Toxicity analysis of busulfan pharmacokinetic therapeutic dose monitoring.

Busulfan-based conditioning regimens are associated with serious toxicities and literature reports increased risk of toxicities when daily area under the curve concentrations exceed 6000 µM-minute. We implemented real time pharmacokinetic-guided therapeutic drug monitoring of busulfan for myeloablative conditioning regimens. The objective was to compare toxicity of intravenous busulfan before and after therapeutic drug monitoring implementation. The primary endpoint was incidence of hepatotoxicity. Medical records were retrospectively reviewed with weight-based dose Busulfan/Cyclophosphamide (BuCy) conditioning from August 2017 through March 2018 (N = 14) and therapeutic drug monitoring from April 2018 through December 2018 (N = 22). Recipients of busulfan therapeutic drug monitoring were younger than those receiving weight-based dose (median: 45 vs. 58 years, p = 0.008). No other baseline differences were observed. There was no difference in hepatotoxicity between therapeutic drug monitoring and weight-based dose (median 1 vs. 0 days, p = 0.40). In the therapeutic drug monitoring group, 45% of patients had increases and 41% had decreases in busulfan dose after Bu1. Repeat pharmacokinetic after Bu2 were required in 32% of patients. A pharmacokinetic dose monitoring program for myeloablative conditioning intravenous busulfan regimens may be considered a safe practice in stem cell transplant recipients. The majority of patients receiving pharmacokinetic-guided therapeutic drug monitoring required dose changes and therapeutic drug monitoring patients had no significant difference in toxicity compared to those receiving weight-based dose.

Therapeutic Dose Monitoring of Busulfan Is Associated with Reduced Risk of Relapse in Non-Hodgkin Lymphoma Patients Undergoing Autologous Stem Cell Transplantation.

Optimal administration of busulfan (Bu) is hampered by variable and unpredictable drug metabolism in individual patients. At our institution, Bu was previously administered with fixed weight-based dosing (WBD) in combination with cyclophosphamide (Cy) and etoposide (E) for patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT). In 2014, we adopted real-time pharmacokinetic (PK)-guided therapeutic drug monitoring (TDM) of Bu for all NHL patients undergoing Bu-containing ASCT. Here we compare outcomes of NHL patients who underwent ASCT with Bu/Cy/E using WBD and those who did so using TDM of Bu. We studied 336 consecutive adult NHL patients who underwent ASCT with Bu/Cy/E using WBD from January 2007 to December 2013 (n = 258) or TDM from May 2014 to December 2017 (n = 78), excluding patients with mantle cell lymphoma. Clinical outcomes, including relapse, nonrelapse mortality (NRM), progression-free survival (PFS), and overall survival (OS), hepatotoxicity and pulmonary toxicity were compared in the 2 groups. To adjust for differences in baseline characteristics between the groups, propensity-matched cohorts of WBD and TDM patients were also studied. After the first dose of Bu, the dose was increased in 36% of the patients and decreased in 41%. Changes in pulmonary and liver function from baseline to transplantation were not different between the 2 groups, although these changes showed significantly less variability with TDM than with WBD. Relapse was significantly lower and PFS was improved with TDM; 2-year estimates were 19% for TDM and 38% for WBD for relapse (P = .004) and 69% and 55%, respectively, for PFS (P = .038). No significant between-group differences in NRM or OS were seen. In multivariable analysis, TDM remained prognostic for lower risk of relapse (hazard ratio [HR], .52; 95% confidence interval [CI], .30 to .89; P = .018), but did not remain prognostic for PFS (HR, .74; 95% CI, .48 to 1.16; P = .19). Propensity-matched cohorts displayed similar patterns of outcomes. In subset analysis based on disease status at ASCT, TDM was associated with less relapse and better PFS than WBD for patients who underwent transplantation in less than complete remission (CR) compared with those who underwent transplantation in CR. Compared with WBD, PK-directed TDM of Bu reduces the incidence of relapse when used in combination with Cy and E for patients with NHL undergoing ASCT, particularly for patients in less than CR. These data support the continued use of personalized PK-guided dosing for all NHL patients undergoing ASCT with Bu-containing preparative regimens.

KPTN gene homozygous variant-related syndrome in the northeast of Brazil: A case report.

Alteration of the KPTN gene, responsible for the coding of kaptin (a protein involved in actin cytoskeletal dynamics), causes a syndrome characterized by macrocephaly, neurodevelopmental delay and epileptic seizures. We report the first Brazilian case of KPTN gene variation, previously described in nine subjects from four interlinked families from an Amish community in Ohio, two Estonian siblings and a 9-year-old boy from Kansas City. We report a case of KPTN-related syndrome in a 5-year-old child which presented macrocephaly, muscular hypotonia, and global development delay. The neurological examination revealed below-expected performance in coordination and balance tests, dyspraxia, and hand-mouth synkinesia. Expressive language was characterized by phono-articulatory imprecision, abundance of phonological processes and morphosyntactic immaturity. Neuropsychological assessment revealed intellectual disability with impairment of verbal and executive functions. Exome sequencing was performed. Analysis revealed a homozygous 2-nucleotide duplication c.597_598dup p.(Ser200Ilefs*55) in the KPTN gene, which is predicted to lead to a translational frameshift and formation of a premature stop codon. The phenotypic profile is similar to the cases described in the other families. Presence of macrocephaly and delayed development indicate the possibility of KPTN gene variation. Genetic testing should be carried out at an early stage in order to reach a timely diagnosis.

Evaluation of a medication intensity screening tool used in malignant hematology and bone marrow transplant services to identify patients at risk for medication-related problems.

Background In 2014, a screening tool was implemented at Medical University of South Carolina (MUSC) Health to identify patients who are at risk for medication-related events. Patients are classified as high-risk if they meet one of the following criteria: receiving anticoagulation therapy, taking more than 10 scheduled medications upon admission, or readmission within the past 30 days. The goal of this study was to determine risk criteria specific to the malignant hematology (MH) and bone marrow transplant (BMT) patients. Methods A retrospective chart review of 114 patients admitted and discharged from the MH/BMT services between 1 September 2015 and 31 October 2015 was performed. A pharmacist-conducted medication history was completed and documented, and all interventions at admission and throughout hospitalization were categorized by severity and by value of service. The primary objective was to evaluate if patients in the MH/BMT services have more medication-related interventions documented upon admission compared with patients who are not screened as high risk. The secondary objectives were to evaluate the different types and severities of interventions made by pharmacists during the entire hospital stay, and to determine if there are certain characteristics that can help identify hematology/oncology high-risk patients. Results More interventions documented upon admission in the high-risk group as a whole when compared with the not high-risk group (73 vs. 31), but when normalized per patients in each group, there was an equal number of interventions (1.0). The most common interventions were to modify regimen (36%) and discontinue therapy (16%). The patient characteristics associated with high-risk included neutropenia, lower average platelet counts on admission, and longer length of stay. Conclusion The screening tool does not further differentiate an already complex MH/BMT patient population. Pharmacists may be more useful at capturing errors or changes during a patient's hospital stay instead of upon admission. Thrombocytopenia, neutropenia, and active infections may correlate with higher-risk status.

Early de-escalation of antibiotic therapy in hospitalized cellular therapy adult patients with febrile neutropenia.

Febrile neutropenia (FN) is an oncologic emergency frequently encountered in hematopoietic cell transplant (HCT) and chimeric antigen receptor (CAR) T-cell therapy patients, which requires immediate initiation of broad-spectrum antibiotics. Data regarding antibiotic de-escalation (DE) in neutropenic patients are limited, and guideline recommendations vary. A clinical protocol for antibiotic DE of broad-spectrum agents was implemented if patients were afebrile after 72 hours and had no clinical evidence of infection. The primary endpoint was the difference in the number of antibiotic therapy days between the pre-and post-DE protocol implementation group. Secondary endpoints included rates of subsequent bacteremia during index hospitalization, 30-day mortality, and hospital length of stay. Retrospective chart reviews were conducted to assess outcomes for patients who received allogeneic HCT, autologous HCT, or CAR T-cell therapy under the antibiotic de-escalation protocol (post-DE) compared to those who did not (pre-DE). The pre-DE group underwent HCT/CAR T-cell from February 2018 through September 2018 (n=64), and the post-DE group from February 2019 through September 2019 (n=67). The median duration of antibiotics was significantly lower in the post-DE group (6 days; range 3-60 days) compared to the pre-DE group (8 days; range 3-31 days) (p=0.034). There were no differences in any secondary endpoints. We conclude that antibiotic DE in neutropenic HCT or CAR T-cell therapy patients treated with broad-spectrum antibiotics for at least three days who are afebrile and without documented infection appears to be a safe and effective practice. Adopting it significantly reduces the number of days of antibiotics without compromising patient outcomes.

Prophylactic Trimethoprim-Sulfamethoxazole for Allogeneic Hematopoietic Stem Cell Transplant Recipients During the Pre-engraftment Period.

BACKGROUND: Our institution has used trimethoprim-sulfamethoxazole (TMP-SMX) as the antibacterial agent of choice for infection prophylaxis during the pre-engraftment period in the allogeneic transplant (allo-HCT) population. METHODS: This retrospective, single center study was developed to compare the safety of that antibacterial prophylaxis to fluoroquinolones in allo-HCT. The primary endpoint was time to neutrophil engraftment. RESULTS: A total of 366 patients were reviewed (TMP-SMX n = 332, fluoroquinolone n = 34). No difference in days to neutrophil engraftment was found (median 15 versus 16 days, p = 0.62). Hyperkalemia was more common in the TMP-SMX cohort (32.2% versus 14.7%, p = 0.035); this did not contribute to a higher rate of agent discontinuation or arrhythmia. There was no significant difference in the incidence of neutropenic fever; however, those in the TMP-SMX cohort were more likely to have microbiologically confirmed bacteremia (24.1% versus 8.8% respectively, p = 0.043). There was no significant difference in infections. No long-term implication of prophylactic antibacterial agent selection was observed in terms of graft-versus-host-disease, underlying disease relapse, or mortality. CONCLUSION: The use of TMP-SMX was associated with a higher likelihood of bacteremia and hyperkalemia; however, this did not result in increased hospital stay, escalation of care, or mortality. The use of TMP-SMX for prophylaxis during the pre-engraftment period for allo-HCT recipients is safe and effective.

Chimeric antigen receptor T-cell therapy: Challenges and framework of outpatient administration.

Adoptive cellular therapy has made a landmark change within the treatment paradigm of several hematologic malignancies, and novel cellular therapy products, such as chimeric antigen receptor T-cell therapy (CART), have demonstrated impressive efficacy and produced durable responses. However, the CART treatment process is associated with significant toxicities, healthcare resource utilization, and financial burden. Most of these therapies have been administered in the inpatient setting due to their toxicity profile. Improved toxicity management strategies and a better understanding of cellular therapy processes are now established. Therefore, efforts to transition CART to the outpatient setting are warranted with the potential to translate into enhanced patient quality of life and cost savings. A successful launch of outpatient CART requires several components including a multidisciplinary cellular therapy team and an outpatient center with appropriate clinical space and personnel. Telemedicine should be incorporated for closer monitoring. Additionally, clear criteria for admission upon clinical decompensation, a pathway for prompt inpatient transition, and clear toxicity management guidelines should be implemented. Effective education about cellular therapy and toxicity management is imperative, especially for the Emergency Department and Intensive Care Unit teams. Here, we have outlined the various logistical and clinical considerations required for the care of CART patients, which will aid centers to establish an outpatient CART program.

A Novel PACS1 Variant Associated With Schuurs-Hoeijmakers Syndrome Phenotype in an Indigenous Descendant in Brazil: A Case Report.

Schuurs-Hoeijmakers syndrome, an autosomal dominant disorder associated with mutations in the PACS1 gene, was initially identified in two unrelated children of European descent from a cohort of individuals with intellectual disabilities. This gene alteration significantly reduced cranial cartilaginous structures, inducing craniofacial alterations predominantly in a dominant-negative fashion. In this paper, we report a novel variant of PACS1 associated with Schuurs-Hoeijmakers syndrome: a boy aged two years and nine months of indigenous descent presenting with motor stereotypies, atypical sensory searches, language delay, and low socio-interactional reciprocity. Whole exome sequencing confirmed the presence of a heterozygous missense mutation c.943C>T p. (Arg315Trp) in the PACS1 gene. The phenotypic profile identified was similar to the other cases of Schuurs-Hoeijmakers syndrome described in the literature. This report highlights the importance of considering the possibility of PACS1 gene alterations and a diagnosis of Schuurs-Hoeijmakers syndrome in patients presenting craniofacial alterations associated with autistic features, psychomotor and language development delay.

Top 100 cited noninvasive neuromodulation clinical trials.

INTRODUCTION: Introduction: Transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) are noninvasive neuromodulation techniques used as therapeutic and research tools for several neuropsychiatric conditions. Given the exponential scientific growth of this field, we aimed to systematically review the most cited clinical trials using TMS or tDCS. AREAS COVERED: A de-novo keyword search strategy identified and characterized the 100 most-cited trials. Total citation count for the most cited trials was 13,204. Articles were published between 2008 and 2014 in 50 different journals with a median impact factor of 6.52 (IQR 3.37). Almost half of the top cited papers were investigating mechanisms of action in healthy subjects. Most studies were feasibility trials and only five were pivotal trials, including the ones used for recent FDA approval. Seven articles were interlinked with another article by at least 25 citations and eight authors had collaborated with at least one other author. EXPERT OPINION: Although there has been a significant increase in interest for rTMS and tDCS, most of the cited clinical trials are still small feasibility studies, what reinforced the need for more robust clinical trials (larger samples sizes and effects sizes) to better define clinical effectiveness.

Principles of designing a clinical trial: optimizing chances of trial success.

PURPOSE OF REVIEW: Clinical trials are essential to advance health care and develop new therapies. In this review we discuss the underlying principles of clinical trial design with an emphasis on assessing design risks that lead to trial failure as well as negative trials. While of general interest, this is perhaps particularly timely for the neuromodulation community, given the paucity of well-designed trials in the field. We give some examples from the phantom limb pain (PLP) literature. RECENT FINDINGS: It is critical to gather as much preliminary data as possible and to know how to interpret it in order to choose an appropriate trial design. Therefore, the investigator needs to effectively assess the likely trial design risk/benefit ratio with a view to maximizing the chance of a meaningful outcome, whether this outcome rejects or fails to reject the null hypothesis. This analysis is especially important in a complex and heterogeneous disorder such as PLP, which has had many negative trials. SUMMARY: We discuss the factors pertaining to a strong trial design benefit/risk assessment, how late trial phases require greater support from preliminary data, how to design trials to minimize risks, maximize benefits, and optimize internal validity as well as the chances of a positive outcome. We highlight the need for investigators to incorporate best practice in trial design to increase the chances of success, to always anticipate unexpected challenges during the trial.

Resin matrix ceramics - mechanical, aesthetic and biological properties / Cerâmicas de matriz resinosa - propriedades mecânicas, estéticas e biológicas

ABSTRACT Resin matrix ceramics consist in a polymeric matrix with predominantly inorganic refractory compounds which may include porcelain, glass, ceramics, and glass ceramics, and are divided into three subgroups: Nanoceramics, Vitroceramics, and Zirconia-silica. The aim of this study was to compare, through a literature review, the mechanical and biological properties of resin matrix ceramics, with glass matrix ceramics and polycrystalline ceramics. After reviewing 44 articles found in the US National Library of Medicine (PubMed) database (studies published in English, human clinical studies, in vitro or in vivo studies) that evaluated some properties of this material, such as elasticity modulus, wear resistance, adhesiveness, stain resistance and hardness, this article concluded that, although they belong to the same group, resin matrix ceramics are different from each other due to their microstructures. Moreover, when compared to other ceramic groups, it showed some superior properties, such as flexural strength, fatigue strength and internal adaptation.

RESUMO A cerâmica de matriz resinosa consiste em uma matriz polimérica contendo compostos refratários predominantemente inorgânicos que podem incluir porcelana, vidro, cerâmica e cerâmica vítrea. A cerâmica de matriz resinosa é subdividida em três subgrupos: nanocerâmica, vitrocerâmica e zircônia-sílica. O objetivo deste estudo foi comparar as propriedades mecânicas e biológicas, por meio de uma revisão da literatura, das cerâmicas de matriz resinosa comprando-as com cerâmicas de matriz vítrea e cerâmicas policristalinas. Após revisão de literatura de 44 artigos pesquisados na base de dados da Biblioteca Nacional de Medicina (PUBMED) dos EUA (estudos publicados no idioma inglês, estudos clínicos em humanos, estudos in vitro ou in vivo) que avaliaram algumas propriedades deste material, como módulo de elasticidade, resistência ao desgaste, adesividade, resistência a manchas e dureza, este estudo concluiu que, embora pertençam ao mesmo grupo, as cerâmicas de matriz resinosa têm características diferentes umas das outras devido às suas diferentes microestruturas. Além disso, quando comparada aos demais grupos cerâmicos, apresentou algumas propriedades superiores, como resistência à flexão, resistência à fadiga e adaptação interna.

Avaliação das Boas Práticas de Fabricação do serviço de alimentaçâo em um supermercado localizado no shopping center na cidade de Maceió/AL / Assessment of good manufacturing practices of the food service in a supermarket located in the shopping center in the city of Maceió/AL

O objetivo deste estudo foi avaliar as Boas Práticas de Fabricação do serviço de alimentação de um supermercado. Para realização do diagnóstico foi utilizado um check list adaptado da legislação federal. Conforme os percentuais de itens atendidos o estabelecimento foi classificado de médio risco de contaminação com 68,26% de itens conformes. Os blocos que obtiveram menos conformidades foram edificação e instalações (33,3%), higienização de instalações, equipamentos, móveis e utensílios (33,3%), produção e transporte de alimentos (36,3%) e controle de saúde e hábitos de higiene dos manipuladores de alimentos (33,3%). Conclui-se que a verificação continua das Boas Práticas é uma ferramenta expressiva para diagnosticar não conformidades do serviço e conseqüentemente realizar a correção adequada para que o mesmo não comercialize alimentos que venham a ser uma fonte de contaminação biológica e passível de causar doenças transmitidas por alimentos gerando danos à saúde dos seus funcionários e clientes.

Verificação das boas práticas em serviços de alimentação de supermercados localizados na cidade de Maceió/AL / Verification of good practices in food service of supermarkets located in the city of Maceió/AL

A qualidade sanitária é um fator decisivo na escolha de um serviço de alimentação por parte da população. O objetivo do estudo foi realizar um diagnóstico das Boas Práticas em duas unidades de alimentação e nutrição pertencentes a uma rede de supermercados em Maceió-AL. Para realização do diagnóstico foi utilizado um check-list a partir da RDC nº 275/2002, analisando 108 itens. Obteve-se um resultado de 75% e 69,5% de conformidades e 25% e 30,5% de não conformidades nas Unidades I e II respectivamente, classificando ambas como de médio risco de contaminação. Conclui-se que as duas Unidades possuem não conformidades e que estas devem ser corrigidas, porém a diferença entre elas é de apenas 5,5%, portanto, apesar das unidades possuírem responsáveis técnicos diferentes, existe uma correlação gerencial tornando desta forma mais fácil as adequações, fator importante para fidelizar a qualidade de atendimento ao cliente nesta rede de supermercados.