The purpose of this review is to explore how metabolomics can help uncover mechanisms through which physical activity may influence the progression of cardiovascular aging. Cardiovascular aging is a process of functional and structural changes in older adults which can progress to cardiovascular disease. Metabolomics profiling is an investigative tool that can track the diverse changes which occur in human biochemistry with physical activity and aging. This mini review will summarize published investigations in metabolomics and physical activity, with a specific focus on the metabolic pathways that connect physical activity with cardiovascular aging.

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 clinicopathological 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. Follicular lymphoma (FL) is among the most common subtype of non-Hodgkin lymphoma (NHL), accounting for over one-fifth of NHL worldwide 1 . It is a heterogeneous group of tumours that originate from centrocytes and centroblasts among germinal centre B cells 2 . It is also well-known that FL has a propensity to transform to diffuse large B-cell lymphoma (DLBCL) at a rate of approximately 3% per year for the first 15 years 3,4 . Histological transformation (HT) to DLBCL portends a poor prognosis with a median survival of 14 to 27 months 3,5,6 .Multiple studies have elucidated various clinical and molecular markers predicting for HT and overall survival (OS) post-HT. High-risk Follicular Lymphoma International Prognostic Index (FLIPI), grade 3 histology, stage III or IV disease, low serum albumin and high serum lactate dehydrogenase (LDH) levels are commonly cited as risk factors for HT 5,7-9 . Molecular alterations such as TP53 10 and CDKN2A/B mutations 11 , as well as www.nature.com/scientificreports www.nature.com/scientificreports/ 50.0%, 24.5%, 18.9% and 6.6% of the cohort, with a predicted 5-year OS of 100%, 62%, 40% and 0% and a predicted 5-year PFS of 81%, 60%, 41% and 0% respectively (p < 0.0001) (Table 7) (Fig. 3b).Using the CGI, we were able to more precisely stratify patients into 4 unique prognostic risk groups as compared to the 3 risk groups using the earlier initial prognostic model. Most patients initially categorised as low risk remained in the same group, with 3.3...

Aim Composite follicular lymphoma with diffuse large B-cell lymphoma (FL/DLBCL) is an uncommon hematological neoplasm. The aim of this study was to examine clinico-pathological features of patients with FL/DLBCL and investigate relevant predictors of survival outcome. Methodology Patients with histologically-proven FL/DLBCL at diagnosis (n=106) and who were subsequently treated with Rituximab-based chemotherapy from 2002-2017 at the National Cancer Centre Singapore were retrospectively analyzed. Survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional models. Results The cohort consisted of 72 men and 34 women with a median age of 59 years (range, 24-82). The cell of origin by Han's algorithm was GCB in 37.7%, ABC in 58.5% and unknown in 3.8%. Eight patients (7.5%) were double-hit for c-MYC, BCL2 and/or BCL6 rearrangements. In a multivariate model inclusive of known clinico-pathological parameters at diagnosis, presence of B symptoms (p = 0.0122), stage 3 or 4 lymphoma (p = 0.0166) and double-hit genotype (p = 0.0045) were independently prognostic for worse overall survival (OS). These factors, excluding B symptoms, were similarly prognostic for progression-free survival (PFS). Including first-line treatment data in the multivariate model, lack of complete response (p < 0.0001) and use of chemotherapy regimens other than R-CHOP (p = 0.0360) alongside presence of B symptoms (p = 0.0022), were the only remaining independent prognostic variables for worse OS. Classification by cell of origin was not prognostic. A Clinico-Genotypic Index derived from point-wise addition of all five adverse parameters (score of 0, 1, 2, 3-4) revealed four prognostic risk groups accounting for 25%, 30%, 25% and 20% of the cohort, with a predicted 5-year OS of 100%, 95%, 57% and 19% respectively (p < 0.0001). Conclusion A Clinico-Genotypic Index derived from clinical and molecular factors can classify patients with composite FL/DLBCL into distinct prognostic groups. Han's algorithm has no prognostic value in this disease entity. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Aim: Composite histologies of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) may be present synchronously at diagnosis or metachronously at the time of transformation of a formerly diagnosed FL. The aim of this study was to examine their clinico-pathological characteristics and treatment outcomes. Method: Patients who were consecutively diagnosed with composite FL/DLBCL (n=120) and FL (n=346) from 2001-2017 at the National Cancer Centre Singapore were retrospectively analyzed. Chi-squared tests and multivariate logistic regression were performed to evaluate clinico-pathological associations between the two cohorts. Survival analysis was performed using the Kaplan-Meier method and the log-rank test. Results: Amongst the FL cases, 21 patients (6.1%) with metachronous transformed FL/DLBCL were identified. The median lag time from diagnosis of FL to DLBCL transformation was 47 months (range, 7.8-168). Clinico-pathological features in synchronous and metachronous FL/DLBCL were similar, with both entities demonstrating a male preponderance (67% male and 33% female). Median age at diagnosis was 67 years (range, 41-81) and 60 years (range, 24-90) for metachronous and synchronous FL/DLBCL, respectively. The cell-of-origin by Han's criteria was similar (metachronous: GCB 52%, ABC 43%, unknown 5%; synchronous: GCB 38%, ABC 57%, unknown 5%; p = 0.21), as were the occurrence of C-MYC/BCL2/BCL6 double-hit rearrangements. However, survival from the time of DLBCL development was significantly worse (median, 3 vs 12 years) for metachronous compared to synchronous FL/DLBCL (HR 2.20, 95%CI 0.88-5.49, p = 0.022). Double-hit, advanced stage, and use of non-RCHOP regimens (OR 7.54, 95%CI 2.84-20.1, p = 0.0001) were associated with lack of complete response to chemotherapy. In metachronous FL/DLBCL, the R-CHOP regimen was less commonly used (77% vs 56%, p = 0.049). Correspondingly, complete response to chemotherapy was less likely in metachronous cases (38% vs 63%, p = 0.037). Conclusion: Metachronous and synchronous FL/DLBCL share similar clinico-pathological characteristics. A preceding diagnosis of FL however, predicts for significantly worse survival outcomes and suboptimal responses to chemotherapy. Disclosures No relevant conflicts of interest to declare.

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin's lymphoma that occurs in patients who are elderly and immunocompromised. The most common treatment for PCNSL is high-dose methotrexate-based chemotherapy. Studies have suggested that the radiological response to high-dose methotrexate-based chemotherapy is associated with improved neurocognitive ability that remains stable upon follow-up. However, no study involving patients with an extremely poor neurological status before chemotherapy initiation has been reported, and the neurological prognosis of this group of patients remains unknown. The current case study described 3 patients with PCNSL diagnosed via biopsy who had comatose neurological states due to disease progression prior to treatment. All patients were treated with high-dose methotrexate-based chemotherapy. However, although effective radiological responses to treatment were achieved, no meaningful neurological or cognitive recovery was documented. Patients with PCNSL exhibiting a baseline comatose state have a poor neurological prognosis even with an effective tumour response to chemotherapy. Therefore, rapid detection and prompt treatment are crucial in patients with this disease.