[Management of EGFR mutated non-small cell lung carcinoma patients]. / Analyse de la prise en charge des cancers bronchiques avec mutation du gène de l'EGFR.

INTRODUCTION: Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small-cell lung cancer (NSCLC). Over the past decade, the management of NSCLC-carrying EGFR mutation has evolved considerably with the use of tyrosine kinase inhibitors (TKIs). The main objective of this retrospective study was to analyze the evolution of therapeutic strategies in a cohort of patients with metastatic or locally advanced EGFR- mutated NSCLC. METHODS: Data on patients with EGFR-mutated NSCLC, eligible for TKIs, and treated between 2010 to 2019 were collected. The main therapeutic strategies adopted following progression under TKIs and the prognostic factors for survival were analyzed. RESULTS: The median age of the 177 patients was included in the cohort was 70years. The majority of patients (77.4%) received TKIs as first-line treatment, while 16.4% received chemotherapy. Osimertinib initiation as second-line treatment was a factor for better prognosis (OR=0.5). Finally, change of chemotherapy line was the main therapeutic strategy adopted for 41.3% of the patients having relapsed under TKIs. DISCUSSION: Therapeutic management of EGFR-mutated NSCLC patients was in accordance with regional, national and international recommendations. The characterization of progression under TKI therapy has become systematic, allowing better adaption of therapeutic strategies.

Deletion of osteopontin or bone sialoprotein induces opposite bone responses to mechanical stimulation in mice.

Osteopontin (OPN) and Bone Sialoprotein (BSP) are co-expressed in bone and display overlapping and complementary physiological properties. Both genes show a rapid expression response to mechanical stimulation. We used mice with single and double deletions (DKO) of BSP and OPN to assess the specificity of their roles in skeletal adaptation to loading. Two-month-old Wild-Type (WT), BSP knockout (BSP-/-), OPN-/- and DKO male mice were submitted to two mechanical stimulation regimen (n = 10 mice/group) respectively impacting trabecular bone (Hypergravity, HG) and cortical bone (Whole Body Vibration, WBV). HG increased trabecular bone volume (BV/TV) in WT femur through reduced resorption, and in BSP-/- mice femur and vertebra through increased bone formation. In contrast, HG increased the turnover of OPN-/- bone, resulting in reduced femur and vertebra BV/TV. HG did not affect DKO bones. Similarly, WBV increased cortical thickness in BSP-/- mice and decreased it in OPN-/-, without affecting structurally WT and DKO bone. Vibrated BSP-/- mice displayed increased endocortical bone formation with a drop in Sclerostin expression, and reduced periosteal osteoclasts with lower Rankl and Cathepsin K expression. In contrast, vibrated OPN-/- endocortical bone displayed decreased formation and increased osteoclast coverage. Therefore, under two regimen (HG and WBV) targeting distinct bone compartments, absence of OPN resulted in bone loss while lack of BSP induced bone gain, reflecting divergent structural adaptations. Strikingly, absence of both proteins led to a relative insensitivity to either mechanical challenge. Interplay between OPN and BSP thus appears as a key element of skeletal response to mechanical stimulation.

[A complex case of miliary pulmonary tuberculosis following intravesical BCG therapy]. / Un cas complexe de miliaire pulmonaire post-BCG thérapie pour carcinome urothélial.

Bladder cancer (urothelial carcinoma in 90 % of cases) is the most common neoplasia of the urinary tract. Superficial carcinoma represents 70-80 % of bladder cancers. The treatment of these tumours includes, after transuretral resection, intravesical Bacillus Calmette-Guerin (BCG) instillation therapy. This treatment constitutes, by its immune-mediated anti-tumoral action, the first step of immunotherapy in cancer. Severe complications (granulomatosis, hypersensitivity pneumonitis or orchitis) are rare (0.5-2 %). Here we report a complex case of pulmonary granulomatosis secondary to BCG therapy. This is a 74-year-old male, treated for superficial bladder carcinoma by transuretral resection (pT1G3) and then endovesical instillations of BCG therapy for two months. Two years later, a new transuretral resection shows an infiltrating urothelial carcinoma pT2G3. The extension balance finds a persistent micro-nodular pulmonary infiltrate. A broncho-alveolar lavage is then realised but no mycobacteria was found. A surgical biopsy of a nodule is performed and revealed a histiocytic reaction without any neoplastic element. Detection of Mycobacterium tuberculosis by Polymerase Chain Reaction (PCR) was finally positive. In the absence of a secondary lesion, the patient had a cysto-prostatectomy and began a tritherapy against tuberculosis. Post-BCG therapy granulomatosis is a rare complication but should remain a differential diagnosis in front of the appearance of pulmonary nodes in patients who have received posttransuretral resection BCG instillations. Mycobacterial DNA PCR research remains the most sensitive examination.

Les carcinomes urothéliaux superficiels de vessies représentent 70 à 80 % des tumeurs de la vessie. Leur traitement comprend, après résection transurétrale, une BCG (Bacille de Calmette et Guérin) thérapie par instillations endovésicales. Les complications sévères (granulomatose, pneumopathie d'hypersensibilité ou orchite) sont rares (0,5-2 %) mais nous rapportons ici un cas complexe de granulomatose pulmonaire secondaire à une BCG thérapie. Il s'agit d'un homme de 74 ans, traité pour un carcinome urothélial superficiel de vessie par résection endo-urétrale (pT1G3) puis instillations endovésicales de BCG thérapie. Deux années après, une nouvelle résection transurétrale objective un carcinome urothélial infiltrant pT2G3. Le bilan d'extension retrouve un infiltrat pulmonaire micronodulaire persistant. Un lavage bronchoalvéolaire ne retrouve pas de bacilles acido-alcoolo-résistants. La biopsie chirurgicale d'un nodule retrouve une réaction histiocytaire sans élément néoplasique. La Polymerase Chain Reaction (PCR) à la recherche de mycobactérie du groupe tuberculosis revient finalement positive. En l'absence de lésion secondaire, le patient a bénéficié d'une cystoprostatectomie et a débuté dans les suites une trithérapie antituberculeuse. La granulomatose post-BCG thérapie est une complication rare, mais doit rester un diagnostic différentiel devant l'apparition de micronodules pulmonaires chez les patients ayant reçu des instillations de BCG post-résection transurétrale. La recherche par PCR d'ADN de mycobactéries reste l'examen le plus sensible.

Obesity and chemotherapy administration: between empiric and mathematic method review.

Introduction: Obesity is a major risk factor for chronic disease and cancer development. Therapeutic management of obese patients with cancer is a real challenge for physician because of the alteration of antineoplastic pharmacokinetics parameters in this population. In routine clinical practices, chemotherapy doses in obese patients are arbitrarily capped or adjusted to an ideal weight to minimize excessive toxicities. Material and methods: The main goal of this review is to describe the current state of knowledge concerning the correlation between the adjustment of BSA (capping or ideal weight) and the rates of global toxicities and survival outcomes in obese patients under chemotherapy in different types of cancer. We searched in the Medline database (via PubMed) in order to identify all publications of literature reviews whose subject chemotherapy dosing in obese population. Results: Only a single study was pointing toward increased of global toxicities of full weight dosing. Furthermore, some studies suggests that the practice of limiting doses in overweight and obese patients may negatively influence the quality of care and outcomes in a constantly increasing population. Conclusion: This review highlights the lack of prospective studies focusing on chemotherapy methods of administration in obese patients. At this time, there is no prospective study comparing capping and full weight dose chemotherapy administration in obese patient population.

Deletion of OPN in BSP knockout mice does not correct bone hypomineralization but results in high bone turnover.

The two SIBLING (Small Integrin Binding Ligand N-linked Glycoproteins), bone sialoprotein (BSP) and osteopontin (OPN) are expressed in osteoblasts and osteoclasts. In mature BSP knockout (KO, -/-) mice, both bone formation and resorption as well as mineralization are impaired. OPN-/- mice display impaired resorption, and OPN is described as an inhibitor of mineralization. However, OPN is overexpressed in BSP-/- mice, complicating the understanding of their phenotype. We have generated and characterized mice with a double KO (DKO) of OPN and BSP, to try and unravel their respective contributions. Despite the absence of OPN, DKO bones are still hypomineralized. The SIBLING, matrix extracellular phosphoglycoprotein with ASARM motif (MEPE) is highly overexpressed in both BSP-/- and DKO and may impair mineralization through liberation of its ASARM (Acidic Serine-Aspartate Rich MEPE associated) peptides. DKO mice also display evidence of active formation of trabecular, secondary bone as well as primary bone in the marrow-ablation repair model. A higher number of osteoclasts form in DKO marrow cultures, with higher resorption activity, and DKO long bones display a localized and conspicuous cortical macroporosity. High bone formation and resorption parameters, and high cortical porosity in DKO mice suggest an active bone modeling/remodeling, in the absence of two key regulators of bone cell performance. This first double KO of SIBLING proteins thus results in a singular, non-trivial phenotype leading to reconsider the interpretation of each single KO, concerning in particular matrix mineralization and the regulation of bone cell activity.