Search

Introduction: Cervical cancer (CC) is one of the leading causes of cancer-related deaths in low- and middle-income countries, where it is often diagnosed as symptomatic, which is common in advanced stages. The most common symptom of CC is vaginal bleeding, which can lead to anemia and an indication of blood transfusions (BT) before initiating cancer treatment. However, the implication of BT in the survival of patients with CC remains unclear. Objective: We conducted a systematic review and meta-analysis that investigated the association between BT and survival outcomes in patients with CC. Methodology: A systematic search of the PubMed, Embase, and Cochrane databases was conducted in July 2024. The search strategy employed the MeSH terms: “cervical cancer” AND “blood transfusion.” Inclusion criteria were (1) articles reporting on CC patients who received blood transfusions before curative treatment (2) report of disease-free survival (DFS) and overall survival (OS) as main outcomes. Exclusion criteria included (1) reviews, (2) case reports (3) BT after or during oncology treatment. Data extraction and quality assessment were performed independently by two reviewers. Hazard ratios (HR) for DFS and OS were calculated using a random-effects model, with heterogeneity assessed using the I2 metric and Cochran's Q test in Review Manager 5.4 software. Results: The initial search yielded 723 articles, of which 3 met the inclusion criteria and were included in this review. These studies encompassed 1301 patients, of whom 492 (37.8%) received BT before their curative therapy, which was chemoradiation. The analysis demonstrated that patients who received BT had a worse prognosis, with an HR of 2.78 for OS (95% CI 1.27-6.11; p = 0.01; I2 = 0%). An analysis with 2 studies demonstrated an HR of 2.55 for DFS (95% CI 1.41-4.62; p = 0.01; I2 = 0%). Discussion: Our findings demonstrate that in patients with CC, pre-treatment BT is associated with noticeably poorer OS and DFS. This result suggests that BT is a poor predictor of survival outcomes. There are numerous possible explanations for this correlation. Given that BT is known to cause immunosuppression, tumor development and metastasis may be encouraged. Furthermore, pro-inflammatory mediators that may be present in BT may further contribute to an unfavorable tumor microenvironment. Although these elements were not examined in our analysis, additional variables including the length of time blood products are stored or the existence of particular blood groups may potentially be important. Conclusion: Our findings suggest that pre-treatment blood transfusion is associated with significantly worse OS and DFS in cervical cancer patients. These results highlight the need for further prospective research to confirm this association, as well as to explore alternative strategies to manage anemia and cancer-related blood loss in this population, promoting personalized treatment strategies that optimize outcomes for women with cervical cancer.

Objective: Evaluate the factors associated with infection by Leishmania spp. in Bone Marrow Transplant (BMT) recipients due to hematological malignancies, in relation to clinical profile, tumor diagnosis, infection treatment, general mortality, infection relapses and graft infection. Material and methods: The search was carried out on the PUBMED, Embase and Google Scholar platforms using the terms “Leishmaniasis”, “Hematopoietic Stem Cell Transplant”, and the appropriate Boolean operators. Rayyan® and Microsoft Excel® software were used to select articles and interpret results. Results: 72 articles were found. Six duplicates and 54 articles that did not focus on the association between leishmaniasis and BMT due to hematological malignancies were excluded. Only 12 articles were included in the review, from 2001 to 2023. Of these, 7 studies were series or case reports on leishmaniasis in patients undergoing BMT, totaling 9 clinical cases. 78% of patients were male, with a mean age of 41-years.Lymphoblastic and myeloid leukemias predominated (55.6%) and 66.7% of patients underwent allogeneic BMT. 55.6% of patients were affected by Graft-Versus-Host Disease (GVHD) and 33.3% had associated infections (cytomegalovirus and Aspergillus spp.). The most common symptoms of the infection were: pancytopenia (88.9%); splenomegaly (55.6%); fever (44.4%); digestive involvement (22.2%); and skin or mucosal involvement (22.2%). The diagnosis was based on the presence of amastigotes in the bone marrow biopsy. Before diagnosis, 55.5% of patients were submitted to different clinical hypotheses: hemophagocytic lymphohistiocytosis (60.0%); viruses (20.0%); and acute GVHD (20.0%). The majority (88.9%) were treated with intravenous liposomal amphotericin B (L-AmB), which affected renal function in 25% of patients. 44.4% had recurrences of the infection (on average 4.3-months after the first treatment). Only one patient experienced allograft rejection and death. Discussion: Leishmaniasis is common in immunocompromised patients, especially due to acquired immunodeficiency syndrome. However, the literature has increasing descriptions of cases in transplant recipients, mainly kidney and liver transplants (the most common transplants). Few reports have been made in the literature about such infection in BMT, this being the only review on the subject in the literature. Infection with Leishmania spp. should always be considered in the differential of febrile pancytopenias, especially with splenomegaly. However, the clinic can be varied and the symptoms will not always be definitive. In the reality of BMT, it is difficult to clinically differentiate leishmaniasis from recurrences of hematological tumors and complications associated with transplantation, as they all present very similar and non-specific findings (such as fever, splenomegaly and pancytopenia). Immunosuppression, due to neoplasia or BMT therapy, makes the diagnosis of protozoosis even more difficult. Conclusion: Infection with Leishmania spp. in hematological patients, especially those undergoing hematopoietic stem cell transplantation, it should not be forgotten by the hematologist, as it can cause severe morbidity, mortality, and clinical complications, especially in cases of late diagnosis.

Introduction: Precursor B-cell acute lymphoblastic leukemia (B-ALL) primarily affects children and adolescents, it is a fast-growing disease that can be fatal if not treated in time. Even with the advances in treatment, an important number of patients still have recurrence and consequently a poor prognosis. Objective: The aim of this study was to develop a prognostic risk score based on transcriptomic and clinical data of pediatric B-ALL. Methods: We retrospectively collected RNA-seq and clinical information, including age, sex, white blood cell count at diagnosis, central nervous system (CNS) involvement, and minimal residual disease (MRD) on day 29 of treatment of 132 B-ALL patients from the Therapeutically Applicable Research to Generate Effective Treatments. First, we determined which genes were differentially expressed between patients who had a relapse versus those who did not. These genes were then subjected to univariate Cox and Lasso-Cox regression, an artificial intelligence algorithm that chose the most important genes and created our model. For this, 92 patients were used for training and 40 for validation. Subsequently, a prognostic score was generated according to the numerical expression value of eight genes, among which three genes (ALX4, CHRNA2, and FUT7) were related to better survival, and five were related to poorer survival (CHPF, FOXO6, PTCH1, SH3BP4, and TAFA5). According to the median score, we classified our patients into high and low risk, then performed an analysis of differentially expressed functions between the groups. We used the area under the curve (AUC) to assess the prediction ability of the model. Subsequently, a multivariate Cox analysis was performed, incorporating our model with clinical information, using hazard ratios (HR) and 95% confidence intervals (CI). The following variables were used: male or female sex, age above or below 10 years, CNS involvement or not, white blood cell count above or below 30,000 cells/mm³, and MRD greater or lower than 0.01. Results: The AUC of the model was 0.72 for 5 years, showing a good predictive capacity. Multivariate Cox regression indicated that age over 10 years (HR 1.84; CI 1.08-3.12; p = 0.02), MRD > 0.01 (HR 1.86; CI 1.07-3.22; p = 0.03), and our risk score (HR 3.81; CI 2.74-5.30; p < 0.001) were significant prognostic factors. Functional analysis revealed that in the high-risk group, the most upregulated biological processes were cytoplasmic translation and aerobic respiration. The most impacted pathways included ribosome, thermogenesis, oxidative phosphorylation, and chemical carcinogenesis mediated by reactive oxygen species. Discussion: White blood cell count, CNS involvement, age, and MRD are well-established prognostic factors for B-ALL. In our study, age over 10 years and MRD > 0.01 were confirmed as significant prognostic factors. Although white blood cell count and CNS involvement were relevant, they did not show statistical significance in our analysis. Thus, our risk score, which presented a good AUC and a high HR, proved to be an important prognostic factor, suggesting that it can improve risk stratification. Conclusion: We developed an effective risk score for B-ALL, demonstrating good predictive ability based on gene expression. We offer a useful tool for risk stratification and management of patients.

Introduction: Acute Myeloid Leukemia (AML) is one of the most prevalent hematologic neoplasms in elderly patients. Standard treatment is based on intensive anthracycline induction chemotherapy, which is highly immunosuppressive, leading to a significant risk of death and complications due to opportunistic infections. To mitigate this, antifungal prophylaxis (AFP) is recommended to prevent invasive fungal infections (IFI). Nevertheless, an important part of AML patients is not eligible for the standard treatment due to fragility and other clinical comorbidities. For this subset of patients, the combination of the BCL-2 inhibitor venetoclax (VEN) and a hypomethylating agent (HMA) has emerged as an important therapeutic alternative. However, the evidence supporting the use of AFP in this specific patient population remains insufficient. Objective: We conducted a systematic review and meta-analysis evaluating the efficacy and safety of AFP in AML patients undergoing VEN + HMA treatment. Methods: We conducted a comprehensive search of the PubMed, EMBASE, and Cochrane databases to identify articles comparing the prevalence of IFI in AML patients undergoing treatment with VEN+HMA in groups with and without AFP. Relevant data were extracted and exported to the R software. We calculated risk ratios (RR) and their respective 95% confidence intervals (CI). The ’meta’ and ’metafor’ packages in R were utilized to perform a random-effects meta-analysis according to the method described by DerSimonian and Laird. Heterogeneity was assessed using the I²statistic, with I² > 50% indicating significant heterogeneity. A two-tailed p-value of 0.05 was considered statistically significant. Results: The initial search encompassed 871 studies, of which 5 were included to this review, with a total of 793 patients. The majority of them were male (60.5%), with a median age of 64 years (range 18-94). The incidence of IFI were lower in the AFP group (42 of 467, 8.9%) compared to the no use of AFP (30 of 316, 9.5%), with a RR of 0.58 (95% CI 0.37-0.9; p = 0.019; I² = 0%). However, in our sensibility analysis for only confirmed IFI, the risk to development of IFI did not differ between groups (RR 0.53; 95% CI 0.26-1.05; p = 0.068; I² = 20%). Discussion: To the best of our knowledge, this is the first systematic review and meta-analysis to evaluate the benefit of AFP in AML patients undergoing treatment with VEN+ HMA. Immunosuppression resulting from cancer treatment can be fatal for a significant subset of AML patients. While the incidence of IFI can reach as high as 36% with cytotoxic regimens, and mortality rates can reach 50%, the incidence of IFI in VEN+HMA treatment is substantially lower, around 5-10%, similar to our findings. However, the lower incidence of IFI in the VEN+HMA setting raises questions about the generalizability of our analysis. It is possible that a specific subset of these patients, particularly those with poor prognostic factors, may still derive benefit from AFP. Conclusion: IFI are a less common occurrence in AML patients undergoing VEN+ HMA treatment than anthracycline regimens, but still occur frequently. However, while the use of AFP holds the potential to benefit this subset of patients, the evidence for this review is not definitive, highlighting the need for prospective studies to clarify the role of AFP before implementation in clinical practice. Until then, the decision to use AFP in this group of patients should be individualized.

Objetivo: O linfoma difuso de grandes células B (LDGCB) é a forma mais comum de linfoma não-Hodgkin. Apesar dos avanços terapêuticos, uma parcela importante dos pacientes não responde adequadamente ao tratamento padrão, sendo necessário identificar novos marcadores que possam orientar abordagens personalizadas e ajudar a esclarecer os mecanismos moleculares do LDGCB. Portanto, o objetivo desse estudo é investigar o valor prognóstico dos marcadores PDSS2, DERL1, CUL2, GRP75 e SMAD4 no LDGCB, considerando suas funções de supressão tumoral ou oncogênese descritas em outras neoplasias. Além disso, relacioná-los com características clinicopatológicas e outros marcadores já consolidados na literatura (TP53, MYC, BCL2, BCL6, EZH2 e Ki-67). Métodos: Amostras e dados clínicos de 139 casos de LDGCB foram obtidas dos arquivos do Instituto do Câncer do Ceará, englobando o período de 2012 a 2017, com a aprovação do conselho de ética. O algoritmo de Hans foi utilizado para determinação do fenótipo de centro germinativo (CG) ou de não-centro germinativo (nCG). Microarranjos de tecidos foram confeccionados com áreas representativas dos tumores para realização de imuno-histoquímica. As análises estatísticas foram feitas utilizando o programa Jamovi 2.3. Para comparações qualitativas foi utilizado o teste de qui quadrado e para análises de sobrevida o teste logrank. Resultados: O gênero masculino foi discretamente predominante (53%), sendo a mediana da idade 61 anos e 75 amostras foram classificadas como CG (54%) e 64 como nCG (46%). O tratamento mais utilizado foi o R-CHOP, com 94 pacientes. Na análise de sobrevida, nenhum marcador demonstrou resultados estatisticamente significativos, assim como na diferença da resposta ao R-CHOP. SMAD4 foi associado a uma maior chance de sintomas B (p = 0,02) e a positividade para GRP75 a um maior risco de estadiamento avançado (III e IV, p = 0,03). Em relação às amostras de subtipo CG, PDSS2 teve associação com CUL2 (p < 0,01) e com GRP75 (p < 0,01). Adicionalmente, CUL2 apresentou relação com GRP75 (p < 0,01) e com SMAD4 (p = 0,02), GRP75 com EZH2 (p = 0,03) e SMAD4 com BCL2 (p = 0,04). No grupo nCG, CUL2 foi relacionado com PDSS2 (p = 0,04), com DERL1 (p < 0,01) e com GRP75 (p < 0,01), PDSS2 com SMAD4 (p < 0,01) e GRP75 com a superexpressão de TP53 (p = 0,01). Discussão: Relações clínico-patológicas relevantes foram identificadas com os marcadores propostos. Uma possível explicação para a associação de SMAD4 com sintomas B é seu papel como segundo mensageiro na via de TGF-β, sugerindo uma ligação entre a ativação dessa via inflamatória e a manifestação desses sintomas em LDGCB. GRP75 foi descrito por outros estudos como indutor de crescimento celular e de metástase, sendo, de acordo com nossos resultados, um possível marcador de progressão de LDGCB. Ademais, foram observadas diferenças entre os fenótipos CG e nCG. Nesse aspecto, em CG, PDSS2 se relaciona com CUL2 e GRP75, enquanto em nCG, com CUL2 e SMAD4. CUL2 interage também com GRP75 e SMAD4 em CG, mas com DERL1 e GRP75 em nCG. GRP75 se associa a TP53 em nCG, e SMAD4 a BCL2 em CG. Conclusão: SMAD4 positivo representa uma maior probabilidade de sintomas B, GRP75 emerge como um possível indutor de progressão no LDGCB. Adicionalmente, a expressão diferencial desses marcadores nos fenótipos CG e nCG sugerem vias moleculares heterogêneas entre esses subtipos.

Introdução: A doença linfoproliferativa pós-transplante (DLPT) é um distúrbio de proliferações linfoides favorecido pela imunossupressão crônica necessária após transplante de órgão sólido ou transplante alogênico de células hematopoiéticas. A DLPT pós-transplante hepático é mais comum em pacientes pediátricos e com infecção por vírus Epstein-barr (EBV). Objetivo: Relatar o caso de uma paciente jovem transplantada hepática, com diagnóstico de doença linfoproliferativa pós-transplante (DLPT) e posterior recidiva agressiva da neoplasia após o tratamento quimioterápico. Relato de caso: Paciente do sexo feminino, 19 anos, com transplante hepático por hepatite autoimune em fevereiro de 2022, em uso regular de tacrolimus, everolimus e prednisona, evoluiu com quadro de tosse, febre e presença de múltiplos linfonodos sugestivos de doença linfoproliferativa pós-transplante (DLPT). Realizada imunohistoquímica em março/2023 a partir de produto da biópsia de adenoide, que confirmou DLPT monomórfica de células B. Sorologias para hepatites virais e HIV foram negativas, porém PCR-EBV foi positivo e em aumento desde outubro/2022. Prescrito inicialmente 6 ciclos de R-CHOP (rituximabe, ciclofosfamida, doxorrubicina e prednisona), devidamente concluídos em agosto/2023. Após a conclusão dos 6 ciclos, foi realizado um PET-CT de controle, que evidenciou atividade da doença linfoproliferativa, com presença de lesões em cólon sigmoide. Paciente evoluiu com dor abdominal tipo cólica em baixo ventre e dor epigástrica, diarreia até duas vezes ao dia líquida-pastosa, sem sangue, alternada com quadros de constipação, levando a internação em fevereiro/2024. Evoluiu com piora clínica progressiva, apresentando insuficiência renal dialítica, infecção de corrente sanguínea refratária ao tratamento, insuficiência respiratória por derrame pleural extenso, com necessidade de intubação e, posteriormente, traqueostomia devido à dificuldade de desmame da ventilação mecânica. Ainda, manifestou distensão abdominal persistente e sepse de foco pulmonar, evoluindo para óbito em abril/2024. Foi indicado o protocolo R-ICE (rituximabe, ifosfamida, carboplatina, etoposídeo), mas a paciente não esteve em estabilidade clínica necessária para o início deste tratamento. Discussão: A DLPT é a malignidade mais comum em casos complicados de transplantes de órgãos sólidos. É mais frequente no pós-transplante de coração, pulmão, intestino ou múltiplos órgãos, enquanto o risco é menor (1–5%) em receptores de transplante renal e hepático. A infecção por Epstein-barr-vírus (EBV) é o principal fator de risco para o estabelecimento desta neoplasia, mas o grau de imunossupressão, a idade, a raça do receptor, o tipo de aloenxerto e as variações genéticas do hospedeiro também representam importantes fatores que influenciam. A classificação patológica segundo a OMS, divide a DLPT em quatro categorias: lesões precoces, DLPT polimórfica, DLPT monomórfica e DLPT tipo Linfoma de Hodgkin clássico. DLPT monomórfica é um grupo heterogêneo de tumores compostos de células malignas monoclonais, principalmente, de origem de células B. Inicialmente, pode ser assintomático ou apresentar quadro clínico inespecífico, com manifestação de febre, inapetência, perda de peso e linfadenopatias. Em casos de DLPT monomórfica, a quimioterapia é geralmente indicada e apresenta uma boa resposta. Conclusão: Este relato destaca o risco de manifestação de linfoma agressivo em casos menos comuns de DLPT após transplante hepático.

Objectives: This review aims to analyze the benefits of bone marrow transplantation (BMT) in patients positive for the Human Immunodeficiency Virus (HIV) with hematological malignancies and to understand the limitations of BMT in this scenario, as well as to obtain perspectives on the long-term therapeutic potential of the procedure. Materials and methods: This is a literature review conducted by analyzing articles published between 2008 and 2024, written in English, obtained through the PubMed and BVS databases. The descriptors used are in accordance with the Health Sciences Descriptors System (DeCS), being: “Stem cell transplantation”, “Bone marrow transplantation”, “AIDS-related lymphoma” and “HIV-related lymphoma”. Results: The reality of patients with HIV infection was revolutionized with the advent of Highly Active Antiretroviral Therapy (HAART), which increased their survival and reduced the prevalence of opportunistic diseases. However, the incidence of Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL) remains increased in HIV+ patients. In this sense, before the advent of HAART, stem cell transplantation was not feasible for HIV+ patients, due to the post-transplant course being characterized by multiple opportunistic infections and high rates of neoplastic relapse. After the emergence of HAART, mortality due to infections was reduced, but lymphoma control remains a challenge, due to drug interactions. Selected articles showed that HAART patients with HL and NHL undergoing chemotherapy followed by BMT had similar complete remission and survival rates to HIV-negative patients, with progression-free survival ranging from 49.5-85% and overall survival from 63.5-81%. This variation is due to different chemotherapy regimens, patient selection criteria, and viral load. Allogeneic hematopoietic stem cell transplantation in HIV+, despite the not so vast experimental basis in the literature, can be performed safely and lead to long-lasting remissions, as well as having a remote potential to eradicate HIV infection, with 6 cases already reported in the literature. Furthermore, transplantation-related toxicity, event-free survival, relapse rate, and overall survival of HIV+ patients were similar to those of HIV-negative patients, but there is a higher risk of infection. Discussion: The review pointed out clear benefits of allogeneic hematopoietic stem cell transplantation in HIV-positive patients, significantly increasing the overall survival of this group, with results similar to those of HIV-negative patients (despite having shown greater susceptibility to infections). In addition, it is noteworthy that this procedure was only possible after the development of HAART, which allowed for greater control of the infection. However, to achieve these benefits, the use of prophylactic and supportive measures is necessary, in addition to performing the procedure in specialized centers. Conclusion: Allogeneic BMT in HIV-positive patients has proven beneficial for both the treatment of lymphoma. Thus, this procedure is a therapeutic possibility for advanced lymphomas in this group of patients in tertiary care centers, with due care directed to the HIV+ patient and with hematological neoplasia.

Introdução: O mieloma múltiplo (MM) é uma neoplasia hematológica caracterizada pela proliferação desregulada de plasmócitos na medula óssea, representando 1% das neoplasias malignas. No Brasil, entre 2020 e 2023, foram diagnosticados 16.113 novos casos. Cerca de 5-15% dos pacientes com MM desenvolvem amiloidose primária (AL), uma condição rara associada à secreção de cadeias leves de imunoglobulina pelas células neoplásicas, que formam fibras amiloides depositadas em vários tecidos, causando danos orgânicos. Relatamos o caso de um paciente com MM de cadeias leves Kappa/Lambda e comprometimento sistêmico por AL. Relato de caso: EC, homem, 60 anos, natural e procedente de Fortaleza-CE, procurou assistência médica em abril de 2023 com sintomas de síncope, astenia, calafrios e dores intensas. Exames iniciais revelaram hipotensão ortostática severa e nefropatia com proteinúria de 3,5 g/24h e Cr: 1,79 mg/dL. O ecocardiograma mostrou miocárdio hiperecogênico com sinais de depósito no ventrículo esquerdo. O hemograma revelou picos monoclonais gama, anemia leve com Hb: 10,2 g/dL e hemácias: 3,45 milhões/mm³. O paciente também apresentou perda ponderal de 24% em 3 meses. Em junho de 2023, biópsia de coxim gorduroso mostrou depósitos amiloides, confirmando AL e TC evidenciou áreas ósseas líticas. Em julho de 2023, mielograma e citometria da medula óssea indicaram medula hipercelular para a idade com hiperplasia de três linhagens celulares e plasmocitose. A imunofenotipagem revelou positividade para CD138 e CD38, com clonalidade Kappa/Lambda inconclusiva. Em agosto de 2023, estudo imuno-histoquímico diagnosticou MM com deposição sistêmica de proteína amiloide e relação Kappa/Lambda de 1/15. Com o diagnóstico de MM, o paciente iniciou 8 ciclos de quimioterapia com ciclofosfamida, dexametasona e bortezomibe, além de pamidronato. Relatou manchas equimóticas e edema em pés, mãos e região periorbitária. Atualmente (04/08/2024), está internado em estado estável, aguardando transplante de medula óssea previsto para 07/08. Discussão: O mieloma múltiplo e a amiloidose são doenças proliferativas das células plasmáticas, classificadas como gamapatias monoclonais. Em um paciente com mieloma múltiplo, a presença de síndrome nefrótica, miocardiopatia, equimoses periorbitárias, entre outros sinais, deve suscitar a suspeita de amiloidose primária. A combinação de mieloma múltiplo e amiloidose indica um mau prognóstico. O tratamento dessas duas doenças requer quimioterapia e, em alguns casos, transplante de medula óssea. O uso de novos medicamentos, bem como a seleção criteriosa dos candidatos ao transplante de medula, pode melhorar a sobrevida desses pacientes com neoplasias hematológicas ainda incuráveis. Conclusão: O caso demonstra a complexidade do manejo clínico de pacientes com MM associado à AL. A coexistência dessas condições agrava o prognóstico, exigindo abordagem terapêutica multifacetada. A combinação de quimioterapia e transplante de medula óssea é fundamental, com novos fármacos e seleção de candidatos ao transplante potencialmente melhorando a sobrevida. A natureza incurável dessas neoplasias ressalta a necessidade de pesquisa contínua e desenvolvimento de novas estratégias terapêuticas. O acompanhamento contínuo e manejo adequado das complicações são cruciais para a qualidade de vida desses pacientes, evidenciando a importância de uma abordagem integrada e personalizada.

Objetivos: Avaliar os estudos mais recentes atinentes à utilização de nanomateriais no contexto de uma terapia dirigida contra a leucemia. Materiais e métodos: Trata-se de uma revisão de literatura, de natureza descritiva, frente à análise de artigos publicados, entre os anos de 2020 e 2024, nas bases de dados PubMed e Cell Press Journals. Para isso, utilizou-se os descritores em inglês “nanomaterials”, “target therapy”e “leukemia”. Após passar pelos critérios de inclusão e exclusão, o estudo resultou em uma amostra total de cinco artigos de revisão selecionados: três (3) do PubMed e dois (2) do Cell Press Journals. Resultados: As terapias atuais evidenciadas no tratamento da leucemia abrangem, principalmente, a quimioterapia, a radioterapia, o transplante de células-tronco, a imunoterapia e a terapia direcionada. Nesse aspecto, o surgimento de novas interfaces terapêuticas – como o uso de nanomateriais – representa um avanço proeminente para a melhoria dos resultados terapêuticos. Esses materiais são compostos por partículas que possuem tamanho inferior a 1000 nm e detêm propriedades físicas, químicas e biológicas singulares, as quais conferem reatividade aprimorada, maior absorção celular e alta relação área de superfície/volume. Os estudos pontuam, quanto ao mecanismo de ação dos nanomateriais, a sua reverência em possibilitar a administração direcionada de medicamentos. Essas nanopartículas podem atuar como ligantes ou anticorpos que se ligam, de forma seletiva, às células cancerígenas e administram, no local do tumor, medicamentos de forma direta. Ainda quanto à farmacodinâmica dessas partículas, os nanomateriais também podem liberar medicamentos de forma controlada, podendo prolongar a ação de quimioterápicos. Essas partículas conseguem, também, aumentar a absorção e o transporte de medicamentos através das membranas celulares, auxiliando no combate à resistência a múltiplos medicamentos. Discussão: O uso de nanomateriais em terapias dirigidas à leucemia é de suma importância, tendo em vista os seus benefícios para a maior eficácia terapêutica. Uma abordagem inovadora utiliza nanopartículas de ouro como carreadores de doxorrubicina, um medicamento quimioterápico. Ao serem ativadas por laser, essas nanopartículas liberam esse fármaco de forma controlada, direcionando-o para células cancerígenas, permitindo, assim, um tratamento mais personalizado. Fora isso, esses materiais também podem aumentar a sensibilidade e a especificidade de exames de imagem, como a RM e a TC. As propriedades fluorescentes, magnéticas e ópticas desses nanomateriais permitem a visualização direta e indireta de tumores. Por exemplo, nanopartículas de ouro funcionalizadas com peptídeos específicos permitem a visualização de células cancerígenas por TC. Contudo, empecilhos podem ser notados quanto à aplicabilidade do uso das nanopartículas no tratamento da leucemia, haja vista que a síntese de nanomateriais com características uniformes e reprodutíveis é complexa e pode ser difícil de escalar para produção em massa. Conclusão: Portanto, a nanotecnologia empregada na terapia direcionada à leucemia pode trazer oportunidades e aplicações específicas. Atrelada a isso, a administração de fármacos nanomédicos tem forte potencial terapêutico e desempenha funções farmacodinâmicas e farmacocinéticas importantes para a maximização de tecnologias terapêuticas emergentes no combate à leucemia.

Introduction/objectives: Sickle cell disease (SCD) is the most common monogenic blood disorder worldwide, causing reduced life expectancy to the patients. The innovative CRISPR-Cas9 gene-editing technology, pioneered by Jennifer Doudna and Emmanuelle Charpentier, has emerged as a potential curative treatments for SCD. This review aims to comprehensively explore the latest advancements in CRISPR-Cas9 for SCD treatment. Methods: This is a literature review carried out through the analysis of articles published between 2016 and 2024 obtained through a search in the PubMed database. The descriptors used were: (Sickle cell disease) AND (CRISPR). A total of 12 articles were selected based on these criteria. Results: The development and regulatory approvals of therapeutic CRISPR-Cas9 for patients with SCD has been crucial in improving curative treatment options. This gene therapy involves targeting the BCL11A erythroid-specific enhancer to induce the expression of fetal hemoglobin (HbF), which can alleviate the clinical manifestations of this hemoglobinopathy. This approach aims to correct the genetic defect at its source, offering a potential functional cure for SCD. Discussion: Sickle cell disease (SCD) is a group of inherited red blood cell disorders characterized by the production of abnormal hemoglobin, specifically hemoglobin S (HbS). This genetic defect is caused by a point mutation in the β-globin gene on chromosome 11, and leads the hemoglobin molecules to polymerize under low oxygen conditions, resulting in the deformation of red blood cells into a rigid, sickle shape. Besides hemoglobin polymerization, the pathophysiology of SCD involves: vaso-occlusive crisis, hemolytic anemia, splenic dysfunction and organ damage. This can result in ischemia, tissue damage, and severe pain. Chronic vaso-occlusion and microinfarctions can cause damage to various organs, including the liver, kidneys, lungs, and bones. SCD is managed through a combination of symptomatic treatments, disease-modifying therapies, but curative treatment options for SCD remain very limited. Symptomatic treatments include hydroxyurea, which increases fetal hemoglobin (HbF) levels, reducing vaso-occlusive crises; L-glutamine, Voxelotor and Crizanlizumab. The only established curative treatment was allogeneic hematopoietic stem cell transplantation (HSCT), but this option is limited by donor availability and risks of graft-versus-host disease. Therefore, CRISPR-Cas9 technology has a great potential as a curative treatment of SCD, once his approach has shown promising results in clinical trials, with patients achieving high levels of HbF and significant clinical improvements, including the elimination of vaso-occlusive episodes. These studies led to important regulatory agents approvals in Europe and the USA. Conclusion: CRISPR-Cas9 therapy has a great potential to provide a durable and potentially curative treatment for SCD. By reactivating HbF production, CRISPR-Cas9 can mitigate the pathophysiological effects of HbS polymerization, thereby reducing the frequency of vaso-occlusive crises and improving overall hematologic parameters. This represents a significant advancement over traditional treatments, which primarily focus on symptom management and reducing complications, leading to significant clinical benefits and offering a promising therapeutic avenue for this debilitating disease.

Background: Metastatic colorectal cancer (mCRC) remains a significant clinical challenge. While anti-EGFR inhibitors have improved survival rates, their long-term efficacy is limited by disease progression, which is often associated with the development of acquired resistance mutations. However, some patients may regain sensitivity to anti-EGFR agents after alternative therapies, suggesting a potential benefit for rechallenge strategies. Our study aims to conduct a systematic review and meta-analysis to comprehensively evaluate the efficacy and safety of EGFR rechallenge in patients with mCRC., Methods: A systematic search of the MEDLINE, EMBASE, and Cochrane databases was conducted between October 28 and December 24, 2023, to identify clinical trials investigating treatment regimens incorporating panitumumab or cetuximab as a rechallenge strategy. Pooled proportions or hazard ratios (HR) were calculated using a random effects model. Inter-study heterogeneity was assessed using the I 2 ., Results: Among the 2105 articles identified through the search, 13 met the predetermined inclusion criteria. Of these, 12 were phase II studies, encompassing 92.3% of the patient population. Cetuximab was administered to 302 patients (75.1%), whereas panitumumab was utilized in 100 patients (24.9%).A pooled analysis of eight studies demonstrated an objective response rate of 20.50% (95% CI 7.94 to 33.07) and a disease control rate of 67.35% (95% CI 58.60 to 76.09). The median progression-free survival was estimated at 3.5 months (95% CI 2.68-6.69), with a median OS of 9.8 months (95% CI 6.71-12.89). Patients exhibiting RAS wild-type status in circulating tumor DNA (ctDNA) analysis derived enhanced benefits from anti-EGFR rechallenge (HR: 0.41; 95% CI 0.28-0.60, I 2  = 60%). Common grade 3 or higher treatment-related adverse events included neutropenia (22.8%) and rash (14.9%)., Conclusion: This meta-analysis underscores the efficacy and safety of anti-EGFR rechallenge as a promising therapeutic approach for a subset of patients afflicted with mCRC. The observed correlation between wild-type RAS status, as determined through ctDNA analysis, and improved OS signals the prospect of precision oncology in guiding treatment decisions., Competing Interests: Declarations. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Conflicts of Interest and Source of Funding: The authors declare no competing interest or source fundings.

Background and Aim: Type 2 diabetes mellitus (T2DM) is intrinsically linked to various etiologies of liver disease, with 69% of patients having concomitant metabolic dysfunction-associated steatotic liver disease (MASLD). Studies suggest glucagon-like peptide-1 receptor agonists (GLP-1RAs) can ameliorating liver disease. With this analysis, we address the gap in knowledge about the effectiveness of these agents in preventing different major adverse liver outcomes (MALOs)., Methods: PubMed, Embase, and The Cochrane Central of Trials were searched for articles reporting MALOs in T2DM patients. Publication bias-identifying methods, quality assessment and sensitivity analyses (subgroup analyses, leave-one-out meta-analyses, and meta-regression) were employed. Statistical analyses were performed in R using the "meta" and "metafor" packages., Results: Nine cohort studies from 535 identified articles encompassing 579 256 T2DM patients were included in the main analyses. GLP-1RA use was associated with reduced risks of hepatocellular carcinoma (HR 0.74, 95% CI 0.56-0.96) and cirrhosis decompensation (HR 0.68, 95% CI 0.65-0.72). Within the latter, variceal bleeding and hepatic encephalopathy prevention were found to be significantly reduced. Egger's test, Begg's test, and funnel-plot analysis yielded no publication bias. No significant differences were observed in preventing cirrhosis or hepatic failure. Meta-regression analysis revealed a positive correlation between hepatocellular carcinoma incidence and both male sex and longer follow-up duration., Conclusions: This meta-analysis improves our understanding of the hepatoprotective effects of GLP-1RAs in T2DM patients and supports existing research, exhibiting superiority over other antidiabetic medications for hepatoprotection in this subgroup. Additional long-term follow-up studies are necessary to further validate these findings., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Compared with normal-weight patients, obese patients with bipolar I disorder (BD) suffer more manic and depressive episodes and make more suicide attempts. In the general population, obesity is associated with reduced total brain volume (TBV) and gray matter volume (GMV), but the neurobiology of obesity in BD has not been investigated., Methods: We used magnetic resonance imaging to examine TBV, GMV, white matter volume (WMV), as well as frontal, parietal, occipital, and temporal lobe volumes, in 55 healthy subjects (17 overweight/obese and 38 normal weight) and 57 patients with BD following their first manic episode (20 overweight/obese and 37 normal weight)., Results: Linear regression analyses demonstrated that when other predictors of brain volume were accounted for, increased body mass index (BMI) in healthy subjects was significantly associated with decreased TBV and GMV. In contrast, increased BMI in patients with BD was significantly associated with decreased WMV and temporal lobe volume, areas of known vulnerability in early BD., Conclusions: This is the first published report to show a relationship between elevated BMI and reduced brain volumes in BD, or any psychiatric illness. Our results suggest that obesity is associated with unique neurobiological changes in BD. They further imply a possible biological mechanism underlying the association between obesity and a more severe illness course in BD., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Antidepressant-associated manic and hypomanic episodes have been reported in bipolar I disorder but are rare in major depressive disorder (MDD). Several lines of evidence suggest that bipolar II disorder is a distinct illness from bipolar I disorder and MDD. The risk of antidepressant-associated mood elevations (AAME) in bipolar II disorder relative to bipolar I disorder and MDD is unknown., Data Sources: We conducted a computer-aided MEDLINE search encompassing the dates 1949 to February 2008, using the keywords antidepressant and mania, antidepressant and hypomania, antidepressant and bipolar, fluoxetine and bipolar, fluvoxamine and bipolar, sertraline and bipolar, paroxetine and bipolar, citalopram and bipolar, escitalopram and bipolar, venlafaxine and bipolar, mirtazapine and bipolar, bupropion and bipolar, monoamine oxidase inhibitor and bipolar, phenelzine and bipolar, tranylcypromine and bipolar, tricyclic and bipolar, imipramine and bipolar, amitriptyline and bipolar, nortriptyline and bipolar, and desipramine and bipolar., Study Selection: All prospective English-language studies, including randomized, controlled trials (RCTs), open-label studies, and naturalistic treatment reports, were eligible for inclusion. We located 13 studies, including 7 RCTs, that reported rates of antidepressant-associated mood elevations in bipolar I disorder versus bipolar II disorder, and 5, including 4 RCTs, that reported rates in bipolar II disorder versus MDD., Data Extraction: Data were combined to estimate mean switch rates and subjected to meta-analysis to determine the relative risks of antidepressant-associated mood elevations in bipolar I disorder versus bipolar II disorder and in bipolar II disorder versus MDD., Data Synthesis: The mean rates of antidepressant-associated mood elevations in studies comparing bipolar I disorder and bipolar II disorder were 14.2% and 7.1%, respectively, in acute trials (less than 16 weeks), and 23.4% and 13.9%, respectively, in maintenance studies. The mean rates in reports comparing bipolar II disorder and MDD were 8.1% and 1.5%, respectively, in acute trials, and 16.5% and 6.0%, respectively, in maintenance studies. The relative risk (RR) of antidepressant-associated mood elevations was greater in bipolar I disorder than bipolar II disorder (RR = 1.78, 95% CI = 1.24 to 2.58, p = .002), and higher in bipolar II disorder than MDD (RR = 2.77, 95% CI = 1.26 to 6.09, p = .01). Mood elevations occurred almost exclusively into hypomania in MDD and bipolar II disorder, while patients with bipolar I disorder experienced manias and hypomanias with similar frequencies., Conclusions: The risk of antidepressant-associated mood elevations in bipolar II disorder is intermediate between that in bipolar I disorder and MDD., (Copyright 2008 Physicians Postgraduate Press, Inc.)

Broncho-mediastinal fistulaes are a very rare condition, existing only a report of a case related with primary lung cancer. The authors present a clinical case of a white 58-year-old man, with previous history of cigarette smoking and diabetes, with fever, productive cough and progressive dyspnea, with radiological evidence of right inferior lobar pneumonia. We noticed a radiological deterioration, despite the high spectrum antibiotic therapy, so he was submitted to thoracic computerized tomography and broncofibroscopy, which revealed extensive infiltration of the principal and intermediary bronchioles with a broncho-mediastinal-esophagic fistula. The histological exam revealed a pavimentam cellular carcinoma.