Use of Valacyclovir for the treatment of cytomegalovirus antigenemia after hematopoietic stem cell transplantation

10.1186/s12878-015-0028-2BMC Hematology151

The Ethics of Neonatal Resuscitation

Decisions about initiating resuscitation are often based on the best-interest principle, which considers the chance of survival, pain of attempted resuscitation, and subsequent benefits or burdens that continued living with potential disability may bring. For neonates at 23–25 weeks gestation, this decision is difficult given the uncertain prognosis. It is thus reasonable to defer to parental wishes given that the family has to bear the burden of taking care of the child. Adequate and early antenatal counselling is important to enable parents to make an informed decision. Further studies of local long-term outcomes are needed to identify better markers for outcomes to help guide resuscitation decisions

Delayed diagnosis of Shwachman diamond syndrome with short telomeres and a review of cases in Asia

Inherited bone marrow failure syndrome (IBMFS) including Shwachman Diamond Syndrome (SDS) can present initially to the hematologist with myelodysplastic syndrome (MDS). Accurate diagnosis affects choice of chemotherapy, donor selection, and transplant conditioning. We report a case of delayed diagnosis of SDS in a family with another child with aplastic anemia, and review reported cases of SDS in Asia. This highlights the gap in identifying inherited bone marrow failure syndromes in adults with hematologic malignancies.Published versio

A phase 2 study of carfilzomib, cyclophosphamide and dexamethasone as frontline treatment for transplant-eligible MM with high-risk features (SGH-MM1)

10.1038/s41408-021-00544-xBLOOD CANCER JOURNAL11

The Singapore General Hospital Peritoneal Dialysis Programme from 2000–2008

Introduction: There is lack of data regarding outcomes of peritoneal dialysis (PD) in Singapore. The aim of this study is to retrospectively evaluate the patient characteristics, technique survival, and patient survival in a single centre. Methods: The retrospective review included 1,015 adults (47.3% female, 72.6% Chinese, mean age 58±12.4 years, mean follow-up 39.7±27.7 months) initiated on PD at the Singapore General Hospital from January 2000 to December 2008. Baseline characteristics, including cause of end-stage renal disease (ESRD), comorbid conditions, and endpoints (ie. death, transfer to HD or transplantation, renal recovery or until last follow-up on 31 December 2010) were collected. Demographic variables and patient and technique survival rates were analysed. Results: The main causes of ESRD were diabetes mellitus (DM) (58.0%), glomerulonephritis (GN) (23.3%) and hypertension (15.4%). The 1, 2, 5 and 10-year patient survival rates were 88.7%, 77.7%, 39.8% and 15.4%, respectively. Causes of death were related to infection (43.1%) and cardiac (37.8%). Patient survival rates were significantly better in PD patients with ESRD due to GN, compared with DM (5-year survival rates of 70.2% versus 22.3%, P <0.001). Patients aged 65 years and older had lower survival rates compared with those aged less than 65 years ( P <0.001). The 1, 2, 5 and 10-year technique survival rates were 92.9%, 85.0%, 64.8% and 32.9%, respectively. Peritonitis was the main cause of technique failure (63.5%), and caused 13.8% of deaths. Technique survival rates were better in patients with ESRD due to GN, compared with DM (5-year survival rates of 70.9% versus 62.0%, P <0.05). Conclusion: In our single-centre retrospective review, technique survival was comparable to other East Asian centres. The poorer patient survival observed in this study may be due to older age and higher comorbidity

High-dose methotrexate is effective for prevention of isolated CNS relapse in diffuse large B cell lymphoma

10.1038/s41408-021-00535-yBLOOD CANCER JOURNAL11

Whole Exome and Transcriptome Sequencing in 1042 Cases Reveals Distinct Clinically Relevant Genetic Subgroups of Follicular Lymphoma

Follicular Lymphoma (FL) is the most common indolent lymphoma derived from light zone germinal center B cells and characterized by a t(14;18) translocation resulting in upregulation of BCL2 in over 80% of cases. This translocation alone is not sufficient for tumorogenesis, and must be combined with additional genetic mutations to transform B cells. FL is incurable and the disease course can be highly varied, with survival ranging from a few months to decades following diagnosis and treatment with standard chemoimmunotherapy. The heterogeneity of FL poses major challenges to identifying the association of genetic alterations and clinical outcome. Current WHO guidelines recommend establishing grade for each FL case with grade 3 thought to be more aggressive than 1 and 2. The genetic basis and clinical implications of grade in FL are unclear. Recent sequencing studies have identified many genes found to be recurrently mutated in FL including KMT2D and CREBBP. However, the degree to which genetic alterations cooperate with each other or contribute to clinical outcome is unclear. Based on the observed mutational rates in follicular lymphoma, we estimated 900 cases were needed to comprehensively delineate the genetic alterations that underlie histologic grade and clinical outcome. Accordingly, we enrolled a cohort of 1042 patients with newly diagnosed FL. All treated patients received rituximab-containing standard regimens. To go beyond the identification of gene-coding events, we developed a very large panel of 110 Mbp covering exonic (~40Mbp) and non-exonic regions (~70Mbp) of interest to enable a wide range of genomic analysis including mutation calling in both coding and non-coding regions, rearrangement detection, viral identification, and copy number analysis. In addition to the whole exome, we extended coverage to include introns, promoters, and untranslated regions of all known driver genes in cancer. We included the entirety of the immunoglobulin loci, T-cell receptor loci and CD3 loci to detect clonotypes and rearrangements. We also included lymphoma-relevant long non-coding RNAs, microRNAs, enhancers, and breakpoint-prone regions. For viral detection, we targeted the genomes of eight cancer-related viruses: Epstein-Barr virus, human papillomavirus, human immunodeficiency virus, hepatitis B, hepatitis C, Kaposi's sarcoma-associated herpesvirus, human T-lymphotropic virus, and Merkel cell polyomavirus. In addition, to enable high resolution identification of copy number variation (CNV) calls, the entire genome was tiled with probes spaced 10kb apart. DNA and RNA were extracted from all tumors and their paired normal samples, prepared into DNA and RNA sequencing libraries and subjected to sequencing on the Illumina platform to a targeted coverage of 150X. Somatic events were identified and further filtered to identify driver events in both coding and non-coding regions. FLs demonstrated a significant degree of genetic heterogeneity with over 100 genes mutated with a frequency of at least 2%. Nearly 100% of FL cases had a mutation in at least one chromatin-modifying gene. The most frequently mutated genes in follicular lymphoma were KMT2D, BCL2, IGLL5 and CREBBP. In addition, we identified frequent mutations in SPEN, BIRC6 and SETD2. To our knowledge, this is the first description of alterations in these genes in FL. Transcriptome analysis indicated a strong correlation between BIRC6 mutations and the previously described immune response 2 signature that is associated with a poor prognosis. We further performed unbiased clustering of genetic alterations in these FL cases. We identified a cluster that was specifically enriched in BCL6 and TP53 alterations and was strongly associated with grade 3 FLs which are predicted to have poorer outcomes with low intensity therapies. We further examined the genetic profiles of 1001 DLBCLs in comparison to this cohort of FLs. Our data indicate a continuum of highly overlapping genetic alterations with DLBCL displaying more complex patterns that included alterations in MYC, TP53 and CDKN2A (mainly copy number losses), indicating shared pathogenetic mechanisms underlying FL and DLBCL, particularly those germinal center B cell origin. Disclosures Koff: Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; Lymphoma Research Foundation: Research Funding; American Association for Cancer Research: Research Funding. Leppä:Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Gang:ROCHE: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic&Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Flowers:AbbVie: Consultancy, Research Funding; Denovo Biopharma: Consultancy; BeiGene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Optimum Rx: Consultancy; Millenium/Takeda: Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Neff:Enzyvant: Consultancy; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fedoriw:Alexion Pharmaceuticals: Other: Consultant and Speaker. Reddy:Genentech: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy; Abbvie: Consultancy. Mason:Sysmex: Honoraria. Behdad:Loxo-Bayer: Membership on an entity's Board of Directors or advisory committees; Thermo Fisher: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Speaker. Burton:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dave:Data Driven Bioscience: Equity Ownership