Lorlatinib for advanced ROS1+ non-small-cell lung cancer: results of the IFCT-1803 LORLATU study.

INTRODUCTION: ROS1-rearranged (ROS1+) non-small-cell lung cancer (NSCLC) is a rare lung cancer with limited treatment options. Phase I-II studies with ROS1-tyrosine kinase inhibitors (TKIs) included small numbers of patients and real-world data are lacking. We investigate the efficacy and safety of lorlatinib, a third-generation TKI targeting ALK and ROS1, in patients with ROS1+ NSCLC treated through an expanded access program. METHODS: Consecutive patients with advanced ROS1+ NSCLC treated with lorlatinib between October 2015 and June 2019 were included. Data were collected from medical records. The primary endpoint was progression-free survival. RESULTS: Out of the 80 patients included, 47(59%) were female, 49(62%) never smokers (less than 100 cigarettes over the lifetime), and 68(85%) had stage IV NSCLC at diagnosis. Most frequent histology was adenocarcinoma (95%) and median age was 58.2 years. At the time of lorlatinib initiation, 51(64%) patients had brain metastases and 55(81%) were PS 0-1. Lorlatinib was administered as second/third/fourth/fifth+ line in 29%/28%/18%/26% of patients. All patients previously received at least one ROS1 TKI, and 55(69%) previously received chemotherapy. Median follow-up from lorlatinib initiation was 22.2 months. Median progression-free survival and overall survival from lorlatinib initiation were 7.1 months [95% confidence interval (CI) 5.0-9.9 months] and 19.6 months (95% CI 12.3-27.5 months). Median duration of treatment with lorlatinib was 7.4 months (95% CI 6.5-13.1 months). Overall response and disease control rates were 45% and 82%, respectively. The central nervous system response rate was 72%. Treatment was stopped due to toxicity in 10 patients (13%). The safety profile was consistent with previously published data. CONCLUSIONS: Lorlatinib is a major treatment option for advanced refractory ROS1+ NSCLC in treatment strategy.

[Pituitary metastasis revealing a lung cancer]. / Métastase hypophysaire symptomatique révélant un cancer bronchique.

INTRODUCTION: Pituitary metastases are rare and difficult to diagnose. Their optimal approach and management remains to be defined. CASE REPORT: We report the case of a 56-year-old patient suffering from squamous cell lung carcinoma who developed pituitary metastasis with secondary hypopituitarism, the symptoms of which were initially attributed to depression. CONCLUSION: Pituitary metastases can be difficult to diagnose, which may lead to delays in care, which can be fatal.

[A case of mediastinal angiosarcoma]. / Angiosarcome médiastinal: à propos d'un cas.

INTRODUCTION: Mediastinal angiosarcoma is a rare intrathoracic tumour and the therapeutic approach remains poorly codified. CASE REPORT: We report the case of a 65-year-old female patient presenting with chest pain. Further exploration revealed an anterior mediastinal mass with pericardial invasion. Transthoracic biopsy gave the diagnosis of angiosarcoma. Multimodal treatment with neoadjuvant chemotherapy (doxorubicin 20 mg/m(2), Ifosfamide 2500 mg/m(2), Uromitexan® 2500 mg/m(2)) and surgery followed by adjuvant radiotherapy has led to remission of the tumour that has persisted for 12 months. CONCLUSION: Systematic recording of such conditions in dedicated registries could contribute to enhance the description of the clinical and pathological characteristics, thus helping define the principles of specific management.

[Targeting insulin-like growth factors in the treatment of cancer]. / Rôle de la voie de l'IGF dans les cancers bronchiques.

INTRODUCTION: The insulin-like growth factor I receptor (IGF-IR) pathway plays a major role in cancer growth, tumor cell survival and resistance to therapy. BACKGROUND: Preclinical evidence that targeting the IGF-IR is effective in cancer treatment has been accumulating for almost 2 decades. Early clinical trials revealed an acceptable safety profile together with pharmacodynamic evidence that the receptor can be targeted successfully. It is premature to draw conclusions regarding the therapeutic potential of this class of compounds but well-documented single-agent activity was noted during phase I evaluations, and recent evidence from a phase-II study suggests that co-administration of an anti-IGF-1R antibody with chemotherapy for non-small-cell lung cancer (NSCLC) improves objective response rate and progression-free survival. VIEWPOINTS: These early results are a strong indication for continued research on the targeting of IGF-R, particularly in the treatment of NSCLC. CONCLUSIONS: Today, IGF-1R targeting appears a promising approach, more than two dozen compounds have been developed and clinical trials are underway.

[Interstitial lung disease and anti-TNF-alpha therapy in rheumatoid arthritis: Two different patterns?]. / Pneumopathie interstitielle diffuse et anti-TNF-alpha dans la polyarthrite rhumatoïde : deux formes différentes ?

The first lung complications of anti-TNF-alpha therapy in rheumatoid arthritis (RA) that were reported were infections. Recently, interstitial lung disease (ILD) has been described as a consequence of this treatment. We report two cases of women treated with anti-TNF-alpha therapy for RA who both developed exacerbations of their preexisting ILD thought to be due to the treatment. In one case, this complication occurred 2 months after anti-TNF-alpha therapy, whereas the delay of occurrence was 26 months in the second case. Based on these two cases and on the first 40 observations in the literature, we hypothesize that ILD may be exacerbated according to two distinct patterns during anti-TNF-alpha treatment for RA, occurring early (most frequently) or late after treatment was started, with a mean of 4 and 26 months, respectively. Other features that may differ between these two presentations include the risk factors, the anti-TNF-alpha molecule used, the histopathological pattern, and the prognosis.

Homozygous variant rs2076530 of BTNL2 and familial sarcoidosis.

RATIONALE: Despite extensive studies, the pathogenesis of sarcoidosis is largely unknown. Although multiple environmental and putative infectious agents have been proposed, none was retained as a major contributor to the disease occurrence. Genetic predisposition to sarcoidosis was considered as a significant factor and numerous candidate genes have been reviewed. This last point was reinforced since the discovery of a pathogenic polymorphism (rs2076530 or G > A) of the BTNL2 gene, leading to an early truncation of the protein, which increases the relative risk of the disease. BTNL2 is known to act as a co-stimulatory molecule, inducing a negative signal to T-lymphocyte activation and the mutated gene is responsible for a truncated protein and disruption of membrane localization. OBJECTIVES: Our work attempted to confirm this observation in a highly penetrant familial form of sarcoidosis. RESULTS: In this family, the disease was diagnosed in 5 members through 3 generations. Despite individual clinical specificities, all displayed severe forms of the disease. Peripheral blood samples were collected from 3 patients and 2 additional healthy children of the fourth generation. Analysis of the BTNL2 gene confirmed the presence of the pathogenic variant of BTNL2 on both alleles (A/A homozygous genotype) in all subjects tested. CONCLUSIONS: Our data suggest that the absence of a membrane anchored BTNL2 protein may increase genetic susceptibility to sarcoidosis and familial occurrence of the disease. This observation assessed the putative pathogenic involvement of the rs2076530 variant of BTNL2 in the development of this granulomatosis disease.

[Thymic tumours, autoimmune neutropaenia and autoimmune haemolytic anaemia]. / Tumeurs épithéliales thymiques, neutropénie et anémie hémolytique auto-immunes.

INTRODUCTION: Although an association between thymic tumour and autoimmune disease (including autoimmune cytopenia) has been established, the association between thymic tumour and autoimmune neutropenia has rarely been reported, with only 13 cases described in the literature. OBSERVATION: We report on a 30 year old man diagnosed with autoimmune neutropenia who had been treated for invasive thymic tumour one year previously. He successfully responded to cyclosporin and steroids therapy. A few months later, the patient presented with autoimmune haemolytic anaemia after prematurely halting his own immunosuppressive treatment. CONCLUSION: This observation brings additional insights about the clinical features, biology and treatment of autoimmune neutropenia associated with thymic tumours and underlines the potential severity of such an association. Furthermore, the association of a thymic tumour with both autoimmune neutropaenia and autoimmune haemolytic anaemia has not been reported previously.

[Nocardial pulmonary infection]. / Infections pulmonaires à Nocardia.

INTRODUCTION: Nocardial pneumonias are due to a genus of aerobic, filamentous, partly acid-alcohol fast, mainly Gram positive, actinomycetes. CASE REPORT: We report here two cases of nocardial pneumonia. The first was a 62 year old man with a history of fludaribine treatment and bone marrow transplant for lymphocytic leukaemia. During the investigation of pyrexia evidence of N. farcinica infection was found in the bronchial secretions. The second case was a man of 61 receiving long term corticosteroids and cytotoxic chemotherapy. Investigation of a pneumonia with pleural effusion found evidence, on culture of blood and pleural fluid, of disseminated infection with N. nova (cerebral, pleural, pulmonary and splenic). CONCLUSION: Nocardiosis is a rare cause of pneumonia mainly occurring in immuno-compromised adults (corticosteroid therapy, HIV infection, transplantation, cancer or leukaemia). It should be suspected in the presence of pleuro-pulmonary symptoms associated with neurological and cutaneous signs, general deterioration and weight loss. The microbiology laboratory should be advised of this eventuality as soon as possible in order to optimise the search for the organism.