Stem cell transplantation of children with Acute Leukemia

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Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma

High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1, RAD51C or RAD51D was identified. In five of six paired post-progression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations

Waldenstrom's Macroglobulinemia : report of 8 cases

Background: Waldenstrom's Macroglobulinemia (WM) is a lymphoproliferative disorder characterized by neoplastic B-lymphocytes infiltrating the bone marrow and other lymphoid organs with the production of monoclonal IgM protein. Patients and Methods: In this report, we review the cases of WM seen at IRCH, AIIMS, New Delhi, in the last 5 years. Criteria for diagnosis included serum monoclonal IgM protein along with 20 percent bone marrow lymphocytes. Eight cases were included in the study with a median age of 59.5 years at diagnosis and male/female ratio 7:1. Two patients were asymptomatic at diagnosis. The common clinical features at presentation were fatigue (100 percent), malaise (100 percent), bleeding tendencies (66.6 percent), symptoms suggestive of hyperviscosity (33.3 percent). Anemia was seen in 75 percent cases, hepatomegaly in 37.5 percent cases, splenomegaly in 25 percent cases, lymphadenopathy in 12.5 percent cases. None had peripheral neuropathy. Laboratory investigations revealed a mean Hb8.1g/dl, mean TLC 6.2' 10/1, mean platelet count 1.09 ' 10/1 and mean ESR 100.6 mm/hr. 75 percent cases had diffuse bone marrow involvement by lympho/lymphoplasmacytoid cells. The mean serum M spike concentration was 3.18g/dl and all the patients had IgM kappa subtype. As initial therapy, 5 patients received Chlorambucil/Prednisolone, 1 patient received VAD chemotherapy and the other 2 asymptomatic patients were observed without any therapy. None had complete response. 2 had partial response while 3 had minimal response. One of the asymptomatic case progressed after a period of 18 months of observation. 7 out of 8 cases were alive at the time last follow up. The overall median survival was 19.5 months and progression free survival was 16.3 months. Conclusion: Though a rare disorder, high clinical suspicion is required to diagnose WM. Therapy with Chlorambucil/Prednisolone provides adequate disease control

High dose chemotherapy followed by autologous haemopoietic stem cell transplant in multiple myeloma

Background: High dose chemotherapy followed by autologous stem cell transplant is currently used for the treatment of patients with advanced multiple myeloma. However, there are no reports of the results of this treatment modality in Indian patients. Methods. Fifty patients with advanced multiple myeloma underwent treatment with high dose melphalan followed by autologous stem cell transplant (bone marrow: 7; peripheral blood stem cells: 43). The patients' ages ranged from 26 to 65 years (median: 52 years) and 35 were men. All patients had receivedchemotherapyinitiallywithameanof9.4cycles(range: 1-36). Thirty patients had evidence of chemosensitive disease at the time of transplant. The mean interval from diagnosis to transplant was 17.5 months (range: 3-129 months) and the mediannumberofmononuclearcellsinfusedwas4.86×108 per kg (range: 2-10.48). Results. Post-transplant, 43 of 50 patients engrafted. The median number of days to engraftment (absolute neutrophil count >500/cmm) was 12 (range: 9-24) and to achieve platelet transfusion independence (>20 000/cmm) was 13 (range: 8-36). Seven patients died prior to engraftment. Grade III-IV oral mucos it is wast he major non-haematologicaltoxicity. Excluding the 4patients who had complete response prior to the transplant and continued in the same status post-transplant, 31/46 patients (67%) responded; complete response was achieved in 25 (54%) and partial response in 6 (13%). Patients with chemosensitive disease had higher rates of complete response; 20 of 26 patients with partial response at transplant achieved complete response compared to 5 of 20 patients with persistent/refractory disease (p<0.01). Currently, 34 of 50 (68%) patients are alive, 17 (34%) disease-free, 6 with disease are on salvage therapy, 11 (22%) with positive monoclonal protein but asymptomatic are under observation. Nine (18%) patients have died; 8 due to progressive disease and 1 of an unrelatedcause. Themedian follow up for the entire group is 26 months (range: 1-144 months). The Kaplan-Meier probability of overall and progression-free survival for the whole group at 30 months is 62%±8.11% (SE) and 42%±9.54% (SE), respectively. A haemoglobin level £10 g/dl (p<0.003) affected the survival adversely. Chemo sensitive disease (p<0.008) at transplant and complete response post- transplant(p<0.0001) were associated with significantly longer survival. Conclusion. High dose melphalan followed by autologous stem cell transplantation is an effective treatment for patients with advanced multiple myeloma and achievement of complete response is associated with improved survival

LUMOS - Low and Intermediate Grade Glioma Umbrella Study of Molecular Guided TherapieS at relapse: Protocol for a pilot study

Introduction Grades 2 and 3 gliomas (G2/3 gliomas), when combined, are the second largest group of malignant brain tumours in adults. The outcomes for G2/3 gliomas at progression approach the dismal outcomes for glioblastoma (GBM), yet there is a paucity of trials for Australian patients with relapsed G2/3 gliomas compared with patients with GBM. LUMOS will be a pilot umbrella study for patients with relapsed G2/3 gliomas that aims to match patients to targeted therapies based on molecular screening with contemporaneous tumour tissue. Participants in whom no actionable or no druggable mutation is found, or in whom the matching drug is not available, will form a comparator arm and receive standard of care chemotherapy. The objective of the LUMOS trial is to assess the feasibility of this approach in a multicentre study across five sites in Australia, with a view to establishing a national molecular screening platform for patient treatment guided by the mutational analysis of contemporaneous tissue biopsies Methods and analysis This study will be a multicentre pilot study enrolling patients with recurrent grade 2/3 gliomas that have previously been treated with radiotherapy and chemotherapy at diagnosis or at first relapse. Contemporaneous tumour tissue at the time of first relapse, defined as tissue obtained within 6 months of relapse and without subsequent intervening therapy, will be obtained from patients. Molecular screening will be performed by targeted next-generation sequencing at the reference laboratory (PathWest, Perth, Australia). RNA and DNA will be extracted from representative formalin-fixed paraffin embedded tissue scrolls or microdissected from sections on glass slides tissue sections following a review of the histology by pathologists. Extracted nucleic acid will be quantified by Qubit Fluorometric Quantitation (Thermo Fisher Scientific). Library preparation and targeted capture will be performed using the TruSight Tumor 170 (TST170) kit and samples sequenced on NextSeq 550 (Illumina) using NextSeq V.2.5 hi output reagents, according to the manufacturer's instructions. Data analysis will be performed using the Illumina BaseSpace TST170 app v1.02 and a custom tertiary pipeline, implemented within the Clinical Genomics Workspace software platform from PierianDx (also refer to section 3.2). Primary outcomes for the study will be the number of patients enrolled and the number of patients who complete molecular screening. Secondary outcomes will include the proportion of screened patients enrolled; proportion of patients who complete molecular screening; the turn-around time of molecular screening; and the value of a brain tumour specific multi-disciplinary tumour board, called the molecular tumour advisory panel as measured by the proportion of patients in whom the treatment recommendation was refined compared with the recommendations from the automated bioinformatics platform of the reference laboratory testing. Ethics and dissemination The study was approved by the lead Human Research Ethics Committee of the Sydney Local Health District: Protocol No. X19-0383. The study will be conducted in accordance with the principles of the Declaration of Helsinki 2013, guidelines for Good Clinical Practice and the National Health and Medical Research Council National Statement on Ethical Conduct in Human Research (2007, updated 2018 and as amended periodically). Results will be disseminated using a range of media channels including newsletters, social media, scientific conferences and peer-reviewed publications. Trial registration number ACTRN12620000087954; Pre-results. </p