Real-world outcomes of treatment for acute lymphoblastic leukemia during adolescence in a financially restricted environment: Results at a single center in Latin America.

OBJECTIVE: There is a paucity of the studies of adolescents with acute lymphoblastic leukemia (ALL). This is more noticeable in low- and middle-income countries. The international 5-year event-free survival (EFS) and overall survival (OS) for this age group is around 80%, with pediatric-inspired protocols offering better results. METHODS: A retrospective analysis of adolescents aged 16-20 diagnosed with ALL during the period 2004-2015 treated with a high-risk pediatric protocol at an academic center from a middle-income country was performed. Five-year OS and EFS were estimated by the Kaplan-Meier analysis. Hazard ratios of relapse and death were estimated by the Cox regression model. RESULTS: Five-year EFS and OS for 57 adolescents were 23.3% and 48.9%, respectively. From the 41 patients who achieved complete remission, 24 (58.5%) relapsed. Bone marrow and central nervous system were the most frequent sites of relapse. Hazard ratio of treatment failure and death for patients with organomegaly at diagnosis was 2.026 and 2.970, respectively. Treatment-related toxicity developed in 31 (54.4%) patients and febrile neutropenia was the most frequent in 14 (24.6%) cases. Twelve patients (21.1%) had poor adherence to treatment. CONCLUSIONS: High relapse rate and low 5-year EFS compared with international standards, was documented. Use of intensified pediatric regimens, adherence to proven effective medications, improved supportive care, and prevention of abandonment are necessary to improve survival rates in these patients.

Dopamine production in neurotensin receptor 1 neurons is required for diet-induced obesity and increased day eating on a high-fat diet.

OBJECTIVE: This study aimed to determine a dopaminergic circuit required for diet-induced obesity in mice. METHODS: We created conditional deletion mutants for tyrosine hydroxylase (TH) using neurotensin receptor 1 (Ntsr1) Cre and other Cre drivers and measured feeding and body weight on standard and high-fat diets. We then used an adeno-associated virus to selectively restore TH to the ventral tegmental area (VTA) Ntsr1 neurons in conditional knockout (cKO) mice. RESULTS: Mice with cKO of Th using Vglut2-Cre, Cck-Cre, Calb1-Cre, and Bdnf-Cre were susceptible to obesity on a high-fat diet; however, Ntsr1-Cre Th cKO mice resisted weight gain on a high-fat diet and did not experience an increase in day eating unlike their wild-type littermate controls. Restoration of TH to the VTA Ntsr1 neurons of the Ntsr1-Cre Th cKO mice using an adeno-associated virus resulted in an increase in weight gain and day eating on a high-fat diet. CONCLUSIONS: Ntsr1-Cre Th cKO mice failed to increase day eating on a high-fat diet, offering a possible explanation for their resistance to diet-induced obesity. These results implicate VTA Ntsr1 dopamine neurons as promoting out-of-phase feeding behavior on a high-fat diet that could be an important contributor to diet-induced obesity in humans.

Systematic literature review and meta-analysis on use of Thrombopoietic agents for chemotherapy-induced thrombocytopenia.

BACKGROUND: Currently, there are no approved options to prevent or treat chemotherapy-induced thrombocytopenia (CIT). We performed a systematic literature review and meta-analysis on use of thrombopoietic agents for CIT. PATIENTS AND METHODS: We searched Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed, EMBASE, ClinicalTrials.gov, and health technology assessments from January 1995 to March 2021 for studies evaluating thrombopoietic agents for CIT, including recombinant human thrombopoietin (rhTPO), megakaryocyte growth and development factor (MGDF), romiplostim, and eltrombopag. Random effects meta-analyses were conducted for efficacy and safety endpoints. RESULTS: We screened 1503 titles/abstracts, assessed 138 articles, and abstracted data from 39 publications (14 recombinant human thrombopoietin, 7 megakaryocyte growth and development factor, 9 romiplostim, 8 eltrombopag, and 1 romiplostim/eltrombopag). Random effects meta-analyses of data from multiple studies comparing thrombopoietic agents versus control (comparator, placebo, or no treatment) showed that thrombopoietic agents did not significantly improve chemotherapy dose delays and/or reductions (21.1% vs 40.4%, P = 0.364), grade 3/4 thrombocytopenia (39.3% vs 34.8%; P = 0.789), platelet transfusions (16.7% vs 31.7%, P = 0.111), grade ≥ 2 bleeding (6.7% vs 16.5%; P = 0.250), or thrombosis (7.6% vs 12.5%; P = 0.131). However, among individual studies comparing thrombopoietic agents with placebo or no treatment, thrombopoietic agents positively improved outcomes in some studies, including significantly increasing mean peak platelet counts (186 x 109/L with rhTPO vs 122 x 109/L with no treatment; P < 0.05) in one study and significantly increasing platelet count at nadir (56 x 109/L with rhTPO vs 28 x 109/L with not treatment; P < 0.05) in another study. Safety findings included thrombosis (n = 23 studies) and bleeding (n = 11), with no evidence of increased thrombosis risk with thrombopoietic agents. CONCLUSION: Our analyses generate the hypothesis that thrombopoietic agents may benefit patients with CIT. Further studies with well-characterized bleeding and platelet thresholds are warranted to explore the possible benefits of thrombopoietic agents for CIT.

An audit of platelet transfusion indications in acute leukaemia patients: six-year experience at an Academic Centre.

BACKGROUND: Platelet transfusion plays a critical role in the supportive treatment of acute leukaemia patients who receive chemotherapy and haematopoietic stem cell transplantation (HSCT). There are few studies assessing appropriateness of platelet transfusion in this population. An audit was conducted to determine how appropriately platelets are transfused in acute leukaemia patients at a tertiary care health institution. MATERIALS AND METHODS: A six-year retrospective audit was conducted in acute lymphoblastic (ALL) and acute myeloid leukaemia (AML) patients in an Academic Centre. Episodes were assessed as either appropriate or inappropriate based on guidelines from the British Society for Haematology (BSH). Pre-transfusion platelet count, transfusion indication, World Health Organization (WHO) bleeding score, and antibiotic use were all documented. RESULTS: Overall, 745 platelet transfusion episodes in 154 patients were audited. The proportion of episodes appropriately indicated according to BSH guidelines was 75.3%. Paediatrics and Internal Medicine had the lowest and highest proportion of appropriateness by department at 63.9% and 86.8%, respectively. The best alignment to guidelines was found on the wards (82.3%). Inpatient cases were significantly better indicated (p=0.002), whereas therapeutic and HSCT-related transfusions were not. The majority of inappropriate transfusions had a pre-transfusion count >20×109/L without a valid justification (45.1%), whereas appropriate episodes were mainly accounted for by a pre-transfusion count <10×109/L (69%). DISCUSSION: The 25% rate of inappropriate platelet transfusion in acute leukaemia patients underscores the learning needs of physicians, particularly those in training, regarding adequate use of platelets in haematologic malignancies to optimise its utilisation and patient outcome.

Advances in gene therapy for hemophilia.

Hemophilia is a hereditary disorder that can be life-threatening in individuals who have severe spontaneous bleeding resulting from minor trauma or surgery. Although replacement therapy of the missing exogenous factor has improved patients' quality of life, it has not been possible to establish a long-term treatment. Due to the severity of the disease and the need for repetitive doses throughout the patient's life, replacement therapy has become a high-cost treatment option; therefore, the development of self-sustainable long-term therapies is critical. Hemophilia is a good candidate for gene therapy because it is a monogenic disease that can be counteracted by expression of the missing factor. In this article, we review some of the most relevant advances in gene therapy for this illness.

Eleutherodactylus frogs show frequency but no temporal partitioning: implications for the acoustic niche hypothesis.

Individuals in acoustic communities compete for the use of the sound resource for communication, a problem that can be studied as niche competition. The acoustic niche hypothesis presents a way to study the partitioning of the resource, but the studies have to take into account the three dimensions of this niche: time, acoustic frequency, and space. I used an Automated Digital Recording System to determine the partitioning of time and acoustic frequency of eight frogs of the genus Eleutherodactylus from Puerto Rico. The calling activity was measured using a calling index. The community exhibited no temporal partitioning since most species called at the same time, between sunset and midnight. The species partitioned the acoustic frequency of their signals, which, in addition to the microhabitat partitioning, can provide some insight into how these species deal with the problem. This data also suggest that monitoring projects with this group should take place only before midnight to avoid false negatives.