GSTZ1 genotypes correlate with dichloroacetate pharmacokinetics and chronic side effects in multiple myeloma patients in a pilot phase 2 clinical trial

Dichloroacetate (DCA) is an investigational drug targeting the glycolytic hallmark of cancer by inhibiting pyruvate dehydrogenase kinases (PDK). It is metabolized by GSTZ1, which has common polymorphisms altering enzyme or promoter activity. GSTZ1 is also irreversibly inactivated by DCA. In the first clinical trial of DCA in a hematological malignancy, DiCAM (DiChloroAcetate in Myeloma), we have examined the relationship between DCA concentrations, GSTZ1 genotype, side effects, and patient response. DiCAM recruited seven myeloma patients in partial remission. DCA was administered orally for 3 months with a loading dose. Pharmacokinetics were performed on day 1 and 8. Trough and peak concentrations of DCA were measured monthly. GSTZ1 genotypes were correlated with drug concentrations, tolerability, and disease outcomes. One patient responded and two patients showed a partial response after one month of DCA treatment, which included the loading dose. The initial half‐life of DCA was shorter in two patients, correlating with heterozygosity for GSTZ1*A genotype, a high enzyme activity variant. Over 3 months, one patient maintained DCA trough concentrations approximately threefold higher than other patients, which correlated with a low activity promoter genotype (−1002A, rs7160195) for GSTZ1. This patient displayed the strongest response, but also the strongest neuropathy. Overall, serum concentrations of DCA were sufficient to inhibit the constitutive target PDK2, but unlikely to inhibit targets induced in cancer. Promoter GSTZ1 polymorphisms may be important determinants of DCA concentrations and neuropathy during chronic treatment. Novel dosing regimens may be necessary to achieve effective DCA concentrations in most cancer patients while avoiding neuropathy.This work was supported by The Canberra Hospital Private Practice Trust Fund, Cancer Council ACT Project Grant APP1103848, and the Monaro Committee for Cancer Researc

Classification of Heart Disease Using Resilient Back Propagation Algorithm

Heart disease diagnosis is a complex taskwhich requires much experience and knowledge.Traditional way of predicting Heart disease isdoctor’s examination or number of medical testssuch as ECG, Stress Test, and Heart MRI etc.Computer based information along with advancedneural network techniques are used forappropriate results. In many application domains,classification of complex measurements isessential in a diagnosis process. Correctclassification of measurements may in fact be themost critical part of the diagnostic process.Neural Networks have emerged as an importanttool for classification. In this system, we intend todetermine whether a patient has heart disease ornot and if we have heart disease what stage is it byusing multilayer feed forward neural network withresilient back propagation algorithm .Experiments were evaluated on some publicdatasets collected from the Cleveland ClinicFoundation in the UCI (University of California,Irvine) machine learning repository in order totest this system

Australasian Trends in Allogeneic Stem Cell Transplantation for Myelofibrosis in the Molecular Era: A Retrospective Analysis from the Australasian Bone Marrow Transplant Recipient Registry

To review the updated trends of national practice and outcomes in transplantation to treat myelofibrosis (MF), we retrospectively evaluated 142 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) for primary (n = 94) or secondary (n = 48) MF at an Australian/New Zealand transplantation center between 2006 and 2017. The median duration of follow-up was 51.8 months (range, 3.1 to 148 months). The median age at allo-HSCT was 56 years (range, 26 to 69 years). Fifty-two percent of the patients had HLA-identical sibling donors, and 45% had matched unrelated donors (UD). Conditioning regimens were predominantly reduced intensity (83%). Before transplantation, 16% of the patients had undergone splenectomy or splenic irradiation, and 38% (n = 54) received JAK inhibitor therapy. JAK2 mutation testing was performed in 66.9% of the patients, whereas other mutations (CALR, MPL, ASXL1, SRSF2, U2AF1Q57, EZH2, and IDH1/2) were rarely tested (1.4% to 8.4%). Only 4.2% of patients had next-generation sequencing mutation analysis. The median time to neutrophil engraftment was 19 days (range, 10 to 43 days), and the median time to platelet engraftment was 27 days (range, 13 to 230 days). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 21.4% at 100 days, and that of extensive chronic GVHD (cGVHD) at 5 years was 18.1%. Overall survival (OS) was 67% at 1 year and 57% at 5 years. GVHD-free, relapse-free survival was 54% at 1 year and 42% at 5 years. The cumulative incidence of nonrelapse mortality (NRM) was 16% at 100 days and 25% at 1 year. In multivariate analysis, age ≥65 years and use of an UD were identified as significant unfavorable risk factors for OS and NRM. Use of an UD increased the incidence of aGVHD, whereas administration of antithymocyte globulin/alemtuzumab lowered the risk of both aGVHD and cGVHD. Pretransplantation splenectomy/splenic irradiation had a positive influence on time to engraftment. There have been no improvements in the outcomes of allo-HSCT for MF in Australasia over the last decade, with a low uptake of molecular genomic technology due to limited access to funding

Are we using the relevant questionnaires to assess health related quality of life in multiple myeloma patients in the era of new generation targeted and novel immunotherapies?

  Therapeutic advances have significantly improved the survival of multiple myeloma (MM) patients. Clinicians and researchers should ensure that patients with this incurable cancer are not only living longer, but also living better. Several validated questionnaires are available and frequently used to assess health related quality of life (HRQOL). However, they were developed >20 years ago before the era of new generation treatments, which have unique toxicity profiles. Introduction of new treatment combinations and maintenance therapies also means that these questionnaires may not be able to fully capture all HRQOL aspects. To better understand which of these aspects are truly important, we asked MM patients and healthcare professionals (HCP) from a single centre to indicate the level of relevance of each item in 9 HRQOL questionnaires. Our results revealed that patients ranked items related to social functioning, receiving information about MM and involvement in their management as most relevant. In contrast, HCPs placed highest relevance to items corresponding to symptoms from MM or treatment toxicities. Subgroup analysis of patients revealed additional topics that were deemed relevant: those ≤70 y.o. were more concerned about disease progression whereas those >70 y.o. prioritised items related to physical function; patients with renal impairment and bone disease found having energy and pain more relevant than in the general MM cohort. These findings can contribute to guiding the content development of new HRQOL tools relevant to both MM patients as a whole, as well as specific subgroups receiving newer treatments. </p

Allogeneic hematopoietic stem cell transplantation outcome in oldest known surviving patients with Wiskott-Aldrich syndrome

Regardless of their age, adult patients with Wiskott-Aldrich syndrome should be considered for hematopoietic stem cell transplantation if clinically indicated

Acute immune signatures and their legacies in severe acute respiratory syndrome coronavirus-2 infected cancer patients

Given the immune system's importance for cancer surveillance and treatment, we have investigated how it may be affected by SARS-CoV-2 infection of cancer patients. Across some heterogeneity in tumor type, stage, and treatment, virus-exposed solid cancer patients display a dominant impact of SARS-CoV-2, apparent from the resemblance of their immune signatures to those for COVID-19+ non-cancer patients. This is not the case for hematological malignancies, with virus-exposed patients collectively displaying heterogeneous humoral responses, an exhausted T cell phenotype and a high prevalence of prolonged virus shedding. Furthermore, while recovered solid cancer patients' immunophenotypes resemble those of non-virus-exposed cancer patients, recovered hematological cancer patients display distinct, lingering immunological legacies. Thus, while solid cancer patients, including those with advanced disease, seem no more at risk of SARS-CoV-2-associated immune dysregulation than the general population, hematological cancer patients show complex immunological consequences of SARS-CoV-2 exposure that might usefully inform their care