Rapid, complete and sustained tumour response to the TRK inhibitor larotrectinib in an infant with recurrent, chemotherapy-refractory infantile fibrosarcoma carrying the characteristic ETV6-NTRK3 gene fusion.

BACKGROUND: The ETV6-NTRK3 gene fusion is present in the majority of cases of infantile fibrosarcoma (IFS) and acts as a potent oncogenic driver. We report the very rapid, complete, and sustained response of an advanced, chemotherapy-refractory, recurrent IFS to targeted treatment with the oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib. PATIENT AND METHODS: A male infant born with a large congenital IFS of the tongue had the tumour surgically resected at age 4 days. Within 2 months, he developed extensive lymph node recurrence that progressed during two cycles of vincristine-doxorubicin-cyclophosphamide chemotherapy. At screening, a large right cervical mass was clinically visible. Magnetic resonance imaging (MRI) revealed bilateral cervical and axillary lymph node involvement as well as infiltration of the floor of the mouth. The largest lesion measured 5.5×4.5×4.4 cm (ca. 55 cm3). The patient started outpatient oral larotrectinib at 20 mg/kg twice daily at age 3.5 months. RESULTS: After 4 days on treatment, the parents noted that the index tumour was visibly smaller and softer. The rapid tumour regression continued over the following weeks. On day 56 of treatment, the first scheduled control MRI showed the target lesion had shrunk to 1.2×1.2×0.8 cm (ca. 0.6 cm3), corresponding to a complete response according to the Response Evaluation Criteria In Solid Tumors version 1.1. This response was maintained over subsequent follow-up visits, and on day 112 at the second control MRI the target lymph node was completely normal. At last follow-up, the disease remained in complete remission after 16 months on larotrectinib, with negligible toxicity and no safety concerns. CONCLUSION(S): Selective TRK inhibition by larotrectinib offers a novel, highly specific and highly effective therapeutic option for IFS carrying the characteristic ETV6-NTRK3 gene fusion. Its use should be considered when surgery is not feasible. (NCT02637687).

Rapid, complete and sustained tumour response to the TRK inhibitor larotrectinib in an infant with recurrent, chemotherapy-refractory infantile fibrosarcoma carrying the characteristic ETV6-NTRK3 gene fusion.

BACKGROUND: The ETV6-NTRK3 gene fusion is present in the majority of cases of infantile fibrosarcoma (IFS) and acts as a potent oncogenic driver. We report the very rapid, complete, and sustained response of an advanced, chemotherapy-refractory, recurrent IFS to targeted treatment with the oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib. PATIENT AND METHODS: A male infant born with a large congenital IFS of the tongue had the tumour surgically resected at age 4 days. Within 2 months, he developed extensive lymph node recurrence that progressed during two cycles of vincristine-doxorubicin-cyclophosphamide chemotherapy. At screening, a large right cervical mass was clinically visible. Magnetic resonance imaging (MRI) revealed bilateral cervical and axillary lymph node involvement as well as infiltration of the floor of the mouth. The largest lesion measured 5.5×4.5×4.4 cm (ca. 55 cm3). The patient started outpatient oral larotrectinib at 20 mg/kg twice daily at age 3.5 months. RESULTS: After 4 days on treatment, the parents noted that the index tumour was visibly smaller and softer. The rapid tumour regression continued over the following weeks. On day 56 of treatment, the first scheduled control MRI showed the target lesion had shrunk to 1.2×1.2×0.8 cm (ca. 0.6 cm3), corresponding to a complete response according to the Response Evaluation Criteria In Solid Tumors version 1.1. This response was maintained over subsequent follow-up visits, and on day 112 at the second control MRI the target lymph node was completely normal. At last follow-up, the disease remained in complete remission after 16 months on larotrectinib, with negligible toxicity and no safety concerns. CONCLUSION(S): Selective TRK inhibition by larotrectinib offers a novel, highly specific and highly effective therapeutic option for IFS carrying the characteristic ETV6-NTRK3 gene fusion. Its use should be considered when surgery is not feasible. (NCT02637687).

Kidney allograft offers: Predictors of turndown and the impact of late organ acceptance on allograft survival.

There is growing interest in understanding patterns of organ acceptance and reducing discard. Little is known about how donor factors, timing of procurement, and geographic location affect organ offer decisions. We performed a retrospective cohort study of 47 563 deceased donor kidney match-runs from 2007 to 2013. Several characteristics unrelated to allograft quality were independently associated with later acceptance in the match-run: Public Health Service increased-risk donor status (adjusted odds ratio [aOR] 2.49, 95% confidence interval [CI] 2.29-2.69), holiday or weekend procurement (aOR 1.11, 95% CI 1.07-1.16), shorter donor stature (aOR 1.53 for <150 cm vs reference >180 cm, 95% CI 1.28-1.94), and procurement in an area with higher intensity of market competition (aOR 1.71, 95% CI 1.62-1.78) and with the longest waiting times (aOR 1.41, 95% CI 1.34-1.49). Later acceptance in the match-run was associated with delayed graft function but not all-cause allograft failure (adjusted hazard ratio 1.01, 95% CI 0.96-1.07). Study limitations include a lack of match-run data for discarded organs and the possibility of sequence inaccuracies for some nonlocal matches. Interventions are needed to reduce turndowns of viable organs, especially when decisions are driven by infectious risk, weekend or holiday procurement, geography, or other donor characteristics unrelated to allograft quality.

Outcomes of organ transplants when the donor is a prior recipient.

Organ shortage continues to challenge the field of transplantation. One potential group of donors are those who have been transplant recipients themselves, or Organ Donation After Transplant (ODAT) donors. We conducted a retrospective cohort study to describe ODAT donors and to compare outcomes of ODAT grafts versus conventional grafts. From October 1, 1987 to June 30, 2015, 517 former recipients successfully donated 803 organs for transplant. Former kidney recipients generally survived a median of approximately 4 years before becoming an ODAT donor whereas liver, lung, and heart recipients generally survived less than a month prior to donation. In the period June 1, 2005 to December 31, 2014, liver grafts from ODAT donors had a significantly higher risk of graft failure compared to non-ODAT liver transplants (P = .008). Kidney grafts donated by ODAT donors whose initial transplant occurred >1 year prior were associated with significantly increased graft failure (P = .012). Despite increased risk of graft failure amongst certain ODAT grafts, 5-year survival was still high. ODAT donors should be considered another form of expanded criteria donor under these circumstances.

Changing Metrics of Organ Procurement Organization Performance in Order to Increase Organ Donation Rates in the United States.

The shortage of deceased-donor organs is compounded by donation metrics that fail to account for the total pool of possible donors, leading to ambiguous donor statistics. We sought to assess potential metrics of organ procurement organizations (OPOs) utilizing data from the Nationwide Inpatient Sample (NIS) from 2009-2012 and State Inpatient Databases (SIDs) from 2008-2014. A possible donor was defined as a ventilated inpatient death ≤75 years of age, without multi-organ system failure, sepsis, or cancer, whose cause of death was consistent with organ donation. These estimates were compared to patient-level data from chart review from two large OPOs. Among 2,907,658 inpatient deaths from 2009-2012, 96,028 (3.3%) were a "possible deceased-organ donor." The two proposed metrics of OPO performance were: (1) donation percentage (percentage of possible deceased-donors who become actual donors; range: 20.0-57.0%); and (2) organs transplanted per possible donor (range: 0.52-1.74). These metrics allow for comparisons of OPO performance and geographic-level donation rates, and identify areas in greatest need of interventions to improve donation rates. We demonstrate that administrative data can be used to identify possible deceased donors in the US and could be a data source for CMS to implement new OPO performance metrics in a standardized fashion.

Kidney Transplantation From a Donor With Sickle Cell Disease.

In the United States, >100 000 patients are waiting for a kidney transplant. Given the paucity of organs available for transplant, expansion of eligibility criteria for deceased donation is of substantial interest. Sickle cell disease (SCD) is viewed as a contraindication to kidney donation, perhaps because SCD substantially alters renal structure and function and thus has the potential to adversely affect multiple physiological processes of the kidney. To our knowledge, transplantation from a donor with SCD has never been described in the literature. In this paper, we report the successful transplantation of two kidneys from a 37-year-old woman with SCD who died from an intracranial hemorrhage. Nearly 4 mo after transplant, both recipients are doing well and are off dialysis. The extent to which kidneys from donors with SCD can be safely transplanted with acceptable outcomes is unknown; however, this report should provide support for the careful expansion of kidneys from donors with SCD without evidence of renal dysfunction and with normal tissue architecture on preimplantation biopsies.

Improving Organ Utilization to Help Overcome the Tragedies of the Opioid Epidemic.

Death rates from drug overdoses have nearly doubled since 2003, with over 47 000 deaths in 2014. This is largely attributable to the opioid epidemic. If the unfortunate deaths of otherwise healthy people have yielded an increase in organ donors, then this might serve as perhaps the only comforting factor among this tragic and unnecessary loss of life. In this viewpoint, we present data from the Organ Procurement and Transplantation Network (OPTN) that show how the greatest relative increases in the mechanism of death among deceased donors from 2003 to 2014 were drug overdoses. Unfortunately, despite the absolute increase in the number of donors who died from a drug overdose, the mean organ yield was significantly lower than in other categories, in part due to concerns about disease transmission. In this paper, we present data on the changes in donation from donors with a drug overdose as a result of the opioid epidemic and discuss the need to educate transplant candidates and their physicians about the low risk of disease transmission compared to the greater risk of dying on a transplant waitlist.

Deceased Donor Intervention Research: A Survey of Transplant Surgeons, Organ Procurement Professionals, and Institutional Review Board Members.

Innovative deceased donor intervention strategies have the potential to increase the number and quality of transplantable organs. Yet there is confusion over regulatory and legal requirements, as well as ethical considerations. We surveyed transplant surgeons (n = 294), organ procurement organization (OPO) professionals (n = 83), and institutional review board (IRB) members (n = 317) and found wide variations in their perceptions about research classification, risk assessment for donors and organ transplant recipients, regulatory oversight requirements, and informed consent in the context of deceased donor intervention research. For instance, when presented with different research scenarios, IRB members were more likely than transplant surgeons and OPO professionals to feel that study review and oversight were necessary by the IRBs at the investigator, donor, and transplant center hospitals. Survey findings underscore the need to clarify ethical, legal, and regulatory requirements and their application to deceased donor intervention research to accelerate the pace of scientific discovery and facilitate more transplants.

Donor Hemodynamics as a Predictor of Outcomes After Kidney Transplantation From Donors After Cardiac Death.

Donation after cardiac death is an important source of transplantable organs, but evidence suggests donor warm ischemia contributes to inferior outcomes. Attempts to predict recipient outcome using donor hemodynamic measurements have not yielded statistically significant results. We evaluated novel measures of donor hemodynamics as predictors of delayed graft function and graft failure in a cohort of 1050 kidneys from 566 donors. Hemodynamics were described using regression line slopes, areas under the curve, and time beyond thresholds for systolic blood pressure, oxygen saturation, and shock index (heart rate divided by systolic blood pressure). A logistic generalized estimation equation model showed that area under the curve for systolic blood pressure was predictive of delayed graft function (above median: odds ratio 1.42, 95% confidence interval [CI] 1.06-1.90). Multivariable Cox regression demonstrated that slope of oxygen saturation during the first 10 minutes after extubation was associated with graft failure (below median: hazard ratio 1.30, 95% CI 1.03-1.64), with 5-year graft survival of 70.0% (95%CI 64.5%-74.8%) for donors above the median versus 61.4% (95%CI 55.5%-66.7%) for those below the median. Among older donors, increased shock index slope was associated with increased hazard of graft failure. Validation of these findings is necessary to determine the utility of characterizing donor warm ischemia to predict recipient outcome.

Associations of Perfusate Biomarkers and Pump Parameters With Delayed Graft Function and Deceased Donor Kidney Allograft Function.

Hypothermic machine perfusion (HMP) is increasingly used in deceased donor kidney transplantation, but controversy exists regarding the value of perfusion biomarkers and pump parameters for assessing organ quality. We prospectively determined associations between perfusate biomarkers (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule 1, IL-18 and liver-type fatty acid-binding protein [L-FABP]) and pump parameters (resistance and flow) with outcomes of delayed graft function (DGF) and 6-mo estimated GFR (eGFR). DGF occurred in 230 of 671 (34%) recipients. Only 1-h flow was inversely associated with DGF. Higher NGAL or L-FABP concentrations and increased resistance were inversely associated with 6-mo eGFR, whereas higher flow was associated with higher adjusted 6-mo eGFR. Discarded kidneys had consistently higher median resistance and lower median flow than transplanted kidneys, but median perfusate biomarker concentrations were either lower or not significantly different in discarded compared with transplanted kidneys. Notably, most recipients of transplanted kidneys with isolated "undesirable" biomarker levels or HMP parameters experienced acceptable 6-mo allograft function, suggesting these characteristics should not be used in isolation for discard decisions. Additional studies must confirm the utility of combining HMP measurements with other characteristics to assess kidney quality.

Increasing the Number of Organ Transplants in the United States by Optimizing Donor Authorization Rates.

While recent policies have focused on allocating organs to patients most in need and lessening geographic disparities, the only mechanism to increase the actual number of transplants is to maximize the potential organ supply. We conducted a retrospective cohort study using OPTN data on all "eligible deaths" from 1/1/08 to 11/1/13 to evaluate variability in donor service area (DSA)-level donor authorization rates, and to quantify the potential gains associated with increasing authorization rates. Despite adjustments for donor demographics (age, race/ethnicity, cause of death) and geographic factors (rural/urban status of donor hospital, statewide participation in deceased-donor registries) among 52 571 eligible deaths, there was significant variability (p < 0.001) in donor authorization rates across the 58 DSAs. Overall DSA-level adjusted authorization rates ranged from 63.5% to 89.5% (median: 72.7%). An additional 773-1623 eligible deaths could have been authorized, yielding 2679-5710 total organs, if the DSAs with authorization rates below the median and 75th percentile, respectively, implemented interventions to perform at the level of the corresponding reference DSA. Opportunities exist within the current organ acquisition framework to markedly improve DSA-level donor authorization rates. Such initiatives would mitigate waitlist mortality while increasing the number of transplants.

An Assessment of HIV-Infected Patients Dying in Care for Deceased Organ Donation in a United States Urban Center.

Organ transplantation is an acceptable option for human immunodeficiency virus (HIV)-infected patients with end-stage kidney or liver disease. With worse outcomes on the waitlist, HIV-infected patients may actually be disproportionately affected by the organ shortage in the United States. One potential solution is the use of HIV-infected deceased donors (HIVDD), recently legalized by the HIV Organ Policy Equity (HOPE) Act. This is the first analysis of patient-specific data from potential HIVDD, retrospectively examining charts of HIV-infected patients dying in care at six HIV clinics in Philadelphia, Pennsylvania from January 1, 2009 to June 30, 2014. Our data suggest that there are four to five potential HIVDD dying in Philadelphia annually who might yield two to three kidneys and three to five livers for transplant. Extrapolated nationally, this would approximate 356 potential HIVDD yielding 192 kidneys and 247 livers annually. However, several donor risk indices raise concerns about the quality of kidneys that could be recovered from HIVDD as a result of older donor age and comorbidities. On the other hand, livers from these potential HIVDD are of similar quality to HIV-negative donors dying locally, although there is a high prevalence of positive hepatitis C antibody.

The Risk of End-Stage Renal Disease Among Living Donor Liver Transplant Recipients in the United States.

Since initiation of model for end-stage liver disease (MELD)-based allocation for liver transplantation, the risk of posttransplant end-stage renal disease (ESRD) has increased. Recent US data have demonstrated comparable, if not superior survival, among recipients of living donor liver transplants (LDLT) when compared to deceased donor liver transplant (DDLT) recipients. However, little is known about the incidence of ESRD post-LDLT. We analyzed linked Scientific Registry of Transplant Recipients (SRTR) and US Renal Data System (USRDS) data of first-time liver-alone transplant recipients from February 27, 2002 to March 1, 2011, and restricted the cohort to recipients with a laboratory MELD score ≤25 not on dialysis prior to transplantation, in order to evaluate the incidence of ESRD post-LDLT, and to compare the incidence among LDLT versus DDLT recipients. There were 28 707 DDLT and 1917 LDLT recipients included in the analyses. The 1-, 3- and 5-year unadjusted risk of ESRD was 1.7%, 2.9% and 3.4% in LDLT recipients, compared with 1.5%, 3.0% and 4.8% in DDLT recipients (p > 0.05), respectively. In multivariable competing risk Cox regression models, there was no association between receiving an LDLT and risk of ESRD (sub-hazard ratio: 0.99, 95% CI: 0.77-1.26, p = 0.92). In conclusion, the incidence of ESRD post-LDLT in the United States is low, and there are no significant differences among LDLT and DDLT recipients with MELD scores ≤25 at transplantation.

Waiting time and explant pathology in transplant recipients with hepatocellular carcinoma: a novel study using national data.

Risk factors for hepatocellular carcinoma (HCC) recurrence after liver transplantation have been well described. It has been surmised that longer time on the waitlist may select for tumors with a lower-risk of recurrence posttransplant, as patients with unfavorable tumor characteristics would be delisted due to tumor progression. Utilizing national explant pathology records from transplant recipients waitlisted with T2 HCC exception points, this study explored the correlation between waiting time and the development of pathologic HCC features associated with increased risk of tumor recurrence. Of 1976 explant pathology reports submitted nationally between April 8, 2012 and June 30, 2013, 1453 (73.5%) were from recipients with automatic T2 HCC exception points. There was no association between pretransplant waiting time and the proportion of HCC explants with either: (i) a poorly differentiated tumor; (ii) macrovascular invasion; (iii) HCC beyond Milan or University of California San Francisco criteria; (iv) HCC beyond the "up-to-seven" criteria; or (v) extra-hepatic or lymph node involvement. Though there was a statistically significant increase in microvascular invasion in recipients with pretransplant waiting 6-12 months, this association was not seen when adjusted for United Network for Organ Sharing region. These findings suggest that waiting time alone may not select for tumors with more favorable characteristics.

Improving outcomes in DCDD liver transplantation: there can only be strength in numbers.

In the United States, liver transplantation using donation after circulatory determination of death (DCDD) donors is challenged by persistently inferior graft survival compared with donation after neurological death (DND), along with declining rates of liver transplantation relative to the total number of DCDD donors. Advances in adult-to-adult living donor liver transplantation graft survival temporally related to the Adult-to-Adult Living Donor Liver Transplantation Cohort Study consortium suggest that a similarly focused collaborative effort may serve to stimulate evolution within DCDD liver transplantation. Without a multi-center consortium to support innovative trials, the current state of DCDD liver transplantation is unlikely to progress.