Donor CMV Reactivation as a Novel Risk Factor for CMV Replication in Seropositive Liver Transplant Recipients.

Risk factors for cytomegalovirus (CMV) viremia in CMV seropositive liver transplant recipients are incompletely defined and have focused primarily on recipient factors. We hypothesized that active CMV replication (CMV viremia) in seropositive donors might increase the risk for CMV viremia in recipients, as reported for other viruses in organ transplantation. METHODS: From January 3, 2009, to July 27, 2015, stored plasma from consecutive CMV seropositive liver donors was retrospectively tested for CMV viremia by PCR. From April 20, 2012, to July 27, 2015, CMV seropositive recipients of a liver transplant from the donors during this time period received preemptive therapy for CMV prevention (valganciclovir therapy for CMV viremia ≥250 IU/mL). The association of recipient factors and donor CMV viremia with viremia in recipients was assessed. RESULTS: Among 317 CMV-seropositive donors, CMV viremia was detected in 11 (3.5%) and was associated with longer time to collection after admission and bacteremia. Among 115 CMV-seropositive liver recipients, 5 (4.3%) received an organ from a donor with CMV viremia. Donor CMV viremia was independently associated with higher incidence of CMV viremia ≥250 IU/mL and shorter time to onset of CMV viremia ≥250 IU/mL in recipients: 4 (80%) versus 26 (23.6%), P = 0.02, and hazard ratio 8.55 (2.60-28.10), P = 0.003, respectively. CONCLUSION: Donor CMV reactivation is associated with CMV viremia in seropositive orthotopic liver transplant recipients receiving preemptive therapy, identifying a novel potential risk factor for CMV infection in seropositive liver transplant recipients. Future studies should independently validate and assess these findings in other organ transplant settings.

Is there an association between body mass index and 21-gene recurrence score?

PURPOSE: The 21-gene recurrence score (RS) is an established predictor of recurrence for early stage, hormone receptor positive breast cancer. The association between RS and other risk factors such as obesity has not been fully explored. We hypothesized that patients with obesity may present with primary breast cancers with higher recurrence scores. METHODS: We identified 1546 patients who have body mass index (BMI) recorded around the time of RS assay. Obesity was classified as per CDC definitions of overweight (BMI 25-30 kg/m2) and obesity (BMI >30 kg/m2). RS was assessed as a continuous variable and according to pre- and post-TAILORx classifications. Kaplan Meier survival analysis was employed to assess the interaction between RS and BMI on overall survival (OS) and disease-free survival (DFS). RESULTS: In univariate analyses, the median RS in patients with overweight was 15, which was significantly lower than the median RS (16) of patients with normal weight (p = 0.03). The overall recurrence rate of patients with obesity was 4.1%, which was significantly worse than the overall recurrence rate of patients with normal and overweight of 2.6% and 1.5%, respectively (p = 0.05). In multivariate analyses using the inverse probability weighted regression adjustment (IPWRA) method to adjust for imbalances between subgroups, patients with overweight or obesity had significantly lower RS than patients with normal weight, correlating to an average decrease in RS value of 2.37 and 1.71, respectively (both p < 0.01). A similar relationship was seen between BMI categories and RS as a categorical variable stratified according to pre- or post-TAILORx categories. This inverse effect was predominantly seen in post-menopausal patients. Despite the generally lower RS in patients with obesity, a high RS in these patients is associated with diminished DFS (p = 0.04). CONCLUSION: Tumors in post-menopausal women with higher BMI generally have lower RS. DFS is significantly worse in women with obesity whose RS ≥ 30. The reasons for poor outcomes for postmenopausal patients with obesity despite lower presenting RS merits further study.

Kidney transplantation and donation in the transgender population: A single-institution case series.

The medical needs of the transgender population are increasingly recognized within the US health care system. Hormone therapy and gender-affirming surgery present distinct anatomic, hormonal, infectious, and psychosocial issues among transgender kidney transplant donors and recipients. We present the first reported experience with kidney transplantation and donation in transgender patients. A single-center case series (January 2014-December 2018) comprising 4 transgender kidney transplant recipients and 2 transgender living donors was constructed and analyzed. Experts in transplant surgery, transplant psychiatry, transplant infectious disease, pharmacy, and endocrinology were consulted to discuss aspects of care for these patients. Four transgender patients identified as male-to-female and 2 as female-to-male. Three of 6 had gender-affirming surgeries prior to transplant surgery, 1 of whom had further procedures posttransplant. Additionally, 4 patients were on hormone therapy. All 6 had psychiatric comorbidities. The 4 grafts have done well, with an average serum creatinine of 1.45 mg/dL at 2 years (range 1.01-1.85 mg/dL). However, patients encountered various postoperative complications, 1 of which was attributable to modified anatomy. Thus, transgender kidney transplant patients can present novel challenges in regard to surgical considerations as well as pre- and posttransplant care. Dedicated expertise is needed to optimize outcomes for this population.

Refining the indications for neoadjuvant chemotherapy for patients with HER2+ breast cancer: A single institution experience.

BACKGROUND: We aim to compare the clinical outcomes of patients with early-stage HER2+ breast cancer treated with adjuvant chemotherapy (AC) and neoadjuvant chemotherapy (NAC). METHODS: Patients with non-metastatic HER2+ breast cancer treated from 2009 to 2018 at our institution comprised our study cohort (n = 1254). Pathologic complete response (pCR) was defined as the absence of invasive disease in the breast and axilla after NAC. Log-rank, Kaplan-Meier, and inverse probability of treatment weighting were used to assess differences in disease-free and overall survival between groups stratified by AC vs. NAC and pCR vs. non-pCR. RESULTS: The majority received AC (n = 787 or 62.8%) while 467 (37.2%) patients received NAC. Median follow up for AC and NAC groups was 46 and 28 months, respectively. The crude disease-free survival and overall survival of our study cohort were 92.2% and 89.1% for AC, 89.1% and 82.2% for NAC pCR, and 68.1% and 60.0% for NAC non-pCR, respectively. For clinical stage ≥IIB patients, NAC conferred a positive but statistically nonsignificant treatment effect over AC in multivariate analysis. CONCLUSIONS: After adjusting for imbalances in our subgroups, we found that, regardless of the sequence of chemotherapy (AC vs. NAC), patients with early-stage HER2+ breast cancer had excellent outcomes.

Inpatient Pain Medication Administration: Understanding the Process and Its Delays.

BACKGROUND: A patient's impression of quality of care is strongly influenced by pain management. MATERIALS AND METHODS: We sought to understand the process of pro re nata (PRN) pain medication administration through direct observation and use of timestamped data from the electronic medical record (EMR). The total time from nurse notification to administration was compared between PRN narcotics, non-narcotic pain, and nonpain medications. RESULTS: We noted two pathways: patient-initiated requests and nurses preemptively asking about pain. We observed 44 instances of PRN medication administration (33 narcotics, 5 non-narcotics, 6 nonpain). Patients waited a median of 14.5 min for all PRN medications, interquartile range 6.5, 36. There was no significant difference in times for the patient-initiated pathway (n = 39, median 15 min, [7, 40]) compared to preemptive rounding (n = 5, 10 min [5, 30]), P = 0.88. Narcotics (median 14 min, [5, 30]) did not take longer than non-narcotic (11, [10, 88]) or nonpain medications (19.5, [11, 40]), P = 0.75. Electronic medical record data included only the time from medication retrieval to administration, which took approximately 5 min for all medications. CONCLUSIONS: Medication administration is complex, comprising multiple vital steps. The findings of this study suggest opportunities for process improvement that may enhance the experience and overall satisfaction of the surgical patient.

Twelve-Month Outcomes After Transplant of Hepatitis C-Infected Kidneys Into Uninfected Recipients: A Single-Group Trial.

Background: Organs from hepatitis C virus (HCV)-infected deceased donors are often discarded. Preliminary data from 2 small trials, including THINKER-1 (Transplanting Hepatitis C kidneys Into Negative KidnEy Recipients), suggested that HCV-infected kidneys could be safely transplanted into HCV-negative patients. However, intermediate-term data on quality of life and renal function are needed to counsel patients about risk. Objective: To describe 12-month HCV treatment outcomes, estimated glomerular filtration rate (eGFR), and quality of life for the 10 kidney recipients in THINKER-1 and 6-month data on 10 additional recipients. Design: Open-label, nonrandomized trial. (ClinicalTrials.gov: NCT02743897). Setting: Single center. Participants: 20 HCV-negative transplant candidates. Intervention: Participants underwent transplant with kidneys infected with genotype 1 HCV and received elbasvir-grazoprevir on posttransplant day 3. Measurements: The primary outcome was HCV cure. Exploratory outcomes included 1) RAND-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) quality-of-life scores at enrollment and after transplant, and 2) posttransplant renal function, which was compared in a 1:5 matched sample with recipients of HCV-negative kidneys. Results: The mean age of THINKER participants was 56.3 years (SD, 6.7), 70% were male, and 40% were black. All 20 participants achieved HCV cure. Hepatic and renal complications were transient or were successfully managed. Mean PCS and MCS quality-of-life scores decreased at 4 weeks; PCS scores then increased above pretransplant values, whereas MCS scores returned to baseline values. Estimated GFRs were similar between THINKER participants and matched recipients of HCV-negative kidneys at 6 months (median, 67.5 vs. 66.2 mL/min/1.73 m2; 95% CI for between-group difference, -4.2 to 7.5 mL/min/1.73 m2) and 12 months (median, 72.8 vs. 67.2 mL/min/1.73 m2; CI for between-group difference, -7.2 to 9.8 mL/min/1.73 m2). Limitation: Small trial. Conclusion: Twenty HCV-negative recipients of HCV-infected kidneys experienced HCV cure, good quality of life, and excellent renal function. Kidneys from HCV-infected donors may be a valuable transplant resource. Primary Funding Source: Merck.

Risk Factors for Nonplatelet Thromboxane Generation After Coronary Artery Bypass Graft Surgery.

BACKGROUND: Persistent thromboxane (TX) generation while receiving aspirin therapy is associated with an increased risk of cardiovascular events. The Reduction in Graft Occlusion Rates (RIGOR) study found that aspirin-insensitive TXA2 generation, indicated by elevated urine 11-dehydro-TXB2 (UTXB2) 6 months after coronary artery bypass graft surgery, was a potent risk factor for vein graft thrombosis and originated predominantly from nonplatelet sources. Our goal was to identify risks factors for nonplatelet TXA2 generation. METHODS AND RESULTS: Multivariable modeling was performed by using clinical and laboratory variables obtained from 260 RIGOR subjects with verified aspirin-mediated inhibition of platelet TXA2 generation. The strongest variable associated with UTXB2 6 months after surgery, accounting for 47.2% of the modeled effect, was urine 8-iso-prostaglandin (PG)F2α, an arachidonic acid metabolite generated nonenzymatically by oxidative stress (standardized coefficient 0.442, P<0.001). Age, sex, race, lipid therapy, creatinine, left ventricular ejection fraction, and aspirin dose were also significantly associated with UTXB2 (P<0.03), although they accounted for only 4.8% to 10.2% of the modeled effect. Urine 8-iso-PGF2α correlated with risk of vein graft occlusion (odds ratio 1.67, P=0.001) but was not independent of UTXB2. In vitro studies revealed that endothelial cells generate TXA2 in response to oxidative stress and direct exposure to 8-iso-PGF2α. CONCLUSIONS: Oxidative stress-induced formation of 8-iso-PGF2α is strongly associated with nonplatelet thromboxane formation and early vein graft thrombosis after coronary artery bypass graft surgery. The endothelium is potentially an important source of oxidative stress-induced thromboxane generation. These findings suggest therapies that reduce oxidative stress could be useful in reducing cardiovascular risks associated with aspirin-insensitive thromboxane generation.

Surgical management of early and late ureteral complications after renal transplantation: techniques and outcomes.

BACKGROUND: In this study, we present our experience with ureteral complications requiring revision surgery after renal transplantation and compare our results to a matched control population. METHODS: We performed a retrospective analysis of our database between 1997 and 2012. We divided the cases into early (<60 d) and late repairs. Kaplan-Meier and Cox proportional hazards models were used to compare graft survival between the intervention cohort and controls generated from the Scientific Registry of Transplant Recipients data set. RESULTS: Of 2671 kidney transplantations, 51 patients were identified as to having undergone 53 ureteral revision procedures; 43.4% of cases were performed within 60 d of the transplant and were all associated with urinary leaks, and 49% demonstrated ureteral stenosis. Reflux allograft pyelonephritis and ureterolithiasis were each the indication for intervention in 3.8%; 15.1% of the lesions were located at the anastomotic site, 37.7% in the distal segment, 7.5% in the middle segment, 5.7% proximal ureter, and 15.1% had a long segmental stenosis. In 18.9%, the location was not specified. Techniques used included ureterocystostomy (30.2%), ureteroureterostomy (34%), ureteropyelostomy (30.1%), pyeloileostomy (1.9%), and ureteroileostomy (3.8%). No difference in overall graft survival (HR 1.24 95% CI 0.33-4.64, p = 0.7) was detected when compared to the matched control group. CONCLUSION: Using a variety of techniques designed to re-establish effective urinary flow, we have been able to salvage a high percentage of these allografts. When performed by an experienced team, a ureteric complication does not significantly impact graft survival or function as compared to a matched control group.

Time course of pathologic changes in kidney allografts of positive crossmatch HLA-incompatible transplant recipients.

BACKGROUND: Recipients of incompatible allografts are at increased risk of graft loss. We hypothesized that analysis of sequential biopsies from these grafts could define progression of graft lesions and identify features predictive of progression. METHODS: We studied the time course of histologic injury in 745 kidney graft biopsies from 129 patients transplanted with a positive crossmatch human leukocyte antigen-incompatible kidney between 2000 and 2010 (follow-up of 1-9 years). RESULTS: Graft survival was 98% at 1 year and 80% at 5 years after transplantation. Throughout follow-up, 70% of patients experienced rejection, with 52% showing subclinical rejection in the first year. Cell-mediated rejection was more frequent than antibody-mediated rejection throughout follow-up. Transplant glomerulopathy (TxGN; cg≥1) developed in 47% of patients over the period of the study, as early as 3 months in a few patients. TxGN was preceded by glomerulitis in more than 90% of cases, with a median time interval of 12 months. Glomerulitis and detectable posttransplantation donor-specific antibodies were risk factors for TxGN (P<0.0001 and P<0.05). C4d-negative antibody-mediated rejection manifesting as capillaritis (g≥1 and ptc≥1) with detectable donor-specific antibodies was observed in some recipients (<20%). There was progressively higher average tubulointerstitial scarring (ci+ct) from 3 to 6 to 12 months (P<0.001). CONCLUSIONS: Despite good graft survival, a significant incidence of biopsy-proven rejection occurred in this subset of closely monitored human leukocyte antigen-incompatible recipients throughout follow-up. Microcirculation inflammation, particularly glomerulitis, irrespective of C4d, is associated with a high risk of development of TxGN at 1 year.

Histologic phenotype on 1-year posttransplantation biopsy and allograft survival in HLA-incompatible kidney transplants.

BACKGROUND: The correlation between histopathologic phenotypes and allograft outcomes among patients desensitized for donor-specific antibody (HLA-incompatible) is unknown. METHODS: We analyzed 1-year biopsies from desensitized recipients transplanted between 1999 and 2010 and estimated graft survival for each histologic phenotype identified. Median time posttransplant for the 1-year biopsy was 367 days (interquartile range 357-388 days) and median follow-up of all patients post-1-year biopsy was 42 months (interquartile range 19.5-65 months). RESULTS: Transplant glomerulopathy was present in 25.0% of biopsies and resulted in worse graft survival (66.7% vs. 96.7%, P<0.001). C4d positivity and transplant glomerulopathy together portended exceptionally poor graft survival (33.3% vs. 97.2%, P<0.001). Microcirculation inflammation was prevalent, with glomerulitis and peritubular capillaritis found in 60.0% and 47.6% of 1-year biopsies, respectively. Glomerulitis was associated with worse graft survival (82.1% vs. 98.1%, P=0.004), whereas capillaritis was not (88.1% vs. 97.7% respectively, P=0.091). Among C4d-negative HLA-incompatible recipients (82.6% of biopsies), no difference in graft survival was observed between patients with or without microcirculation inflammation in contrast to previous reports by other investigators. Patients who had no C4d deposition, transplant glomerulopathy, or microcirculation inflammation had a 100.0% graft survival. On Cox regression analysis, no independent histopathological parameter was associated with graft survival. CONCLUSIONS: We have identified several histopathologic phenotypes in HLA-incompatible kidney recipients that correlate with allograft outcomes. Characterization of these phenotypes is the first step towards better understanding the pathophysiologic basis of chronic antibody-mediated allograft injury and individualizing therapeutic intervention.

Females with subclavian vein thrombosis may have an increased risk of hypercoagulability.

BACKGROUND: Subclavian vein thrombosis (SVT) is usually caused by vigorous activity or extensive use of the upper extremity. Patients are tested for hypercoagulability if they present with a spontaneous clot unassociated with such activity. The objective of this study was to determine the prevalence of hypercoagulability in patients undergoing first rib resection and scalenectomy presenting with SVT. METHODS: Using a prospectively maintained database from August 2003 through June 2011, patients were retrospectively reviewed for hypercoagulability testing and clinical outcomes. RESULTS: One hundred forty-three patients (79 females and 64 males; mean [range] age, 32 [16-71] years) presented with SVT, of whom 55 patients (43 females and 12 males; mean age, 32 [16-61] years) had undergone hypercoagulable testing. Fourteen patients (25.5%) (12 females and 2 males; mean age, 27 [16-46] years) had an abnormal hypercoagulable profile. A factor V Leiden mutation was present in 6 patients, protein S deficiency in 4, a plasminogen-activator inhibitor-1 (PAI-1) deficiency in 2, and 1 patient each with protein C deficiency, anticardiolipin antibodies, factor VII mutation, factor II mutation, and antiphospholipid antibodies. Immediate and long-term postoperative vein patency was similar to patients without hypercoagulability. Patients were placed on lifelong anticoagulation therapy if they had a PAI-1, protein C, or protein S deficiency. CONCLUSIONS: Patients with hypercoagulability do as well with first rib resection and scalenectomy for SVT as those without hypercoagulability. In our patient subset, more females were tested owing to a history of spontaneous thrombosis and an increased incidence of hypercoagulable disorders. Because of our findings, we believe younger women with SVT should undergo hypercoagulable testing to identify the need for long-term anticoagulation therapy.

Translational research in surgical disease.

OBJECTIVE: To review cutting-edge, novel, implemented and potential translational research and to provide a glimpse into rich, innovative, and brilliant approaches to everyday surgical problems. DATA SOURCES: Scientific literature and unpublished results. STUDY SELECTION: Articles reviewed were chosen based on innovation and application to surgical diseases. DATA EXTRACTION: Each section was written by a surgeon familiar with cutting-edge and novel research in their field of expertise and interest. DATA SYNTHESIS: Articles that met criteria were summarized in the manuscript. CONCLUSIONS: Multiple avenues have been used for the discovery of improved means of diagnosis, treatment, and overall management of patients with surgical diseases. These avenues have incorporated the use of genomics, electrical impedence, statistical and mathematical modeling, and immunology.

Statistical modeling of the volume-outcome effect for carotid endarterectomy for 10 years of a statewide database.

OBJECTIVE: We aimed to achieve accurate statistical modeling of a putative relationship between carotid endarterectomy (CEA) annual surgeon and hospital volume and in-hospital mortality. DESIGN OF STUDY: We performed a secondary data analysis of 10 years (1994-2003) of the Maryland hospital discharge database. Annual volume was defined as the total number of procedures performed for the time in the dataset divided by the total years in the dataset. Non-linear relationships between death and average volumes were explored with logit-transformed lowess smoothing functions, followed by random effect models and inspection of data likelihood under each combination of spline knots. A marginal model with generalized estimating equations was used to represent population-average response as a function of covariates and to account for clustering in the data. Patient comorbidity was assessed using the Deyo modification of the Charlson Index. SETTING: The Maryland hospital discharge database is a 100% sample of all hospitals in the state. SUBJECTS: CEA was identified through ICD-9 and diagnosis codes, using a previously reported algorithm. MAIN OUTCOME MEASURE: Estimated odds ratios predicting in-hospital death, alpha set at 0.05. RESULTS: During the study period, 22,772 patients with surgeon identifiers underwent CEA in Maryland, resulting in 123 in-hospital deaths (0.54%). The crude odds ratio of death for the entire surgeon dataset was 0.9838, meaning that the odds of death decreased by an average of 0.0162 for each additional annual procedure. Surgeon volume of four to 15 CEAs per year was highly significant: for an increase in annual surgeon volume by one procedure per year, the estimated odds of death decreased by 0.065 when controlling for hospital volume, age, and comorbidity (P = .351). Surgeons in other volume categories also demonstrated lower odds of death with increased annual volume, but these odds ratios did not attain statistical significance. Surgeons performing 15 CEAs per year had an odds ratio of 0.997 (P = .485). Hospitals that saw >130 CEAs per year had an odds ratio of death of 0.945 per additional procedure, or 0.055 decrease in the odds of death (P = 0.013), whereas hospitals performing /=130 CEAs per year) showing a statistically significant decrease in the odds ratio of death. As studies on volume-outcome relationships can have important implications for health policy and surgical training, such studies should consider non-linear effects in their modeling of procedural volume.

Steroid avoidance in liver transplantation: meta-analysis and meta-regression of randomized trials.

Steroid use after liver transplantation (LT) has been associated with diabetes, hypertension, hyperlipidemia, obesity, and hepatitis C (HCV) recurrence. We performed meta-analysis and meta-regression of 30 publications representing 19 randomized trials that compared steroid-free with steroid-based immunosuppression (IS). There were no differences in death, graft loss, and infection. Steroid-free recipients demonstrated a trend toward reduced hypertension [relative risk (RR) 0.84, P = 0.08], and statistically significant decreases in cholesterol (standard mean difference -0.41, P < 0.001) and cytomegalovirus (RR 0.52, P = 0.001). In studies where steroids were replaced by another IS agent, the risks of diabetes (RR 0.29, P < 0.001), rejection (RR 0.68, P = 0.03), and severe rejection (RR 0.37, P = 0.001) were markedly lower in steroid-free arms. In studies in which steroids were not replaced, rejection rates were higher in steroid-free arms (RR 1.31, P = 0.02) and reduction of diabetes was attenuated (RR 0.74, P = 0.2). HCV recurrence was lower with steroid avoidance and, although no individual trial reached statistical significance, meta-analysis demonstrated this important effect (RR 0.90, P = 0.03). However, we emphasize the heterogeneity of trials performed to date and, as such, do not recommend basing clinical guidelines on our conclusions. We believe that a large, multicenter trial will better define the role of steroid-free regimens in LT.