Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer.

BACKGROUND: Selumetinib (AZD6244, ARRY-142886)+docetaxel increases median overall survival (OS) and significantly improves progression-free survival (PFS) and objective response rate (ORR) compared with docetaxel alone in patients with KRAS mutant, stage IIIB/IV non-small-cell lung cancer (NSCLC; NCT00890825). METHODS: Retrospective analysis of OS, PFS, ORR and change in tumour size at week 6 for different sub-populations of KRAS codon mutations. RESULTS: In patients receiving selumetinib+docetaxel and harbouring KRAS G12C or G12V mutations there were trends towards greater improvement in OS, PFS and ORR compared with other KRAS mutations. CONCLUSION: Different KRAS mutations in NSCLC may influence selumetinib/docetaxel sensitivity.

Randomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: results from the IFCT-0802 trial†.

BACKGROUND: This randomized phase II-III trial sought to evaluate the efficacy and safety of adding bevacizumab (Bev) following induction chemotherapy (CT) in extensive small-cell lung cancer (SCLC). PATIENTS AND METHODS: Enrolled SCLC patients received two induction cycles of CT. Responders were randomly assigned 1:1 to receive four additional cycles of CT alone or CT plus Bev (7.5 mg/kg), followed by single-agent Bev until progression or unacceptable toxicity. The primary end point was the percentage of patients for whom disease remained controlled (still in response) at the fourth cycle. RESULTS: In total, 147 patients were enrolled. Partial response was observed in 103 patients, 74 of whom were eligible for Bev and randomly assigned to the CT alone group (n = 37) or the CT plus Bev group (n = 37). Response assessment at the end of the fourth cycle showed that disease control did not differ between the two groups (89.2% versus 91.9% of patients remaining responders in CT alone versus CT plus Bev, respectively; Fisher's exact test: P = 1.00). Progression-free survival (PFS) since randomization did not significantly differ, with a median PFS of 5.5 months [95% confidence interval (CI) 4.9% to 6.0%] versus 5.3 months (95% CI 4.8% to 5.8%) in the CT alone and CT plus Bev groups, respectively [hazard ratio (HR) for CT alone: 1.1; 95% CI 0.7% to 1.7%; unadjusted P = 0.82]. Grade ≥2 hypertension and grade ≥3 thrombotic events were observed in 40% and 11% of patients, respectively, in the CT plus Bev group. Serum vascular endothelial growth factor (VEGF) and soluble VEGF receptor titrations failed to identify predictive biomarkers. CONCLUSION: Administering 7.5 mg/kg Bev after induction did not improve outcome in extensive SCLC patients.

IFCT-1502 CLINIVO: real-world evidence of long-term survival with nivolumab in a nationwide cohort of patients with advanced non-small-cell lung cancer.

BACKGROUND: Immunotherapy using inhibitors targeting immune checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) is currently the standard of care in patients with advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We carried out a nationwide cohort retrospective study of consecutive patients with advanced, refractory NSCLC who received nivolumab as second to later lines of treatment as part of the expanded access program. Key objectives were to assess the efficacy and safety of nivolumab and the efficacy of first post-nivolumab treatment. RESULTS: Nine hundred and two patients were enrolled: 317 (35%) with squamous cell carcinoma and 585 (65%) with non-squamous cell carcinoma. Median age was 64 years; there were 630 (70%) men, 795 (88%) smokers, 723 (81%) patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0/1, 197 (22%) patients with brain metastases, and 212 (27%) with liver metastases. Best response was partial response for 16.2% and stable disease (SD) for 30.5%. Progression-free survival and overall survival (OS) rates at 2, 3, and 5 years were 8% and 25%, 6% and 16%, and 4% and 10%, respectively. At multivariate analysis, ECOG PS ≥2 [hazard ratio (HR) = 2.13, 95% confidence interval (95% CI) 1.78-2.55, P < 0.001], squamous histology (HR = 1.17, 95% CI 1.01-1.36, P = 0.04), and presence of central nervous system metastases (HR = 1.29, 95% CI 1.08-1.54, P = 0.005) were significantly associated with lower OS. Four hundred and ninety-two patients received at least one treatment after discontinuation of nivolumab, consisting of systemic therapies in 450 (91%). Radiation therapy was delivered to 118 (24%) patients. CONCLUSION: The CLINIVO cohort represents the largest real-world evidence cohort with the use of immune checkpoint inhibitor in advanced, metastatic NSCLC after failure of first-line chemotherapy, with long-term follow-up and analysis of subsequent therapies. Our data confirm the efficacy of nivolumab in a cohort larger than that reported in landmark clinical trials and identify prognostic factors, which reinforces the need for accurate selection of patients for treatment with immune checkpoint inhibitors. Our data indicate that oligoprogression is frequent after nivolumab exposure and provide a unique insight into the long-term survival.

[Pulmonary artery intimal sarcoma]. / Sarcome intimal de l'artère pulmonaire.

Pulmonary artery sarcoma is a rare tumor. We present a case of intimal sarcoma arising from right pulmonary artery and left lower pulmonary vein observed in a 44-year-old man with a non-productive cough. Computed tomographic scans and magnetic resonance imaging showing filling defect enhancement contributed early, suggesting the diagnosis of primary vascular tumor, hypothesis confirmed by pathologist findings.

[An unusual cause of chylothorax: primary amyloidosis]. / Une cause exceptionnelle de chylothorax: l'amylose primitive.

BACKGROUND: Amyloidosis is a large family of diseases defined by the presence of extra cellular protein deposits which can remain localised but are generally diffuse. Pleural involvement with effusion is rare (6% only), and difficult to diagnose because the clinical signs are non-specific. OBSERVATION: We report the case of a 77 year old man, hospitalized for anasarca, with recurring pleural effusions despite two drainages and talcage. Pleural aspiration revealed a chylothorax. ProBNP was high: 24000 ng/l. Echocardiography revealed a restrictive cardiomyopathy and suggested the diagnosis of a systemic disease. Negative peripheral biopsies led us to perform an endomyocardial biopsy, which confirmed the diagnosis of amyloidosis AL. CONCLUSION: We report an original case of primary amyloidosis presenting as a chylothorax and confirmed by an endomyocardial biopsy. We highlight the multi factorial character of pleural effusions associated with amyloidosis. This explains the delay in treatment and the disease's critical nature (median survival 2 months). The prognostic value of proBNP is also emphasised.

[Multifocal serous chorioretinopathy secondary to the use of MEK inhibitors: Illustration and example of management through two case reports]. / Choriorétinopathie séreuse multifocale secondaire à l'utilisation des inhibiteurs MEK : illustration et exemple de prise en charge à travers 2 cas.

New targeted treatments are being used for patients affected by certain types of cancers with specific gene dysregulation. These new treatments transform the prognosis for the patients but the exact way in which they work is often incompletely known. This can prove to be problematic with regard to potential side effects. Ophthalmologic side effects are particularly difficult to detect in animal models. MEK inhibitors are among these new targeted treatments for which the indications are broad. One of the reported side effects of MEK inhibitors is the appearance of atypical multifocal serous chorioretinopathies which, when present, occur rapidly after starting the treatment and disappear soon after stopping it. We report two documented cases of serous chorioretinopathies secondary to the use of selumetinib, an MEK inhibitor. Both patients were followed for several months after initiating the treatment, using angiography, OCT, and filtered photographs. Only a very few cases have been reported, and the detailed description of two clear-cut cases and their management, as well as a review of the current literature, seems a good way to approach the management of this complication.

Aminoacylation of Phaseolus vulgaris cytoplasmic, chloroplastic and mitochondrial tRNAsPro and tRNAsLys by homologous and heterologous enzymes.

The cytoplasmic prolyl-tRNA synthetase can be separated by hydroxyapatite chromatography, from the enzyme present in the chloroplasts and in the mitochondria (organellar enzyme). The cytoplasmic lysyl-tRNA synthetase can also be separated from the organellar enzyme. There are two tRNAsPro in the cytoplasm; they can be charged by the cytoplasmic enzyme, but not by the organellar enzyme or the Escherichia coli enzyme. Chloroplasts contain, in addition to the two cytoplasmic tRNAsPro, one chloroplast-specific tRNAPro, which is not recognized by the cytoplasmic enzyme, but can be charged by the organellar or the E. coli enzyme. Mitochondria contain, in addition to the two cytoplasmic tRNAsPro, two mitochondria-specific tRNAsPro, which are not recognized by the cytoplasmic enzyme, but can be charged by the organellar or the E. coli enzyme. There are two tRNAsLys in the cytoplasm. Both can be charged by the cytoplasmic enzyme, but one can be charged by the organellar or E. coli enzyme. Chloroplasts contain in addition to one cytoplasmic tRNALys, one chloroplast-specific tRNALys which can only be charged by the organellar or E. coli enzyme. Mitochondria contain, in addition to one cytoplasmic tRNALys, one mitochondria-specific tRNALys which can only be charged by the organellar or E. coli enzyme.

Somatic embryogenesis and organogenesis induced on the immature zygotic embryo of sunflower (Helianthus annum L.) cultivated in vitro: role of the sugar.

Immature zygotic embryos of sunflower constitute an experimental system where the change of a single key factor (sucrose concentration) conditions the in vitro morphogenesis to either organogenesis (87 mM sucrose) or somatic embryogenesis (350 mM sucrose). Experiments with a variety of culture media differing in the sugar type and concentration, as well as osmotic pressure, indicate that a minimal threshold level of both, sugar supply and osmotic pressure, are required for somatic embryogenesis, but not organogenesis, to occur. The nature of the sugar used, though, was less important.

Sequences of initiator and elongator methionine tRNAs in bean mitochondria : Localization of the corresponding genes on maize and wheat mitochondrial genomes.

Two bean mitochondria methionine transfer RNAs, purified by RPC-5 chromatography and two-dimensional gel electrophoresis, have been sequenced usingin vitro post-labeling techniques.One of these tRNAs(Met) has been identified by formylation using anE. coli enzyme as the mitochondrial tRNAF (Met). It displays strong structural homologies with prokaryotic and chloroplast tRNAF (Met) sequences (70.1-83.1%) and with putative initiator tRNAm (Met) genes described for wheat, maize andOenothera mitochondrial genomes (88.3-89.6%).The other tRNA(Met), which is the mitochondrial elongator tRNAF (Met), shows a high degree of sequence homology (93.3-96%& with chloroplast tRNAm (Met), but a weak homology (40.7%) with a sequenced maize mitochondrial putative elongator tRNAm (Met) gene.Bean mitochondrial tRNAF (Met) and tRNAm (Met) were hybridized to Southern blots of the mitochondrial genomes of wheat and maize, whose maps have been recently published (15, 22), in order to locate the position of their genes.

Sequence and codon recognition of bean mitochondria and chloroplast tRNAsTrp: evidence for a high degree of homology.

Bean mitochondria and chloroplast tRNAsTrp, purified by RPC-5 chromatography and two-dimensional gel electrophoresis, have been sequenced using post-labeling techniques. The high degree of sequence homology between bean mitochondria and chloroplast tRNAsTrp shows that these two tRNAs are coded for by closely related genes which have probably evolved from a common ancestor gene. The anticodon of bean mitochondria tRNATrp is CmCA, which can recognize UGG (the codon for tryptophan in the universal code) and is complementary neither to UGA (which codes for tryptophan in mammalian and yeast mitochondria) nor to CGG (which could be a tryptophan codeword in plant mitochondria).