Although the over-expression of angiogenic factors is reported in diffuse large B-cell lymphoma (DLBCL), the poor response to anti-VEGF drugs observed in clinical trials suggests that angiogenesis in these tumours might be driven by VEGF-independent pathways. We show that sphingosine kinase-1 (SPHK1), which generates the potent bioactive sphingolipid sphingosine-1-phosphate (S1P), is over-expressed in DLBCL. A meta-analysis of over 2000 cases revealed that genes correlated with SPHK1 mRNA expression in DLBCL were significantly enriched for tumour angiogenesis meta-signature genes; an effect evident in both major cell of origin (COO) and stromal subtypes. Moreover, we found that S1P induces angiogenic signalling and a gene expression programme that is present within the tumour vasculature of SPHK1-expressing DLBCL. Importantly, S1PR1 functional antagonists, including Siponimod, and the S1P neutralising antibody, Sphingomab, inhibited S1P signalling in DLBCL cells in vitro. Furthermore, Siponimod, also reduced angiogenesis and tumour growth in an S1P-producing mouse model of angiogenic DLBCL. Our data define a potential role for S1P signalling in driving an angiogenic gene expression programme in the tumour vasculature of DLBCL and suggest novel opportunities to target S1P-mediated angiogenesis in patients with DLBCL.

Background:The clinical and prognostic significance of "inadequate" cervical smear is unknown, even though women with repeated inadequate smears are referred for colposcopy in the National Health Service (NHS) Cervical Screening Programme. Aim: To follow up a cohort of women with inadequate cervical smears over the following five years to examine outcomes, including detection of high grade cervical intraepithelial neoplasia (CIN). Methods: The study comprised 1972 women with an inadequate cervical smear reported at Walsall Hospitals NHS Trust between 1 April 1995 and 31 March 1996. Results of cervical smears and biopsies taken over the following five years were reviewed to confirm the outcome. Findings: Within five years, 2.2% of women with an inadequate cervical smear developed histologically confirmed high grade CIN, which was higher than the 1.3% seen among all women with cervical smear tests reported at the same laboratory over the same period, although the difference was not significant at the 95% level of confidence. Where inadequacy resulted from or was contributed to by "polymorphs obscuring", the risk of subsequent development/detection of high grade CIN was 2.6%. Conclusions: Women with inadequate cervical smears had an increased risk of detection of high grade CIN in the following five years compared with "all women". This increased risk was not significant, although if a larger number of women had been studied significance may have been reached, so that further studies are needed. The increased risk appeared to be at least partially dependent on the reason for inadequacy.

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Aims Lynch syndrome (LS) is associated with an increased risk of developing endometrial carcinoma (EC) and ovarian carcinoma (OC). There is considerable variability in current practices and opinions related to screening of newly diagnosed patients with EC/OC for LS. An online survey was undertaken to explore the extent of these differences. Methods and results An online questionnaire was developed by a panel of experts and sent to all members of the British Association of Gynaecological Pathologists (BAGP) and the International Society of Gynecological Pathologists (ISGyP). Anonymised results were received and analysed. Thirty‐six BAGP and 44 ISGyP members completed the survey. More than 90% of respondents were aware of the association of LS with both EC and OC, but 34% were not aware of specific guidelines for LS screening. Seventy‐one per cent of respondents agreed that universal screening for LS should be carried out in all newly diagnosed EC cases, with immunohistochemistry (IHC) alone as the preferred approach. Only 36% of respondents currently performed IHC or microsatellite instability testing on all newly diagnosed EC cases, with most of the remaining respondents practising selective screening, based on clinical or pathological features or both. A significant minority of respondents (35%) believed that patient consent was required before performance of mismatch repair (MMR) protein IHC. Almost all respondents favoured the use of standardised terminology for reporting MMR protein staining results, and this is proposed herein. Conclusion There is wide support for universal LS screening in patients with EC, but this survey highlights areas of considerable variation in practice.