The Use of the Protease Inhibitor, Saquinavir, to Treat Anal Cancer Spheroids Derived From Human Papillomavirus Transgenic Mice.

BACKGROUND: Anal cancer is associated with high-risk human papillomavirus infection and oncoprotein expression. We have identified several protease inhibitors, used to treat HIV, that decrease oncogene expression. OBJECTIVE: The aim of this project is to determine whether saquinavir, a protease inhibitor, results in a treatment response in anal cancer spheroids. DESIGN: K14E6/E7 transgenic mice (n = 5), which express human papillomavirus 16 oncoproteins E6 and E7 in their epithelium, were treated topically at the anus with a carcinogen, 7,12-dimethylbenz[a]anthracene, to promote anal tumor growth. Tumors were excised and digested, and cells were plated. The tumor cells form 3D multicellular aggregates known as spheroids. SETTINGS: This study was performed in an American Association for Accreditation of Laboratory Animal Care-approved facility. INTERVENTIONS: Spheroids were placed in treatment groups: no treatment, vehicle (dimethyl sulfoxide), and 15 µM saquinavir. Spheroids were imaged immediately pretreatment and 24 hours posttreatment. MAIN OUTCOME MEASURES: Spheroid diameters were measured using ImageJ and mean percent reduction was calculated for each spheroid to determine treatment effect on spheroid growth. Analysis of variance using pairwise comparisons was performed with Fisher protected least significant difference tests. RESULTS: The no-treatment (n = 119 spheroids) and vehicle (n = 126 spheroids) groups demonstrated an increase in spheroid diameter during the treatment period. In contrast, spheroids treated with saquinavir (n = 151 spheroids) demonstrated a statistically significant percent reduction compared to the no-treatment ( p < 0.0001) and vehicle ( p = 0.002) groups. LIMITATIONS: A limitation of these data is that some human error is likely present given that images were analyzed by 3 different scientists. CONCLUSIONS: Saquinavir leads to a statistically significant percent reduction in mice anal tumor spheroid growth ex vivo compared to control groups. Protease inhibitor therapy may be an effective treatment or adjuvant therapy to the Nigro protocol to promote anal cancer tumor regression. See Video Abstract at http://links.lww.com/DCR/C82 . EL USO DEL INHIBIDOR DE LA PROTEASA, SAQUINAVIR, PARA TRATAR LOS ESFEROIDES DEL CNCER ANAL DERIVADOS DE RATONES TRANSGNICOS PARA EL VPH: ANTECEDENTES:El cáncer anal está asociado con la infección por el virus del papiloma humano de alto riesgo y la expresión de oncoproteínas. Hemos identificado varios inhibidores de la proteasa, utilizados para tratar el VIH, que disminuyen la expresión del oncogén.OBJETIVO:El objetivo de este proyecto es determinar si los esferoides de cáncer anal responden al tratamiento con inhibidor de la proteasa, Saquinavir.DISEÑO:Ratones transgénicos K14E6/E7 (n = 5), que expresan las oncoproteínas E6 y E7 del VPH16 en su epitelio, fueron tratados tópicamente en el ano con carcinógeno, 7,12 dimetilbenz[a]antraceno, para promover el crecimiento del tumor anal. Los tumores se extirparon y digirieron, y las células se sembraron en placas. Las células tumorales forman agregados multicelulares tridimensionales, conocidos como esferoides.ESCENARIO:Este estudio se realizó en un centro aprobado por la Asociación Estadounidense para la Acreditación de Cuidado de Animales de Laboratorio.INTERVENCIONES:Se colocaron esferoides en grupos de tratamiento: sin tratamiento, vehículo (sulfóxido de dimetilo) y saquinavir 15 µM. Se tomaron imágenes de los esferoides inmediatamente antes del tratamiento y 24 horas después del tratamiento.PRINCIPALES MEDIDAS DE RESULTADO:Los diámetros de los esferoides se midieron con ImageJ y se calculó el porcentaje medio de reducción de cada esferoide para determinar el efecto del tratamiento sobre el crecimiento de los esferoides. El análisis de varianza mediante comparaciones por pares se realizó con las pruebas de diferencia mínima significativa protegida de Fisher.RESULTADOS:Los grupos sin tratamiento (n =119 esferoides) y vehículo (n=126 esferoides) demostraron un aumento en el diámetro del esferoide durante el período de tratamiento. Por el contrario, los esferoides tratados con saquinavir (n =151 esferoides) demostraron una reducción porcentual estadísticamente significativa en comparación con los grupos sin tratamiento ( p < 0,0001) y con vehículo (p = 0,002).LIMITACIONES:una limitación de estos datos es que es probable que haya algún error humano dado que las imágenes fueron analizadas por tres científicos diferentes.CONCLUSIONES:Saquinavir conduce a una reducción porcentual estadísticamente significativa en el crecimiento de esferoides de tumores anales en ratones ex-vivo en comparación con los grupos de control. La terapia con inhibidores de la proteasa puede ser un tratamiento eficaz o una terapia adyuvante del protocolo Nigro para promover la regresión del tumor del cáncer anal. Consulte Video Resumen en http://links.lww.com/DCR/C82 . (Traducción-Dr. Felipe Bellolio ).

Anal Cancer Prevention Through the Topical Use of Single or Dual PI3K/mTOR Inhibitors.

INTRODUCTION: Anal dysplasia and anal cancer are major health problems. This study seeks to determine if inhibition of mTOR and/or PI3K pathways is effective at anal cancer prevention in mice with/without established precancerous lesions of the anus (anal dysplasia). METHODS: K14E6/E7 mice were entered into the study at 5 wk, 15 wk, or 25 wk of age. Mice were treated with a topical carcinogen, 7,12-Dimethylbenz[a]anthracene (DMBA), which ensures carcinoma development within 20 wk. Treatment groups included: no treatment, DMBA only, topical Pictilisib (PI3K inhibitor) with/without DMBA, topical Sapanisertib (mTOR inhibitor) with/without DMBA, and topical Samotolisib (dual PI3K/mTOR inhibitor) with/without DMBA. Mice underwent weekly observations for anal tumor development (tumor-free survival). After 20 wk of treatment, anal tissue was harvested and evaluated histologically for squamous cell carcinoma (SqCC). RESULTS: All topical treatments in conjunction with DMBA increased tumor-free survival in mice that started treatment at 15 wk of age when compared to DMBA-only treatment, except for Pictilisib + DMBA in males. Topical Sapanisertib increased tumor-free survival in mice regardless of starting treatment age. When examining tissue for microscopic evidence of SqCC, only topical Samotolisib in males decreased SqCC in the 15 wk starting mice. CONCLUSIONS: Sapanisertib, the mTOR inhibitor, had the greatest effect, in terms of increasing tumor-free survival, regardless of starting time point or sex. Unlike the other treatments, Samotolisib, the dual PI3K/mTOR inhibitor, decreased microscopic evidence of SqCC when starting treatment at 15 wk of age but only in male mice.

Rethinking Routine Intensive Care After Cytoreductive Surgery With Heated Intraperitoneal Chemotherapy: The Fiscal Argument.

BACKGROUND: Patients undergoing cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) are frequently admitted to the intensive care unit (ICU) for mitigation of potential complications, although ICU length of stay (LOS) is a significant driver of cost. This study asked whether a fiscal argument could be made for the selective avoidance of ICU admission after CRS/HIPEC. METHODS: Prospective data for select low-risk patients (e.g., lower peritoneal cancer index [PCI]) admitted to the intermediate care unit (IMC) instead of the ICU after CRS/HIPEC were matched with a historic cohort routinely admitted to the ICU. Cohort comparisons and the impact of the intervention on cost were assessed. RESULTS: The study matched 81 CRS/HIPEC procedures to form a cohort of 49 pre- and 15 post-intervention procedures for patients with similar disease burdens (mean PCI, 8 ± 6.7 vs. 7 ± 5.1). The pre-intervention patients stayed a median of 1 day longer in the ICU (1 day [IQR, 1-1 day] vs. 0 days [IQR, 0-0 days]) and had a longer LOS (8 days [IQR, 7-11 days] vs. 6 days [IQR, 5.5-9 days]). Complications and complication severity did not differ statistically. The median total hospital cost was lower after intervention ($30,845 [IQR, $30,181-$37,725] vs. $41,477 [IQR, $33,303-$51,838]), driven by decreased indirect fixed cost ($8984 [IQR, $8643-$11,286] vs. $14,314 [IQR, $12,206-$18,266]). In a weighted multiple variable linear regression analysis, the intervention was associated with a savings of $2208.68 per patient. CONCLUSIONS: Selective admission to the IMC after CRS/HIPEC was associated with $2208.68 in savings per patient without added risk. In this era of cost-conscious practice of medicine, these data highlight an opportunity to decrease cost by more than 5% for patients undergoing CRS/HIPEC.

Blood products and liver transplantation: A strategy to balance optimal preparation with effective blood stewardship.

BACKGROUND: Unanticipated transfusion requirements during liver transplantation can delay lifesaving intraoperative resuscitation and strain blood bank resources. Risk-stratified preoperative blood preparation can mitigate these deleterious outcomes. STUDY DESIGN AND METHODS: A two-tiered blood preparation protocol for liver transplantation was retrospectively evaluated. Eleven binary variables served as criteria for high-risk (HR) allocation. Primary outcomes included red blood cell (RBC), plasma (FFP), and platelet (Plt) utilization. Secondary outcomes included product under- and overpreparation. Contingency tables for transfusion requirements above the population means were generated using 15 clinical variables. Modified protocols were developed and retrospectively optimized using the study population. RESULTS: Of 225 recipients, 102 received HR preoperative orders, which correlated to higher intraoperative transfusion requirements. However, univariate analysis identified only two statistical risk factors per product: Hgb ≤7.8 g/dl (p < .001) and MELD ≥38 (p = .035) for RBCs, Hgb ≤7.8 g/dl (p = .002) and acute alcoholic hepatitis (p = 0.015) for FFP, and Hgb ≤7.8 g/dl (p = .001) and normothermic liver preservation (p = .037) for Plts. Based on these findings, we developed modified protocols for individual products, which were evaluated retrospectively for their effectiveness at reducing under-preparatory events while limiting product overpreparation. Cohort statistics were used to define the preparation strategy for each protocol. Retrospective comparative analysis demonstrated the superiority of the modified protocols by improving the under-preparation rate from 24% to <10% for each product, which required a 1.56-fold and 1.44-fold increase in RBC and FFP overpreparation, respectively. Importantly, there was no difference in Plt overpreparation. DISCUSSION: We report translatable data-driven blood bank preparation protocols for liver transplantation.

Risk factors for high level cytomegalovirus viremia in liver transplant recipients and associated outcomes.

PURPOSE: To evaluate epidemiology, risk-factors, and outcomes of high-level (HL) cytomegalovirus (CMV) viremia in liver transplant recipients. METHODS: Adult patients receiving a liver transplant between 1/1/2017 and 9/30/2020 were evaluated. Viral loads at University of Wisconsin Health Clinical Laboratories were required to allow for numerical comparison. Primary objective was incidence and outcomes of HL CMV viremia (viral-load > 100 000 IU/ml). Secondary objective was to elucidate risk factors to allow targeted interventions. RESULTS: Two hundred nine patients met inclusion criteria; 175 kept their graft for at least 240 days. Of these nine patients developed HL CMV, 28 developed low-level (LL CMV, viral-load 250-100 000 IU/ml), and 138 did not develop CMV viremia. When comparing these three groups via classic statistical methods time from transplant to viremia was similar (HL 158 ± 77 days, LL 150 ± 76 days). Clinical factors were also similar with the exception of donor seropositivity (HL 87.5%, LL 70.4%, No CMV 49.6%, p = 0.025). HL CMV was significantly associated with graft loss (p < 0.0001) on Kaplan-Meier analysis; graft loss in the LL CMV group did not differ from the no CMV group (p = 0.96). To allow valid assessment of risk factors in the total study population (n = 209), models of time-varying covariates were used, and Cox proportional hazards ratios were calculated. In this analysis, HL CMV was associated with a significantly increased risk of graft loss (HR 5.6, p = 0.0016). When investigating risk factors associated with HL CMV, donor seropositivity significantly increased risk (HR 8.85, 95% CI 1.13-71.43, p = 0.038). Pretransplant total bilirubin (HR 1.04, 95% CI 0.998-1.07, p = 0.06) trended toward significance. Recipient seronegativity, liver disease, clinical and allocation model for end-stage liver disease (MELD), transplant surgery duration, age, sex, induction immunosuppression, and maintenance immunosuppression were not significantly associated with development of HL CMV. CONCLUSION: HL CMV after liver transplant is uncommon but is associated with a significantly increased risk of graft loss that is not present in those patients who develop LL CMV or do not develop CMV viremia. Given these negative graft effects, CMV stewardship interventions targeting recipients of CMV seropositive allografts are warranted. Future larger scale studies evaluating the potential role of other factors in risk stratification are needed.

Risk factors and outcomes for delayed kidney graft function in simultaneous heart and kidney transplant recipients: A UNOS/OPTN database analysis.

There are no prior studies assessing the risk factors and outcomes for kidney delayed graft function (K-DGF) in simultaneous heart and kidney (SHK) transplant recipients. Using the OPTN/UNOS database, we sought to identify risk factors associated with the development of K-DGF in this unique population, as well as outcomes associated with K-DGF. A total of 1161 SHK transplanted between 1998 and 2018 were included in the analysis, of which 311 (27%) were in the K-DGF (+) group and 850 in the K-DGF (-) group. In the multivariable analysis, history of pretransplant dialysis (OR: 3.95; 95% CI: 2.94 to 5.29; p < .001) was significantly associated with the development of K-DGF, as was donor death from cerebrovascular accident and longer cold ischemia time of either organ. SHK recipients with K-DGF had increased mortality (HR: 1.99; 95% CI: 1.52 to 2.60; p < .001) and death censored kidney graft failure (HR: 3.51; 95% CI: 2.29 to 5.36; p < .001) in the multivariable analysis. Similar outcomes were obtained when limiting our study to 2008-2018. Similar to kidney-only recipients, K-DGF in SHK recipients is associated with worse outcomes. Careful matching of recipients and donors, as well as peri-operative management, may help reduce the risk of K-DGF and the associated detrimental effects.

Valganciclovir prophylaxis extension from 3 to 6 months in high-risk pancreas-transplant recipients does not impact incidence of cytomegalovirus infection at 12 months.

PROBLEM: Incidence and impact of CMV infection in pancreas-transplant recipients (PTRs) in the valganciclovir prophylaxis era has not been completely elucidated. METHODS: Adult D+/R- PTRs were divided into a current era (1/1/2011-12/31/17; 6-month PPX) and a historic era (1/1/2003-12/31/09; 3-month PPX). PRIMARY OBJECTIVE: effect of prophylaxis extension on the incidence of CMV infection. SECONDARY OBJECTIVE: impact of extension on valganciclovir-related toxicity (leukopenia) and transplant outcomes. RESULTS: There were 177 D+/R- PTRs in the study period (historic:98, current:79). Prophylaxis extension resulted in significant reduction of CMV infection from 25.4% to 10.9% at 6 months, (57% reduction, p = .021). However, 1-year rates of CMV infection (historic:31% vs current:36%) and end-organ disease (historic:7.7% vs current:6.9%) were not different (p = .93). Prophylaxis extension significantly increased leukopenia (white blood cell count<3 K/uL) at 6 months (historic:9.5% vs current:28.6%, p = .018). On multivariable analysis prophylaxis extension was not associated with reduced rates of CMV infection (p = .99) or CMV end-organ disease (p = .3). Additionally, there was no significant difference in rejection (p = .2), graft survival (p = .08), death-censored graft survival(p = .07) or patient survival (p = .6). CONCLUSIONS: Prophylaxis extension in D+/R- PTRs appears to delay time to first CMV but not reduce overall incidence. These findings suggest a hybrid approach, incorporating antiviral withdrawal and protocolized monitoring, may be needed to improve CMV-related outcomes.

A pilot study of an intensified ganciclovir dosing strategy for treatment of cytomegalovirus disease in kidney and/or pancreas transplant recipients.

PROBLEM: Mathematical modeling suggests aggressive ganciclovir dosing in the first week of cytomegalovirus disease (CMV) treatment may improve response. This has not been evaluated clinically. METHODS: Adult kidney and/or pancreas transplant recipients admitted with CMV (4/29/19-7/15/20) received IV ganciclovir(10 mg/kg Q12 h × 7 days) with step-down to standard-of-care (SOC) dosing thereafter (5 mg/kg Q12). A SOC cohort admitted before implementation of the dosing strategy (10/20/16-3/2/19) served as a comparator. PRIMARY OBJECTIVE: rate of viral clearance (delta log CMV) at therapy day 7. SECONDARY OBJECTIVE: safety/short term efficacy. RESULTS: Fifty-four patients met inclusion criteria; 22 high-dose, 32 SOC. Demographics were similar with the exception of more women (45.4% vs. 15.6%,P = .03) and higher presenting viral-load in the high-dose group (log 6.0±.7 vs. log 5.2±1.2, P = .02). High-dose resulted in significantly greater response to therapy at day 7 (log -.92±.51 vs. log -.56±.79, P = .04). Change in WBC at day 7 was not different (-.49±1.92 vs. -.45±5.1, P = .97). Short-term clinical outcomes were similar between groups including mean hospital length-of-stay (P = .52), readmission rates (30 d: P = .38; 90 d: P = .5) and achievement of CMV viral-load less-than-lower-limit-of-quantification by day 90 (73% vs. 84%, P = .06). Rejection after CMV as well as graft/patient survival were similar between groups (P = .56, P > .99, P > .99). CONCLUSION: A high-dose IV ganciclovir strategy results in improved viral clearance kinetics without safety concerns and similar short term clinical outcomes.

Pre-transplant bariatric surgery is associated with increased fungal infection after liver transplant.

AIM: The impact of pre-transplant (pre-TXP) bariatric surgery (BS) on outcomes after liver transplant (LTX) has not been completely elucidated. Roux-en Y gastric bypass (RYGB) is one of the most common BS procedures. The primary objective of this study was to identify the risk of infection in LTX recipients with pre-TXP RYGB. METHODS: Adult patients with LTX between 1/1/2001 and 9/30/2018 at our center were screened for pre-TXP RYGB; patients with gastrectomy via sleeve or banding were excluded. Patients with no history of BS pre- or post-transplant were placed in a comparator group, matched 2:1 via incidence density sampling on age epoch. RESULTS: There were 16 LTX recipients with pre-TXP RYGB matched to 32 controls. Median time from RYGB to transplant was 11.7 years. Mean weight loss was 66 ± 19 kg. There were significantly more women with pre-TXP RYGB than in the matched control (RYGB:68.8% vs control:25%, P = .009). Demographics were otherwise similar between groups. Pre-TXP RYGB did not significantly increase hospital or ICU length of stay (P = .5, P = .3) but was associated with a significantly increased rate of fungal infection at 1 year (RYGB:33.4% vs control:9.7%, P = .01), and a numerical trend to increased bacterial infection (RYGB:56.2% vs control:32.2%, P = .09). CONCLUSION: Despite the substantial weight loss attributed to BS, patients with pre-TXP RYGB demonstrated increased rates of fungal infection after transplant and trended toward increased bacterial infection. While the anatomical complexity associated with LTX surgery after RYGB did not appear to significantly affect ICU or hospital length of stay, it may have contributed to overall infectious risk, and possibly to impaired survival. Additionally, bypass of the host natural barrier defenses of the stomach could also have contributed to infectious risk. Our findings highlight the complexity of this patient population. Future prospective studies are needed to investigate risk of infection after LTX in the setting of pre-Txp BS. Potential modification in fungal prophylaxis protocols to include pre-TXP RYGB may be warranted.

Impact and outcomes of primary cytomegalovirus disease in seronegative abdominal solid organ transplant recipients of cytomegalovirus unexposed donors (D-/R-).

BACKGROUND: Primary cytomegalovirus (CMV) disease in high-risk (D+/R-) abdominal solid organ transplant recipients (aSOTRs) is well described, however, little is known of primary CMV disease in low-risk (D-/R-) patients. METHODS: Observational study of adult aSOTRs between 1/1/2009 and 9/1/2019 screened based on serostatus at transplant; D-/R- and D+/R- patients were included. PRIMARY OBJECTIVE: Describe epidemiology of primary CMV in D-/R- aSOTRs. SECONDARY OBJECTIVE: Compare infectious and transplant-related outcomes of primary CMV disease in the first 90 days (early CMV) between D-/R- and D+/R-. RESULTS: Of 782 D-/R- aSOTRs in the study period, 13 developed CMV at any time after transplant to last follow-up. Of 671 D+/R- patients, 186 developed CMV. Early CMV disease was significantly more common in the D-/R- group (54% vs 15.6%, P = .0005) despite populations being similar demographically, including allograft subtype. D-/R- patients with early CMV disease had median viral load >100 000 IU/mL and 42.9% had end-organ manifestations; 71.4% required hospital admission. Immunosuppressive therapy was adjusted in 100% of patients, there was an approximately 14.3% rate of antiviral resistance and 28.6% had concomitant opportunistic infection. These findings were similar to D+/R- patients. There was no difference in risk of rejection or all-cause mortality associated with early CMV disease, however, graft loss was significantly higher in D-/R-. CONCLUSION: D-/R- aSOTRs infrequently develop CMV, however, when it occurs, they present with disease manifestations similar to and graft outcomes inferior to D+/R- with CMV. Additionally, the majority of CMV disease in D-/R- occurs in the first 90 days after transplant, suggesting possible donor subclinical infection or transfusion source. The complicated course in D-/R- is likely caused by low clinical suspicion. Awareness of disease severity and aggressive upfront management may promote positive outcomes.

A comparison of rates and severity of chronic kidney disease in deceased-donor and living-donor liver transplant recipients: times matter

Background/aim: The progression of chronic kidney disease (CKD) in recipients of living-donor liver transplant (LDLT) compared to deceased-donor liver transplant (DDLT) has not been studied in the literature. We hypothesize that CKD stage progression in LDLT recipients is reduced compared to that of their DDLT counterparts. Materials and methods: A retrospective study was undertaken including 999 adult, single-organ, primary liver transplant recipients (218 LDLT and 781 DDLT) at 2 centers between January 2003 and December 2012, in which CKD progression and regression were evaluated within the first 3 years after transplantation. Results: Waiting time from evaluation to transplantation was significantly lower in LDLT patients compared to recipients of DDLT. CKD stage progression from preoperative transplant evaluation to transplantation was significantly greater in DDLT. Deceased-donor liver transplant recipients continued to have higher rates of clinically significant renal disease progression (from stage I­II to stage III­V) across multiple time points over the first 3 years posttransplant. Furthermore, a greater degree of CKD regression was observed in recipients of LDLT. Conclusion: It can be concluded that LDLT provides excellent graft and patient survival, significantly reducing the overall incidence of clinically significant CKD stage progression when compared to DDLT. Moreover, there is a significantly higher incidence of CKD stage regression in LDLT compared to DDLT. These observations were maintained in both high and low model for end-stage liver disease(MELD)populations. This observation likely reflects earlier access to transplantation in LDLT as one of the contributing factors to preventing CKD progression.

Alemtuzumab induction for retransplantation after primary transplant with alemtuzumab induction
.

BACKGROUND: Lymphocyte-depleting induction with alemtuzumab (ALEM) or rabbit antithymocyte-globulin (rATG) is commonly used at retransplantation. It is unknown which agent is preferable, particularly when ALEM was used at primary transplant. OBJECTIVE: Evaluate outcomes after ALEM at retransplant following primary transplant with ALEM induction (ALEM-ALEM) as compared to retransplant with rATG (ALEM-rATG). MATERIALS AND METHODS: Single-center, observational cohort study of adult patients receiving kidney or pancreas transplant between January 1, 2001 and December 12, 2016. RESULTS: 45 patients (16 ALEM-ALEM and 29 ALEM-rATG) met inclusion criteria. The ALEM-ALEM group had fewer days between transplants (621.0 ± 821.8 vs. 2,024.4 ± 1,285.8, p = 0.049), lower panel-reactive-antibodies (PRA) prior to transplant 2 (15.7 ± 31.5 vs. 53.2 ± 37.8; p = 0.0003), and more pancreas secondary transplants, although this was not statistically significant (ALEM-ALEM 37.5% vs. ALEM-rATG 10.3%, p = 0.05). The ALEM-ALEM group experienced a significantly higher rate of fungal infection (ALEM-ALEM 46.8% vs. ALEM-rATG 11.3%, p = 0.02). When adjusted in a multivariate model, this trend persisted (HR 3.97, CI 0.95 - 16.5, p = 0.05). A subgroup analysis of patients receiving a kidney for both transplant 1 and 2 to remove the possible confounding effect of pancreas allografts also found incidence of fungal infection at 1 year to be significantly higher in the ALEM-ALEM group (ALEM-ALEM 25% vs. ALEM-rATG 9.3%, p = 0.025). Rejection rates were not different between groups at 1 year (ALEM-ALEM 25% vs. ALEM-rATG 24.2%). Rates of cytomegalovirus (CMV) infection, BK polyomavirus infection, patient and graft survival were also similar. CONCLUSION: Patients with repeat courses of ALEM induction across multiple transplants may have a higher incidence of fungal infection. Future studies are needed to explore this risk, particularly in light of current drug manufacturer allocation practices and potential increased utilization by transplant centers.

Prostate Transition Zone Fibrosis is Associated with Clinical Progression in the MTOPS Study.

PURPOSE: Medications targeting androgen receptor activity (eg finasteride) or smooth muscle contractility (eg doxazosin) do not resolve lower urinary tract symptoms indicative of lower urinary tract dysfunction in an important subgroup of men. Recently fibrosis has been implicated as another pathobiology contributing to male lower urinary tract symptoms but to our knowledge no systematic studies have been done to assess fibrosis in the context of medical treatment. We determine whether fibrotic changes in the prostate transition zone are associated with an increased risk of clinical progression in participants treated with doxazosin, finasteride or finasteride plus doxazosin in the MTOPS (Medical Therapy of Prostatic Symptoms) study. MATERIALS AND METHODS: Transition zone biopsy tissues from men who did or did not experience clinical progression on placebo, doxazosin, finasteride or combination therapy were assessed for collagen content and architectural changes using picrosirius red birefringence and CT-FIRE (Curvelet Transform-Fiber Extraction) analysis. Correlations were made with annotated demographic and clinical data. Statistical analyses were done with the Pearson correlation coefficient, ANOVA and the t-test. RESULTS: High levels of wavy, aligned prostate transition zone collagen significantly correlated with an increased risk of clinical progression among MTOPS trial participants treated with doxazosin plus finasteride, particularly those with a high body mass index. CONCLUSIONS: Fibrotic changes in the prostate transition zone are associated with an increased risk of clinical progression in men treated with doxazosin plus finasteride. Antifibrotic therapeutics might provide a new treatment approach in men with lower urinary tract dysfunction who do not respond to current medical treatment approaches.

Safety of Antithymocyte Globulin in Patients Undergoing Liver Transplantation With Livers From Donation After Circulatory Death Donors.

Background: Studies suggest that rabbit-antithymocyte globulin (rATG) decreases biliary complications (BCs) after donation-after-circulatory-death-donor liver transplantation (DCD LTx), but safety data are lacking. Objective: Our aim was to assess the safety of rATG for this indication. The secondary end point was efficacy of rATG for this indication. Methods: Adult recipients of DCD LTx were divided into 2 cohorts: protocolized use of rATG in the modern era (July 1, 2013, to December 31, 2016) and a historical control without rATG (January 1, 2005, to June 30, 2013). Incidence of infection, leukopenia, and thrombocytopenia were compared for the safety assessment, incidence of BCs, ischemic cholangiopathy (IC), and transplant outcomes for the efficacy assessment. Results: A total of 83 patients met inclusion criteria: 42 in the historical cohort and 41 in the modern cohort. The modern cohort had significantly fewer bacterial infections at 3 months (historical 54.8% vs modern 23%; P = 0.004) and 1 year (historical 62.1% vs modern 34.2%, P = 0.004). The modern cohort also had fewer fungal infections at these time points (historical 33.3% and 47.9% vs modern 15% and 15%; P = 0.001). There were no significant differences in platelet or white blood cell reduction between groups. There was a nonsignificant, but numerical, trend toward reduced IC/BC in the modern cohort at 1 year (IC: historical 30.1% vs modern 13.2%, P = 0.08; BC: historical 51% vs modern 37.5%, P = 0.13). There was no difference in graft/patient survival. Conclusion and Relevance: Our data suggest no major safety issues with rATG in DCD LTx. Our study should ease clinical apprehension surrounding rATG use for this indication. Future prospective studies are needed to further evaluate the role of rATG and its impact on efficacy end points.

Epidemiology, Risk Factors, and Outcomes After Early Posttransplant Clostridiodes difficile Infection in Renal Transplant Recipients.

BACKGROUND: Modifiable risk-factors associated with Clostridioides difficile infection (CDI) in renal-transplant (RTX) have not been clearly established and peri-transplant risk has not been described. OBJECTIVE: Evaluate epidemiology, risk-factors and outcomes after CDI occurring in the first 90 days after RTX (CDI-90).Methods: Observational cohort study/survival analysis of adult RTX recipients from 1/1/2012-12/31/2015. Primary outcome was CDI-90 incidence/risk-factors. Secondary outcome was evaluation of post-90 day transplant outcomes. RESULTS: 982 patients met inclusion criteria; 46 with CDI-90 and 936 without (comparator). CDI incidence in the total population was 4.7% at 90 days, 6.3% at 1 year, and 6.4% at 3 years. Incidence of CDI-90 was 5%; time to diagnosis was 19.4±25 days (median 7). Risk-factors for CDI-90 were alemtuzumab induction (Hazard ratio [HR] 1.5, 95% CI(1.1-2.0), p = 0.005) and age at transplant (HR 1.007/year, 95% CI (1.002-1.012), p= 0.007). However, risk-factors for CDI at any time were different; donation-after-circulatory-death (DCD) donor (HR 2.5 95% CI (1.3-4.9), p = 0.008) and female gender (HR 1.6 95% CI (1.0-2.7), p = 0.049). On Kaplan-Meier, CDI-90 appeared to have an impact on patient/graft survival, however when analyzed in a multivariable stepwise Cox proportional hazards model, only age was significantly associated with survival (p = 0.002). CONCLUSION AND RELEVANCE: Incidence of CDI-90 is low, mostly occurring in the first post-operative month. Risk-factors vary temporally based on time from transplant. In the early post-op period induction agent and age at transplant are significant, but not after. Associations between CDI and negative graft outcomes appear to be largely driven by age. Future studies validating these risk-factors as well as targeted prophylaxis strategies and their effect on long term graft outcomes and the host microbiome are needed.

Evaluation of infectious risk and outcomes in the hmong renal transplant population.

BACKGROUND: Hmong ethnicity has been associated with infection, particularly fungal. The risk of infection after transplant in the Hmong population is unknown. METHODS: Observational study of adult renal transplant (RTX) recipients between 1/1/1994 and 12/31/2015. Primary objective was to identify infectious risk in the Hmong RTX population as compared to non-Hispanic whites (NHW). Secondary objective was to evaluate transplant outcomes. RESULTS: There was a total of 2599 patients in the study window; 95 Hmong, 2504 NHW. The Hmong population had significantly fewer bacterial and fungal infections at 1 and 3 years (Bacterial: Hmong 21.7%, 32.4% vs NHW 36.9%, 46.7%, P = .004; Fungal: Hmong 3.3%, 5.7% vs NHW 12.7%, 16.6%, P = .0005) and improved graft and patient survival at 1, 5, and 10 years (Graft: Hmong 92.6%, 78.4%, 61.9% vs NHW 90.7%, 72.2%, 48.5%, P = .006; Patient: Hmong 97.8%, 94.5%, 83.3% vs NHW 95.3%, 82.1%, 62.1% P < .001). Spectrum of bacterial infection was similar, but with significantly more Staphylococcal infection in the NHW population. Blastomycoses were the major fungal pathogen in Hmong (2/3, 67%) vs Candida in NWH (77%). When minimally adjusted for PRA and age, rates of bacterial infection (HR 0.69, 95% CI 0.48-0.99, P = .047), fungal infection (HR 0.39, 95% CI 0.17-0.87, P = .02), and mortality (HR 0.5, 95% CI 0.28-0.88, P = .02) were more favorable in the Hmong population. When analyzed in a stepwise Cox proportional hazards model; Hmong ethnicity was not a significant risk factor for graft failure, rejection, CMV, BK, or fungal infection after RTX and was associated with reduced risk of bacterial infection (HR 0.61, 95% CI 0.4-0.9, P = .02) and mortality (HR 0.51, 95% CI 0.27-0.96, P = .04). CONCLUSIONS: Despite concern regarding infective risk in the Hmong population, infection after RTX is no higher than NHW comparator. In all analyses, the Hmong population has equal or better outcomes. It does not appear variance in standard infection prophylaxis is necessary for the Hmong population after RTX.

A targeted fungal prophylaxis protocol with static dosed fluconazole significantly reduces invasive fungal infection after liver transplantation.

BACKGROUND: Invasive fungal infection (IFI) after liver transplant (LTx) is associated with extensive morbidity and mortality. Targeted prophylaxis reduces risk, but qualifying criteria, drug of choice and regimen are unclear and compliance is inconsistent. OBJECTIVE: Assess the impact of a risk factor-based fungal prophylaxis protocol (FPP) after LTx on fungal infection rates, fungal epidemiology, and transplant outcomes. METHODS: Observational cohort study of adult LTx recipients between July 1, 2009, and June 30, 2017. Patients in the FPP group were given a set dose of 400 mg fluconazole without renal adjustment on POD 1-14 via pharmacist delegation protocol. RESULTS: One hundred and eighty-nine patients met inclusion criteria; 50 in the FPP and 139 in the pre-implementation comparator group. Of those who would be considered high-risk, 22.3% received antifungal prophylaxis prior to FPP implementation vs 92% after implementation (P < .0001). There were significantly fewer fungal infections in the FPP group at 1 year (12.5% vs 26.6%, P = .03). IFI in the pre-implementation control group was due to Candida species in 95% of cases; 30% were species with reduced fluconazole susceptibility. IFI in the FPP group was due to Candida species in all cases, and no isolates had reduced fluconazole susceptibility. Aspergillus did not account for any IFI between the groups. One-year patient and graft survival were similar between groups. In a multivariable model accounting for patient and donor age, donor type, MELD, and cold ischemic time, FPP was protective against fungal infection (HR 0.3, P = .015). FPP did not significantly impact graft survival (HR 0.4, P = .14), but trended toward improved patient survival. (HR 0.18, P = .06). CONCLUSION: Implementation of a targeted FPP utilizing static dosing of fluconazole 400 mg × 14 days to those that meet high-risk criteria significantly reduces invasive fungal infection after liver transplant. Use of this protocol did not adversely affect fungal epidemiology and may have a positive impact on allograft and patient survival. Future large prospective studies are needed to better evaluate survival impact.

Endocrine disruptor bisphenol A is implicated in urinary voiding dysfunction in male mice.

Estrogens, acting synergistically with androgens, are known from animal experiments to be important in lower urinary tract symptoms (LUTS) and benign prostate enlargement. Human exposure to environmental estrogens occurs throughout the life span, but the urologic health risks in men are largely unknown. Bisphenol A (BPA) is an endocrine disruptor implicated in male urogenital malformations. Given the role of estrogens in male LUTS, we studied the effects of BPA administered in combination with testosterone (T) on the urinary voiding behavior of adult male mice. Adult male mice underwent subcutaneous implantation with slow-release pellets of 25 mg BPA or 2.5 mg estradiol-17ß (E2), plus 25 mg T, and were compared with untreated (UNT) mice that underwent sham surgery. We studied urinary voiding behavior noninvasively for 1 mo before treatment and for 4 mo after treatment. After euthanasia, we evaluated bladder volume and mass. Mice treated with T+BPA had increased bladder volume ( P < 0.05) and mass ( P < 0.01) compared with UNT mice. After 4 mo of treatment with T+BPA, three of five mice developed voiding dysfunction in the form of droplet voiding or an intermediate pattern of voiding different from both UNT and T+E2-treated mice. Treatment of male mice with BPA or estradiol induces voiding dysfunction that manifests at later time points, implicating the endocrine disruptor, BPA, as a contributor to male LUTS.

The Impact of Hospital Neoadjuvant Therapy Utilization on Survival Outcomes for Pancreatic Cancer.

BACKGROUND: Many surgeons advocate the use of neoadjuvant treatment for resectable pancreatic cancer, however little is known about variation in the utilization of neoadjuvant therapy (NAT) at the hospital level. METHODS: The National Cancer Data Base was used to identify patients undergoing resection for pancreatic cancer between 2006 and 2014 at high-volume centers. Hospitals were grouped by NAT utilization using standard deviations (SD) from the mean as follows: high neoadjuvant utilizers (> 2 SDs above the mean, > 40% of patients receiving NAT); medium-high (1-2 SDs, 27-40%), medium (0-1 SD, 14-26%); or low (- 1.1 to 0 SDs, < 14%). Overall survival (OS) was compared across NAT utilization groups. RESULTS: Among 107 high-volume centers, 20,119 patients underwent resection. The proportion of patients receiving NAT varied widely among hospitals, ranging from 0 to 74%, with only five centers using NAT in > 40% of patients. These five hospitals had the longest median OS at 28.9 months, compared with 21.1 months for low neoadjuvant utilizers (p < 0.001). On multivariable analysis, high and medium-high NAT utilization predicted improved OS, with a hazard ratio (HR) of 0.68 (95% confidence interval [CI] 0.56-0.83, p < 0.001) and 0.80 (95% CI 0.68-0.95, p = 0.010), respectively, compared with low utilizers. After excluding patients who underwent NAT, there remained an association of improved OS with high NAT utilization (HR 0.74, 95% CI 0.60-0.93, p = 0.009). CONCLUSION: High-volume hospitals that more commonly utilize NAT demonstrated longer survival for all patients treated at those centers. In addition to altering patient selection for surgery, high neoadjuvant utilization may be a marker of institutional factors that contribute to improved outcomes.

Ipsilateral versus contralateral placement of the pancreas allograft in pancreas after kidney transplant recipients.

BACKGROUND: In a diabetic, uremic kidney transplant recipient that may receive a future pancreas after kidney (PAK) transplant, the kidney is typically implanted on the left side in anticipation of the subsequent pancreas transplant on the right side. In this study, we sought to determine if ipsilateral PAK (iPAK) is as safe as contralateral PAK (cPAK). METHODS: The 115 PAK transplants (iPAK n = 57, cPAK n = 58) were performed from 1997-2010 and results were compared between the groups. RESULTS: Kidney graft survival and pancreas graft survival was similar between the two groups. Kidney graft function according to serum creatinine and eGFR was not different between the cPAK and the iPAK groups and there were no episodes of kidney graft thrombosis in either group. Subgroup analyses focusing on donor source also did not show worse outcomes for graft survivals in iPAK group when compared to cPAK group. CONCLUSIONS: Pancreas and kidney graft survival in PAK transplants is unaffected by the surgical procedure and iPAK is safe.