Sex disparity in liver allocation within Eurotransplant.

In Eurotransplant, relatively more females than males die while waiting for a liver transplantation, and relatively fewer females are transplanted. With adult liver transplantation candidates listed between 2007 and 2019 (n=21,170), we study whether sex disparity is inherent to the Model for End-stage Liver Disease (MELD) scoring system, or the indirect result of a small candidate body size limiting access to transplantation. Cox proportional hazards models are used to quantify the direct effect of sex on waitlist mortality, independent of sex's effect through MELD scores, and the direct effect of sex on the transplantation rate, independent of sex's effect through MELD and candidate body size. Adjusted waitlist mortality hazard ratios for female sex are insignificant (HR: 1.03, 95%-CI: 0.88-1.20). We thus lack evidence that MELD systematically underestimates waitlist mortality rates for females. Transplantation rates are 25% lower for females than males in unadjusted analyses (HR: 0.74, 95%-CI: 0.71-0.77), but hazard ratios become insignificant with adjustment for mediators (HR: 0.98, 95%-CI: 0.93-1.04), most importantly candidate body size. Sex disparity in Eurotransplant thus appears to be largely a consequence of lower transplantation rates for females, which are explained by sex differences in body size.

Revising model for end-stage liver disease from calendar-time cross-sections with correction for selection bias.

BACKGROUND: Eurotransplant liver transplant candidates are prioritized by Model for End-stage Liver Disease (MELD), a 90-day waitlist survival risk score based on the INR, creatinine and bilirubin. Several studies revised the original MELD score, UNOS-MELD, with transplant candidate data by modelling 90-day waitlist mortality from waitlist registration, censoring patients at delisting or transplantation. This approach ignores biomarkers reported after registration, and ignores informative censoring by transplantation and delisting. METHODS: We study how MELD revision is affected by revision from calendar-time cross-sections and correction for informative censoring with inverse probability censoring weighting (IPCW). For this, we revised UNOS-MELD on patients with chronic liver cirrhosis on the Eurotransplant waitlist between 2007 and 2019 (n = 13,274) with Cox models with as endpoints 90-day survival (a) from registration and (b) from weekly drawn calendar-time cross-sections. We refer to the revised score from cross-section with IPCW as DynReMELD, and compare DynReMELD to UNOS-MELD and ReMELD, a prior revision of UNOS-MELD for Eurotransplant, in geographical validation. RESULTS: Revising MELD from calendar-time cross-sections leads to significantly different MELD coefficients. IPCW increases estimates of absolute 90-day waitlist mortality risks by approximately 10 percentage points. DynReMELD has improved discrimination over UNOS-MELD (delta c-index: 0.0040, p < 0.001) and ReMELD (delta c-index: 0.0015, p < 0.01), with differences comparable in magnitude to the addition of an extra biomarker to MELD (delta c-index: ± 0.0030). CONCLUSION: Correcting for selection bias by transplantation/delisting does not improve discrimination of revised MELD scores, but substantially increases estimated absolute 90-day mortality risks. Revision from cross-section uses waitlist data more efficiently, and improves discrimination compared to revision of MELD exclusively based on information available at listing.

The impact of endoxifen-guided tamoxifen dose reductions on endocrine side-effects in patients with primary breast cancer.

BACKGROUND: Tamoxifen is important in the adjuvant treatment of hormone-sensitive breast cancer and substantially reduces recurrence; however, almost 50% of patients are non-compliant mainly due to side-effects. The aim of this study was to investigate whether endoxifen-guided tamoxifen dose reduction could lead to fewer side-effects. MATERIALS AND METHODS: Effects of tamoxifen dose reduction were investigated in patients with bothersome side-effects and endoxifen levels ≥32 nM and compared to patients with side-effects who remained on tamoxifen 20 mg. Endocrine symptoms and health-related quality of life (HR-QOL) were assessed after 3 months with the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire. RESULTS: Tamoxifen dose was reduced in 20 patients, 17 of whom were assessable for side-effect analyses. A clinically relevant improvement of >6 points was observed in endocrine symptoms and HR-QOL in 41% and 65% of the patients, respectively. In total, there was a significant and clinically relevant improvement in endocrine symptoms [5.7, 95% confidence interval (CI) -0.5-11.5] and HR-QOL (8.2, 95% CI 0.9-15.4) after dose reduction. This was not seen in patients whose doses were not reduced (n = 60). In 21% of patients, endoxifen dropped slightly below the 16-nM threshold (12.8, 15.5, 15.8, 15.9 nM). CONCLUSIONS: Endoxifen-guided dose reduction of tamoxifen significantly improved tamoxifen-related side-effects and HR-QOL. Nearly 80% of patients remained above the most conservative endoxifen threshold.

Single-Center Case Series of Donor-Related Malignancies: Rare Cases With Tremendous Impact.

BACKGROUND: Donor-related malignancy is a rare complication of organ transplantation. METHODS: In this case series, we discuss three cases of donor-related cancers in kidney transplant recipients who were registered in our center between 1979 and 2015. They account for an incidence of 0.29% of donor-related malignancies of a total of 1015 transplanted kidney grafts (deceased and living donors). The three cases that we describe presented in different ways and with different severity, although the response to the initiated treatment was comparable. RESULTS: All three patients not only survived their cancer episode but also had a complete oncological remission and underwent successful second kidney transplantation, accounting for a 100% survival rate in our small cohort. CONCLUSIONS: Despite the very low incidence of this complication, transplant clinicians must be aware of the occurrence of donor-related malignancies when selecting a donor and should be able to diagnose and treat a case of donor-related cancer.

Vulvar mucinous adenocarcinoma with neuroendocrine differentiation: A case report and review of the literature.

BACKGROUND: There are limited cases in literature of patients with mucinous adenocarcinoma of the vulva with neuroendocrine differentiation have. With this new case, we aim to provide an overview of the existing literature and present a tool with relevant markers for the pathologist in the differential diagnosis. CASE DESCRIPTION: A 92-year-old multiparous, Caucasian woman presented with a 8 cm spherical tumor of the left major labium. Since the initial punch biopsy was not conclusive, a local resection was performed. Histopathological examination showed mucus production, large pools of mucin with trabeculae and cribriform glandular structures with strongly atypical columnar epithelium. Additional immunohistochemical analysis demonstrated expression of: CEA, CK7, EMA, and the neuroendocrine markers synaptophysin and chromogranin supporting the diagnosis. CONCLUSION: In this report, we present a new case of a mucinous adenocarcinoma of the vulva with neuroendocrine differentiation based immunohistochemical analysis. Due to the indolent tumor behavior, partial vulvectomy is the therapy of choice.

Structural and evolutionary relationships between two families of bacterial extracytoplasmic chaperone proteins which function cooperatively in fimbrial assembly.

Gram-negative purple bacteria possess pairs of extracytoplasmic, ATP-independent, fimbrium-specific chaperone proteins which cooperatively function in the assembly of this extracellular organelle. The two non-homologous families of these proteins have been termed "Fimbrial chaperone family no. 1" (FCF1) and "Fimbrial chaperone family no. 2" (FCF2). The eleven sequenced or partially sequenced members of each of these two protein families were analysed. Their sequences were multiply aligned, and average similarity and hydropathy plots were generated. Statistical analyses of the sequences revealed that the short FCF1 proteins (of about 240 residues) have been better conserved through evolutionary time than have the much larger FCF2 proteins (of about 830 residues). Moreover, the N-terminal thirds of the FCF2 proteins are better conserved than the central or C-terminal thirds of these proteins. Phylogenetic tree construction revealed that, in general, the two proteins which cooperate in the assembly of a particular fimbrial type have similar positions on their respective phylogenetic trees, suggesting that the two proteins evolved in parallel as a functional unit. Two exceptions were noted, however. In one case, a hybrid protein appears to have arisen, possibly by genetic recombination. In another case, the two proteins of a particular pair may have evolved separately and come together late in the evolutionary process to provide their cooperative function.