Early prediction of ventricular peritoneal shunt dependency in aneurysmal subarachnoid haemorrhage patients by recurrent neural network-based machine learning using routine intensive care unit data.

Aneurysmal subarachnoid haemorrhage (aSAH) can lead to complications such as acute hydrocephalic congestion. Treatment of this acute condition often includes establishing an external ventricular drainage (EVD). However, chronic hydrocephalus develops in some patients, who then require placement of a permanent ventriculoperitoneal (VP) shunt. The aim of this study was to employ recurrent neural network (RNN)-based machine learning techniques to identify patients who require VP shunt placement at an early stage. This retrospective single-centre study included all patients who were diagnosed with aSAH and treated in the intensive care unit (ICU) between November 2010 and May 2020 (n = 602). More than 120 parameters were analysed, including routine neurocritical care data, vital signs and blood gas analyses. Various machine learning techniques, including RNNs and gradient boosting machines, were evaluated for their ability to predict VP shunt dependency. VP-shunt dependency could be predicted using an RNN after just one day of ICU stay, with an AUC-ROC of 0.77 (CI: 0.75-0.79). The accuracy of the prediction improved after four days of observation (Day 4: AUC-ROC 0.81, CI: 0.79-0.84). At that point, the accuracy of the prediction was 76% (CI: 75.98-83.09%), with a sensitivity of 85% (CI: 83-88%) and a specificity of 74% (CI: 71-78%). RNN-based machine learning has the potential to predict VP shunt dependency on Day 4 after ictus in aSAH patients using routine data collected in the ICU. The use of machine learning may allow early identification of patients with specific therapeutic needs and accelerate the execution of required procedures.

Plasma pTau-217 and N-terminal tau (NTA) enhance sensitivity to identify tau PET positivity in amyloid-ß positive individuals.

INTRODUCTION: We set out to identify tau PET-positive (A+T+) individuals among amyloid-beta (Aß) positive participants using plasma biomarkers. METHODS: In this cross-sectional study we assessed 234 participants across the AD continuum who were evaluated by amyloid PET with [18 F]AZD4694 and tau-PET with [18 F]MK6240 and measured plasma levels of total tau, pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers to predict tau positivity in Aß+ individuals. RESULTS: Highest associations with tau positivity in Aß+ individuals were found for plasma pTau-217 (AUC [CI95% ] = 0.89 [0.82, 0.96]) and NTA-tau (AUC [CI95% ] = 0.88 [0.91, 0.95]). Combining pTau-217 and NTA-tau resulted in the strongest agreement (Cohen's Kappa = 0.74, CI95%  = 0.57/0.90, sensitivity = 92%, specificity = 81%) with PET for classifying tau positivity. DISCUSSION: The potential for identifying tau accumulation in later Braak stages will be useful for patient stratification and prognostication in treatment trials and in clinical practice. HIGHLIGHTS: We found that in a cohort without pre-selection pTau-181, pTau-217, and NTA-tau showed the highest association with tau PET positivity. We found that in Aß+ individuals pTau-217 and NTA-tau showed the highest association with tau PET positivity. Combining pTau-217 and NTA-tau resulted in the strongest agreement with the tau PET-based classification.

14-3-3 [Formula: see text]-reported early synaptic injury in Alzheimer's disease is independently mediated by sTREM2.

INTRODUCTION: Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears. METHODS: We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ([Formula: see text]) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages. RESULTS: 14-3-3 [Formula: see text] was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 [Formula: see text] correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss. CONCLUSIONS: Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation.

Calcium channel ß3 subunit regulates ATP-dependent migration of dendritic cells.

Migratory dendritic cells (migDCs) continuously patrol tissues and are activated by injury and inflammation. Extracellular adenosine triphosphate (ATP) is released by damaged cells or actively secreted during inflammation and increases migDC motility. However, the underlying molecular mechanisms by which ATP accelerates migDC migration is not understood. Here, we show that migDCs can be distinguished from other DC subsets and immune cells by their expression of the voltage-gated calcium channel subunit ß3 (Cavß3; CACNB3), which exclusively facilitates ATP-dependent migration in vitro and during tissue damage in vivo. By contrast, CACNB3 does not regulate lipopolysaccharide-dependent migration. Mechanistically, CACNB3 regulates ATP-dependent inositol 1,4,5-trisphophate receptor-controlled calcium release from the endoplasmic reticulum. This, in turn, is required for ATP-mediated suppression of adhesion molecules, their detachment, and initiation of migDC migration. Thus, Cacnb3-deficient migDCs have an impaired migration after ATP exposure. In summary, we identified CACNB3 as a master regulator of ATP-dependent migDC migration that controls tissue-specific immunological responses during injury and inflammation.

Experimental renal transplantation in rats improves cardiac dysfunction caused by chronic kidney disease while LVH persists.

Background: Chronic kidney disease (CKD) causes congestive heart failure (CHF) with systolic dysfunction and left ventricular hypertrophy (LVH), which is a major contributor to increased mortality in CKD patients. It remains unclear whether cardiovascular changes that occur during the course of CKD can be reversed when renal function is restored by transplantation. Methods: To investigate this, chronic kidney disease was established in F344 rats by subtotal nephrectomy (SNx) for 8 weeks, followed by transplantation of a functional kidney from an isogenic F344 donor. SNx rats without transplantation and sham-operated animals served as controls. Renal function was assessed before and throughout the experiment. In addition, cardiac ultrasound was performed at weeks 0, 8, 12 and 16. At the end of the experiment, intra-arterial blood pressure was measured and kidneys and hearts were histologically and molecularly examined. Results: Eight weeks after SNx, rats developed marked renal dysfunction associated with significant glomerulosclerosis and tubulointerstitial fibrosis, but also an increase in left ventricular mass. After transplantation, renal function normalized but relative heart weight and ventricular mass as assessed by ultrasound scans showed no reduction compared with SNx controls. However, left ventricular wall thickness, fractional shortening and ejection fraction was normalized by renal transplantation. At 8 weeks after kidney transplantation, cardiac expression of BNP and FGF23 was also at levels comparable to healthy controls, whereas these factors were significantly increased in SNx rats. Cardiac fibrosis, as measured by fibronectin mRNA expression, was completely normalized, whereas cardiac fibronectin protein was still slightly but not significantly increased in transplanted animals compared to controls. In addition, the myofibroblast marker collagen 1, as assessed by immunohistochemistry, was significantly increased in SNx rats and also normalized by renal transplantation. Interestingly, CD68+ macrophages were significantly reduced in the hearts of SNx rats and in transplanted animals at slightly higher levels compared to controls. Conclusion: Restoration of renal function by kidney transplantation normalized early cardiac changes at most functional and molecular levels, but did not completely reverse LVH. However, further studies are needed to determine whether restoration of renal function can also reverse LVH at a later time point.

A phase 1 study in healthy participants to characterize the safety and pharmacology of inclacumab, a fully human anti-P-selectin antibody, in development for treatment of sickle cell disease.

PURPOSE: We evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of intravenous (IV) inclacumab, a fully human IgG4 anti-P-selectin monoclonal antibody in development for the treatment of sickle cell disease, at doses up to and exceeding those previously tested in healthy individuals. METHODS: In this phase 1, open-label, single-ascending-dose study, 15 healthy participants were enrolled into cohorts receiving 20 mg/kg (n = 6) or 40 mg/kg (n = 9) IV inclacumab and observed for up to 29 weeks post-dose. Safety, PK parameters, thrombin receptor-activating peptide (TRAP)-activated platelet-leukocyte aggregate (PLA) formation, P-selectin inhibition, plasma soluble P-selectin, and anti-drug antibodies were characterized. RESULTS: Two inclacumab-related treatment-emergent adverse events were reported in 1 participant; no dose-limiting toxicities were observed. Plasma PK parameters were generally dose-proportional, with a terminal half-life of 13 to 17 days. Mean TRAP-activated PLA formation decreased within 3 h from the start of infusion, and inhibition was sustained for ~ 23 weeks. Mean P-selectin inhibition > 90% was observed up to 12 weeks post-dose. The mean ratio of free to total soluble P-selectin decreased rapidly from pre-dose to end of infusion, then increased gradually to 78% of the baseline ratio by week 29. Treatment-emergent anti-drug antibodies were observed in 2 of 15 participants (13%), without apparent impact on safety, PK, or PD. CONCLUSIONS: Inclacumab was well tolerated, with PK as expected for a monoclonal antibody against a membrane-bound target and a long duration of PD effects after both single IV doses, supporting a prolonged dosing interval. TRIAL REGISTRATION: ACTRN12620001156976; registered November 4, 2020.

Vagus nerve inflammation contributes to dysautonomia in COVID-19.

Dysautonomia has substantially impacted acute COVID-19 severity as well as symptom burden after recovery from COVID-19 (long COVID), yet the underlying causes remain unknown. Here, we hypothesized that vagus nerves are affected in COVID-19 which might contribute to autonomic dysfunction. We performed a histopathological characterization of postmortem vagus nerves from COVID-19 patients and controls, and detected SARS-CoV-2 RNA together with inflammatory cell infiltration composed primarily of monocytes. Furthermore, we performed RNA sequencing which revealed a strong inflammatory response of neurons, endothelial cells, and Schwann cells which correlated with SARS-CoV-2 RNA load. Lastly, we screened a clinical cohort of 323 patients to detect a clinical phenotype of vagus nerve affection and found a decreased respiratory rate in non-survivors of critical COVID-19. Our data suggest that SARS-CoV-2 induces vagus nerve inflammation followed by autonomic dysfunction which contributes to critical disease courses and might contribute to dysautonomia observed in long COVID.

History of cerebrovascular disease but not dementia increases the risk for secondary vascular events during SARS-CoV-2 infection with presumed Omicron variant: a retrospective observational study.

BACKGROUND AND PURPOSE: This study aimed to investigate if pre-existing neurological conditions, such as dementia and a history of cerebrovascular disease, increase the risk of severe outcomes including death, intensive care unit (ICU) admission and vascular events in patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in 2022, when Omicron was the predominant variant. METHODS: A retrospective analysis was conducted of all patients with SARS-CoV-2 infection, confirmed by polymerase chain reaction test, admitted to the University Medical Center Hamburg-Eppendorf from 20 December 2021 until 15 August 2022. In all, 1249 patients were included in the study. In-hospital mortality was 3.8% and the ICU admission rate was 9.9%. Ninety-three patients with chronic cerebrovascular disease and 36 patients with pre-existing all-cause dementia were identified and propensity score matching by age, sex, comorbidities, vaccination status and dexamethasone treatment was performed in a 1:4 ratio with patients without the respective precondition using nearest neighbor matching. RESULTS: Analysis revealed that neither pre-existing cerebrovascular disease nor all-cause dementia increased mortality or the risk for ICU admission. All-cause dementia in the medical history also had no effect on vascular complications under investigation. In contrast, an increased odds ratio for both pulmonary artery embolism and secondary cerebrovascular events was observed in patients with pre-existing chronic cerebrovascular disease and myocardial infarction in the medical history. CONCLUSION: These findings suggest that patients with pre-existing cerebrovascular disease and myocardial infarction in their medical history may be particularly susceptible to vascular complications following SARS-CoV-2 infection with presumed Omicron variant.

Clinical surrogates of dysautonomia predict lethal outcome in COVID-19 on intensive care unit.

BACKGROUND: Unpredictable vegetative deteriorations made the treatment of patients with acute COVID-19 on intensive care unit particularly challenging during the first waves of the pandemic. Clinical correlates of dysautonomia and their impact on the disease course in critically ill COVID-19 patients are unknown. METHODS: We retrospectively analyzed data collected during a single-center observational study (March 2020-November 2021) which was performed at the University Medical Center Hamburg-Eppendorf, a large tertiary medical center in Germany. All patients admitted to ICU due to acute COVID-19 disease during the study period were included (n = 361). Heart rate variability (HRV) and blood pressure variability (BPV) per day were used as clinical surrogates of dysautonomia and compared between survivors and non-survivors at different time points after admission. Intraindividual correlation of vital signs with laboratory parameters were calculated and corrected for age, sex and disease severity. RESULTS: Patients who deceased in ICU had a longer stay (median days ± IQR, survivors 11.0 ± 27.3, non-survivors 14.1 ± 18.7, P = 0.85), in contrast time spent under invasive ventilation was not significantly different (median hours ± IQR, survivors 322 ± 782, non-survivors 286 ± 434, P = 0.29). Reduced HRV and BPV predicted lethal outcome in patients staying on ICU longer than 10 days after adjustment for age, sex, and disease severity. Accordingly, HRV was significantly less correlated with inflammatory markers (e.g. CRP and Procalcitonin) and blood carbon dioxide in non-survivors in comparison to survivors indicating uncoupling between autonomic function and inflammation in non-survivors. CONCLUSIONS: Our study suggests autonomic dysfunction as a contributor to mortality in critically ill COVID-19 patients during the first waves of the pandemic. Serving as a surrogate for disease progression, these findings could contribute to the clinical management of COVID-19 patients admitted to the ICU. Furthermore, the suggested measure of dysautonomia and correlation with other laboratory parameters is non-invasive, simple, and cost-effective and should be evaluated as an additional outcome parameter in septic patients treated in the ICU in the future.

Absence of self-reported neuropsychiatric and somatic symptoms after Omicron variant SARS-CoV-2 breakthrough infections.

Persistent somatic and neuropsychiatric symptoms have been frequently described in patients after infection with severe acute respiratory syndrome coronavirus 2 even after a benign clinical course of the acute infection during the early phases of the coronavirus severe acute respiratory syndrome coronavirus 2 pandemic and are part of Long COVID. The Omicron variant emerged in November 2021 and has rapidly become predominant due to its high infectivity and suboptimal vaccine cross-protection. The frequency of neuropsychiatric post-acute sequelae after infection with the severe acute respiratory syndrome coronavirus 2 Omicron and adequate vaccination status is not known. Here, we aimed to characterize post-acute symptoms in individuals with asymptomatic or mildly symptomatic breakthrough infection with severe acute respiratory syndrome coronavirus 2. These individuals had either proven infection with the Omicron variant (n = 157) or their infection occurred in 2022 where Omicron was the predominant variant of severe acute respiratory syndrome coronavirus 2 in Germany (n = 107). This monocentric cross-sectional study was conducted at the University Medical Center Hamburg-Eppendorf between 11 February 2022 and 11 April 2022. We employed questionnaires addressing self-reported somatic symptom burden (Somatic Symptom Scale 8) and neuropsychiatric symptoms including mood (Patient Health Questionnaire 2), anxiety (Generalized Anxiety Disorder 7), attention (Mindful Attention Awareness Scale) and fatigue (Fatigue Assessment Scale) in a cohort of hospital workers. Scores were compared between 175 individuals less than 4 weeks after positive testing for severe acute respiratory syndrome coronavirus 2, 88 individuals more than 4 weeks after positive testing and 87 severe acute respiratory syndrome coronavirus 2 uninfected controls. The majority (n = 313; 89.5%) of included individuals were vaccinated at least three times. After recovery from infection, no significant differences in scores assessing neuropsychiatric and somatic symptoms were detected between the three groups (severe acute respiratory syndrome coronavirus 2 uninfected controls, individuals less and more than 4 weeks after positive testing) independent of age, sex, preconditions and vaccination status. In addition, self-reported symptom burden did not significantly correlate with the number of vaccinations against severe acute respiratory syndrome coronavirus 2, time from recovery or the number of infections. Notably, in all three groups, the mean scores for each item of our questionnaire lay below the pathological threshold. Our data show that persistent neuropsychiatric and somatic symptoms after recovery from severe acute respiratory syndrome coronavirus 2 infection in fully vaccinated hospital workers do not occur more frequently than that in uninfected individuals. This will guide healthcare professionals in the clinical management of patients after recovery from breakthrough infections with severe acute respiratory syndrome coronavirus 2.

Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination.

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.

Identification of early neurodegenerative pathways in progressive multiple sclerosis.

Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand-receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease.

Potential association of the prognostic index and survival in patients with p16-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: The aim was to assess the prognostic value of the newly proposed prognostic index (PI) in patients with p16-positive oropharyngeal squamous cell carcinoma. METHODS: Patients treated with primary surgery from 2012 to 2019 with available preoperative (0-2 days) values of C­reactive protein and white blood cell counts needed for calculation of the PI, were included. Main outcome measures were overall survival (OS) and disease-free survival (DFS). The PI was dichotomized into low (PI = 0) and high (PI ≥ 1). RESULTS: In this study 36 patients were included. Average overall (OS) and disease-free survival (DFS) were 3.3 years (range 0.2-12.3 years) and 2.8 years (0.0-9.8 years), respectively. The overall mortality was 16.7% (n = 6) and a recurrent disease was observed in 30.6% of patients (n = 11). Low PI was associated with better overall survival (mean OS 10.1 ± 1.4 years, 95% confidence interval, CI 7.3-12.9 years vs. 1.9 ± 0.4, 95% CI 1.3-2.6 years, p < 0.01; mean DFS 8.5 ± 0.7 years, 95% CI 7.1-9.6 years vs. 1.0 ± 0.3 years, 95% CI 0.5-1.5 years, p < 0.01). CONCLUSION: The PI might be an easily obtainable outcome prognosticator in p16-positive oropharyngeal squamous cell carcinoma patients. Analyzing routinely obtained blood samples can contribute to identifying high-risk patients.

Multi-dimensional and longitudinal systems profiling reveals predictive pattern of severe COVID-19.

COVID-19 is a respiratory tract infection that can affect multiple organ systems. Predicting the severity and clinical outcome of individual patients is a major unmet clinical need that remains challenging due to intra- and inter-patient variability. Here, we longitudinally profiled and integrated more than 150 clinical, laboratory, and immunological parameters of 173 patients with mild to fatal COVID-19. Using systems biology, we detected progressive dysregulation of multiple parameters indicative of organ damage that correlated with disease severity, particularly affecting kidneys, hepatobiliary system, and immune landscape. By performing unsupervised clustering and trajectory analysis, we identified T and B cell depletion as early indicators of a complicated disease course. In addition, markers of hepatobiliary damage emerged as robust predictor of lethal outcome in critically ill patients. This allowed us to propose a novel clinical COVID-19 SeveriTy (COST) score that distinguishes complicated disease trajectories and predicts lethal outcome in critically ill patients.

CD161a-positive natural killer (NK) cells and α-smooth muscle actin-positive myofibroblasts were upregulated by extrarenal DPP4 in a rat model of acute renal rejection.

AIMS: Systemic inhibition of dipeptidyl peptidase 4 (DPP4) showed a protective effect in several transplant models. Here we assessed the specific role of extrarenal DPP4 in renal transplant rejection. METHODS: Kidneys from wildtype (wt) F344 rats were either transplanted in wt Dark Agouti or congenic rats not expressing DPP4. The remaining, not transplanted donor kidney served as healthy controls. To investigate early inflammatory events rats were sacrificed 3 days after transplantation and kidneys were evaluated for inflammatory cells, capillary rarefaction, proliferation, apoptosis and myofibroblasts by immunohistochemistry. RESULTS: Capillary ERG-1-positive endothelial cells were significantly more abundant in renal cortex when transplanted into DPP4 deficient compared to wt recipients. In contrast, TGF-ß and myofibroblasts were reduced by more than 25% in kidneys transplanted into DPP4 deficient compared to wt recipients. Numbers of CD161a-positive NK-cells were significantly lower in allografts in DPP4 deficient compared to wt recipients. Numbers of all other investigated immune cells were not affected by the lack of extrarenal DPP4. CONCLUSION: In early transplant rejection extrarenal DPP4 is involved in the recruitment of NK-cells and early fibrosis. Beneficial effects were less pronounced than reported for systemic DPP4 inhibition, indicating that renal DPP4 is an important player in transplantation-mediated injury.

Impact of pretherapeutic neutrophil-to-lymphocyte ratio, serum albumin, body-mass index, and advanced lung cancer inflammation index on clinical outcome in sinonasal squamous cell carcinoma.

BACKGROUND: Squamous cell carcinoma of the nasal cavity and paranasal sinuses is a rare and aggressive cancer entity with poor survival rates. Data on this group of head and neck tumors are scarce. Inflammation and cachexia-based markers and their impact on clinical outcome have been studied in several cancer groups. The aim of this study was to evaluate their prognostic potential in sinonasal squamous cell carcinoma. PATIENTS AND METHODS: This retrospective analysis included all patients treated for sinonasal squamous cell carcinoma at a tertiary referral center between 2002 and 2015. Patients were divided into groups with low and high pretherapeutic values based on the values of serum albumin (ALB, median 41.6 g/l), neutrophil-to-lymphocyte ratio (NLR, median 3.5), body-mass index (BMI, median 24.7), or advanced lung cancer inflammation index (ALI, median 29.5). Main outcome measures were overall survival (OS) and disease-free survival (DFS). Statistical analysis included calculation of survival differences using log-rank tests, hazard ratios (HR), and respective 95% confidence intervals (CI). RESULTS: 41 patients were included. Low ALB values did not influence OS (median OS not reached in both groups; p = 0.59, HR = 0.75, CI = 0.3-2.1) or DFS (median DFS 0.9 years vs 2.2 years; p = 0.6, HR = 0.8, CI = 0.4-1.8). High NLR was significantly associated with worse OS rates (median OS not reached vs 1.7 years, p = 0.02, HR = 3.4, CI = 1.0-108) but with no influence on DFS (median DFS 3.1 years vs 0.8 years; p = 0.15, HR = 1.8, CI = 0.8-4.2). Similar results were observed for patients with low ALI (median OS 1.7 years vs not reached; p = 0.03, HR = 0.3, CI = 0.1-0.9 and median DFS 0.8 years vs 2.2 years; p = 0.58, HR = 0.8, CI = 0.3-1.8). BMI was the strongest prognosticator in our study. Low pretherapeutic BMI was linked to significantly worse OS (median OS 1.4 years vs not reached; p = 0.003, HR = 0.2, CI = 0.0-0.6) and DFS (median DFS 0.8 years vs not reached; p = 0.02, HR = 0.4, CI = 0.2-0.8). In multivariate analysis BMI was revealed as an independent marker for OS (p = 0.015). No marker reached the level of significance in regard to DFS in multivariate analysis. CONCLUSION: Pretherapeutic BMI had a superior prognostic value in patients with sinonasal squamous cell carcinoma in comparison with other tested variables. BMI may be a simple tool for estimating clinical outcome in SNSCC. However, larger studies are necessary to validate our results.

Evaluation of the cancer stem cell marker DCLK1 in patients with lymph node metastases of head and neck cancer.

BACKGROUND: Lymph node metastases are frequently detected in head and neck squamous cell carcinoma (HNSCC) patients. Little is known about biomarkers expressed in lymph node metastases or their influence on clinical outcome. Doublecortin-like kinase 1 (DCLK1) is one marker that might be associated with outcome, owing to its correlation with stem cell-like characteristics. METHODS: We assessed the expression of DCLK1 in 74 postoperatively irradiated patients in histologically confirmed HNSCC lymph node metastases. Statistical analysis of the association with DCLK1 on clinical outcomes was performed. RESULTS: DCLK1 was expressed in 63.5% of our patient cohort. DCLK1(+) HNSCC patients, compared with those without DCLK1 expression, showed a significantly poorer time to recurrence. Moreover, we observed a significantly poorer time to recurrence in HPV(-) HNSCC patients, and significantly shorter overall and disease-free survival rates in HPV(-) oropharyngeal cancer patients, compared with HPV(+) patients with these cancers. HPV(+) patients showed no significant differences in survival time according to DCLK1 expression. However, recurrent disease occurred in only DCLK1(+) patients. Mulitivariate analysis showed that DCLK1 expression in lymph node metastases is an independent marker for recurrence. CONCLUSION: DCLK1 expression might be associated with poorer clinical outcomes in HNSCC patients, specifically in HPV(-) move patients. However, larger studies are required to verify our results.

Selective Vulnerability of αOFF Retinal Ganglion Cells during Onset of Autoimmune Optic Neuritis.

Retinal ganglion cells (RGCs), a diverse body of neurons which relay visual signals from the retina to the higher processing regions of the brain, are susceptible to neurodegenerative processes in several diseases affecting the retina. Previous evidence shows that RGCs are damaged at early stages of autoimmune optic neuritis (AON), prior to subsequent degeneration of the optic nerve. In order to study cell type-specific vulnerability of RGCs we performed immunohistochemical and patch-clamp electrophysiological analyses of RGCs following induction of AON using the experimental autoimmune encephalomyelitis model in Brown Norway rats. We report that αRGCs are more susceptible to degeneration than the global RGC population as a whole, with functional and structural changes beginning even prior to demyelination and inflammatory infiltration of the optic nerve (where the RGC axons reside). Functional classification of αRGCs into OFF-sustained, OFF-transient and ON-sustained subtypes revealed that αOFF RGCs (both sustained and transient subtypes) are more vulnerable than αON RGCs, as indicated by reductions in light-evoked post-synaptic currents and retraction of dendritic arbours. Classification of neuronal susceptibility is a first step in furthering our understanding of what underlies a neuron's vulnerability to degenerative processes, necessary for the future development of effective neuroprotective strategies.