Sex and the Relationship Between Cardiometabolic Risk Factors and Estimated GFR Decline: A Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Females have a higher prevalence of chronic kidney disease (CKD) than males, but are less likely to be treated with kidney replacement therapy (KRT). We studied the interaction between sex and the association of cardiometabolic risk factors for the decline in kidney function over time. STUDY DESIGN: A population-based cohort study. SETTING & PARTICIPANTS: 1,127,731 adults living in Wales, UK, within the Secure Anonymised Information Linkage Databank. EXPOSURES: Sex and risk factors including age, estimated glomerular filtration rate (eGFR), cardiometabolic conditions, smoking, and socioeconomic deprivation. These risk factors were defined using primary care records. OUTCOMES: The yearly declines in eGFR and the risk of incident kidney failure defined as long-term KRT and/or sustained eGFR<15mL/min/1.73m2. ANALYTICAL APPROACH: Linear mixed effects models and Cox proportional hazards analysis. RESULTS: The average decline in eGFR age ≤73 was equal in males and females. After age 73, eGFR decline was faster in males than females, particularly for males with heart failure (males -1.22 mL/min/1.73m2 per year: 95% confidence interval (CI) -1.25 to -1.20 versus females -0.87mL/min/1.73m2: CI -0.89 to -0.85) and current smokers (males -1.58 mL/min/1.73m2 per year: CI -1.60 to -1.55 versus females -1.27 mL/min/1.73m2: CI -1.29 to -1.25). Socioeconomic deprivation was one of the most impactful risk factors on eGFR decline among females age >73, whereas cardiometabolic risk factors were more important among males. Older females at baseline were less likely to develop incident kidney failure than older males (p-value for age<0.001). LIMITATIONS: Study of people who were almost exclusively White and who had blood laboratory test data. Reliance on creatinine-based eGFR. Albuminuria and body mass index data were incomplete. CONCLUSIONS: eGFR decline was faster in males than in females especially in the setting of heart failure and smoking. Socioeconomic deprivation was an important risk factor associated with eGFR decline, particularly for females. While further work is required to explore less well-recognised risk factors these findings may inform clinical management strategies of CKD overall and within sex-specific groups.

Sex differences in cancer outcomes across the range of eGFR.

BACKGROUND AND HYPOTHESIS: People with chronic kidney disease (CKD) have increased incidence and mortality from most cancer types. We hypothesised that odds of presenting with advanced cancer may vary according to differences in eGFR, that this could contribute to increased all-cause mortality and that sex differences may exist. METHODS: Data were from Secure Anonymised Information Linkage Databank, including people with de-novo cancer diagnosis (2011-2017) and two kidney function tests within two years prior to diagnosis to determine baseline eGFR (mL/min/1.73m2). Logistic regression models determined odds of presenting with advanced cancer by baseline eGFR. Cox proportional hazards models tested associations between baseline eGFRcr and all-cause mortality. RESULTS: eGFR < 30 was associated with higher odds of presenting with advanced cancer of prostate, breast and female genital organs, but not other cancer sites. Compared to eGFR > 75-90, eGFR < 30 was associated with greater hazards of all-cause mortality in both sexes, but the association was stronger in females (female: HR 1.71, 95%CI 1.56-1.88; male versus female comparison HR 0.88, 95%CI 0.78-0.90). CONCLUSIONS: Lower or higher eGFR was not associated with substantially higher odds of presenting with advanced cancer across most cancer sites, but was associated with reduced survival. A stronger assocation with all-cause mortality in females compared to males with eGFR < 30 is concerning and warrants further scrutiny.

Relative survival in patients with cancer and kidney failure.

BACKGROUND AND HYPOTHESIS: The population with kidney failure is at increased risk of cancer and associated mortality. Relative survival can provide insight into the excess mortality, directly or indirectly, attributed to cancer in the population with kidney failure. METHODS: We estimated relative survival for people all ages receiving dialysis (n = 4089) and kidney transplant recipients (n = 3253) with de novo cancer, and for the general population with cancer in Australia and New Zealand (n = 3 043 166) over the years 1980-2019. The entire general population was the reference group for background mortality, adjusted for sex, age, calendar year and country. We used Poisson regression to quantify excess mortality ratios. RESULTS: Five-year relative survival for all-site cancer was markedly lower than the general population for people receiving dialysis (0.25, 95%CI:0.23-0.26) and kidney transplant recipients (0.55, 95%CI:0.53-0.57). In dialysis, excess mortality was more than double (2.16, 95%CI:2.08-2.25) that of the general population with cancer and for kidney transplant recipients 1.34 higher (95%CI:1.27-2.41). There was no difference in excess mortality from lung cancer between people with kidney failure and the general population with cancer. Comparatively, there was a significant survival deficit for people with kidney failure, compared to the general population with cancer, for melanoma, breast cancer and prostate cancers. CONCLUSION: Decreased cancer survival in kidney failure may reflect differences in multi-morbidity burden, reduced access to treatment, or greater harm from or reduced efficacy of treatments. Our findings support research aimed at investigating these hypotheses.

Transmission and Non-transmission of Melanoma From Deceased Solid Organ Donors to Transplant Recipients: Risks and Missed Opportunities.

BACKGROUND: Biovigilance concerns are in tension with the need to increase organ donation. Cancer transmission risk from donor to recipient may be overestimated, as non-transmission events are rarely reported. We sought to estimate melanoma transmission risk in deceased organ donation and identify missed opportunities for donation in an Australian cohort with high melanoma prevalence. METHODS: We used a population-based approach and linked deceased organ donors, transplant recipients, and potential donors forgone, 2010-2018, with the Central Cancer Registry (CCR), 1976-2018. We identified melanomas using ICD-O-3 classification, assessed the probability of transmission, and compared suspected melanoma history in potential donors forgone with melanoma notifications in the CCR. RESULTS: There were 9 of 993 donors with melanoma in CCR; 4 in situ low-risk and 5 invasive high-to-unacceptable risk. Four were unrecognized before donation. Of 16 transplant recipients at risk, we found 0 of 14 transmission events (2 recipients had insufficient follow-up). Of 35 of 3588 potential donors forgone for melanoma risk alone, 17 were otherwise suitable for donation; 6 of 35 had no melanoma in CCR, 2 of 35 had in situ melanomas and 9 of 35 had thin invasive melanomas (localized, ≤0.8 mm thickness). CONCLUSIONS: Our findings contribute to current evidence that suggests donors with melanomas of low metastatic potential may provide an opportunity to safely increase organ donation and so access to transplantation.

Sex differences in associations between creatinine and cystatin C-based kidney function measures with stroke and major bleeding.

PURPOSE: We sought to explore whether adding kidney function biomarkers based on creatinine (eGFRCr), cystatin C (eGFRCys) or a combination of the two (eGFRCr-Cys) could improve risk stratification for stroke and major bleeding, and whether there were sex differences in any additive value of kidney function biomarkers. METHOD: We included participants from the UK Biobank who had not had a previous ischaemic or haemorrhagic stroke or major bleeding episode, and who had kidney function measures available at baseline. Cause-specific Cox proportional hazards models tested associations between eGFRCr, eGFRCys and eGFRCr-Cys (mL/min/1.73 m2) with ischaemic and haemorrhagic stroke, major bleeding (gastrointestinal or intracranial, including haemorrhagic stroke) and all-cause mortality. FINDINGS: Among 452,879 eligible participants, 246,244 (54.4%) were women. Over 11.5 (IQR 10.8-12.2) years, there were 3706 ischaemic strokes, 795 haemorrhagic strokes, 26,025 major bleeding events and 28,851 deaths. eGFRCys was more strongly associated with ischaemic stroke than eGFRCr: an effect that was more pronounced in women (men - HR: 1.16, 95% CI: 1.12-1.19; female to male comparison - HR: 1.11, 95% CI: 1.05-1.16, per 10 mL/min/1.73 m2 decline in eGFRCys). This interaction effect was also demonstrated for eGFRCr-Cys, but not eGFRCr. eGFRCys and eGFRCr-Cys were more strongly associated with major bleeding and all-cause mortality than eGFRCr in both men and women. Event numbers were small for haemorrhagic stroke. DISCUSSION: To a greater degree than is seen in men, eGFRCr underestimates risk of ischaemic stroke and major bleeding in women compared to eGFRCys. The difference between measures is likely explained by non-GFR biology of creatinine and cystatin C. CONCLUSION: Enhanced measurement of cystatin C may improve risk stratification for ischaemic stroke and major bleeding and clinical treatment decisions in a general population setting, particularly for women.

Cost-effectiveness of Interventions to Increase Utilization of Kidneys From Deceased Donors With Primary Brain Malignancy in an Australian Setting.

Kidneys from potential deceased donors with brain cancer are often foregone due to concerns of cancer transmission risk to recipients. There may be uncertainty around donors' medical history and their absolute transmission risk or risk-averse decision-making among clinicians. However, brain cancer transmissions are rare, and prolonging waiting time for recipients is harmful. Methods: We assessed the cost-effectiveness of increasing utilization of potential deceased donors with brain cancer using a Markov model simulation of 1500 patients waitlisted for a kidney transplant, based on linked transplant registry data and with a payer perspective (Australian government). We estimated costs and quality-adjusted life-years (QALYs) for three interventions: decision support for clinicians in assessing donor risk, improved cancer classification accuracy with real-time data-linkage to hospital records and cancer registries, and increased risk tolerance to allow intermediate-risk donors (up to 6.4% potential transmission risk). Results: Compared with current practice, decision support provided 0.3% more donors with an average transmission risk of 2%. Real-time data-linkage provided 0.6% more donors (1.1% average transmission risk) and increasing risk tolerance (accepting intermediate-risk 6.4%) provided 2.1% more donors (4.9% average transmission risk). Interventions were dominant (improved QALYs and saved costs) in 78%, 80%, and 87% of simulations, respectively. The largest benefit was from increasing risk tolerance (mean +18.6 QALYs and AU$2.2 million [US$1.6 million] cost-savings). Conclusions: Despite the additional risk of cancer transmission, accepting intermediate-risk donors with brain cancer is likely to increase the number of donor kidneys available for transplant, improve patient outcomes, and reduce overall healthcare expenditure.

Potential organ donors with primary brain tumours: missed opportunities for donation and transplantation identified in Australian cohort study 2010-2015.

BACKGROUND: Potential organ donors with primary brain tumours (PBT) frequently donate, however some may be declined due to uncertainty about tumour classification or transmission risk to transplant recipients. We sought to describe transmission risk and donation outcome of potential donors with PBT, including identifying missed opportunities for transplantation, and any PBT transmission events. METHODS: We undertook a population-based cohort study in NSW of all potential donors 2010-2015. PBT potential donors were characterized according to tumour grade and transmission risk, and whether they donated organs. Data linkage was used to determine agreement of risk assessment of potential donors to that in the Biovigilance Register, and to identify any PBT transmissions. RESULTS: Of 2957 potential donors, 76 (3%) had PBTs. There was agreement of risk assessment in 44 (58%) cases. PBT potential donors had fewer comorbidities (1.6 vs. 2.1, P = 0.006) than non-PBT potential donors. Forty-eight (63%) potential donors were declined for non-PBT reasons, 18 (24%) were declined because of perceived PBT transmission risk and 10 (13%) donated. All PBT donors had WHO-I or -II tumours, and none had a ventriculo-pertioneal shunt. No transmission events occurred. CONCLUSION: Donors with WHO-I/II PBT appear to have minimal risk of tumour transmission in solid organ transplantation; it is reassuring that no PBT transmission occurred. There is evidence of risk aversion to referrals with WHO-III/IV tumours. There exists opportunity to improve potential donor risk assessment at the time of referral using integrated data sets, and to increase organ donation and transplantation rates through greater utilization of PBT referrals.

Cancer Mortality in People Receiving Dialysis for Kidney Failure: An Australian and New Zealand Cohort Study, 1980-2013.

RATIONALE & OBJECTIVE: Cancer is a significant cause of morbidity in the population with kidney failure; however, cancer mortality in people undergoing dialysis has not been well described. We sought to compare cancer mortality in people on dialysis for kidney failure with cancer mortality in the general population. STUDY DESIGN: A retrospective cohort study using linked health-administrative and dialysis registry data. SETTING & PARTICIPANTS: All people receiving dialysis represented in the Australian and New Zealand Dialysis and Transplantation Registry, 1980-2013. EXPOSURE: Dialysis; hemodialysis (HD) and peritoneal dialysis (PD). OUTCOME: Death and underlying cause of death ascertained using health administrative data and classified using International Classification of Diseases, Tenth Revision, Australian Modification (ICD-10-AM) codes. ANALYTICAL APPROACH: Indirect standardization on age at death, sex, year, and country to estimate standardized mortality ratios (SMR). RESULTS: Over 269,598 person years of observation, 34,100 deaths occurred among 59,648 people on dialysis, including 3,677 cancer deaths. The relative risk of all-site cancer death in dialysis was twice (SMR, 2.4 [95% CI, 2.33-2.49]) that of the general population and highest for oral and pharynx cancers (SMR, 24.3 [95% CI, 18.0-31.5]) and multiple myeloma (SMR, 22.5 [95% CI, 20.3-23.9]). Women on dialysis had a significantly higher risk of all-site cancer mortality (SMR, 2.7 [95% CI, 2.59-2.89]) compared with men (SMR, 2.3 [95% CI, 2.17-2.36]) (P < 0.001). People on HD (SMR, 2.2 [95% CI, 2.11-2.30]) experienced greater excess deaths from all-site cancer compared with people on PD (SMR, 1.3 [95% CI, 1.23-1.44]). Excess deaths have gradually decreased over time for all-site, multiple myeloma, and kidney cancers (P < 0.001) but have not kept up with improvements in the general population. By contrast, among people receiving dialysis, excess deaths increased for colorectal and lung cancers (P < 0.001). LIMITATIONS: Confirmation of cancer diagnoses and population incidence data were not available; inability to exclude pre-existing cancers. CONCLUSIONS: People on dialysis experience excess all-site and site-specific cancer mortality compared with the general population. Mortality differs by modality type, age, and sex. Understanding the role of kidney failure and other morbidities in the treatment of cancer is important for shared decision-making regarding cancer treatments and identifying potential approaches to improve outcomes.

Perceived Versus Verified Cancer History and Missed Opportunities for Donation in an Australian Cohort of Potential Deceased Solid Organ Donors.

BACKGROUND: There is an imperative to maximize donation opportunities given ongoing organ shortages, but donor suitability assessments can be challenging. METHODS: We analyzed an Australian cohort of potential deceased donors 2010 to 2013 to explore misclassification of cancer risk and potential strategies for improvement (decision support, real-time data linkage to existing data sets, and increasing risk tolerance). Cancer history perceived at referral was compared with verified cancer history in linked health records. Transmission risks were based on clinical guidelines. Potential donors declined due to cancer but verified low risk were missed opportunities; those accepted but verified high risk were excess-risk donors. RESULTS: Among 472 potentially suitable donor referrals, 132 (28%) were declined because of perceived transmission risk and 340 (72%) donated. Assuming a low-risk threshold, there were 38/132 (29%) missed opportunities and 5/340 (1%) excess-risk donors. With decision support, there would have been 5 (13%) fewer missed opportunities and 2 (40%) more excess-risk donors; with real-time data linkage, 6 (16%) fewer missed opportunities and 2 (40%) fewer excess-risk donors; and with increased risk tolerance, 6 (16%) fewer missed opportunities and 11 (220%) more excess-risk donors. CONCLUSIONS: Potential donors' cancer history is typically incomplete at referral. There are missed opportunities where decision support or more accurate cancer history could safely increase organ donors.

Prevalence of anal cytological abnormalities and high-risk human papillomavirus prevalence in kidney transplant recipients: A cross-sectional study.

BACKGROUND: Transplant recipients are at high-risk of anal squamous cell cancer. We aimed to estimate the prevalence of high-risk human papillomavirus (HPV) and high-grade squamous intraepithelial lesion (HSIL) and assess characteristics associated with results METHODS: We recruited kidney transplant recipients in a single-center, 2015-2018. Participants completed a clinical questionnaire and received an anal-swab sent for HPV-DNA and cytological testing RESULTS: A total of 97 (74%) of 125 recipients approached consented to participate. Participants were median 47 (IQR 40-55) years, 60% male and median 4.5 (IQR .9-13) months-since-transplant. Of 86 assessable samples, at least one HPV genotype was detected in 15 (17%) participants; 1 (1%) HPV16, 8 (9%) other high-risk HPV. Of 76 assessable cytology samples, 9 (12%) showed evidence of abnormality; 1 (1%) HSIL, 1 (1%) atypical-squamous-cells, cannot exclude HSIL. Both HSIL recipients had high-risk HPV and biopsy confirmed HSIL. High-risk HPV was detected in six (9%) recipients with normal cytology. History of sexually transmitted infection, and abnormal cervical pap smear in women, was associated with high-risk HPV and HSIL CONCLUSIONS: High-risk HPV and HSIL testing may identify kidney transplant recipients at higher risk of anal cancer. Longitudinal studies are needed to describe the natural history of anal cancer in transplant recipients.

Cancer transmissions and non-transmissions from solid organ transplantation in an Australian cohort of deceased and living organ donors.

Evidence on cancer transmission from organ transplantation is poor. We sought to identify cases of cancer transmission or non-transmission from transplantation in an Australian cohort of donors and recipients. We included NSW solid organ deceased donors 2000-2012 and living donors 2004-2012 in a retrospective cohort using linked data from the NSW Biovigilance Register (SAFEBOD). Central Cancer Registry (CCR) data 1972-2013 provided a minimum one-year post-transplant follow-up. We identified cancers in donors and recipients. For each donor-recipient pair, the transmission was judged likely, possible, unlikely, or excluded using categorization from international guidelines. In our analysis, transmissions included those judged likely, while those judged possible, unlikely, or excluded were non-transmissions. In our cohort, there were 2502 recipients and 1431 donors (715 deceased, 716 living). There were 2544 transplant procedures, including 1828 (72%) deceased and 716 (28%) living donor transplants. Among 1431 donors, 38 (3%) had past or current cancer and they donated to 68 recipients (median 6.7-year follow-up). There were 64 (94%) non-transmissions, and 4 (6%) transmissions from two living and two deceased donors (all kidney cancers discovered during organ recovery). Donor transmitted cancers are rare, and selected donors with a past or current cancer may be safe for transplantation.

Safety and Biovigilance in Organ Donation (SAFEBOD): Protocol for a Population-Based Cohort Study.

BACKGROUND: Tension lies between the need to increase access to organ transplantation and the equally urgent need to prevent inadvertent transmission of infectious diseases or cancer from organ donors. Biovigilance, or the evaluation of potential donors, is often time-pressured and may be based on incomplete information. OBJECTIVE: The Safety and Biovigilance in Organ Donation (SAFEBOD) study aims to improve estimates of infection and cancer transmission risk and explore how real-time data access could support decision-making. METHODS: We will link existing donor referral, actual donor, recipient, and health-outcome data sets from 2000-2015 in New South Wales. Organ donor data sets will include the Organ Donor Characterizing Risk-Profile of Donors Study, the National Organ Matching System, the Australian and New Zealand Organ Donor Register, and the Australian and New Zealand Living Donor Kidney Register. Recipient data sets will include the Australian and New Zealand Dialysis and Transplant Register, the Australian and New Zealand Cardiothoracic Register, the Australian and New Zealand Islet and Pancreas Register, and the Australian and New Zealand Liver Transplant Register. New South Wales health outcome data sets will include HIV and AIDS Notifications and Surveillance Data, the Notifiable Conditions Information Management System, Admitted Patient Data Collection, Emergency Department Data Collection, the Central Cancer Registry, and the Cause of Death Data Collection. We will link organ donors to transplant recipients and health outcomes data sets using probabilistic data-matching based on personal identifiers. Transmission and nontransmission events will be determined by comparing previous cases in donors and posttransplant cases in recipients. We will compare the perceived-risk at referral with the verified risk from linked health outcome data sets and the odds of cancer or contracting an infectious disease in organ recipients from donors based on their transmission-risk profile and estimate recipient survival by donor transmission risk group. RESULTS: Data were requested from each of the listed registries in September 2018, and data collection is ongoing. Linked data from all listed data sets are expected to be complete in September 2020. CONCLUSIONS: The SAFEBOD study will overcome current limitations in organ donation by accessing comprehensive information on referred organ donors and recipients in existing data sets. The study will provide robust estimates of disease transmission and nontransmission events based on recent data. It will also describe the agreement between perceived risk estimated at the time of referral and verified risk when all health outcome data are accessible. The improved understanding of transmission and nontransmission events will inform clinical decisions and highlight where current policies can be revised to broaden the acceptance of deceased donors. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/18282.

Cancer mortality in kidney transplant recipients: An Australian and New Zealand population-based cohort study, 1980-2013.

Cancer burden is increasing in kidney transplant recipients, but differences in mortality compared to the general population remain unclear. We sought to compare cancer mortality in paediatric and adult kidney transplant recipients with the general population and describe any differences, by site, age and sex, country and over time. We included kidney transplant recipients from the Australian and New Zealand Dialysis and Transplantation Registry, 1980-2013. Date of death and underlying cause of death were ascertained by data-linkage and classified using ICD10AM codes. Indirect standardisation was used to estimate standardised mortality ratios (SMR). There were 5,284 deaths in 17,628 kidney transplant recipients over 175,084 person-years of observation, including 1,061 (20%) cancer deaths. Relative cancer mortality was higher than the general population for all-site (SMR 2.9, 95% CI 2.7-3.1) cancer and highest for nonmelanoma skin cancer (SMR 50.9, 95% CI 43.5-59.6) and lymphoma (SMR 42.2, 95% CI 35.3-50.5). Relative cancer mortality decreased with increasing age in men (p < 0.001) and women (p = 0.001) but never reached parity with the general population. Relative mortality did not change with age for skin and lip, or colorectal cancers (p-value >0.1). Only relative colorectal cancer mortality increased over time (p = 0.002). Our study shows cancer mortality in kidney transplant recipients was higher than expected in the general population. The magnitude of excess mortality varied by cancer site, age and sex. Further evidence is needed to identify whether this variation is due to differences at diagnosis or access and effectiveness of cancer treatments in this population.

Epidemiology and Comorbidity Burden of Organ Donor Referrals in Australia: Cohort Study 2010-2015.

Increasing organ donation rates in Australia have been exceeded by a rise in potential donor referrals not proceeding to donate. Referral evaluation is resource-intensive. We sought to characterize organ donor referrals in New South Wales, Australia, and identify predictors of referrals not proceeding to donation. METHODS: We performed a cohort study of NSW Organ and Tissue Donation Service logs 2010-2015, describing the prevalence and impact of comorbidities on referral outcome. Logistic regression was used to identify comorbidities influencing outcome and predict probability of donation. RESULTS: Of 2977 referrals, 669 (22%) donated and 2308 (78%) did not. Despite increasing donation rates, the proportion proceeding to donate declined 2010-2015. Among referrals, the prevalence of all comorbidities except cerebrovascular disease increased and was higher among nondonors. History of cardiac disease, ≥65 years of age, chronic kidney or liver disease, malignancy, and absence of cerebrovascular disease were all significantly (P < 0.01) associated with non donation. Hypertension and diabetes did not significantly impact outcome. Predicted probability of donation varied from <1% to 54% depending on comorbidity burden of the referral. CONCLUSIONS: Comorbidity burden among donor referrals is increasing. The presence of particular comorbidities may significantly impact referral outcome. A better understanding of referral characteristics associated with non donation may improve the efficiency of the referral process in the context of encouraging routine referrals.

Transplant Recipients and Anal Neoplasia Study: Design, Methods, and Participant Characteristics of a Prevalence Study.

Kidney recipients have anal cancer rates 3 times higher than the general population in Australia and New Zealand. High-risk human papillomavirus (HPV) genotypes are implicated in the majority of anal cancers. Establishing the epidemiology of anal HPV infection and precursors of anal cancer in transplant recipient populations is 1 consideration in any potential screening program. The Transplant and Anal Neoplasia Study is a cross-sectional study of the prevalence of anal cytological abnormalities and HPV deoxyribonucleic acid in kidney transplant recipients, as well as evaluating the acceptability of an anal cancer screening intervention. The study aims to recruit 100 kidney transplant recipients, older than 18 years, in Australia. Transplant recipients attending for a protocol biopsy at 3 and 12 months and annually posttransplant are approached to participate. Participants undergo an anal swab, which is then analyzed using liquid-based cytological examination and tested for the detection of 37 anogenital HPV deoxyribonucleic acid genotypes. Participants also complete a demographic and behavioral questionnaire that covers sexual behavior, history of anal symptoms, and possible anal cancer risk factors. Associations will be tested using multiple regression analysis. Recruitment for the study began in 2015 and is ongoing. To date, 96 (77%) of 125 kidney transplant recipients approached have consented to the study. The mean age is 48 (median, 47 y; range, 20-76 y), 59% are male, and Northwest European (58%) represented the largest ethnic group. No participants self-identified as Aboriginal or Torres Strait Islander. High consent rates and positive qualitative results suggest that a larger screening program may be well received by kidney transplant recipients, with increased resources and some modification to the timing of approach. Further results of the study will inform the possible implementation of a larger screening trial for prevention of anal cancers in kidney and other solid organ transplant recipients.

Weekend effect: analysing temporal trends in solid organ donation.

BACKGROUND: Research suggests patients treated over weekends experience poorer outcomes. Only one US-based study explored this weekend effect in organ donation, specifically the kidney discard rate. In Australia potential donors are referred to a donation service, and donation proceeds if family consent is granted and the donor is deemed medically suitable to donate. Organ procurement occurs when utilization is almost certain hence discard rates are much lower than in the USA. We aimed to characterize the effect of weekend referral on organ donation in Australia. METHODS: We retrospectively reviewed all New South Wales Organ and Tissue Donation Service logs from 2010 to 2016. Our primary outcome was progression to organ procurement, and secondary outcomes were family consent and meeting medical suitability thresholds. We used logistic regression with random effects adjusting for clustering of referral hospitals. RESULTS: Of 3496 potential donors referred for consideration, 694 (20%) progressed to organ procurement. There were fewer referrals on weekends (average 415 versus 588 for weekdays). However, donation rates were no lower for weekend compared to weekday referrals (adjusted OR 1.17; 95% CI 0.95, 1.44). Family consent (adjusted OR 1.20; 95% CI 1.00, 1.44) and medical suitability (adjusted OR 1.15; 95% CI 0.96, 1.38) were not lower for weekend compared to weekday referrals. Similar results were found for all sensitivity analyses conducted. CONCLUSIONS: In Australia, the donation pathway operates consistently throughout the week, with donation no less likely to proceed on weekends and holidays. This finding contrasts with findings in the USA.

Mutation Analysis of Cell-Free DNA and Single Circulating Tumor Cells in Metastatic Breast Cancer Patients with High Circulating Tumor Cell Counts.

PURPOSE: The purpose of this study was to directly compare mutation profiles in multiple single circulating tumor cells (CTC) and cell-free DNA (cfDNA) isolated from the same blood samples taken from patients with metastatic breast cancer (MBC). We aimed to determine whether cfDNA would reflect the heterogeneity observed in 40 single CTCs. EXPERIMENTAL DESIGN: CTCs were enumerated by CELLSEARCH. CTC count was compared with the quantity of matched cfDNA and serum CA15-3 and alkaline phosphatase (ALP) in 112 patients with MBC. In 5 patients with ≥100 CTCs, multiple individual EpCAM-positive CTCs were isolated by DEPArray and compared with matched cfDNA and primary tumor tissue by targeted next-generation sequencing (NGS) of about 2,200 mutations in 50 cancer genes. RESULTS: In the whole cohort, total cfDNA levels and cell counts (≥5 CTCs) were both significantly associated with overall survival, unlike CA15-3 and ALP. NGS analysis of 40 individual EpCAM-positive CTCs from 5 patients with MBC revealed mutational heterogeneity in PIK3CA, TP53, ESR1, and KRAS genes between individual CTCs. In all 5 patients, cfDNA profiles provided an accurate reflection of mutations seen in individual CTCs. ESR1 and KRAS gene mutations were absent from primary tumor tissue and therefore likely either reflect a minor subclonal mutation or were acquired with disease progression. CONCLUSIONS: Our results demonstrate that cfDNA reflects persisting EpCAM-positive CTCs in patients with high CTC counts and therefore may enable monitoring of the metastatic burden for clinical decision-making. Clin Cancer Res; 23(1); 88-96. ©2016 AACR.

Next Generation Sequencing of Circulating Cell-Free DNA for Evaluating Mutations and Gene Amplification in Metastatic Breast Cancer.

BACKGROUND: Breast cancer tissues are heterogeneous and show diverse somatic mutations and somatic copy number alterations (CNAs). We used a novel targeted next generation sequencing (NGS) panel to examine cell-free DNA (cfDNA) to detect somatic mutations and gene amplification in women with metastatic breast cancer (MBC). METHODS: cfDNA from pretreated patients (n = 42) and 9 healthy controls were compared with matched lymphocyte DNA by NGS, using a custom 158 amplicon panel covering hot-spot mutations and CNAs in 16 genes, with further validation of results by droplet digital PCR. RESULTS: No mutations were identified in cfDNA of healthy controls, whereas exactly half the patients with metastatic breast cancer had at least one mutation or amplification in cfDNA (mean 2, range 1-6) across a total of 13 genes. Longitudinal follow up showed dynamic changes to mutations and gene amplification in cfDNA indicating clonal and subclonal response to treatment that was more dynamic than cancer antigen 15-3 (CA15-3). Interestingly, at the time of blood sampling disease progression was occurring in 7 patients with erb-b2 receptor tyrosine kinase 2 (ERBB2) gene amplification in their cfDNA and 3 of these patients were human epidermal growth factor receptor 2 (HER2) negative at diagnosis, suggesting clonal evolution to a more aggressive phenotype. Lastly, 6 patients harbored estrogen receptor 1 (ESR1) mutations in cfDNA, suggesting resistance to endocrine therapy. Overall 9 of 42 patients (21%) had alterations in cfDNA that could herald a change in treatment. CONCLUSIONS: Targeted NGS of cfDNA has potential for monitoring response to targeted therapies through both mutations and gene amplification, for analysis of dynamic tumor heterogeneity and stratification to targeted therapy.