Time-varying prognostic effects of primary tumor sidedness and grade after curative liver resection for colorectal liver metastases.

BACKGROUND: The veracity of the proportional hazards (PH) requirement is rarely scrutinized in most areas of cancer research, although fulfilment of this assumption underpins widely-used Cox survival models. We sought to critically appraise the existence of prognostic factors with time-dependent effects and to characterize their impact on survival among CLM patients. METHODS: Consecutive patients who underwent liver resection with curative intent for CLM at the Singapore General Hospital were identified from a prospectively-maintained database. We evaluated PH of 55 candidate variables, and parameters which departed significantly from proportionality were included in Cox models that incorporated an interaction term to account for time-dependent effects. As sensitivity analyses, we fitted Weibull mixture 'cure' models to handle long plateaus in the tails of survival curves, and also analyzed the restricted mean survival time. RESULTS: 318 consecutive patients who underwent curative liver resection for CLM between Jan 2000 and Nov 2016 were included in this analysis. Hazard ratios for tumor grade (poorly-versus well- and moderately-differentiated) were found to decrease from 3.135 (95% CI: 1.637-6.003) at 12 months to 2.048 (95% CI: 1.038-4.042) after 24 months, and ceased to be significant at 26 months. Compared to left-sided tumors, a right-sided tumor location was found to portend worse prognosis for the first 10 months after resection but subsequently confer a survival benefit due to a crossing of survival curves. Corroborating this observation, long-term cure fractions were estimated to be 25.5% (95% CI: 17.4%-33.6%) and 34.2% (95% CI: 17.4%-50.9%) among patients with left-sided and right-sided primary disease respectively. CONCLUSION: Primary tumor sidedness and grade appear to exert time-varying prognostic effects in CLM patients undergoing curative liver resection.

Mapping the human DC lineage through the integration of high-dimensional techniques.

Dendritic cells (DC) are professional antigen-presenting cells that orchestrate immune responses. The human DC population comprises two main functionally specialized lineages, whose origins and differentiation pathways remain incompletely defined. Here, we combine two high-dimensional technologies-single-cell messenger RNA sequencing (scmRNAseq) and cytometry by time-of-flight (CyTOF)-to identify human blood CD123+CD33+CD45RA+ DC precursors (pre-DC). Pre-DC share surface markers with plasmacytoid DC (pDC) but have distinct functional properties that were previously attributed to pDC. Tracing the differentiation of DC from the bone marrow to the peripheral blood revealed that the pre-DC compartment contains distinct lineage-committed subpopulations, including one early uncommitted CD123high pre-DC subset and two CD45RA+CD123low lineage-committed subsets exhibiting functional differences. The discovery of multiple committed pre-DC populations opens promising new avenues for the therapeutic exploitation of DC subset-specific targeting.

Expanding the donor pool for liver transplantation in the setting of an "opt-out" scheme: 3 years after new legislation.

INTRODUCTION: The revised Human Organ Transplant Act (HOTA) was implemented in Singapore in July 2004. We aim to evaluate expanding the potential donor pool for liver transplant in Singapore with the inclusion of marginal donors. MATERIALS AND METHODS: All donor referrals between July 2004 and June 2007 were studied. All potential deceased liver donors were heart-beating. After being reviewed by the transplant coordinator, potential donors were assessed by a transplant hepatologist and a transplant surgeon for suitability of organ donation strictly based on the programme's donor assessment protocol. Reasons for rejection as potential donors were documented. The clinical characteristics of all donor referrals were retrospectively reviewed, and an independent decision was made as to whether liver retrieval in each rejected case might have been possible. RESULTS: Among the 128 potential donor referrals, 20 donors (15.6%) underwent liver retrieval. Of the 20 livers retrieved, 16 were implanted and 4 were not implanted (3 unfit recipients, and 1 donor liver with 40% steatosis). Another 10 donor livers were assessed intraoperatively and were rejected because of varying levels of steatosis. Of these livers assessed, 5 donor livers had steatosis <40% and 5 had steatosis >40%. Of the remaining potential donors, 45 were deemed not possible because of prolonged hypotension (9), on-going or unresolved sepsis (13), high-risk behaviour (4), non-actualisation (8), or pre-existing medical conditions (11). Another 53 donors may potentially have been suitable donors but were rejected because of possible sepsis (13), no suitable recipients (12), transient hypotension (10), transient abnormal liver function test (6), history of alcohol ingestion (5), non-actualisation because of consent (4) and other reasons (3). Overall, it was deemed that 61 donors (47.7%) might potentially have been suitable liver donors. CONCLUSIONS: Despite new legislation (HOTA) in Singapore, the utilisation of cadaveric donor livers showed no increase in the last 3 years. By expanding our donor criteria to include marginal donors, we could potentially increase the availability of deceased donor livers to meet our waiting list demands.