Response to therapy in Richter syndrome: a systematic review with meta-analysis of early clinical trials.

Introduction and aims: Richter syndrome (RS) represents the clonal evolution of chronic lymphocytic leukemia with histological transformation into a high-grade B cell lymphoma (diffuse large B cell lymphoma - DLBCL) or Hodgkin lymphoma. Considering that RS is an uncommon condition with poor prognosis, few high-quality evidence is available. To overcome this unmet need, this meta-analysis aimed to pool efficacy of early clinical trials in Richter syndrome (DLBCL subtype). Methods: MEDLINE, Scopus and Web of Science were searched up to May of 2023 to identify clinical trials decoying efficacy. The pooled complete response, objective response and intension-to-treat failure rates were calculated by pharmacological categories (classical chemotherapy, immunochemotherapy, immunotherapy, Bruton-tyrosine kinase inhibitors, targeted approaches, cell-based therapies and combinatorial regimens) using the Der-Simonian and Laird random-effects model. The Freeman-Tukey double arcsine method was used to estimate variance and confidence intervals. Heterogeneity was assessed using the I2 method. Results: Overall, from 1242 studies identified, 30 were included, pooling data from 509 patients. The higher efficacy rates when, cell-based therapies were excluded, were achieved by immunochemotherapeutic regimens followed by combinatorial regimens, with complete response rates of 21.54% (IC95%14.93-28.87) and 23.77% (IC95% 8.70-42.19), respectively. Bispecific antibodies (alone or coupled with a chemotherapy debulking strategy) overtook Bruton tyrosine kinase inhibitors response rates. The latter, although achieving objective response rates above average, presented scarce complete response rates. Checkpoint inhibitors alone usually do not lead to complete responses, but their effectiveness may improve when combined with other agents, unveiling the importance of immune microenvironmental modulation. Conclusion: This is the first meta-analysis of early clinical trials assessing the impact of different therapeutics in RS. By analyzing the pooled efficacy estimates, our work suggests the role of a tailor-made bridging therapy for young patients with RS eligible for allogeneic hematopoietic stem cell transplantation (alloSCT), formally the only curative strategy.

Oncolytic viruses in hematological malignancies: hijacking disease biology and fostering new promises for immune and cell-based therapies.

The increased tropism for malignant cells of some viruses has been highlighted in recent studies, prompting their use as a strategy to modify the transcriptional profile of those cells, while sparing the healthy ones. Likewise, they have been recognized as players modulating microenvironmental immunity, namely through an increase in antigen-presenting, natural-killer, and T CD8+ cytotoxic cells by a cross-priming mechanism elicited by tumor-associated antigens. The immunomodulatory role of the oncolytic virus seems relevant in hematological malignancies, which may relapse as a result of a proliferative burst elicited by an external stimulus in progenitor or neoplastic stem cells. By reprogramming the host cells and the surrounding environment, the potential of virotherapy ranges from the promise to eradicate the minimal measurable disease (in acute leukemia, for example), to the ex vivo purging of malignant progenitor cells in the setting of autologous bone marrow transplantation. In this review, we analyze the recent advances in virotherapy in hematological malignancies, either when administered alone or together with chemotherapeutic agents or other immunomodulators.

Chemotherapeutic properties and side-effects associated with the clinical practice of terpene alkaloids: paclitaxel, docetaxel, and cabazitaxel.

Over the years, many biological and synthetic agents have been explored and tested in attempts to halt the spread of cancer and/or cure it. Currently, several natural compounds have and are being considered in this regard. For example, paclitaxel is a potent anticancer drug that originates from the tree Taxus brevifolia. Paclitaxel has several derivatives, namely, docetaxel and cabazitaxel. These agents work by disrupting microtubule assembling dynamics and inducing cell cycle arrest at the G2/M phase of the cell cycle, ultimately triggering apoptosis. Such features have helped to establish paclitaxel as an authoritative therapeutic compound against neoplastic disorders. After the completion of compound (hemi) synthesis, this drug received approval for the treatment of solid tumors either alone or in combination with other agents. In this review, we explore the mechanisms of action of paclitaxel and its derivatives, the different formulations available, as well as the molecular pathways of cancer resistance, potential risks, and other therapeutic applications. In addition, the role of paclitaxel in hematological malignancies is explored, and potential limitations in the therapeutic use of paclitaxel at the clinical level are examined. Furthermore, paclitaxel is known to cause increased antigen presentation. The immunomodulatory potential of taxanes, alone or in combination with other pharmacologic agents, is explored. Despite terpene-alkaloids derivatives' anti-mitotic potential, the impact of this class of drugs on other oncogenic pathways, such as epithelial-to-mesenchymal transition and the epigenetic modulation of the transcription profile of cancer cells, is also analyzed, shedding light on potential future chemotherapeutic approaches to cancer.

Oxidative Stress and Inflammation in B-Cell Lymphomas.

Mature lymphoid neoplasms arise de novo or by the transformation of more indolent lymphomas in a process that relies on the stepwise accumulation of genomic and transcriptomic alterations. The microenvironment and neoplastic precursor cells are heavily influenced by pro-inflammatory signaling, regulated in part by oxidative stress and inflammation. Reactive oxygen species (ROSs) are by-products of cellular metabolism able to modulate cell signaling and fate. Moreover, they play a crucial role in the phagocyte system, which is responsible for antigen presentation and the selection of mature B and T cells under normal conditions. Imbalances in pro-oxidant and antioxidant signaling can lead to physiological dysfunction and disease development by disrupting metabolic processes and cell signaling. This narrative review aims to analyze the impact of reactive oxygen species on lymphomagenesis, specifically examining the regulation of microenvironmental players, as well as the response to therapy for B-cell-derived non-Hodgkin lymphomas. Further research is needed to investigate the involvement of ROS and inflammation in the development of lymphomas, which may unravel disease mechanisms and identify innovative therapeutic targets.

Robust, maintainable, emergency invasive mechanical ventilator. / Ventilador mecânico invasivo de emergência resistente e de fácil manutenção.

OBJECTIVE: To develop a simple, robust, safe and efficient invasive mechanical ventilator that can be used in remote areas of the world or war zones where the practical utility of more sophisticated equipment is limited by considerations of maintainability, availability of parts, transportation and/or cost. METHODS: The device implements the pressure-controlled continuous mandatory ventilation mode, complemented by a simple assist-control mode. Continuous positive airway pressure is also possible. The consumption of compressed gases is minimized by avoiding a continuous flow of oxygen or air. Respiratory rates and inspiration/expiration time ratios are electronically determined, and an apnea/power loss alarm is provided. RESULTS: The pressure profiles were measured for a range of conditions and found to be adjustable within a ± 2.5cmH2O error margin and stable well within this range over a 41-hour period. Respiratory cycle timing parameters were precise within a few percentage points over the same period. The device was tested for durability for an equivalent period of four months. Chemical and biological tests failed to identify any contamination of the gas by volatile organic compounds or microorganisms. A ventilation test on a large animal, in comparison with a well established ventilator, showed that the animal could be adequately ventilated over a period of 60 minutes, without any noticeable negative aftereffects during the subsequent 24-hour period. CONCLUSION: This ventilator design may be viable, after further animal tests and formal approval by the competent authorities, for clinical application in the abovementioned atypical circumstances.

OBJETIVO: Desenvolver um ventilador mecânico invasivo simples, resistente, seguro e eficiente que possa ser utilizado em áreas remotas do mundo ou zonas de guerra, em que a utilidade prática de equipamentos mais sofisticados é limitada por questões de manutenção, disponibilidade de peças, transporte e/ou custo. MÉTODOS: O dispositivo implementa o modo de ventilação mandatória contínua com pressão controlada, complementado por um simples modo assisto-controlado. Pode-se também utilizar a pressão positiva contínua nas vias aéreas. Ao se evitar o fluxo contínuo de oxigênio ou ar, minimiza-se o consumo de gases comprimidos. As taxas respiratórias e as relações de tempo de inspiração e expiração são determinadas eletronicamente. Além disso, conta com um alarme de apneia/falta de energia. RESULTADOS: Os perfis de pressão foram medidos para uma série de condições, sendo considerados ajustáveis dentro de uma margem de erro de ± 2,5cmH2O, e foram considerados bem estáveis dentro dessa variação durante um período de 41 horas. Os parâmetros de tempo do ciclo respiratório foram precisos dentro de alguns pontos percentuais durante o mesmo período. O dispositivo foi testado quanto à durabilidade por um período equivalente a 4 meses. Os testes químicos e biológicos não conseguiram identificar qualquer contaminação do gás por compostos orgânicos voláteis ou micro-organismos. Em comparação com um ventilador bem estabelecido, o teste de ventilação em um animal de grande porte mostrou que este poderia ser ventilado adequadamente durante um período de 60 minutos, sem quaisquer efeitos negativos perceptíveis durante o período subsequente de 24 horas. CONCLUSÃO: Este projeto de ventilador pode ser viável após novos testes em animais e aprovação formal pelas autoridades competentes, para aplicação clínica nas circunstâncias atípicas anteriormente mencionadas.

Ventilador mecânico invasivo de emergência resistente e de fácil manutenção / Robust, maintainable, emergency invasive mechanical ventilator

RESUMO Objetivo: Desenvolver um ventilador mecânico invasivo simples, resistente, seguro e eficiente que possa ser utilizado em áreas remotas do mundo ou zonas de guerra, em que a utilidade prática de equipamentos mais sofisticados é limitada por questões de manutenção, disponibilidade de peças, transporte e/ou custo. Métodos: O dispositivo implementa o modo de ventilação mandatória contínua com pressão controlada, complementado por um simples modo assisto-controlado. Pode-se também utilizar a pressão positiva contínua nas vias aéreas. Ao se evitar o fluxo contínuo de oxigênio ou ar, minimiza-se o consumo de gases comprimidos. As taxas respiratórias e as relações de tempo de inspiração e expiração são determinadas eletronicamente. Além disso, conta com um alarme de apneia/falta de energia. Resultados: Os perfis de pressão foram medidos para uma série de condições, sendo considerados ajustáveis dentro de uma margem de erro de ± 2,5cmH2O, e foram considerados bem estáveis dentro dessa variação durante um período de 41 horas. Os parâmetros de tempo do ciclo respiratório foram precisos dentro de alguns pontos percentuais durante o mesmo período. O dispositivo foi testado quanto à durabilidade por um período equivalente a 4 meses. Os testes químicos e biológicos não conseguiram identificar qualquer contaminação do gás por compostos orgânicos voláteis ou micro-organismos. Em comparação com um ventilador bem estabelecido, o teste de ventilação em um animal de grande porte mostrou que este poderia ser ventilado adequadamente durante um período de 60 minutos, sem quaisquer efeitos negativos perceptíveis durante o período subsequente de 24 horas. Conclusão: Este projeto de ventilador pode ser viável após novos testes em animais e aprovação formal pelas autoridades competentes, para aplicação clínica nas circunstâncias atípicas anteriormente mencionadas.

ABSTRACT Objective: To develop a simple, robust, safe and efficient invasive mechanical ventilator that can be used in remote areas of the world or war zones where the practical utility of more sophisticated equipment is limited by considerations of maintainability, availability of parts, transportation and/or cost. Methods: The device implements the pressure-controlled continuous mandatory ventilation mode, complemented by a simple assist-control mode. Continuous positive airway pressure is also possible. The consumption of compressed gases is minimized by avoiding a continuous flow of oxygen or air. Respiratory rates and inspiration/expiration time ratios are electronically determined, and an apnea/power loss alarm is provided. Results: The pressure profiles were measured for a range of conditions and found to be adjustable within a ± 2.5cmH2O error margin and stable well within this range over a 41-hour period. Respiratory cycle timing parameters were precise within a few percentage points over the same period. The device was tested for durability for an equivalent period of four months. Chemical and biological tests failed to identify any contamination of the gas by volatile organic compounds or microorganisms. A ventilation test on a large animal, in comparison with a well established ventilator, showed that the animal could be adequately ventilated over a period of 60 minutes, without any noticeable negative aftereffects during the subsequent 24-hour period. Conclusion: This ventilator design may be viable, after further animal tests and formal approval by the competent authorities, for clinical application in the abovementioned atypical circumstances.

Digestive tract MALT lymphoma, an unusual location.

The authors describe a case of a rectal mucosa-associated lymphoid tissue lymphoma in a 78-year-old female patient, manifested as rectal bleeding. Despite being commonly diagnosed in the localized form, this patient had supradiaphragmatic involvement on disease staging. Immunochemotherapy was proposed due to the disseminated involvement and poorer prognosis.

Honey: Another Alternative in the Fight against Antibiotic-Resistant Bacteria?

Antibacterial resistance has become a challenging situation worldwide. The increasing emergence of multidrug-resistant pathogens stresses the need for developing alternative or complementary antimicrobial strategies, which has led the scientific community to study substances, formulas or active ingredients used before the antibiotic era. Honey has been traditionally used not only as a food, but also with therapeutic purposes, especially for the topical treatment of chronic-infected wounds. The intrinsic characteristics and the complex composition of honey, in which different substances with antimicrobial properties are included, make it an antimicrobial agent with multiple and different target sites in the fight against bacteria. This, together with the difficulty to develop honey-resistance, indicates that it could become an effective alternative in the treatment of antibiotic-resistant bacteria, against which honey has already shown to be effective. Despite all of these assets, honey possesses some limitations, and has to fulfill a number of requirements in order to be used for medical purposes.