Clinical characteristic and survival outcomes of patients with advanced NSCLC according to KRAS mutational status in the French real-life ESME cohort.

PURPOSE: The RAS/MEK signaling pathway is essential in carcinogenesis and frequently altered in non-small-cell lung cancer (NSCLC), notably by KRAS mutations (KRASm) that affect 25%-30% of non-squamous NSCLC. This study aims to explore the impact of KRASm subtypes on disease phenotype and survival outcomes. PATIENTS AND METHODS: We conducted a retrospective analysis of the French Epidemiological Strategy and Medical Economics database for advanced or metastatic lung cancer from 2011 to 2021. Patient demographics, histology, KRASm status, treatment strategies, and outcomes were assessed. RESULTS: Of 10 177 assessable patients for KRAS status, 17.6% had KRAS p.G12C mutation, 22.6% had KRAS non-p.G12C mutation, and 59.8% were KRASwt. KRASm patients were more often smokers (96.3%) compared with KRASwt (85.8%). A higher proportion of programmed death-ligand 1 ≥50% was found for KRASm patients: 43.5% versus 38.0% (P < 0.01). KRASm correlated with poorer outcomes. First-line median progression-free survival was shorter in the KRASm than the KRASwt cohort: 4.0 months [95% confidence interval (CI) 3.7-4.3 months] versus 5.1 months (95% CI 4.8-5.3 months), P < 0.001. First-line overall survival was shorter for KRASm than KRASwt patients: 12.6 months (95% CI 11.6-13.6 months) versus 15.4 months (95% CI 14.6-16.2 months), P = 0.012. First-line chemoimmunotherapy offered better overall survival in KRAS p.G12C (48.8 months) compared with KRAS non-p.G12C (24.0 months) and KRASwt (22.5 months) patients. Second-line overall survival with immunotherapy was superior in the KRAS p.G12C subgroup: 12.6 months (95% CI 8.1-18.6 months) compared with 9.4 months (95% CI 8.0-11.4 months) for KRAS non-p.G12C and 9.6 months (8.4-11.0 months) for KRASwt patients. CONCLUSION: We highlighted distinct clinical profiles and survival outcomes according to KRASm subtypes. Notably KRAS p.G12C mutations may provide increased sensitivity to immunotherapy, suggesting potential therapeutic implications for sequencing or combination of therapies. Further research on the impact of emerging KRAS specific inhibitors are warranted in real-world cohorts.

[Sotorasib treatment in KRAS G12C-mutated non-small cell lung cancer: Experience in the Tours university hospital]. / Traitement par sotorasib en autorisation d'accès précoce dans le cancer pulmonaire non à petites cellules mutées KRAS G12C : expérience du centre hospitalier régional universitaire de Tours.

Following the CodeBreak 100 study, since 2021 sotorasib has been available in France, with authorization for early access in treatment of non-small cell lung cancer with a KRAS G12C mutation. Our retrospective observational study was designed to determine the efficacy and safety of sotorasib under real-life conditions in patients treated at the Tours CHRU. Our study of 15 patients showed sotorasib to be effective in 47% of cases, with overall survival of 4 months and median progression-free survival of 5.5 months for responders. Tumor control was achieved in 7/8 (87%) of patients with PS of 0 or 1 and in 1/7 (14%) of patients with a PS of 2 or greater. Grade 3 acute hepatitis occurred in 3/15 patients (20%). While sotorasib is an interesting therapeutic option, with efficacy that seems better in patients in good general condition, it entails a possible risk of drug-induced hepatitis, which remains to be specified in dedicated studies.

[Primary pleural epithelioid hemangioendothelioma, an often-misdiagnosed rare tumor]. / Hémangioendothéliome épithélioïde pleural, une tumeur rare de diagnostic difficile : à propos d'un cas et revue de la littérature.

INTRODUCTION: Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor that develops in various organs. Primary pleural epithelioid hemangioendothelioma is an exceptional occurrence, with only forty cases reported in the literature. On account of its rarity, pleural EHE is difficult to diagnose. Differential diagnoses such as malignant pleural mesothelioma or lung carcinoma are often initially suspected. METHODS: We herein describe the case of a 52-year-old man presenting with a primary pleural epithelioid hemangioendothelioma revealed by thoracic pain and having evolved for three months. Having reviewed the literature, we consider the clinical presentation and diagnosis modalities of this rare tumor. RESULTS: After an initial diagnosis of lung carcinoma, an ultrasound-guided biopsy was performed, confirming the diagnosis of pleural EHE in our patient. Ours is the first case of pleural EHE to be diagnosed with ultrasound-guided echography. Presentation of pleural EHE is often clinically and radiologically nonspecific. Most diagnoses are obtained by thoracoscopy, which allows for targeted biopsies and evacuation of pleural effusion. CONCLUSION: The diagnostic process for this rare tumor must be rigorous. Ultrasound-guided biopsy may be considered, provided that the lesions are accessible.

Final results of the IFCT-0803 study, a phase II study of cetuximab, pemetrexed, cisplatin, and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non-squamous, non-small-cell lung cancer.

PURPOSE: Roughly 20% of patients with non-small-cell lung cancer exhibit locally advanced, unresectable, stage III disease. Concurrent platinum-based chemoradiotherapy is the backbone treatment, which is followed by maintenance immunotherapy, yet with poor long-term prognosis. This phase II trial (IFCT-0803) sought to evaluate whether adding cetuximab to cisplatin and pemetrexed chemoradiotherapy would improve its efficacy in these patients. MATERIALS AND METHODS: Eligible patients received weekly cetuximab (loading dose 400mg/m2 day 1; subsequent weekly 250mg/m2 doses until two weeks postradiotherapy). Chemotherapy comprised cisplatin (75mg/m2) and pemetrexed (500mg/m2), both delivered on day 1 of a 21-day cycle of maximally four. Irradiation with maximally 66Gy started on day 22. Disease control rate at week 16 was the primary endpoint. RESULTS: One hundred and six patients were included (99 eligible patients). Compliance exceeded 95% for day 1 of chemotherapy cycles 1 to 4, with 76% patients receiving the 12 planned cetuximab doses. Maximal grade 3 toxicity occurred in 63% patients, and maximal grade 4 in 9.6%. The primary endpoint involving the first 95 eligible patients comprised two (2.1%) complete responses, 57 (60.0%) partial responses, and 27 (28.4%) stable diseases. This 90.5% disease control rate (95% confidence interval [95% CI]: 84.6%-96.4%) was achieved at week 16. After median 63.0-month follow-up, one-year and two-year survival rates were 75.8% and 59.5%. Median overall survival was 35.8months (95% CI: 23.5-NR), and median progression-free survival 14.4months (95% CI: 11.2-18.8), with one-year and two-year progression-free survival rates of 57.6% and 34.3%. CONCLUSION: These survival rates compare favourably with published data, thus justifying further development of cetuximab-based induction chemoradiotherapy.

RADIORYTHMIC: Phase III, Opened, Randomized Study of Postoperative Radiotherapy Versus Surveillance in Stage IIb/III of Masaoka Koga Thymoma after Complete Surgical Resection.

INTRODUCTION: Thymomas are rare intrathoracic malignancies that may be aggressive and difficult to treat. Knowledge and level of evidence for treatment strategies are mainly based on retrospective studies or expert opinion. Currently there is no strong evidence that postoperative radiotherapy after complete resection of localized thymoma is associated with survival benefit in patients. RADIORYTHMIC is a phase III, randomized trial aiming at comparing postoperative radiotherapy versus surveillance after complete resection of Masaoka-Koga stage IIb/III thymoma. Systematic central pathologic review will be performed before patient enrollment as per the RYTHMIC network pathway. PATIENTS AND METHODS: Three hundred fourteen patients will be included; randomization 1:1 will attribute either postoperative radiotherapy (50-54 Gy to the mediastinum using intensity-modulated radiation therapy or proton beam therapy) or surveillance. Stratification criteria include histologic grading (thymoma type A, AB, B1 vs B2, B3), stage, and delivery of preoperative chemotherapy. Patient recruitment will be mainly made through the French RYTHMIC network of 15 expert centers participating in a nationwide multidisciplinary tumor board. Follow-up will last 7 years. The primary endpoint is recurrence-free survival. Secondary objectives include overall survival, assessment of acute and late toxicities, and analysis of prognostic and predictive biomarkers. RESULTS: The first patient will be enrolled in January 2021, with results expected in 2028.

Somatic profile in lung cancers is associated to reproductive factors in never-smokers women: Results from the IFCT-1002 BioCAST study.

BACKGROUND: Lung cancer in women is on the rise, with a higher proportion occurring in lifelong never-smokers. Lung cancer in never-smokers (LCINS) exhibits a high frequency of driver oncogene alterations. In this study, we aimed to investigate whether exposure to reproductive factors in women with LCINS may modulate the molecular pattern. METHODS: All newly diagnosed LCINSs were included in a prospective, observational study (IFCT-1002 BioCAST). Each patient responded to a questionnaire including reproductive factors. Biomarker test results were also collected. RESULTS: Two hundred and sixty women were included in this analysis, and 166 alterations were characterized. EGFR mutation frequency proved greater among patients with late menarche (74% in age>14 vs. 40% and 41% for 12-14 and ≤12 years, respectively; P=0.020) and tended to decrease with increasingly late age at menopause. In multivariate analysis, EGFR mutation frequency increased by 23% per increment of 1 year of age at menarche (P=0.048), and by 9% for each year at age at first birth (P=0.035). ALK alteration frequency was greater in women with high parity (50% in≥5 vs. 12% and 7% for 1-4 and nulliparity, respectively; P=0.021). CONCLUSION: In a cohort of women LCINSs, female hormonal factors appear to impact molecular pattern.

An integrated protocol for targeted mutagenesis with CRISPR-Cas9 system in the pea aphid.

CRISPR-Cas9 technology is a very efficient functional analysis tool and has been developed in several insects to edit their genome through injection of eggs with guide RNAs targeting coding sequences of genes of interest. However, its implementation in aphids is more challenging. Aphids are major pests of crops worldwide that alternate during their life cycle between clonality and sexual reproduction. The production of eggs after mating of sexual individuals is a single yearly event and is necessarily triggered by a photoperiod decrease. Fertilized eggs then experience an obligate 3-month diapause period before hatching as new clonal colonies. Taking into consideration these particularities, we developed in the pea aphid Acyrthosiphon pisum a step-by-step protocol of targeted mutagenesis based on the microinjection within fertilized eggs of CRISPR-Cas9 components designed for the editing of a cuticular protein gene (stylin-01). This protocol includes the following steps: i) the photoperiod-triggered induction of sexual morphs (2 months), ii) the mating and egg collection step (2 weeks), iii) egg microinjection and melanization, iv) the 3-month obligate diapause, v) the hatching of new lineages from injected eggs (2 weeks) and vi) the maintenance of stable lineages (2 weeks). Overall, this 7-month long procedure was applied to three different crosses in order to estimate the impact of the choice of the genetic combination on egg production dynamics by females as well as hatching rates after diapause. Mutation rates within eggs before diapause were estimated at 70-80%. The hatching rate of injected eggs following diapause ranged from 1 to 11% depending on the cross and finally a total of 17 stable lineages were obtained and maintained clonally. Out of these, 6 lineages were mutated at the defined sgRNAs target sites within stylin-01 coding sequence, either at the two alleles (2 lineages) or at one allele (4 lineages). The final germline transmission rate of the mutations was thus around 35%. Our protocol of an efficient targeted mutagenesis opens the avenue for functional studies through genome editing in aphids.

[Immunotherapy in non-small cell lung cancer: inhibition of PD1/PDL1 pathway]. / Immunothérapie dans le cancer bronchique non à petites cellules: inhibition de la voie PD1/PDL1.

Despite recent advances in targeted therapy of non-small cell lung cancer (NSCLC), many patients do not benefit from these therapies. Inhibition of PD1/PDL1 is an interesting therapeutic target which restores the immune system against tumor cells. PD1 is located on lymphocytes and PDL1 on the antigen presenting cells. PD1 and PDL1 are co-inhibition molecules and their interaction results in immune tolerance against tumor cells. Anti-PD1 and anti-PDL1 antibodies have been developed to restore immune system in solid cancer including NSCLC. In phase I, studies assessing nivolumab, an anti-PD1 antibody, objective responses were observed in 13 to 18% of NSCLC patients failing previous treatment. The data obtained with anti-PDL1 antibodies is similar with objective responses ranging from 6 to 22%. The encouraging results of phase I/II studies must be confirmed in ongoing phase III studies. Anti-PD1 and anti-PDL1 antibodies exposed to new adverse events including auto-immune diseases whose support is not codified. Questions about treatment duration and criteria evaluation are not resolved. These treatments pave the way for immunomodulation in NSCLC treatment.

[Effect of tinzaparin on survival in non-small-cell lung cancer after surgery. TILT: tinzaparin in lung tumours]. / Effet de la tinzaparine sur la mortalité du cancer bronchique non à petites cellules opéré.

BACKGROUND: Experimental and clinical findings suggest that low molecular-weight heparins may improve overall survival in patients with cancer. The evidence is still limited and additional studies are needed to confirm these preliminary findings. METHODS: Patients with completely resected stage I, II or IIIA (T3N1) histologically confirmed non-small-cell lung cancer will be included in a prospective, controlled, randomized, multicenter open trial. Patients in the control group will receive usual postoperative care including chemotherapy when indicated. Patients in the experimental group will receive tinzaparin given subcutaneously as a daily 100 IU/kg dose for 90 days along with usual postoperative care. Patients will be followed-up for three to eight years. Main end-point is the overall survival. Five hundred and fifty patients are needed to demonstrate a 10% absolute increase in survival in the experimental group. EXPECTED RESULTS: A 10% absolute increase in the survival rate is expected in the patients receiving tinzaparin.

Acute hepatitis B after autologous stem cell transplantation in a man previously infected by hepatitis B virus.

We report a case of acute hepatitis B after autologous stem cell transplantation (ASCT) in a patient with low-grade non-Hodgkin's lymphoma. At diagnosis of the hematological disease, the patient had the characteristic serology of a previous hepatitis B infection, being Ag HBs negative, hepatitis B virus core antibody positive (anti-HBC) and hepatitis B virus surface antibody weakly positive. He developed fatal hepatitis B after autologous stem cell transplantation, suggesting reactivation consequent to immunosuppression.

[Symptomatic myocardial bridges. Apropos of 6 cases]. / Ponts myocarardiques symptomatiques. Apropos de 6 cas.

Myocardial bridge is often considered to be a simple anatomical variation often observed during coronary angiography. The responsibility of this condition for myocardial ischaemia is however uncommon and the physiopathological mechanisms are not well understood. The authors report 6 cases of myocardial bridge associated with myocardial infarction of unstable angina. The main features of this condition are discussed with respect to a review of the literature. Patients are usually young and male; the left anterior descending artery is the most commonly affected vessel: factors triggering ischaemia are discussed: coronary spasm, tachycardia and thrombosis at the site of the myocardial bridge. The diagnosis can only be made by coronary angiography showing reduction of the systolic diameter of the artery which may be accentuated by certain pharmacological tests such as injection of glyceryl trinitrate as used in the series.