Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study.

BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. METHODS: We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. FINDINGS: Associations exceeding the genome-wide significance threshold (p<5 × 10(-8)) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1) having the strongest association with NKTCL susceptibility (p=4·21 × 10(-19), odds ratio [OR] 1·84 [95% CI 1·61-2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10(-14)). This association is distinct from MHC associations with Epstein-Barr virus infection. INTERPRETATION: To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. FUNDING: Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).

AL amyloidosis: Singapore Myeloma Study Group consensus guidelines on diagnosis, treatment and management.

AL amyloidosis is the most common form of systemic amyloidosis. However, the non-specific nature of presenting symptoms requires the need for a heightened clinical suspicion to detect unexplained manifestations in the appropriate clinical setting. Early detection and treatment are crucial as the degree of cardiac involvement emerges as a primary prognostic predictor of survival in a patient with AL amyloidosis. Following the diagnosis of AL amyloidosis with appropriate tissue biopsies, prompt treatment with a bortezomib, cyclophosphamide and dexamethasone-based first-line induction with or without daratumumab should be initiated. The goal of treatment is to achieve the best haematologic response possible, ideally with involved free light chain <20 mg/L, as it offers the best chance of organ function improvement. Treatment should be changed if patients do not achieve a partial response within 2 cycles of treatment or very good partial response after 4 cycles or after autologous stem cell transplant, as achievement of profound and prolonged clonal responses translates to better organ response and long-term outcomes. Early involvement of multidisciplinary subspecialists such as renal physicians, cardiologists, neurologists, and gastroenterologists for optimal maintenance and support of involved organs is recommended for optimal management of patients with AL amyloidosis.

CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes.

Antibody-dependent cellular cytotoxicity (ADCC) is exerted by immune cells expressing surface Fcγ receptors (FcγRs) against cells coated with antibody, such as virus-infected or transformed cells. CD16, the FcγRIIIA, is essential for ADCC by NK cells, and is also expressed by a subset of human blood monocytes. We found that human CD16- expressing monocytes have a broad spectrum of ADCC capacities and can kill cancer cell lines, primary leukemic cells and hepatitis B virus-infected cells in the presence of specific antibodies. Engagement of CD16 on monocytes by antibody bound to target cells activated ß2-integrins and induced TNFα secretion. In turn, this induced TNFR expression on the target cells, making them susceptible to TNFα-mediated cell death. Treatment with TLR agonists, DAMPs or cytokines, such as IFNγ, further enhanced ADCC. Monocytes lacking CD16 did not exert ADCC but acquired this property after CD16 expression was induced by either cytokine stimulation or transient transfection. Notably, CD16+ monocytes from patients with leukemia also exerted potent ADCC. Hence, CD16+ monocytes are important effectors of ADCC, suggesting further developments of this property in the context of cellular therapies for cancer and infectious diseases.

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

BACKGROUND: Valacyclovir has been used for prophylaxis against cytomegalovirus (CMV) infection after hematopoietic stem cell transplantation (HSCT). We investigated the efficacy and safety of high-dose Valacyclovir as pre-emptive therapy in patients with CMV antigenemia after HSCT. METHODS: In a retrospective single center study of 61 patients, we compared the rates of viral clearance, recurrent antigenemia and adverse events in patients with pp65 CMV antigenemia who received high dose Valacyclovir (n = 15), Valganciclovir (n = 16), and Foscarnet (n = 30). RESULTS: Overall, 60/61 (98 %) of cases achieved CMV antigenemia clearance by day 28, and no patient developed CMV disease. After adjusting for age, sex, diagnosis, CMV serological status, donor type, CMV antigen level, graft-versus-host disease (GVHD) therapy, and conditioning regimen, there were no significant differences in the rates of viral clearance at day 14 in patients who received Valganciclovir (0.18, 95 % confidence interval (CI) 0.01 to 2.15, p = 0.17) and Foscarnet (OR 0.22, 95 % CI 0.03 to 2.40, p = 0.22), compared with Valacyclovir (assigned OR = 1.00). Recurrent antigenemia by day 180 after clearance of the initial CMV episode occurred in 34/61 (56 %) of patients. Using the multivariate model adjusting for the same covariates, there were also no significant differences in secondary episodes of CMV between treatment groups. With regards to adverse effect monitoring, Foscarnet led to significantly increased creatinine levels (P = 0.009), while Valganciclovir led to significant decrease in neutrophil counts (P = 0.012). CONCLUSION: High dose Valacyclovir is a potential alternative to Valganciclovir and Foscarnet in the stable post-HSCT patient who has cytopenia and is not keen for inpatient treatment of CMV antigenemia.

Methotrexate-induced myelopathy mimicking subacute combined degeneration of the spinal cord.

Methotrexate (MTX), a folate antagonist, is widely used to treat hematological malignancies. Although it is known to cause myelopathy, little is known about the pathophysiology and natural history of this myelopathy. We describe a 42-year-old woman with acute lymphoblastic leukemia who was treated with chemotherapy consisting of intrathecal MTX who developed a progressive myelopathy. The myelopathy mimicked, radiologically, subacute combined degeneration (SACD) of the spinal cord. This myelopathy mimicking SACD could be explained by the folate antagonism of MTX. The progressive clinical signs and serial MRI in this patient further our understanding of the natural progression of this myelopathy.