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Introduction: Short-term fasting protects against renal ischemia reperfusion injury (IRI). mTOR signaling is downregulated and may be involved in its protective effect. Rapamycin is considered a possible mimetic as it inhibits the mTOR pathway. This study examines the effect of rapamycin on renal IRI. Material and Methods: Mice were divided into four groups: ad libitum (AL), fasted (F), AL treated with rapamycin (AL+R), and F treated with rapamycin (F+R). Rapamycin was administered intraperitoneally 24 h before bilateral renal IRI was induced. Survival was monitored for 7 days. Renal cell death, regeneration, and mTOR activity were determined 48 h after reperfusion. Oxidative stress resistance of human renal proximal tubular and human primary tubular epithelial cells after rapamycin treatment was determined. Results: All F and F+R mice survived the experiment. Although rapamycin substantially downregulated mTOR activity, survival in the AL+R group was similar to AL (10%). Renal regeneration was significantly reduced in AL+R but not in F+R. After IRI (48 h), pS6K/S6K ratio was lower in F, F+R, and AL+R groups compared to AL fed animals (p = 0.02). In vitro, rapamycin also significantly downregulated mTOR activity (p < 0.001) but did not protect against oxidative stress. Conclusion: Rapamycin pretreatment does not protect against renal IRI. Thus, protection against renal IRI by fasting is not exclusively mediated through inhibition of mTOR activity but may involve preservation of regenerative mechanisms despite mTOR downregulation. Therefore, rapamycin cannot be used as a dietary mimetic to protect against renal IRI. [ABSTRACT FROM AUTHOR]

Introduction: Aorto-iliac vascular disease (AVD) is frequently found during the workup for kidney transplantation. However, recommendations on screening and management are lacking. We aimed to assess differences in screening, management, and acceptance of these patients for transplantation by performing a survey among transplant surgeons. Second, we aimed to identify center- and surgeon-related factors associated with decline or acceptance of kidney transplant candidates with AVD. Methods: A survey was sent to transplant surgeons and urologists. The survey contained general questions (part I) and 2 patient-based cases (part II) with Trans-Atlantic Inter-Society Consensus (TASC) D and B AVD supported with videos of their CT scans. Results: One hundred ninety-one (20.3%) participants responded; 171 were currently involved in kidney transplantation: 161 (94.2%) completed part I and 145 (84.8%) part II. Screening for AVD was often (38.5%) restricted to high-risk patients. The majority of respondents (67.7%) rated "technical problems" as the most important concern in case of AVD, followed by "increased mortality risk because of cardiovascular comorbidity" (29.8%). Pretransplant vascular interventions to facilitate transplantation were infrequently performed (71.4% mentioned <10 per year). Ninety (64.3%) respondents answered that an open vascular procedure should preferably be performed prior to kidney transplantation while 42 (30.0%) respondents preferred a simultaneous open vascular procedure. The decline rate was higher in the TASC D case compared to the TASC B case (26.9% and 9.7%, respectively). Respondents from centers with expertise in pretransplant vascular interventions were more likely to accept both patients with TASC D and B for transplantation. Conclusion: There is no uniformity in the screening, management, and acceptance of patients with AVD for transplantation. If a center declines a patient with AVD because of technical concerns, the patient should be referred for a second opinion to a tertiary center with expertise in pretransplant vascular interventions. Multidisciplinary meetings including a vascular surgeon and a cardiologist could help optimize these patients for transplantation. [ABSTRACT FROM AUTHOR]

Prediction of the risk of cardiovascular events (CVE's) is important to optimize outcomes after kidney transplantation. Aortoiliac stenosis is frequently observed during pre‐transplant screening. We hypothesized that these patients are at higher risk of post‐transplant CVE's due to the joint underlying atherosclerotic disease. Therefore, we aimed to assess whether aortoiliac stenosis was associated with post‐transplant CVE's. This retrospective, single‐center cohort study included adult kidney transplant recipients, transplanted between 2000 and 2016, with contrast‐enhanced imaging available. Aortoiliac stenosis was classified according to the Trans‐Atlantic Inter‐Society Consensus (TASC) II classification and was defined as significant in case of ≥50% lumen narrowing. The primary outcome was CVE‐free survival. Eighty‐nine of 367 patients had significant aortoiliac stenosis and were found to have worse CVE‐free survival (median CVE‐free survival: stenosis 4.5 years (95% confidence interval (CI) 2.8–6.2), controls 8.9 years (95% CI 6.8–11.0); log‐rank test P <.001). TASC II C and D lesions were independent risk factors for a post‐transplant CVE with a hazard ratio of 2.15 (95% CI 1.05–4.38) and 6.56 (95% CI 2.74–15.70), respectively. Thus, kidney transplant recipients with TASC II C and D aortoiliac stenosis require extensive cardiovascular risk management pre‐, peri,‐ and post‐transplantation. [ABSTRACT FROM AUTHOR]

Preclinical data suggests that protein and calorie restriction (PCR) might improve treatment tolerability without impairing antitumor efficacy. Therefore, we have studied the influence of PCR on irinotecan pharmacokinetics and toxicity. In this crossover trial, patients with liver metastases of solid tumors were included and randomized to treatment with irinotecan preceded by 5 days of PCR (~ 30% caloric and ~ 70% protein restriction) during the first cycle and a second cycle preceded by a normal diet or vice versa. Pharmacokinetic blood sampling and biopsies of both healthy liver and liver metastases were performed. The primary end point was the relative difference in geometric means for the active metabolite SN‐38 concentration in healthy liver analyzed by a linear mixed model. No significant differences were seen in irinotecan (+ 16.8%, P = 0.22) and SN‐38 (+ 9.8%, P = 0.48) concentrations between PCR and normal diet in healthy liver, as well as in liver metastases (irinotecan: −38.8%, P = 0.05 and SN‐38: −13.8%, P = 0.50). PCR increased irinotecan plasma area under the curve from zero to 24 hours (AUC0–24h) with 7.1% (P = 0.04) compared with normal diet, whereas the SN‐38 plasma AUC0–24h increased with 50.3% (P < 0.001). Grade ≥ 3 toxicity was not increased during PCR vs. normal diet (P = 0.69). No difference was seen in neutropenia grade ≥ 3 (47% vs. 32% P = 0.38), diarrhea grade ≥ 3 (5% vs. 21% P = 0.25), and febrile neutropenia (5% vs. 16% P = 0.50) during PCR vs. normal diet. In conclusion, plasma SN‐38 exposure increased dramatically after PCR, whereas toxicity did not change. PCR did not alter the irinotecan and SN‐38 exposure in healthy liver and liver metastases. PCR might therefore potentially improve the therapeutic window in patients treated with irinotecan. [ABSTRACT FROM AUTHOR]

BACKGROUND: Quercetin is a flavonoid with reported antioxidant, anti-inflammatory and anti-aging effects, and may limit muscle wasting in cancer cachexia. OBJECTIVE: To investigate the effect of quercetin on muscle wasting in the murine C26 cancer-cachexia model and assess the feasibility of non-invasive micro-CT analysis of skeletal muscle. MATERIALS AND METHODS: Custom CRM(P) diets supplemented with 250 mg/kg quercetin (Q) were obtained. Thirty CD2F1 mice were equally randomized to non-tumor-bearing (NTB), C26 tumor-bearing (TB), TB + Q. All groups started their allocated diet and underwent hindlimb micro-CT. Bodyweight, food intake, and grip-strength were recorded periodically. After 21 days, repeat micro-CT was performed. Gastrocnemius (GCM) and tibialis anterior (TA) muscles were resected. mRNA expression of MuRF1, Atrogin-1, myogenin, and MyoD was determined. RESULTS: NTB and TB + Q gained 9.4% and 5.3% bodyweight respectively, TB lost 3.9%. Hind limb skeletal muscle volume remained stable for NTB and TB + Q, whereas TB decreased from 242.0 mm3 to 212.8 mm3. Mean GCM muscle weight was 175.2 mg (NTB), 171.3 mg (TB + Q) versus 125.5 mg (TB). A tendency towards decreased expression of atrogin-1 and MuRF1 was observed in TB + Q. CONCLUSION: Dietary quercetin supplementation limits bodyweight loss and muscle wasting in the C26-cancer-associated cachexia model. [ABSTRACT FROM AUTHOR]

Mass spectrometry‐based techniques can be applied to investigate collagen with respect to identification, quantification, supramolecular organization, and various post‐translational modifications. The continuous interest in collagen research has led to a shift from techniques to analyze the physical characteristics of collagen to methods to study collagen abundance and modifications. In this review, we illustrate the potential of mass spectrometry for in‐depth analyses of collagen. [ABSTRACT FROM AUTHOR]

No curative treatment options are available for advanced hepatocellular carcinoma (HCC). Anti‐PD1 antibody therapy can induce tumor regression in 20% of advanced HCC patients, demonstrating that co‐inhibitory immune checkpoint blockade has therapeutic potential for this type of cancer. However, whether agonistic targeting of co‐stimulatory receptors might be able to stimulate anti‐tumor immunity in HCC is as yet unknown. We investigated whether agonistic targeting of the co‐stimulatory receptor GITR could reinvigorate ex vivo functional responses of tumor‐infiltrating lymphocytes (TIL) freshly isolated from resected tumors of HCC patients. In addition, we compared GITR expression between TIL and paired samples of leukocytes isolated from blood and tumor‐free liver tissues, and studied the effects of combined GITR and PD1 targeting on ex vivo TIL responses. In all three tissue compartments, CD4+FoxP3+ regulatory T cells (Treg) showed higher GITR−expression than effector T‐cell subsets. The highest expression of GITR was found on CD4+FoxP3hiCD45RA− activated Treg in tumors. Recombinant GITR‐ligand as well as a humanized agonistic anti‐GITR antibody enhanced ex vivo proliferative responses of CD4+ and CD8+ TIL to tumor antigens presented by mRNA‐transfected autologous B‐cell blasts, and also reinforced proliferation, IFN‐γ secretion and granzyme B production in stimulations of TIL with CD3/CD28 antibodies. Combining GITR ligation with anti‐PD1 antibody nivolumab further enhanced tumor antigen‐specific responses of TIL in some, but not all, HCC patients, compared to either single treatment. In conclusion, agonistic targeting of GITR can enhance functionality of HCC TIL, and may therefore be a promising strategy for single or combinatorial immunotherapy in HCC. What's new? Therapeutic antibodies that block interaction of the T cell co‐inhibitory receptor PD1 can unleash pre‐existing anti‐cancer T cell responses in hepatocellular carcinoma (HCC). However, whether agonistic targeting of co‐stimulatory receptors could stimulate anti‐tumor immunity remains unknown. This study is the first to show that agonistic targeting of the co‐stimulatory receptor GITR can reinforce the functionality of tumor‐infiltrating T cells isolated from human tumors. Combined targeting of PD1 and GITR exerts additive stimulatory effects on ex vivo functionality of tumor‐infiltrating T cells from HCC patients. Targeting of GITR thus emerges as a promising strategy for single or combinatorial immunotherapy in HCC. [ABSTRACT FROM AUTHOR]

The controlling nutritional status (CONUT) score is associated with prognosis in gastrointestinal (GI) cancer patients, but the clinical significance of the CONUT score for postoperative short-term outcome remains controversial. The aim of this study was to investigate the impact of the CONUT score on postoperative outcomes in patients with GI and hepatopancreatobiliary (HPB) cancers. We conducted a systematic literature search of Embase, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google Scholar. Meta-analyses were performed to estimate the pooled risk ratio (RR) for postoperative complications in patients with lower -CONUT score versus higher CONUT score. Furthermore, we explored the most appropriate cutoff value of the CONUT score to predict postoperative complications. Ten retrospective studies (5,138 patients) were included in this meta-analysis. Patients with higher CONUT score had an increased risk of mortality (RR 5.38, 95% CI 2.19–13.2, p < 0.001, I2 = 0%), postoperative major complications (RR 1.56, 95% CI 1.05–2.33, p= 0.03, I2 = 79%), and overall complications (RR 1.38, 95% CI 1.16–1.63, p < 0.001, I2 = 6%). We found that the cutoff of CONUT ≤4 vs. CONUT ≥5 had the highest pooled RR compared with other cutoff values (RR 4.79, 95% CI 0.97–23.5, p= 0.05, I2 = 91%). In conclusion, the present study suggests that the preoperative CONUT score was associated with an increased risk of mortality and complications in GI and HPB surgical oncology. Patients with higher CONUT score as compared with those having a lower score had approximately a fivefold mortality risk and an increased risk up to 55% on major and overall complications after GI and HPB surgery. Our analysis indicates that the appropriate cutoff value of the CONUT score to predict postoperative major complications would be between 4 and 5. The preoperative evaluation of the CONUT score would be helpful for predicting the risk of postoperative outcomes. [ABSTRACT FROM AUTHOR]

Background: Low skeletal muscle mass is associated with increased postoperative morbidity and worse survival following resection for perihilar cholangiocarcinoma (PHC). We investigated the predictive value of skeletal muscle mass and density for overall survival (OS) of all patients with suspected PHC, regardless of treatment. Methods: Baseline characteristics and parameters regarding disease and treatment were collected from all patients with PHC from 2002 to 2014. Skeletal muscle mass and density were measured at the level of the third lumbar vertebra on CT. The association between skeletal muscle mass and density with OS was investigated using the Kaplan-Meier method and Cox survival. Results: Median OS in 233 included patients did not differ between those with and without low skeletal muscle mass (p = 0.203), whereas a significantly different median OS (months) was observed between patients with low (HR 7.0, 95% CI 4.7–9.3) and high (HR 12.1, 95% CI 8.1–16.1) skeletal muscle density (p = 0.004). Low skeletal muscle density was independently associated with decreased OS (HR 1.78, 95% CI 1.03–3.07, p = 0.040) within the first 6 months but not after 6 months (HR 0.68, 95% CI 0.44–1.07, p = 0.093), after adjusting for age, tumour size and suspected peritoneal or other distant metastases on imaging. Conclusion: A time-dependent effect of skeletal muscle density on OS was found in patients with PHC, regardless of subsequent treatment. Low skeletal muscle density may identify patients at risk for early death. [ABSTRACT FROM AUTHOR]

Background/Aims: The 5-year postoperative follow-up for patients undergoing curative treatment for colorectal cancer (CRC) is labour intensive. We assessed the added value of a dedicated nonphysician clinician (NPC) in the follow-up of patients after resection for CRC. Methods: Patients were divided into 2 groups as defined by the number of follow-up visits in the first year, including intensive (≥3×) and minimal (≤2×). Involvement of an NPC, diagnosis of disease recurrence and the course of the disease were determined. Results: Of the 681 patients, 79.9% belonged to the “intensive” and 21.1% to the “minimal” group. Involvement of an NPC resulted in a higher adherence to follow-up (84.3 vs. 73.9%, p = 0.001). Overall, patients in regular follow-up less often had multifocal recurrence (47.1 vs. 73.7%, p = 0.04), and a better survival after recurrence (SAR; hazard ratio [HR] 3.604, p < 0.001). The “intensive” group had a significantly better overall survival compared to the “minimal” group (HR 1.71, p = 0.013). Conclusion: Adherence to surveillance programs after resection for CRC is better in hospitals with a dedicated NPC. Overall, patients' adherence to follow-up resulted in less multifocal disease recurrence at the time of diagnosis as compared to patients presenting with symptoms and a better 3-year SAR. [ABSTRACT FROM AUTHOR]

Background The association between body composition (e.g. sarcopenia or visceral obesity) and treatment outcomes, such as survival, using single-slice computed tomography (CT)-based measurements has recently been studied in various patient groups. These studies have been conducted with different software programmes, each with their specific characteristics, of which the inter-observer, intra-observer, and inter-software correlation are unknown. Therefore, a comparative study was performed. Methods Fifty abdominal CT scans were randomly selected from 50 different patients and independently assessed by two observers. Cross-sectional muscle area (CSMA, i.e. rectus abdominis, oblique and transverse abdominal muscles, paraspinal muscles, and the psoas muscle), visceral adipose tissue area (VAT), and subcutaneous adipose tissue area (SAT) were segmented by using standard Hounsfield unit ranges and computed for regions of interest. The inter-software, intra-observer, and inter-observer agreement for CSMA, VAT, and SAT measurements using FatSeg, OsiriX, ImageJ, and sliceOmatic were calculated using intra-class correlation coefficients (ICCs) and Bland-Altman analyses. Cohen's κ was calculated for the agreement of sarcopenia and visceral obesity assessment. The Jaccard similarity coefficient was used to compare the similarity and diversity of measurements. Results Bland-Altman analyses and ICC indicated that the CSMA, VAT, and SAT measurements between the different software programmes were highly comparable (ICC 0.979-1.000, P < 0.001). All programmes adequately distinguished between the presence or absence of sarcopenia (κ = 0.88-0.96 for one observer and all κ = 1.00 for all comparisons of the other observer) and visceral obesity (all κ = 1.00). Furthermore, excellent intra-observer (ICC 0.999-1.000, P < 0.001) and inter-observer (ICC 0.998-0.999, P < 0.001) agreement for all software programmes were found. Accordingly, excellent Jaccard similarity coefficients were found for all comparisons (mean ≥ 0.964). Conclusions FatSeg, OsiriX, ImageJ, and sliceOmatic showed an excellent agreement for CSMA, VAT, and SAT measurements on abdominal CT scans. Furthermore, excellent inter-observer and intra-observer agreement were achieved. Therefore, results of studies using these different software programmes can reliably be compared. [ABSTRACT FROM AUTHOR]

A minority of living kidney donors (between 5-25%) have poor psychological outcomes after donation. There is mixed evidence on the influence of medical complications on these outcomes. We examined whether medical complications among donors and recipients predicted changes in donors' mental health (psychological symptoms and well-being) between predonation and 1 year postdonation. One-hundred and forty-five donors completed questionnaires on mental health predonation and 3 and 12 months postdonation. Number of recipient rehospitalizations and donor complications (none; minor; or severe) were obtained from medical records at 3 and 12 months after surgery. Multilevel regression analyses were used to examine the association between medical complications and changes in donors' mental health over time after controlling for sociodemographic characteristics. We found that donor complications ( P = 0.003) and recipient rehospitalizations ( P = 0.001) predicted an increase in donors' psychological symptoms over time. Recipient rehospitalizations also predicted a decrease in well-being ( P = 0.005) over time; however, this relationship became weaker over time. We conclude that medical complications experienced by either the donor or recipient is a risk factor for deterioration in donors' mental health after living kidney donation. Professionals should monitor donors who experience medical complications and offer additional psychological support when needed. [ABSTRACT FROM AUTHOR]

Circadian clock genes regulate 10-15% of the transcriptome, and might function as tumor suppressor genes. Relatively little is known about the circadian clock in tumors and its effect on surrounding healthy tissues. Therefore, we compared the 24-hr expression levels of key circadian clock genes in liver and kidney of healthy control mice with those of mice bearing C26 colorectal tumor metastases in the liver. Metastases were induced by injection of C26 colorectal carcinoma cells into the spleen. Subsequently, tumor, liver and kidney tissue was collected around the clock to compare circadian rhythmicity. Expression levels of five clock genes ( Rev-Erbα, Per1, Per2, Bmal1 and Cry1) and three clock-controlled genes (CCGs; Dbp, p21 and Wee1) were determined by qRT-PCR. Liver and kidney tissue of healthy control mice showed normal 24-hr oscillations of all clock genes and CCGs, consistent with normal circadian rhythmicity. In colorectal liver metastases, however, 24-hr oscillations were completely absent for all clock genes and CCGs except Cry1. Liver and kidney tissue of tumor-bearing mice showed a shift in clock periodicity relative to control mice. In the liver we observed a phase advance, whereas in the kidney the phase was delayed. These data show that hepatic metastases of C26 colon carcinoma with a disrupted circadian rhythm phase shift liver and kidney tissue clocks, which strongly suggests a systemic effect on peripheral clocks. The possibility that tumors may modify peripheral clocks to escape from ordinary circadian rhythms and in this way contribute to fatigue and sleep disorders in cancer patients is discussed. [ABSTRACT FROM AUTHOR]

Pretransplant removal of antiblood group ABO antibodies is the cornerstone of all current ABO-incompatible (ABOi) transplantation programmes. In our protocol, plasmapheresis (PP) is performed with a plasmafilter followed by immunoadsorption (IA) of anti-ABO antibodies. The bleeding complications of this technique are not known. We analysed the data of all 65 consecutive ABOi kidney transplantations between March 2006 and October 2013 and compared these with matched 130 ABO-compatible (ABOc) kidney transplantations. Cases differed from controls in the pre-operative regimen, which included IA-PP and rituximab, tacrolimus, mycophenolate mofetil, prednisone and immunoglobulines. Data on platelet count, blood loss and red blood cell (EC) transfusions during 48 h postoperatively were collected. ABOi patients received EC transfusions more frequently than controls (29% vs. 12%, P = 0.005). Intra-operative blood loss was higher (544 vs. 355 ml, P < 0.005) and they experienced more major bleeding (≥3 EC within 24 h, 15% vs. 2%, P < 0.0005). Platelet count decreased by 28% after the pre-operative IA. In a multivariate model, only the number of pre-operative IAs was associated with the number of ECs given (OR per IA 1.9, P < 0.05). ABOi kidney transplant recipients have a high postoperative bleeding risk, correlating with the number of pre-operative IA sessions performed. [ABSTRACT FROM AUTHOR]

Although the infiltration of mesenchymal stem (stromal) cells (MSCs) into different tumors is widely recognized in animal models, the question whether these MSCs have a positive or negative effect on disease progression remains unanswered. The aim of this study is to investigate whether human hepatocellular carcinoma (HCC) harbors MSCs and whether these MSCs affect tumor growth. We observed that cells capable of differentiation into both adipocyte and osteocyte lineages and expressing MSC markers can be cultured from surgically resected HCC tissues. In situ staining of human HCC tissues with a STRO-1 antibody showed that the tumor and tumor-stromal region are significantly enriched with candidate MSCs compared with adjacent tissue (n = 12, P < 0.01). In mice, coengraftment of a human HCC cell line (Huh7) with MSCs resulted in substantially larger tumors compared with paired engraftment of Huh7 alone (n = 8, P < 0.01). Consistently, coculturing Huh7 with irradiated MSCs significantly increased the number and the size of colonies formed. This enhancement of Huh7 colony formation was also observed by treatment of MSC-conditioned medium (MSC-CM), suggesting that secreted trophic factors contribute to the growth-promoting effects. Genome-wide gene expression array and pathway analysis confirmed the upregulation of cell growth and proliferation-related processes and downregulation of cell death-related pathways by treatment of MSC-CM in Huh7 cells. In conclusion, these results show that MSCs are enriched in human HCC tumor compartment and could exert trophic effects on tumor cells. Thus, targeting of HCC tumor MSCs may represent a new avenue for therapeutic intervention. [ABSTRACT FROM PUBLISHER]

Although anti-EGFR therapy has established efficacy in metastatic colorectal cancer, only 10-20% of unselected patients respond. This is partly due to KRAS and BRAF mutations, which are currently assessed in the primary tumor. To improve patient selection, assessing mutation status in circulating tumor cells (CTCs), which possibly better represent metastases than the primary tumor, could be advantageous. We investigated the feasibility of KRAS and BRAF mutation detection in colorectal CTCs by comparing three sensitive methods and compared mutation status in matching primary tumor, liver metastasis and CTCs. CTCs were isolated from blood drawn from 49 patients before liver resection using CellSearch™. DNA and RNA was isolated from primary tumors, metastases and CTCs. Mutations were assessed by co-amplification at lower denaturation temperature-PCR (Transgenomic™), real-time PCR (EntroGen™) and nested Allele-Specific Blocker (ASB-)PCR and confirmed by Sanger sequencing. In 43 of the 49 patients, tissue RNA and DNA was of sufficient quantity and quality. In these 43 patients, discordance between primary and metastatic tumor was 23% for KRAS and 7% for BRAF mutations. RNA and DNA from CTCs was available from 42 of the 43 patients, in which ASB-PCR was able to detect the most mutations. Inconclusive results in patients with low CTC counts limited the interpretation of discrepancies between tissue and CTCs. Determination of KRAS and BRAF mutations in CTCs is challenging but feasible. Of the tested methods, nested ASB-PCR, enabling detection of KRAS and BRAF mutations in patients with as little as two CTCs, seems to be superior. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) may be diagnosed in the absence of cirrhosis. However, little is known about prognostic factors for the survival of HCC patients with a non-cirrhotic liver in the absence of well-established risk factors. Method: Survival rates and risk factors for survival and recurrence were analysed in all patients diagnosed between 2000 and 2010 with HCC in a non-cirrhotic liver and in the absence of well-established risk factors. Results: Ninety-four patients were analysed. Treatment with curative intent consisted of surgical resection in 43 patients (46%) and radiofrequency ablation in 4 patients (4%). In patients treated with curative intent and alive 30 days after treatment (n = 40), 1- and 5-year overall survival rates were 95 and 51%, respectively. Patients with a high preoperative α-fetoprotein (AFP) serum level, the presence of microvascular invasion in the resected specimen, a complicated postoperative course and a major resection, due to a greater tumour volume, had a significantly worse outcome and a higher recurrence rate. In multivariate analysis, a high AFP serum level at presentation was significantly associated with recurrence and a worse survival. Conclusion: HCC presenting in a non-cirrhotic liver in the absence of well-established risk factors has a poor prognosis. Increased AFP serum levels are significantly associated with clinical outcome. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In deceased donor kidney transplantation donor age is known to influence graft survival. The influence of living donor age on graft survival is questioned. We compared the influence of living and deceased donor age on the outcome of renal transplantation. All 1821 transplants performed in our center between 1990 and 2009 were included in the analysis. Observation was until April 2012. A total of 941 patients received a deceased donor kidney and 880 a living donor kidney. In multivariate Cox analysis, recipient age, maximum and current panel reactive antibodies, transplant year, HLA-mismatches, donor age, donor gender, donor type, delayed graft function, and calcineurin inhibitor (CNI) and prednisone as initial immunosuppression were found to have a significant influence on death-censored graft failure. The influence of both living and deceased donor age followed a J-shaped curve, above 30 years the risk increased with increasing age. Donor type and donor age had an independent influence. The graft failure risk of deceased donor transplantation is almost twice that of living donor transplantation so that a 60-year-old living donor kidney has the same graft failure risk as a 20-year-old deceased donor kidney. [ABSTRACT FROM AUTHOR]

Purpose: To explore the potential use of magnetic resonance imaging (MRI) in predicting the outcome for patients with hepatocellular carcinoma (HCC), imaging characteristics were correlated with pathological findings and clinical outcome. Materials and Methods: With permission from the Ethical Board, clinical data and tissues of resected HCC patients were collected, including the preoperative MRI. The role of MRI characteristics on recurrence and survival were evaluated with univariate and multivariate analyses. Results: Between January 2000 and December 2008, 87 patients with 104 HCCs were operated on. Microvascular invasion was present in 55 lesions (53%). HCC was characterized as well differentiated in 15 lesions (14%), as moderate in 50 lesions (48%), and as poorly differentiated in 34 lesions (33%). Due to preoperative treatment in five lesions (5%) no vital tumor was left. In 85 lesions (88%) washout of contrast was noted. Of the 87 patients, 28 (32%) with 37 lesions developed HCC recurrence; these patients had microvascular invasion significantly more often and a moderate or poorly differentiated tumor ( P < 0.001 and P = 0.025, respectively). MRI more often showed washout when HCC was moderately or poorly differentiated ( P < 0.001) or microvascular invasion was present ( P = 0.032). Conclusion: Differentiation grade and microvascular invasion are significantly associated with the presence of washout demonstrated on dynamic contrast-enhanced MRI. J. Magn. Reson. Imaging 2012;36:641-647. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: To examine recent trends in gallbladder cancer (GBC) in the general population in the Western world, cancer registration data on GBC in the Netherlands were analyzed. Methods: Trends in incidence, treatment and survival, according to gender, age and stage of disease, between 1989 and 2008 for 3,917 patients were studied. Rates were age-standardized to the European standard population (European Standardized Rates - ESR). Results: The incidence rate for GBC in the Netherlands decreased rapidly during the period of 1989-2008, except for males younger than 60 years. Overall survival remained stable, short-term (3-month) and long-term (5-year) relative survival among surgically treated patients increased significantly. Treatment patterns for GBC changed. Surgery decreased from 55% in 1989 to 38% in 2008 (p < 0.001). Chemotherapy and/or irradiation increased from 1.0 to 5.8% (p < 0.001). Receiving best supportive care increased from 44% in 1989 to 57% in 2008 (p < 0.001). Conclusion: The incidence rate for GBC in the Netherlands has decreased rapidly. Treatment patterns for GBC have changed and survival among surgically treated patients has increased. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Hepatocellular adenoma (HCA) in pregnant women requires special considerations because of the risk of hormone induced growth and spontaneous rupture, which may threaten the life of both mother and child. Due to scarcity of cases there is no evidence-based algorithm for the evaluation and management of HCA during pregnancy. Most experts advocate that women with HCA should not get pregnant or advise surgical resection before pregnancy. Whether it is justified to deny a young woman a pregnancy, as the biological behavior may be less threatening than presumed depends on the incidence of HCA growth and the subsequent clinical events during pregnancy. We aim to investigate the management and outcome of HCA during pregnancy and labor based on a prospectively acquired online database in the Netherlands. Methods/design: The Pregnancy And Liver adenoma Management (PALM) - study is a multicentre prospective study in three cohorts of pregnant patients. In total 50 pregnant patients, ≥ 18 years of age with a radiologically and/or histologically proven diagnosis of HCA will be included in the study. Radiological diagnosis of HCA will be based on contrast enhanced MRI. Lesions at inclusion must not exceed 5 cm. The study group will be compared to a healthy control group of 63 pregnant patients and a group of 63 pregnant patients with diabetes mellitus without HCA. During their pregnancy HCA patients will be closely monitored by means of repetitive ultrasound (US) at 14, 20, 26, 32 and 38 weeks of gestation and 6 and 12 weeks postpartum. Both control groups will undergo US of the liver at 14 weeks of gestation to exclude HCA lesions in the liver. All groups will be asked to fill out quality of life related questionnaires. Discussion: The study will obtain information about the behaviour of HCA during pregnancy, the clinical consequences for mother and child and the impact of having a HCA during pregnancy on the health related quality of life of these young women. As a result of this study we will propose a decision-making model for the management of HCA during pregnancy. Trial registration: Dutch trial register: NTR3034 [ABSTRACT FROM AUTHOR]

van Ginhoven TM, de Bruin RWF, Timmermans M, Mitchell JR, Hoeijmakers JHJ, IJzermans JNM. Preoperative dietary restriction is feasible in live kidney donors. Clin Transplant 2011: 25: 486-494. © 2010 John Wiley & Sons A/S. Dietary restriction (DR), defined as reduced energy intake without malnutrition, confers protection against renal ischemia and reperfusion injury in animal models. This pilot study investigates for the first time the feasibility of pre-operative DR in the clinical setting. Live-kidney donors were randomized between pre-operative DR or ad libitum intake. Seventeen participants were instructed to follow a 30% calorie-restricted diet, followed by one day of water-only fasting prior to surgery. Thirteen participants were allowed to eat ad libitum pre-operatively. Ninety-four percent of the donors adhered to the diet, 31.4% reduction in caloric intake was achieved. Post-operative well-being, appetite and ability to perform daily tasks were not different between both groups. There was no difference in post-transplant graft function of kidneys obtained from DR donors or control donors as determined by serum creatinine levels during the first post-operative month and renograms at post-operative day one. This study shows that mild dietary restriction is feasible in the setting of live-kidney donation. No effect was observed regarding post-operative graft function. Additional studies are warranted to investigate the appropriate regimen of dietary restriction to protecting against ischemia and reperfusion injury, such as increasing the magnitude and/or duration of the reduction in daily caloric intake. [ABSTRACT FROM AUTHOR]

van de Wetering J, Koumoutsakos P, Peeters A, van der Mast BJ, de Kuiper P, IJzermans JNM, Weimar W, Baan CC. Discontinuation of calcineurin inhibitors treatment allows the development of FOXP3+ regulatory T-cells in patients after kidney transplantation. Clin Transplant 2011: 25: 40-46. © 2010 John Wiley & Sons A/S. This study investigated specific gene expression profiles in patients with donor-specific cytotoxic-hyporesponsiveness, reflected by cytotoxic T-lymphocyte precursor frequency (CTLpf). The effect of calcineurin inhibitor (CNI) withdrawal was studied on markers for cytotoxicity (perforin, granzyme B), apoptosis (Fas,FasL), Th1 and Th2 cytokines (IL-2, IL-10), Th1 and Th2 transcription factors (T-bet, GATA 3), Th17 transcription factor and cytokine (RORγt, IL-17), and for immune regulation/activation (CD25, FOXP3). Peripheral blood samples from renal allograft recipients (n = 18) more than two yr after transplantation with stable renal function were analyzed before and four months after CNI withdrawal. Additionally, systolic and diastolic blood pressure, cholesterol, serum creatinine and proteinuria were evaluated, and no significant differences were measured before and after CNI withdrawal. However, CNIs' discontinuation influenced peripheral gene expression profiles. After CNI withdrawal, the mRNA expression of Granzyme B, Perforin, Fas, FasL, T-bet, GATA3 and CD25 were significantly lower than during CNI treatment. After CNI discontinuation, donor-specific CTLpf decreased, while FOXP3 expression discriminated between detectable and non-detectable donor-specific cytolysis reactivity; FOXP3 transcript values were highest in absence of donor-specific cytotoxicity (p < 0.01). Our study shows CNI withdrawal in stable kidney transplant recipients two yr after transplantation is safe. Moreover, discontinuation of CNIs' treatment allows FOXP3+ regulatory T-cells development, resulting in a significant decrease of anti-donor immune reactivity. [ABSTRACT FROM AUTHOR]