Adults with Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia: Considerations for Allogeneic Hematopoietic Cell Transplantation in First Complete Remission

Philadelphia chromosome–like (Ph-like) acute lymphoblastic leukemia (ALL) is a subset of high-risk B cell ALLs. A large proportion of Ph-like ALL cases carry activating kinase mutations that could potentially allow them to be targeted by tyrosine kinase inhibitors. Ph-like ALL is not an uncommon entity, especially among adults, with a frequency exceeding 20%, including in older patients (>60 years old) with ALL. Ph-like ALL is associated with inferior outcomes across all ages, and studies have consistently shown a higher incidence of persistent postinduction minimal residual disease in patients carrying Ph-like ALL compared with other subgroups of ALL, and this translates into inferior leukemia-related outcomes. The inferior outcome of conventional chemotherapy for Ph-like ALL in adults raises the fundamental question of whether all adults with Ph-like ALL require an allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR1) regardless of other presenting features and treatment response parameters. Here we present and discuss several scenarios in which adults with Ph-like ALL underwent or were considered for HCT in CR1 for various reasons. Although the decision to proceed with HCT was clear and indisputable in some of these situations, in others we struggled with the decision to transplant in CR1 because of the lack of published data regarding the efficacy of allogeneic HCT as consolidation for Ph-like ALL. We emphasize the urgent need for developing well-designed studies to address this important question.     

The birth experience and subsequent maternal caregiving attitudes and behavior: a birth cohort study

Archives of Women's Mental Health - Optimal maternal caregiving is critical for children’s healthy development, yet quality of maternal caregiving may be influenced by a negative birth...     

Revised International Staging System Is Predictive and Prognostic for Early Relapse (<24 months) after Autologous Transplantation for Newly Diagnosed Multiple Myeloma

The revised International Staging System (R-ISS) combines ISS with genetic markers and lactate dehydrogenase and can prognosticate newly diagnosed multiple myeloma (MM). Early relapse (<24 months) after upfront autologous hematopoietic cell transplantation (AHCT) strongly predicts inferior overall survival (OS). We examined the ability of R-ISS in predicting early relapse and its independent prognostic effect on postrelapse survival after an early relapse. Using the Center for International Blood and Marrow Transplant Research database we identified MM patients receiving first AHCT within 18 months after diagnosis with available R-ISS stage at diagnosis (n?=?628). Relative risks of relapse/progression, progression-free survival (PFS), and OS were calculated with the R-ISS group as a predictor in multivariate analysis. Among early relapsers, postrelapse survival was tested to identify factors affecting postrelapse OS. The cumulative incidence of early relapse was 23%, 39%, and 50% for R-ISS I, R-ISS II, and R-ISS III, respectively (P < .001). Shorter PFS and OS were seen with higher stage R-ISS. R-ISS was independently predictive for inferior postrelapse OS among early relapsers, as was the presence of ≥3 comorbidities and the use of ≥2 induction chemotherapy lines. R-ISS stage at diagnosis predicts early post-AHCT relapse and independently affects postrelapse survival among early relapsers.     

Stereological examination of curcumin’s effects on hippocampal damage caused by the anti-epileptic drugs phenobarbital and valproic acid in the developing rat brain

The anti-epileptic drugs phenobarbital and valproic acid have an extremely strong negative effect on cognitive processes such as learning and memory in the developing brain. We examined whether or not curcumin has protective effects on neuronal injury caused by these drugs in the developing rat brain. Young male Wistar rats were studied in two groups, a 7 days old and a 14 days old group (35 rats in each). Both groups were then divided into 7 sub-groups as the control, curcumin, dimethylsulfoxide, phenobarbital, valproic acid, phenobarbital + curcumin, and valproic acid + curcumin groups (n = 5 in each group). At 24 h after the intraperitoneal injection of the compounds, the rats were sacrificed, and the hippocampal tissue was subjected to stereological analysis with the optical fractionation method. Total numbers of neurons in the hippocampus of the 7 days old and 14 days old rats were calculated. It was found that treatment with phenobarbital resulted in a loss of 43% of the neurons, and valproic acid induced a loss of 57% of the neurons in the 7 days old rats. Curcumin prevented this loss significantly with only 19% in the phenobarbital group and 41% in the valproic acid group. In the 14 days old rat groups, phenobarbital was found to reduce the number of neurons by 30%, and valproic acid reduced it by 38%. Curcumin treatment limited neuronal loss to 3% in the phenobarbital + curcumin group and 10% in the valproic acid + curcumin group. These data strongly indicate that curcumin is a protective agent and prevents hippocampal neuronal damage induced by phenobarbital and valproic acid treatment.     

The innate immune architecture of lung tumors and its implication in disease progression

Lung malignancies are the leading cause of cancer-related mortality. By virtue of its unique physiological function, the lung microenvironment is highly dynamic and constantly subjected to mechanical, chemical and pathogenic stimuli. Thus, the airways rely on highly organized innate defense mechanisms to rapidly protect against pathogens and maintain pulmonary homeostasis. However, in the context of lung malignancy, these defenses often provide collateral inflammatory insults that can foster tumor progression. This review summarizes the interactions between cancer cells, recruited immune cells and tissue-resident cell subpopulations, such as airway epithelial cells and alveolar macrophages, during homeostasis and disease. Furthermore, we examine the role of the lung immune landscape in response to current therapeutic interventions for cancer. Given the prevalence of lung malignancies, we propose that consideration of lung physiology as a whole is necessary to understand and treat these lethal diseases. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Genetic reprogramming for NK cell cancer immunotherapy with CRISPR/Cas9

Natural killer cells are potent cytotoxic lymphocytes specialized in recognizing and eliminating transformed cells, and in orchestrating adaptive anti-tumour immunity. However, NK cells are usually functionally exhausted in the tumour microenvironment. Strategies such as checkpoint blockades are under investigation to overcome NK cell exhaustion in order to boost anti-tumour immunity. The discovery and development of the CRISPR/Cas9 technology offer a flexible and efficient gene-editing capability in modulating various pathways that mediate NK cell exhaustion, and in arming NK cells with novel chimeric antigen receptors to specifically target tumour cells. Despite the high efficiency in its gene-editing capability, difficulty in the delivery of the CRISPR/Cas9 system remains a major bottleneck for its therapeutic applications, particularly for NK cells. The current review discusses feasible approaches to deliver the CRISPR/Cas9 systems, as well as potential strategies in gene-editing for NK cell immunotherapy for cancers.     

A biomarker for tegumentary and visceral leishmaniasis based on a recombinant Leishmania hypothetical protein

The measures for leishmaniasis control include the precise diagnosis of disease. However, although several recombinant antigens have been tested with this biotechnological purpose, no effective product exists, which could detects patients with the active disease, as well as differentiates them from cured and treated patients. In this study, a conserved Leishmania hypothetical protein, which was identified in Leishmania infantum parasites, but evaluated to presents high homology in the amino acid sequences between distinct parasite species, was evaluated for the diagnosis of tegumentary and visceral leishmaniasis. In addition, PBMCs collected from treated and untreated mucosal leishmaniasis (ML) and visceral leishmaniasis (VL) patients, as well as in healthy subjects living in endemic region of disease, were in vitro stimulated, when IFN-γ, IL-4 and IL-10 levels were evaluated in the cell supernatant. Regarding the serological analyses, ELISA experiments using the recombinant protein (rLiHyL) and a human serological panel revealed high sensitivity and specificity values to detect both diseases, while control antigens showed worst results. Regarding the cellular response, results showed that rLiHyL-stimulated cells produced higher IFN-γ and lower IL-4 and IL-10 levels in the supernatants. Also, the anti-protein antibody production was evaluated in these patients, and data showed higher IgG2 and lower IgG1 levels found in the treated patients and healthy controls, demonstrating the stimulation of a Th1-type response induced by the rLiHyL protein. In conclusion, this hypothetical protein can be considered as antigenic in TL and VL, as well as a vaccine candidate to be tested in future studies to protect against disease.