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Background: The concept of a "textbook outcome" is emerging as a metric for ideal surgical outcomes. We aimed to evaluate the impact of an advanced haemodynamic monitoring (AHDM) algorithm on achieving a textbook outcome in patients undergoing hepatobiliary-pancreatic surgery. Methods: This retrospective, multicentre observational study was conducted across private and public teaching sectors in Victoria, Australia. We studied patients managed by a patient-specific, surgery-specific haemodynamic algorithm or via usual care. The primary outcome was the effect of using a patient-specific, surgery-specific AHDM algorithm for achieving a textbook outcome, with adjustment using propensity score matching. The textbook outcome criteria were defined according to the International Expert Delphi Consensus on Defining Textbook Outcome in Liver Surgery and Nationwide Analysis of a Novel Quality Measure in Pancreatic Surgery. Results: Of the 780 weighted cases, 477 (61.2%, 95% CI: 57.7%-64.6%) achieved the textbook outcome. Patients in the AHDM group had a higher rate of textbook outcomes [n = 259 (67.8%)] than those in the Usual care group [n = 218 (54.8%); p < 0.001, estimated odds ratio (95% CI) 1.74 (1.30-2.33)]. The AHDM group had a lower rate of surgery-specific complications, severe complications, and a shorter hospital length of stay (LOS) [OR 2.34 (95% CI: 1.30-4.21), 1.79 (95% CI: 1.12-2.85), and 1.83 (95% CI: 1.35-2.46), respectively]. There was no significant difference between the groups for hospital readmission and mortality. Conclusions: AHDM use was associated with improved outcomes, supporting its integration in hepatobiliary-pancreatic surgery. Prospective trials are warranted to further evaluate the impact of this AHDM algorithm on achieving a textbook impact on long-term outcomes.
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BACKGROUND: An optimal pharmacological strategy for fast-track cardiac anesthesia (FTCA) is unclear. This study evaluated the effectiveness and safety of an FTCA program using methadone and non-opioid adjuvant infusions (magnesium, ketamine, lidocaine, and dexmedetomidine) in patients undergoing coronary artery bypass grafting. METHODS: This retrospective, multicenter observational study was conducted across private and public teaching sectors. We studied patients managed by a fast-track protocol or via usual care according to clinician preference. The primary outcome was the total mechanical ventilation time in hours adjusted for hospital, body mass index, category of surgical urgency, cardiopulmonary bypass time and EuroSCORE II. Secondary outcomes included successful extubation within four postoperative hours, postoperative pain scores, postoperative opioid requirements, and the development of postoperative complications. RESULTS: We included 87 patients in the fast-track group and 88 patients in the usual care group. Fast-track patients had a 35% reduction in total ventilation hours compared with usual care patients (p = 0.007). Thirty-five (40.2%) fast-track patients were extubated within four hours compared to 10 (11.4%) usual-care patients (odds ratio: 5.2 [95% CI: 2.39-11.08; p < 0.001]). Over 24 h, fast-track patients had less severe pain (p < 0.001) and required less intravenous morphine equivalent (22.00 mg [15.75:32.50] vs. 38.75 mg [20.50:81.75]; p < 0.001). There were no significant differences observed in postoperative complications or length of hospital stay between the groups. CONCLUSION: Implementing an FTCA protocol using methadone, dexmedetomidine, magnesium, ketamine, lignocaine, and remifentanil together with protocolized weaning from a mechanical ventilation protocol is associated with significantly reduced time to tracheal extubation, improved postoperative analgesia, and reduced opioid use without any adverse safety events. A prospective randomized trial is warranted to further investigate the combined effects of these medications in reducing complications and length of stay in FTCA. TRIALS REGISTRATION: The study protocol was registered in the Australian New Zealand Clinical Trials Registry ( https://www.anzctr.org.au/ACTRN12623000060640.aspx , retrospectively registered on 17/01/2023).
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Ponte de Artéria Coronária , Dexmedetomidina , Ketamina , Lidocaína , Metadona , Dor Pós-Operatória , Humanos , Masculino , Feminino , Estudos Retrospectivos , Ponte de Artéria Coronária/métodos , Ponte de Artéria Coronária/efeitos adversos , Metadona/uso terapêutico , Metadona/administração & dosagem , Dexmedetomidina/administração & dosagem , Dexmedetomidina/uso terapêutico , Ketamina/administração & dosagem , Ketamina/uso terapêutico , Pessoa de Meia-Idade , Idoso , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Lidocaína/administração & dosagem , Lidocaína/uso terapêutico , Magnésio/administração & dosagem , Analgésicos Opioides/uso terapêutico , Analgésicos Opioides/administração & dosagem , Resultado do TratamentoRESUMO
Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.
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Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Decitabina , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/uso terapêutico , Azacitidina/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Decitabina/administração & dosagem , Decitabina/uso terapêutico , Decitabina/efeitos adversos , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso de 80 Anos ou mais , Adulto , Pacientes AmbulatoriaisRESUMO
INTRODUCTION: The optimal analgesic modality for patients undergoing hepato-pancreato-biliary (HPB) surgery remains unknown. The analgesic effects of a multimodal intrathecal analgesia (MITA) technique of intrathecal morphine (ITM) in combination with clonidine and bupivacaine compared to ITM alone have not been investigated in these patients. METHODS: We performed a multicenter retrospective study of patients undergoing complex HPB surgery who received ITM, bupivacaine, and clonidine (MITA group) or ITM-only (ITM group) as part of their perioperative analgesia strategy. The primary outcome was the unadjusted oral morphine equivalent daily dose (oMEDD) in milligrams on postoperative day 1. After adjusting for age, body mass index, hospital allocation, type of surgery, operation length, and intraoperative opioid use, postoperative oMEDD use was investigated using a bootstrapped quantile regression model. Other prespecified outcomes included postoperative pain scores, opioid-related adverse events, major complications, and length of hospital stay. RESULTS: In total, 118 patients received MITA and 155 patients received ITM-only. The median (IQR) cumulative oMEDD use on postoperative day 1 was 20.5 mg (8.6:31.0) in the MITA group and 52.1 mg (18.0:107.0) in the ITM group (P < 0.001). There was a variation in the magnitude of the difference in oMEDD use between the groups for different quartiles. For the MITA group, on postoperative day 1, patients in the 25th percentile required 14.0 mg less oMEDD (95% CI: -25.9 to -2.2; P = 0.025), patients in the 50th percentile required 27.8 mg less oMEDD (95% CI: -49.7 to -6.0; P = 0.005), and patients in the 75th percentile required 38.7 mg less oMEDD (95% CI: -72.2 to -5.1; P = 0.041) compared to patients in the same percentile of the ITM group. Patients in the MITA group had significantly lower pain scores in the postoperative recovery unit and on postoperative days 1 to 3. The incidence of postoperative respiratory depression was low (<1.5%) and similar between groups. Patients in the MITA group had a significantly higher incidence of postoperative hypotension requiring vasopressor support. However, no significant differences were observed in major postoperative complications, or the length of hospital stay. CONCLUSION: In patients undergoing complex HPB surgery, the use of MITA, consisting of ITM in combination with intrathecal clonidine and bupivacaine, was associated with reduced postoperative opioid use and resulted in superior postoperative analgesia without risk of respiratory depression when compared to patients who received ITM alone. A randomized prospective clinical trial investigating these two intrathecal analgesic techniques is justified.
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Dor Aguda , Analgesia , Transtornos Relacionados ao Uso de Opioides , Humanos , Analgésicos Opioides/uso terapêutico , Estudos Retrospectivos , Morfina/efeitos adversos , Clonidina/uso terapêutico , Estudos Prospectivos , Bupivacaína/uso terapêuticoRESUMO
INTRODUCTION: Patient-reported antibiotic allergy labels (AALs) are common. These labels have been demonstrated to have a negative impact on use of appropriate antibiotics and patient-related health outcomes. These patients are more likely to receive suboptimal antibiotics, have increased rates of surgical site infections and are more likely to be colonised with multidrug-resistant organisms. Increasing recognition that antibiotic allergy forms a key part of good antimicrobial stewardship has led to calls for greater access to antibiotic allergy assessment.PREPARE is a pilot randomised controlled trial of beta-lactam allergy assessment and point of care delabelling in perioperative patients utilising a validated antibiotic allergy assessment tool that has been repurposed into a smartphone application. The aim of the study is to assess the feasibility and safety of this approach in the perioperative outpatient setting. METHODS AND ANALYSIS: Adult participants requiring elective surgery and are likely to require prophylactic intravenous antibiotics will be recruited. During the intervention phase, participants will be randomised to the intervention or control arm, with control patients receiving usual standard of care. Those randomised to intervention undertake a risk assessment via the smartphone application, with those deemed low risk proceeding to direct oral provocation with either a penicillin or cephalosporin. Study outcomes will be evaluated in the postintervention phase, 30 and 90 days after surgery.Feasibility of intervention delivery and recruitment will be reported as proportions with respective 95% CIs. Participants who experience an antibiotic adverse event will be reported by group with respective 95% CIs and compared using modified Poisson regression model with robust SE estimation. ETHICS AND DISSEMINATION: This protocol has received approval from the Austin Health human research and ethics committee, Heidelberg, Victoria, Australia (HREC/17/Austin/575). Results will be disseminated via publication in peer-reviewed journals as well as presentation at international conferences. TRIAL REGISTRATION NUMBER: ACTRN12620001295932.
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Hipersensibilidade a Drogas , Hipersensibilidade , Adulto , Humanos , Penicilinas , Estudos de Viabilidade , Antibacterianos/uso terapêutico , Hipersensibilidade a Drogas/tratamento farmacológico , Hipersensibilidade/tratamento farmacológico , Vitória , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
OBJECTIVES: To evaluate primarily the relationship between postoperative complications and hospital costs, and secondarily the relationship between postoperative complications and mortality, following radical cystectomy. METHODS: Postoperative complications were retrospectively examined for 147 patients undergoing radical cystectomy at a university hospital between January 2012 and July 2021. Complications were defined and graded using the Clavien-Dindo classification system. In-hospital cost was calculated using an activity-based costing methodology. Regression modelling was used to investigate the relationships among a priori selected perioperative variables, complications, and costs. The effect of complications on postoperative mortality was ascertained using time-dependent coefficients in a Cox proportional hazards regression model. RESULTS: 135 (92%) patients experienced one or more postoperative complications. The medians of hospital cost for patients who experienced no complications and those who experienced complications were $42,796.3 (29,222.9-53,532.5) and $81,050.1 (49,614.8-122,533.6) respectively, p < 0.001. Hospital costs were strongly associated with complication severity: Clavien-Dindo grade II complications increased costs by 45.2% (p < 0.001, 95% CI 19.1%-76.6%), and Clavien-Dindo grade III to V complications increased costs by 107.5% (p < 0.001, 95% CI 52.4%-181.8%). Each additional count of complication and increase in Clavien-Dindo complication grade increased the risk of mortality 1.28-fold (RR = 1.28, p = 0.006, 95% CI 1.08-1.53) and 2.50-fold (RR = 2.50, p = 0.012 95% CI 1.23-5.07) respectively. CONCLUSIONS: These findings demonstrate a high prevalence of complications following cystectomy and significant associated increases in hospital costs and mortality. Postoperative complications are a key target for cost-containment strategies. TRIAL REGISTRATION: Trial Registration: Australian New Zealand Clinical Trials Registry (ACTRN:12622000057785.
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Cistectomia , Neoplasias da Bexiga Urinária , Humanos , Cistectomia/métodos , Estudos Retrospectivos , Custos Hospitalares , Austrália , Complicações Pós-Operatórias/etiologia , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
Background: Understanding the financial implications associated with the complications post-distal pancreatectomy (DP) may be beneficial for the future optimisation of postoperative care pathways and improved cost-efficiency. The primary outcome of this retrospective study was the characterisation of the additional cost associated with postoperative complications following DP. The secondary outcome was the estimation of the prevalence, type and severity of complications post-DP and the determination of which complications were associated with higher costs. Methods: Postoperative complications were retrospectively examined for 62 adult patients undergoing distal pancreatectomy at an Australian university hospital between January 2012 and July 2021. Complications were defined and graded using the Clavien-Dindo (CVD) classification system. In-hospital cost of index admission was calculated using an activity-based costing methodology and was reported in US dollars at 2021 rates. Regression modelling was used to investigate the relationships among selected perioperative variables, complications and costs. Results: 45 patients (72.6%) experienced one or more postoperative complications. The median (IQR) hospital cost in US dollars was 31.6% greater in patients who experienced complications compared to those who experienced no complications ($40,717.8 [27,358.0-59,834.3] vs. $30,946.9 [23,910.8-46,828.1]). Costs for patients with four or more complications were 43.5% higher than for those with three or fewer complications (p = 0.015). Compared to patients with no complications, the median hospital costs increased by 17.1% in patients with minor complications (CVD grade I/II) and by 252% in patients who developed major complication (i.e., CVD grade III/IV) complications. Conclusion: Postoperative complications are a key target for cost-containment strategies. Our findings demonstrate a high prevalence of postoperative complications following distal pancreatectomy with number and severity of postoperative complications being associated with increased hospital costs. (Registered in the Australian New Zealand Clinical Trials Registry [No. ACTRN12622000202763]).
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This study aimed to investigate whether there was an association between an unanticipated prolonged post-anaesthesia care unit (PACU) length of stay and early postoperative deterioration, as defined as the need for a rapid response team activation, within the first seven days of surgery. We conducted a single-centre retrospective cohort study of adult surgical patients, who stayed at least one night in hospital, and were not admitted to critical care immediately postoperatively, between 1 July 2017 and 30 June 2019. A total of 11,885 cases were analysed. PACU length of stay was significantly associated with rapid response team activation on both univariate (odds ratio (OR) per increment 1.57, 95% confidence intervals (CI) 1.45 to 1.69, P < 0.001) and multivariate analysis (OR per increment 1.41, 95% CI 1.28 to 1.55, P < 0.001). Patients who stayed less than one hour were at low risk of deterioration (absolute risk 3.7%). In patients staying longer than one hour, the absolute increase in risk was small but observable within six hours of PACU discharge. Compar\ed to a one-hour length of stay, a five-hour stay had a relative risk of 4.9 (95% CI 3.7 to 6.1). Other factors associated with rapid response team activation included non-elective surgery (OR 1.78, P < 0.001) and theatre length of stay (OR per increment 1.61, P < 0.001). PACU length of stay was also independently associated with predefined complications and unplanned intensive care unit admission postoperatively. In our cohort, an unanticipated prolonged PACU length of stay of over one hour was associated with an increased incidence of rapid response team activation in the first seven days postoperatively.
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Período de Recuperação da Anestesia , Anestesia , Adulto , Estudos de Coortes , Humanos , Tempo de Internação , Estudos RetrospectivosRESUMO
BACKGROUND: The superior parietal lobule (SPL) is involved in somatosensory and visuospatial integration with additional roles in attention, written language, and working memory. A detailed understanding of the exact location and nature of associated white matter tracts could improve surgical decisions and subsequent postoperative morbidity related to surgery in and around this gyrus. OBJECTIVE: To characterize the fiber tracts of the SPL based on relationships to other well-known neuroanatomic structures through diffusion spectrum imaging (DSI)-based fiber tracking validated by gross anatomical dissection as ground truth. METHODS: Neuroimaging data of 10 healthy, adult control subjects was obtained from a publicly accessible database published in Human Connectome Project for subsequent tractographic analyses. White matter tracts were mapped between both cerebral hemispheres, and a lateralization index was calculated based on resultant tract volumes. Post-mortem dissections of 10 cadavers identified the location of major tracts and validated our tractography results based on qualitative visual agreement. RESULTS: We identified 9 major connections of the SPL: U-fiber, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, middle longitudinal fasciculus, extreme capsule, vertical occipital fasciculus, cingulum, and corpus callosum. There was no significant fiber lateralization detected. CONCLUSION: The SPL is an important region implicated in a variety of tasks involving visuomotor and visuospatial integration. Improved understanding of the fiber bundle anatomy elucidated in this study can provide invaluable information for surgical treatment decisions related to this region.
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Conectoma , Substância Branca , Adulto , Humanos , Rede Nervosa , Vias Neurais/diagnóstico por imagem , Lobo Parietal/diagnóstico por imagem , Substância Branca/diagnóstico por imagemRESUMO
Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.
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Doença Enxerto-Hospedeiro , Transplante de Fígado , Linfo-Histiocitose Hemofagocítica , Transtornos da Insuficiência da Medula Óssea , Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/genética , Humanos , Transplante de Fígado/efeitos adversos , Linfo-Histiocitose Hemofagocítica/genética , Mutação/genéticaRESUMO
PURPOSE OF REVIEW: Mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) are common in acute myeloid leukemia (AML), occurring in up to 30% of AML cases. Mutations in IDH leads to abnormal epigenetic regulation in AML cells and blocks differentiation. Inhibitors of mutated IDH1 and IDH2, ivosidenib and enasidenib, respectively, were recently approved by the FDA for relapsed/refractory AML; ivosidenib is also approved for newly diagnosed AML patients not fit for standard chemotherapy. Here, we discuss the clinical development of IDH inhibitors, their unique side effects, and outline future combination approaches in AML. RECENT FINDINGS: IDH inhibitors are well-tolerated but can induce differentiation of AML cells, which leads to the on-target side effect of differentiation syndrome in up to 20% of patients. Although IDH inhibitors demonstrate efficacy as monotherapy, recent trials have shown that they have higher response rates in combination with hypomethylating agents (HMAs). Current trials of IDH inhibitors include combination with standard induction chemotherapy, as maintenance therapy, and in combination with venetoclax-based regimens. IDH inhibitors are active and have a favorable toxicity profile in AML therapy. Current clinical trials are evaluating how to best incorporate IDH inhibitors into combination therapy to optimize outcomes and duration of response for AML patients with IDH mutations.
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Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Desenvolvimento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Humanos , Quimioterapia de Indução , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Quimioterapia de Manutenção , Mutação , Resultado do TratamentoRESUMO
BACKGROUND: It is uncertain whether increases in PaCO2 during surgery lead to an increase in plasma potassium concentration and, if so, by how much. Hyperkalaemia may result in cardiac arrhythmias, muscle weakness or paralysis. The key objectives were to determine whether increases in PaCO2 during laparoscopic surgery induce increases in plasma potassium concentrations and, if so, to determine the magnitude of such changes. METHODS: A retrospective observational study of adult patients undergoing laparoscopic abdominal surgery was perfomed. The independent association between increases in PaCO2 and changes in plasma potassium concentration was assessed by performing arterial blood gases within 15 min of induction of anaesthesia and within 15 min of completion of surgery. RESULTS: 289 patients were studied (mean age of 63.2 years; 176 [60.9%] male, and mean body mass index of 29.3 kg/m2). At the completion of the surgery, PaCO2 had increased by 5.18 mmHg (95% CI 4.27 mmHg to 6.09 mmHg) compared to baseline values (P < 0.001) with an associated increase in potassium concentration of 0.25 mmol/L (95% CI 0.20 mmol/L to 0.31 mmol/L, P < 0.001). On multiple regression analysis, PaCO2 changes significantly predicted immediate changes in plasma potassium concentration and could account for 33.1% of the variance (r2 = 0.331, f(3,259) = 38.915, P < 0.001). For each 10 mmHg increment of PaCO2 the plasma potassium concentration increased by 0.18 mmol/L. CONCLUSION: In patients receiving laparoscopic abdominal surgery, there is an increase in PaCO2 at the end of surgery, which is independently associated with an increase in plasma potassium concentration. However, this effect is small and is mostly influenced by intravenous fluid therapy (Plasma-Lyte 148 solution) and the presence of diabetes. Trial registration Retrospectively registered in the Australian New Zealand Clinical Trials Registry (Trial Number: ACTRN12619000716167).
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Dióxido de Carbono/sangue , Laparoscopia/efeitos adversos , Potássio/sangue , Adulto , Idoso , Austrália , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Acute myeloid leukemia (AML) is a clonal hematologic neoplasm characterized by rapid, uncontrolled cell growth of immature myeloid cells (blasts). There are numerous genetic abnormalities in AML, many of which are prognostic, but an increasing number are targets for drug therapy. One of the most common genetic abnormalities in AML are activating mutations in the FMS-like tyrosine kinase 3 receptor (FLT3). As a receptor tyrosine kinase, FLT3 was the first targetable genetic abnormality in AML. The first generation of FLT3 inhibitors were broad-spectrum kinase inhibitors that inhibited FLT3 among other proteins. Although clinically active, first-generation FLT3 inhibitors had limited success as single agents. This led to the development of a second generation of more selective FLT3 inhibitors. This review focuses on quizartinib, a potent second-generation FLT3 inhibitor. We discuss the clinical trial development, mechanisms of resistance, and the recent FDA decision to deny approval for quizartinib as a single agent in relapsed/refractory AML.
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PURPOSE: Minimizing post-operational neurological deficits as a result of brain surgery has been one of the most pertinent endeavours of neurosurgical research. Studies have utilised fMRIs, EEGs and MEGs in order to delineate and establish eloquent areas, however, these methods have not been utilized by the wider neurosurgical community due to a lack of clinical endpoints. We sought to ascertain if there is a correlation between graph theory metrics and the neurosurgical notion of eloquent brain regions. We also wanted to establish which graph theory based nodal centrality measure performs the best in predicting eloquent areas. METHODS: We obtained diffusion neuroimaging data from the Human Connectome Project (HCP) and applied a parcellation scheme to it. This enabled us to construct a weighted adjacency matrix which we then analysed. Our analysis looked at the correlation between PageRank centrality and eloquent areas. We then compared PageRank centrality to eigenvector centrality and degree centrality to see what the best measure of empirical neurosurgical eloquence was. RESULTS: Areas that are considered neurosurgically eloquent tended to be predicted by high PageRank centrality. By using summary scores for the three nodal centrality measures we found that PageRank centrality best correlated to empirical neurosurgical eloquence. CONCLUSION: The notion of eloquent areas is important to neurosurgery and graph theory provides a mathematical framework to predict these areas. PageRank centrality is able to consistently find areas that we consider eloquent. It is able to do so better than eigenvector and degree central measures.
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Mapeamento Encefálico/métodos , Encéfalo/cirurgia , Planejamento em Saúde/métodos , Neuroimagem/métodos , Neurocirurgia/métodos , Neurocirurgia/normas , Neoplasias Supratentoriais/cirurgia , Adulto , Idoso , Encéfalo/anatomia & histologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Vias Neurais , Neoplasias Supratentoriais/patologia , Adulto JovemRESUMO
PURPOSE OF REVIEW: This review highlights the importance of the Bcl-2 family members in lymphoma cell survival and discusses the approaches to modulate their function, directly or indirectly, to advance lymphoma therapeutics. RECENT FINDINGS: The balance of cell death versus survival is ultimately leveraged at the mitochondria. Mitochondrial outer membrane permeabilization (MOMP) is the critical event that governs the release of pro-apoptotic molecules from the intermembrane mitochondrial space. MOMP is achieved through the coordinated actions of pro- and anti-apoptotic Bcl-2 family member proteins. Recognition of functional alterations among the Bcl-2 family member proteins led to identification of tractable targets to combat hematologic malignancies. A new class of drugs, termed BH3 mimetics, was introduced in the clinic. Venetoclax, a Bcl-2 inhibitor, received regulatory approvals in therapy of chronic lymphocytic leukemia and acute myeloid leukemia. Alternative pro-survival Bcl-2 family proteins, in particular Mcl-1, have been successfully targeted in preclinical studies using novel-specific BH3 mimetics. Finally, anti-apoptotic Bcl-2 family members may be targeted indirectly, via interference with the pro-survival signaling pathways, e.g., phosphoinotiside-3 kinase, B-cell receptor signaling, and NF-κB.
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Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linfoma/tratamento farmacológico , Linfoma/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Linfoma/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: The purpose of this review is to summarize the pathophysiology of systemic mastocytosis, review the most recent clinical trials and drug development in systemic mastocytosis, with a specific focus on the advanced systemic mastocytosis subtypes. RECENT FINDINGS: Systemic mastocytosis is a clonal neoplasm of mast cells that has had a number of successful therapeutic options being developed in the past few years. The first therapeutic agent to be Food and Drug Administration (FDA) approved in decades was midostaurin in 2017 with a 60% response rate % with improvement in both end-organ damage and symptoms. However, complete responses/remissions with midostaurin have been elusive. Additional clinical trials of tyrosine kinase inhibitors that target the proto-oncogene receptor tyrosine kinase (KIT) mutation show great promise. The two drugs with promising early clinical trial data include avapritinib and DCC-2618 with avapritinib showing potential to induce complete remissions. SUMMARY: Therapies for systemic mastocytosis are in a stage of evolution with further elucidation of additional mutations associated with oncogenesis in addition to the most commonly described KIT (give details), ongoing clinical trials could potentially with lead to further targeted therapy and increased complete responses and durable remissions.
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Antineoplásicos/farmacologia , Mastocitose Sistêmica/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Humanos , Mastocitose Sistêmica/metabolismo , Proto-Oncogene Mas , Receptores Proteína Tirosina Quinases/metabolismoRESUMO
A proportion of classical Hodgkin lymphomas harbor the Epstein Barr virus (EBV). We previously demonstrated that associations between Human Leukocyte Antigen (HLA) alleles and susceptibility to EBV+ classical Hodgkin lymphoma differ between European and Chinese populations. Data on Hispanic populations is missing. Here we examined the association between HLA type, tumor cell HLA expression and other characteristics in Hispanic Hodgkin lymphoma patients. Hispanic Hodgkin lymphoma patients diagnosed at the Los Angeles County-University of Southern California Medical Center from 2000-2012 were included (n = 65). Formalin-fixed paraffin-embedded tumor tissue was analyzed for EBV by in situ hybridization and for HLA class I and class II expression by immunohistochemistry. HLA typing was performed by HLA-A specific quantitative PCR of genomic DNA from tissue. Thirty patients (46%) had EBV+ tumors. Expression of HLA class I (p = 0.0006) was significantly associated with EBV+ tumor status in Hispanic patients, similar to Europeans and Chinese. A positive association between HLA class II expression and EBV+ tumor status, as present in large studies in Europeans, was not found (p = 0.06). The prevalences of the specific European HLA-A*01 risk and European HLA-A*02 protective types were not significantly associated with EBV+ tumors among these Hispanic patients, however numbers were too low to draw firm conclusions. The HLA-A*02:07 allele, that is associated with EBV+ Hodgkin lymphoma in Chinese, was absent. In conclusion, the association between EBV positivity in tumor cells and HLA class I expression appears to be consistent across different populations. Larger studies in Hispanics are needed to evaluate HLA allele susceptibility associations.
Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Antígenos HLA/genética , Herpesvirus Humano 4/isolamento & purificação , Doença de Hodgkin/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Feminino , Frequência do Gene , Doença de Hodgkin/genética , Doença de Hodgkin/virologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
B-cell receptor (BCR) associated kinases including spleen tyrosine kinase (SYK) contribute to the pathogenesis of B-cell malignancies. SYK is persistently phosphorylated in a subset of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and SYK inhibition results in abrogation of downstream kinase activity and apoptosis. P505-15 (also known as PRT062607) is a novel, highly selective, and orally bioavailable small molecule SYK inhibitor (SYK IC(50) = 1 nM) with anti-SYK activity that is at least 80-fold greater than its affinity for other kinases. We evaluated the preclinical characteristics of P505-15 in models of NHL and CLL. P505-15 successfully inhibited SYK-mediated B-cell receptor signaling and decreased cell viability in NHL and CLL. Oral dosing in mice prevented BCR-mediated splenomegaly and significantly inhibited NHL tumor growth in a xenograft model. In addition, combination treatment of primary CLL cells with P505-15 plus fludarabine produced synergistic enhancement of activity at nanomolar concentrations. Our findings support the ongoing development of P505-15 as a therapeutic agent for B-cell malignancies. A dose finding study in healthy volunteers has been completed.
Assuntos
Antineoplásicos/farmacologia , Linfócitos B/efeitos dos fármacos , Cicloexilaminas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Vidarabina/análogos & derivados , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linfócitos B/enzimologia , Linfócitos B/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cicloexilaminas/administração & dosagem , Cicloexilaminas/farmacocinética , Cicloexilaminas/uso terapêutico , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Citometria de Fluxo , Humanos , Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma não Hodgkin/enzimologia , Linfoma não Hodgkin/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Fosforilação , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Baço/efeitos dos fármacos , Baço/enzimologia , Quinase Syk , Vidarabina/administração & dosagem , Vidarabina/farmacocinética , Vidarabina/farmacologia , Vidarabina/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Kinases are dysregulated in most cancers, but the frequency of specific kinase mutations is low, indicating a complex etiology in kinase dysregulation. Here, we report a strategy to rapidly identify functionally important kinase targets, irrespective of the etiology of kinase pathway dysregulation, ultimately enabling a correlation of patient genetic profiles to clinically effective kinase inhibitors. Our methodology assessed the sensitivity of primary leukemia patient samples to a panel of 66 small-molecule kinase inhibitors over 3 days. Screening of 151 leukemia patient samples revealed a wide diversity of drug sensitivities, with 70% of the clinical specimens exhibiting hypersensitivity to one or more drugs. From this data set, we developed an algorithm to predict kinase pathway dependence based on analysis of inhibitor sensitivity patterns. Applying this algorithm correctly identified pathway dependence in proof-of-principle specimens with known oncogenes, including a rare FLT3 mutation outside regions covered by standard molecular diagnostic tests. Interrogation of all 151 patient specimens with this algorithm identified a diversity of kinase targets and signaling pathways that could aid prioritization of deep sequencing data sets, permitting a cumulative analysis to understand kinase pathway dependence within leukemia subsets. In a proof-of-principle case, we showed that in vitro drug sensitivity could predict both a clinical response and the development of drug resistance. Taken together, our results suggested that drug target scores derived from a comprehensive kinase inhibitor panel could predict pathway dependence in cancer cells while simultaneously identifying potential therapeutic options.