The Hospital Universitario Ramón y Cajal is a public general hospital located in the Valverde neighborhood, in Madrid, Spain, part of the hospital network of the Servicio Madrileño de Salud.It is one of the healthcare institutions associated to the University of Alcalá for the purpose of clinical internship.
Lurbinectedin in combination with irinotecan showed synergistic antitumor activity in preclinical studies. A phase I/II trial (NCT02611024) evaluated this combination in patients with advanced solid tumors. The phase II stage evaluated the antitumor activity of the recommended dose (RD) (lurbinectedin 2.0 mg/m2 on Day (D)1 plus irinotecan 75 mg/m2 on D1 and D8 q3wk with primary granulocyte colony-stimulating factor prophylaxis) in five tumor-specific cohorts. This pooled analysis describes the safety profile of this combination from 233 patients with different advanced solid tumors treated at the RD. Adverse events (AEs) and laboratory abnormalities were graded using NCI-CTCAE v.4. The most frequent AEs (any grade) related to treatment were fatigue (71
BACKGROUND:Treatment for patients with bilateral adrenal tumours and cortisol excess is not standardised and poses a therapeutic dilemma. Untreated cortisol excess is associated with cardiometabolic morbidity and mortality, but bilateral adrenalectomy causes adrenal insufficiency and possibly life-threatening adrenal crises. Data on cardiovascular outcomes by treatment modality are scarce. In this study we aimed to evaluate mid-term and long-term clinical and biochemical outcomes in patients with bilateral adrenal tumours and cortisol excess by treatment strategy and diagnosis. METHODS:This retrospective, international cohort study (in 30 centres across 10 countries in Europe plus Singapore and the USA) included patients with bilateral adrenal tumours of 10 mm or larger, post-dexamethasone serum cortisol concentration of 50 nmol/L or higher, and at least 36 months of follow-up, with data collection beween Feb 2, 2024, and Jan 31, 2025. Patients were excluded if they had adrenocorticotropin hormone (ACTH)-dependent cortisol excess, ACTH-dependent nodular adrenal hyperplasia, partial glucocorticoid resistance syndrome, a diagnosis inconsistent with benign adrenocortical lesions, or received systemic oral or intravenous glucocorticoids other than replacement therapy following adrenalectomy. Primary endpoints were all-cause mortality and clinical and biochemical remission rates. Secondary endpoints were the incidence of cardiovascular events, prevalence of vascular and metabolic comorbidities, and incidence of adrenal crises. FINDINGS:Of 629 patients who were diagnosed between Jan 1, 2000, and Jan 31, 2022, 105 (17%) had Cushing's syndrome and 524 (83%) had mild autonomous cortisol secretion (MACS), median age was 62 years (IQR 54·0-68·0), and 426 (68%) were female. 85 (81%) of 105 patients with Cushing's syndrome underwent surgery, and 384 (73%) of 524 patients with MACS received non-specific symptomatic treatment (ie, never underwent adrenalectomy or received steroidogenesis inhibitors). Over a median follow-up of 6·8 years, biochemical remission was achieved in 46 (45%) of 102 patients with Cushing's syndrome and in 67 (13%) of 517 patients with MACS. In both groups, 7% of patients died (Cushing's syndrome: seven of 105; MACS: 38 of 524) and 12% (13 of 105) of patients with Cushing's syndrome and 16% (82 of 524) of those with MACS had at least one cardiovascular event, without substantial differences across treatments. Smoking emerged as key modifiable mortality and cardiovascular risk factor in all patients, and in patients with MACS who only received non-specific symptomatic therapy, post-dexamethasone cortisol was also associated with increased mortality. Bilateral adrenalectomy led to full biochemical remission, few non-fatal adrenal crises, and improved arterial hypertension. Unilateral adrenalectomy and steroidogenesis inhibitors yielded heterogeneous biochemical outcomes and no substantial comorbidity improvement. Non-specific symptomatic treatment in MACS was associated with worsening of all investigated comorbidities. INTERPRETATION:Although mortality and cardiovascular event rates were similar across treatments, surgery led to better biochemical control and more favourable comorbidity outcomes. FUNDING:None.
Enzalutamide (ENZA), a next-generation non-steroidal androgen receptor (AR) inhibitor, plays a pivotal role in the management of both hormone-sensitive (HSPC) and androgen deprivation-resistant prostate cancer (ARPC). This paper presents real-world clinical outcomes of ENZA in a subgroup of metastatic HSPC (mHSPC) patients included in the ARON-3 study. Clinical information was extracted retrospectively from medical records at 29 cancer centres in 9 countries worldwide. Overall Survival (OS) was calculated from starting ENZA to death from any cause and the time on treatment (ToT) from ENZA initiation to discontinuation for any reason. The Kaplan–Meier method was used to estimate OS and ToT. PSA90 was defined as a ≥90% PSA reduction from baseline, and PSA0.2 as the achievement of an ultra-low PSA level ≤0.2 ng/ml. Adverse events (AEs) were categorised according to Common Terminology Criteria for Adverse Events v5.0. The study population comprised 424 patients treated with ENZA for mHSPC, of whom 80 (19%) had lymph node-only metastases, 265 (63%) bone-only metastases, and 50 (12%) visceral metastases. 273 patients (64%) had synchronous metastases and 151 (36%) had developed metachronous metastases. A total of 228 patients were diagnosed with low-volume disease, and 196 patients (46%) with high-volume disease. The median ToT was 31.8 months, and the median OS was not reached. The median time to PSA90 (achieved in 76% of patients) and PSA0.2 (59% of patients) was 6.0 months and 8.3 months, respectively. Statistically significant associations were identified between lymph node-only patterns, PSA90 and ultra-low PSA responses, and longer treatment duration and better overall survival. Grade 3–4 AEs were observed in 9% of patients <70 years and in 10% ≥70 years. Real-world clinical practice corroborates the findings from clinical trials, confirming the effectiveness and safety of ENZA in mHSPC patients.
Background:In recent years, generative artificial intelligence and large language models (LLMs) have rapidly advanced, offering significant potential to transform medical education. Several studies have evaluated the performance of chatbots on multiple-choice medical examinations. Objective:The study aims to assess the performance of two LLMs-GPT-4o and OpenAI o1-on the Médico Interno Residente (MIR) 2024 examination, the Spanish national medical test that determines eligibility for competitive medical specialist training positions. Methods:A total of 176 questions from the MIR 2024 examination were analyzed. Each question was presented individually to the chatbots to ensure independence and prevent memory retention bias. No additional prompts were introduced to minimize potential bias. For each LLM, response consistency under verification prompting was assessed by systematically asking, "Are you sure?" after each response. Accuracy was defined as the percentage of correct responses compared to the official answers provided by the Spanish Ministry of Health. It was assessed for GPT-4o, OpenAI o1, and, as a benchmark, for a consensus of medical specialists and for the average MIR candidate. Subanalyses included performance across different medical subjects, question difficulty (quintiles based on the percentage of examinees correctly answering each question), and question types (clinical cases vs theoretical questions; positive vs negative questions). Results:Overall accuracy was 89.8% (158/176) for GPT-4o and 90% (160/176) after verification prompting, 92.6% (163/176) for OpenAI o1 and 93.2% (164/176) after verification prompting, 94.3% (166/176) for the consensus of medical specialists, and 56.6% (100/176) for the average MIR candidate. Both LLMs and the consensus of medical specialists outperformed the average MIR candidate across all 20 medical subjects analyzed, with ≥80% LLMs' accuracy in most domains. A performance gradient was observed: LLMs' accuracy gradually declined as question difficulty increased. Slightly higher accuracy was observed for clinical cases compared to theoretical questions, as well as for positive questions compared to negative ones. Both models demonstrated high response consistency, with near-perfect agreement between initial responses and those after the verification prompting. Conclusions:These findings highlight the excellent performance of GPT-4o and OpenAI o1 on the MIR 2024 examination, demonstrating consistent accuracy across medical subjects and question types. The integration of LLMs into medical education presents promising opportunities and is likely to reshape how students prepare for licensing examinations and change our understanding of medical education. Further research should explore how the wording, language, prompting techniques, and image-based questions can influence LLMs' accuracy, as well as evaluate the performance of emerging artificial intelligence models in similar assessments.
Everolimus is the only approved therapy for patients with advanced neuroendocrine tumors (NET) of lung and thymus and new treatment options are urgently needed. Expression of somatostatin receptor 2 (SSTR2) is frequently seen in functional imaging in lung-NETs opening the opportunity to treat SSTR2 positive patients with radioligand therapies (RLT). Retrospective data suggest a potential meaningful benefit of RLT directed to SSTR2 in lung-NET patients. The LEVEL trial is a randomized, open-label, phase III international trial of 177Lu-edotreotide versus everolimus in patients with progressive, locally advanced or metastatic, and well/moderately differentiated NETs of lung (typical/atypical) or thymic origin. Patients could be treatment-naïve or have progressed (PD) on somatostatin analogues or ≤ 2 additional systemic treatments. Prior RLT or mTOR inhibitors are not permitted. Eligible patients are randomly assigned 3:2 to 6 cycles of 177Lu-edotreotide (total administered activity 7.5 ± 0.7 GBq / cycle) or to oral everolimus 10 mg once daily until PD or unacceptable toxicity. Only patients with positivity in somatostatin receptor imaging will be included. CT or MRI scans are performed every 12 weeks until PD. Blood samples are analyzed at baseline, at 1st tumor assessment, and at PD for pharmacodynamic endpoints. Archival tumor tissue samples will be analyzed for ancillary studies. The primary endpoint is progression-free survival (PFS) according to RECIST v1.1 based on local investigator assessment. Secondary endpoints include overall survival, overall response rate, safety, and quality of life (EORTC QLQ-C30). The expected sample size is 120 patients to demonstrate statistical significant risk reduction of 46.4 www.clinicaltrials.gov : NCT05918302 (June 23rd, 2023).
