The clinical efficacy of PSMA PET/MRI in biochemically recurrent prostate cancer compared with standard of care imaging modalities and confirmatory histopathology: results of a single-centre, prospective clinical trial.

Prospective evidence for the clinical role and efficacy of prostate specific membrane antigen (PSMA) positron emission tomography (PET)/magnetic resonance imaging (MRI) combining MRI characterization and localization of lesions with PET avidity in comparison to conventional imaging is limited. In a prospective clinical trial, we aimed to evaluate the diagnostic yield and therapeutic impact of PSMA PET/MRI in men with biochemical recurrence (BCR) following curative therapy. A single-centre, prospective clinical trial at the Princess Alexandra Hospital recruited 30 patients with BCR. Patients underwent PSMA PET/MRI and concurrent conventional CT chest, abdomen, pelvis and whole-body bone scan. Biopsy was performed when safety possible for histological correlation of identified lesions. Clinical efficacy and impact of PSMA PET findings were evaluated. 30 patients with BCR were recruited (median PSA 0.69 ng/ml). PSMA avid lesions were present in 21 patients (70%). 23 patients were previously treated with definitive surgery, 6 patients received external beam radiotherapy and 1 patient had low dose rate brachytherapy. A total of 8 of 9 lesions biopsied were positive (88.9% histological correlation). PSMA PET/MRI detected local recurrence (p = 0.005) and pelvic lesions (p = 0.06) more accurately than conventional imaging. PSMA PET/MRI may be useful in staging men with biochemical recurrence, especially when PSA is low. Our data demonstrates a high detection rate, especially for locally recurrent disease, and highlights the role of this modality when PSA is low. This modality has the potential to significantly improve prostate cancer detection and may have implications for earlier salvage treatment, avoidance of futile local therapy and change patient management to lead to improved outcomes.

OPTN/SRTR 2018 Annual Data Report: Hepatitis C.

Direct acting antivirals (DAAs) have fundamentally changed the treatment of hepatitis C virus (HCV) infection and reduced the discard rate of HCV-infected organs by offering a treatment option with a high likelihood of cure posttransplant. This has spurred increased interest in transplanting organs from HCV-positive donors into recipients both with and without HCV. In this chapter, we examine data from 2007 to 2018 to determine trends in HCV (+) donor transplants across various organ types. Since 2015, willingness to accept HCV (+) organs increased for candidates waitlisted for kidney, lung, heart, and pancreas transplant, but decreased for those listed for intestine transplant. For candidates listed for liver transplant, willingness to accept HCV (+) organs decreased from 2007 to 2017, but began increasing in 2017. Willingness to accept was not concentrated in a single US geographic area, and there was substantial variation among transplant programs and donation service areas. Numbers of anti-HCV (+) donor kidney, heart, lung, and liver transplants have increased considerably in the past few years. Short-term allograft survival for kidney and liver transplant recipients of anti-HCV (+) organs appears to be comparable to that for recipients of anti-HCV (-) organs in an unadjusted analysis. However, an unadjusted analysis indicates that long-term allograft survival may be worse. Kidney transplant between HCV-infected donors and uninfected recipients with posttransplant DAA treatment is an emerging area. Short-term data are promising, with similar 1-year allograft survival compared with HCV-uninfected donor to HCV-uninfected recipient kidney transplants in unadjusted analyses. However, long-term data are lacking and close monitoring in the future is warranted.

OPTN/SRTR 2018 Annual Data Report: Pancreas.

The overall number of pancreas transplants continued to increase to 1027 in 2018, after a nadir of 947 in 2015. New additions to waiting list remained stable, with 1485 candidates added in 2018. Proportions of patients with type II diabetes waiting for transplant (14.6%) and undergoing transplant (14.8%) have steadily increased since 2016. Waiting times for simultaneous pancreas/kidney transplant have decreased; median months to transplant was 13.5 for simultaneous pancreas/kidney transplant and 19.7 for pancreas transplant alone in 2018. Outcomes, including patient and kidney survival, as well as rejection rates, have improved consistently over the past several years. Pancreas graft survival data are being collected by the Organ Procurement and Transplantation Network and will be included in a future report once there are sufficient cohorts for analysis.

OPTN/SRTR 2018 Annual Data Report: Kidney.

Despite the ongoing severe mismatch between organ need and supply, data from 2018 revealed some promising trends. For the fourth year in a row, the number of patients waiting for a kidney transplant in the US declined and numbers of both deceased and living donor kidney transplants increased. These encouraging trends are tempered by ongoing challenges, such as a large proportion of listed patients with dialysis time longer than 5 years. The proportion of candidates aged 65 years or older continued to rise, and the proportion undergoing transplant within 5 years of listing continued to vary dramatically nationwide, from 10% to nearly 80% across donation service areas. Increasing trends in the recovery of organs from hepatitis C positive donors and donors with anoxic brain injury warrant ongoing monitoring, as does the ongoing discard of nearly 20% of recovered organs. While the number of living donor transplants increased, racial disparities persisted in the proportion of living versus deceased donors. Strikingly, the total number of kidney transplant recipients alive with a functioning graft is on track to pass 250,000 in the next 1-2 years. The total number of pediatric kidney transplants remained steady at 756 in 2018. Deeply concerning to the pediatric community is the persistently low level of living donor kidney transplants, representing only 36.2% in 2018.

OPTN/SRTR 2017 Annual Data Report: Pancreas.

In 2017, 1492 patients were added to the pancreas transplant waiting list, 964 listed as active, a slight increase from 2016. This is significant because for the first time in the past decade, the steady downward trend in additions to the waiting list has been reversed. Proportions of pancreas donors with cerebrovascular accident as cause of death decreased, with a concomitant increase in proportions with anoxia and head trauma. This is partly a result of the national opioid crisis, and it reflects increasing use of younger donors for pancreas transplant. The 2017 outcome report remains compromised by previous variation in reporting graft failure. Although the OPTN Pancreas Transplantation Committee has approved more precise definitions of pancreas graft failure, implementation of these definitions took place recently, and the data are not reflected in this report.

OPTN/SRTR 2017 Annual Data Report: Kidney.

Many positive trends in kidney transplantation were notable in 2017. Deceased donor kidney transplant rates and counts continued to rise, the kidney transplant waiting list declined for the third year in a row after decades of growth, and both short- and long-term allograft survival continued to improve year over year. In total, more than 220,000 patients were living in the United States with a functioning allograft. With 3 years of data available since implementation of the new kidney allocation system, better prediction of longer-term results of the allocation policy changes became possible. The data also reveal several areas in need of improvement and attention. Overall, the challenge of providing adequate access to kidney transplant persisted nationally, with additional dramatic regional variation. The proportion of living donor kidney transplants in both adults and children continued to fall, and racial disparities in living donor kidney transplant grew in the past decade.

Program-specific transplant rate ratios: Association with allocation priority at listing and posttransplant outcomes.

The Scientific Registry of Transplant Recipients (SRTR) is considering more prominent reporting of program-specific adjusted transplant rate ratios (TRRs). To enable more useful reporting of TRRs, SRTR updated the transplant rate models to adjust explicitly for components of allocation priority. We evaluated potential associations between TRRs and components of allocation priority that could indicate programs' ability to manipulate TRRs by denying or delaying access to low-priority candidates. Despite a strong association with unadjusted TRRs, we found no candidate-level association between the components of allocation priority and adjusted TRRs. We found a strong program-level association between median laboratory Model for End-stage Liver Disease (MELD) score at listing and program-specific adjusted TRRs (r = .37; P < .001). The program-level association was likely confounded by regional differences in donor supply/demand and listing practices. In kidney transplantation, higher program-specific adjusted TRRs were weakly associated with better adjusted posttransplant outcomes (r = -.14; P = .035) and lower adjusted waitlist mortality rate ratios (r = -.15; P = .022), but these associations were absent in liver, lung, and heart transplantation. Program-specific adjusted TRRs were unlikely to be improved by listing candidates with high allocation priority and can provide useful information for transplant candidates and programs.

OPTN/SRTR 2016 Annual Data Report: Pancreas.

The number of pancreas transplants performed in the United States increased by 7.0% in 2016 over the previous year, the first such increase in more than a decade, largely attributable to an increase in simultaneous kidney pancreas transplants. Transplant rates increased in 2016, and mortality on the waiting list decreased. The declining enthusiasm for pancreas after kidney (PAK) transplants persisted. The uniform definition of graft failure was approved by the OPTN Board of Directors in 2015 and will be implemented in early 2018. Meanwhile, SRTR continues to refrain from reporting pancreas graft failure data. The OPTN/UNOS Pancreas Transplantation Committee is seeking to broaden allocation of pancreata across compatible ABO blood types in a proposal out for public comment July 31 to October 2, 2017. A new initiative to provide guidance on the benefits of PAK transplants is also out for public comment.

OPTN/SRTR 2016 Annual Data Report: Kidney.

Data from 2016 show ongoing positive trends in short- and long-term allograft survival, and a decrease in the number of active listed candi- dates for the first time in more than a decade, with a concomitant in- crease in deceased donor kidney transplants. Transplant rates that had changed dramatically for some groups after implementation of the new kidney allocation system in 2014 are stabilizing, allowing for evaluation of new steady states and trends. Many challenges remain in adult kid- ney transplantation, including stagnant rates of living donor transplant, geographic disparities in access to transplant, racial disparities in living donor transplant, and overall a continuing demand for kidneys that far outpaces the supply. For pediatric recipients, a decline in the proportion of living donor transplants is of concern. In 2016, only 34.2% of pediatric transplants were from living donors, compared with 47.2% in 2005. The number of related donors decreased dramatically over the past decade, and the number of unrelated directed transplants performed in pediatric candidates remained low (50).

Broadened Allocation of Pancreas Transplants Across Compatible ABO Blood Types.

BACKGROUND: Current Organ Procurement and Transplantation Network (OPTN) policy restricts certain blood type-compatible simultaneous pancreas and kidney (SPK) transplants. Using the Kidney Pancreas Simulated Allocation Model, we examined the effects of 5 alternative allocation sequences that allowed all clinically compatible ABO transplants. METHODS: The study cohort included kidney (KI), SPK, and pancreas alone (PA) candidates waiting for transplant for at least 1 day between January 1, 2010, and December 31, 2010 (full cohort), and kidneys and pancreata recovered for transplant during the same period. Additionally, because the waiting list has shrunk since 2010, the study population was reduced by random sampling to match the volume of the 2015 waiting list (reduced cohort). RESULTS: Compared with the current allocation sequence, R4 and R5 both showed an increase in SPK transplants, a nearly corresponding decrease in KI transplants, and virtually no change in PA transplants. Life-years from transplant and median years of benefit also increased. The distribution of transplants by blood type changed, with more ABO:A, B, and AB transplants performed, and fewer ABO:O across all transplant types (KI, SPK, PA), with the relative percent changes largest for SPK. DISCUSSION: Broadened ABO compatibility allowances primarily benefitted SPK ABO:A and AB candidates. ABO:O candidates saw potentially reduced access to transplant. The simulation results suggest that modifying the current allocation sequence to incorporate broadened ABO compatibility can result in an increase in annual SPK transplants.

Impact of Protease Inhibitor-Based Anti-Retroviral Therapy on Outcomes for HIV+ Kidney Transplant Recipients.

Excellent outcomes have been demonstrated among select HIV-positive kidney transplant (KT) recipients with well-controlled infection, but to date, no national study has explored outcomes among HIV+ KT recipients by antiretroviral therapy (ART) regimen. Intercontinental Marketing Services (IMS) pharmacy fills (1/1/01-10/1/12) were linked with Scientific Registry of Transplant Recipients (SRTR) data. A total of 332 recipients with pre- and posttransplantation fills were characterized by ART at the time of transplantation as protease inhibitor (PI) or non-PI-based ART (88 PI vs. 244 non-PI). Cox proportional hazards models were adjusted for recipient and donor characteristics. Comparing recipients by ART regimen, there were no significant differences in age, race, or HCV status. Recipients on PI-based regimens were significantly more likely to have an Estimated Post Transplant Survival (EPTS) score of >20% (70.9% vs. 56.3%, p = 0.02) than those on non-PI regimens. On adjusted analyses, PI-based regimens were associated with a 1.8-fold increased risk of allograft loss (adjusted hazard ratio [aHR] 1.84, 95% confidence interval [CI] 1.22-2.77, p = 0.003), with the greatest risk observed in the first posttransplantation year (aHR 4.48, 95% CI 1.75-11.48, p = 0.002), and a 1.9-fold increased risk of death as compared to non-PI regimens (aHR 1.91, 95% CI 1.02-3.59, p = 0.05). These results suggest that whenever possible, recipients should be converted to a non-PI regimen prior to kidney transplantation.

OPTN/SRTR 2015 Annual Data Report: Early effects of the new kidney allocation system.

In December 2014, a new kidney allocation system (KAS) was implemented in the United States in an attempt to improve access to transplant for historically underrepresented groups, and to incorporate longevity matching such that donor kidneys with the longest projected graft survival are given to recipients with the longest projected patient survival. The development of organ allocation policies is often guided by simulated allocation models, computer programs that simulate the arrival of donated organs and new candidates on the waiting list over a 1-year period to project outcomes under a new allocation method. We examined the early outcomes under the new KAS using quarterly data beginning in 2013, revealing whether trends were already underway before implementation. Quarterly data also serve to reveal any bolus effect, or a rapid rise or fall in the proportion of transplants in a given group due to reordering of the list, followed by tapering toward a new steady state. Post-KAS changes were notable for an increase in the proportion of transplants among younger candidates, black and Hispanic candidates, highly sensitized candidates, and those on dialysis for at least 5 years. Transplants among blood type B candidates increased slightly but these candidates remain underrepresented relative to their prevalence on the waiting list. Regional and national sharing increased under the new KAS, but transplants of kidneys with a kidney donor profile index above 85% decreased. Early graft survival appears unchanged, but given the increases in regional sharing, cold ischemia time, and transplants among highly sensitized candidates and candidates with long pretransplant dialysis time, long-term graft survival will need to monitored.

OPTN/SRTR 2015 Annual Data Report: Pancreas.

The number of pancreas transplants performed in the United States stabilized over the last 3 years after nearly a decade of steady decline. Numbers of new additions to the list also stabilized during the same period. Notably, the persistent decline in pancreas after kidney transplants also seems to have abated, at least for now. The first full year of data after implementation of the new pancreas allocation system revealed no change in the distribution of organs between simultaneous pancreas-kidney (SPK) transplant and pancreas transplant alone. The percentage of kidneys used in SPK transplants was also unchanged. While a uniform definition of pancreas graft failure was approved in June 2015, it is awaiting implementation. Meanwhile, SRTR will refrain from publishing pancreas graft failure data in the program-specific reports. Therefore, it is difficult to track trends in outcomes after pancreas transplant over the past 2 years. New initiatives by the OPTN/UNOS Pancreas Transplantation Committee include facilitated pancreas allocation and broadened allocation of pancreata across compatible ABO blood types to increase organ utilization.

OPTN/SRTR 2015 Annual Data Report: Kidney.

The first full year of data after implementation of the new kidney allocation system reveals an increase in deceased donor kidney transplants among black candidates and those with calculated panel-reactive antibodies 98%-100%, but a decrease among candidates aged 65 years or older. Data from 2015 also demonstrate ongoing positive trends in graft and patient survival for both deceased and living donor kidney transplants, but the challenges of a limited supply of kidneys in the setting of increasing demand remain evident. While the total number of patients on the waiting list decreased for the first time in a decade, this was due to a combination of a decrease in the number of candidates added to the list and an increase in the number of candidates removed from the list due to deteriorating medical condition, as well as an increase in total transplants. Deaths on the waiting list remained flat, but this was likely because of an increasing trend toward removing inactive candidates too sick to undergo transplant.

Increased Mortality and Graft Loss With Kidney Retransplantation Among Human Immunodeficiency Virus (HIV)-Infected Recipients.

Excellent outcomes have been demonstrated in primary human immunodeficiency virus (HIV)-positive (HIV+) kidney transplant recipients, but a subset will lose their graft and seek retransplantation (re-KT). To date, no study has examined outcomes among HIV+ re-KT recipients. We studied risk for death and graft loss among 4149 (22 HIV+ vs. 4127 HIV-negative [HIV-]) adult re-KT recipients reported to the Scientific Registry of Transplant Recipients (SRTR) (2004-2013). Compared to HIV- re-KT recipients, HIV+ re-KT recipients were more commonly African American (63.6% vs. 26.7%, p < 0.001), infected with hepatitis C (31.8% vs. 5.0%, p < 0.001) and had longer median time on dialysis (4.8 years vs. 2.1 years, p = 0.02). There were no significant differences in length of time between the primary and re-KT events by HIV status (1.5 years vs. 1.4 years, p = 0.52). HIV+ re-KT recipients experienced a 3.11-fold increased risk of death (adjusted hazard ratio [aHR]: 3.11, 95% confidence interval [CI]: 1.82-5.34, p < 0.001) and a 1.96-fold increased risk of graft loss (aHR: 1.96, 95% CI: 1.14-3.36, p = 0.01) compared to HIV- re-KT recipients. Re-KT among HIV+ recipients was associated with increased risk for mortality and graft loss. Future research is needed to determine if a survival benefit is achieved with re-KT in this vulnerable population.

Prostate Specific Membrane Antigen Positron Emission Tomography May Improve the Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging in Localized Prostate Cancer.

PURPOSE: Positron emission tomography using ligands targeting prostate specific membrane antigen has recently been introduced. Positron emission tomography imaging with (68)Ga-PSMA-HBED-CC has been shown to detect metastatic prostate cancer lesions at a high rate. In this study we compare multiparametric magnetic resonance imaging and prostate specific membrane antigen positron emission tomography of the prostate with whole mount ex vivo prostate histopathology to determine the true sensitivity and specificity of these imaging modalities for detecting and locating tumor foci within the prostate. MATERIALS AND METHODS: In a prospective clinical trial setting 20 patients with localized prostate cancer and a planned radical prostatectomy were recruited. All patients underwent multiparametric magnetic resonance imaging and positron emission tomography before surgery, and whole mount histopathology slides were directly compared to the images. European Society of Urogenital Radiology guidelines for reporting magnetic resonance imaging were used as a template for regional units of analysis. The uropathologist and radiologists were blinded to individual components of the study, and the final correlation was performed by visual and deformable registration analysis. RESULTS: A total of 50 clinically significant lesions were identified from the whole mount histopathological analysis. Based on regional analysis the sensitivity, specificity, positive predictive value and negative predictive value for multiparametric magnetic resonance imaging were 44%, 94%, 81% and 76%, respectively. With prostate specific membrane antigen positron emission tomography the sensitivity, specificity, positive predictive value and negative predictive value were 49%, 95%, 85% and 88%, respectively. Prostate specific membrane antigen positron emission tomography yielded a higher specificity and positive predictive value. CONCLUSIONS: A significant proportion of cancers are potentially missed and underestimated by both imaging modalities. Prostate specific membrane antigen positron emission tomography may be used in addition to multiparametric magnetic resonance imaging to help improve local staging in those patients undergoing retropubic radical prostatectomy.

Pancreas.

Even though pancreas transplant numbers have steadily declined over the past decade, new listings increased in 2014 compared with the previous year, notably for pancreas transplant alone (PTA) and simultaneous pancreas-kidney transplant. The number of new PTAs also increased over the past two years. Whether this is a sustainable trend remains to be seen. Significant events in 2014 included implementation of a new pancreas allocation system and development of a proposed uniform definition of pancreas graft failure. Meanwhile, overall pancreas transplant rates and outcomes continued to improve. Substantial decline in pancreas after kidney transplants remains a serious concern. SRTR has not published pancreas graft failure data in the program-specific reports for the past two years. While this will not change in the near future, the acceptance of a uniform definition of graft failure is a crucial first step toward resuming graft failure reporting. Continued improvements and innovation, both surgical and immunological, will be critical to keep pancreas transplant as a viable option for treatment of insulin-dependent diabetes. As alternative therapies for diabetes such as islet transplant and artificial pancreas are evolving, improved outcomes with minimizations of complications are more important than ever.

Kidney.

Kidney transplant provides significant survival, cost, and quality-of-life benefits over dialysis in patients with end-stage kidney disease, but the number of kidney transplant candidates on the waiting list continues to grow annually. By the end of 2014, nearly 100,000 adult candidates and 1500 pediatric candidates were waiting for kidney transplant. Not surprisingly, waiting times also continued to increase, along with the number of adult candidates removed from the list due to death or deteriorating medical condition. Death censored graft survival has increased after both living and deceased donor transplants over the past decade in adult recipients. The majority of the trends seen over the past 5 years continued in 2014. However, the new allocation system was implemented in late 2014, providing an opportunity to assess changes in these trends in the coming years.

OPTN/SRTR 2013 Annual Data Report: pancreas.

Pancreas listings and transplants decreased during the past decade, most notably pancreas after kidney transplants. Center-reported outcomes of pancreas transplant across all groups, short-term and long-term, improved during the same period. Changes to the pancreas allocation system creating an efficient, uniform national system will be implemented in late 2014. Pancreas-alone and simultaneous pancreas-kidney (SPK) candidates will form a single match-run list with priority to most SPK candidates ahead of kidney-alone candidates to decrease waiting times for SPK candidates, given their higher waitlist mortality compared with nondiabetic kidney transplant candidates. The changes are expected to eliminate local variability, providing more consistent pancreas allocation nationwide. Outcomes after pancreas transplant are challenging to interpret due to lack of a uniform definition of graft failure. Consequently, SRTR has not published data on pancreas graft failure for the past 2 years. The Organ Procurement and Transplantation Network Pancreas Transplantation Committee is working on a definition that could provide greater validity for future outcomes analyses. Challenges in pancreas transplantation include high risk of technical failures, rejection (early and late), and surgical complications. Continued outcome improvement and innovation has never been more critical, as alternatives such as islet transplant and artificial pancreas move closer to clinical application.