Consecutive Liver and Bone Marrow Transplantation for Erythropoietic Protoporphyria: Case Report and Literature Review.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare inherited disease of heme biosynthesis resulting in the accumulation of protoporphyrin, characterized by liver failure in a minority of cases. Although liver transplant (LT) is the therapeutic strategy for advanced hepatic disease, it does not correct the primary defect, which leads to recurrence in liver graft. Thus, hematopoietic stem cell transplantation (HSCT) is an approach for treating EPP. METHODS: We aim to describe the first sequential LT and HSCT for EPP performed in Latin America, besides reviewing the present-day literature. RESULTS: The patient, a 13-year-old female with a history of photosensitivity, presented with symptoms of cholestatic and hepatopulmonary syndrome and was diagnosed with EPP. Liver biopsy demonstrated cirrhosis. She was submitted to a successful LT and showed improvement of respiratory symptoms. However, she had disease recurrence on the liver graft. She underwent a myeloablative HSCT using a matched unrelated donor, conditioning with BuCy (busulfan and cyclophosphamide), and GvHD (graft vs. host disease) prophylaxis with ATG (thymoglobulin), tacrolimus and methotrexate. Neutrophil engraftment occurred on D+18. She has presented mixed chimerism, but normalization of PP levels, being 300 days after HSCT, in good state of health and normal liver function. CONCLUSIONS: Consecutive LT and HSCT for EPP is a procedure that has been described in 10 cases in the literature and, even though these patients are a highly diversified population, studies have shown favorable results. This concept of treatment should be considered in patients with established liver disease.

Extracorporeal photopheresis in chronic graft-versus-host disease: clinical description and economic study.

INTRODUCTION: Although extracorporeal photopheresis (ECP) is a promising second-line therapy in the treatment of chronic graft-versus-host disease (cGVHD), its use is limited by its high cost. This study aims to describe the clinical evolution of patients who underwent ECP therapy for cGVHD and to perform an economic analysis of the therapy METHODS: This was a case series between 2016 and 2020 describing the clinical response to ECP and a micro-cost analysis of the therapy using time-driven activity-based costing. RESULTS: Six patients underwent ECP for corticosteroid-dependent cGVHD The cost per ECP session is 14,960.90 Brazilian reais (BRL), which primarily consists of the ECP kit with an activator (82.78%), followed by the hospital's physical structure (14.66%), human resources (2.48%) and exams/inputs (0.08%). The number of sessions performed ranged from 2 to 42. The total cost of the therapy per patient ranged from BRL 30,000 to 500,000. CONCLUSION: The response of the patient with cGVHD to treatment with ECP was variable. These micro-costing results can be used to develop remuneration and cost control strategies in hematopoietic stem cell transplantation programs, as well as in further economic studies.

Impact of waitlist time on post-HSCT survival: a cohort study at a hospital in southern Brazil.

INTRODUCTION: The time elapsed from diagnosis to hematopoietic stem cell transplantation (HSCT) is influenced by numerous factors. In Brazil, patients using the public health system are also dependent on the availability of HSCT-specific beds in the hematology ward. OBJECTIVE AND METHODS: We conducted a cohort study of listed patients who underwent allogeneic HSCT at a Brazilian public hospital to investigate the impact of the waitlist time on post-HSCT survival. RESULTS: The median time from diagnosis to HSCT was 19 months (IQR, 10 - 43), of which 6 months (IQR, 3 - 9) were spent on the waitlist. The time on the waitlist for HSCT appeared to influence mainly the survival of adult patients (≥ 18 years), with an increasing risk according to this time (RR, 3.53 and 95%CI, 1.81 - 6.88 for > 3 and ≤ 6 months; RR 5.86 and 95%CI, 3.26 - 10.53 for > 6 and ≤ 12 months, and; RR 4.24 and 95%CI, 2.32 - 7.75 for > 12 months). CONCLUSION: Patients who remained on the waitlist for less than 3 months had the highest survival (median survival, 856 days; IQR, 131 - 1607). The risk of reduced survival was about 6-fold higher (95%CI, 2.8 - 11.5) in patients with malignancies.

Activation and expansion of CD8(+) T effector cells in patients with chronic graft-versus-host disease.

We tested the hypothesis that changes in the phenotype of CD8(+) T cells from patients with chronic graft-versus-host disease (cGVHD) correlate with disease activity, and resolve or normalize in clinically tolerant patients successfully withdrawn from immunosuppression therapy (IST). No significant difference was found in the absolute CD8(+) T cell counts among cGVHD patients, tolerant patients, and healthy controls. However, compared with healthy normal controls, CD8(+) T cells from cGVHD patients had decreased expression of the IL-7 receptor and an increase in effector T cells, Ki-67, and perforin expression and apoptosis, suggesting that activation, differentiation, and proliferation of host-reactive CD8(+) effector T cells is a mechanism by which cGVHD is sustained and persists. The increase in effector T cells was most prominent in older patients and patients who were cytomegalovirus seropositive before transplantation. Use of IST was associated with a decreased number of CD45RA(-) CD8(+) effector T cells, a decreased expression of Ki-67, and an increased expression of CD95 (Fas). Together, these results demonstrate that CD8(+) T cells in patients with cGVHD are characterized by an increased level of activation and proliferation, and an expansion of effector cells that appear to be selectively sensitive to IST compared with other CD8(+) T cells. In GVHD-free tolerant patients, CD8(+) T cells showed an increased expression of granzyme and HLA-DR molecules compared with CD8(+) T cells from healthy controls, indicating that clinical tolerance in these patients can occur without full normalization of the CD8(+) T cell phenotype.

Acute necrotizing eosinophilic myocarditis possibly triggered by an antimigraine drug as an uncommon cause of acute heart failure: a case report.

BACKGROUND: Epigastric or chest pain with an abnormal electrocardiogram (ECG) in a young, otherwise healthy patient should trigger an investigation to rule out myocarditis. The myocarditis covers a wide spectrum of severity. The search for the aetiologic factor could be definitive for the success of therapy. CASE SUMMARY: A previously healthy 29-year-old woman presented to the Emergency Room with epigastric pain, eosinophilia, and an abnormal ECG. A thorough evaluation including cardiac magnetic resonance and endomyocardial biopsy was undertaken. A diagnosis of acute necrotizing eosinophilic myocarditis was made. DISCUSSION: The case is particularly unique for its suspected predisposing trigger: an antimigraine drug. A possible systemic hypersensitivity reaction, reflected by the occurrence of concomitant severe serum eosinophilia, acute myocarditis, and central nervous system vasculitis, was successfully treated with steroids, further supporting the diagnosis.

Association of busulfan and cyclophosphamide conditioning with sleep disorders after hematopoietic stem cell transplantation.

New indications and conditioning regimens for hematopoietic stem cell transplantation (HSCT) have emerged in the last 10 years. Previous studies have shown the association of HSCT with late effects such as sleep disorders. The aim of this study was to determine the prevalence and factors associated with sleep disorders following HSCT in a population considering these new trends. Sixty-one individuals 1-10 years after allogeneic HSCT were surveyed using the DSM-IV-TR criteria for sleep disorders. Factors related to conditioning and graft-versus-host disease were collected from medical records. A prevalence of sleep disorders of 26.2% was found. Busulfan-cyclophosphamide conditioning was an independent risk factor in a multivariate analysis (relative risk, RR: 3.74, 95% CI: 1.1-12.6; p = 0.03), which also included sex (RR: 2.37, 95% CI: 1.0-5.7; p = 0.05) and age (RR: 1.03, 95% CI: 0.99-1.07; p = 0.11). Sleep disorders were frequent following HSCT. Patients who were treated with busulfan-cyclophosphamide had a higher risk of developing this complication. Female sex was also possibly a risk factor.

An 8-step framework for implementing time-driven activity-based costing in healthcare studies.

Micro-costing studies still deserving for methods orientation that contribute to achieve a patient-specific resource use level of analysis. Time-driven activity-based costing (TDABC) is often employed by health organizations in micro-costing studies with that objective. However, the literature shows many deviations in the implementation of TDABC, which might compromise the accuracy of the results obtained. One reason for that can be attributed to the non-existence of a step-by-step orientation to conduct cost analytics with the TDABC specific for micro-costing studies in healthcare. This article aimed at exploring the literature and practical cases to propose an eight-step framework to apply TDABC in micro-costing studies for health care organizations. The 8-step TDABC framework is presented and detailed exploring online spreadsheets already coded to demonstrate data structure and math formula building. A list of analyses that can be performed is suggested, including an explanation about the information that each analysis can provide to increase the organization capability to orient decision making. The case study developed show that actual micro-costing of health care processes can be achieved with the 8-step TDABC framework and its use in future researches can contribute to increase the number of studies that achieve high-quality level in cost information, and consequently, in health resource evaluation.

Variation in supportive care practices in hematopoietic cell transplantation.

Hematopoietic cell transplantation is an elective procedure that results in prolonged immune suppression and high treatment-related morbidity and mortality. Transplant centers and physicians use a variety of prophylaxis and monitoring strategies to prevent or minimize complications. Little is known about the variability in these practices. We conducted an international Internet-based survey of 526 physicians to describe the spectrum of supportive care practices employed. Consistency in pretransplant cardiac (96%) and pulmonary (95%) screening, informed consent documentation (93%), and use of antifungal prophylaxis (92%) was observed. Greater heterogeneity was seen in use of myelogenous growth factors, empiric antibiotic therapy, protective isolation procedures, posttransplant monitoring, and environmental and social restrictions. Although some practice differences were associated with physician characteristics and transplant type, most practice variation remained unexplained. These results suggest a need for well-designed observational and interventional studies to provide data about which supportive care practices improve outcomes. For practices proved to be beneficial, publication of guidelines and incorporation of monitoring into quality improvement initiatives may help standardize practices.

Extracorporeal photopheresis in chronic graft-versus-host disease: clinical description and economic study

Abstract Introduction Although extracorporeal photopheresis (ECP) is a promising second-line therapy in the treatment of chronic graft-versus-host disease (cGVHD), its use is limited by its high cost. This study aims to describe the clinical evolution of patients who underwent ECP therapy for cGVHD and to perform an economic analysis of the therapy Methods This was a case series between 2016 and 2020 describing the clinical response to ECP and a micro-cost analysis of the therapy using time-driven activity-based costing. Results Six patients underwent ECP for corticosteroid-dependent cGVHD The cost per ECP session is 14,960.90 Brazilian reais (BRL), which primarily consists of the ECP kit with an activator (82.78%), followed by the hospital's physical structure (14.66%), human resources (2.48%) and exams/inputs (0.08%). The number of sessions performed ranged from 2 to 42. The total cost of the therapy per patient ranged from BRL 30,000 to 500,000. Conclusion The response of the patient with cGVHD to treatment with ECP was variable. These micro-costing results can be used to develop remuneration and cost control strategies in hematopoietic stem cell transplantation programs, as well as in further economic studies.

The use of micro-costing in an economic analysis of allogeneic HSCT in Brazil / O uso do microcusteio na análise econômica do TCTH alogênico no Brasil

Objetivo: O objetivo deste estudo foi estimar os custos do tratamento do transplante de células--tronco hematopoéticas (TCTH) em um centro de referência no Brasil. Métodos: A população do estudo foi composta por pacientes provenientes da lista de TCTH do Sistema Único de Saúde submetidos ao TCTH em um hospital do sul do Brasil, entre 2016 e 2019. A avaliação de custos foi realizada por meio de um estudo de microcusteio, baseado no Time-Driven Activity-based Costing (TDABC) adaptado para estudos econômicos em saúde e incluiu as seguintes etapas: definição da questão de pesquisa, coleta de dados estruturada e análise estatística dos resultados. Resultados: O custo total do TCTH foi de $ 155.110 ($ 92.794 ­ $ 249.146 USD). O TCTH de doador não aparentado compatível foi mais caro do que o TCTH de doador aparentado compatível. Os principais fatores de custo envolvem complicações pós-transplante, principalmente a ocorrência de infecções. Em relação à composição dos custos, exames e procedimentos representam o maior custo em TCTH (45%). Conclusão: Essas estimativas podem ser aplicáveis a novas avaliações de custo-efetividade do TCTH e ajudar os gestores na tomada de decisão em saúde, especialmente em países de média renda

Objective: The objective of this study was to estimate treatment costs of Hematopoietic stem cell transplantation (HSCT) at a reference center in Brazil. Methods: The study population consisted of patients from the Unified Health System HSCT who underwent HSCT in southern Brazil between 2016 and 2019. Costs were measured using a micro-costing approach, based on Time-Driven Activity-based Costing (TDABC) adapted for economic studies in health and included the following steps: definition of the research question, structured data collection, and statistical analysis of results. Results: The total cost of HSCT was $155,110 ($92,794 ­ $249,146 USD). Matched unrelated donor HSCT was more expensive than matched related donor HSCT. The major cost factors involve post- -transplant complications, mainly the occurrence of infections. Concerning cost composition, exams and procedures represent the largest expense in HSCT (45%). Conclusion: These estimates could be applicable to further evaluations for HSCT cost-effectiveness and help healthcare decision-makers in middle-income countries

High prevalence of anemia in children and adult women in an urban population in southern Brazil.

This population-based study was designed to detect the prevalence of anemia in a healthy population of children (18 months to 7 years) and women (14 to 30 years) tested in 2006-2007 in the state of Rio Grande do Sul, Brazil as part of an effort to tackle this massive problem that still affects so many people in the XXI century. Anemia was defined according to the WHO. Capillary blood was measured and socioeconomic status was determined according to the Brazilian Association of Market Research Agencies. The median prevalence of anemia in 2198 children was 45.4% and in 1999 women 36.4%. Anemia decreased with age during childhood; although significantly more prevalent in lower classes individuals, it was also high in the upper classes. There are indirect evidences that the lack of iron supplementation and/or iron fortified food may play a role in it. Professionals and society wise measures of education have to be implemented in order to address possible biologic factors involved in childhood psychosocial development in southern Brazil.

Leucemia mielóide aguda: o olhar dos anos 2000 no Serviço de Hematologia do Hospital de Clínicas de Porto Alegre-RS / Acute myeloid leukemia from the year 2000 point of view Hematology Service - Hospital de Clínicas de Porto Alegre-RS

A leucemia mielóide aguda (LMA) representa uma preocupação para os especialistas, porque perfaz um percentual alto das leucemias no adulto e o sucesso terapêutico ainda é insatisfatório. A partir do ano 2000, o Serviço de Hematologia do Hospital de Clínicas de Porto Alegre definiu estratégias para diagnóstico, tratamento e seguimento das LMAs, de acordo com o subtipo FAB, idade, citogenética e performance status (ECOG). Todos os casos de LMA "de novo"não promielocítica, em adultos (15 a 65 anos) foram acompanhados prospectivamente, desde outubro de 2001, data da implantação do protocolo c,ompreendendo três fases de tratamento: indução com o tradicional "7+3", citarabina 100 mg/m²/dia em infusão contínua em 7d, e daunorrubicina 60 mg/m²/dia em 3d e citarabina intratecal no D1 nas LMA M4 e M5. Após a recuperação medular, segue a consolidação idêntica à indução e posteriormente a intensificação com dois ou três ciclos de altas doses de citarabina 6 g/m²/dia por três dias. Foram diagnosticados, entre outubro/01 e dezembro/05, 69 pacientes portadores de LMA e destes, 39 com LMA "de novo"e idade entre 15 e 65 anos. Neste grupo foram analisadas a taxa de remissão, a taxa de recaída, a refratariedade e o tempo de sobrevida global. No final da observação foram encontrados: a taxa de indução de remissão 75 por cento; aconteceram 12 (40 por cento) recaídas, 7 (19 por cento) foram refratários ao tratamento. A sobrevida global foi 37 por cento em 56 meses, representando um incremento aos resultados obtidos no Serviço na década passada.

Acute myeloid leukemia (AML) is still a concern for hematologists as it represents a significant percentage of adult leukemias and the therapeutic success rates are unsatisfactory. In 2000, the Hematology Department of Hospital de Clínicas de Porto Alegre defined strategies for the diagnosis, treatment and follow up of AML patients according to the FAB subtype classification, age, cytogenetic tests and performance status (ECOG). Patients with promyelocytic leukemia are treated using the AIDA (GIMEMA) protocol with those older than 65 years receiving palliative therapy using hydroxyurea, oral etoposide, thalidomide, subcutaneous cytarabine or an association of drugs. Since October 2001 all our "de novo"AML patients aged 15 to 65 years with non-promyelocytic acute leukemia were prospectively followed up. At diagnosis we start a three phase treatment protocol: induction with a classical "7+3"therapy regimen, that is continuous infusion of 100 mg/m²/day cytarabine for 7 days, 60 mg/m²/day daunorubicin for 3 days and on day 1 an intrathecal cytarabine in AML M4 and M5 cases. After bone marrow recovery, if complete remission is achieved, follow ups involve an identical "7+3"consolidation phase followed by two or three high dose cycles of 6 g/m²/day cytarabine for 3 days. A group of 39 patients diagnosed between October 2001 and December 2005 was followed up until June 2006. Our objectives were to evaluate the effectiveness of the protocol for remission, relapse rates and overall survival. The rate of complete remission was 75 percent. Relapse occurred in 12/29 (40 percent) patients and the overall survival rate at 56 months was 37 percent, showing an improvement on our results of previous decades.

Talidomida e mieloma múltiplo: verificação dos efeitos terapêuticos através de parâmetros clínico e laboratoriais / Thalidomide and multiple myeloma: therapy evaluation using clinical and laboratorial parameters

Nas duas últimas décadas, houve uma mudança radical na terapia e na evolução do mieloma múltiplo(MM), neoplasia hematológica ainda considerada fatal. As pesquisas e investimentos em medicamentos que interferem com a fisiopatogenia e com o microambiente medular estão permitindo o controle e a regressão do clone plasmocitário maligno, mudando as perspectivas da doença. A idéia nova de usar uma droga velha, a talidomida, tem-se mostrado efetiva no MM. Em 1997, apostando nos efeitos imunomoduladores e antiangiogênicos da talidomida, foram iniciados ensaios clínicos para MM refratários. A partir daí, outras ações sobre o plasmócito e microambiente medular foram eficazes contra a doença, não somente em refratários ou recaídos, mas também como terapia de indução e/ou de manutenção da remissão. No Serviço de Hematologia do Hospital de Clínicas de Porto Alegre foram acompanhados 35 portadores de mieloma múltiplo, em uso de doses baixas (100 mg) de talidomida, pelas indicações: 13 - manutenção pós-TMO, 11 - pós-indução, 5 - recaída, 4 - refratariedade e 2 - terapia de indução. O estudo vigorou entre março/01 a dez/03. Os parâmetros avaliados foram: nível Hb, pico da imunoglobulina sérica ou urinária e o número de plasmócitos na medula óssea. As medidas foram tomadas pré-talidomida e após 3, 6 e 12 meses. A taxa de imunoglobulina foi o padrão ouro para avaliação de resposta. Os resultados: a dose terapêutica tolerada em 48 por cento dos pacientes foi 100 mg; 65 por cento dos tratados para induzir remissão (11 pacientes) apresentaram melhora entre 25 por cento-50 por cento no nível da imunoglobulina sérica; 87,5 por cento daqueles que usaram para manutenção de remissão (13 pós-TMO/ 11 pós-indução) mantiveram o mesmo plateau inicial.

Over the last two decades, we have seen a radical change intherapy and progression of multiple myeloma, a malignanthematologic disease that is still considered fatal. Recentinvestment and research on mechanisms that interfere in thephysiopathogenesis and bone marrow microenvironment areturning control and regression of the malignant plasma cellclone into something achievable, which may change expectationsrelated to this disease. The new idea of using an old drug,thalidomide, has shown to be effective in multiple myeloma. In1997, using the known effects of immunomodulation and antiangiogenesisof this drug, clinical trials were started in patients with unresponsive disease. Other therapeutic interventions inthe bone marrow microenvironment and plasma cells have beenadded and proved to be efficacious, not only as a therapy forrefractory patients, but also for induction and/or remissionmaintenance therapy. Thirty-five patients with multiple myelomawere treated with low-dose thalidomide (100 mg) and followedup. .... The study tookplace in the Hematology and Bone Marrow Transplantationservice of the Hospital de Clínicas de Porto Alegre, from March2001 to December 2003. Hemoglobin levels, serum or urineimmunoglobulin peaks and bone marrow plasma cell countswere evaluated. These parameters were assessed before startingwith the drug and after 3.6 and 12 months of usage. Theimmunoglobulin level was considered the gold standard toevaluate the response. The results showed that 100 mg was thetolerable dose for 51% of the patients. Sixty-five percent of thosewho used thalidomide for induction therapy showed a 25 to 50%improvement in immunoglobulin serum levels and 90% of thepatients on maintenance therapy (13 after bone marrowtransplantation, 11 after induction), sustained the sameimmunoglobulin levels of the initial plateau.

Câncer hereditário de mama / Hereditary breast neoplasm

The authors present a brief bibliographic review about familial history in human breast cancer, with special emphasis on the diference between hereditary breast cancer and familial breast cancer

Anemia na gestaçäo / Anemia in pregnancy

Os autores pretendem fazer uma breve revisäo bibliográfica, visando a orientaçäo de médicos e estudantes sobre os aspectos fisiológicos e patológicos da anemia na gestaçäo