Tumour necrosis as assessed with 18F-FDG PET is a potential prognostic marker in diffuse large B cell lymphoma independent of MYC rearrangements.

OBJECTIVES: MYC gene rearrangements in diffuse large B cell lymphomas (DLBCLs) result in high proliferation rates and are associated with a poor prognosis. Strong proliferation is associated with high metabolic demand and tumour necrosis. The aim of this study was to investigate differences in the presence of necrosis and semiquantitative 18F-FDG PET metrics between DLBCL cases with or without a MYC rearrangement. The prognostic impact of necrosis and semiquantitative 18F-FDG PET parameters was investigated in an explorative survival analysis. METHODS: Fluorescence in situ hybridisation analysis for MYC rearrangements, visual assesment, semiquantitative analysis of 18F-FDG PET scans and patient survival analysis were performed in 61 DLBCL patients, treated at a single referral hospital between 2008 and 2015. RESULTS: Of 61 tumours, 21 (34%) had a MYC rearrangement (MYC+). MYC status was neither associated with the presence of necrosis on 18F-FDG PET scans (necrosisPET; p = 1.0) nor associated with the investigated semiquantitative parameters maximum standard uptake value (SUVmax; p = 0.43), single highest SUVmax (p = 0.49), metabolic active tumour volume (MATV; p = 0.68) or total lesion glycolysis (TLG; p = 0.62). A multivariate patient survival analysis of the entire cohort showed necrosisPET as an independent prognostic marker for disease-specific survival (DSS) (HR = 13.9; 95% CI 3.0-65; p = 0.001). CONCLUSIONS: MYC rearrangements in DLBCL have no influence on the visual parameter necrosisPET or the semi-quantiative parameters SUVmax, MATV and TLG. Irrespective of MYC rearrangements, necrosisPET is an independent, adverse prognostic factor for DSS. KEY POINTS: • Retrospective analysis indicates that MYC rearrangement is not associated with necrosis on 18 F-FDG PET (necrosis PET ) scans or semiquantitative 18 F-FDG PET parameters. • Necrosis PET is a potential independent adverse prognostic factor for disease-specific survival in patients with DLBCL and is not influenced by the presence of MYC rearrangements.

Proteinuria triggers renal lymphangiogenesis prior to the development of interstitial fibrosis.

Proteinuria is an important cause of progressive tubulo-interstitial damage. Whether proteinuria could trigger a renal lymphangiogenic response has not been established. Moreover, the temporal relationship between development of fibrosis, inflammation and lymphangiogenesis in chronic progressive kidney disease is not clear yet. Therefore, we evaluated the time course of lymph vessel (LV) formation in relation to proteinuria and interstitial damage in a rat model of chronic unilateral adriamycin nephrosis. Proteinuria and kidneys were evaluated up to 30 weeks after induction of nephrosis. LVs were identified by podoplanin/VEGFR3 double staining. After 6 weeks proteinuria was well-established, without influx of interstitial macrophages and myofibroblasts, collagen deposition, osteopontin expression (tubular activation) or LV formation. At 12 weeks, a ∼3-fold increase in cortical LV density was found (p<0.001), gradually increasing over time. This corresponded with a significant increase in tubular osteopontin expression (p<0.01) and interstitial myofibroblast numbers (p<0.05), whereas collagen deposition and macrophage numbers were not yet increased. VEGF-C was mostly expressed by tubular cells rather than interstitial cells. Cultured tubular cells stimulated with FCS showed a dose-dependent increase in mRNA and protein expression of VEGF-C which was not observed by human albumin stimulation. We conclude that chronic proteinuria provoked lymphangiogenesis in temporal conjunction with tubular osteopontin expression and influx of myofibroblasts, that preceded interstitial fibrosis.