Anti-programmed death ligand 1 immunotherapies in cancer patients with pre-existing systemic sclerosis: A postmarketed phase IV safety assessment study.

OBJECTIVES: Cancer patients with pre-existing autoimmune disease, such as systemic sclerosis (SSc), are excluded from clinical trials, so the data on tolerability and efficacy of immune checkpoint inhibitors in these patients are limited. This study investigated the tolerability and efficacy of anti-programmed death ligand 1 (PD (L)1) immunotherapies in patients with pre-existing SSc. METHODS: Scleronco-01 was a multicentre, nationwide, open-label, phase IV observational study, from 2019 to 2021. RESULTS: Seventeen SSc patients receiving treatment for lung carcinoma (n = 13, 77%), head and neck cancer (n = 2, 12%), melanoma (n = 1, 6%), and colorectal carcinoma (n = 1, 6%) were included. The median (interquartile range) patient age was 60 (34-82) years. Fifteen (88%) patients received anti-PD1 (nivolumab and pembrolizumab) and two (12%) anti-PD-L1 (durvalumab). The median follow-up duration was 12 (range, 2-38) months. Four patients (24%) experienced flare-up of SSc symptoms. Ten patients (59%) developed an immune-related adverse event (grade I-II in 11 patients [65%], grade III-IV in one [6%]) without grade V. The overall response rate was 41% (7/17 patients). The median overall survival was 15.8 (95% confidence interval: 7.3 to not reached) months. CONCLUSION: Anti-PD1 or PD-L1 immunotherapies are suitable options for cancer patients with pre-existing SSc. Longer follow-up periods are required for long-term safety analyses.

Interstitial pneumonia with autoimmune features: Evaluation of connective tissue disease incidence during follow-up.

OBJECTIVES: Among interstitial pneumonia with autoimmune features (IPAF) patients, identifying those at risk to develop a connective tissue disease (CTD) during the disease course is a key issue. The aim of this study was to evaluate the incidence of definite CTD diagnosis in IPAF patients during follow-up. METHODS: We performed a multicentric cohort study of interstitial lung disease (ILD) from 2010 to 2017 in pneumology and immunology departments of tertiary care centers. Patients with a known cause of ILD (including established CTD) at diagnosis were excluded. Among patients with idiopathic ILD and at least three years of follow-up, two groups (IPAF and non-IPAF) were retrospectively analyzed at time of diagnosis. RESULTS: A total of 249 patients with ILD were enrolled, including 70 IPAF and 179 non-IPAF patients. After a mean follow-up time of 77 ± 44 months, 18/70 IPAF patients (26%) had a CTD diagnosis - 9 antisynthetase syndrome, 8 systemic sclerosis and 1 overlap myositis - compared with 4/179 non-IPAF patients (2%). IPAF patients were at higher risk of CTD occurrence at 3 years of follow-up compared to non-IPAF patients (HR 10.1, 95% CI 3.1-33.1, p < 0. 01). IPAF patients progressing to CTD tended to be younger, more often female and have more frequently puffy fingers, capillaroscopy abnormalities and antisynthetase antibodies at diagnosis. CONCLUSIONS: We found that a significant proportion of IPAF patients had associated CTD diagnosis during follow-up. Prospective studies are needed to confirm baseline predictive factors of CTD occurrence in IPAF patients.

Hepatitis B reactivation and immune check point inhibitors.

BACKGROUND: Liver toxicity during immune checkpoint inhibitor treatment is mostly due to immune mediated hepatitis. Viral hepatitis, as well as auto-immune or metabolic hepatitis, are considered as exclusion criteria for ICI induced immune hepatitis diagnosis. However, considering the high prevalence of viral hepatitis B infection and the increasing prescription of immune checkpoint inhibitors, their use in patients with HBV chronic viral infection may be common, even more if patients are treated for hepatocellular carcinoma. Few clinical studies directly deal with the risk of HBV reactivation during ICI therapy and real-life data is currently based on five reported cases of HBV reactivation, one with fatal outcome. In this review, we summarize the current available clinical information about HBV reactivation risk during ICI treatment, its hypothetic mechanism, and propose practical recommendations about verifying and monitoring HBV status throughout the treatment.

Respiratory Distress in SARS-CoV-2 without Lung Damage: Phrenic Paralysis Should Be Considered in COVID-19 Infection.

We describe an overweight COVID-19 patient with respiratory distress preceded by anosmia/dysgeusia with no lung injury shown on CT, angio-CT or ventilation/perfusion scans. Orthopnoea and paradoxical abdominal respiration were identified. Phrenic paralysis, demonstrated by examination of patient breathing, and on x-ray while standing breathing in and out, explained the respiratory distress. This is a rare and previously undescribed neurological complication of COVID-19 infection caused by vagus nerve injury. LEARNING POINTS: Phrenic paralysis must be kept in mind as a rare neurological complication of COVID-19.Vagus nerve palsy is a neurological manifestation as anosmia and dysgeusia, that were already identified in the olfactory system of COVID-19 patients.

Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study.

BACKGROUND: Paraneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy. METHODS: We included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively. FINDINGS: Of the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45-88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1-2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1. INTERPRETATION: Our results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.

Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer.

PURPOSE: Increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to epidermal growth factor receptor (EGFR) -targeted drugs in patients with non-small-cell lung cancer (NSCLC). We investigated whether dual inhibition of MET/EGFR results in clinical benefit in patients with NSCLC. PATIENTS AND METHODS: Patients with recurrent NSCLC were randomly assigned at a ratio of one to one to receive onartuzumab plus erlotinib or placebo plus erlotinib; crossover was allowed at progression. Tumor tissue was required to assess MET status by immunohistochemistry (IHC). Coprimary end points were progression-free survival (PFS) in the intent-to-treat (ITT) and MET-positive (MET IHC diagnostic positive) populations; additional end points included overall survival (OS), objective response rate, and safety. RESULTS: There was no improvement in PFS or OS in the ITT population (n = 137; PFS hazard ratio [HR], 1.09; P = .69; OS HR, 0.80; P = .34). MET-positive patients (n = 66) treated with erlotinib plus onartuzumab showed improvement in both PFS (HR, .53; P = .04) and OS (HR, .37; P = .002). Conversely, clinical outcomes were worse in MET-negative patients treated with onartuzumab plus erlotinib (n = 62; PFS HR, 1.82; P = .05; OS HR, 1.78; P = .16). MET-positive control patients had worse outcomes versus MET-negative control patients (n = 62; PFS HR, 1.71; P = .06; OS HR, 2.61; P = .004). Incidence of peripheral edema was increased in onartuzumab-treated patients. CONCLUSION: Onartuzumab plus erlotinib was associated with improved PFS and OS in the MET-positive population. These results combined with the worse outcomes observed in MET-negative patients treated with onartuzumab highlight the importance of diagnostic testing in drug development.

Desquamative interstitial pneumonia: an analytic review with an emphasis on aetiology.

Desquamative interstitial pneumonia (DIP) is characterised by the accumulation of numerous pigmented macrophages within most of the distal airspace of the lung and, sometimes, the presence of giant cells. Diagnosis of DIP is not easy and requires surgical lung biopsy. DIP is usually associated with tobacco smoke. However, the association between smoking and DIP is less robust than that with respiratory bronchiolitis with interstitial lung disease or pulmonary Langerhans' cell histiocytosis; approximately 10-42% of patients with DIP are nonsmokers. DIP can also occur in patients following exposure to certain inhaled toxins (occupational exposure) and drugs, and may occur in the context of certain viral illnesses and autoimmune diseases. In the context of DIP, occupational exposure should be systematically investigated.

Large thoracomyoplasty and negative pressure therapy for late postpneumonectomy empyema with a retrosternal abscess: a modern version of the Clagett procedure.

A 63-year-old male with a history of cancer, and who had undergone a left pneumonectomy seven years before, presented with deterioration in his general status and recent dyspnea [stage III (New York Heart Association) NYHA]. Imaging revealed a contralateral mediastinal shift and cardiac compression caused by pneumonectomy cavity enlargement and a retrosternal liquid mass. Late empyema associated with a retrosternal abscess caused by Propionibacterium acnes was diagnosed after thoracoscopy and an anterior mediastinotomy. Surgical treatment included an axillary open-window thoracostomy associated with negative pressure therapy (NPT), followed by a large thoracomyoplasty where part of the latissimus dorsi was harvested, and then guided healing. The chest was closed after eight months. This case is an unusual observation of a late post-pneumonectomy empyema with Propionibacterium acnes presenting like recurring cancer, but that was treated effectively using traditional (Clagett procedure) and newer (NPT) strategies.