Purpose Ex-vivo lung perfusion (EVLP) is a validated technique allowing evaluation and reconditioning of damaged donor lungs to make them suitable for transplantation. Moderate hyperthermia is known to exert cytoprotective effect, via induction and accumulation of specific proteins, known as heat shock proteins (HSPs). We hypothesized that thermal preconditioning (TP) with a well-calibrated heat stress applied during EVLP could improve lung graft by reduction of oxidative stress, cell death and inflammation. Methods Male rats were randomly assigned into 2 groups: controls (Ctrl, n=5) or TP (n=5). In both groups, lungs were kept in situ for 1h at room temperature, then flushed with cold Perfadex. Heart-lung block was harvested and kept at 4°C for 1h, then mounted on the EVLP system for 3h. In Ctrl group, the temperature perfusion solution was kept at 37°C the all-time. In the TP group, a heat shock was done for 30 minutes after 1h of EVLP by heating the perfusion solution at 41.5°C. At the end of EVLP, lungs were snap-frozen and kept at -80°C for further tissue analysis. Results Static pulmonary compliance, peak inspiratory pressure, and oxygenation capacity were similar in both groups. We were able to induce HSPs in the TP group (Hspa1a and Hmox-1). In the TP group, we observed a reduction of oxidative stress (carbonyls and MDA), a decrease of apoptosis (Caspase 3 and 7) and a decrease of pro-inflammatory NF-κB transcription factor as well as the expression of inflammation mediators such as TNF-α, IL-1α, IL-1β, CXCL-1 and CCL-2. Conclusion Thermal preconditioning during EVLP decreased oxidative stress, apoptotic cell death, and inflammation of damaged lungs. These findings demonstrate that EVLP in association with thermal preconditioning could be a promising therapeutic platform improving lung quality of damaged donor lungs.

Abstract In this study, we report the clinical features of Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome, design and validate a clinical score to facilitate the identification of patients that should be tested for Kelch-like protein 11 antibodies, and examine in detail the nature of the immune response in both the brain and the tumour samples for a better characterization of the immunopathogenesis of this condition. The presence of Kelch-like protein 11 antibodies was retrospectively assessed in patients referred to the French Reference Center for paraneoplastic neurological syndrome and autoimmune encephalitis with (i) antibody-negative paraneoplastic neurological syndrome [limbic encephalitis (n = 105), cerebellar degeneration (n = 33)] and (ii) antibody-positive paraneoplastic neurological syndrome [Ma2-Ab encephalitis (n = 34), antibodies targeting N-methyl-D-aspartate receptor encephalitis with teratoma (n = 49)]. Additionally, since 1 January 2020, patients were prospectively screened for Kelch-like protein 11 antibodies as new usual clinical practice. Overall, Kelch-like protein 11 antibodies were detected in 11 patients [11/11, 100% were male; their median (range) age was 44 (35–79) years], 9 of them from the antibody-negative paraneoplastic neurological syndrome cohort, 1 from the antibody-positive (Ma2-Ab) cohort and 1 additional prospectively detected patient. All patients manifested a cerebellar syndrome, either isolated (4/11, 36%) or part of a multi-system neurological disorder (7/11, 64%). Additional core syndromes were limbic encephalitis (5/11, 45%) and myelitis (2/11, 18%). Severe weight loss (7/11, 64%) and hearing loss/tinnitus (5/11, 45%) were common. Rarer neurologic manifestations included hypersomnia and seizures (2/11, 18%). Two patients presented phenotypes resembling primary neurodegenerative disorders (progressive supranuclear palsy and flail arm syndrome, respectively). An associated cancer was found in 9/11 (82%) patients; it was most commonly (7/9, 78%) a spontaneously regressed (‘burned-out’) testicular germ cell tumour. A newly designed clinical score (MATCH score: male, ataxia, testicular cancer, hearing alterations) with a cut-off ≥4 successfully identified patients with Kelch-like protein 11 antibodies (sensitivity 78%, specificity 99%). Pathological findings (three testicular tumours, three lymph node metastases of testicular tumours, one brain biopsy) showed the presence of a T-cell inflammation with resulting anti-tumour immunity in the testis and one chronic, exhausted immune response—demonstrated by immune checkpoint expression—in the metastases and the brain. In conclusion, these findings suggest that Kelch-like protein 11 antibody paraneoplastic neurological syndrome is a homogeneous clinical syndrome and its detection can be facilitated using the MATCH score. The pathogenesis is probably T-cell mediated, but the stages of inflammation are different in the testis, metastases and the brain.

Background Conidiobolus spp. (mainly C. coronatus ) are the causal agents of rhino-facial conidiobolomycosis, a limited soft tissue infection, which is essentially observed in immunocompetent individuals from tropical areas. Rare cases of invasive conidiobolomycosis due to C. coronatus or other species ( C.incongruus, C.lamprauges ) have been reported in immunocompromised patients. We report here the first case of invasive pulmonary fungal infection due to Conidiobolus pachyzygosporus in a Swiss patient with onco-haematologic malignancy. Case presentation A 71 year-old female was admitted in a Swiss hospital for induction chemotherapy of acute myeloid leukemia. A chest CT performed during the neutropenic phase identified three well-circumscribed lung lesions consistent with invasive fungal infection, along with a positive 1,3-beta-d-glucan assay in serum. A transbronchial biopsy of the lung lesions revealed large occasionally septate hyphae. A Conidiobolus spp. was detected by direct 18S rDNA in the tissue biopsy and subsequently identified at species level as C. pachyzygosporus by 28S rDNA sequencing. The infection was cured after isavuconazole therapy, recovery of the immune system and surgical resection of lung lesions. Conclusions This is the first description of C. pachyzygosporus as human pathogen and second case report of invasive conidiobolomycosis from a European country.

"A case report on the cytokine signature profile of immunoglobulin G4-related disease." Scandinavian Journal of Rheumatology, 49(4), pp. 332–333

BACKGROUND:Malignant pleural mesothelioma (MPM) is an aggressive malignancy characterised by limited treatment options and a poor prognosis. At relapse after platinum-based chemotherapy, single-agent chemotherapy is commonly used and single-arm trials of immune-checkpoint inhibitors have demonstrated encouraging activity. PATIENTS AND METHODS:PROMISE-meso is an open-label 1:1 randomised phase III trial investigating the efficacy of pembrolizumab (200 mg/Q3W) versus institutional choice single-agent chemotherapy (gemcitabine or vinorelbine) in relapsed MPM patients with progression after/on previous platinum-based chemotherapy. Patients were performance status 0-1 and unselected for programmed cell death ligand 1 (PD-L1) status. At progression, patients randomly assigned to receive chemotherapy were allowed to crossover to pembrolizumab. The primary end point was progression-free survival (PFS), assessed by blinded independent central review (BICR). Secondary end points were overall survival (OS), investigator-assessed PFS, objective response rate (ORR), and safety. Efficacy by PD-L1 status was investigated in exploratory analyses. RESULTS:Between September 2017 and August 2018, 144 patients were randomly allocated (pembrolizumab: 73; chemotherapy: 71). At data cut-off [20 February 2019, median follow-up of 11.8 months (interquartile range: 9.9-14.5)], 118 BICR-PFS events were observed. No difference in BICR-PFS was detected [hazard ratio = 1.06, 95% confidence interval (CI): 0.73-1.53; P = 0.76], and median BICR-PFS (95% CI) for pembrolizumab was 2.5 (2.1-4.2), compared with 3.4 (2.2-4.3) months for chemotherapy. A difference in ORR for pembrolizumab was identified (22%, 95% CI: 13% to 33%), over chemotherapy (6%, 95% CI: 2% to 14%; P = 0.004). Forty-five patients (63%) assigned to chemotherapy received pembrolizumab at progression. With follow-up to 21 August 2019 [17.5 months: (14.8-19.7)], no difference in OS was detected between groups (HR = 1.12, 95% CI: 0.74-1.69; P = 0.59), even after adjusting for crossover. Pembrolizumab safety was consistent with previous observations. Exploratory efficacy analyses by PD-L1 status demonstrated no improvements in ORR/PFS/OS. CONCLUSION:This is the first randomised trial evaluating the efficacy of pembrolizumab in MPM patients progressing after/on previous platinum-based chemotherapy. In biologically unselected patients, although associated with an improved ORR, pembrolizumab improves neither PFS nor OS over single-agent chemotherapy.

Diffuse interstitial lung disease (ILD) is one of the most frequent extra-articular manifestation of rheumatoid arthritis (RA) and is an important factor of morbidity and mortality. However, the physiopathological mechanisms underlying RA-associated ILD remain poorly understood, and disease management is difficult in the absence of effective treatments and international guidelines. The recent identification of genetic variants and mutations similar to those observed in idiopathic pulmonary fibrosis (IPF), a disease affecting exclusively the lung, provides new insights into the understanding of RA-associated ILD. Furthermore, new antifibrotic drugs approved for the treatment of IPF, including pirfenidone and nintedanib, could also prove to be effective for RA-associated ILD. Studies are ongoing to confirm this hypothesis.