Excellent efficacy and beneficial safety during observational 5-year follow-up of rapid steroid withdrawal after renal transplantation (Harmony FU study).

BACKGROUND: We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled 1-year "Harmony" trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared with standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil and corticosteroids. METHODS: The 5-year post-trial follow-up (FU) data were obtained in an observational manner at a 3- and a 5-year visit only for those Harmony patients who consented to participate and covered clinical events that occurred from the second year onwards. RESULTS: Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of RSWD. Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95% confidence interval 0.314-0.976; P = .041).The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original 1-year study period was not compensated by later incidences during FU. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor-specific antibody formation or kidney function did not differ during FU period. CONCLUSIONS: With all the limitations of a post-trial FU study, the Harmony FU data confirm excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy over the course of 5 years after kidney transplantation in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients. Trial registration: Clinical trial registration number: Investigator Initiated Trial (NCT00724022, FU study DRKS00005786).

Risk factors for Epstein-Barr virus reactivation after renal transplantation: Results of a large, multi-centre study.

Epstein-Barr virus (EBV) reactivation is a very common and potentially lethal complication of renal transplantation. However, its risk factors and effects on transplant outcome are not well known. Here, we have analysed a large, multi-centre cohort (N = 512) in which 18.4% of the patients experienced EBV reactivation during the first post-transplant year. The patients were characterized pre-transplant and two weeks post-transplant by a multi-level biomarker panel. EBV reactivation was episodic for most patients, only 12 patients showed prolonged viraemia for over four months. Pre-transplant EBV shedding and male sex were associated with significantly increased incidence of post-transplant EBV reactivation. Importantly, we also identified a significant association of post-transplant EBV with acute rejection and with decreased haemoglobin levels. No further severe complications associated with EBV, either episodic or chronic, could be detected. Our data suggest that despite relatively frequent EBV reactivation, it had no association with serious complications during the first post-transplantation year. EBV shedding prior to transplantation could be employed as biomarkers for personalized immunosuppressive therapy. In summary, our results support the employed immunosuppressive regimes as relatively safe with regard to EBV. However, long-term studies are paramount to support these conclusions.

Insufflation pressure above 25 mm Hg confers no additional benefit over lower pressure insufflation during posterior retroperitoneoscopic adrenalectomy: a retrospective multi-centre propensity score-matched analysis.

BACKGROUND: Insufflation pressures of or in excess of 25 mm Hg CO2 are routinely used during posterior retroperitoneoscopic adrenalectomy (PRA) in most centres. A critical analysis of the surgical literature provides limited evidence to support this strategy. OBJECTIVE: To determine whether high pressure (≥ 25 mm Hg) compared with lower pressure (< 25 mm Hg) retroperitoneoscopy reduces operating time and complications. METHODS: A multi-centre retrospective cohort study was performed using data collected over a period of almost one decade (1st November 2008 until 1st February 2018) from surgical centres in Germany. A total of 1032 patients with benign adrenal tumours were identified. We compared patients undergoing PRA with insufflation pressures of < 25 mm Hg (G20 group) versus ≥ 25 mm Hg (G25 group). A propensity score matching analysis was performed using BMI, tumour size and surgeon's experience as independent variables. The main outcomes were (1) the incidence of perioperative complications and (2) the length of operating time. RESULTS: The baseline patient characteristics were similar in both groups, with the exception of tumour size, BMI and surgeon's experience in PRA. After propensity score matching, perioperative outcomes, especially perioperative complications (3.7% vs. 5.5% in G20 and G25, respectively; p = 0.335) and operation duration (47 min vs. 45 min in G20 and G25, respectively; p = 0.673), did not significantly differ between the groups. CONCLUSION: Neither patient safety nor operative success was compromised when PRA was performed with insufflation pressures below 25 mm Hg. Prospective studies are required to determine whether an optimal insufflation pressure exists that maximizes patient safety and minimizes the risks of post-surgical complications. Nevertheless, our results call for a careful re-evaluation of the routine use of high insufflation pressures during PRA. In the absence of prospective data, commencing PRA with lower insufflation pressures, with the option of increasing insufflation pressures to counter intraoperative bleeding or exposition difficulties, may represent a reasonable strategy.

Simultaneous ipsilateral nephrectomy during kidney transplantation in autosomal dominant polycystic kidney disease: a matched pair analysis of 193 consecutive cases.

BACKGROUND: In end-stage renal transplant recipients with autosomal-dominant polycystic kidney disease (ADPKD), the imperative, optimal timing, and technique of native nephrectomy remains under discussion. The Freiburg Transplant Center routinely performs a simultaneous ipsilateral nephrectomy. METHODS: From April 1998 to May 2017, we retrospectively analyzed 193 consecutive ADPKD recipients, receiving per protocol simultaneous ipsilateral nephrectomy and compared morbidity, mortality, and outcome with 193 non-ADPKD recipients of a matched pair control. RESULTS: The incidence of surgical complications was similar with respect to severe medical, surgical, urological, vascular, and wound-related complications as well as reoperation rates and 30-day mortality. Intraoperative blood transfusions were required more often in the ADPKD (22.8%) compared with the control group (6.7%; p < 0.0001). Early postoperative urinary tract infections occurred more frequent (ADPKD 40.4%/control 29.0%; p = 0.0246). Time of surgery was prolonged by 30 min (ADPKD 169 min; 95%CI 159.8-175.6 min/control 139 min; 95%CI 131.4-145.0 min; p < 0.0001). One-year patient (ADPKD 96.4%/control 95.8%; p = 0.6537) and death-censored graft survival (ADPKD 94.8%/control 93.7%; p = 0.5479) were comparable between both groups. CONCLUSIONS: With respect to morbidity and mortality, per protocol, simultaneous native nephrectomy is a safe procedure. Especially in asymptomatic ADPKD KTx recipients, the number of total operations can be reduced and residual diuresis preserved up until transplantation. In living donation, even preemptive transplantation is possible.

A novel approach reveals that HLA class 1 single antigen bead-signatures provide a means of high-accuracy pre-transplant risk assessment of acute cellular rejection in renal transplantation.

BACKGROUND: Acute cellular rejection (ACR) is associated with complications after kidney transplantation, such as graft dysfunction and graft loss. Early risk assessment is therefore critical for the improvement of transplantation outcomes. In this work, we retrospectively analyzed a pre-transplant HLA antigen bead assay data set that was acquired by the e:KID consortium as part of a systems medicine approach. RESULTS: The data set included single antigen bead (SAB) reactivity profiles of 52 low-risk graft recipients (negative complement dependent cytotoxicity crossmatch, PRA < 30%) who showed detectable pre-transplant anti-HLA 1 antibodies. To assess whether the reactivity profiles provide a means for ACR risk assessment, we established a novel approach which differs from standard approaches in two aspects: the use of quantitative continuous data and the use of a multiparameter classification method. Remarkably, it achieved significant prediction of the 38 graft recipients who experienced ACR with a balanced accuracy of 82.7% (sensitivity = 76.5%, specificity = 88.9%). CONCLUSIONS: The resultant classifier achieved one of the highest prediction accuracies in the literature for pre-transplant risk assessment of ACR. Importantly, it can facilitate risk assessment in non-sensitized patients who lack donor-specific antibodies. As the classifier is based on continuous data and includes weak signals, our results emphasize that not only strong but also weak binding interactions of antibodies and HLA 1 antigens contain predictive information. TRIAL REGISTRATION: ClinicalTrials.gov NCT00724022 . Retrospectively registered July 2008.

Single cohort study: ABO-incompatible kidney transplant recipients have a higher risk of lymphocele formation.

PURPOSE: Since 2004, ABO-incompatible kidney transplantation (ABOi KTx) became an established procedure to expand the living donor pool in Germany. Currently, ABOi KTx comprises > 20% of all living donor KTx. Up to September 2015, > 100 ABOi KTx were performed in Freiburg. Regarding lymphocele formation, only scarce data exist. METHODS: Between April 2004 and September 2015, 106 consecutive ABOi and 277 consecutive ABO-compatible kidney transplantations (ABOc KTx) were performed. Two ABOi and 117 ABOc recipients were excluded due to differences in immunosuppression. One hundred-four ABOi and 160 ABOc KTx patients were analyzed concerning lymphocele formation. RESULTS: The incidence of lymphoceles in ABOi KTx was 25.2% and 10.6% in ABOc KTx (p = 0.003). A major risk factor appeared the frequency of ≥ 8 preoperative immunoadsorption and/or plasmapheresis sessions (OR 5.61, 95% CI 2.31-13.61, p < 0.001). Particularly, these ABOi KTx recipients had a distinctly higher risk of developing lymphocele (40.0% vs. 19.2%, p = 0.044). IA/PE sessions on day of transplantation (no lymphocele 20.0% vs. lymphocele 28.6%, p = 0.362) or postoperative IA/PE sessions (no lymphocele 25.7% vs. lymphocele 24.1%, p = 1.0) showed no influence on formation of lymphoceles. CONCLUSION: In ABOi KTx, the incidence of lymphocele formation is significantly increased compared to ABOc KTx and leads to more frequent surgical reinterventions without having an impact on graft survival.

Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial.

BACKGROUND: Standard practice for immunosuppressive therapy after renal transplantation is quadruple therapy using antibody induction, low-dose tacrolimus, mycophenolate mofetil, and corticosteroids. Long-term steroid intake significantly increases cardiovascular risk factors with negative effects on the outcome, especially post-transplantation diabetes associated with morbidity and mortality. In this trial, we examined the efficacy and safety parameters of rapid steroid withdrawal after induction therapy with either rabbit antithymocyte globulin (rabbit ATG) or basiliximab in immunologically low-risk patients during the first year after kidney transplantation. METHODS: In this open-label, multicentre, randomised controlled trial, we randomly assigned renal transplant recipients in a 1:1:1 ratio to receive either basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and steroid maintenance therapy (arm A), rapid corticosteroid withdrawal on day 8 (arm B), or rapid corticosteroid withdrawal on day 8 after rabbit ATG (arm C). The study was done in 21 centres across Germany. Only participants aged between 18 and 75 years with a low immunological risk who were scheduled to receive a single-organ renal transplant from either a living donor or a deceased donor were considered for enrolment. Patients receiving a second renal transplant were eligible, provided that the first allograft was not lost due to acute rejection within the first year after transplantation. Donor and recipient had to be ABO compatible. Grafts with pre-transplant existing donor-specific human leukocyte antigen (HLA) antibodies were not eligible and the recipients had to have a panel-reactive antibody concentration of 30% or less. Pregnant women and nursing mothers were excluded from the study. The primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) at 12 months. All analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00724022. FINDINGS: Between Aug 7, 2008, and Nov 30, 2013, 615 patients were randomly assigned to arm A (206), arm B (189), and arm C (192). BPAR rates were not reduced by rabbit ATG (9·9%) compared with either treatment arm A (11·2%) or B (10·6%; A versus C: p=0·75, B versus C p=0·87). As a secondary endpoint, rapid steroid withdrawal reduced post-transplantation diabetes in arm B to 24% and in arm C to 23% compared with 39% in control arm A (A versus B and C: p=0·0004). Patient survival (94·7% in arm A, 97·4% in arm B, and 96·9% in arm C) and censored graft survival (96·1% in arm A, 96·8% in arm B, and 95·8% in arm C) after 12 months were excellent and equivalent in all arms. Safety parameters such as infections or the incidence of post-transplantation malignancies did not differ between the study arms. INTERPRETATION: Rabbit ATG did not show superiority over basiliximab induction for the prevention of BPAR after rapid steroid withdrawal within 1 year after renal transplantation. Nevertheless, rapid steroid withdrawal after induction therapy for patients with a low immunological risk profile can be achieved without loss of efficacy and is advantageous in regard to post-transplantation diabetes incidence. FUNDING: Investigator Initiated Trial; financial support by Astellas Pharma GmbH, Sanofi, and Roche Pharma AG.

Effectiveness of triclosan-coated PDS Plus versus uncoated PDS II sutures for prevention of surgical site infection after abdominal wall closure: the randomised controlled PROUD trial.

BACKGROUND: Postoperative surgical site infections are one of the most frequent complications after open abdominal surgery, and triclosan-coated sutures were developed to reduce their occurrence. The aim of the PROUD trial was to obtain reliable data for the effectiveness of triclosan-coated PDS Plus sutures for abdominal wall closure, compared with non-coated PDS II sutures, in the prevention of surgical site infections. METHODS: This multicentre, randomised controlled group-sequential superiority trial was done in 24 German hospitals. Adult patients (aged ≥18 years) who underwent elective midline abdominal laparotomy for any reason were eligible for inclusion. Exclusion criteria were impaired mental state, language problems, and participation in another intervention trial that interfered with the intervention or outcome of this trial. A central web-based randomisation tool was used to randomly assign eligible participants by permuted block randomisation with a 1:1 allocation ratio and block size 4 before mass closure to either triclosan-coated sutures (PDS Plus) or uncoated sutures (PDS II) for abdominal fascia closure. The primary endpoint was the occurrence of superficial or deep surgical site infection according to the Centers for Disease Control and Prevention criteria within 30 days after the operation. Patients, surgeons, and the outcome assessors were masked to group assignment. Interim and final analyses were by modified intention to treat. This trial is registered with the German Clinical Trials Register, number DRKS00000390. FINDINGS: Between April 7, 2010, and Oct 19, 2012, 1224 patients were randomly assigned to intervention groups (607 to PDS Plus, and 617 to PDS II), of whom 1185 (587 PDS Plus and 598 PDS II) were analysed by intention to treat. The study groups were well balanced in terms of patient and procedure characteristics. The occurrence of surgical site infections did not differ between the PDS Plus group (87 [14·8%] of 587) and the PDS II group (96 [16·1%] of 598; OR 0·91, 95% CI 0·66-1·25; p=0·64). Serious adverse events also did not differ between the groups-146 of 583 (25·0%) patients treated with PDS Plus had at least one serious adverse event, compared with 138 of 602 (22·9%) patients treated with PDS II; p=0·39). INTERPRETATION: Triclosan-coated PDS Plus did not reduce the occurrence of surgical site infection after elective midline laparotomy. Innovative, multifactorial strategies need to be developed and assessed in future trials to reduce surgical site infections. FUNDING: Johnson & Johnson Medical Limited.

Pretransplant identification of acute rejection risk following kidney transplantation.

Lack of an accepted definition for 'high immunological risk' hampers individualization of immunosuppressive therapy after kidney transplantation. For recipient-related risk factors for acute rejection, the most compelling evidence points to younger age and African American ethnicity. Recipient gender, body mass, previous transplantation, and concomitant infection or disease do not appear to be influential. Deceased donation now has only a minor effect on rejection risk, but older donor age remains a significant predictor. Conventional immunological markers (human leukocyte antigen [HLA] mismatching, pretransplant anti-HLA alloantibodies, and panel reactive antibodies) are being reassessed in light of growing understanding about the role of donor-specific antibodies (DSA). At the time of transplant, delayed graft function is one of the most clear-cut risk factors for acute rejection. Extended cold ischemia time (≥ 24 h) may also play a contributory role. While it is not yet possible to establish conclusively the relative contribution of different risk factors for acute rejection after kidney transplantation, the available data point to variables that should be taken into account at the time of transplant. Together, these offer a realistic basis for planning an appropriate immunosuppression regimen in individual patients.

Impact of neoadjuvant chemotherapy with PELF-protocoll versus surgery alone in the treatment of advanced gastric carcinoma.

BACKGROUND: In a retrospective study we analyzed the impact of neoadjuvant chemotherapy (CTx) with the PELF - protocol (Cisplatin, Epirubicin, Leukovorin, 5-Fluoruracil) on mortality, recurrence and prognosis of patients with advanced gastric carcinoma, UICC stages Ib-III. METHODS: 64 patients were included. 26 patients received neoadjuvant CTx followed by surgical resection, 38 received surgical resection only. Tumor staging was performed by endoscopy, endosonography, computed tomography and laparoscopy. Patients staged Ib - III received two cycles of CTx according to the PELF-protocol. Adjuvant chemotherapy was not performed at all. RESULTS: Complete (CR) or partial response (PR) was seen in 20 patients (77%), 19% showing CR and 58% PR. No benefit was observed in 6 patients (23%). Two of these 6 patients displayed tumor progression during CTx. Major toxicity was defined as grade 3 to 4 neutropenia or gastrointestinal side effects. One patient died under CTx because of neutropenia and was excluded from the overall patient collective. The curative resection rate was 77% after CTx and 74% after surgery only. The perioperative morbidity rate after CTx was 39% versus 66% after resection only. Recurrence rate after CTx was 38% and 61% after surgery alone; we detected an effective reduction of locoregional recurrence (12% vs. 26%). The overall survival was 38% after CTx and 42% after resection only. The 5-year survival rates were 45% in responders, 20% in non - responders and 42% in only resected patients. A subgroup analysis indicates that responders with stage III tumors may benefit with respect to their 5-year survival in comparable patients without neoadjuvant CTx. As to be expected, non-responders with stage III tumors did not benefit with respect to their survival. The 5-year-survival was approximated using a Kaplan-Meier curve and compared using a log-rank test. CONCLUSION: In patients with advanced gastric carcinoma, neoadjuvant CTx with the PELF- protocol significantly reduces the recurrence rate, especially locoregionally, compared to surgery alone. In our study, there was no overall survival benefit after a 5-year follow-up period. Alone a subgroup of patients with stage III tumors appear to benefit significantly in the long term from neoadjuvant CTx.

The genetic predisposition of natural killer cell to BK virus-associated nephropathy in renal transplant patients.

BK virus (BKV) infection represents a serious complication in renal transplant patients resulting in BKV-associated nephropathy and subsequent allograft loss. Natural killer cells are crucial in the antiviral immune response; however, an understanding of the role of natural killer cells in protection against BKV is limited. To elucidate whether killer-cell immunoglobulin-like receptors and their interaction between donor-/recipient-related ligands have a role in BKV infection, we performed genotyping analysis in 48 kidney transplant recipients with a history of severe BKV infection/BKV-associated nephropathy and 110 recipients with stable renal function and no BKV reactivation. Of interest, we found that telomeric gene content motif was significantly associated with severe course of BKV infection/BKV-associated nephropathy and detected significantly higher percentage of patients with BKV-associated nephropathy carrying low numbers of activating receptors compared with the control group. Detailed analysis of each single receptor revealed significantly lower frequencies of the activating receptor KIR3DS1 in patients with BKV infection/nephropathy as compared with the controls. Thus, our study supports protective effects of activating receptors in BKV infection and suggest natural killer-cell-related genetic predisposition to the development of BKV-associated nephropathy.

Experience with a new prosthetic anal sphincter in three coloproctological centres.

BACKGROUND: Fecal incontinence is a common and severely disabling disorder. For patients with severe fecal incontinence, surgery may prove to be the only adequate treatment option. METHODS: This study reports on 43 patients that were treated with a prosthetic sphincter system between 2005 and 2009 in three coloproctological centres. MAIN OUTCOME MEASURES: complications, anal pressures before and after surgery, fecal continence score. RESULTS: The new artificial sphincter system significantly improves continence but leads to some complications in clinical practice. After implantation of the device, continence improved significantly (Keller & Jostarndt continence score 2.6 to 14.3 (P < 0.01)). With the band activated, resting pressure improved significantly as compared to baseline (10.7 mmHg vs. 66.1 mm Hg, P < 0.01). The same holds for anal sphincter squeeze pressure (32.2 mmHg versus 85.9 mm Hg, P < 0.01). Complications occurred in 21 patients (48.8%): 10 surgical and 13 technical. Two patients were affected by both technical and surgical problems. The median time of the occurrence was 3 months postop. In five patients difficulties arose within the first postoperative month leading to explantation of the device in three patients. 90% of complications occurred in the first year. CONCLUSIONS: The soft anal band of AMI (AAS), a new artificial anal sphincter, improves severe anal incontinence, but it must be regarded as a last treatment option to avoid a stoma.

HAnd Suture Versus STApling for Closure of Loop Ileostomy (HASTA Trial): results of a multicenter randomized trial (DRKS00000040).

OBJECTIVES: The objective of the HASTA trial was to compare hand suture versus stapling loop ileostomy closure in a randomized controlled trial. BACKGROUND: Bowel obstruction is one of the main and the clinically and economically most relevant complication following closure of loop ileostomy after low anterior resection. The best surgical technique for closure of loop ileostomy has not been defined yet. METHODS: HASTA trial is a multicenter pragmatic randomized controlled surgical trial with 2 parallel groups to compare hand suture versus stapling for closure of loop ileostomy. The primary endpoint was the rate of bowel obstruction within 30 days after ileostomy closure. RESULTS: A total of 337 randomized patients undergoing closure of loop ileostomy after low anterior resection because of rectal cancer in 27 centers were included. The overall rate of postoperative ileus after ileostomy closure was 13.4%. Seventeen of 165 (10.3%) patients in the stapler group and 27 of 163 (16.6%) in the hand suture group developed bowel obstruction within 30 days postoperatively [odds ratio (OR) = 1.72; 95% confidence interval (CI): 0.89-3.31 = 0.10]. Duration of surgical intervention was significantly shorter in the stapler group (15 minutes; P < 0.001). Multivariable analysis of potential risk factors did not reveal any significant correlation with development of postoperative ileus. Rate of anastomotic leakage (stapler: 3.0%, hand suture: 1.8%, P = 0.48) did not differ significantly as well as all other secondary endpoints. CONCLUSIONS: Hand-sewn anastomosis versus stapler ileo-ileostomy for ileostomy closure are equally effective in terms of postoperative bowel obstruction, with stapler anastomosis leading to a shorter operation time. Postoperative ileus after ileostomy reversal remains a relevant complication.

Early prediction of renal graft function: Analysis of a multi-center, multi-level data set.

PURPOSE OF THE STUDY: Long-term graft survival rates after renal transplantation are still poor. We aimed to build an early predictor of an established long-term outcomes marker, the estimated glomerular filtration rate (eGFR) one year post-transplant (eGFR-1y). MATERIALS AND METHODS: A large cohort of 376 patients was characterized for a multi-level bio-marker panel including gene expression, cytokines, metabolomics and antibody reactivity profiles. Almost one thousand samples from the pre-transplant and early post-transplant period were analysed and employed for machine learning-assisted prediction. RESULTS: Pre-transplant data led to a prediction achieving a Pearson's correlation coefficient of r=0.38 between measured and predicted eGFR-1y. Two weeks post-transplant, the correlation was improved to r=0.63, and at the third month, to r=0.76. eGFR values were stable throughout the first post-transplant year. Several characteristics were predictive for eGFR, including age of donor and recipient, body mass index, HLA mismatch, cytomegalovirus mismatch and valganciclovir prophylaxis. Additionally, a subset of 19 nuclear magnetic resonance bins of the urine metabolome data was shown to have potential applications in non-invasive eGFR monitoring. Importantly, we identified the expression of the genes TMEM176B and HMMR as potential prognostic markers for changes in the eGFR after the second post-transplantation week. CONCLUSIONS: Our multi-center, multi-level data set represents a milestone in the efforts to predict transplant outcome. While an acceptable predictive capacity was achieved, we are still far from predicting changes in the eGFR precisely. Additional studies employing further marker panels are needed to establish predictors of eGFR-1y for clinical application; herein, gene expression markers seem to hold the most promise.

Minimally invasive partial versus total adrenalectomy for unilateral primary hyperaldosteronism-a retrospective, multicenter matched-pair analysis using the new international consensus on outcome measures.

BACKGROUND: Primary hyperaldosteronism is a recognized risk factor for myocardial infarction, stroke, and atrial fibrillation. Minimally invasive adrenalectomy is the first-line treatment for localized primary hyperaldosteronism. Whether minimally invasive adrenalectomy should be performed using a cortex-sparing technique (partial minimally invasive adrenalectomy) or not (total minimally invasive adrenalectomy) remains a subject of debate. The aim of our study was to evaluate the clinical and biochemical efficacy of both procedures and to examine the morbidity associated with partial minimally invasive adrenalectomy versus total minimally invasive adrenalectomy in a multicenter study. METHODS: Using a retrospective study design, we determined the efficacy, morbidity, and mortality of partial minimally invasive adrenalectomy and total minimally invasive adrenalectomy. The Primary Aldosteronism Surgical Outcome Study classification was used to explore clinical and biochemical success. Matched-pair analysis was used in order to address possible bias. RESULTS: We evaluated 234 matched patients with unilateral primary hyperaldosteronism: 78 (33.3%) underwent partial minimally invasive adrenalectomy, and 156 (66.7%) were treated with total minimally invasive adrenalectomy. Complete clinical success was achieved in 40.6%, and partial clinical success in an additional 52.6% of patients in the entire cohort. Complete biochemical success was seen in 94.0% of patients. Success rates and the incidence of perioperative complications were comparable between groups. Both postoperative hypocortisolism (11.5% vs 25.0% after partial minimally invasive adrenalectomy and total minimally invasive adrenalectomy, respectively; P < .001) and postoperative hypoglycemia (2.6% vs 7.1% after partial minimally invasive adrenalectomy and total minimally invasive adrenalectomy; P = .039) occurred more frequently after total minimally invasive adrenalectomy. CONCLUSION: Our study provides evidence that patients with unilateral primary hyperaldosteronism are good surgical candidates for partial minimally invasive adrenalectomy. Not only is the surgical outcome comparable to that of total minimally invasive adrenalectomy, but also postsurgical morbidity, particularly in terms of hypocortisolism and hypoglycemia, may be reduced.

Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma.

Background: Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab. Patients and Methods: In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14-24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1-90%). Results: Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with long-term (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%. Conclusions: Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions. The combination treatment is now being systematically examined in a phase II clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]) in ATC/PDTC patients.

Sex-Associated Differences in Cytomegalovirus Prevention: Prophylactic Strategy is Potentially Associated With a Strong Kidney Function Impairment in Female Renal Transplant Patients.

Post-transplantation cytomegalovirus (CMV) syndrome can be prevented using the antiviral drug (val)ganciclovir. (Val)ganciclovir is typically administered following a prophylactic or a pre-emptive strategy. The prophylactic strategy entails early universal administration, the pre-emptive strategy, early treatment in case of infection. However, it is not clear which strategy is superior with respect to transplantation outcome; sex-specific effects of these prevention strategies are not known. We have retrospectively analyzed 540 patients from the multi-centre Harmony study along eight pre-defined visits: 308 were treated according to a prophylactic, 232 according to a pre-emptive strategy. As expected, we observed an association of prophylactic strategy with lower incidence of CMV syndrome, delayed onset and lower viral loads compared to the pre-emptive strategy. However, in female patients, the prophylactic strategy was associated with a strong impairment of glomerular filtration rate one year post-transplant (difference: -11.8 ± 4.3 ml min-1·1.73 m-2, p = 0.006). Additionally, we observed a tendency of higher incidence of acute rejection and severe BK virus reactivation in the prophylactic strategy group. While the prophylactic strategy was more effective for preventing CMV syndrome, our results suggest for the first time that the prophylactic strategy might lead to inferior transplantation outcomes in female patients, providing evidence for a strong association with sex. Further randomized controlled studies are necessary to confirm this potential negative effect.

Evidence of Interleukin-2-Receptor-Antibody Induction in Low-Risk Living Donor Kidney Transplantation: A Single-Center Pilot Study.

BACKGROUND: The recommended standard immunosuppressive therapy for renal transplant recipients comprises an initial induction therapy mainly with an interleukin-2-receptor antibody (IL2-RA) and a triple maintenance therapy. With tacrolimus and mycophenolate acid it is unknown whether IL2-RA application affects the short- and long-term results. This question is addressed in the present analysis. METHODS: From July 2007 to June 2019 a total of 127 living donor kidney transplant recipients meeting the center-specific definition of immunologic low risk situation (first transplantation, HLA-mismatch ≤3, panel reactive antibody ≤10%) were identified. In 83 recipients with a first-degree relationship to the donor we omitted the IL2-RA induction (IL2-RA-). The remaining 44 recipients, mostly not first-degree relatives, served as controls (IL2-RA+). Biopsy-proven acute rejection and long-term patient and graft survival rates were compared. RESULTS: Biopsy-proven acute rejection rates after 3 months were similar in both groups with 4.8% (IL2-RA-) vs 13.7% (IL2-RA+; P = .0937), including borderline rejection rates of 18.0% (IL2-RA-) vs 18.3% (IL2-RA+; P = 1.000), respectively. Ten-year long-term survival rates were comparable between the IL2-RA- and the IL2-RA+ group with 95.6% vs 93.5% (patient survival; P = .5465) and 92.1% vs 90.6% (death-censored graft survival; P = .8893). CONCLUSION: For low-risk living donor kidney transplant recipients with first-degree relationship to the donor, it is safe to omit induction therapy with IL2-RA.