Results of the prospective multicenter SoLKiD cohort study indicate bio-psycho-social outcome risks to kidney donors 12 months after donation.

The outcome after living kidney donation was assumed to be comparable to that of the general population. However, recent register studies reveal negative changes in kidney function, quality of life and fatigue. Avoiding methodological issues of previous studies, the Safety of the Living Kidney Donor (SoLKiD) cohort study analyzed the outcome of donors in a multicenter and interdisciplinary fashion. Donor data were collected pre-donation and two-, six- and 12-months post-donation in 20 German transplantation centers. Primary parameters were kidney function, quality of life, and fatigue. Secondary endpoints were blood pressure, hemoglobin, hemoglobin A1c, body mass index, depression and somatization. Parameters were analyzed with non-parametric statistical tests and a mixed model regression for changes in time, their clinical relevance and interaction encompassing 336 donors with mean age of 52 years. Most of the physical secondary parameters, depression, and quality of life showed little or no changes and regained their pre-donation level. Kidney function decreased significantly with a 37% loss of glomerular filtration rate and an increase of donors with chronic kidney disease stage 3 from 1.5% pre-donation to about 50%. Donors consistently showed increased fatigue and somatization. Mental fatigue increased from 10.6% to 28.1%. The main influencing factors for decreased kidney function and increased fatigue were their respective pre-donation levels, and donor age for kidney function and subject stress level in fatigue. Thus, our study showed that a significant number of donors developed clinically relevant changes in physical and mental health and emphasizes the urgent need to inform potential donors about these risks.

High microsatellite instability (MSI-H) is associated with distinct clinical and molecular characteristics and an improved survival in early Colon cancer (CC); real world data from the AIO molecular registry Colopredict Plus.

Colorectal cancer is one of the leading malignancies and still accounts for almost 25 000 deaths in Germany each year. Although there is accumulating data on the molecular basis, treatment and clinical outcome of patients within clinical trials evidence from the real-world setting is mostly lacking. We started the molecular registry trial Colopredict Plus in 2013 to collect clinical and molecular data from a real-world cohort of patients with early colon cancer stage II and III in 70 German colon cancer centers focusing on the prognostic impact of high microsatellite instability. In this interim report, we characterize a clinical cohort of 2615 patients, of whom 1787 tissue probes were analyzed. Microsatellite status was assessed using immunhistochemistry and fragment length analysis, with a concordance of 91.4 %. These established histopathological methods are sensitive and cost-effective. The median age was 72 years, significantly higher compared to clinical trial populations, with a median Charlson Comorbidity Index of 3. The stage-dependent incidence of microsatellite instability was 23.7 % and was associated with female gender, BRAF-mutation, UICC stage II and localization in the right colon. Survival calculated in disease free, relapse free and overall survival significantly differed between MSI-H and MSS, in favor of MSI-H patients. Multivariate age-adjusted analyses of relapse-free survival, disease-free survival, and overall survival highlighted microsatellite instability as a robust and positive prognostic marker for early colon cancer independent of age.

Investigation of the physical and psychosocial outcomes after living kidney donation - a multicenter cohort study (SoLKiD - Safety of Living Kidney Donors).

BACKGROUND: Over the last years, living kidney donation (LKD) has been established for patients with endstage renal failure as an alternative to post mortem donation, which is limited by organ scarcity and long lasting waiting periods. From an ethical perspective, the increase in LKD requires that donors' physical, psychological, and social harm has to be minimized as much as possible and the risk should not exceed the generally expected consequences of nephrectomy. Despite of numerous, mainly retrospective studies about the postoperative outcome of LKD over the last years from different countries, it becomes apparent that there is a lack of comprehensive prospective multicenter research in this field worldwide. Therefore, the main aim of the study is to examine the physical and psychosocial outcome of living kidney donors in a prospective design before and after transplantation in an interdisciplinary approach (surgery, nephrology, psychosocial medicine). METHODS/DESIGN: The goal of the study is to investigate such aspects as the impact of gender- and age-specific factors on LKD outcome, donor outcome in correlation to the health status of the recipient, the medical and psychosocial risk of a healthy subject undergoing the LKD procedure. The study is carried out as a nationwide multicenter study. All adult living kidney donors with sufficient knowledge in the German, Russian, or Turkish language, informed consent, and place of residence in Germany are included. In a naturalistic design (cohort study), clinical data and self-report measures (questionnaires) of 320 donors are collected before and 8 weeks, 6 and 12 months after donation. Primary outcome parameters are the kidney function (estimated GFR) and the quality of life (SF-36) of the donor. Secondary outcome parameters are data about physical (e.g., wound healing, blood pressure) and psychosocial (fatigue, depression, anxiety, somatization) outcome after donation. DISCUSSION: Previous studies on the postoperative outcome of living kidney donors have methodological limitations and/or were carried out in countries with different healthcare systems, e.g. United States, Norway, Canada, United Kingdom. Thus, results cannot be generalized and are not particularly applicable to the risks of mainly caucasian living kidney donors in the German healthcare system. The study design overcomes these disadvantages in that it provides a prospective multicenter design. TRIAL REGISTRATION: German Clinical Trials Register DRKS00006552 (22 September 2014).

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.

Successful management of passenger lymphocyte syndrome in an ABO-compatible, nonidentical isolated bowel transplant: a case report and review of the literature.

BACKGROUND: Passenger lymphocyte syndrome (PLS), a subtype of graft-versus-host disease, is a rare disorder encountered mainly in ABO-mismatched hematopoietic stem cell transplantation and infrequently in all types of ABO-mismatched solid organ transplantation. We here report the fifth case of PLS in small bowel transplantation (SBTx) and the first one describing the successful management of PLS in a cadaveric, isolated SBTx. CASE REPORT: A 60-year-old Caucasian female with blood group A D+ suffering from short bowel syndrome received a small bowel transplant from a 32-year-old Caucasian female with blood group O D+ (HLA mismatch 2/6). After onset of massive hemolysis on Postoperative Day 9 the positive direct and indirect antiglobulin tests showing antibodies against A1 and A2 red blood cells (RBCs) led to the diagnosis of PLS. This complication was successfully treated by transfusion of blood group O RBC transfusions, increased immunosuppression, and plasmapheresis. CONCLUSION: In the event of severe hemolysis and anemia after ABO-mismatched SBTx, PLS should be considered. In our case successful treatment consisted of transfusion of donor-specific RBCs, increased immunosuppression, and plasmapheresis.

Early conversion from cyclosporine to everolimus following living-donor kidney transplantation: outcomes at 5 years posttransplant in the randomized ZEUS trial.

AIMS: To assess 5-year efficacy, renal, and safety outcomes following early conversion from cyclosporine to everolimus vs. a standard cyclosporine-based regimen in living-donor kidney transplant (LDKT) recipients. MATERIALS AND METHODS: The ZEUS study was a randomized, open-label, 1-year, multicenter study in which 300 de novo kidney transplant recipients continued to receive cyclosporine or converted to everolimus at 4.5 months post-transplant, with annual follow-up visits to 5 years post-transplant. RESULTS: Of the 80 LDKT patients who were randomized, 75 completed the 1-year core study and 60 attended the 5-year follow-up visit. At year 5, 15/31 (48.4%) everolimus patients and 20/29 (69.0%) cyclosporine patients remained on the study drug. Mean adjusted estimated glomerular filtration rate (GFR) at year 5 in LDKT recipients was 67.2 vs. 60.8 mL/min/1.73m2 for everolimus vs. cyclosporine (mean difference 6.4 mL/min/1.73m2; p = 0.031). For patients who remained on study drug, the mean difference was 13.2 mL/min/1.73m2 (p = 0.003), but no significant difference was seen in patients who switched from study drug (mean -2.6 mL/min/1.73m2, p = 0.701). Patient and graft survival rates were similar with everolimus and cyclosporine. Biopsy-proven acute rejection occurred in 22.0% vs. 7.5% of LDKT patients randomized to everolimus vs. cyclosporine (p = 0.116). Only 1 LDKT patient discontinued everolimus due to adverse events during years 1 - 5. CONCLUSIONS: Early initiation of everolimus with calcineurin-inhibitor (CNI) withdrawal after LDKT improved graft function to 5 years post-transplant compared to standard CNI-based therapy. The renal benefit was concentrated in patients who remained on everolimus. An increase in mild acute rejection was not associated with long-term graft loss.

Procalcitonin--a Marker for Anastomotic Insufficiency after Pancreatoduodenectomy?

BACKGROUND: Anastomotic insufficiency after pancreatoduodenectomy (PD) represents a major complication in pancreatic surgery. Early detection and treatment of pancreatic fistulas (PF) are essential for the outcome of affected patients. Procalcitonin (PCT) is a biochemical marker which allows detection of bacterial infections. The aim of this study was to evaluate if PCT is suitable for early detection of PF after PD. METHODS: In this prospective study patients undergoing PD from 08/2010 to 09/2012 were included into three groups: (1) patients without complications (n = 19), (2) patients with postoperative infections (n = 14) and (3) PF (n = 7). Using a defined study protocol, clinical (e.g., vital signs, drain fluid, etc.) and laboratory parameters (full blood count, inflammatory markers) were assessed daily for the first ten postoperative days. RESULTS: 76 patients were assessed. 40 (52.6%) patients underwent PD and were included. CRP and PCT demonstrated an initial peak at the 1st to 3rd postoperative day with subsequent normalization. Patients with postoperative infections and PF showed a significant increase of PCT and CRP (p < 0.05) compared to patients without complications. Leucocyte counts demonstrated a variance in all three groups and clinical use for detection of complications was not evident. CONCLUSIONS: Patients with a postoperative complication revealed significantly increased levels of PCT and CRP without the expected normalization. PCT and/or CRP did not enable a distinction between patients with PF or postoperative infections. Thus, PCT does not seem to be suitable for detecting PF after PD and its use in the postoperative course after PD cannot be recommended.

Impact of human albumin infusion on organ function in orthotopic liver transplantation--a retrospective matched-pair analysis.

BACKGROUND: The purpose of this study was to retrospectively analyze the impact of human albumin (HA) substitution on organ function in patients undergoing orthotopic liver transplantation (OLT). METHODS: We retrospectively analyzed chart data of 15 hypoalbuminemic patients who received continuous infusion of HA (100 g/d) for seven d following OLT and matched them with 15 control patients for severity scores at admission. Primary endpoint was a difference in mean "sequential organ failure assessment" (SOFA) score during 14 d following OLT. Secondary endpoints included SOFA subscores, length of intensive care unit (ICU) stay, ICU mortality, one-yr mortality, fluid balance, colloid osmotic pressure (COP), serum albumin, and total protein concentrations. RESULTS: Substitution of HA was associated with a lower mean SOFA score as compared to control (11.0 ± 3.6 vs. 13.4 ± 3.7; p < 0.001). Patients treated with HA also exhibited lower cardiovascular SOFA subscore and higher COP, serum albumin, and total protein concentrations. There were no significant differences in fluid balance, length of ICU stay, ICU mortality, or one-yr mortality. CONCLUSIONS: The present data suggest that continuous infusion of HA may preserve cumulative organ function (as measured by SOFA score) with emphasis on cardiovascular function in patients following OLT.

The microRNA-200 family--a potential diagnostic marker in hepatocellular carcinoma?

BACKGROUND: Hepatocellular carcinoma (HCC) represents the main cause of death among patients with cirrhotic liver disease, but little is known about mechanisms of cirrhosis associated carcinogenesis. We investigated the diagnostic impact of microRNA-200 (miR-200) family members as important epigenetic regulators of epithelial-mesenchymal transition (EMT) to differentiate between patients with HCC and liver cirrhosis. METHODS: Expression of the miR-200 family was investigated by qRT-PCR in specimens of HCC patients with and without cirrhosis. Benign specimens with and without cirrhosis served as controls. Expression of the EMT markers ZEB-1, E-cadherin and vimentin was examined using immunohistochemistry. RESULTS: MiR-200a and miR-200b were significantly downregulated in HCC (miR-200a: -40.1% (P = 0.0002); miR-200b: -52.3% (P = 0.0002)), and in HCC cirrhotic tissue (miR-200a: -40.2% (P = 0.004); miR-200b: -51.1% (P = 0.007)) compared to liver cirrhosis. Spearman's Rho analysis revealed a significant negative correlation of miR-200a and miR-200b to the expression of the mesenchymal markers Vimentin (P < 0.007) and ZEB-1 (P < 0.0005) and a significant positive correlation to the epithelial marker E-cadherin (P < 0.0002). CONCLUSIONS: MiR-200 family members and their targets are significantly deregulated in HCC and liver cirrhosis. The miR-200 family is able to distinguish between cirrhotic and HCC tissue and could serve as an early marker for cirrhosis-associated HCC.

Efficacy and safety of conversion from cyclosporine to everolimus in living-donor kidney transplant recipients: an analysis from the ZEUS study.

Conversion of living-donor kidney transplant patients from calcineurin inhibitor therapy to an mTOR inhibitor is poorly documented. In the prospective, multicentre ZEUS study, 300 kidney transplant recipients without prior rejection (Banff grade >1) and serum creatinine ≤265 µmol/l were randomized to continue cyclosporine or convert to everolimus at 4.5 months post-transplant. In a post hoc analysis of 80 living-donor recipients, adjusted estimated GFR (Nankivell) at month 12 (the primary endpoint) was 74.3 (95% CI [70.7, 77.9]) ml/min/1.73 m(2) with everolimus versus 63.8 (95% CI [60.0, 67.7]) ml/min/1.73 m(2) ) with cyclosporine, a difference of 10.5 ml/min/1.73 m(2) in favour of everolimus (P < 0.001). From randomization to month 12, adjusted estimated GFR increased by a mean of 9.8 (95% CI [6.2, 13.4]) ml/min/1.73 m(2) with everolimus versus -0.7 (95% CI [-4.6, 3.1]) ml/min/1.73 m(2) ) (P < 0.001) with cyclosporine. There were six biopsy-proven acute rejection episodes in everolimus-treated patients (five Banff grade I) and one episode in cyclosporine-treated patients (Banff grade 1). Overall safety profile was similar between groups. Discontinuation due to adverse events occurred in three everolimus patients (7.1%) and five cyclosporine patients (13.2%) between randomization and month 12. Initiation of everolimus with early elimination of calcineurin therapy is associated with a significant renal benefit at 12 months post-transplant that is observed in both living and deceased-donor recipients. (clinicaltrials.gov NCT00154310).

Aorto-hepatic bypass in liver transplantation in the MELD-era: outcomes after supraceliac and infrarenal bypasses.

PURPOSE: Poor arterial inflow during orthotopic liver transplantation (OLT) may necessitate arterial revascularisation using aorto-hepatic bypasses with supraceliac (SC) or infrarenal (IR) allografts. This study compared both techniques focusing on the patients' preoperative conditions, postoperative graft/organ function, complications and survival. METHODS: Fifteen out of 114 OLT patients underwent revascularisation (7 IR/8 SC) between 2005 and 2008 and were included in the study. The patients' records were reviewed retrospectively. RESULTS: IR patients presented with a higher BMI, received more male donor organs and their reperfusion sequence was predominately portal venous (SC: primary arterial). SC patients presented a significantly worse preoperative creatinine clearance and a trend towards a higher MELD score. The postoperative graft/organ function, morbidity and mortality did not differ between the groups despite a trend towards a worse survival in the SC group. A deteriorated preoperative creatinine clearance and higher MELD score negatively impacted the survival. Postoperative bleeding episodes and major re-interventions also affected the outcome. CONCLUSIONS: We found no evidence for superiority of either bypass technique in our OLT patients. The trend toward a worse survival in SC patients was most likely caused by the worse preoperative conditions of these patients and highlights the importance of the impact of the MELD score on the outcome after OLT.

Heartburn relief with bicarbonate-rich mineral water: results of the randomised, placebo-controlled phase-III trial STOMACH STILL.

OBJECTIVE: We assessed whether the bicarbonate-rich mineral water Staatl. Fachingen STILL is superior over conventional mineral water in relieving heartburn. DESIGN: Multicentre, double-blind, randomised, placebo-controlled trial STOMACH STILL in adult patients with frequent heartburn episodes since ≥6 months and without moderate/severe reflux oesophagitis. Patients drank 1.5 L/day verum or placebo over the course of the day for 6 weeks. Primary endpoint was the percentage of patients with reduction of ≥5 points in the Reflux Disease Questionnaire (RDQ) score for 'heartburn'. Secondary endpoints included symptom reduction (RDQ), health-related quality of life (HRQOL, Quality of Life in Reflux and Dyspepsia (QOLRAD)), intake of rescue medication and safety/tolerability. RESULTS: Of 148 randomised patients (verum: n=73, placebo: n=75), 143 completed the trial. Responder rates were 84.72% in the verum and 63.51% in the placebo group (p=0.0035, number needed to treat=5). Symptoms improved under verum compared with placebo for the dimension 'heartburn' (p=0.0003) and the RDQ total score (p=0.0050). HRQOL improvements under verum compared with placebo were reported for 3 of 5 QOLRAD domains, that is, 'food/drink problems' (p=0.0125), 'emotional distress' (p=0.0147) and 'vitality' (p=0.0393). Mean intake of rescue medication decreased from 0.73 tablets/day at baseline to 0.47 tablets/day in week 6 in the verum group, whereas in the placebo group it remained constant during the trial. Only three patients had treatment-related adverse events (verum: n=1, placebo: n=2). CONCLUSION: STOMACH STILL is the first controlled clinical trial demonstrating superiority of a mineral water over placebo in relieving heartburn, accompanied by an improved HRQOL. TRIAL REGISTRATION NUMBER: EudraCT 2017-001100-30.

Lasting response by vertical inhibition with cetuximab and trametinib in KRAS-mutated colorectal cancer patient-derived xenografts.

Although approximately half of all metastatic colorectal cancers (mCRCs) harbour mutations in KRAS or NRAS, hardly any progress has been made regarding targeted treatment for this group over the last few years. Here, we investigated the efficacy of vertical inhibition of the RAS-pathway by targeting epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase kinase (MEK) in patient-derived xenograft (PDX) tumours with primary KRAS mutation. In total, 19 different PDX models comprising 127 tumours were tested. Responses were evaluated according to baseline tumour volume changes and graded as partial response (PR; ≤ - 30%), stable disease (SD; between -30% and +20%) or progressive disease (PD; ≥ + 20%). Vertical inhibition with trametinib and cetuximab induced SD or PR in 74% of analysed models, compared to 24% by monotherapy with trametinib. In cases of PR by vertical inhibition (47%), responses were lasting (as long as day 137), with a low incidence of secondary resistance (SR). Molecular analyses revealed that primary and SR was driven by transcriptional reprogramming activating the RAS pathway in a substantial fraction of tumours. Together, these preclinical data strongly support the translation of this combination therapy into clinical trials for CRC patients.

Impact of adjuvant therapy in patients with invasive intraductal papillary mucinous neoplasms of the pancreas: an international multicenter cohort study.

BACKGROUND: Adjuvant therapy prolongs survival in patients with pancreatic ductal adenocarcinoma. However, no clear guidelines are available regarding the oncologic effects of adjuvant therapy (AT) in resected invasive intraductal papillary mucinous neoplasms (IPMN). The aim was to investigate the potential role of AT in patients with resected invasive IPMN. MATERIALS AND METHODS: From 2001 to 2020, 332 patients with invasive pancreatic IPMN were retrospectively reviewed in 15 centres in eight countries. Propensity score-matched and stage-matched survival analyses were conducted. RESULTS: A total of 289 patients were enroled in the study after exclusion (neoadjuvant therapy, unresectable disease, uncertain AT status, and stage IV). A total of 170 patients were enroled in a 1:1 propensity score-matched analysis according to the covariates. In the overall cohort, disease-free survival was significantly better in the surgery alone group than in the AT group ( P =0.003), but overall survival (OS) was not ( P =0.579). There were no significant differences in OS in the stage-matched analysis between the surgery alone and AT groups (stage I, P =0.402; stage II, P =0.179). AT did not show a survival benefit in the subgroup analysis according to nodal metastasis (N0, P =0.481; N+, P =0.705). In multivariate analysis, node metastasis (hazard ratio, 4.083; 95% CI, 2.408-6.772, P <0.001), and cancer antigen 19-9 greater than or equal to 100 (hazard ratio, 2.058; 95% CI, 1.247-3.395, P =0.005) were identified as adverse prognostic factors in resected invasive IPMN. CONCLUSION: The current AT strategy may not be recommended to be performed with resected invasive IPMN in stage I and II groups, unlike pancreatic ductal adenocarcinoma. Further investigations of the potential role of AT in invasive IPMN are recommended.

Coinhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills pancreatic cancer via readthrough transcription.

Pancreatic carcinoma lacks effective therapeutic strategies resulting in poor prognosis. Transcriptional dysregulation due to alterations in KRAS and MYC affects initiation, development, and survival of this tumor type. Using patient-derived xenografts of KRAS- and MYC-driven pancreatic carcinoma, we show that coinhibition of topoisomerase 1 (TOP1) and bromodomain-containing protein 4 (BRD4) synergistically induces tumor regression by targeting promoter pause release. Comparing the nascent transcriptome with the recruitment of elongation and termination factors, we found that coinhibition of TOP1 and BRD4 disrupts recruitment of transcription termination factors. Thus, RNA polymerases transcribe downstream of genes for hundreds of kilobases leading to readthrough transcription. This occurs during replication, perturbing replisome progression and inducing DNA damage. The synergistic effect of TOP1 + BRD4 inhibition is specific to cancer cells leaving normal cells unaffected, highlighting the tumor's vulnerability to transcriptional defects. This preclinical study provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors to treat pancreatic carcinomas addicted to oncogenic drivers of transcription and replication.

Functional noninvasive detection of glycolytic pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) lacks effective treatment options beyond chemotherapy. Although molecular subtypes such as classical and QM (quasi-mesenchymal)/basal-like with transcriptome-based distinct signatures have been identified, deduced therapeutic strategies and targets remain elusive. Gene expression data show enrichment of glycolytic genes in the more aggressive and therapy-resistant QM subtype. However, whether the glycolytic transcripts are translated into functional glycolysis that could further be explored for metabolic targeting in QM subtype is still not known. METHODS: We used different patient-derived PDAC model systems (conventional and primary patient-derived cells, patient-derived xenografts (PDX), and patient samples) and performed transcriptional and functional metabolic analysis. These included RNAseq and Illumina HT12 bead array, in vitro Seahorse metabolic flux assays and metabolic drug targeting, and in vivo hyperpolarized [1-13C]pyruvate and [1-13C]lactate magnetic resonance spectroscopy (HP-MRS) in PDAC xenografts. RESULTS: We found that glycolytic metabolic dependencies are not unambiguously functionally exposed in all QM PDACs. Metabolic analysis demonstrated functional metabolic heterogeneity in patient-derived primary cells and less so in conventional cell lines independent of molecular subtype. Importantly, we observed that the glycolytic product lactate is actively imported into the PDAC cells and used in mitochondrial oxidation in both classical and QM PDAC cells, although more actively in the QM cell lines. By using HP-MRS, we were able to noninvasively identify highly glycolytic PDAC xenografts by detecting the last glycolytic enzymatic step and prominent intra-tumoral [1-13C]pyruvate and [1-13C]lactate interconversion in vivo. CONCLUSION: Our study adds functional metabolic phenotyping to transcriptome-based analysis and proposes a functional approach to identify highly glycolytic PDACs as candidates for antimetabolic therapeutic avenues.

Outcome of supraselective transarterial chemoembolization in patients with hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is the most common tumor in cirrhotic patients with a median survival of only 8-10 months if untreated. Supraselective transarterial chemoembolization (STACE) is supposed to be a well-established method for treating HCC patients. In the present study, we evaluated the effect of STACE on post-transplant survival in patients with HCC. MATERIAL AND METHODS: The charts of 53 HCC patients were retrospectively analyzed. Twenty-seven patients had STACE as a bridging therapy while 26 patients were scheduled for liver transplantation (LTX) without prior STACE therapy. A total of 53% of the patients who underwent LTX preoperatively fulfilled the Milan criteria, while 70.6% fulfilled the expanded University of California, San Francisco (UCSF) transplant criteria. Primary endpoint was the post-transplant survival. Statistical analysis included Kaplan-Meier-method, log rank, and chi square tests. RESULTS: Between the LTX groups (STACE vs. non-STACE), there was no significant difference in terms of age, Child classification, Okuda stage, co-morbidities, underlying disease, and post-transplant survival (p > 0.05). Independent of prior STACE, however, disease-free survival after LTX was highly significantly prolonged if LTX was performed within 3 months after initial diagnosis of HCC (p < 0.01) or if patients met the expanded transplant UCSF criteria (p = 0.02). Post-transplant survival did not depend on tumor size. CONCLUSIONS: We conclude that STACE performed prior to LTX does not secure any post-transplant survival benefit, while early LTX, i.e. within 3 months after HCC diagnosis, does improve survival regardless of whether STACE was performed or not. Additionally, fulfillment of the expanded transplant UCSF criteria leads to a prolonged post-transplant survival.

Impact of failed allograft nephrectomy on initial function and graft survival after kidney retransplantation.

The management of an asymptomatic failed renal graft remains controversial. The aim of our study was to explore the effect of failed allograft nephrectomy on kidney retransplantation by comparing the outcome of recipients who underwent graft nephrectomy prior to retransplantation with those who did not. Retrospective comparison of patients undergoing kidney retransplantation with (group A, n = 121) and without (group B, n = 45) preliminary nephrectomy was performed, including subgroup analysis with reference to patients with multiple (≥2) retransplantations and patients of the European Senior Program (ESP). Nephrectomy leads to increased panel reactive antibody (PRA) levels prior to retransplantation and is associated with significantly increased rates of primary nonfunction (PNF; P = 0.05) and acute rejection (P = 0.04). Overall graft survival after retransplantation was significantly worse in group A compared with group B (P = 0.03). Among the subgroups especially ESP patients showed a shorter graft survival after previous allograft nephrectomy. On the multivariate analysis, pretransplant graft nephrectomy and PRA >70% were independent and significant risk factors associated with graft loss after kidney retransplantation. Nephrectomy of the failed allograft was not beneficial for retransplant outcome in our series. Patients with failed graft nephrectomy tended to have a higher risk of PNF and acute rejection after retransplantation. The possibility that the graft nephrectomy has a negative impact on graft function and survival after retransplantation is worth studying further.

Acute antibody-mediated rejection in paediatric renal transplant recipients.

Acute antibody-mediated rejections (aAMR) after renal transplantation are defined by rapidly deteriorating graft function, detection of donor-specific antibodies (DSA) and characteristic histological features. In adults, anti-rejection strategies comprise intravenous immunoglobulin (IVIG), steroid pulses, plasmapheresis and rituximab. Data of children with aAMR are scarce. We report four episodes of aAMR in three children (aged 10, 10 and 11 years respectively) occurring early after renal transplantation. Pre-transplant complement-dependent cytotoxicity crossmatches were negative; in the case of re-transplantation repeated antigens were excluded. Basic immunosuppression comprised cyclosporine A, MMF and steroids. All four rejection episodes were histologically proven and associated with acute renal failure. De novo DSAs were detected in two aAMRs; one patient was additionally tested positive for AT1-receptor antibodies. All aAMRs were treated with steroid pulses, tacrolimus, MMF, IVIG, plasmapheresis and one single dose of rituximab. Despite therapy one graft was lost; in the remaining three cases kidney function re-established within 1-8 weeks. At follow-up, 14, 15 and 22 months' post-rejection their GFRs were 65, 88 and 105 ml/min/1.73 m(2) respectively. A combined therapy of steroid pulses, IVIG, plasmapheresis and rituximab is potentially effective in the treatment of aAMR in children.

Course of a HBsAg positive liver transplantation in a hepatitis B and D virus coinfected recipient.

The increasing demand for transplantation has led to consideration of liver grafts from donors exposed to hepatitis B virus (HBV). Six transplantations of liver grafts from hepatitis B surface antigen (HBsAg) positive donors have been reported; two recipients suffered from HBV/HDV (hepatitis Delta virus) coinfection and were followed up for 10-12 months. Here, we report a 56 months follow-up of a HBV/HDV-coinfected recipient of a HBsAg positive liver graft. Posttransplant combination prophylaxis consisted of hepatitis immunoglobulin, lamivudine and adefovir dipivoxil. HBsAg remained positive during stable posttransplant follow-up and subclinical HDV reinfection with low replication rate was detected at 1 month. Pegylated interferon therapy was introduced after documentation of histological evidence of mild chronic hepatitis, but without virological response after 48 weeks. Finally, antiviral treatment was switched to tenofovir disoproxil fumarate. More than 50 months posttransplant the recipient revealed clinical symptoms of decompensated liver cirrhosis and has been relisted for liver transplantation. In conclusion HBsAg positive liver grafts in HBsAg positive recipients with HDV coinfection may result in virological recurrence and rapid development of liver cirrhosis.