Osimertinib for EGFR-Mutant Lung Cancer with Brain Metastases: Results from a Single-Center Retrospective Study.

INTRODUCTION: Osimertinib is a third-generation tyrosine kinase inhibitor, initially approved for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) with T790M acquired resistance, and now approved in the first-line setting. However, data supporting the use of osimertinib in untreated brain metastases are limited, although it has established central nervous system (CNS) activity. Our study compares the clinical outcomes of patients experiencing progressing brain metastases treated with cranial irradiation and osimertinib with those treated with osimertinib alone. METHODS: Forty patients who were treated with osimertinib at the Stanford Cancer Center from November 2015 to December 2016 were identified by searching an electronic medical record database. Eleven patients had progressing brain metastases and did not receive radiation (group A), 9 patients had progressing brain metastases and received radiation when starting osimertinib (group B), and 20 patients had stable brain metastases at the time of initiating osimertinib (group C). Patient and disease characteristics, radiographic responses, and survival outcomes were evaluated retrospectively for the three groups. RESULTS: The CNS response rate was 32.3%. Median time to treatment failure (TTF), overall progression-free survival (PFS), and overall survival (OS) were 10.0 months (95% confidence interval [CI], 4.5-11.8), 8.8 months (95% CI, 6.2-12.1), and 16.2 months, respectively. Median TTF was 15.1 months for group A (95% CI, 1.7-28.5), 7.7 months for group B (95% CI, 0-15.5), and 10.7 months for group C (95% CI, 9.0-12.5). The median PFS was 8.8 months for group A (95% CI, 4.3-13.4), not reached for group B, and 8.4 months for group C (95% CI, 5.6-11.1). The median OS was not reached for group A and C, and was 16.2 months for group B. There was no apparent difference in TTF, PFS, or OS between the three groups. CONCLUSION: Receiving radiation prior to starting osimertinib for patients with progressing brain metastases did not prolong TTF, PFS, or OS in our series. To minimize the risks of radiation-related toxicity, delaying radiation could be considered for some patients with EGFR-mutant NSCLC with brain metastases who initially respond to osimertinib in the second-line setting. IMPLICATIONS FOR PRACTICE: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor recently approved for the first-line treatment of EGFR-mutant non-small cell lung cancer. Although it appears to have central nervous system (CNS) activity, most clinical trials have excluded patients with untreated, progressing brain metastases. This study included patients with stable and progressing CNS metastases treated with osimertinib and found no apparent differences in median time to treatment failure, time to progression, and overall survival in patients who received osimertinib alone compared with those who received osimertinib and radiosurgery. This may support a clinician's decision to defer radiation for selected patients with untreated brain metastases who are candidates for osimertinib therapy.

Scedosporium apiospermum infection of the urinary system with a review of treatment options and cases in the literature.

Infection with Scedosporium species is associated with a significant morbidity and mortality and is becoming increasingly common, especially in immunocompromised patients. We describe the presentation and successful management of an immunocompromised patient with Scedosporium apiospermum infection of the upper urinary tract system, a rare disease manifestation. The current literature on urinary tract scedosporiosis is further reviewed with emphasis on treatment options and limitations of current antifungal therapy.

Differential methylation of the promoter and first exon of the RASSF1A gene in hepatocarcinogenesis.

AIM: Aberrant methylation of the promoter, P2, and the first exon, E1, regions of the tumor suppressor gene RASSF1A, have been associated with hepatocellular carcinoma (HCC), albeit with poor specificity. This study analyzed the methylation profiles of P1, P2 and E1 regions of the gene to identify the region of which methylation most specifically corresponds to HCC and to evaluate the potential of this methylated region as a biomarker in urine for HCC screening. METHODS: Bisulfite DNA sequencing and quantitative methylation-specific polymerase chain reaction assays were performed to compare methylation of the 56 CpG sites in regions P1, P2 and E1 in DNA isolated from normal, hepatitic, cirrhotic, adjacent non-HCC, and HCC liver tissue and urine samples for the characterization of hypermethylation of the RASSF1A gene as a biomarker for HCC screening. RESULTS: In tissue, comparing HCC (n = 120) with cirrhosis and hepatitis together (n = 70), methylation of P1 had an area under the receiver operating characteristics curve (AUROC) of 0.90, whereas methylation of E1 and P2 had AUROC of 0.84 and 0.72, respectively. At 90% sensitivity, specificity for P1 methylation was 72.9% versus 38.6% for E1 and 27.1% for P2. Methylated P1 DNA was detected in urine in association with cirrhosis and HCC. It had a sensitivity of 81.8% for α-fetoprotein negative HCC. CONCLUSION: Among the three regions analyzed, methylation of P1 is the most specific for HCC and holds great promise as a DNA marker in urine for screening of cirrhosis and HCC.

P2X2 receptors in pyramidal neurons are critical for regulating vulnerability to chronic stress.

Rationale: Stress is a major risk factor for the development of depression. However, the underlying molecular mechanisms of stress vulnerability in depression are largely uncharacterized. Methods: P2X2 receptors (a major receptor for gliotransmitter-ATP) in the medial prefrontal cortex (mPFC) were identified by real-time qPCR, western blots and RNAscope in situ hybridization in chronic social defeat stress model (CSDS). We generated P2X2 conditional knockout mice and overexpressed AAV-P2X2 in CamkIIα-Cre mice. The depression-like behaviors were assessed via CSDS, subthreshold social defeat stress (SSDS), social interaction test (SI), forced interaction test (FIT), forced swimming test (FST), sucrose preference test (SPT), novel stressed feeding (NSF) and open field test (OFT). The neuronal activity and synapse function of P2X2 receptors in the mPFC were detected by in vivo fiber-photometry, patch-clamp techniques and neuronal morphometric analysis. Results: We identified that P2X2 receptors were increased in the mPFC of susceptible mice in CSDS. Conditional knockout of P2X2 receptors in pyramidal neurons promoted resilience of chronic stress-induced depressive-like behaviors, whereas pyramidal neurons - specific gain of P2X2 in the mPFC increased vulnerability to depressive-like behaviors. In vivo fiber-photometry, electrophysiology and neuronal morphometric analysis showed P2X2 receptors regulated neuronal activity and synapse function in the mPFC. Conclusions: Overall, our studies reveal a critical role of P2X2 in mediating vulnerability to chronic stress and identify P2X2 as a potential therapeutic target for treatment of stress-related mood disorders.

Preeclampsia associated changes in volume density of fetoplacental vessels in Chinese women and mouse model of preeclampsia.

INTRODUCTION: Preeclampsia (PE) is associated with abnormal placental vascular structure. However, the volume density of fetoplacental vessels in PE remains unclear. Additionally, manually annotated CT angiography, which is widely used to analyze placental vessels, has issues regarding inaccuracy. Thus, computer-aided CT angiography for analyzing the volume density of fetoplacental vessels would facilitate the understanding of PE pathogenesis. METHODS: We performed computer-aided CT angiography to compare differences in placentas among 17 women with PE and 34 normotensive women. The contrast ratio in CT angiography was significantly enhanced using a three-dimensional (3-D) Hessian matrix algorithm. The PE-like mouse model was established by administration of 125 mg/kg/day NG-nitro-l-arginine methyl ester (l-NAME) for 10 days. The presence of endothelial marker CD31 was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The expression of angiogenic factors (PlGF, VEGFA, and sFlt1) in placentas was detected using qRT-PCR and western blotting. RESULTS: The volume density in fetoplacental vessels and CD31 expression were significantly reduced in women with PE and l-NAME-induced mice. Additionally, the downregulation of angiogenic factors (PlGF/VEGFA) and upregulation of an anti-angiogenic factor (sFlt1) were determined in a mouse model. DISCUSSION: Contrast-enhanced CT angiography with the aid of a 3-D Hessian matrix algorithm was performed. PE significantly affects the formation of vascular vessels, resulting in a lower volume density of fetoplacental vessels in humans and mice. This may be explained by the abnormal release of angiogenic factors during PE.

Resveratrol reverses the programmed high-susceptibility to non-alcoholic fatty liver disease by targeting the hepatic SIRT1-SREBP1c pathway in prenatal ethanol-exposed rat offspring.

An increased susceptibility to non-alcoholic fatty liver disease (NAFLD) in female rat offspring that experienced prenatal ethanol exposure (PEE) has been previously demonstrated. The present study further investigated the potential mechanism. Based on the results from both fetal and adult studies of offspring rats that experienced PEE (4 g/kg/day), the fetal weight, serum glucose and triglyceride levels decreased significantly and hepatocellular ultra-structure was altered. Fetal livers exhibited inhibited expression and activity of sirtuin 1 (SIRT1), enhanced expression of lipogenic genes: sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FASN), acetyl-coenzyme A carboxylase α (ACCα), stearyl-coenzyme A desaturase 1 (SCD1). In adult offspring fed with high-fat diet, the PEE offspring revealed obviously catch-up growth, increased food intake, elevated serum metabolic phenotypes, suppressed hepatic SIRT1-SREBP1c pathway, and formation of NAFLD. Resveratrol (the chemical activator of SIRT1) could remarkably reverse the serum metabolic phenotypes and alleviate the hepatocyte steatosis in relation to the PEE offspring through activating the hepatic SIRT1-SREBP1c pathway. Therefore, increased susceptibility to diet-induced NAFLD in PEE offspring appears to be mediated by intrauterine programming of hepatic lipogenesis via the SIRT1-SREBP1c pathway. This altered programming effect could partially be reversed by resveratrol intervention after birth in PEE offspring rats.

Environmentally Friendly and Efficient Hornet Nest Envelope-Based Photothermal Absorbers.

Water shortage is a critical global issue that threatens human health, environmental sustainability, and the preservation of Earth's climate. Desalination from seawater and sewage is a promising avenue for alleviating this stress. In this work, we use the hornet nest envelope material to fabricate a biomass-based photothermal absorber as part of a desalination isolation system. This system realizes an evaporation rate of 3.98 kg m-2 h-1 under one-sun illumination, with prolonged evaporation rates all above 4 kg m-2 h-1. This system demonstrates a strong performance of 3.86 kg m-2 h-1 in 3.5 wt % saltwater, illustrating its effectiveness in evaporation seawater. Thus, with its excellent evaporation rate, great salt rejection ability, and easy fabrication approach, the hornet nest envelope constitutes a promising natural material for solar water treatment applications.

Reducing Telemetry Use Is Safe: A Retrospective Analysis of Rapid Response Team and Code Events After a Successful Intervention to Reduce Telemetry Use.

Interventions guiding appropriate telemetry utilization have successfully reduced use at many hospitals, but few studies have examined their possible adverse outcomes. The authors conducted a successful intervention to reduce telemetry use in 2013 on a hospitalist service using educational modules, routine review, and financial incentives. The association of reduced telemetry use with the incidence of rapid response team (RRT) and code activations was assessed in a retrospective cohort study of 210 patients who experienced a total of 233 RRT and code events on the inpatient internal medicine services from January 2012 through March 2015 at a tertiary care center. The incidence of adverse events for the hospitalist service was not significantly different during the intervention and postintervention period as compared to the preintervention period. Reducing inappropriate telemetry use was not associated with an increase in the incidence rates of RRT and code events.

Time on Therapy for at Least Three Months Correlates with Overall Survival in Metastatic Renal Cell Carcinoma.

With 15 drugs currently approved for the treatment of metastatic renal cell carcinoma (mRCC) and even more combination regimens with immunotherapy on the horizon, there remains a distinct lack of molecular biomarkers for therapeutic efficacy. Our study reports on real-world clinical outcomes of mRCC patients from a tertiary academic medical center treated with empirically selected standard-of-care therapy. We utilized the Stanford Renal Cell Carcinoma Database (RCCD) to report on various outcome measures, including overall survival (OS) and the median number of lines of targeted therapies received from the time of metastatic diagnosis. We found that most metastatic patients did not survive long enough to attempt even half of the available targeted therapies. We also noted that patients who failed to receive a clinical benefit within the first two lines of therapy could still go on to experience clinical benefit in later lines of therapy. The term, "clinical benefit" was assigned to a line of therapy if a patient remained on drug treatment for three months or longer. Moreover, patients with clinical benefit in at least one line of therapy experienced significantly longer OS compared to those who did not have clinical benefit in at least one line of therapy. Developing biomarkers that identify patients who will receive clinical benefit in individual lines of therapy is one potential strategy for achieving rational drug sequencing in mRCC.

Domestic Violence Counseling in Rural Northern China: Gender, Social Harmony, and Human Rights.

Domestic violence (DV) affects over a third of Chinese women in a relationship. Focusing on ethnographic data from six staff members and six DV survivors at a rural, state-affiliated women's center in China in 2010, this article relies on Henrietta Moore's notion of the poststructuralist gendered subject to examine how the staff draw on discourses about gender and social harmony in persuading women to stay in their marriages, rather than on human rights discourses that emphasize survivor safety. It shows that DV survivors are frequently sent back to dangerous homes where their health is placed at risk.

Shared Decision-Making During Inpatient Rounds: Opportunities for Improvement in Patient Engagement and Communication.

BACKGROUND: Shared decision-making (SDM) improves patient engagement and may improve outpatient health outcomes. Little is known about inpatient SDM. OBJECTIVE: To assess overall quality, provider behaviors, and contextual predictors of SDM during inpatient rounds on medicine and pediatrics hospitalist services. DESIGN: A 12-week, cross-sectional, single-blinded observational study of team SDM behaviors during rounds, followed by semistructured patient interviews. SETTING: Two large quaternary care academic medical centers. PARTICIPANTS: Thirty-five inpatient teams (18 medicine, 17 pediatrics) and 254 unique patient encounters (117 medicine, 137 pediatrics). INTERVENTION: Observational study. MEASUREMENTS: We used a 9-item Rochester Participatory Decision-Making Scale (RPAD) measured team-level SDM behaviors. Same-day interviews using a modified RPAD assessed patient perceptions of SDM. RESULTS: Characteristics associated with increased SDM in the multivariate analysis included the following: service, patient gender, timing of rounds during patient's hospital stay, and amount of time rounding per patient (P < .05). The most frequently observed behaviors across all services included explaining the clinical issue and matching medical language to the patient's level of understanding. The least frequently observed behaviors included checking understanding of the patient's point of view, examining barriers to follow-through, and asking if the patient has any questions. Patients and guardians had substantially higher ratings for SDM quality compared to peer observers (7.2 vs 4.4 out of 9). CONCLUSIONS: Important opportunities exist to improve inpatient SDM. Team size, number of learners, patient census, and type of decision being made did not affect SDM, suggesting that even large, busy services can perform SDM if properly trained.