.

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Can clinical neurophysiology assist in patient selection for DBS in pediatric dystonia?

Globus pallidus internus (GPi) deep brain stimulation (DBS) has become established as an effective treatment for disabling, medically refractory generalized, segmental and focal dystonia (Coubes et al., 2004; Vidailhet et al., 2005; Kupsch et al., 2006; Volkmann et al., 2014). The greatest improvement in dystonia after GPi DBS occurs in isolated idiopathic or genetic (primary) dystonia, which respond better than acquired (secondary) dystonia (Eltahawy et al., 2004; Andrews et al., 2010; Vidailhet et al., 2009; Vidailhet et al., 2013).

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Neurophysiological correlates of word processing deficits in isolated reading and isolated spelling disorders

In English speaking countries, developmental dyslexia (DD) is primarily defined as a reading disorder which is characterized by deficits in word reading accuracy, that are frequently accompanied by spelling problems. The association between reading and spelling deficits is in line with theories of literacy development that generally assume a close, bidirectional relationship between reading and spelling development (e.g. Frith, 1985), with correlation scores of .77-.86 between the two domains (for a review see Ehri, 1997).

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Abnormal cortical brain integration of somatosensory afferents in ALS

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset neurodegenerative condition characterized by the loss of motor neurons at cortical, brainstem and spinal levels (Kiernan et al., 2011). ALS is widely considered as a pure motor degeneration; sensory impairment is not a recognised feature of ALS or regarded as secondary to motor impairment (Fincham and Van Allen, 1964; Feller et al., 1966; Schulte-Mattler et al., 1999). However, in addition to the 10 % patients describing frank paraesthesia and neuropathic pain, sensory impairments have been reported in up to 60 % patients, including abnormal vibration, cutaneous and heat thresholds.

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Promoting LGBTQ Inclusivity in Palliative Care

When I first published my research on the perspectives of the lesbian and gay community regarding end-of-life care, advance care planning, and disclosure of sexual orientation a decade and a half ago,1,2 there was little awareness of the unique concerns and experiences of this community, or the importance of cultural proficiency in serving these individuals in palliative care settings. With growing interest in addressing the health needs and disparities among diverse cultural and demographic populations, it has been increasingly common for professional articles, conference presentations, and clinical guidelines to consider whether and how hospice and palliative care providers serve the LGBTQ community.

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Rapid and Simultaneous Determination of the Iodine Value and Saponification Number of Edible Oils by FTIR Spectroscopy

Abstract

A rapid method was developed to facilitate the Fourier transform infrared (FTIR) spectroscopy analysis of edible oils using disposable polyethylene (PE) films as sample support for the determination of the iodine value (IV) and saponification number (SN). For direct IV analysis, quantification was achieved using the cis and trans double band region (3206–2992 cm⁻¹) by a partial least squares calibration model, whereas SN was directly determined using the area in carbon chain skeleton vibration absorption region (781–650 cm⁻¹). The proposed method is applicable to various edible oils ranging in IV from 7.0 g/100 g to 190.0 g/100 g and SN from 162.7 mg/g to 222.0 mg/g with good precision and accuracy (relative standard deviations 0.39% and 0.32%, respectively) relative to the AOCS standard methods but with markedly less sample preparation and analytical effort.

Practical applications: Standard titration methods for determining the IV and SN of edible oils are labor intensive and require complex solvents and reagents. The PE-film-based FTIR method was more sensitive than attenuated total reflectance-FTIR method and free from problems associated with the viscosity of oils, which is practical and easy to operate. The method can further simplify and facilitate simultaneous FTIR IV and SN analyses and is applicable to various edible oils over a wide range.

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Magnetic drug targeting simulations in blood flows with fluid-structure interaction

Summary

We present fluid-structure interaction (FSI) simulations of magnetic drug targeting (MDT) in blood flows. In this procedure, a drug is attached to ferromagnetic particles in order to externally direct it to a specific target after it is injected inside the body. The goal is to minimize the healthy tissue affected by the treatment and to maximize the number of particles that reach the target location. MDT has been studied both experimentally and theoretically by several authors. In recent years, computational fluid dynamics (CFD) simulations of MDT in blood flows have been carried out to obtain further insight on the combination of parameters that provide the best capture efficiency. However, to this day, no computational study addressed MDT in an FSI setting. With this paper, we aim to fill this gap and investigate the impact of the solid deformation on the capture efficiency. This article is protected by copyright. All rights reserved.

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Volume Increases and Shared Decision-making in Joint Replacement Bundles

No abstract available

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Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance

Objective

Sorafenib is the only effective therapy for advanced hepatocellular carcinoma (HCC). Combinatory approaches targeting mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)- and phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)/protein-kinase B(AKT) signalling yield major therapeutic improvements. RAS proteins regulate both RAF/MAPK and PI3K/AKT signalling. However, the most important RAS isoform in carcinogenesis, Kirsten rat sarcoma (KRAS), remains unexplored in HCC.

Design

Human HCC tissues and cell lines were used for expression and functional analysis. Sorafenib-resistant HCC cells were newly generated. RNA interference and the novel small molecule deltarasin were used for KRAS inhibition both in vitro and in a murine syngeneic orthotopic HCC model.

Results

Expression of wild type KRAS messenger RNA and protein was increased in HCC and correlated with extracellular-signal regulated kinase (ERK) activation, proliferation rate, advanced tumour size and poor patient survival. Bioinformatic analysis and reporter assays revealed that KRAS is a direct target of microRNA-622. This microRNA was downregulated in HCC, and functional analysis demonstrated that KRAS-suppression is the major mediator of its inhibitory effect on HCC proliferation. KRAS inhibition markedly suppressed RAF/ERK and PI3K/AKT signalling and proliferation and enhanced apoptosis of HCC cells in vitro and in vivo. Combinatory KRAS inhibition and sorafenib treatment revealed synergistic antitumorigenic effects in HCC. Sorafenib-resistant HCC cells showed elevated KRAS expression, and KRAS inhibition resensitised sorafenib-resistant cells to suppression of proliferation and induction of apoptosis.

Conclusions

KRAS is dysregulated in HCC by loss of tumour-suppressive microRNA-622, contributing to tumour progression, sorafenib sensitivity and resistance. KRAS inhibition alone or in combination with sorafenib appears as novel promising therapeutic strategy for HCC.

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Melt Electrospinning Writing of Three-dimensional Poly(ε-caprolactone) Scaffolds with Controllable Morphologies for Tissue Engineering Applications

This protocol serves as a comprehensive guideline to fabricate scaffolds via electrospinning with polymer melts in a direct writing mode. We systematically outline the process and define the appropriate parameter settings for achieving targeted scaffold architectures.

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Plant Promoter Analysis: Identification and Characterization of Root Nodule Specific Promoter in the Common Bean

Promoter expression analyses are crucial to improving the understanding of gene regulation and the spatiotemporal expression of target genes. Herein we present a protocol to identify, isolate, and clone a plant promoter. Further, we describe the characterization of the nodule-specific promoter in the common bean hairy roots.

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Probiotic strain Stenotrophomonas acidaminiphila BJ1 degrades and reduces chlorothalonil toxicity to soil enzymes, microbial communities and plant roots

Chlorothalonil, a non-systemic and broad-spectrum fungicide, is widely used to control the pathogens of agricultural plants. Although microbial degradation of chlorothalonil is known, we know little about the ...

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Homologous recombination deficiency (HRD) status predicts response to standard neoadjuvant chemotherapy in patients with triple-negative or BRCA1/2 mutation-associated breast cancer

Abstract

Purpose

Defects in the homologous recombination (HR) DNA repair pathway sensitize tumors to therapeutics that target this pathway. A significant proportion of triple-negative breast cancers (TNBC) carry HR defects. The HRD assay is highly associated with sensitivity to neoadjuvant platinum-based chemotherapy in TNBC. Standard chemotherapy consists of some combination of an anthracycline, cyclophosphamide, and taxane. This study assesses the association of HR deficiency status with response to standard neoadjuvant chemotherapy in TNBC or BRCA1/2 mutation-associated breast cancer.

Methods

Tumor samples were retrospectively obtained from 45 TNBC patients and 2 BRCA1/2 mutant, hormone receptor-positive/HER2-negative breast cancer patients who received anthracycline- and/or taxane-based neoadjuvant chemotherapy at Stanford University or Cedars-Sinai Medical Centers. The HRD score and tumor BRCA1/2 mutation status were determined from baseline tumor biopsies. HR deficient tumors were those with a HRD score of ≥ 42 or a tumor BRCA1/2 mutation. Response was categorized by the residual cancer burden (RCB) index.

Results

HR deficient patients were more likely to achieve a pathologic complete response (pCR) compared with non-deficient patients (OR 13.06, CI 1.52–11.241, p = 0.0028). Among BRCA1/2 mutation wild-type patients, HR deficient patients were more likely to achieve a pCR (OR 16, 95% CI 1.65–160.41, p = 0.0041) compared with HR non-deficient patients. Further, HRD scores were highly concordant pre- and post-therapy (Spearman correlation > 99%).

Conclusions

HR deficiency status is significantly associated with response to standard neoadjuvant chemotherapy in TNBC. This observation is consistent with the mechanisms of action of doxorubicin and cyclophosphamide as DNA damaging agents.

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The Gasdermin-D pore acts as a conduit for IL-1β secretion in mice

Abstract

The pro-inflammatory cytokine IL-1β is well known for its role in host defense and the initiation of potent inflammatory responses. It is processed from its inactive pro-form by the inflammatory caspase-1 into its mature bioactive form, which is then released from the cell via an unconventional secretion mechanism. Recently, gasdermin-D has been identified as a new target of caspase-1. After proteolytical cleavage of gasdermin-D, the N-terminal fragment induces pyroptosis, a lytic cell death, by forming large permeability pores in the plasma membrane. Here we show using the murine system that gasdermin-D is required for IL-1β secretion by macrophages, dendritic cells and partially in neutrophils, and that secretion is a cell-lysis-independent event. Liposome transport assays in vitro further demonstrate that gasdermin-D pores are large enough to allow the direct release of IL-1β. Moreover, IL-18 and other small soluble cytosolic proteins can also be released in a lysis-independent but gasdermin-D-dependent mode, suggesting that the gasdermin-D pores allow passive the release of cytosolic proteins in a size-dependent manner.

This article is protected by copyright. All rights reserved

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No significant impact of response to prior androgen receptor-axis-targeted agents on the efficacy of subsequent docetaxel in patients with metastatic castration-resistant prostate cancer

Abstract

Background

To investigate whether the response to an androgen receptor-axis-targeted (ARAT) agent is associated with the efficacy of subsequent docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients.

Methods

This study included 114 consecutive mCRPC patients, comprising 54 and 60 patients who progressed with abiraterone acetate (AA) and enzalutamide (Enz), respectively, before the introduction of docetaxel. The impact of the response to either ARAT agent on the activity of docetaxel was assessed.

Results

Following ARAT therapy, a prostate-specific antigen (PSA) response was observed in 73 of the 114 patients, of whom 33 and 40 received AA and Enz, respectively. In the 114 patients, PSA response to docetaxel was achieved in 48 (42.1%) patients, and median PSA progression-free survival (PFS) and overall survival (OS) with docetaxel were 7.2 and 17.5 months, respectively. No significant difference was noted in PSA response rate, PSA PFS or OS with docetaxel between responders and non-responders to a prior ARAT agent in the overall 114 patients, 54 receiving AA and 60 receiving Enz. Despite the absence of a significant impact of the response to a prior ARAT agent on PSA PFS or OS by univariate analysis, independent prognostic predictors were identified by multivariate analysis, as performance status (PS) for PSA PFS, and PS and visceral metastasis for OS.

Conclusions

Disease control by docetaxel may not be affected by the response to a prior ARAT agent. Therefore, a prior response to an ARAT agent should not influence the decision on the subsequent introduction of docetaxel for mCRPC patients.

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Arthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathies

Arthrogryposis multiplex congenita affects approximately 1 in 3,000 individuals of different ethnic backgrounds and displays an equal incidence in males and females. The underlying mechanism for congenital contracture of the joints is decreased fetal movement during intrauterine development. This disorder is associated with over 400 medical conditions and 350 known genes that display considerable variability in phenotypic expression. In this report, four fetal or perinatal autopsy cases of arthrogryposis were studied by gross morphology, microscopic histopathologic examination, and whole genome sequencing of postmortem DNA. Two stillborn sibling fetuses with arthrogryposis, pterygia, and amyoplasia had compound heterozygous pathogenic variants in NEB. A neonate with a histopathologic diagnosis of nemaline myopathy had a heterozygous de novo pathogenic variant in ACTA1. Another stillborn infant with pterygia and arthrogryposis had a heterozygous de novo likely pathogenic variant in BICD2. These cases demonstrate the utility of whole genome sequencing as the principal diagnostic method of lethal forms of skeletal muscle disorders that present with arthrogryposis and muscle amyoplasia/hypoplasia. Molecular diagnosis provides an opportunity for studying patterns of inheritance and for family counseling concerning future pregnancies.

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Laribacter hongkongensis: clinical presentation, epidemiology and treatment. A review of the literature and report of the first case in Denmark

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Infectious spondylodiscitis: 5-year analysis of a tertiary hospital in Portugal

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Sex Differences in Diagnoses, Treatment and Outcomes for Emergency Department Patients with Chest Pain and Elevated Cardiac Troponin

Abstract

Objective

While sex differences in the treatment and outcomes of subjects with acute coronary syndromes are well documented, little is known about the impact of cardiac troponin (cTn) levels obtained in the emergency department (ED) on the observed sex differences. We sought to determine whether cTn levels by chest pain features modify sex differences in diagnosis, treatment and outcomes in patients presenting with chest pain suggestive of ischemia.

Methods

All adults presenting to two hospitals in Vancouver, Canada between May 2008 and Mar 2013 with ischemic chest pain and with cTn testing were included in the study. Outcomes were obtained through data linkage with population-based administrative datasets, including Vital Statistics (death), discharge abstract database (hospitalizations) and PharmaNet (medications). Cumulative event rates for the composite MACE endpoint (death, MI, incident admission for heart failure or for angina requiring diagnostic catheterization or revascularization), were estimated for each sex and cTn level using the Kaplan-Meier method; Cox models were used to estimate hazard ratios (HR) and 95% CIs for one-year MACE and seven-day catheterization. Logistic models were used to estimate odds ratios (OR) and 95% CI for 90-day medication use.

Results

Over the five-year study period, 25,539 patients presented to the ED with chest pain of which 7,272 (2,933 females and 4,339 males) met the inclusion criteria. Among patients with chest pain with cardiac features/history and cTn > 99^th percentile, females were less likely to be diagnosed with MI (46.4% vs. 57.5%). Females in the cTnI > 99^th percentile group had the worst outcomes with a one-year MACE rate of 22.7% (95% CI 18.5, 27.7) versus 18.8% (95% CI 16.2, 21.6), though this difference was attenuated and not statistically significant after adjustment for baseline differences. Overall, females underwent fewer diagnostic catheterizations than males within seven days of admission to the ED. Even when cTn was above the 99^th percentile and the chest pain was cardiac in nature, 48.4% of females underwent a diagnostic catheterization compared to 64.3% of males, p<0.001. Within 90 days of discharge, females were less likely to use the evidence-based cardiac medications. The most striking sex differences were noted when cTnI levels were > 99^th percentile and when the chest pain was cardiac in nature; males filled 25% more prescriptions for statins than their female counterparts. Adjustment for baseline differences did not attenuate this difference.

Conclusions

Sex differences in diagnosis and treatment after presentation to the ED with chest pain are not explained by differences in chest pain features or levels of cTn. Even when females have cardiac chest pain and cTn levels > 99^th percentile, they are less likely to be diagnosed with MI, less likely to undergo diagnostic cardiac catheterization within seven days, and less likely to use evidence-based cardiac medications, but they have the highest one-year MACE rate. The higher MACE rate appears to be driven by the higher burden of comorbid conditions.

This article is protected by copyright. All rights reserved.

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Genome profile in a extremely rare case of pulmonary sclerosing pneumocytoma presenting with diffusely-scattered nodules in the right lung

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Some chemotherapeutics-treated colon cancer cells display a specific phenotype being a combination of stem-like and senescent cell features

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Lymphatic vessel involvement is predictive for lymph node metastasis and an important prognostic factor in endometrial cancer

Abstract

Background

Lymphovascular space involvement is reported to be an important risk factor in endometrial cancer. This study was conducted to evaluate the separate prognostic effects of lymphatic invasion and venous invasion on the outcomes of patients with endometrial cancer.

Methods

From 2006 to 2013, 189 histologically confirmed endometrial cancer patients were examined. To study the venous invasion (v) of the endometrial cancer, Victoria blue–H&E staining—which positively stains the elastic fibers of vessels—was performed. Immunohistochemical staining with D2-40 was used to study the lymphatic invasion (ly) of the endometrial cancer.

Results

The median age of the patients was 57 (range 25–84) years. ly(+) and/or v(+) patients were significantly more likely to present an advanced cancer stage, G3 tumor, and deep myometrial invasion than ly(−)/v(−) patients. The incidence of lymph node metastasis was high in ly(+) patients, and that of ovarian metastasis was high in v(+) patients. Lymphatic vessel invasion was significantly correlated with regional lymph node metastasis. We found a significantly higher incidence of distant metastasis in ly(+) patients. Most recurrences in ly(+)/v(−) patients occurred in lymph nodes, while those in ly(+)/v(+) patients occurred mainly at distant organs. Finally, the prognosis was significantly poorer for ly(+) patients, in whom lymphatic invasion was an independent prognostic factor along with distant metastasis.

Conclusions

Our study suggests that by separately evaluating lymphatic invasion and blood vessel invasion in endometrial cancer cases, useful information for predicting lymph node metastasis and recurrence sites as well as prognostic information can be obtained.

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Visual outcomes, efficacy, and surgical complications associated with intracameral phenylephrine 1.0%/ketorolac 0.3% administered during cataract surgery

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Cancers, Vol. 10, Pages 3: Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells

Cancers, Vol. 10, Pages 3: Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells

Cancers doi: 10.3390/cancers10010003

Authors: Yoshiaki Sunami Artur Rebelo Jörg Kleeff

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030, and the overall 5-year survival rate is currently less than 7%. Cancer cells frequently exhibit reprogramming of their metabolic activity. It is increasingly recognized that aberrant de novo lipid synthesis and reprogrammed lipid metabolism are both associated with the development and progression of various cancers, including pancreatic cancer. In this review, the current knowledge about lipid metabolism and lipid droplets in pancreatic cancer is discussed. In the first part, molecular mechanisms of lipid metabolism and roles of enzymes involved in lipid metabolism which are relevant for pancreatic cancer research are presented. Further, preclinical studies and clinical trials with drugs/inhibitors targeting cancer metabolic systems in cancer are summarized. An increase of our knowledge in lipid metabolism in pancreatic cancer cells and in tumor stroma is important for developing novel strategies of future individualized therapies of pancreatic cancer.

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Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with doxorubicin-based adjuvant chemotherapy (SWOG S9313)

Abstract

Background

Homologous recombination deficiency (HRD) causing alterations have been reported in triple-negative breast cancer (TNBC). We hypothesized that TNBCs with HRD alterations might be more sensitive to anthracycline plus cyclophosphamide-based chemotherapy and report on HRD status and BRCA1 promoter methylation (PM) as prognostic markers in TNBC patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG9313.

Patients and Methods

425 TNBC patients were identified from S9313. HRD score, tumor BRCA1/2 sequencing and BRCA1 PM, were performed on DNA isolated from FFPE tissue. Positive HRD status was defined as either a deleterious tumor BRCA1/2 (tBRCA) mutation and/or a pre-defined HRD score ≥ 42. Markers were tested for prognostic value on DFS and OS using Cox regression models adjusted for treatment assignment and nodal status.

Results

HRD status was determined in 89% (379/425) of cases. Of these, 67% were HRD-positive (27% with tBRCA mutation, 40% tBRCA negative but HRD score ≥42). HRD-positive status was associated with a better DFS (HR = 0.72; 95% CI 0.51– 1.00; p=0.049) and non-significant trend towards better OS (HR = 0.71; 95% CI 0.48– 1.03; p=0.073). High HRD score (≥42) in tBRCA-negative patients (n=274) was also associated with better DFS (HR = 0.64; 95% CI 0.43-0.94; p=0.023) and OS (HR = 0.65; 95% CI 0.42-1.00; p=0.049). BRCA1 PM was evaluated successfully in 82% (348/425) and detected in 32% of cases. The DFS HR for BRCA1 PM was similar to that for HRD, but did not reach statistical significance (HR = 0.79; 95% CI 0.54-1.17; p=0.25).

Conclusions

HRD positivity was observed in two-thirds of TNBC patients receiving adjuvant AC and was associated with better DFS. HRD status may identify TNBC patients who receive greater benefit from AC based chemotherapy and should be evaluated further in prospective studies.

Clinical Trials Number

Int0137 (The trial pre-dates Clinicaltrial.Gov website establishment)

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Safety of an anti-PD-1 immune checkpoint inhibitor in a liver transplant recipient

anti-PD-1liver transplantation

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CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two Phase II trials

Background

Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two Phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261).

Patients and methods

Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg once daily (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS).

Results

Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% (27/50; 95% confidence interval [CI] 39, 68), and 92% (46/50; 95% CI 81, 98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS DoR (22% maturity) was not reached (range: 1–15 months); at 9 months, 75% (95% CI 53, 88) of patients were estimated to remain in response. Median follow up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population.

Conclusions

Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that previously reported.

ClinicalTrials.gov number

NCT01802632; NCT02094261

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Insulinoma-associated Protein 1 (INSM1) Differentiates Carcinoid Tumorlets of the Lung from Pulmonary Meningothelial-Like Nodules

Abstract

Insulinoma-associated protein 1 (INSM1) is a zinc-finger transcription factor isolated from pancreatic insulinoma tissue. This protein controls expression of a neuroendocrine phenotype and is responsible for transcription of synaptophysin and chromogranin. In recent years, it has emerged as a sensitive and specific immunohistochemical marker of neuroendocrine neoplasms, and is currently the only commercially available nuclear marker of neuroendocrine differentiation.

This article is protected by copyright. All rights reserved.

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