Treatment patterns and outcomes of older patients with mantle cell lymphoma in an Asian population.

BACKGROUND: Significant progress has been made in the treatment outcomes of mantle cell lymphoma (MCL) since the introduction of cytarabine and rituximab in modern regimens. However, older patients may not readily tolerate these agents nor derive benefit. We investigated the impact of age on treatment patterns and clinical outcomes of MCL patients in an Asian population. METHODS: A retrospective study was conducted on patients (n = 66) diagnosed with MCL at the National Cancer Centre Singapore between 1998 and 2018. The median follow-up duration was 40 months. Survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional models. RESULTS: The median age of the cohort was 59 years (range, 26-84), with a male predominance (73%). The majority (86%) had advanced stage 3-4 disease at diagnosis. Compared with younger patients, older patients aged ≥60 years (n = 32; 48.5%) presented more frequently with B-symptoms (75% vs 38%, p = 0.0028), anaemia (75% vs 35%, p = 0.0013), and carried higher prognostic risk scores (sMIPI high risk 84% vs 56%, p = 0.016). Non-cytarabine-based induction chemotherapy was more commonly administered in older patients (76% vs 32%, p = 0.0012). The 5-year overall survival (OS) and progression-free survival (PFS) was 68 and 25% respectively. In a multivariable model, older age (HR 3.42, 95%CI 1.48-7.92, p = 0.004) and anemia (HR 2.56, 95%CI 1.10-5.96, p = 0.029) were independently associated with poorer OS while older age (HR 2.24, 95%CI 1.21-4.14, p = 0.010) and hypoalbuminemia (HR 2.20, 95%CI 1.17-4.13, p = 0.014) were independently associated with poorer PFS. In an exploratory analysis, maintenance rituximab following induction chemotherapy improved PFS in younger patients, with median PFS of 131 months and 45 months with or without maintenance therapy respectively (HR 0.39, 95%CI 0.16-0.93, p = 0.035). In contrast, no survival benefit was observed in older patients. CONCLUSIONS: We demonstrated in our analysis that older patients with MCL may harbor adverse clinical features and may not derive benefit from maintenance rituximab, highlighting the need for further research in this area of need.

A Clinico-Genotypic Prognostic Index for De Novo Composite Diffuse Large B-Cell Lymphoma Arising from Follicular Lymphoma in Asian patients treated in the Rituximab Era.

Composite follicular lymphoma with diffuse large B-cell lymphoma (FL/DLBCL) is uncommonly found on lymph node biopsy and represents a rare haematological malignancy. We aim to examine clinico-pathological features of patients with FL/DLBCL and investigate predictors of survival outcome. We included in our retrospective study patients with histologically-proven FL/DLBCL at diagnosis (n = 106) and who were subsequently treated with rituximab-based chemoimmunotherapy from 2002-2017 at the National Cancer Centre. The cohort consisted of 34 women and 72 men with a median age of 59 years (range, 24-82). In a multivariate model inclusive of known clinico-pathological parameters at diagnosis, advanced stage (p = 0.0136), presence of MYC and/or BCL6 rearrangement (p = 0.0376) and presence of B symptoms (p = 0.0405) were independently prognostic for worse overall survival (OS). The only remaining independent prognostic variables for worse OS after including first-line treatment data in the model were use of chemotherapy regimens other than R-CHOP (p = 0.0360) and lack of complete response to chemotherapy (p < 0.0001) besides the presence of B symptoms (p = 0.0022). We generated a Clinico-Genotypic Index by point-wise addition of all five adverse parameters (score of 0-1, 2, 3, 4-5) which revealed four prognostic risk groups with a predicted 5-year OS of 100%, 62%, 40% and 0% (p < 0.0001) accounting for 50.0%, 24.5%, 18.9% and 6.6% of the cohort respectively. We propose that R-CHOP should be the recommended first-line regimen for composite FL/DLBCL.

Evaluation of the PIK3 pathway in peripheral T-cell lymphoma and NK/T-cell lymphoma.

Peripheral T-cell lymphomas (PTCL) and natural killer (NK)/T-cell lymphomas (NKTCL) are a heterogeneous group of aggressive malignancies with dismal outcomes and limited treatment options. While the phosphatidylinositol 3-kinase (PIK3) pathway has been shown to be highly activated in many B-cell lymphomas, its therapeutic relevance in PTCL and NKTCL remains unclear. The aim of this study is to investigate the expression of PIK3 and phosphatase and tensin homolog (PTEN) in these subtypes of lymphoma and to identify potential therapeutic targets for clinical testing. Therefore, the expression of PIK3α, PIK3ß, PIK3γ, PIK3δ and PTEN was analyzed in 88 cases of PTCL and NKTCL samples by immunohistochemistry. All PTCL and NKTCL samples demonstrated high expression of PIK3 isoforms. In particular, high PIK3α expression was significantly associated with poor survival, even after adjustment for age, International Prognostic Index (IPI) score and anthracycline-based chemotherapy in first line. Notably, copanlisib, a pan-class I inhibitor with predominant activities towards PIK3α and PIK3δ isoforms, effectively inhibited phosphorylation of AKT, 4E-BP-1 and STAT3, causing G0 /G1 cell cycle arrest and resulting in suppression of tumour cell growth in vitro and in vivo. This study provides evidence that targeting the PIK3 pathway, particularly simultaneous inhibition of PIK3α and δ, could be a promising approach for the treatment of PTCL and NKTCL.

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

BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL. METHODS: We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12 650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL. FINDINGS: Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20 402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83 × 10-16; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35 × 10-26 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants. INTERPRETATION: Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention. FUNDING: Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute.

A clinicohaematological prognostic model for nasal-type natural killer/T-cell lymphoma: A multicenter study.

Extranodal NK/T-cell lymphoma, nasal type (NKTL) is an aggressive type of non-Hodgkin lymphoma closely associated with Epstein-Barr virus and characterized by varying degrees of systemic inflammation. We aim to examine the prognostic significance of peripheral blood neutrophil-lymphocyte ratio (NLR) in patients with NKTL. Therefore, we conducted a retrospective review of 178 patients with biopsy-proven NKTL from the National Cancer Centre Singapore and Samsung Medical Center, South Korea. Using receiver operating curve analysis, an optimal cut-off for high NLR (>3.5) in predicting overall survival (OS) was derived. Survival analysis was performed using the Kaplan-Meier method and multivariable Cox proportional regression. In patients with high NLR, estimated 5-year OS was 25% compared to 53% in those with low NLR. In multivariable analysis, high NLR, in addition to age ≥60 years, presence of B-symptoms and stage III/IV at diagnosis, was independently correlated with worse OS (HR 2.08; 95% CI 1.36 to 3.18; p = 0.0008) and progression-free survival (HR 1.66; 95% CI 1.11 to 2.46; p = 0.0128). A new prognostic index (NABS score) derived from these factors stratified patients into low (0), low-intermediate (1), high-intermediate (2) and high (3-4) risk subgroups, which were associated with 5-year OS of 76.5%, 55.7%, 29.2% and 0% respectively. In conclusion, high NLR is an independent prognostic marker and the NABS model can be used to risk-stratify NKTL patients.

Myocardial infarction in the C57BL/6J mouse: a quantifiable and highly reproducible experimental model.

INTRODUCTION: The laboratory mouse is a powerful tool in cardiovascular research. In this report, we describe a method for a reproducible mouse myocardial infarction model that would allow subsequent comparative and quantitative studies on molecular and pathophysiological variables. METHODS: (A) The distribution of the major coronary arteries including the septal artery in the left ventricle of the C57BL/6J mice (n=20) was mapped by perfusion of latex dye or fluorescent beads through the aorta. (B) The territory of myocardial infarction after the ligation of the most proximal aspect of the left anterior descending (LAD) coronary artery was quantified. (C) The consistency in the histological changes parallel to the infarction at different time points was analyzed. RESULTS: (A) The coronary artery tree of the mouse is different from human and, particularly, in regard to the blood supply of the septum. (B) Contrary to previous belief, the septal coronary artery in the mouse is variable in origin. (C) A constant ligation of the LAD immediately below the left auricular level ensures a statistically significant reproducible infarct size. (D) The ischemic changes can be monitored at a histological level in a way similar to what is described in the human. CONCLUSION: We illustrate a method for maximal reproducibility of experimental acute myocardial infarction in the mouse model, due to a consistent loss of perfusion in the lower half of the left ventricle. This will allow the study of molecular and physiological variables in a controlled and quantifiable experimental model environment.

Whole bone marrow transplantation induces angiogenesis following acute ischemia.

Several recent studies have shown that purified subsets of bone marrow (BM) cells can differentiate into endothelial, cardiac, and other cell types. During coronary artery bypass graft (CABG) surgery, sternal BM is routinely discarded. To determine if this BM can be used to induce angiogenesis and augment perfusion of the cardiac tissues after CABG, a simplified and more practical approach of using whole BM extract was tried to determine whether it would be adequate for the induction of BM-derived angiogenesis in experimental acute limb ischemia. BM was prepared from FVB/N-TgN(TIE2 lacZ)182 Sato (Tie2-lacZ) or B6.129S7-Gtrosa 26 (Rosa 26) mice that express beta-galactosidase (beta-gal) in endothelial cells and most adult tissues, respectively. Acute limb ischemia was induced in either C57BL6/J or FVB/N mice by double ligation of the left femoral artery just distal to the profunda femoral artery branch. Occlusion of the ligated artery was verified by angiography. The study group (n = 31) received an intramuscular injection of 50 micro l containing 1 x 10(6) BM cells, 5 mm proximal to the site of ligation. Experimental controls (n = 21) had an intramuscular injection of 50 micro l of saline. Angiogenesis in the mice was assessed by histological analysis. BM-derived beta-gal(+) cells were observed to aggregate in the vicinity of the ligated artery and not in the injected musculature BM-derived endothelial cells were incorporated within capillaries and small size blood vessels near the site of ligation. Generation of BM-derived blood vessels in experimental acute limb ischemia does not require purification of specific subset of cells. The elimination of cell purification will enhance the ease of using BM transplantation in generating blood vessels.