A phase 3b study of venetoclax and azacitidine or decitabine in an outpatient setting in patients with acute myeloid leukemia.

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.

Evidence for phonon hardening in laser-excited gold using x-ray diffraction at a hard x-ray free electron laser.

Studies of laser-heated materials on femtosecond timescales have shown that the interatomic potential can be perturbed at sufficiently high laser intensities. For gold, it has been postulated to undergo a strong stiffening leading to an increase of the phonon energies, known as phonon hardening. Despite efforts to investigate this behavior, only measurements at low absorbed energy density have been performed, for which the interpretation of the experimental data remains ambiguous. By using in situ single-shot x-ray diffraction at a hard x-ray free-electron laser, the evolution of diffraction line intensities of laser-excited Au to a higher energy density provides evidence for phonon hardening.

Frequency of and associations with alterations of medical emergency team calling criteria in a teaching hospital emergency department.

BACKGROUND: Medical emergency team (METs), activated by vital sign-based calling criteria respond to deteriorating patients in the hospital setting. Calling criteria may be altered where clinicians feel this is appropriate. Altered calling criteria (ACC) has not previously been evaluated in the emergency department (ED) setting. OBJECTIVES: The objectives of this study were to (i) describe the frequency of ACC in a teaching hospital ED and the number and type of vital signs that were modified and (ii) associations between ACC in the ED and differences in the baseline patient characteristics and adverse outcomes including subsequent MET activations, unplanned intensive care unit (ICU) admissions and death within 72 h of admission. METHODS: Retrospective observational study of patients presenting to an academic, tertiary hospital ED in Melbourne, Australia between January 1st, 2019 and December 31st, 2019. The primary outcome was frequency and nature of ACC in the ED. Secondary outcomes included differences in baseline patient characteristics, frequency of MET activation, unplanned ICU admission, and mortality in the first 72 h of admission between those with and without ACC in the ED. RESULTS: Amongst 14 159 ED admissions, 725 (5.1%) had ACC, most frequently for increased heart or respiratory rate. ACC was associated with older age and increased comorbidity. Such patients had a higher adjusted risk of MET activation (odds ratio [OR]: 3.14, 95% confidence interval [CI]: 2.50-3.91, p = <0.001), unplanned ICU admission (OR: 1.97, 95% CI: 1.17-3.14, p = 0.016), and death (OR: 3.87, 95% CI: 2.08-6.70, p = 0.020) within 72 h. CONCLUSIONS: ACC occurs commonly in the ED, most frequently for elevated heart and respiratory rates and is associated with worse patient outcomes. In some cases, ACC requires consultant involvement, more frequent vital sign monitoring, expeditious inpatient team review, or ICU referral.

Intensive care unit admission from the emergency department in the setting of National Emergency Access Targets.

Purpose: Since the introduction of National Emergency Access Targets (NEATs) in 2012 there has been little research examining patients admitted to the intensive care unit (ICU).We assessed differences in baseline characteristics and outcomes of patients admitted from the Emergency Department (ED) to the ICU within 4 hours compared with patients who were not. Methods: This retrospective observational study included all adults (≥18 years old) admitted to the ICU from the ED of Austin Hospital, Melbourne, Australia, between 1 January 2017 and 31st December 2019 inclusive. Results: 1544 patients were admitted from the ED to the ICU and 65% had an ED length of stay (EDLOS) > 4 hour. Such patients were more likely to be older, female, with less urgent triage category scores and lower illness severity. Sepsis and respiratory admission diagnoses, and winter presentations were significantly more prevalent in this group.After adjustment for confounders, patients with an EDLOS > 4 hours had lower hospital mortality; 8% v 21% (p = 0.029; OR, 1.62), shorter ICU length of stay 2.2 v 2.4 days (p = 0.043), but a longer hospital length of stay 6.2 v 6.8 days (p = < 0.001). Conclusion: Almost two thirds of patients breached the NEAT of 4 hours. These patients were more likely to be older, female, admitted in winter with sepsis and respiratory diagnoses, and have lower illness severity and less urgent triage categories. NEAT breach was associated with reduced hospital mortality but an increased hospital length of stay.

Multimodal intrathecal analgesia (MITA) with morphine for reducing postoperative opioid use and acute pain following hepato-pancreato-biliary surgery: A multicenter retrospective study.

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.

X-ray Thomson scattering spectra from density functional theory molecular dynamics simulations based on a modified Chihara formula.

We study ab initio approaches for calculating x-ray Thomson scattering spectra from density functional theory molecular dynamics simulations based on a modified Chihara formula that expresses the inelastic contribution in terms of the dielectric function. We study the electronic dynamic structure factor computed from the Mermin dielectric function using an ab initio electron-ion collision frequency in comparison to computations using a linear-response time-dependent density functional theory (LR-TDDFT) framework for hydrogen and beryllium and investigate the dispersion of free-free and bound-free contributions to the scattering signal. A separate treatment of these contributions, where only the free-free part follows the Mermin dispersion, shows good agreement with LR-TDDFT results for ambient-density beryllium, but breaks down for highly compressed matter where the bound states become pressure ionized. LR-TDDFT is used to reanalyze x-ray Thomson scattering experiments on beryllium demonstrating strong deviations from the plasma conditions inferred with traditional analytic models at small scattering angles.

Ethics and the Future of Meaningful Work: Introduction to the Special Issue.

The world of work over the past 3 years has been characterized by a great reset due to the COVID-19 pandemic, giving an even more central role to scholarly discussions of ethics and the future of work. Such discussions have the potential to inform whether, when, and which work is viewed and experienced as meaningful. Yet, thus far, debates concerning ethics, meaningful work, and the future of work have largely pursued separate trajectories. Not only is bridging these research spheres important for the advancement of meaningful work as a field of study but doing so can potentially inform the organizations and societies of the future. In proposing this Special Issue, we were inspired to address these intersections, and we are grateful to have this platform for advancing an integrative conversation, together with the authors of the seven selected scholarly contributions. Each article in this issue takes a unique approach to addressing these topics, with some emphasizing ethics while others focus on the future aspects of meaningful work. Taken together, the papers indicate future research directions with regard to: (a) the meaning of meaningful work, (b) the future of meaningful work, and (c) how we can study the ethics of meaningful work in the future. We hope these insights will spark further relevant scholarly and practitioner conversations.

Postoperative complications and hospital costs following open radical cystectomy: A retrospective study.

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.

Study protocol for PREPARE: a phase II feasibility/safety randomised controlled trial on PeRiopErative Penicillin AlleRgy TEsting.

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.

High-flow oxygen via oxygenating mouthguard in short upper gastrointestinal endoscopy: A randomised controlled trial.

BACKGROUND: Anaesthetic care during upper gastrointestinal (GI) endoscopy has the unique challenge of maintaining ventilation and oxygenation via a shared upper airway. Supplemental oxygen is recommended by international society guidelines, however, the optimal route or rate of oxygen delivery is not known. Various oxygen delivery devices have been investigated to improve oxygenation during upper GI endoscopy, however, these are limited by commercial availability, costs and in some cases, the expertise required for insertion. Anecdotally at our centre, higher flows of supplemental oxygen can safely be delivered via an oxygenating mouthguard routinely used during upper GI endoscopic procedures. AIM: To assess the incidence of hypoxaemia (SpO2 < 90%) in patients undergoing upper GI endoscopy receiving supplemental oxygen using an oxygenating mouthguard at 20 L/min flow compared to standard nasal cannula (SNC) at 2 L/min flow. METHODS: A single centre, prospective, randomised clinical trial at two sites of an Australian tertiary hospital between October 2020 and September 2021 was conducted. Patients undergoing elective upper gastrointestinal endoscopy under deep sedation were randomised to receive supplemental oxygen via high-flow via oxygenating mouthguard (HFMG) at 20 L/min flow or SNC at 2 L/min flow. The primary outcome was the incidence of hypoxaemia of any duration measured by pulse oximetry. Intraprocedural-related, procedural-related, and sedation-related adverse events and patient-reported outcomes were also recorded. RESULTS: Three hundred patients were randomised. Eight patients were excluded after randomisation. 292 patients were included in the intention-to-treat analysis. The incidence of hypoxaemia was significantly reduced in those allocated HFMG. Six patients (4.4%) allocated to HFMG experienced an episode of hypoxaemia, compared to thirty-four (22.1%) patients allocated to SNC (P value < 0.001). No significant difference was observed in the rates of adverse events or patient-reported outcome measures. CONCLUSION: The use of HFMG offers a novel approach to reducing the incidence of hypoxaemia during short upper gastrointestinal endoscopic procedures in low-risk patients undergoing deep sedation.

The Association of Postoperative Complications and Hospital Costs Following Distal Pancreatectomy.

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]).

The association between unanticipated prolonged post-anaesthesia care unit length of stay and early postoperative deterioration: A retrospective cohort study.

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.

Anatomy and White Matter Connections of the Superior Parietal Lobule.

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.

Graft-versus-host disease after liver transplantation is associated with bone marrow failure, hemophagocytosis, and DNMT3A mutations.

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.

IDH Inhibitors in AML-Promise and Pitfalls.

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.

The association of acute hypercarbia and plasma potassium concentration during laparoscopic surgery: a retrospective observational study.

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).

Profile of Quizartinib for the Treatment of Adult Patients with Relapsed/Refractory FLT3-ITD-Positive Acute Myeloid Leukemia: Evidence to Date.

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.

Cell Death Pathways in Lymphoid Malignancies.

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.