The Design and Rationale of a Phase 2b, Randomized, Double-Blinded, and Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Lomecel-B in Older Adults with Frailty.

BACKGROUND: Frailty in older adults is a rapidly growing unmet medical need. It is an aging-related syndrome characterized by physical decline leading to higher risk of adverse health outcomes. OBJECTIVES: To evaluate the efficacy of Lomecel-B, an allogeneic medicinal signaling cell (MSC) formulation, in older adults with frailty. DESIGN: This multicenter, randomized, parallel-arm, double-blinded, and placebo-controlled phase 2b trial is designed to evaluate dose-range effects of Lomecel-B for frailty on physical functioning, patient-reported outcomes (PROs), frailty status, and biomarkers. SETTING: Eight enrolling clinical research centers, including the Miami Veterans Affairs Medical Center. PARTICIPANTS: Target enrollment is 150 subjects aged 70-85 years of any race, ethnicity, or gender. Enrollment criteria include a Clinical Frailty Score of 5 ("mild") or 6 ("moderate"), a 6MWT of 200-400 m, and serum tumor necrosis factor-alpha (TNF-α) ≥2.5 pg/mL. INTERVENTION: A single intravenous infusion of Lomecel-B (25, 50, 100, or 200 million cells) or placebo (N=30/arm). Patients are followed for 365 days for safety, and the efficacy assessments performed at 90, 180, and 270 days. MEASUREMENTS: The primary endpoint is change in 6MWT in the Lomecel-B-treated arms versus placebo at 180 days post-infusion. Secondary and exploratory endpoints include change in: 6MWT and other physical function measures at all time points; PROs; frailty status; cognitive status; and an inflammatory biomarkers panel. A pre-specified sub-study examines vascular/endothelial biomarkers. Safety is evaluated throughout the trial. RESULTS: The trial is conducted under a Food and Drug Administration Investigational New Drug (IND), with Institutional Review Board approval, and monitoring by an NIH-appointed independent Data Safety Monitoring Board. CONCLUSION: This clinical trial investigates the use of a regenerative medicine strategy for frailty in older adults. The results will further the understanding of the potential for Lomecel-B in the geriatric condition of frailty.

Acute nonlymphoblastic leukemia in children treated for acute lymphoblastic leukemia with an intensive regimen including teniposide.

Some cases of conversion from acute lymphoblastic leukemia (ALL) to acute nonlymphoblastic leukemia (ANLL) at relapse have been reported recently. We report three cases initially diagnosed as having ALL and showing morphological, cytochemical, and immunophenotypic features of ANLL at relapse (lineage switch). Conversion was observed among 14 patients who developed bone marrow relapse while undergoing intensive treatment with our ALL protocol, which includes teniposide, and that had been administered to 62 patients. The three cases converted at first relapse, with a mean time of 20 months (13-29 months). Clinical and immunologic characteristics of T-cell leukemia were present in one patient. Changes documented in cytogenetic studies are discussed. The underlying mechanisms for the lineage switch remain unclear as does its relation with mixed lineage leukemias, but we believe that drugs employed in our therapy protocol could have had an influence on this conversion.

Hepatosplenic candidiasis in children with acute leukemia.

Three children with acute lymphoblastic leukemia developed disseminated fungal disease predominantly involving the liver and spleen. The three patients were undergoing induction chemotherapy and had neutropenia when they presented prolonged fever not responsive to antibiotics. Once neutropenia was recovered, hepatosplenomegaly leukocytosis, elevated serum alkaline phosphatase, and hypoechoic areas in the spleen and liver ultrasound were observed. All fungal blood cultures were negative, with the diagnosis being confirmed by histologic study. One of the patients died without achieving control of the candidiasis. The other two patients received prolonged antifungal treatment concurrently with chemotherapy and both are alive, one of them cured and in complete remission. The increasing frequency of this infection in recent years and the importance of a prompt and prolonged administration of antifungal therapy to obtain the cure are discussed.

[Mitral valve replacement in children with a Björk-Shiley prosthesis]. / Reemplazo valvular mitral en niños con protésis de Björk-Shiley.

This report documents our experience with mitral valve replacement in children. Between 1978 and 1982, 30 replacements have been performed in patients under 15 years of age. Twenty seven patients (90%) with rheumatic heart disease and 3 (10%) had congenital disease. Their functional capacity prior to operation was as follows: Nine patients fell into class II, 18 into class III and 2 into class IV. Preoperative cardiac catheterization, was undertaken in 26 patients, the mean pulmonary arterial wedge pressure was 27.4 +/- 8 mmHg, the pulmonary artery mean pressure was 48 +/- 20 mmHg, the left ventricular end diastolic pressure was 11.7 +/- 5.6 mmHg. One child died in the operative period. Twenty six patients (90%) have been followed for a mean period of 22.7 months. Late mortality occurred in three patients (11%). Bacterial endocarditis, thromboembolism and valve maldisfunction were not present. The post operative NYHA functional class was as follows: twenty two children fell into class I, and one patient fell into class II. The actuarial survival rate 5 years after operation was 79%. We believe that the Björk-Shiley prosthesis offer excellent results in children when repair of the natural valve is not possible.

Reemplazo valvular mitral en ninos con protesis de Bjork-Shiley. / Mitral valve replacement in children with Bjork-Shiley prosthesis

Se analiza la experiencia con protesis de Bjork-Shiley en ninos. Entre enero de 1978 y junio de 1982 se efectuaron 30 reemplazos valvulares en ninos con edad promedio de 13 anos. En 27 pacientes (90%), la lesion era reumatica y en 3 casos (10%) lo era congenita. La clase funcional pre-operatoria fue: clase II en 9 pacientes, clase III en 18 pacientes y clase IV en 2 casos. De este lote se efectuo cateterismo cardiaco preoperativo en 26 pacientes, siendo la PCP de 27.4 +/- 8 mmHg, la presion media de la arteria pulmonar de 48 +/- 20 mmHg y la presion diastolica final del ventriculo izquierdo de 11.7 +/- 5.6 mmHg. La mortalidad operatoria fue de un caso (3.3%). De los 29 sobrevivientes se efectuo seguimiento en 26 casos (90%) con promedio de 22.7 meses. Hubo 3 muertes tardias (11%). No se observaron trombosis de la protesis, embolismo periferico ni endocarditis. De los 23 pacientes sobrevivientes, 22 pasaron a clase funcional I y un caso a clase II. La sobrevida actuarial a 5 anos es de 79%. Concluimos que el reemplazo con protesis de Bjork-Shiley en ninos es una muy buena alternativa cuando no es posible efectuar plastia y reconstruccion de la valvula mitral