A Randomized Phase II Trial Comparing the Efficacy and Safety of Pioglitazone, Clarithromycin and Metronomic Low-Dose Chemotherapy with Single-Agent Nivolumab Therapy in Patients with Advanced Non-small Cell Lung Cancer Treated in Second or Further Line (ModuLung).

Background: Most non-small cell lung cancers occur in elderly and frequently comorbid patients. Therefore, it is necessary to evaluate the efficacy of biomodulatory active therapy regimen, concertedly interfering with tumor-associated homeostatic pathways to achieve tumor control paralleled by modest toxicity profiles. Patients and Methods: The ModuLung trial is a national, multicentre, prospective, open-label, randomized phase II trial in patients with histologically confirmed stage IIIB/IV squamous (n = 11) and non-squamous non-small cell (n = 26) lung cancer who failed first-line platinum-based chemotherapy. Patients were randomly assigned on a 1:1 ratio to the biomodulatory or control group, treated with nivolumab. Patients randomized to the biomodulatory group received an all-oral therapy consisting of treosulfan 250 mg twice daily, pioglitazone 45 mg once daily, clarithromycin 250 mg twice daily, until disease progression or unacceptable toxicity. Results: The study had to be closed pre-maturely due to approval of immune checkpoint inhibitors (ICi) in first-line treatment. Thirty-seven patients, available for analysis, were treated in second to forth-line. Progression-free survival (PFS) was significantly inferior for biomodulation (N = 20) vs. nivolumab (N = 17) with a median PFS (95% confidence interval) of 1.4 (1.2-2.0) months vs. 1.6 (1.4-6.2), respectively; with a hazard ratio (95% confidence interval) of 1.908 [0.962; 3.788]; p = 0.0483. Objective response rate was 11.8% with nivolumab vs. 5% with biomodulation, median follow-up 8.25 months. The frequency of grade 3-5 treatment related adverse events was 29% with nivolumab and 10% with biomodulation. Overall survival (OS), the secondary endpoint, was comparable in both treatment arms; biomodulation with a median OS (95% confidence interval) of 9.4 (6.0-33.0) months vs. nivolumab 6.9 (4.6-24.0), respectively; hazard ratio (95% confidence interval) of 0.733 [0.334; 1.610]; p = 0.4368. Seventy-five percent of patients in the biomodulation arm received rescue therapy with checkpoint inhibitors. Conclusions: This trial shows that the biomodulatory therapy was inferior to nivolumab on PFS. However, the fact that OS was similar between groups gives rise to the hypothesis that the well-tolerable biomodulatory therapy may prime tumor tissues for efficacious checkpoint inhibitor therapy, even in very advanced treatment lines where poor response to ICi might be expected with increasing line of therapy.

Extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS) in fulminant blastomycosis in Germany.

In fulminant blastomycosis with multiorgan failure, the earliest diagnosis possible is crucial for successful treatment. If severe acute respiratory distress syndrome (ARDS) develops, miniaturised veno-venous extracorporeal membrane oxygenation (ECMO) might provide a unique and efficacious possibility to prolong the time frame for diagnosis and the beginning of treatment. This is the first report on a case of fatal blastomycosis in Germany. It reminds us to add exotic infections to the differential diagnosis in patients with refractory pneumonia in the era of worldwide tourism.

General aneurysmatosis due to cheese consumption: complications of an endocarditis caused by Lactococcus cremoris.

We describe a case of endocarditis due to Lactococcus cremoris associated with cheese consumption, that caused multiple mycotic aneurysms. Antibiotic treatment combined with surgical and radiological interventions resulted in full recovery.

Effects of dynamic bilevel positive airway pressure support on central sleep apnea in men with heart failure.

BACKGROUND: Treatment with continuous positive airway pressure (CPAP) improves cardiac function in chronic heart failure (CHF) patients with central sleep apnea (CSA)-Cheyne-Stokes respiration (CSR) by stabilizing ventilation, but frequently central apneas and hypopneas persist. Our objective was to test the hypothesis that flow-targeted dynamic bilevel positive airway pressure (BPAP) support (BiPAP autoSV; Respironics; Murrysville, PA) effectively suppresses CSR-CSA in CHF patients. METHODS: We studied 14 CHF patients with CSR-CSA (and residual CSA on positive airway pressure therapy) during 3 consecutive nights: (1) diagnostic polysomnography, (2) CPAP (n=10) or BPAP (n=4) titration, and (3) dynamic flow-targeted dynamic BPAP support with an expiratory positive airway pressure (EPAP) set to suppress obstructive respiratory events, and an inspiratory positive airway pressure (IPAP) dynamically ranging between 0 and 15 cm H2O above the EPAP. RESULTS: CPAP or BPAP significantly reduced the apnea-hypopnea index (AHI) [mean+/-SD, 46+/-4 events/h to 22+/-4 events/h; p=0.001] compared to the first night without treatment. Flow-targeted dynamic BPAP support (mean EPAP, 6.5+/-1.7 cm H2O; maximal IPAP, 21.9+/-2.1 cm H2O) further reduced the AHI to 4+/-1/h of sleep compared to the untreated (p<0.001) and CPAP or BPAP night (p=0.002). After the first night of flow-targeted dynamic BPAP support, patients rated on an analog scale (range, 0 to 10) the treatment as comfortable (6.9+/-0.6), and the sleep quality as improved compared to previous nights (7.4+/-0.6). CONCLUSION: Flow-targeted dynamic BPAP support effectively suppresses CSR-CSA in patients with CHF and is well tolerated.