Immune checkpoint inhibitors-related encephalitis in melanoma and non-melanoma cancer patients: a single center experience.

BACKGROUND: Treatment with immune checkpoint inhibitors (ICI) has greatly improved survival for patients with a number of malignant diseases in recent years. Neurological immune-related adverse events (n-irAE) of varying severity have been reported in the literature. We aimed to identify the incidence of n-irAE, focusing on immune-related encephalitis (IRE), in patients treated with ICI for multiple non-hematological malignancies in our institution. METHODS: All patients with histologically verified cancer that received treatment with ICI at the Sheba Medical Center between January 2017 and August 2019 were surveyed. Medical records for each patient were reviewed and information regarding n-irAE was recorded. RESULTS: In total, 1993 patients were included. Eleven cases of IRE were recorded, affecting 0.55% of patients overall, eight had non-melanoma cancer. Eight patients had made a full recovery. CONCLUSIONS: IRE is a n-irAE more frequent than previously reported, particularly in non-melanoma patients. The diagnostic criteria and optimal treatment needs to be determined. ICI re-challenge after IRE can be considered for selected patients.

A qualitative study on negative attitude toward electrocardiogram learning among undergraduate medical students.

OBJECTIVE: Negative affect state toward learning has a substantial impact on the learning process, academic performance, and practice of a particular subject, but such attitude toward electrocardiogram (ECG) learning has still received relatively little attention in medical education research. In spite of the significant emphasis in investigating ECG teaching method, the educators would not be able to address ECG incompetency without understanding the negative perception and attitude toward ECG learning. The purpose of this study was to assess the undergraduate students' difficulties in ECG learning and hence help educators design appropriate ECG learning curriculum to instill competent skill in ECG interpretation based on this outcome. MATERIALS AND METHODS: A total of 324 undergraduate preclinical (year 2) and clinical (year 3-5) medical students participated in this study. The research design used thematic analysis of an open-ended questionnaire to analyze the qualitative data. RESULTS: The thematic analysis detected five major emergent themes: lack of remembering (18.2%), lack of understanding (28.4%), difficulty in applying (3.6%), difficulty in analysis (15.1%), and difficulty in interpretation (17.8%), of which addressing these challenges could be taken as a foundation step upon which medical educators put an emphasis on in order to improve ECG teaching and learning. CONCLUSION: Negative attitude toward ECG learning poses a serious threat to acquire competency in ECG interpretation skill. The concept of student's memorizing ECG is not a correct approach; instead, understanding the concept and vector analysis is an elementary key for mastering ECG interpretation skill. The finding of this study sheds light into a better understanding of medical students' deficient points of ECG learning in parallel with taxonomy of cognitive domain and enables the medical teachers to come up with effective and innovative strategies for innovative ECG learning in an undergraduate medical curriculum.

Identification of an excellent prognosis subset of human papillomavirus-associated oropharyngeal cancer patients by quantification of intratumoral CD103+ immune cell abundance.

BACKGROUND: Accurate prognostic stratification of human papillomavirus-associated oropharyngeal cancers (HPV+OPSCC) is required to identify patients potentially suitable for treatment deintensification. We evaluated the prognostic significance of CD103, a surface marker associated with tissue-resident memory T cells (TRMs), in two independent cohorts of patients with HPV+OPSCC. PATIENTS AND METHODS: The abundance and distribution of CD103+ immune cells were quantified using immunohistochemistry in a cohort of 189 HPV+OPSCC patients treated with curative intent and correlated with outcome. Findings were then validated in an independent cohort comprising 177 HPV+OPSCCs using univariable and multivariable analysis. Intratumoral CD103+ immune cells were characterized by multispectral fluorescence immunohistochemistry and gene expression analysis. RESULTS: High intratumoral abundance of CD103+ immune cells using a ≥30% cut-off was found in 19.8% of tumors in the training cohort of HPV+OPSCC patients and associated with excellent prognosis for overall survival (OS) with adjusted hazard ratio (HR) of 0.13 [95% confidence interval (CI) 0.02-0.94, P = 0.004]. In the independent cohort of HPV+OPSCCs, 20.4% had high intratumoral CD103+ abundance and an adjusted HR for OS of 0.16 (95% CI 0.02-1.22, P = 0.02). Five year OS of patients with high intratumoral CD103 was 100% across both cohorts. The C-statistic for the multivariate prognostic model with stage and age was significantly improved in both cohorts with the addition of intratumoral CD103+ cell abundance. On the basis of spatial location, co-expression of CD8 and CD69, and gene expression profiles, intratumoral CD103+ cells were consistent with TRMs. CONCLUSION: Quantification of intratumoral CD103+ immune cell abundance provides prognostic information beyond that provided by clinical parameters such as TNM-staging, identifying a population of low risk HPV+OPSCC patients who are good candidates for trials of deintensification strategies.

L3 skeletal muscle index (L3SMI) is a surrogate marker of sarcopenia and frailty in non-small cell lung cancer patients.

Background: Non-small cell lung cancer (NSCLC) is a common and highly lethal disease. As advanced treatment modalities are being developed, improved prognostication methods are sought. L3 skeletal muscle index (L3SMI) and alanine aminotransferase (ALT) levels are accepted surrogate markers of sarcopenia and related frailty. We aimed to evaluate the potential association of these markers with NSCLC patients' survival. Methods: A retrospective, single-center study of an NSCLC patients' cohort. L3SMI was calculated based on skeletal muscle area on computed tomography scans at the level of the L3 vertebra. Clinical data were extracted from clinical charts. Results: A total of 140 patients (56.4% males, median age 66 [range 37-86]) were included in this study, 32% were diagnosed at stage 3 and 45% at stage 4. During the follow-up duration (median of 1.9 years; range 1 month to 6.4 years), 102 patients (72.8%) died. Patients' characteristics that were found to be associated with increased mortality were performance status, albumin and tumor stage at diagnosis. Sarcopenia, defined as low L3SMI (lower than 41 cm2/m2 for women and lower than 53 cm2/m2 for men) was significantly associated with higher risk of mortality compared with patients with normal L3SMI values (77.2%, vs 64.6%, p=0.013) in univariate analysis, but not in a multiple regression analysis. Conclusion: Low L3SMI could serve as a surrogate marker for sarcopenia and frailty and, as such, facilitate the prognostication process of NSCLC patients.

Modeling plant composition as community continua in a forest landscape with LiDAR and hyperspectral remote sensing.

In light of the need to operationalize the mapping of forest composition at landscape scales, this study uses multi-scale nested vegetation sampling in conjunction with LiDAR-hyperspectral remotely sensed data from the G-LiHT airborne sensor to map vascular plant compositional turnover in a compositionally and structurally complex North Carolina Piedmont forest. Reflecting a shift in emphasis from remotely sensing individual crowns to detecting aggregate optical-structural properties of forest stands, predictive maps reflect the composition of entire vascular plant communities, inclusive of those species smaller than the resolution of the remotely sensed imagery, intertwined with proximate taxa, or otherwise obscured from optical sensors by dense upper canopies. Stand-scale vascular plant composition is modeled as community continua: where discrete community-unit classes at different compositional resolutions provide interpretable context for continuous gradient maps that depict n-dimensional compositional complexity as a single, consistent RGB color combination. In total, derived remotely sensed predictors explain 71%, 54%, and 48% of the variation in the first three components of vascular plant composition, respectively. Among all remotely sensed environmental gradients, topography derived from LiDAR ground returns, forest structure estimated from LiDAR all returns, and morphological-biochemical traits determined from hyperspectral imagery each significantly correspond to the three primary axes of floristic composition in the study site. Results confirm the complementarity of LiDAR and hyperspectral sensors for modeling the environmental gradients constraining landscape turnover in vascular plant composition and hold promise for predictive mapping applications spanning local land management to global ecosystem modeling.

Frequency and prognostic significance of p16(INK4A) protein overexpression and transcriptionally active human papillomavirus infection in laryngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV) infection is a powerful prognostic biomarker in a subset of head and neck squamous cell carcinomas, specifically oropharyngeal cancers. However, the role of HPV in non-oropharyngeal sites, such as the larynx, remains unconfirmed. METHODS: We evaluated a cohort of 324 laryngeal squamous cell carcinoma (LSCC) patients for the expression of p16(INK4A) (p16) protein by immunohistochemistry (IHC) and for high-risk HPV E6 and E7 mRNA transcripts by RNA in situ hybridisation (ISH). p16 expression and HPV status were correlated with clinicopathological features and outcomes. RESULTS: Of 307 patients assessable for p16 IHC, 20 (6.5%) were p16 positive. Females and node-positive patients were more likely to be p16 positive (P<0.05). There were no other significant clinical or demographic differences between p16-positive and -negative cases. There was no difference in overall survival (OS) between p16-positive and -negative patients with 2-year survival of 79% in each group (HR=0.83, 95% CI 0.36-1.89, P=0.65). There was no statistically significant difference in failure-free survival (FFS) with 2-year FFS of 79% and 66% for p16-positive and -negative patients, respectively (HR=0.60, 95% CI 0.26-1.36, P=0.22). Only seven cases were found to be HPV RNA ISH positive, all of which were p16 IHC positive. There was no statistically significant difference in OS between patients with HPV RNA ISH-positive tumours compared with -negative tumours with 2-year survival of 86% and 71%, respectively (HR=0.76, 95% CI 0.23-2.5, P=0.65). The 2-year FFS was 86% and 59%, respectively (HR=0.62, 95% CI 0.19-2.03, P=0.43). CONCLUSIONS: p16 overexpression is infrequent in LSCC and the proportion of cases with high-risk HPV transcripts is even lower. There are no statistically significant correlations between p16 IHC or HPV RNA ISH status and OS or disease outcomes.

PPARγ activation inhibits cerebral arteriogenesis in the hypoperfused rat brain.

AIMS: PPARγ stimulation improves cardiovascular (CV) risk factors, but without improving overall clinical outcomes. PPARγ agonists interfere with endothelial cell (EC), monocyte and smooth muscle cell (SMC) activation, function and proliferation, physiological processes critical for arterial collateral growth (arteriogenesis). We therefore assessed the effect of PPARγ stimulation on cerebral adaptive and therapeutic collateral growth. METHODS: In a rat model of adaptive cerebral arteriogenesis (3-VO), collateral growth and function were assessed (i) in controls, (ii) after PPARγ stimulation (pioglitazone 2.8 mg kg(-1); 10 mg kg(-1) compared with metformin 62.2 mg kg(-1) or sitagliptin 6.34 mg kg(-1)) for 21 days or (iii) after adding pioglitazone to G-CSF (40 µg kg(-1) every other day) to induce therapeutic arteriogenesis for 1 week. Pioglitazone effects on endothelial and SMC morphology and proliferation, monocyte activation and migration were studied. RESULTS: PPARγ stimulation decreased cerebrovascular collateral growth and recovery of hemodynamic reserve capacity (CVRC controls: 12 ± 7%; pio low: -2 ± 9%; pio high: 1 ± 7%; metformin: 9 ± 13%; sitagliptin: 11 ± 12%), counteracted G-CSF-induced therapeutic arteriogenesis and interfered with EC activation, SMC proliferation, monocyte activation and migration. CONCLUSION: Pharmacologic PPARγ stimulation inhibits pro-arteriogenic EC activation, monocyte function, SMC proliferation and thus adaptive as well as G-CSF-induced cerebral arteriogenesis. Further studies should evaluate whether this effect may underlie the CV risk associated with thiazolidinedione use in patients.

Cancer of unknown primary: a population-based analysis of temporal change and socioeconomic disparities.

BACKGROUND: Cancer of unknown primary (CUP) is the fourth most common cause of cancer death. With advanced diagnostics and treatments, we investigated the proportion of cancers diagnosed as CUP, treatment outcomes and association with socioeconomic disparities. METHODS: We analysed trends in CUP diagnosis and outcome within the Surveillance, Epidemiology, and End Results registry between 1973 and 2008. RESULTS: The percentage of all cancers diagnosed as CUP has decreased over time comprising <2% of cancers since 2007. A higher proportion of CUP was diagnosed in the elderly, females, blacks and residents of less affluent or less educated counties. Median survival of all CUP patients was 3 months, with no improvement over time. The 5-year survival significantly improved in those with squamous histology (squamous cell carcinoma; SCC) but only marginally in non-SCC. Factors associated with a longer survival on multivariate analysis included white race; female; <65 years old; most recent decade at diagnosis; SCC; married; a histological diagnosis; and treatment with radiotherapy (all P<0.001). Despite the improvement in survival with radiotherapy, its use was less frequent in females and blacks. CONCLUSION: The percentage of cancers diagnosed as CUP is decreasing but prognosis remains poor, particularly in non-SCC CUP. However, significant socioeconomic disparities exist in diagnosis and survival, suggesting inequalities in access to diagnostic investigations and treatment.

Performance evaluation of a pilot-scale anaerobic membrane bioreactor (AnMBR) treating ethanol thin stillage.

The ethanol industry has grown rapidly during the past ten years, mainly due to increasing oil prices. However, efficient and cost-effective solutions for treating thin stillage wastewater have still to be developed. The anaerobic membrane bioreactor (AnMBR) technology combines classical anaerobic treatment in a completely-stirred tank reactor (CSTR) with membrane separation. The combination of these two technologies can achieve a superior effluent quality and also increase biogas production compared to conventional anaerobic solutions. A pilot-scale AnMBR treating thin stillage achieved very high treatment efficiencies in terms of chemical oxygen demand (COD) and total suspended solids (TSS) removal (>98%). An average permeate flux of 4.3 L/m2 x h was achieved at relatively low transmembrane pressure (TMP) values (0.1-0.2 bars) with flat-sheet membranes. Experience gained during the pilot-scale studies provides valuable information for scaling up of AnMBRs treating complex and high-strength wastewaters.

Extracellular ATP attenuates ischemia-induced caspase-3 cleavage in human endothelial cells.

BACKGROUND: Apoptotic death of endothelial cells (EC) plays a crucial role for the development of ischemic injury. In the present study we investigated the impact of extracellular Adenosine-5'-triphosphate (ATP), either released from cells or exogenously added, on ischemia-induced apoptosis of human EC. METHODS AND RESULTS: To simulate ischemic conditions, cultured human umbilical vein endothelial cells (HUVEC) were exposed to 2 h of hypoxia (Po(2)<4mm Hg) in serum-free medium. Ischemia led to a 1.7-fold (+/-0.4; P<0.05) increase in EC apoptosis compared to normoxic controls as assessed by immunoblotting and immunocytochemistry of cleaved caspase-3. Ischemia-induced apoptosis was accompanied by a 2.3-fold (+/-0.5; P<0.05) increase of extracellular ATP detected by using a luciferin/luciferase assay. Addition of the soluble ecto-ATPase apyrase, enhancing ATP degradation, increased ischemia-induced caspase-3 cleavage. Correspondingly, inhibition of ATP breakdown by addition of the selective ecto-ATPase inhibitor ARL67156 significantly reduced ischemia-induced apoptosis. Extracellular ATP acts on membrane-bound P2Y- and P2X-receptors to induce intracellular signaling. Both, ATP and the P2Y-receptor agonist UTP significantly reduced ischemia-induced apoptosis in an equipotent manner, whereas the P2X-receptor agonist αß-me-ATP did not alter caspase-3 cleavage. The anti-apoptotic effects of ARL67156 and UTP were abrogated when P2-receptors were blocked by Suramin or PPADS. Furthermore, extracellular ATP led to an activation of MEK/ERK- and PI3K/Akt-signaling pathways. Accordingly, inhibition of MEK/ERK-signaling by UO126 or inhibition of PI3K/Akt-signaling by LY294002 abolished the anti-apoptotic effects of ATP. CONCLUSION: The data of the present study indicate that extracellular ATP counteracts ischemia-induced apoptosis of human EC by activating a P2Y-receptor-mediated signaling reducing caspase-3 cleavage.

Interaction-induced beats of Friedel oscillations in quantum wires.

We analyze the spectrum of electron density oscillations in an interacting one-dimensional electron system with an impurity. The system's inhomogeneity is characterized by different values of Fermi wave vectors kF=k L/R on left or right side of the scatterer, leading to a Landauer dipole formation. We demonstrate, that while in the noninteracting system the Friedel oscillations possess only one periodicity related to the local kF, say kL on the left side, the interplay of the interactions and the Landauer dipole generates an additional peak in the spectrum of density oscillations at the counterpart kR. Being only present in correlated systems, the position and shape of this spectral feature, which in coordinate space is observable as a beating pattern in the Friedel oscillations, reveals many important details about the nature of interactions. Thus it has a potential to become an investigation tool in condensed matter physics.

Headache and temporomandibular disorders: evidence for diagnostic and behavioural overlap.

To assess the diagnostic and behavioural overlap of headache patients with temporomandibular disorders (TMD), individuals recruited from the general population with self-described headaches were compared with non-headache controls. The examination and diagnostic procedures in the Research Diagnostic Criteria (RDC) for TMD were applied to both sets of subjects by a blinded examiner. Following their examination, subjects used experience sampling methods to obtain data on pain, tooth contact, masticatory muscle tension, emotional states and stress. Results showed that a significantly higher proportion of the headache patients received an RDC/TMD diagnosis of myofascial pain than non-headache controls. Headache patients also reported significantly more frequent and intense tooth contact, more masticatory muscle tension, more stress and more pain in the face/head and other parts of the body than non-headache controls. These results are similar to those reported for TMD patients and they suggest that headache patients and TMD patients overlap considerably in diagnosis and oral parafunctional behaviours.

Electronic and atomic shell structure in aluminium nanowires.

We report experiments on aluminium nanowires in ultra-high vacuum at room temperature that reveal a periodic spectrum of exceptionally stable structures. Two 'magic' series of stable structures are observed: at low conductance, the formation of stable nanowires is governed by electronic shell effects whereas for larger contacts atomic packing dominates. The crossover between the two regimes is found to be smooth. A detailed comparison of the experimental results to a theoretical stability analysis indicates that, while the main features of the observed electron-shell structure are similar to those of alkali and noble metals, a sequence of extremely stable wires plays a unique role in aluminium. This series appears isolated in conductance histograms and can be attributed to 'superdeformed' non-axisymmetric nanowires.

Jahn-Teller distortions and the supershell effect in metal nanowires.

A stability analysis of metal nanowires shows that a Jahn-Teller deformation breaking cylindrical symmetry can be energetically favorable, leading to stable nanowires with elliptic cross sections. The sequence of stable cylindrical and elliptical nanowires allows for a consistent interpretation of experimental conductance histograms for alkali metals, including both the electronic shell and supershell structures. It is predicted that for gold, elliptical nanowires are even more likely to form since their eccentricity is smaller than for alkali metals. The existence of certain metastable superdeformed nanowires is also predicted.

Risk behaviours and benign prostatic hyperplasia.

OBJECTIVE: To identify risk factors for benign prostatic hyperplasia (BPH). SUBJECTS AND METHODS: Medical history data, including reported urological conditions and treatments, and risk factor data were collected from 34 694 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a randomized controlled trial designed to evaluate methods for the early detection of cancer. RESULTS: Asian men had the lowest risks (odds ratio, 95% confidence interval) for nocturia (0.7, 0.5-0.9), physician-diagnosed BPH (0.3, 0.2-0.5) and transurethral prostatectomy (TURP, 0.2, 0.1-0.6), while risks for Whites and Blacks were similar for most measures of BPH. Greater alcohol intake was associated with decreased nocturia (P trend = 0.002), BPH (P trend < 0.001) and TURP (P trend < 0.001). Current tobacco use was associated with decreased nocturia (0.8, 0.7-0.9), BPH (0.7, 0.6-0.8) and TURP (0.6, 0.4-0.8) but dose-response patterns were weak. CONCLUSION: Asian-Americans have the lowest risk of clinical BPH. Alcohol and possibly cigarettes are related to a lower risk for BPH.

Interplay of Rayleigh and Peierls instabilities in metallic nanowires.

A quantum-mechanical stability analysis of metallic nanowires within the free-electron model is presented. The stability is determined by an interplay of electron-shell effects, the Rayleigh instability due to surface tension, and the Peierls instability. Although the latter effect limits the maximum length also for wires with "magic radii," it is found that nanowires in the micrometer range can be stable at room temperature.

Bayesian monitoring of a phase 2 chemoprevention trial in high-risk cohorts for prostate cancer.

The objective of phase 2 cancer chemoprevention trials is to evaluate whether a chemopreventive agent will cause significant modulation of intermediate endpoint biomarkers (IEB) in patients at high risk for the disease. A phase 2 chemoprevention trial of 4-hydroxyphenyl retinamide (4-HPR) versus placebo was conducted in men with a histologic diagnosis of early prostate cancer and scheduled to have radical prostatectomy. A Bayesian monitoring method was used to sequentially monitor this trial for evidence of biological activity or ineffectiveness based on a single IEB variable. Different prior distributions were used and posterior distributions were obtained to calculate the probability that treatment differences are greater than or less than a predetermined clinically significant effect. The interim analysis of transforming growth factor-alpha expression indicated a high probability of insufficient biological activity of 4-HPR on this IEB. This study demonstrates the potential utility of Bayesian methods in the decision-making process in the conduct of phase 2 chemoprevention trials.

The effect of isolated soy protein on plasma biomarkers in elderly men with elevated serum prostate specific antigen.

PURPOSE: We performed a randomized double-blind crossover pilot study in elderly men with elevated prostate specific antigen (PSA) on the effects of the daily consumption of 2 soy beverages, each containing 20 gm. of isolated soy protein, on the isoflavone concentration in blood and urine, and on the 3 serum biomarkers cholesterol, PSA and the soluble p105 component of the p185erbB-2 proto-oncogene. MATERIALS AND METHODS: A total of 34 men supplemented their diet by consuming 1 of 2 soy protein beverages assigned randomly twice daily for a 6-week period. In a second 6-week period they consumed the other soy protein beverage. The beverage ISP+ provided 42 mg. of genistein and 27 mg. of daidzein daily, whereas the other beverage, ISP-, provided only 2.1 and 1.3 mg. of these isoflavones daily, respectively. Blood and 24-hour urine samples were obtained before the study, at 2-week intervals during the study and 2 weeks after study completion. RESULTS: ISP+ and to a lesser extent ISP- substantially increased the serum concentration and urinary output of the isoflavones and their metabolites. Serum cholesterol was significantly decreased by ISP+ irrespective of the order in which the 2 soy beverages were administered and in apparent correlation with the total isoflavone concentration. There was no significant effect of the soy beverages on serum PSA and p105erbB-2 values. CONCLUSIONS: This study reveals that short-term exposure of elderly men with elevated serum PSA values to soy protein containing isoflavones decreases serum cholesterol but not the serum biomarkers PSA and p105erbB-2.