Cenicriviroc for the treatment of COVID-19: first interim results of a randomised, placebo-controlled, investigator-initiated, double-blind phase II trial.

OBJECTIVES: C-C-chemokine receptors (CCRs) are expressed on a variety of immune cells and play an important role in many immune processes, particularly leukocyte migration. Comprehensive preclinical research demonstrated CCR2/CCR5-dependent pathways as pivotal for the pathophysiology of severe COVID-19. Here we report human data on use of a chemokine receptor inhibitor in patients with COVID-19. METHODS: Interim results of a 2:1 randomised, placebo-controlled, investigator-initiated trial on the CCR2/CCR5-inhibitor Cenicriviroc (CVC) 150 mg BID orally for 28 d in hospitalised patients with moderate to severe COVID-19 are reported. The primary endpoint is the subject's responder status defined by achieving grade 1 or 2 on the 7-point ordinal scale of clinical improvement on day 15. RESULTS: Of the 30 patients randomised, 18 were assigned to receive CVC and 12 to placebo. Efficient CCR2- and CCR5 inhibition was demonstrated through CCL2 and CCL4 elevation in CVC-treated patients (485% and 80% increase on day 3 compared to the baseline, respectively). In the modified intention-to-treat population, 82.4% of patients (14/17) in the CVC group met the primary endpoint, as did 91.7% (11/12) in the placebo group (OR = 0.5, 95% CI = 0.04-3.41). One patient treated with CVC died of progressive acute respiratory distress syndrome, and the remaining had a favourable outcome. Overall, treatment with CVC was well tolerated, with most adverse events being grade I or II and resolving spontaneously. CONCLUSIONS: Our interim analysis provides proof-of-concept data on CVC for COVID-19 patients as an intervention to inhibit CCR2/CCR5. Further studies are warranted to assess its clinical efficacy.

Functional limitations 12 months after SARS-CoV-2 infection correlate with initial disease severity: An observational study of cardiopulmonary exercise capacity testing in COVID-19 convalescents.

BACKGROUND: Cardiopulmonary Exercise Testing (CPET) provides a comprehensive assessment of pulmonary, cardiovascular and musculosceletal function. Reduced CPET performance could be an indicator for chronic morbidity after COVID-19. METHODS: Patients ≥18 years with confirmed PCR positive SARS-CoV-2 infection were offered to participate in a prospective observational study of clinical course and outcomes of COVID-19. 54 patients completed CPET, questionnaires on respiratory quality of life and performed pulmonary function tests 12 months after SARS-CoV-2 infection. RESULTS: At 12 months after SARS-CoV-2 infection, 46.3% of participants had a peak performance and 33.3% a peak oxygen uptake of <80% of the predicted values, respectively. Further impairments were observed in diffusion capacity and ventilatory efficiency. Functional limitations were particularly pronounced in patients after invasive mechanical ventilation and extracorporeal membrane oxygenation treatment. Ventilatory capacity was reduced <80% of predicted values in 55.6% of participants, independent from initial clinical severity. Patient reported dyspnea and respiratory quality of life after COVID-19 correlated with CPET performance and parameters of gas exchange. Risk factors for reduced CPET performance 12 months after COVID-19 were prior intensive care treatment (OR 5.58, p = 0.004), SGRQ outcome >25 points (OR 3.48, p = 0.03) and reduced DLCO (OR 3.01, p = 0.054). CONCLUSIONS: Functional limitations causing chronic morbidity in COVID-19 survivors persist over 12 months after SARS-CoV-2 infection. These limitations were particularly seen in parameters of overall performance and gas exchange resulting from muscular deconditioning and lung parenchymal changes. Patient reported reduced respiratory quality of life was a risk factor for adverse CPET performance.

Endoscopic Lung Volume Reduction with One-Way Valves in Patients with Severe Chronic Obstructive Pulmonary Disease with Hypercapnia.

BACKGROUND: Robust clinical evidence on the efficacy and safety of endoscopic lung volume reduction (ELVR) with one-way valves in patients with severe lung emphysema with chronic hypercapnic respiratory failure is lacking. OBJECTIVE: The aim of this study was to compare patient characteristics, clinical outcome measures, and incidences of adverse events between patients with severe COPD undergoing ELVR with one-way valves and with either a partial pressure of carbon dioxide (pCO2) of ≤45 mm Hg or with pCO2 >45 mm Hg. METHODS: This was a multicentre prospective study of patients with severe lung disease who were evaluated based on lung function, exercise capacity (6-min walk test [6-MWT]), and quality-of-life tests. RESULTS: Patients with pCO2 ≤45 mm Hg (n = 157) and pCO2 >45 mm Hg (n = 40) showed similar baseline characteristics. Patients with pCO2 ≤45 mm Hg demonstrated a significant increase in forced expiratory volume in 1 s (p < 0.001), a significant decrease in residual volume (RV) (p < 0.001), and significant improvements in the quality of life and 6-MWT at the 3-month follow-up. Patients with pCO2 >45 mm Hg had significant improvements in RV only (p < 0.05). There was a significant decrease in pCO2 between baseline and follow-up in hypercapnic patients, relative to the decrease in patients with pCO2 ≤45 mm Hg (p = 0.008). Patients who were more hypercapnic at baseline showed a greater reduction in pCO2 after valve placement (r = -0.38, p < 0.001). Pneumothorax was the most common adverse event in both groups. CONCLUSIONS: ELVR with one-way valves seems clinically beneficial with a remarkably good safety profile for patients with chronic hypercapnic respiratory failure.

Severity of respiratory failure and computed chest tomography in acute COVID-19 correlates with pulmonary function and respiratory symptoms after infection with SARS-CoV-2: An observational longitudinal study over 12 months.

INTRODUCTION: Prospective and longitudinal data on pulmonary injury over one year after acute coronavirus disease 2019 (COVID-19) are sparse. We aim to determine reductions in pulmonary function and respiratory related quality of life up to 12 months after acute COVID-19. METHODS: Patients with acute COVID-19 were enrolled into an ongoing single-centre, prospective observational study and prospectively examined 6 weeks, 3, 6 and 12 months after onset of COVID-19 symptoms. Chest CT-scans, pulmonary function and symptoms assessed by St. Georges Respiratory Questionnaire were used to evaluate respiratory limitations. Patients were stratified according to severity of acute COVID-19. RESULTS: Median age of all patients was 57 years, 37.8% were female. Higher age, male sex and higher BMI were associated with acute-COVID-19 severity (p < 0.0001, 0.001 and 0.004 respectively). Also, pulmonary restriction and reduced carbon monoxide diffusion capacity was associated with disease severity. In patients with restriction and impaired diffusion capacity, FVC improved over 12 months from 61.32 to 71.82, TLC from 68.92 to 76.95, DLCO from 60.18 to 68.98 and KCO from 81.28 to 87.80 (percent predicted values; p = 0.002, 0.045, 0.0002 and 0.0005). The CT-score of lung involvement in the acute phase was associated with restriction and reduction in diffusion capacity in follow-up. Respiratory symptoms improved for patients in higher severity groups during follow-up, but not for patients with initially mild disease. CONCLUSION: Severity of respiratory failure during COVID-19 correlates with the degree of pulmonary function impairment and respiratory quality of life in the year after acute infection.

Impact of Ventilation Modes on Bronchoscopic Chartis Assessment Outcome in Candidates for Endobronchial Valve Treatment.

BACKGROUND: Endobronchial valve therapy has proven to reduce lung hyperinflation and decrease disease burden in patients with severe lung emphysema. Exclusion of collateral ventilation (CV) of the targeted lobe by using an endobronchial assessment system (Chartis; PulmonX, Drive Redwood City, CA, USA) in combination with software-based fissure integrity analysis (FCS [fissure completeness score]) of computed tomography scans of the lung are established tools to select appropriate patients for endobronchial valve treatment. So far, there is no conclusive evidence if the ventilation mode during bronchoscopy impacts the outcome of Chartis assessments. METHODS: Patients with Chartis assessments and software-based quantification of FCS (StratX; PulmonX, Drive Redwood City, CA, USA) were enrolled in this retrospective study. During bronchoscopy, pulmonary fissure integrity was evaluated with the Chartis assessment system in each patient first under spontaneous breathing and subsequently under high-frequency (HF) jet ventilation. RESULTS: In total, 102 patients were analyzed. Four Chartis phenotypes CV positive (CV+), CV negative (CV-), low flow, and low plateau in spontaneous breathing and HF jet ventilation were identified. The frequency of each Chartis phenotype per lobe was similar in both settings. When comparing Chartis assessments in spontaneous breathing and HF jet ventilation, there was an overall good concordance rate for all analyzed fissures. In agreement, receiver operating characteristic analysis of the FCS showed an almost similar prediction for CV+ and CV- status independent of the ventilation modes. CONCLUSION: Chartis assessment in spontaneous breathing and HF jet ventilation had similar rates in detecting CV in lung emphysema. Our results suggest that both modes are equivalent for the assessment of CV.

A proteomic survival predictor for COVID-19 patients in intensive care.

Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Additional tools are also needed to monitor treatment, including experimental therapies in clinical trials. Comprehensively capturing human physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index, and APACHE II score showed limited performance in predicting the COVID-19 outcome. Instead, the quantification of 321 plasma protein groups at 349 timepoints in 50 critically ill patients receiving invasive mechanical ventilation revealed 14 proteins that showed trajectories different between survivors and non-survivors. A predictor trained on proteomic measurements obtained at the first time point at maximum treatment level (i.e. WHO grade 7), which was weeks before the outcome, achieved accurate classification of survivors (AUROC 0.81). We tested the established predictor on an independent validation cohort (AUROC 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that plasma proteomics can give rise to prognostic predictors substantially outperforming current prognostic markers in intensive care.

Role of IL-17 in atopy-A systematic review.

PURPOSE OF REVIEW: Atopy is defined as the genetic predisposition to react with type I allergic diseases such as food-, skin-, and respiratory allergies. Distinct molecular mechanisms have been described, including the known Th2 driven immune response. IL-17A (IL-17) is mainly produced by Th17 cells and belongs to the IL-17 family of cytokines, IL-17A to F. While IL-17 plays a major role in inflammatory and autoimmune disorders, more data was published in recent years elucidating the role of IL-17 in allergic diseases. The present study aimed to elaborate specifically the role of IL-17 in atopy. METHODS: A systematic literature search was conducted in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials, regarding IL-17 and atopy/allergic diseases. RESULTS: In total, 31 novel publications could be identified (food allergy n = 3, allergic asthma n = 7, allergic rhinitis [AR] n = 10, atopic dermatitis [AD] n = 11). In all allergic diseases, the IL-17 pathway has been investigated. Serum IL-17 was elevated in all allergic diseases. In AR, serum and nasal IL-17 levels correlated with the severity of the disease. In food allergies, serum IL-17E was also elevated in children. In AD, there is a trend for higher IL-17 values in the serum and skin specimen, while it is more expressed in acute lesions. In allergic asthma, serum IL-17 levels were increased. In two studies, higher serum IL-17 levels were found in severe persistent asthmatic patients than in intermittent asthmatics or healthy controls. Only one therapeutic clinical study exists on allergic diseases (asthma patients) using a monoclonal antibody against the IL-17 receptor A. No clinical efficacy was found in the total study population, except for a subgroup of patients with (post-bronchodilator) high reversibility. SUMMARY: The role of IL 17 in the pathogenesis of allergic diseases is evident, but the involvement of the Th17 cytokine in the pathophysiological pathway is not conclusively defined. IL-17 is most likely relevant and will be a clinical target in subgroups of patients. The current data indicates that IL-17 is elevated more often in acute and severe forms of allergic diseases.

A time-resolved proteomic and prognostic map of COVID-19.

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.

CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity.

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons.

Endoscopic lung volume reduction with endobronchial valves in very low D LCO patients: results from the German Registry - Lungenemphysemregister e.V.

BACKGROUND: Endoscopic lung volume reduction (ELVR) with valves has been suggested to be the key strategy for patients with severe emphysema and concomitant low diffusing capacity of the lung for carbon monoxide (D LCO). However, robust evidence is still missing. We therefore aim to compare clinical outcomes in relation to D LCO for patients treated with ELVR. METHODS: We assessed D LCO at baseline and 3 months follow-up and compared pre- and postprocedural pulmonary function test, quality of life, exercise capacity and adverse events. This is a retrospective subanalysis of prospectively collected data from the German Lung Emphysema Registry. RESULTS: In total, 121 patients treated with ELVR were analysed. Thirty-four patients with a D LCO ≤20% and 87 patients with a D LCO >20% showed similar baseline characteristics. After ELVR, there was a decrease of residual volume (both p<0.001 to baseline) in both groups, and both demonstrated better quality of life (p<0.01 to baseline). Forced expiratory volume in 1 s (FEV1) improved significantly only in patients with a D LCO >20% (p<0.001 to baseline). Exercise capacity remained almost unchanged in both groups (p=0.3). The most frequent complication for both groups was a pneumothorax (D LCO ≤20%: 17.6% versus D LCO >20%: 16.1%; p=0.728). However, there were no significant differences in other adverse events between both groups. CONCLUSIONS: ELVR improves lung function as well as quality of life in patients with D LCO >20% and D LCO ≤20%. Adverse events did not differ between groups. Therefore, ELVR should be considered as a treatment option, even in patients with a very low D LCO.

An Integrative Approach of the Fissure Completeness Score and Chartis Assessment in Endobronchial Valve Treatment for Emphysema.

Purpose: Lung volume reduction using one-way endobronchial valves is a bronchoscopic treatment for patients with severe emphysema without collateral ventilation between the treatment target lobe and the ipsilateral lobe(s). CT-scan fissure analysis is often used as a surrogate to predict the absence of collateral ventilation. We aimed to evaluate the predictive value of the fissure completeness score (FCS) compared to the functional Chartis measurement of collateral ventilation and to provide cut-off values of the FCS in patient selection. Patients and Methods: Multicenter study in patients eligible for treatment with one-way valves. The FCS was calculated by quantitative CT analysis (Thirona, the Netherlands) and compared to status of interlobar collateral ventilation measured with Chartis system (PulmonX, USA). Thresholds were calculated for the predictive values of the presence of collateral ventilation. Results: An FCS >95% of the left major fissure had a positive predictive value (PPV) of 91%, with 1 in 11 fissures demonstrating collateral ventilation with Chartis measurement, whereas an FCS of ≤80% had a negative predictive value (NPV) of 100% for the presence of collateral ventilation. For the right major fissure, the NPV was 100% for an FCS ≤90%, but 69.7% for the right upper lobe fissure. Conclusion: Quantitative CT analysis is recommended in all patients evaluated for endobronchial valves. Patients with incomplete fissures (left major fissure: FCS <80%; right major fissure: <90%) can be excluded from Chartis measurement and endobronchial valve treatment. In patients with more complete fissures, the FCS is not specific enough for endobronchial valve treatment decisions. In this case, additional Chartis measurements are always recommended in the right lung. For the left lung, Chartis assessments may be omitted if the FCS is >95%.

HIV transmission by human bite: a case report and review of the literature-implications for post-exposure prophylaxis.

We report a case of a probable HIV-1 transmission by human bite. The analyzed data from ten previously reported  suspected or allegedly confirmed HIV transmissions revealed a deep bleeding bite wound as the primary risk factor. A high HIV plasma viral load and bleeding oral lesions are present most of the time during HIV transmission by bite. HIV post-exposure prophylaxis (PEP) should be recommended in case of a bleeding wound resulting from a bite of an HIV-infected person. PEP was missed in this presented case.

Pemetrexed-Based Chemotherapy Is Inferior to Pemetrexed-Free Regimens in Thyroid Transcription Factor 1 (TTF-1)-Negative, EGFR/ALK-Negative Lung Adenocarcinoma: A Propensity Score Matched Pairs Analysis.

INTRODUCTION: Thyroid transcription factor 1 (TTF-1) is a prognostic biomarker in lung adenocarcinoma; however, TTF-1-positive patients also display more favorable factors like actionable target mutations. In contrast, TTF-1-negative cancer is a poorly described entity. We performed a retrospective study to characterize a TTF-1-negative phenotype and to evaluate outcome depending on the chemotherapy regimen applied in the EGFR/ALK-negative population. PATIENTS AND METHODS: Phenotypic traits were analyzed in 741 patients with evaluable TTF-1 expression status, among them 529 patients with platinum-based first-line chemotherapy, with disease diagnosed between 2009 and 2016 at a tertiary referral university hospital. The influence of TTF-1 and several cofactors on progression-free survival and overall survival (OS) were analyzed using a 1:1 propensity score matching model, depending on the platinum doublet chemotherapy's incorporating pemetrexed or not, with subsequent Cox regression. RESULTS: TTF-1 negativity implied a distinct cancer phenotype with the predominance of male sex, worse Eastern Cooperative Oncology Group performance status, greater metastatic burden at primary diagnosis, and more adrenal gland metastases. These patients had improved progression-free survival (hazard ratio, 0.42; P = .001) and OS (hazard ratio, 0.40; P < .001) when gemcitabine-, taxane-, or vinorelbine-based regimens were provided instead of pemetrexed. None of the regimens was superior in TTF-1-positive patients with regard to OS. Overall, TTF-1 expression was strongly prognostic with a substantial increase in progression-free survival (hazard ratio, 0.54; P < .001) and OS (hazard ratio, 0.53; P < .001). CONCLUSION: TTF-1 negativity is associated with a distinct cancer phenotype. Incorporation of this biomarker may be helpful when choosing an appropriate therapy regimen.

Studying the pathophysiology of coronavirus disease 2019: a protocol for the Berlin prospective COVID-19 patient cohort (Pa-COVID-19).

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions. METHODS: Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, and pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up. RESULTS: Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional, and health-related quality-of-life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care, (ii) facilitate comprehensive data collection in medical care facilities with varying resources, and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany. CONCLUSION: We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents. TRIAL REGISTRATION: Registered at the German registry for clinical studies (DRKS00021688).

Indwelling pleural catheters for non-malignant pleural effusions: report on a single centre's 10 years of experience.

BACKGROUND: Recurrent pleural effusion is a common cause of dyspnoea, cough and chest pain during the course of infectious pleurisy and non-malignant diseases like congestive heart failure (CHF) or liver cirrhosis with hepatic hydrothorax (HH). With regard to the chronic character of the underlying diseases, indwelling pleural catheters (IPC) are increasingly used, not only assuring immediate symptom relief but also potentially leading to pleurodesis without sclerosing agents. PATIENTS AND METHODS: In this single-centre retrospective observational study, patient characteristics, procedural variables and outcome in patients with IPC in non-malignant pleural effusion (NMPE) were evaluated and prognostic factors for pleurodesis were identified. RESULTS: From 2006 to 2017, 54 patients received 62 IPC, of whom 48.4% with CHF and 43.5% with HH. The median length of insertion was 1.5 months (IQR 0.6-2.9 months), the median survival time after insertion 3.2 months (IQR 1.1-16.0). An adequate symptom relief was achieved in 93.2% with no need for subsequent interventions. In patients surviving ≥30 days after IPC insertion, pleurodesis was observed in 45.9%, being associated to age (<55 years, p=0.02), the primary diagnosis (p=0.03) and interventions for the underlying disease (p<0.001). Complications occurred in 24.2% of all procedures (n=15), the majority concerning mechanical obstructions (n=10) and infections (n=4). Patients with HH had an excess risk for complications (37.3%). CONCLUSION: Efficacy in symptom relief and a generally manageable safety profile recommend IPC as a first-line treatment option in NMPE, where disease-specific treatments are exhausted. Caution is warranted in patients with HH due to an excess risk for complications.

Indwelling pleural catheters for malignancy-associated pleural effusion: report on a single centre's ten years of experience.

INTRODUCTION: Recurrent pleural effusion is a common cause of dyspnoea, cough and chest pain during the course of malignant diseases. Chemical pleurodesis had been the only definitive treatment option until two decades ago. Indwelling pleural catheters (IPC) emerged as an alternative, not only assuring immediate symptom relief but also potentially leading to pleurodesis in the absence of sclerosing agents. METHODS: In this single-centre retrospective observational study patient characteristics, procedural variables and outcome in a large population of patients with IPC in malignancy were evaluated and prognostic factors for pleurodesis were identified. RESULTS: From 2006 to 2016, 395 patients received 448 IPC, of whom 121 (30.6%) had ovarian, 91 (23.0%) lung and 45 (11.4%) breast cancer. The median length of IPC remaining in place was 1.2 months (IQR, 0.5-2.6), the median survival time after insertion 2.0 months (IQR, 0.6-6.4). An adequate symptom relief was achieved in 94.9% of all patients, with no need for subsequent interventions until last visit or death. In patients surviving ≥30 days after IPC insertion, pleurodesis was observed in 44.5% and was more common in patients < 60 years (HR, 1.72; 95% CI, 1.05-2.78; p = 0.03). The use of an additional talc slurry via the IPC was highly predictive for pleurodesis (HR 6.68; 95% CI, 1.44-31.08; p = 0.02). Complications occurred in 13.4% of all procedures (n = 60), 41.8% concerning infections (local infections at the tunnel/exit site (n = 14) and empyema (n = 11)), and 98.3% being low or mild grade (n = 59). Complication rates were higher in men than women (18.6 vs. 12.4%, p = 0.023). CONCLUSION: High efficacy in symptom relief and a favourable safety profile confirm IPC as suitable first line option in most malignant pleural effusions. The study presents the largest dataset on IPC in gynaecologic cancer to date. Gender-specific differences in complication rates warrant further study.

Human Anti-fungal Th17 Immunity and Pathology Rely on Cross-Reactivity against Candida albicans.

Th17 cells provide protection at barrier tissues but may also contribute to immune pathology. The relevance and induction mechanisms of pathologic Th17 responses in humans are poorly understood. Here, we identify the mucocutaneous pathobiont Candida albicans as the major direct inducer of human anti-fungal Th17 cells. Th17 cells directed against other fungi are induced by cross-reactivity to C. albicans. Intestinal inflammation expands total C. albicans and cross-reactive Th17 cells. Strikingly, Th17 cells cross-reactive to the airborne fungus Aspergillus fumigatus are selectively activated and expanded in patients with airway inflammation, especially during acute allergic bronchopulmonary aspergillosis. This indicates a direct link between protective intestinal Th17 responses against C. albicans and lung inflammation caused by airborne fungi. We identify heterologous immunity to a single, ubiquitous member of the microbiota as a central mechanism for systemic induction of human anti-fungal Th17 responses and as a potential risk factor for pulmonary inflammatory diseases.

Local ablative treatment for synchronous single organ oligometastatic lung cancer-A propensity score analysis of 180 patients.

INTRODUCTION: Local ablative treatment (LAT) improves outcome in lung cancer with oligometastatic disease (OMD) and potentially leads to long term survival. The aim of this retrospective study was to evaluate and quantify the additional benefit of LAT in synchronous OMD and to further identify prognostic factors for survival. PATIENTS AND METHODS: A propensity score-matched pairs analysis was performed on a set of patient and disease variables in 180 patients, treated for synchronous single organ OMD including non small-cell and neuroendocrine lung cancer with ≤4 metastases between 2000 and 2016 in 3 lung cancer centers in Berlin, Germany. Patients either received LAT for all sites of disease (intervention group) by means of surgery or stereotactic radiotherapy, or standard chemotherapy, if necessary combined with a local treatment with palliative intent (control group). RESULTS: Median follow-up time was 32.2 and 18.8 months for the intervention and control group, respectively. Substantial benefits in median progression-free survival (PFS, 25.1 vs. 8.2 months; HR, 0.30; 95% CI, 0.21-0.43; p < 0.001) and overall survival (OS, 60.4 vs. 22.5 months; HR, 0.42; 95% CI, 0.28-0.62; p < 0.001) were associated with LAT. Histology of adenocarcinoma and T1a primaries also predicted a favorable prognosis concerning PFS and OS. More favorable nodal stage (N0-2 vs. 3) and solitary metastases were associated with an extended PFS, whereas initial ECOG-PS (0-1 vs. 2) predicted OS. CONCLUSIONS: LAT was the strongest predictor for PFS and OS in OMD with ≤4 metastases. Survival in the control group identifies OMD as a subset of lung cancer with a generally more favorable prognosis.