BACKGROUND:The standard treatment for older patients (aged ≥70 years) with localised, unresectable head and neck squamous-cell carcinoma is standard fractionated radiotherapy (SF-RT). However, its high toxicity and multiple fractions lead physicians to deliver tailored hypofractionated split-course radiotherapy (HSC-RT). The aim of the study was to compare these two radiotherapy methods in older patients. METHODS:This non-inferiority, multicentre, open-label, randomised controlled trial was done in 30 treating centres (cancer centres, university and general hospitals, and private clinics) across France and Monaco. Patients aged 70 years or older, assessed as frail by geriatric evaluation, with stage II-IV head and neck squamous-cell carcinoma and in curative intent were randomly assigned (1:1) to receive either SF-RT (70 Gy, 35 fractions over 7 weeks) or HSC-RT (55 Gy, 20 fractions, two courses of 2 weeks with 2 weeks stop). Randomisation was done by minimisation, and physicians and patients were not masked to the treatment group. The primary endpoint was the proportion of patients alive with complete locoregional response at 6 months, analysed in all randomly assigned patients (intention-to-treat population). The non-inferiority margin was set at 16%. The study was sponsored by the Groupe d'Oncologie Radiothérapie Tête et Cou (GORTEC) and is registered with ClinicalTrials.gov, NCT01864850. FINDINGS:Between Oct 21, 2013, and Aug 22, 2018, 102 patients were randomly assigned to the HSC-RT group and 100 patients to the SF-RT group. One patient in the HSC-RT group refused treatment and follow-up and so was excluded, resulting in 101 patients in the HSC-RT group. Median age was 82 years (IQR 77-86); 145 (72%) were male and 56 (28%) were female. Median follow-up for overall survival was 56·6 months (IQR 41-69). In the intent-to-treat population, 35 (35%) of 101 patients were alive with complete locoregional response at 6 months in the HSC-RT group versus 33 (33%) of 100 patients in the SF-RT group (difference +2%, 95% CI -11 to 15). In the per-protocol population, 35 (36%) of 97 patients were alive with complete locoregional response at 6 months in the HSC-RT group versus 33 (35%) of 95 patients in the SF-RT group (difference +1%, -12 to 15). Median overall survival was 13·0 months (95% CI 10·3 to 17·0) in the HSC-RT group versus 18·9 months (14·3 to 30·9) in the SF-RT group (hazard ratio 1·32, 95% CI 0·97 to 1·81). Eight patients died between radiotherapy start and 30 days after radiotherapy end (five [5%] in the HSC-RT group and three [3%] in the SF-RT group). One patient in the HSC-RT group had a grade 4 adverse event (kidney failure), as did four in the SF-RT group (two mucositis, one septic shock, and one hemiplegia). Acute adverse events grade 3-5 occurred in 33 (36%) of 91 patients in the HSC-RT group and in 44 (47%) of 93 patients in the SF-RT group (p=0·13; difference -11%, 95% CI -25 to 3). INTERPRETATION:Compared with SF-RT, HSC-RT did not decrease the 6-month complete locoregional response rate and could be an option for frail older patients. However, given the survival results, it should only be offered to patients deemed unsuitable for SF-RT after geriatric assessment. FUNDING:French programme PAIR-VADS 2011 (sponsored by the French National Cancer Institute, Fondation ARC, and Ligue Contre le Cancer), GEMLUC, and GEFLUC.
BACKGROUND:Data are needed on the effect of oxygen delivered through a high-flow nasal cannula, as compared with standard oxygen therapy, on intubation and mortality in patients with acute hypoxemic respiratory failure. METHODS:In this multicenter, open-label trial, we randomly assigned patients who had acute hypoxemic respiratory failure to receive high-flow-oxygen or standard-oxygen therapy. All the patients had a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 200 or less, a respiratory rate of more than 25 breaths per minute, and pulmonary infiltrate on chest imaging. The primary outcome was death by day 28. RESULTS:A total of 1116 patients underwent randomization. Of these patients, 1110 (556 in the high-flow-oxygen group and 554 in the standard-oxygen group) were included in the analysis. Mortality at day 28 was 14.6% (in 81 of 556 patients) in the high-flow-oxygen group and 14.6% (in 81 of 554 patients) in the standard-oxygen group (difference, -0.05 percentage points; 95% confidence interval [CI], -4.21 to 4.10; P = 0.98). The incidence of intubation by day 28 was 42.4% (in 236 of 556 patients) in the high-flow-oxygen group and 48.4% (in 268 of 554 patients) in the standard-oxygen group (difference, -5.93 percentage points; 95% CI, -11.78 to -0.08). Serious adverse events (cardiac arrest or pneumothorax) occurred during spontaneous breathing in 13 patients (2.3%) in the high-flow-oxygen group and in 6 patients (1.1%) in the standard-oxygen group. CONCLUSIONS:Among patients with acute hypoxemic respiratory failure, the use of oxygen delivered through a high-flow nasal cannula did not significantly reduce mortality at day 28. (Funded by the French Ministry of Health and Fisher and Paykel Healthcare; SOHO ClinicalTrials.gov number, NCT04468126.).
Background and ObjectivesDevelopmental and epileptic encephalopathies (DEEs) with early burst-suppression EEG (EIDEE-BS) are among the most severe neonatal epileptic syndromes, typically presenting in the first months of life with refractory seizures and profound neurodevelopmental impairment. Although variants in the KCNQ2, STXBP1, and SCN2A genes are recognized as major causes, the full genetic spectrum remains uncertain. We aimed to delineate the electroclinical characteristics, genetic etiologies, and long-term outcomes in a large MRI-negative EIDEE-BS cohort.MethodsWe retrospectively analyzed 110 patients with BS EEG enrolled from a database of 1,540 individuals with suspected genetic epilepsies (2008-2023). Clinical, EEG, and genetic data were systematically collected. Patients were stratified into 4 groups: KCNQ2, STXBP1, "other pathogenic variants," and "without a genetic diagnosis." EEG traces were reviewed independently, and outcomes were assessed through long-term follow-up.ResultsPathogenic or likely pathogenic variants were identified in 62.7% of patients and involved 23 genes, including 2 copy number variants. KCNQ2 (n = 24) and STXBP1 (n = 16) accounted for one-third of diagnoses, whereas SCN2A (n = 3) and KCNT1 (n = 2) were less frequent. In KCNQ2 cases, seizures and BS onset occurred earlier than in STXBP1 cases: mean 2 days vs 6 weeks for seizures and 3 days vs 2 months for BS, respectively. A typical BS pattern (bursts longer than suppressions) strongly correlated with KCNQ2 and STXBP1 variants. Novel associations were found with DPM1, GRIN2A, KCNT2, PIGO, PURA, WWOX, and candidate genes (KMT2E, SNAP25, and SYT1). Most variants were de novo heterozygous; however, recessive and X-linked inheritance patterns were also observed. Mortality was high (25%), primarily from status epilepticus and complications of severe disability. Most patients (72.5%) had persistent seizures at follow-up (a mean of 6.5 years), as well as profound intellectual disabilities, irrespective of genotype.DiscussionThis large series highlights the strong monogenic basis of EIDEE-BS. KCNQ2, STXBP1, and SCN2A were the most commonly affected genes. Early EEG features, particularly BS timing and morphology, can help anticipate the underlying genotype and guide precision therapy, including the early use of sodium channel blockers in selected cases. These findings support recent ILAE reclassification efforts and underscore the importance of comprehensive genomic testing for improved diagnosis and counseling.
France conducted 193 nuclear tests (both atmospheric and underground) from 1966 to 1996 in the Pacific. The mortality in a sub-cohort of male veterans (n=26,514) who were monitored for external radiation exposure during their participation in the tests has been studied for the period from 1966 to 2015. The mortality was compared to those of the French population using standardized mortality ratios (SMRs), then estimated according to dosimetry status using categorical regression models adjusted for attained age, calendar period, and military unit. “Non-null dosimetry” (at least one positive dosimetric result, i.e., higher than the threshold value of 0.2 mSv) was reported for 8% of the veterans. In total, 8,094 deaths were recorded. The all-cause and major causes SMRs were < 1. The SMR estimated for tumors was close to 1, i.e., the sub-mortality was lower than that of other major causes of death. There were non-significant excesses in the "non-null dosimetry" group relative to the "null dosimetry" group for deaths related to mesothelioma and thyroid, central nervous system, bone, and hematological malignancies. A sensitivity analysis performed on veterans (after the exclusion of health services) who wore their first dosimeter during atmospheric tests highlighted significant excess mortality for bone tumors, hematological malignancies and non-Hodgkin lymphomas. Further analyses should consider extended follow-up and include ionizing radiation doses and the dates of exposure.
TPS9614 Background: cSCC is the second most common skin cancer, predominantly affecting elderly individuals. Most cSCCs are diagnosed at an early stage and cured with surgery. Recurrences are usually detected during routine clinical examinations or imaging (lymph-node ultrasound, cervicothoracic CT scan). In patients considered at high-risk, local recurrence rates may reach up to 30%. To date, no randomized trial has established the optimal management of cSCCs at high risk of recurrence after complete resection, and indications for adjuvant radiotherapy are only based on local practices or retrospective studies showing variable and contradictory results. Methods: This ongoing randomized phase III trial (NCT06692556) compares the efficacy and safety of two commonly used strategies (adjuvant radiotherapy versus surveillance) in patients with cSCC at high risk of recurrence. Key eligibility criteria include age ≥ 18 years, histologically confirmed localized cSCC, complete surgical resection and high-risk of recurrence, defined as: 1) microscopic peri nerval involvement (PNI) with or without one additional risk factor, or 2) the presence of two or three risk factors (excluding microscopic PNI): immunosuppression, tumor diameter > 20 mm, specific location (lip/ear/temple), deep invasion (thickness > 6 mm or invasion beyond the subcutaneous fat), poor differentiation or desmoplasia. The primary endpoint is recurrence free-survival, defined as the time from the date of randomization to the date of first documented relapse (local, regional or metastatic) or the date of death. Secondary endpoints include local and metastatic recurrence-free survival, overall survival, safety and quality of life (EORTC QLQ-C30 and QLQ-ELD14). Exploratory objectives include progression-free survival after treatment for local recurrence in the surveillance arm. A total of 120 events will provide 80% power to detect a significant improvement of the recurrence-free survival in favor of the radiotherapy arm (HR=0.6) at a 2-sided alpha risk of 5%. Considering a two-years recurrence-free survival rate of 60% in the control arm, an accrual period of 18 months, 36 months follow-up for the last patient, and 10% of non-evaluable patients, a total of 266 patients is required (133 par arm). Since the start of recruitment (February 2025), 38 patients have been randomized. 35 French health institutions will contribute to recruitment. Clinical trial information: NCT06692556 .
