Case report: Therapy-related myeloid neoplasms in three pediatric cases with medulloblastoma.

Introduction: Medulloblastoma is the most common malignant brain tumor in children, often requiring intensive multimodal therapy, including chemotherapy with alkylating agents. However, therapy-related complications, such as therapy-related myeloid neoplasms (t-MNs), can arise, particularly in patients with genetic predisposition syndromes. This case report presents three pediatric cases of medulloblastoma with subsequent development of t-MNs, highlighting the potential role of genetic predisposition and the importance of surveillance for hematological abnormalities in long-term survivors. Case presentation: We describe three cases of pediatric medulloblastoma who developed t-MNs after receiving chemotherapy, including alkylating agents. Two of the patients had underlying genetic predisposition syndromes (TP53 pathologic variants). The latency period between initial diagnosis of medulloblastoma and the development of secondary cancer varied among the cases, ranging from 17 to 65 months. The three cases eventually succumbed from secondary malignancy, therapy-related complications and progression of primary disease, respectively. Conclusions: This report highlights the potential association between genetic predisposition syndromes and the development of therapy-related myeloid neoplasms in pediatric medulloblastoma survivors. It underscores the importance of surveillance for hematological abnormalities among such patients.

Successful haploidentical hematopoietic stem cell transplantation (HSCT) and durable engraftment by repeated donor lymphocyte infusions for a Chinese patient with transfusion-dependent hemoglobin (Hb) Hammersmith and massive splenomegaly.

BACKGROUND: Hemoglobin (Hb) Hammersmith is a rare form of unstable ß-chain hemoglobinopathy causing hemolytic anemia. This rare event led to a more serious transfusion-dependent phenotype in a patient. It was successfully cured by haploidentical hematopoietic stem cell transplantation (HSCT). METHODS AND RESULTS: A 9-year-old mainland Chinese male with a history of neonatal unconjugated hyperbilirubinemia was diagnosed to have hemoglobin (Hb) Hammersmith. He required regular blood transfusion but was unable to be transfused to desired parameters for 8 years prior to transplant due to social and geographical reasons. He subsequently developed marrow hyperplasia and progressive splenomegaly (down to umbilicus level), suggestive of extramedullary hematopoiesis. Eventually, the family came to Hong Kong and complied to a more intensive transfusion regimen and preconditioning chemotherapy 3 months prior to transplant. He underwent haploidentical HSCT using paternal TCRαß/CD45RA-depleted graft but suffered from graft rejection, despite splenic irradiation for massive splenomegaly. It was successfully salvaged with second HSCT with unmanipulated graft from the same donor with additional serotherapy and donor lymphocyte infusions. CONCLUSION: Allogenic haploidentical HSCT for hemoglobin Hammersmith is feasible but adequate immunosuppression during conditioning is crucial. Precise adoptive cell therapy can promote durable engraftment.

Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations.

The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety-eight young adults (range: 21-60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54-myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of -5/5q- (P < .001) and -17/17p- (P < .001), but not -7/7q- (P = .370). This "typical" CK/MK AML subtype was associated with significantly lower presenting white cell counts, higher number of karyotypic abnormalities, and inferior leukemia-free and overall survivals, compared with CK/MK AML without the typical features. Blood or bone marrow samples from typical CK/MK AML patients showed defective p53 signaling upon induction by etoposide. In vitro drug sensitivity analysis showed that they were sensitive to APR-246 that targeted mutant p53, but resistant to MDM2 antagonist MI-77301. Novel therapeutic strategies targeting TP53 mutations in CK/MK AML should be developed and tested in clinical trials.

Next-generation sequencing with a 54-gene panel identified unique mutational profile and prognostic markers in Chinese patients with myelofibrosis.

Current prognostication in myelofibrosis (MF) is based on clinicopathological features and mutations in a limited number of driver genes. The impact of other genetic mutations remains unclear. We evaluated for mutations in a myeloid panel of 54 genes using next-generation sequencing. Multivariate Cox regression analysis was used to determine prognostic factors for overall survival (OS) and leukaemia-free survival (LFS), based on mutations of these genes and relevant clinical and haematological features. One hundred and one patients (primary MF, N = 70; secondary MF, N = 31) with a median follow-up of 49 (1-256) months were studied. For the entire cohort, inferior OS was associated with male gender (P = 0.04), age > 65 years (P = 0.04), haemoglobin < 10 g/dL (P = 0.001), CUX1 mutation (P = 0.003) and TP53 mutation (P = 0.049); and inferior LFS was associated with male gender (P = 0.03), haemoglobin < 10 g/dL (P = 0.04) and SRSF2 mutations (P = 0.008). In primary MF, inferior OS was associated with male gender (P = 0.03), haemoglobin < 10 g/dL (P = 0.002), platelet count < 100 × 109/L (P = 0.02), TET2 mutation (P = 0.01) and CUX1 mutation (P = 0.01); and inferior LFS was associated with haemoglobin < 10 g/dL (P = 0.02), platelet count < 100 × 109/L (P = 0.02), TET2 mutations (P = 0.01) and CUX1 mutations (P = 0.04). These results showed that clinical and haematological features and genetic mutations should be considered in MF prognostication.

The smoke-free legislation in Hong Kong: its impact on mortality.

OBJECTIVES: To examine trends in deaths for conditions associated with secondhand smoke exposure over the years prior to and following the implementation of a smoke-free policy in Hong Kong. DESIGN: Time-series study. SETTING: Death registration data from Hong Kong Special Administrative Region (SAR) Government Census and Statistics Department. PARTICIPANTS: All deaths registered from 1 January 2001 to 31 December 2011. MAIN OUTCOME MEASURES: Deaths for conditions associated with passive smoking include cardiovascular disease (CVD), respiratory disease and other causes. RESULTS: There was a decline in the annual proportional change for ischaemic heart disease (IHD), acute myocardial infarction (AMI) and CVD mortality in the year after the intervention for all ages and those aged 65 years or older. There were also clear declines in the cool season peaks for these three conditions in the first postintervention year. There was a further drop in the cool season peak for AMI among all ages in the year after the exemptions ceased. No declines in annual proportional change or changes in seasonal peaks of mortality were found for any of the control conditions. CONCLUSIONS: The findings in this study add to the evidence base, as summarised in the Surgeon General's report, extending the impact of effective smoke-free legislation to those aged 65 years or older and to cerebrovascular events in younger age groups. They also reinforced the need for comprehensive, enforced and effective smoke-free laws if the full extent of the health gains are to be achieved.

Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia.

Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is frequently detected in acute myeloid leukemia (AML) patients and is associated with a dismal long-term prognosis. FLT3 tyrosine kinase inhibitors provide short-term disease control, but relapse invariably occurs within months. Pim protein kinases are oncogenic FLT3-ITD targets expressed in AML cells. We show that increased Pim kinase expression is found in relapse samples from AML patients treated with FLT3 inhibitors. Ectopic Pim-2 expression induces resistance to FLT3 inhibition in both FLT3-ITD-induced myeloproliferative neoplasm and AML models in mice. Strikingly, we found that Pim kinases govern FLT3-ITD signaling and that their pharmacological or genetic inhibition restores cell sensitivity to FLT3 inhibitors. Finally, dual inhibition of FLT3 and Pim kinases eradicates FLT3-ITD(+) cells including primary AML cells. Concomitant Pim and FLT3 inhibition represents a promising new avenue for AML therapy.

Community end-of-life care among Chinese older adults living in nursing homes.

AIM: The aim of the present study was to investigate the preference and willingness-to-pay (WTP) of older Chinese adults for community end-of-life care in a nursing home rather than a hospital. METHODS: A total of 1540 older Chinese adults from 140 nursing homes were interviewed. Four hypothetical questions were asked to explore their preferences for end-of-life care. Using a discrete choice approach, specific questions explored acceptable trade-offs between three attributes: availability of doctors onsite, attitude of the care staff and additional cost of care per month. RESULTS: Approximately 35% of respondents preferred end-of-life care in the nursing home, whereas 23% of them would consider it in a better nursing home. A good attitude of staff was the most important attribute of the care site. Respondents were willing to pay an extra cost of US$5 (HK$39) per month for more coverage of doctor's time, and US$49 (HK$379) for a better attitude of staff in the nursing home. The marginal WTP for both more coverage of doctor's time and better attitude of staff amounted to US$54 (HK$418). Respondents on government subsidy valued the cost attribute more highly, as expected, validating the hypothesis that those respondents would be less willing to pay an additional cost for end-of-life care. CONCLUSIONS: Older Chinese adults living in nursing homes are willing to pay an additional fee for community end-of-life care services in nursing homes. Both the availability of the doctor and attitudes of nursing home staff are important, with the most important attribute being the staff attitudes. Geriatr Gerontol Int 2013; 14: 273-284.

A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression.

Fetal hemoglobin (HbF) is regulated as a multigenic trait. By genome-wide association study, we confirmed that HBS1L-MYB intergenic polymorphisms (HMIP) and BCL11A polymorphisms are highly associated with HbF in Chinese ß-thalassemia heterozygotes. In this population, the variance in HbF resulting from the HMIP is 13.5%; that resulting from the BCL11A polymorphism is 6.4%. To identify the functional variant in HMIP, we used 1000 Genomes Project data, single nucleotide polymorphism imputation, comparisons of association results across populations, potential transcription factor binding sites, and analysis of phylogenetic conservation. Based on these studies, a hitherto unreported association between HbF expression and a 3-bp deletion, between 135 460 326 and 135 460 328 bp on chromosome 6q23 was found. This 3-bp deletion is in complete linkage disequilibrium with rs9399137, which is the single nucleotide polymorphism in HMIP most significantly associated with HbF among Chinese, Europeans, and Africans. Chromatin immunoprecipitation assays confirmed erythropoiesis-related transcription factors binding to this region in K562 cells. Based on transient expression of a luciferase reporter plasmid, the DNA fragment encompassing the 3-bp deletion polymorphism has enhancer-like activity that is further augmented by the introduction of the 3-bp deletion. This 3-bp deletion polymorphism is probably the most significant functional motif accounting for HMIP modulation of HbF in all 3 populations.

Pneumococcal native aortic valve endocarditis with mycotic abdominal aortic aneurysm, paraspinal and iliopsoas abscesses and pneumonia revealing a multiple myeloma.

We report a rare case of multiple myeloma presenting with native aortic valve endocarditis with secondary embolic mycotic abdominal aortic aneurysm, contiguous paraspinal and iliopsoas abscesses, and pneumonia due to Streptococcus pneumoniae in a Chinese man. He was treated with aortic valve replacement, endovascular stenting of aneurysm, image-guided drainage of abscesses, and a 6-week course of endocarditic antibiotic therapy followed by chronic suppressive antibiotic therapy. Cases of multiple myeloma presenting with invasive pneumococcal infection were reviewed.

Sickle cell disease caused by heterozygosity for Hb S and novel LCR deletion: Report of two patients.

The b-globin gene LCR is located approximately 6 kb upstream of the embryonic epsilon-globin gene, and is made up of five DNase I hypersensitive sites (HSs), HS 1-5. LCR plays a pivotal role in regulating the expression of downstream epsilon-, (G)gamma-, (A)gamma-, delta-, and beta-globin genes in cis [1]. Deletions removing the LCR and parts of the downstream beta-globin gene cluster in patients have been described [2]. These individuals present with a (gammadeltabeta)0-thalassemia carrier phenotype. We now report two patients with severe sickle cell disease who were compound heterozygous for Hb S mutation and novel LCR deletion. In one case, HS 1-3 were deleted; in the other, HS 1-5 were deleted. In both cases, the b-like globin genes in cis to the LCR deletions were intact. Genotypically, both patients appeared to have sickle cell trait. Coinherited with either LCR deletion, these individuals presented as sickle cell disease patients. The breakpoints of these LCR deletions were defined. These results affirm that HS 2 and 3 are primarily responsible for conferring erythroid specific high-level expression of cis-linked beta-like globin genes. Furthermore, LCR deletions might cause hemolytic disease of newborns.

A unique case of B cell lymphoma relapsing as CD4/CD56 blastic neoplasm.

A patient with history of B cell lymphoma treated with rituximab-based chemotherapy relapsed with a blastic CD4+/CD56+ neoplasm that was negative for CD20, CD79a and CD3. The relapse morphology and immunophenotyping were unusual and plasmacytoid dendritic cell (PDC) tumor enters the differential diagnosis. However, expressions of Oct-2 and CD10 in the relapse tumor were both more compatible with B cell than PDC lineage. Molecular investigations showed clonal rearrangements for both immunoglobulin heavy chain (IgH) and T cell receptor (TCR) gamma chain gene by polymerase chain reaction (PCR). Furthermore, a clonal relationship with the original B cell lymphoma was demonstrated for all PCR products. Our case illustrated the potential pitfalls and ambiguity of lineage classification based on morphology and immunophenotyping alone, especially for rare and poorly defined entities.

BCL11A is a major HbF quantitative trait locus in three different populations with beta-hemoglobinopathies.

Increased HbF levels or F-cell (HbF containing erythrocyte) numbers can ameliorate the disease severity of beta-thalassemia major and sickle cell anemia. Recent genome-wide association studies reported that single nucleotide polymorphisms (SNPs) in BCL11A gene on chromosome 2p16.1 were correlated with F-cells among healthy northern Europeans, and HbF among Sardinians with beta-thalassemias. In this study, we showed that SNPs in BCL11A were associated with F-cell numbers in Chinese with beta-thalassemia trait, and with HbF levels in Thais with either beta-thalassemia or HbE trait and in African Americans with sickle cell anemia. Taken together, the data suggest that the functional motifs responsible for modulating F-cells and HbF levels reside within a 3 kb region in the second intron of BCL11A.