ABSTRACT
BACKGROUND: The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the different targets and payloads, we evaluated the safety and efficacy of SG + EV in a phase I trial in mUC (NCT04724018). PATIENTS AND METHODS: Patients with mUC and Eastern Cooperative Oncology Group performance status ≤1 who had progressed on platinum and/or immunotherapy were enrolled. SG + EV were administered on days 1 + 8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities during cycle 1. The number of patients treated at each of four pre-specified dose levels (DLs) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival, and overall survival were secondary endpoints. RESULTS: Between May 2021 and April 2023, 24 patients were enrolled; 1 patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41-88 years); 11 patients received ≥3 lines of therapy. Seventy-eight percent (18/23) of patients experienced grade ≥3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase II doses are SG 8 mg/kg with EV 1.25 mg/kg with granulocyte colony-stimulating factor support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% confidence interval 47% to 87%) with three complete responses; three patients had progressive disease as best response. With a median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months. CONCLUSIONS: The combination of SG + EV was assessed at different DLs and a safe dose for phase II was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted.
Subject(s)
Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal , Camptothecin/analogs & derivatives , Carcinoma, Transitional Cell , Immunoconjugates , Urinary Bladder Neoplasms , Humans , Adult , Middle Aged , Aged , Aged, 80 and over , Bayes Theorem , Urinary Bladder Neoplasms/drug therapy , Immunoconjugates/adverse effectsABSTRACT
BACKGROUND: The pancreas is an exo-endocrine organ that undergoes rapid autolysis soon after death, which limits its utility in academics and research. The timeline of autolytic changes of pancreatic islets and its immunoreactivity is limited in the literature. Decay score has been used to grade the autolytic changes in organs like the brain, lung and liver. However, reports are not available in the pancreas/pancreatic islets. Knowledge regarding the decay score may be used as a torchbearer for the immunoreactivity of human pancreatic islets in autopsy cases. The present study is aimed to provide an optimal cut-off time based on the decay score before which pancreatic specimens should be collected for the purpose of immunohistochemical studies (IHC) of pancreatic islets. MATERIALS AND METHODS: Serial sections of 20 adult human pancreases obtained from the autopsy were subjected to haematoxylin and eosin (H&E) and immunohistochemical staining. Autolytic changes of pancreatic islets were graded by using decay score in H&E sections, which was compared with the results of the immunohistochemical reactivity of pancreatic islets in IHC sections. RESULTS AND CONCLUSIONS: Pancreatic islets immunoreactivity was found to be well preserved in the samples collected early within 9 hours with a decay score of less than 1.4. There was an inverse relation of decay score and immunoreactivity of pancreatic islets. The decay score of less than 1.4 has better-preserved immunoreactivity than having more than 1.4. This knowledge will help researchers working in the field of the endocrine pancreas.
Subject(s)
Islets of Langerhans , Adult , Autopsy , Humans , Liver , Pancreas , Staining and LabelingABSTRACT
Fifty children in the age-group 1.75-10 years, admitted for cure of strabismus, were anaesthetised with intramuscular ketamine. Half the patients, at random, were given intravenous atropine, while anaesthetised, 5 minutes before operative interference. ECG recording of Lead 2 showed an oculacardiac dysthythmic response to muscle pull in 19 of the 25 unatropinised patients. The atropinised patients failed to show evidence of muscle induced dysrhythmia in any of the subjects (0%) The 25 control traces in the atropinised subjects showed no dysrhythmia after 5 minutes, but the possible immediate transitory dysrhythmic effects of atropine in the presence of ketamine anaesthesia is the subject of further study.
