How comparable are patient outcomes in the "real-world" with populations studied in pivotal AML trials?

Despite an increasing desire to use historical cohorts as "synthetic" controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012-2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.

Accuracy and Reliability of Smartphone Virtual Shade-Matching Technique: An In Vitro Study.

PURPOSE: To determine and compare the accuracy and reliability of shade matching using the conventional and smartphone virtual methods. MATERIALS AND METHODS: A phantom head with both maxillary central incisors removed was set up. A central incisor of various standard shades was inserted into the phantom head. Five undergraduate and five postgraduate students were asked to select the closest shade to match the central incisor using the Vita Classic shade guide. The procedure was then repeated using images taken by a smartphone. Each technique was repeated three times. Differences in accuracy of shade matching between the two techniques for every shade tab and between undergraduate and postgraduate dental students were compared using chi-square statistical analysis. The P value was set at .001. Differences in intra-rater and inter-rater reliability between the two techniques and among the three sessions were compared using paired t test and analysis of variance (ANOVA), respectively, with a P value of .05. The reliability of both techniques was further measured using Cohen kappa statistical test. RESULTS: The smartphone virtual shade-matching technique showed significantly higher accuracy in shade matching with most of the tested shade tabs than the conventional method (P < .001), irrespective of observers' clinical experience. Higher repeatability was found in the virtual technique than the conventional technique, with higher intra-rater and inter-rater reliability observed. CONCLUSION: Smartphone virtual shade matching showed better accuracy and reliability than the conventional method and could be used as an alternative shade-matching method.

Ultrasound-Guided Scalp Blocks for an Awake Craniotomy: A Case Report.

Ultrasound-guided scalp blocks may revolutionize regional anesthesia for neurosurgery. In this report, we demonstrate that ultrasound-guided scalp blocks can be used effectively for a craniotomy. A 48-year-old patient with a brain tumor at the motor cortex was scheduled for an awake craniotomy. Ultrasound-guided scalp blocks targeting the bilateral supraorbital, supratrochlear, zygomaticotemporal, auriculotemporal, greater auricular, lesser occipital, greater occipital, and third occipital nerves were performed. A total of 29 mL of levobupivacaine 0.3% was used. No additional local anesthetic agent was given for skull pinning, skin incision, or the craniotomy. Postoperatively, the patient remained pain-free, and she was discharged without complications.

Trends in direct oral anticoagulant use in patients presenting with acute stroke.

Acute ischaemic strokes occur despite the use of direct oral anticoagulants (DOACs). A retrospective review was conducted at a high-volume primary stroke centre over a 3-year period to assess the acute management of stroke presentations in patients prescribed DOACs. During the time period of the study, 103 of 195 anticoagulated stroke patients presented within the timeframe for thrombolysis and only 15 patients had DOAC plasma level assays performed. Of these 103, 5 received thrombolysis; however, DOAC level was not a factor in these cases.

Chronic Subdural Hematoma Drainage Under Local Anesthesia with Sedation versus General Anesthesia and Its Outcome.

BACKGROUND: Burr hole drainage is the criterion standard treatment for chronic subdural hematoma (CSDH), a common neurosurgical condition. However, apart from the surgical technique, the method of anesthesia also has a significant impact on postoperative patient outcome. Currently, there are limited studies comparing the use of local anesthesia with sedation (LA sedation) versus general anesthesia (GA) in the drainage of CSDH. The objective of this study was to compare the morbidity and mortality outcomes of using LA sedation versus GA in CSDH burr hole drainage. METHODS: This retrospective study presents a total of 257 operations in 243 patients from 2 hospitals. A total of 130 cases were operated under LA sedation in hospital 1 and 127 cases under GA in hospital 2. Patient demographics and presenting features were similar at baseline. RESULTS: Values are shown as LA sedation versus GA. Postoperatively, most patients recovered well in both groups with Glasgow Outcome Scale scores of 4-5 (96.2% vs. 88.2%, respectively). The postoperative morbidity was significantly increased by an odds ratio of 5.44 in the GA group compared with the LA sedation group (P = 0.005). The mortality was also significantly higher in the GA group (n = 5, 3.9%) than the LA sedation group (n = 0, 0.0%; P = 0.028). The CSDH recurrence rate was 4.6% in the LA sedation group versus 6.3% in the GA group. No intraoperative conversion from LA sedation to GA was reported. CONCLUSIONS: This study demonstrates that CSDH drainage under LA sedation is safe and efficacious, with a significantly lower risk of postoperative mortality and morbidity when compared with GA.

Inconsistent idealizations and inferentialism about scientific representation.

Inferentialists about scientific representation hold that an apparatus's representing a target system consists in the apparatus allowing "surrogative inferences" about the target. I argue that a serious problem for inferentialism arises from the fact that many scientific theories and models contain internal inconsistencies. Inferentialism, left unamended, implies that inconsistent scientific models have unlimited representational power, since an inconsistency permits any conclusion to be inferred. I consider a number of ways that inferentialists can respond to this challenge before suggesting my own solution. I develop an analogy to exploitable glitches in a game. Even though inconsistent representational apparatuses may in some sense allow for contradictions to be generated within them, doing so violates the intended function of the apparatus's parts and hence violates representational "gameplay".

Evaluation of immature platelet fraction as a marker of dengue fever progression.

OBJECTIVES: Progression of dengue is often associated with thrombocytopenia resulting from viral-induced bone marrow suppression and immune-mediated peripheral platelet consumption. Immature platelet fraction (IPF), which can be measured using a haematology analyser, is a precursor indicating platelet formation in the bone marrow. This study evaluated the trend of IPF as an early recovery indicator of platelets in dengue patients with thrombocytopenia, and its relationship with severe dengue in conjunction with reticulocyte count. METHODS: Hospitalized patients with dengue were enrolled and followed-up daily until discharge. Blood investigations included daily full blood counts and IPF measured using a haematology analyser. RESULTS: In total, 287 patients with confirmed dengue were enrolled in this study, 25 of whom had severe dengue. All patients had a decreasing trend in platelet count in the first week of illness, concomitant with an increasing trend in the percentage of immature platelets to total platelets (IPF%) for more than 3 days prior to platelet recovery. IPF% was significantly increased in patients with severe dengue compared with patients with non-severe dengue on days 3-5 after the onset of fever. Reticulocyte count increased significantly in patients with severe dengue on day 5. CONCLUSIONS: IPF can be utilized as an early recovery indicator of platelets in patients with dengue and thrombocytopenia.

Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia.

PURPOSE: Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (mIDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition-related differentiation and apoptosis. PATIENTS AND METHODS: This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed mIDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922). RESULTS: Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). mIDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission. CONCLUSION: Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving mIDH1 mutation clearance.

Utility of directional high-density mapping catheter (AdvisorTM HD Grid) in complex scar-related atrial tachycardia.

Mapping of scar-related atrial tachycardias (AT) can be challenging even with the use of high-density (HD) mapping catheter. AdvisorTM HD Grid is the only directional HD mapping catheter which not only identify local electrical signal but more importantly capture the direction of wave front propagation especially in low voltage zone. Accordingly, we present a case of complex scar-related AT with the use of AdvisorTM HD Grid which showed clear fractionated signal at isthmus area as compare to the absence of signal on ablation catheter at the same area despite adequate contact force. Ablation at this area terminated the tachycardia.

Comparing the outcome of monitored anaesthesia care and local anaesthesia for carpal tunnel syndrome surgery by neurosurgeons

@#Introduction: Carpal tunnel syndrome (CTS) is the commonest median nerve entrapment neuropathy of the hand, up to 90% of all nerve compression syndromes. The disease is often treated with conservative measures or surgery. The senior author initially intended to treat his own neurosurgical patients concurrently diagnosed with carpal tunnel syndrome in 2014, subsequently, he began to pick up more referrals from the primary healthcare group over the years. This has led to the setup of a peripheral and spine clinic to act as a hub of referrals. Objective: Department of Neurosurgery Sarawak aimed to evaluate the surgical outcome of carpal tunnel release done over five years. Methods: The carpal tunnel surgeries were done under local anaesthesia (LA) given by neurosurgeons (Bupivacaine 0.5% or Lignocaine 2%). Monitored anaesthesia care (MAC) was later introduced by our hospital neuroanaesthetist in the beginning of 2018 (Target-controlled infusion propofol and boluses of fentanyl). We looked into our first 17 cases and compared these to the two anaesthesia techniques (LA versus MAC + LA) in terms of patient’s pain score based on visual analogue scale (VAS). Results: Result showed MAC provided excellent pain control during and immediately after the surgery. None experienced anaesthesia complications. There was no difference in pain control at post-operation one month. Both techniques had equal good clinical outcome during patients’ clinic follow up. Conclusion: Neurosurgeons provide alternative route for CTS patients to receive surgical treatment. Being a designated pain free hospital, anaesthetist collaboration in carpal tunnel surgery is an added value and improves patients overall experience and satisfaction.

Efficacy and safety of nilotinib 300 mg twice daily in patients with chronic myeloid leukemia in chronic phase who are intolerant to prior tyrosine kinase inhibitors: Results from the Phase IIIb ENESTswift study.

BACKGROUND: Some patients receiving a tyrosine kinase inhibitor (TKI) for the first-line treatment of chronic phase chronic myeloid leukemia (CML-CP) experience intolerable adverse events. Management strategies include dose adjustments, interrupting or discontinuing therapy, or switching to an alternative TKI. METHODS: This multicenter, single-arm, Phase IIIb study included CML-CP patients intolerant of, but responsive to, first-line treatment with imatinib or dasatinib. All patients were switched to nilotinib 300 mg bid for up to 24 months. The primary endpoint was achievement of MR4.5 (BCR-ABL transcript level of ≤0.0032% on the International Scale) by 24 months. RESULTS: Twenty patients were enrolled in the study (16 imatinib-intolerant, 4 dasatinib-intolerant); which was halted early because of low recruitment. After the switch to nilotinib 300 mg bid, MR4.5 at any time point up to month 24 was achieved in 10 of 20 patients (50%) in the full analysis set. Of the non-hematological adverse events associated with intolerance to prior imatinib or dasatinib, 74% resolved within 12 weeks of switching to nilotinib 300 mg bid. CONCLUSION: Nilotinib 300 mg bid shows minimal cross intolerance in patients with CML-CP who have prior toxicities to other TKIs and can lead to deep molecular responses.

Cellular Immunotherapy for Hematologic Malignancies: Beyond Bone Marrow Transplantation.

Immunotherapy has changed treatment practices for many hematologic malignancies. Even in the current era of targeted therapy, chemotherapy remains the backbone of treatment for many hematologic malignancies, especially in acute leukemias, where relapse remains the major cause of mortality. Application of novel immunotherapies in hematology attempts to harness the killing power of the immune system against leukemia and lymphoma. Cellular immunotherapy is evolving rapidly for high-risk hematologic disorders. Recent advances include chimeric antigen-receptor T cells, mesenchymal stromal/stem cells, dendritic cell tumor vaccines, cytokine-induced killer cells, and virus-specific T cells. The advantages of nontransplantation cellular immunotherapy include suitability for patients for whom transplantation has failed or is contraindicated, and a potentially less-toxic treatment alternative to transplantation for relapsed/refractory patients. This review examines those emerging cellular immunotherapies that are changing treatment paradigms for patients with hematologic malignancies.

Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia.

MYH9-related disorders (MYH9-RDs) caused by mutation of the MYH9 gene which encodes non-muscle myosin heavy-chain-IIA (NMMHC-IIA), an important motor protein in hemopoietic cells, are the most commonly encountered cause of inherited macrothrombocytopenia. Despite distinguishing features including an autosomal dominant mode of inheritance, giant platelets on the peripheral blood film accompanied by leucocytes with cytoplasmic inclusion bodies (döhle-like bodies), these disorders remain generally under-recognized and often misdiagnosed as immune thrombocytopenia (ITP). This may result in inappropriate treatment with corticosteroids, immunosupressants and in some cases, splenectomy. We explored the efficacy of next generation sequencing (NGS) with a candidate gene panel to establish the aetiology of thrombocytopenia for individuals who had been referred to our center from hematologists in the Australasian region in whom the cause of thrombocytopenia was suspected to be secondary to an inherited condition but which remained uncharacterized despite phenotypic investigations. Pathogenic MYH9 variants were detected in 15 (15/121, 12.4%) individuals and the pathogenecity of a novel variant of uncertain significance was confirmed in a further two related individuals following immunofluorescence (IF) staining performed in our laboratory. Concerningly, only one (1/17) individual diagnosed with MYH9-RD had been referred with this as a presumptive diagnosis, in all other cases (16/17, 94.1%), a diagnosis was not suspected by referring clinicians, indicating a lack of awareness or a failing of our diagnostic approach to these conditions. We examined the mean platelet diameter (MPD) measurements as a means to better identify and quantify platelet size. MPDs in cases with MYH9-RDs were significantly larger than controls (p < 0.001) and in 91% were greater than a previously suggested threshold for platelets in cases of ITP. In addition, we undertook IF staining in a proportion of cases and confirm that this test and/or NGS are satisfactory diagnostic tests. We propose that fewer cases of MYH9-RDs would be missed if diagnostic algorithms prioritized IF and/or NGS in cases of thrombocytopenia associated with giant platelets, even if döhle-like bodies are not appreciated on the peripheral blood film. Finally, our report describes the long-term use of a thrombopoietin agonist in a case of MYH9-RD that had previously been diagnosed as ITP, and demonstrates that treatment with these agents may be possible, and is well tolerated, in this group of patients.

The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia: a phase Ib/II study.

Therapeutic options are limited in relapsed/refractory acute myeloid leukemia (AML). We evaluated the maximum tolerated dose (MTD) and preliminary efficacy of mammalian target of rapamycin (mTOR) inhibitor, everolimus (days 5-21) in combination with azacitidine 75 mg/m2 subcutaneously (days 1-5 and 8-9 every 28 days) in 40 patients with relapsed (n = 27), primary refractory (n = 11) or elderly patients unfit for intensive chemotherapy (n = 2). MTD was not reached following everolimus dose escalation (2.5, 5 or 10 mg; n = 19) to the 10 mg dose level which was expanded (n = 21). Major adverse events (grade > 2) were mostly disease-related: neutropenia (73%), thrombocytopenia (67%), mucositis (24%) and febrile neutropenia (19%). Overall survival (OS) of the entire cohort was 8.5 months, and overall response rate (ORR; including CR/CRi/PR/MLFS) was 22.5%. Furthermore, a landmark analysis beyond cycle 1 revealed superior OS and ORR in patients receiving 2.5 mg everolimus with azoles, compared to those without azoles (median OS 12.8 vs. 6.0 months, P = 0.049, and ORR 50% vs. 16%, P = 0.056), potentially due to achievement of higher everolimus blood levels. This study demonstrates that everolimus in combination with azacitidine is tolerable, with promising clinical activity in advanced AML.

Post-transitional adaptation of the left heart in uncomplicated, very preterm infants.

BACKGROUND: The postnatal period in preterm infants involves multiple physiological changes occurring immediately after birth and continuing for days or weeks. To recognise and treat compromise, it is important to measure cardiovascular function. The aim of this study was to describe longitudinal left ventricular function using conventional and novel echocardiography techniques in preterm infants who did not experience significant antenatal or postnatal complications and treatments. METHODS: We prospectively obtained cardiac ultrasound images at days 3, 7, 14, 21, and 28 in 25 uncomplicated, preterm infants <30 weeks of gestation. Speckle tracking analysis of the four chambers and short-axis images provided parameters of left ventricular volume, deformation, and basal myocardial velocities. The patent ductus arteriosus, cardiac dimensions, and atrial volume were also measured. RESULTS: Stroke volume increased by 24% during the study period (1.05-1.30 ml/kg, p<0.05). Cardiac length, diameter, and systolic basal myocardial velocity increased with unchanged wall stress and deformation parameters. Diastolic function parameters resembled that of the fetus with predominance of atrial contraction compared with early diastolic velocities. Blood pressure and estimates of left ventricular filing pressure increased, suggesting that left ventricular compliance did not change in this period. CONCLUSION: Stroke volume increased in the first 28 days after preterm birth. The preterm heart adapted by increasing its size, while maintaining systolic and atrial function, independent of early diastolic maturation. Longitudinal deformation of the left ventricle remained unchanged, suggesting relatively preserved function with maturation.

Cardiac Function After the Immediate Transitional Period in Very Preterm Infants Using Speckle Tracking Analysis.

BACKGROUND: The postnatal period in preterm infants involves multiple physiologic changes starting directly after birth and continuing for days or weeks. To recognize and treat compromise, it is important to measure cardiovascular function. We used a novel technique (speckle tracking echocardiography, STE) to measure cardiac function in this period. METHODS: We obtained cardiac ultrasound images at day 3, 7, 14, 21 and 28 in preterm infants <30-week gestation. Conventional measures included cardiac size, left ventricular stroke volume, atrial volume and the patent ductus arteriosus (PDA). Four chamber images were analyzed with STE, which provided parameters of left ventricular volume, longitudinal deformation and myocardial velocities. RESULTS: Images of 54 infants (gestational age 23-29 weeks) were analyzed. STE-derived stroke volume correlated well with conventional echocardiography-derived stroke volume, but agreement was suboptimal. Most STE parameters showed good reliability. All volume parameters and systolic and atrial velocities increased over time. Cardiac deformation and early diastolic velocity did not change. A PDA was associated with 33 % increased stroke volume at day 3 up to 98 % at day 28 with a spherically enlarged heart and increased filling pressure. CONCLUSION: Speckle tracking echocardiography analysis is a feasible and reliable technique that can simultaneously obtain systolic and diastolic volumes, longitudinal deformation and myocardial velocities from one ultrasound window. Preterm hearts maintain cardiac function well during the first weeks of life, even with increased preload as a consequence of a PDA.