Pretransplant malignancy in pediatrics is not a risk factor for renal graft failure.

BACKGROUND: In adults, pretransplant malignancy (PTM) negatively impacts patient survival due to immunosuppression regimens influencing post-transplantation tumor growth. Few reports investigate the outcomes of pediatric kidney transplantation with PTM. We compare transplant outcomes for pediatric patients with PTM to matched controls, including cancer types extending beyond Wilms tumor. METHODS: The United Network of Organ Sharing Database was queried to identify pediatric transplant recipients with histories of PTM. All PTM patients were matched to non-PTM patients, at a 1:1 ratio, with 0.001 match tolerance. Matching variables included transplant year, recipient age, recipient gender, recipient race, donor type, and prior transplant. Death-censored graft and patient survival were analyzed. All statistics were reported with 95% confidence intervals (CI). RESULTS: After propensity matching, 285 PTM and 285 non-PTM patients were identified, with transplant dates from 1990 to 2020. Median Kidney Donor Profile Index values were comparable between cohorts, 17% and 12%, respectively (p = .065). Kaplan-Meier analysis revealed that PTM patients did not have a significantly different rate of death-censored graft failure, compared to the non-PTM group [HR 0.76; 95% CI (0.54-1.1)]. There was also no difference in the overall survival between the two groups of patients [HR 1.1; 95% CI (0.66-2.0)]. CONCLUSION: A history of pediatric malignancy has minimal independent effect on their post-transplant survival. Additionally, pediatric patients with PTM demonstrated equivalent rates of graft survival. Thus, in contrast to adults, renal failure in children with history of pediatric malignancies should not be considered a complicating factor for renal transplantation.

Missed Opportunities to Diagnose and Treat Tertiary Hyperparathyroidism After Transplant.

INTRODUCTION: Tertiary hyperparathyroidism (3HPT) is common after renal transplant. However, guidelines for diagnosis are not clear and few patients are treated surgically. This study aims to determine rates of diagnosis and treatment of 3HPT in renal transplant patients with hypercalcemia. MATERIALS AND METHODS: This retrospective chart review identified all renal transplant recipients at a single tertiary care institution between 2011 and 2021. Patients with post-transplant hypercalcemia (> 10.2 mg/dL) were identified. The time in months of index hypercalcemia was noted. Measurement of parathyroid hormone (PTH) levels after index hypercalcemia was determined and noted as elevated if > 64 pg/mL at least 6 mo after transplant. Documentation of symptoms of hyperparathyroidism, a diagnosis of hyperparathyroidism in the electronic medical record, and medical or surgical management of patients with classic 3HPT (elevated calcium and PTH) were determined. RESULTS: Of 383 renal transplant recipients, hypercalcemia was identified in 132 patients. The majority of hypercalcemic patients had PTH levels measured (127, 96.2%). PTH was elevated in 109 (82.6%). Among the 109 patients with classic 3HPT, 54 (49.5%) had a documented diagnosis of hyperparathyroidism in the electronic medical record (P = 0.01). Kidney stones or abnormal DEXA scan were present in 16 (14.7%) and 18 (16.5%), respectively. Most patients were managed non-surgically (101, 92.6%); calcimimetics were prescribed for 42 (38.5%, P = 0.01). Eight (7.3%) patients with classic 3HPT were referred to a surgeon (P = 0.35); all were initially prescribed calcimimetics (P = 0.001). CONCLUSIONS: 3HPT is underdiagnosed in patients with elevated calcium and PTH levels post-transplant. A significant percentage of these patients go without surgical referral and curative treatment.

Challenges with non-descriptive compliance labeling of end-stage renal disease patients in accessibility for renal transplantation.

Non-descriptive and convenient labels are uninformative and unfairly project blame onto patients. The language clinicians use in the Electronic Medical Record, research, and clinical settings shapes biases and subsequent behaviors of all providers involved in the enterprise of transplantation. Terminology such as noncompliant and nonadherent serve as a reason for waitlist inactivation and limit access to life-saving transplantation. These labels fail to capture all the circumstances surrounding a patient's inability to follow their care regimen, trivialize social determinants of health variables, and bring unsubstantiated subjectivity into decisions regarding organ allocation. Furthermore, insufficient Medicare coverage has forced patients to ration or stop taking medication, leading to allograft failure and their subsequent diagnosis of noncompliant. We argue that perpetuating non-descriptive language adds little substantive information, increases subjectivity to the organ allocation process, and plays a major role in reduced access to transplantation. For patients with existing barriers to care, such as racial/ethnic minorities, these effects may be even more drastic. Transplant committees must ensure thorough documentation to correctly encapsulate the entirety of a patient's position and give voice to an already vulnerable population.

Does race impact outcomes after parathyroidectomy for secondary and tertiary hyperparathyroidism?

BACKGROUND: Racial disparities in care exist for diseases with heterogeneous treatment guidelines. The impact of these disparities on outcomes after parathyroidectomy for secondary(2HPT) and tertiary hyperparathyroidism(3HPT) was explored. METHODS: The 2015-2019 NSQIP datasets were used. Patients who underwent parathyroidectomy for 2HPT and 3HPT were identified and analyzed separately. Patients were stratified by race (white vs. non-white); demographics, comorbidities, and outcomes were compared. Studied outcomes included 30-day morbidity, mortality, unplanned reoperation, readmission, and postoperative length of stay(LOS). RESULTS: There were 1,150 patients with 2HPT and 262 with 3HPT. For 2HPT, 65.5% were non-white; morbidity, reoperation, and prolonged LOS(>3days) occurred disproportionately more often in non-white patients. Non-white race was independently associated with morbidity; higher ASA class and alkaline phosphatase levels were associated with prolonged LOS. For 3HPT, 53.1% were non-white; a prolonged LOS(>1day) occurred disproportionately more often in non-white patients. Higher alkaline phosphatase levels were independently associated with prolonged LOS. CONCLUSION: Race and markers of advanced disease negatively impact outcomes after parathyroidectomy for 2HPT and 3HPT. Attention to racial disparities and earlier referral may positively impact outcomes.

Simple Prediction Score for Developing Surgical Site Infection after Clean Neck Operation.

Background: Clean neck operations (thyroidectomies, parathyroidectomies, and lymph node resection) are among the most common procedures performed in the United States. Surgical site infections (SSIs) after clean neck operations are rare, but the consequences are devastating and often life-threatening. The aim of this study was to develop a score that will identify patients at high risk for developing a SSI after a clean neck procedure. Materials and Methods: Patients with either thyroidectomies, parathyroidectomies, or lymph node resection of the neck were identified from the 2016 and 2017 databases of the American College of Surgeons National Surgical Quality Improvement Program and were used for this analysis. Our primary goal was to build a scoring system with which we will be able to identify patients at high risk for SSI after a clean neck operation. Results: Of a total of 99,877 patients, 72,719 patients had a thyroidectomy, 22,043 patients had parathyroidectomy, and 5,115 patients had lymph node resection of the neck. Multivariable logistic regression identified the following independent risk factors associated with post-operative SSI: male gender (adjusted odds ratio [aOR], 1.25; 95% confidence interval [CI], 1.03-1.51), diabetes mellitus (aOR, 1.34; 95% CI, 1.07-1.67), smoking (aOR, 1.66; 95% CI, 1.36-2.04), pre-operative steroid use (aOR, 1.75; 95% CI, 1.21-2.53), cancer diagnosis (aOR, 1.44; 95% CI, 1.17-1.77), radical lymphadenectomies (aOR, 2.94; 95% CI, 2.16-4), and total operative time ≥198 minutes (aOR, 2.25; 95% CI, 1.82-2.78). Afterward, we developed a prognostic score for calculating the odds of having post-operative SSI. One point was allotted for each of the aforementioned factors, except lymphadenectomies where two points were allotted, and operative time was excluded. Our score was associated with a stepwise higher risk of post-operative SSI after a clean neck operation. Conclusions: Pre-operative and intra-operative factors can predict which patients undergoing a clean neck surgery may develop SSI. Our prognostic score may help guide surgeons identify patients at high-risk for SSI after clean neck surgery and these patients might benefit from prophylactic use of antibiotic agents.

Outcomes of Older Patients in the Recent Era of Heart Kidney Transplantation.

BACKGROUND AND OBJECTIVE: Variable age thresholds are often used at transplant centers for simultaneous heart and kidney transplantation (HKT). We hypothesize that selected older recipients enjoy comparable outcome to younger recipients in the current era of HKT. METHODS: We performed a retrospective analysis of HKT outcomes in the United Network for Organ Sharing (UNOS) registry from 2006 to 2018, classifying patients by age at transplant as ≥ 65 or < 65 years. The primary outcome was patient death. Secondary outcomes included all-cause kidney graft failure and death-censored kidney allograft failure. RESULTS: Of 973 patients, 774 (80%) were younger than 65 years (mean 52 ± 10 years) and 199 (20%) were 65 years or older (mean 67 ± 2 years). The older HKT cohort had fewer blacks (22% vs 35%, P = .01) and women (12 vs 18%, P = .04). Fewer older patients received dialysis (30% vs 54%, P < .001) and mechanical support (36% vs 45%, P = .03) before HKT. Older recipients received organs from slightly older donors. The median follow-up time was shorter for patients 65 years or older than for the younger group (2.3 vs 3.3 years, P < .001). Patient survival was similar between the groups (mean 8.8 vs 9.8 years, P = .3), with the most common causes of death being cardiovascular (29%) and infectious complications (28%). There was no difference in all-cause kidney graft survival (mean 8.7 vs 9.3 years, P = .8). Most commonly, recipients died with a functional renal allograft (59.8%), and this occurred more commonly in older patients (81.4% vs 54.8%, P = .001). Cox proportional hazard modeling showed that higher donor age (hazard ratio [HR] 1.015, P = .01; HR 1.022, P = .02) and use of pre-transplant dialysis (HR 1.5, P = .004; HR 1.8, P = .006) increased the risk for both all-cause and death-censored kidney allograft failure, respectively. CONCLUSIONS: Our study showed that carefully selected older patients have outcomes similar to those of a younger cohort and argues for comprehensive evaluation of the recipients with age as part of comorbidity assessment rather than use of an arbitrary age threshold for candidacy.

Fatty liver: The metabolic syndrome increases major hepatectomy mortality.

BACKGROUND: As the obesity epidemic worsens, the prevalence of fatty liver disease has increased. However, minimal data exist on the impact of combined fatty liver and metabolic syndrome on hepatectomy outcomes. Therefore, the aim of this analysis is to measure the outcomes of patients who do and do not have a fatty liver undergoing hepatectomy in the presence and absence of the metabolic syndrome. METHODS: Patients with fatty and normal livers undergoing major hepatectomy (≥3 segments) were identified in the 2014 to 2018 American College of Surgeon National Surgical Quality Improvement Program database. Patients undergoing partial hepatectomy and those with missing liver texture data were excluded. Propensity matching was used and adjusted for multiple variables. A subgroup analysis stratified by the metabolic syndrome (body mass index ≥30 kg/m2, hypertension and diabetes) was performed. Demographics and outcomes were compared by χ2 and Mann-Whitney tests. RESULTS: Of 2,927 hepatectomies, 30% of patients (N = 863) had a fatty liver. The median body mass index was 28.6, and the metabolic syndrome was present in 6.3% of patients (N = 184). After propensity matching, 863 patients with fatty and 863 with normal livers were compared. Multiple outcomes were significantly worse in patients with fatty livers (P <.05), including serious morbidity (32% vs 24%), postoperative invasive biliary procedures (15% vs 10%), organ space infections (11% vs 7.8%), and pulmonary complications. Patients with fatty livers and the metabolic syndrome had significantly increased postoperative cardiac arrests, pulmonary embolisms, and mortality (P < .05). CONCLUSION: Fatty liver disease is associated with significantly worse outcomes after major hepatectomy. The metabolic syndrome confers an increased risk of postoperative mortality.

Tissue repair and stem cell renewal in carcinogenesis.

Cancer is increasingly being viewed as a stem cell disease, both in its propagation by a minority of cells with stem-cell-like properties and in its possible derivation from normal tissue stem cells. But stem cell activity is tightly controlled, raising the question of how normal regulation might be subverted in carcinogenesis. The long-known association between cancer and chronic tissue injury, and the more recently appreciated roles of Hedgehog and Wnt signalling pathways in tissue regeneration, stem cell renewal and cancer growth together suggest that carcinogenesis proceeds by misappropriating homeostatic mechanisms that govern tissue repair and stem cell self-renewal.

Hedgehog signalling in prostate regeneration, neoplasia and metastasis.

Metastatic cancers adopt certain properties of normal cells in developing or regenerating organs, such as the ability to proliferate and alter tissue organization. We find here that activity of the Hedgehog (Hh) signalling pathway, which has essential roles in developmental patterning, is required for regeneration of prostate epithelium, and that continuous pathway activation transforms prostate progenitor cells and renders them tumorigenic. Elevated pathway activity furthermore distinguishes metastatic from localized prostate cancer, and pathway manipulation can modulate invasiveness and metastasis. Pathway activity is triggered in response to endogenous expression of Hh ligands, and is dependent upon the expression of Smoothened, an essential Hh response component that is not expressed in benign prostate epithelial cells. Monitoring and manipulating Hh pathway activity may thus offer significant improvements in diagnosis and treatment of prostate cancers with metastatic potential.

Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours.

Activation of the Hedgehog (Hh) signalling pathway by sporadic mutations or in familial conditions such as Gorlin's syndrome is associated with tumorigenesis in skin, the cerebellum and skeletal muscle. Here we show that a wide range of digestive tract tumours, including most of those originating in the oesophagus, stomach, biliary tract and pancreas, but not in the colon, display increased Hh pathway activity, which is suppressible by cyclopamine, a Hh pathway antagonist. Cyclopamine also suppresses cell growth in vitro and causes durable regression of xenograft tumours in vivo. Unlike in Gorlin's syndrome tumours, pathway activity and cell growth in these digestive tract tumours are driven by endogenous expression of Hh ligands, as indicated by the presence of Sonic hedgehog and Indian hedgehog transcripts, by the pathway- and growth-inhibitory activity of a Hh-neutralizing antibody, and by the dramatic growth-stimulatory activity of exogenously added Hh ligand. Our results identify a group of common lethal malignancies in which Hh pathway activity, essential for tumour growth, is activated not by mutation but by ligand expression.

Liver Ischemia Reperfusion Injury, Enhanced by Trained Immunity, Is Attenuated in Caspase 1/Caspase 11 Double Gene Knockout Mice.

Ischemia reperfusion injury (IRI) during liver transplantation increases morbidity and contributes to allograft dysfunction. There are no therapeutic strategies to mitigate IRI. We examined a novel hypothesis: caspase 1 and caspase 11 serve as danger-associated molecular pattern (DAMPs) sensors in IRI. By performing microarray analysis and using caspase 1/caspase 11 double-knockout (Casp DKO) mice, we show that the canonical and non-canonical inflammasome regulators are upregulated in mouse liver IRI. Ischemic pre (IPC)- and post-conditioning (IPO) induce upregulation of the canonical and non-canonical inflammasome regulators. Trained immunity (TI) regulators are upregulated in IPC and IPO. Furthermore, caspase 1 is activated during liver IRI, and Casp DKO attenuates liver IRI. Casp DKO maintained normal liver histology via decreased DNA damage. Finally, the decreased TUNEL assay-detected DNA damage is the underlying histopathological and molecular mechanisms of attenuated liver pyroptosis and IRI. In summary, liver IRI induces the upregulation of canonical and non-canonical inflammasomes and TI enzyme pathways. Casp DKO attenuate liver IRI. Development of novel therapeutics targeting caspase 1/caspase 11 and TI may help mitigate injury secondary to IRI. Our findings have provided novel insights on the roles of caspase 1, caspase 11, and inflammasome in sensing IRI derived DAMPs and TI-promoted IRI-induced liver injury.

Endovascular intervention for iliac vein thrombosis after simultaneous kidney-pancreas transplant.

May-Thurner syndrome (MTS) is an anatomic variant where the overlying right common iliac artery compresses and chronically obstructs the left common iliac vein, leading to thrombosis. Interventions for symptomatic MTS include endovascular thrombectomy and stenting. Occluding venous thrombus can be fatal to transplanted allografts. No guidelines exist for patients with MTS after simultaneous kidney-pancreas transplant. A 57-year-old female with ESRD and diabetes mellitus underwent a kidney-pancreas transplant. Post-operative imaging revealed a compressed left CIV with an occlusive thrombus threatening the renal graft. Thrombectomy with stent placement was performed, maintaining patency of both allograft venous outflows. Post-intervention the patient has demonstrated preserved kidney and pancreas allograft function through 1 year of follow-up. Interventions for MTS in patients after transplant are challenging given the complex allograft vascular reconstruction. We present a case which demonstrates that angiographic interventions for MTS can be safely performed after simultaneous kidney-pancreas transplant.

In vitro and ex vivo delivery of short hairpin RNAs for control of hepatitis C viral transcript expression.

Recurrent hepatitis C virus (HCV) infection is the most common cause of graft loss and patient death after transplantation for HCV cirrhosis. Transplant surgeons have access to uninfected explanted livers before transplantation and an opportunity to deliver RNA interference-based protective gene therapy to uninfected grafts. Conserved HCV sequences were used to design short interfering RNAs and test their ability to knockdown HCV transcript expression in an in vitro model, both by transfection and when delivered via an adeno-associated viral vector. In a rodent model of liver transplantation, portal venous perfusion of explanted grafts with an adeno-associated viral vector before transplantation produced detectable short hairpin RNA transcript expression after transplantation. The ability to deliver anti-HCV short hairpin RNAs to uninfected livers before transplantation and subsequent exposure to HCV offers hope for the possibility of preventing the currently inevitable subsequent infection of liver grafts with HCV.

Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis.

Previous studies have demonstrated that the Hedgehog (Hh) signaling pathway plays a critical role in the development and patterning of many endodermally derived tissues. We have investigated the role of Sonic hedgehog (Shh) in formation of the prostate gland by examining the urogenital phenotype of Shh mutant fetuses. Consistent with earlier work reporting an essential role for Shh in prostate induction, we have found that Shh mutant fetuses display abnormal urogenital development and fail to form prostate buds. Unexpectedly, however, we have discovered that this prostate defect could be rescued by three different methods: renal grafting, explant culture in the presence of androgens, and administration of dihydrotestosterone (DHT) to pregnant mice, indicating that the prostate defect in Shh mutants is due to insufficient levels of androgens. Furthermore, we find that the inhibition of Hh pathway signaling by treatment with cyclopamine does not block prostate formation in explant culture, but instead produces morphological defects consistent with a role for Hh signaling in ductal patterning. Taken together, our studies indicate that the initial organogenesis of the prostate proceeds independently of Shh, but that Shh or other Hh ligands may play a role in subsequent events that pattern the prostate.

Medulloblastoma growth inhibition by hedgehog pathway blockade.

Constitutive Hedgehog (Hh) pathway activity is associated with initiation of neoplasia, but its role in the continued growth of established tumors is unclear. Here, we investigate the therapeutic efficacy of the Hh pathway antagonist cyclopamine in preclinical models of medulloblastoma, the most common malignant brain tumor in children. Cyclopamine treatment of murine medulloblastoma cells blocked proliferation in vitro and induced changes in gene expression consistent with initiation of neuronal differentiation and loss of neuronal stem cell-like character. This compound also caused regression of murine tumor allografts in vivo and induced rapid death of cells from freshly resected human medulloblastomas, but not from other brain tumors, thus establishing a specific role for Hh pathway activity in medulloblastoma growth.