Kidney transplantation following iliac revascularization in severe atherosclerosis: a comparative study.

BACKGROUND: Kidney transplantation (KT) has become the standard of care for patients with end-stage renal disease. However, as atherosclerosis progresses with time on dialysis, it causes increasing difficulties in implanting the graft. This is a comparative study analyzing complications and graft survival of recipients with iliac revascularization before transplantation. METHODS: Between January 2006 and December 2015, 1691 kidney transplants were performed at our institution. We retrospectively analyzed eighteen patients with peripheral arterial disease (PAD) with the necessity of vascular revascularization before kidney transplantation to protect the inflow to the renal graft and to optimizing blood supply to the extremities. The primary endpoint included patient survival and graft survival. The secondary endpoints evaluate perioperative and early postoperative complication rates after kidney transplantation. RESULTS: All patients enrolled in this study underwent two consecutive surgical procedures. No patient reported limb loss, and there was no additional perioperative morbidity or mortality related to the vascular procedure. Primary endpoints such as graft survival without dialysis and overall patient survival show 1-month survival of 100%, 1-year survival of 94.1%, and 5-year survival of 84.70%, respectively. One graft failure occurred 8 months after transplantation due to acute rejection, and there were two deaths over follow-up period due to myocardial infarction. CONCLUSIONS: Vascular repair before kidney transplantation is safe, and results are suggestive that it prolongs graft survival. These promising results should encourage other centers to address vascular repair before the transplantation to optimize blood supply to the extremity and the future graft. Although, the interpretation of our results must be cautiously because of the small and heterogeneous sample size, and the limitations of retrospective study design. Prospective trials with larger study populations are needed to confirm the results of this study and to identify significant differences.

First-in-man controlled rewarming and normothermic perfusion with cell-free solution of a kidney prior to transplantation.

Cold preservation sensitizes organ grafts to exacerbation of tissue injury upon reperfusion. This reperfusion injury is not fully explained by the mere re-introduction of oxygen but rather is pertinent to the immediate rise in metabolic turnover associated with the abrupt restoration of normothermia. Here we report the first clinical case of gradual resumption of graft temperature upon ex vivo machine perfusion from hypothermia up to normothermic conditions using cell-free buffer as a perfusate. A kidney graft from an extended criteria donor was put on the machine after 12.5 hours of cold storage. During ex vivo perfusion, perfusion pressure and temperature were gradually elevated from 30 mm Hg and 8°C to 75 mm Hg and 35°C, respectively. Perfusate consisted of diluted Steen solution, oxygenated with 100% oxygen. Final flow rates at 35°C were 850 mL/min. The kidney was transplanted without complications and showed good immediate function. Serum creatinine fell from preoperative 720 µmol/L to 506 µmol/L during the first 24 hours after transplantation. Clearance after 1 week was 43.1 mL/min. Controlled oxygenated rewarming prior to transplantation can be performed up to normothermia without blood components or artificial oxygen carriers and may represent a promising tool to mitigate cold-induced reperfusion injury or to evaluate graft performance.

Successful early sofosbuvir-based antiviral treatment after transplantation of kidneys from HCV-viremic donors into HCV-negative recipients.

BACKGROUND: Transplanting kidneys from deceased donors with hepatitis C virus (HCV) viremia has been controversial for some time. Direct-acting antiviral agents have been shown to be highly effective in treating HCV infection. We report our experience with transplanting kidneys from HCV-positive donors with detectable viremia into HCV-negative recipients, followed by early treatment with a sofosbuvir-based antiviral regimen. METHODS: Data were collected from seven HCV-negative recipients receiving kidneys from five deceased HCV-viremic donors. Before transplantation, all intentional transplanted recipients had given informed consent regarding the acceptance of an HCV-viremic kidney. Recipients were closely monitored after transplant with measurements of HCV viremia, liver and renal function, and trough levels of immunosuppressive drugs. RESULTS: Four donors were infected with HCV genotype 1; the other with HCV genotype 3a. HCV viremia was detectable in all seven renal transplant recipients within 3 days after transplant. After determination of HCV genotype, antiviral treatment with a sofosbuvir-based regimen (sofosbuvir/ledipasvir, n = 4; sofosbuvir/velpatasvir, n = 3) was initiated within a median of 7 days after transplantation and was continued for 8 to 12 weeks. For all recipients, viral load was below the level of detection at the end of treatment, and all exhibited a sustained virologic response 12 weeks later. All recipients exhibited normal liver enzyme activity at the end of treatment. Renal allograft function and trough levels of tacrolimus remained stable. CONCLUSIONS: Early administration of a sofosbuvir-based regimen to HCV-negative recipients of kidneys from HCV-viremic donors is feasible and safe. The definition of an optimal therapeutic approach warrants further investigation.

Hepatic artery and biliary complications in liver transplant recipients with radioembolization bridging treatment for hepatocellular carcinoma.

BACKGROUND: Locoregional bridging treatments are commonly applied in patients with hepatocellular carcinoma (HCC) prior to liver transplantation to prevent tumor progression during waiting time. It remains unknown whether pre-transplant radioembolization treatment may increase the prevalence of hepatic artery and biliary complications post-transplant. METHODS: We performed a retrospective review of 173 consecutive patients with HCC who underwent liver transplantation at our transplant center between January 2007 and December 2016. RESULTS: Radioembolization bridging treatment was applied in 42 patients while 131 patients received other or no forms of bridging treatment. The overall prevalence of intra-operative and early post-operative hepatic artery complications was 9.5% in the radioembolization group and 9.2% in the control group (P = 1.000). Biliary complications were significantly less frequent in the radioembolization group (4.8% vs 17.6%, P = .0442). In multivariable analysis, radioembolization was not significantly associated with an increased risk of arterial complications. Considering biliary complications, radioembolization bridging treatment was the only factor significantly associated with decreased odds (OR 0.187 (0.039, 0.892), P = .036). CONCLUSIONS: Radioembolization is not associated with higher odds of hepatic artery complications following liver transplantation. There may even be a protective effect regarding biliary complications. Radioembolization as a bridge to transplantation may effectively be applied without compromising successful liver transplantation.

Reconditioning by end-ischemic hypothermic in-house machine perfusion: A promising strategy to improve outcome in expanded criteria donors kidney transplantation.

This clinical study evaluates end-ischemic hypothermic machine perfusion (eHMP) in expanded criteria donors (ECD) kidneys. eHMP was initiated upon arrival of the kidney in our center and continued until transplantation. Between 11/2011 and 8/2014 eHMP was performed in 66 ECD kidneys for 369 (98-912) minutes after 863 (364-1567) minutes of cold storage (CS). In 49 of 66 cases, the contralateral kidney from the same donor was preserved by static CS only and accepted by another Eurotransplant (ET) center. Five (10.2%) of these kidneys were ultimately judged as "not transplantable" by the accepting center and discarded. After exclusion of early unrelated graft losses, 43 kidney pairs from the same donor were eligible for direct comparison of eHMP vs CS only: primary non-function and delayed graft function (DGF) were 0% vs 9.3% (P=.04) and 11.6% vs 20.9% (P=.24). There was no statistically significant difference in 1-year graft survival (eHMP vs CS only: 97.7% vs 88.4%, P=.089). In a multivariate analysis, eHMP was an independent factor for prevention of DGF (OR: 0.28, P=.041). Development of DGF was the strongest risk factor for 1-year graft failure (Renal resistance: 38.2, P<.001). In summary, eHMP is a promising reconditioning technique to improve the quality and acceptance rate of suboptimal grafts.

Donor information based prediction of early allograft dysfunction and outcome in liver transplantation.

BACKGROUND & AIMS: Poor initial graft function was recently newly defined as early allograft dysfunction (EAD) [Olthoff KM, Kulik L, Samstein B, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl 2010; 16: 943]. Aim of this analysis was to evaluate predictive donor information for development of EAD. METHODS: Six hundred and seventy-eight consecutive adult patients (mean age 51.6 years; 60.3% men) who received a primary liver transplantation (LT) (09/2003-12/2011) were included. Standard donor data were correlated with EAD and outcome by univariable/multivariable logistic regression and Cox proportional hazards to identify prognostic donor factors after adjustment for recipient confounders. Estimates of relevant factors were utilized for construction of a new continuous risk index to develop EAD. RESULTS: 38.7% patients developed EAD. 30-day survival of grafts with and without EAD was 59.8% and 89.7% (P < 0.0001). 30-day survival of patients with and without EAD was 68.5% and 93.1% (P < 0.0001) respectively. Donor body mass index (P = 0.0112), gGT (P = 0.0471), macrosteatosis (P = 0.0006) and cold ischaemia time (CIT) (P = 0.0031) were predictors of EAD. Internal cross validation showed a high predictive value (c-index = 0.622). CONCLUSIONS: Early allograft dysfunction correlates with early results of LT and can be predicted by donor data only. The newly introduced risk index potentially optimizes individual decisions to accept/decline high risk organs. Outcome of these organs might be improved by shortening CIT.

Combined liver and kidney transplantation and kidney after liver transplantation in children: Indication, postoperative outcome, and long-term results.

CLKT and sequential KALT are decided on a case-by-case basis in children for special indications such as ARPKD or PH1. We report on 21 children who underwent CLKT or KALT at our hospital between 1998 and 2013. Eleven children were diagnosed with PH1 and six with ARPKD. Other diagnosis were Joubert syndrome (n = 1), nephronophthisis (n = 1), CF (n = 1), and hepatocellular carcinoma (n = 1). Children (12 males, nine females) were aged 7.8 ± 6.2 yr (range, 10 months to 18 yr) at time of transplantation. Average wait time was 1.9 ± 0.9 yr (range, four months to 2.3 yr). Fifteen patients received dialysis prior to transplantation. In PH1 patients, four children received CLKT, five received KALT, and two infants have received only an LTx, whereas all six patients with ARPKD received CLKT. In patients with other indications, CLKT was performed in three cases and KALT in one girl. Cumulative 10-yr survival of all 21 patients was 78.4%. At the time of transfer into adult care, 13 patients retained stable liver and kidney function. Regardless the underlying diagnosis, CLKT and KALT can be performed in children with good surgical outcomes and long-term survival.

Using pediatric liver grafts (≤ 6 yr) for adult recipients: A considerable option?

In LT, the common policy is to allocate pediatric liver grafts to pediatric recipients. Pediatric organs are also offered to adults if there is no pediatric recipient. However, they are rarely accepted for adult recipients. So far, there is no information available reporting outcome of LT in adult recipients using pediatric livers from donors ≤ 6 yr. In this study, we included nine adult recipients (seven females and two males) who received grafts from children ≤ 6 yr from January 2008 to December 2013. We evaluated the graft quality, the GBWR and analyzed the recipients' perioperative course. Laboratory samples and graft perfusion were analyzed. Nine adults with a median age of 49 yr (range: 25-65) and a median weight of 60 kg (range: 48-64) underwent LT with a pediatric donor graft. Median donor age was five yr (range: 3-6). Median GBWR was 1.02 (range: 0.86-1.45). After a median follow-up of 3.9 yr (range: 11 months-6.6 yr), patient survival was 100%; graft survival was 89%. One patient needed re-transplantation on the second postoperative day due to PNF. Eight recipients were discharged from the ICU after 2-9 days with a regular graft function. Doppler scans revealed regular flow patterns at any time. Only if denied for pediatric recipients, the use of pediatric livers from donors ≤ 6 yr for adult recipients is a considerable option.

Glutamate dehydrogenase and alkaline phosphatase as very early predictors of hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUND: Although long-term survival rates for patients undergoing liver transplant (LT) for hepatocellular carcinoma (HCC) are good, the relatively high rate of tumor recurrence after LT necessitates the identification of biological parameters that supplement morphological predictors of recurrence. METHOD: From chart review we identified 175 patients who received liver transplantation due to HCC at our center between January 2000 and December 2013. We documented demographic and clinical data, as well as clinicopathological characteristics of the tumors, with a focus on liver values at the time of LT. RESULTS: HCC recurred in 23% of LT patients. Most recurrences (59%) occurred within 12 months after LT; hardly any recurrence was detected later than 3 years after LT. Recurrence was positively correlated with tumor size, tumor stage and alpha-fetoprotein level (AFP), and it was most likely with certain causes of liver disease. Interestingly, tumor recurrence was independently predicted by serum levels of glutamate dehydrogenase (GLDH) and alkaline phosphatase (AP) at the time of LT. CONCLUSIONS: Because all HCC recurrence occurs within 36 months after LT, HCC detected more than 3 years after LT may be considered de novo. Liver values, with GLDH and AP being the most preponderant, serve as easy-to-assess biomarkers which contribute to predict the risk of tumor recurrence.

Endoscopic treatment of pediatric post-transplant biliary complications is safe and effective.

BACKGROUND AND AIM: Biliary complications (BC) after liver transplantation (LT) are associated with significant morbidity and mortality. Incidence of BC after pediatric LT is more than 10%. In adults, treatment by endoscopic retrograde cholangiopancreaticography (ERCP) is successful. As data in pediatric patients are limited, endoscopic treatment of BC in a pediatric cohort in a German transplant center was analyzed. METHODS: LT recipients <18 years of age who were endoscopically treated for BC at University Hospital Essen were retrospectively analyzed. Characteristics of LT, endoscopic treatment measures, clinical and endoscopic presentation of BC, and outcomes after endoscopic treatment were evaluated. RESULTS: Seventeen patients (median age 12 years) with clinical signs of BC were treated endoscopically using ERCP. Eleven patients had received a full-size liver, and six a left-sided living-donor transplant graft. In 12 patients, the bile ducts were accessible via Vater's papilla and five patients had a bilioenteric anastomosis. Biliary sphincterotomy was done in 13 patients. Eleven patients presented with stricture of the biliary anastomosis (AST), either isolated (nine) or in combination with biliary cast syndrome (BCS) or biliary leakage (one patient each). Ischemia-type biliary lesions (ITBL) were found in two patients. Five patients suffered from BCS, either as isolated pathology (two) or in combination with AST, bile leak or ITBL. In one patient, biliary access via the major papilla was not obtainable. CONCLUSIONS: BC in pediatric LT were treated safely and successfully in pediatric patients when the biliary tract was accessible. The most common complications were AST, BCS and ITBL.

Polo-like kinase 2 is a mediator of hedgehog survival signaling in cholangiocarcinoma.

UNLABELLED: Cholangiocarcinoma (CCA) cells paradoxically express the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and thus rely on potent survival signals to circumvent cell death by TRAIL. Hedgehog (Hh) signaling is an important survival pathway in CCA. Herein, we further examine the mechanisms whereby Hh signaling mediates apoptosis resistance in CCA, revealing a pivotal role for the cell division regulating serine/threonine kinase polo-like kinase 2 (PLK2). We employed 50 human CCA samples (25 intrahepatic and 25 extrahepatic CCA) as well as human KMCH-1, Mz-CHA-1, and HUCCT-1 CCA cells for these studies. In vivo experiments were conducted using a syngeneic rat orthotopic CCA model. In human samples, polo-like kinase (PLK)1/2/3-immunoreactive cancer cells were present in the preponderance of intra- and extrahepatic CCA specimens. Inhibition of Hh signaling by cyclopamine reduced PLK2, but not PLK1 or PLK3, messenger RNA and protein expression in vehicle-treated and sonic Hh-treated CCA cells, confirming our previous microarray study. PLK2 regulation by Hh signaling appears to be direct, because the Hh transcription factors, glioma-associated oncogene 1 and 2, bind to the PLK2 promotor. Moreover, inhibition of PLK2 by the PLK inhibitor, BI 6727 (volasertib), or PLK2 knockdown was proapoptotic in CCA cells. BI 6727 administration or PLK2 knockdown decreased cellular protein levels of antiapoptotic myeloid cell leukemia 1 (Mcl-1), an effect reversed by the proteasome inhibitor, MG-132. Finally, BI 6727 administration reduced Mcl-1 protein expression in CCA cells, resulting in CCA cell apoptosis and tumor suppression in vivo. CONCLUSION: PLK2 appears to be an important mediator of Hh survival signaling. These results suggest PLK inhibitors to be of therapeutic value for treatment of human CCA.

Coagulation management with factor concentrates in liver transplantation: a single-center experience.

BACKGROUND: Allogeneic blood products transfusion during liver transplantation (LT) can be associated with increased morbidity and mortality. Data on thromboelastometry (ROTEM)-guided coagulation management with coagulation factor concentrates (CFCs)-fibrinogen concentrate and/or prothrombin complex concentrate (PCC)-are sparse. We aimed to retrospectively evaluate the safety events observed with this approach in our clinic. STUDY DESIGN AND METHODS: LT patients from January 2009 to December 2010 (n = 266) were identified by chart review. A ROTEM-based algorithm with CFC guided the hemostatic therapy. Doppler ultrasound was used to evaluate thrombosis in the hepatic artery, portal vein, and hepatic veins. Stroke, myocardial ischemia, pulmonary embolism, and transfusion variables were recorded. Patients receiving CFC were included in the CFC group (n = 156); those not receiving CFC were included in the non-CFC group (n = 110). Safety events were compared between these two groups. RESULTS: Allogeneic transfusion(s) in the 266 patients was low, with medians of 2 (interquartile range [IQR], 0-5), 0 (IQR 0-0), and 0 (IQR 0-1) units for red blood cells (RBCs), fresh-frozen plasma (FFP), and platelets (PLTs), respectively. Ninety-seven of 266 LTs (36.5%) were performed without RBCs transfusion, 227 (85.3%) without FFP, and 190 (71.4%) without PLTs. There were no significant differences in thrombotic, thromboembolic, and ischemic adverse events occurrence between the CFC group and the non-CFC group (11/156 patients vs. 5/110; p = 0.31). CONCLUSION: In LT, ROTEM-guided treatment with fibrinogen concentrate and/or PCC did not appear to increase the occurrence of thrombosis and ischemic events compared to patients who did not receive these concentrates.

MELD at POD 1 as a predictor of outcome in liver allografts with peak AST >5000 U/l.

Perioperative liver graft injury is associated with elevation of aminotransferases after orthotopic liver transplantation (OLT). Values above 5000 U/l usually are regarded as extreme liver graft injury (ELGI). Some patients and organs recover from this critical condition. The aim of the study was to evaluate factors contributing to graft and patient survival after ELGI. From chart review we identified 64 of 917 OLT adult patients (median age 54.2 years; 68.8% males) transplanted between 11/2003 and 02/2012, who presented ELGI after OLT. Donor and recipient factors were analyzed and correlated with the outcome by univariable and multivariable methods. Multivariable cox proportional hazards showed that recipient's BMI (P = 0.01), model for end stage liver disease (MELD) score before OLT (P = 0.02) and laboratory MELD score 24 h after OLT (P = 0.01) were independently associated with patient survival. 30-days and 12-months survival in patients with a postoperative laboratory MELD higher than 31 was 21.4%, while patients with a postoperative laboratory MELD lower than 31 displayed 30-days and 12-months survival rates of 80% and 71.8%, respectively (P < 0.001). Retransplantation in the setting of ELGI after OLT should be based on all available data. Utilization of the postoperative labMELD enables the transplant physician within 24 h after transplantation to identify necessity of retransplantation objectively.

PD-L1 expression associates with favorable survival of patients with cancer of unknown primary (CUP) not treated with checkpoint inhibitors.

PURPOSE: Cancer of unknown primary (CUP) is a heterogeneous entity with limited overall survival (OS) in most patients. Prognostic biomarkers are needed, particularly for treatment stratification. We investigated the impact of programmed death-ligand 1 (PD-L1) expression as prognostic marker in immunotherapy-naïve CUP patients. METHODS: Clinical data from patients with confirmed CUP diagnosis according to ESMO guidelines, treated at the West German Cancer Center, Essen from 2015 to 2021, were analyzed. Patients treated with checkpoint inhibitors were excluded. PD-L1 expression was assessed in tumor tissues following established guidelines. RESULTS: Of a cohort of 132 patients, 62 patients, including 30 patients with prognostically unfavorable CUP, met inclusion criteria and were evaluable for PD-L1 expression. Comparing PD-L1 Tumor Proportional Score (TPS) and Combined Positive Score (CPS) revealed almost complete concordance (96.2 %). Patients with PD-L1-positive CUP (TPS ≥1 %; n = 36; 58 %) had superior overall survival (median not reached) as compared to patients with PD-L1-negative CUP (median 14 months, 95 %CI 10.0-18.0; HR 0.3, p < 0.001). The benefit of PD-L1 positivity (n = 12; 40 %) was maintained in the unfavorable CUP subgroup (median 20 months, 95 %CI 3.0-37.0 versus 10 months, 95 %CI 3.1-16.9; HR 0.4, p = 0.032). In PD-L1-positive CUP there was a positive correlation between the level of PD-L1 expression and survival (TPS ≥50 %: median survival not reached, HR 0.1; TPS 1 to 49 %: OS: 77 months, HR 0.4). CONCLUSION: PD-L1 expression associates with favorable survival in checkpoint inhibitor-naïve CUP patients. This implies a role of cancer immunity in CUP biology and may nominate PD-L1 for patient stratification in further studies and clinical care.

Risk Factor Analysis for Developing Major Complications Following Esophageal Surgery-A Two-Center Study.

BACKGROUND: Esophagectomy carries a high risk of morbidity and mortality compared to other major surgeries. With the aim of creating an easy-to-use clinical preoperative risk assessment tool and to validate previously described risk factors for major complications following surgery, esophagectomies at two tertiary medical centers were analyzed. METHODS: A total of 450 patients who underwent esophagectomy for esophageal carcinoma at the University Medical Centre, Hamburg, or at the Medical Center University Duisburg-Essen, Germany (January 2008 to January 2020) were retrospectively analyzed. Epidemiological and perioperative data were analyzed to identify the risk factors that impact major complication rates. The primary endpoint of this study was to determine the incidence of major complications. RESULTS: The mean age of the patients was 63 years with a bimodal distribution. There was a male predominance across the cohort (81% vs. 19%, respectively). Alcohol abuse (p = 0.0341), chronic obstructive pulmonary disease (p = 0.0264), and cardiac comorbidity (p = 0.0367) were associated with a significantly higher risk of major complications in the multivariate analysis. Neoadjuvant chemotherapy significantly reduced the risk of major postoperative complications (p < 0.0001). CONCLUSIONS: Various patient-related risk factors increased the rate of major complications following esophagectomy. Patient-tailored prehabilitation programs before esophagectomy that focus on minimizing these risk factors may lead to better surgical outcomes and should be analyzed in further studies.

AI-based digital histopathology for perihilar cholangiocarcinoma: A step, not a jump.

Introduction: Perihilar cholangiocarcinoma (PHCC) is a rare malignancy with limited survival prediction accuracy. Artificial intelligence (AI) and digital pathology advancements have shown promise in predicting outcomes in cancer. We aimed to improve prognosis prediction for PHCC by combining AI-based histopathological slide analysis with clinical factors. Methods: We retrospectively analyzed 317 surgically treated PHCC patients (January 2009-December 2018) at the University Hospital of Essen. Clinical data, surgical details, pathology, and outcomes were collected. Convolutional neural networks (CNN) analyzed whole-slide images. Survival models incorporated clinical and histological features. Results: Among 142 eligible patients, independent survival predictors were tumor grade (G), tumor size (T), and intraoperative transfusion requirement. The CNN-based model combining clinical and histopathological features demonstrates proof of concept in prognosis prediction, limited by histopathological complexity and feature extraction challenges. However, the CNN-based model generated heatmaps assisting pathologists in identifying areas of interest. Conclusion: AI-based digital pathology showed potential in PHCC prognosis prediction, though refinement is necessary for clinical relevance. Future research should focus on enhancing AI models and exploring novel approaches to improve PHCC patient prognosis prediction.

KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape.

PURPOSE: Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary KIT mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL). However, clinical benefit in fourth line remains limited and the molecular mechanisms of ripretinib resistance are largely unknown. PATIENTS AND METHODS: Progressing lesions of 25 patients with GISTs refractory to ripretinib were sequenced for KIT resistance mutations. Resistant genotypes were validated and characterized using novel cell line models and in silico modeling. RESULTS: GISTs progressing on ripretinib were enriched for secondary mutations in the ATP-binding pocket (AP), which frequently occur in cis with preexisting AL mutations, resulting in highly resistant AP/AL genotypes. AP/AL mutations were rarely observed in a cohort of progressing GIST samples from the preripretinib era but represented 50% of secondary KIT mutations in patients with tumors resistant to ripretinib. In GIST cell lines harboring secondary KIT AL mutations, the sole genomic escape mechanisms during ripretinib drug selection were AP/AL mutations. Ripretinib and sunitinib synergize against mixed clones with secondary AP or AL mutants but do not suppress clones with AP/AL genotypes. CONCLUSION: Our findings underscore that KIT remains the central oncogenic driver even in late lines of GIST therapy. KIT-inhibitor combinations may suppress resistance because of secondary KIT mutations. However, the emergence of KIT AP/AL mutations after ripretinib treatment calls for new strategies in the development of next-generation KIT inhibitors.

Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors (GIST): the EORTC STBSG experience.

BACKGROUND: Preoperative imatinib therapy of locally advanced GIST may facilitate resection and decrease morbidity of the procedure. METHODS: We have pooled databases from 10 EORTC STBSG sarcoma centers and analyzed disease-free survival (DFS) and disease-specific survival (DSS) in 161 patients with locally advanced, nonmetastatic GISTs who received neoadjuvant imatinib. OS was calculated from start of imatinib therapy for locally advanced disease until death or last follow-up (FU) after resection of the GIST. DFS was calculated from date of resection to date of disease recurrence or last FU. Median FU time was 46 months. RESULTS: The primary tumor was located in the stomach (55%), followed by rectum (20%), duodenum (10%), ileum/jejunum/other (11%), and esophagus (3%). The tumor resection after preoperative imatinib (median time on therapy, 40 weeks) was R0 in 83%. Only two patients have demonstrated disease progression during neoadjuvant therapy. Five-year DSS/DFS rates were 95/65%, respectively, median OS was 104 months, and median DFS was not reached. There were 56% of patients who continued imatinib after resection. Thirty-seven GIST recurrences were diagnosed (only 5 local relapses). The most common mutations affected exon 11 KIT (65%). Poorer DFS was related to primary tumor location in small bowel and lack of postoperative therapy with imatinib. CONCLUSIONS: Our analysis comprising the largest group of GIST patients treated with neoadjuvant imatinib in routine practice indicates excellent long-term results of combined therapy in locally advanced GISTs.

Lipid peroxidation products in machine perfusion of older donor kidneys.

BACKGROUND: Owing to the shortage of donors, organs with an increased risk potential such as grafts recovered from expanded criteria donors are increasingly being used in transplants. Machine perfusion (MP) technology offers the possibility of determining the biomarkers in the perfusion solution so that conclusions might be drawn regarding the effectiveness of organ preservation and organ viability. METHODS: All kidneys from the MP arm of our multicenter, randomized, controlled trial of MP whose donors were aged 55 years or older were included in the present study. The biomarkers, total glutathione-S-transferase (GST), α-GST, and π-GST and markers for lipid peroxidation and cell decay were determined in the MP perfusate and correlated with the outcomes after kidney transplantation. RESULTS: A total of 111 machine perfused kidneys were included in the present study. The mean donor age was 64.1 ± 6.6 y. The average cold ischemic time was 13.8 ± 5.3 h. Total GST, α-GST, and lipid peroxidation markers were significantly elevated at the end of MP. However, according to the multivariate analysis, only the lipid peroxidation markers were independent predictors of delayed graft function after transplantation. CONCLUSIONS: Our data suggest that routine determination of lipid peroxidation markers in the perfusate of expanded criteria donor kidneys can provide the opportunity to identify the kidneys that have sustained severe oxidative damage and should be excluded from transplantation. Additional analysis of a larger cohort with more primary nonfunction cases is needed to confirm these findings.

Kidney grafts from donors ≤ 5 yr of age: single kidney transplantation for pediatric recipients or en bloc transplantation for adults?

Kidneys from donors ≤5 yr of age represent a controversial issue. The purpose of this study was to compare the transplant outcomes as single and single/en bloc grafts into pediatric and adult KT recipients, respectively. All recipients of kidneys from donors ≤5 yr old transplanted at our institution from 3/2003 to 12/2010 were evaluated, and corresponding data were analyzed. There were 11 pediatric and 14 adult recipients. Median donor age and body weight were 38 months and 14 kg, respectively. PNF, n = 2 and DGF, n = 1 were observed only among adult recipients. Five-yr graft survival was 100% for children and 86% for adults. There were no significant differences in graft and patient survival, PNF, DGF, acute rejection, or postoperative complications among children/single (n = 10), adults/en bloc (n = 10), and adults/single (n = 4) KT. Major complications were documented in six adult recipients and one pediatric recipient after en bloc KT. Pediatric recipients showed significantly higher GFR during the first post-transplant year. Kidneys from donors ≤5 yr of age have at least as good outcomes as when transplanted as single allografts into children. Although the study-volume is small, it seems that children benefit from a pediatric-oriented allocation policy.