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Among renal transplant recipients, renal cell carcinoma in the native kidneys represents the most common solid tumor. At the Department of Surgery, Transplantation and Gastroenterology of Semmelweis University annual control abdominal ultrasound examination is recommended for transplant patients. Our goal was to evaluate the effectiveness of the ultrasound screening program at our institute and to learn about the characteristics of shrunken kidney tumors.Retrospectively, we processed the results of abdominal and pelvic ultrasound examinations of 1687 kidney transplant patients, which were performed at our institute between January 1, 2012 and December 31, 2016.A total of 26 tumors were detected during the abovementioned period of time, of which 18 were renal cancers. Renal cancer was significantly (P = 0.029) more common in men. Seventeen renal cancers were classified as stage I and one as stage IV disease. The mean time of dialysis was 37.73 ± 24.37 months. The mean time between kidney transplantation and tumor recognition was 7.9 ± 6.29 years. The 5-year survival was 66%; however, it should be noted that only 1 patient lost his life due to his tumor disease. The mean time between the last 2 ultrasound examinations was 27.8 ± 23.89 months. Only 57% of tumors were detected by screening. No significant differences in tumor size, stage, and survival could be detected between screened and nonscreened renal cancer patients.Ultrasound examination at least every 2 years is an effective tool for the early detection of renal cell carcinoma of the shrunken kidneys.

Metabolic characteristics of kidney cancers have mainly been obtained from the most frequent clear cell renal cell carcinoma (CCRCC) studies. Moreover, the bioenergetic perturbances that affect metabolic adaptation possibilities of papillary renal cell carcinoma (PRCC) have not yet been detailed. Therefore, our study aimed to analyze the in situ metabolic features of PRCC vs. CCRCC tissues and compared the metabolic characteristics of PRCC, CCRCC, and normal tubular epithelial cell lines. The protein and mRNA expressions of the molecular elements in mammalian target of rapamycin (mTOR) and additional metabolic pathways were analyzed in human PRCC cases compared to CCRCC. The metabolic protein expression pattern, metabolite content, mTOR, and metabolic inhibitor sensitivity of renal carcinoma cell lines were also studied and compared with tubular epithelial cells, as “normal” control. We observed higher protein expressions of the “alternative bioenergetic pathway” elements, in correlation with the possible higher glutamine and acetate consumption in PRCC cells instead of higher glycolytic and mTOR activity in CCRCCs. Increased expression of certain metabolic pathway markers correlates with the detected differences in metabolite ratios, as well. The lower lactate/pyruvate, lactate/malate, and higher pyruvate/citrate intracellular metabolite ratios in PRCC compared to CCRCC cell lines suggest that ACHN (PRCC) have lower Warburg glycolytic capacity, less pronounced pyruvate to lactate producing activity and shifted OXPHOS phenotype. However, both studied renal carcinoma cell lines showed higher mTOR activity than tubular epithelial cells cultured in vitro, the metabolite ratio, the enzyme expression profiles, and the higher mitochondrial content also suggest increased importance of mitochondrial functions, including mitochondrial OXPHOS in PRCCs. Additionally, PRCC cells showed significant mTOR inhibitor sensitivity and the used metabolic inhibitors increased the effect of rapamycin in combined treatments. Our study revealed in situ metabolic differences in mTOR and metabolic protein expression patterns of human PRCC and CCRCC tissues as well as in cell lines. These underline the importance in the development of specific new treatment strategies, new mTOR inhibitors, and other anti-metabolic drug combinations in PRCC therapy.

Introduction Following renal transplantation, the incidence of malignancies is 3–5 times higher than that of healthy individuals. Among other type of cancers, the risk of urological tumors is also elevated. However, only a few cases of de novo transitional cell carcinomas occurring in renal allografts have been reported. Case report A 63-year-old tertiary transplanted male patient was urgently hospitalized for a painless macroscopic hematuria. Ultrasonography revealed pyelectasis and a hematoma in the renal pelvis. A percutaneous nephrostomy tube was inserted. An anterograde pyelography was performed later, where a filling defect was still observable in the location of the previously reported hypoechoic mass. Contrast-enhanced ultrasonography showed enhancement of the lesion. An ultrasound-guided percutaneous biopsy was performed. The histologic evaluation revealed a high-grade transitional cell carcinoma. A whole-body staging computed tomography scan did not show signs of metastatic disease. The renal allograft was surgically removed. No disease progression was observed during the 21-month follow-up period. Conclusions Painless hematuria and asymptomatic hydronephrosis occurring after kidney transplantation should raise the possibility of urothelial carcinoma in the kidney graft. Contrast-enhanced ultrasound should be considered as a first-line diagnostic modality because it is easily accessible and does not raise concerns about nephrotoxicity or radiation burden.

Several monoclonal antibodies and inhibitors targeting signalling pathways are being used in personalised medicine. Anti-EGFR antibodies seem to be effective, however, therapy resistance often occurs in colon carcinoma cases. mTOR inhibitors (mTORIs) could have a potential role in the breakthrough of therapy resistance. The mTOR activity related protein expression patterns and the in vitro effects of EGFR inhibitors (EGFRIs), mTORIs and their combinations were studied in different colon carcinoma cell lines (with different genetic backgrounds). Alamar Blue test and flow cytometry were used to analyse the in vitro proliferation and apoptotic effects of cetuximab, gefitinib, cisplatin, rapamycin, PP242 and NVP-BEZ235. The expressions of mTOR activity related proteins (p-70S6K, p-S6, Rictor, p-mTOR, Raptor) were studied by Western blot, immunocytochemistry and Duolink staining. The EGFRI resistance of the studied colon carcinoma cell lines related to their known mutations were confirmed, neither gefitinib nor cetuximab inhibited the proliferation or induced apoptosis in vitro. Individual differences in Rictor and Raptor expressions were detected by Western blot and immunocytochemistry beside elevated mTOR activity of these different colon carcinoma cell lines. These expression patterns correlated to the mTORIs sensitivity differences, moreover, mTORIs could enhance the effects of EGFRIs and other in vitro treatments. Our results suggest that mTORI combinations could be helpful in both EGFRI and platinum-based therapy of colon carcinomas. Moreover, we suggest determining both mTOR complex activity and mutations in Akt/mTOR signalling pathways for selecting the appropriate mTORIs and patients in potential future combination treatments.

Introduction Immunosuppressive therapy used after organ transplantation represents a considerable oncological risk. Abdominal ultrasound examinations play an essential role in the oncological screening of organ transplant patients. Our aim was to study the effectiveness of the ultrasound screening protocol currently used in our clinic. Methods Reports of screening abdominal ultrasound examinations of kidney transplant recipients were processed at the Department of Transplantation and Surgery of Semmelweis University from January 2012 to December 2015. Results In 1478 studies, 14 patients were diagnosed with a malignant tumor, 11 of which were formed in the native shrunken kidney. The mean age for tumor diagnosis was 55.6 ± 12.6 years, and 80% of the patients diagnosed with tumor were male. On average, 7.5 ± 4.6 years passed between the transplantation and recognition of the tumor. All of the kidney tumors were diagnosed at an early stage: histologic examination of removed kidneys showed 73% pT1a- and 17% pT1b-stage tumors. Conclusion In our study, early stage shrunken kidney cancers were outstandingly the most common post-transplant malignancies found by ultrasound screening. Annual ultrasound examinations as part of our current screening protocol allowed the detection of tumors at an early stage in kidney transplant recipients.

Aims Tumour heterogeneity and altered activation of signalling pathways play important roles in therapy resistance. The PI3K/Akt/mTOR signalling network is a well-known regulator of several functions that contribute to tumour growth. mTOR exists in two functionally different multiprotein complexes. We aimed to determine mTOR activity-related proteins in clinically followed, conventionally treated colon carcinomas and to analyse the correlation between clinical data and mTORC1 and mTORC2 activity. Methods Immunohistochemistry was performed with different antibodies on tissue microarray blocks from 103 patients with human colorectal adenocarcinoma. mTORC1- and mTORC2-related activity were scored on different stainings including analysis of the expression of Raptor and Rictor—specific elements of mTORC1 and C2 complexes. The staining scores and clinical/survival data were compared and analysed. Results Detailed characterisation showed stage and grade independent high mTOR activity in 74% of cases. High mTOR activity was present in mTORC1 and/or mTORC2 complexes; >60% of cases had mTORC2-related high mTOR activity. Based on our analysis, high mTOR activity and Rictor overexpression could be markers of a bad prognosis. Combined phosphoprotein and Rictor/Raptor expression evaluation revealed even stronger statistical correlation with prognosis. Conclusions The presented staining panel could be appropriate and highly recommended for the accurate specification of mTORC1 and C2 activity of tumour tissues. This could help in the selection of mTOR inhibitors and can provide information about prognosis, which may guide decisions about the intensity of therapy.

Introduction Kidney transplantation improves survival and life quality for patients with end-stage renal disease (ESRD), however, immunosuppression leads to increased risk of cancer, including renal cell carcinoma (RCC). The PI3K/Akt/mTOR pathway has a fundamental role in renal physiology and its inhibitors are used as immunosuppressive as well as antitumour agents. Recent studies suggest that immunosuppressive regimen, especially calcineurin inhibitors, may affect mTOR pathway activation. The aim of our study was to analyse the expression of mTORC1 and mTORC2-related proteins in RCCs developed in kidneys of transplant recipients and healthy individuals as controls. Material and methods Expression of p-mTOR (catalytic subunit of mTORC1 and mTORC2), p-S6 (mTORC1-related protein) and Rictor (mTORC2-related protein) was assessed in RCC tissues obtained from 46 kidney transplant recipients (15 clear cell RCCs, 31 papillary RCCs) and 46 healthy individuals (28 clear cell RCCs, 18 papillary RCCs) using IHC on tissue microarrays. Tissues from patients with ESRD (n=10) and normal kidney (n=3) were also studied. Results and discussions In normal kidney, expression of p-S6 and p-mTOR was weak in tubular epithelial cells. In contrast, expression of Rictor was high in the epithelium of both proximal and distal tubules. In ESRD, expression of p-mTOR, p-S6, and Rictor appeared to be higher in transplant recipients (n=6) compared to those who have not received immunosuppression (n=4). Expression of p-mTOR and Rictor was significantly higher in RCCs of diseased native kidneys of renal transplant recipients compared to RCCs developed in healthy individuals (p 0.01 and p 0.001, respectively) providing information about mTORC2 activation in post-transplant RCCs. According to previous observations, expression of p-S6 was significantly higher in clear cell RCCs as compared to papillary RCCs in both post-transplant and non-transplant patients (p 0.01 and p 0.05, respectively). Conclusion Our results highlighted the role of mTORC2 in the pathobiology of post-transplant RCCs. There are insufficient evidences for the protective role of mTORC1 inhibitors as immunosuppressive agents against post-transplant malignancies. Use of dual mTORC1/C2 inhibitors in the antitumour and immunosuppressive therapy needs further investigation and may represent a promising opportunity in the treatment or prevention of post-transplant RCCs. Supported by the UNKP-17–3, Bolyai Found of Hungarian Academy Sciences, and Semmelweis University Innovation Found STIA-KF-17.

Mycophenolic acid (MPA)/mycophenolate mofetil (MMF), a powerful immunosuppressive agent was tested on human B-lymphoma cells (Epstein-Barr virus +/-) in vitro and in SCID mouse xenograft model. Proliferation, apoptotic activity and tumor volume were evaluated. MPA inhibited lymphoma cell proliferation and induced apoptosis (50-60% at 72 h). In vivo, oral administration significantly inhibited subcutaneous tumor growth. Immunohistochemistry showed significantly decreased proliferation rate and higher apoptotic activity in tumors treated with MMF. Xenografted lymphoma cells remained sensitive to MPA. Our results suggest that MPA may be recommended as an additional component of lymphoma chemotherapeutical regimens, with special considerations to post-transplant lymphomas.

Background Post-transplantation tumors (PTTs) are the greatest limiting factor for patient survival following organ transplantation. Aim To describe the incidence and main characteristics of malignancies developed in patients who underwent kidney transplantation in Budapest between 1973 and 2014. Methods During this period, the essential data for PTTs were repeatedly evaluated. In this study, the results from 1990, 1995, 2000, 2006, and 2013 were evaluated. Results Incidence of PTTs increased from 2.3% to 11.1%. Male/female ratio was 2:1. Skin, native kidney, and lung cancers were the most common tumors during the entire observation period. Lymphoma was seen rarely at the beginning and became common in 2013. The same was observed in the most frequent general population tumors (colorectal, breast, hepatic, prostate, gastric cancer, and malignant melanoma) where the occurrence increased in the last 10 years. Mean age of patients increased from 35.7 to 56.5 years. During the last 20 years, age of recipients increased: above 50 years from 22.9% to 40.5%, and above 60 years from 8.2% to 23.1%. Patient survival was different according to tumor stage at discovering, i.e. renal cell carcinoma was usually discovered in stage I. resulting in a 66.1% 5-year survival rate, whereas 43.5% of colorectal cancers were diagnosed in stage IV, with a 13.9% 5-year survival rate. Conclusion The frequency of PTTs and proportion of elderly persons undergoing transplants are continuously increasing. Tumor stage is a determining factor for patient survival. Recognition of precancerous conditions, diagnosis of tumors in early stage, and oncological screening can improve survival time.

Introduction Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Orthotopic liver transplantation (OLT) is the best therapy of choice for early, unresectable HCC. The Hungarian Liver Transplantation Program was launched in 1995 at the Department of Transplantation and Surgery, Semmelweis University, Budapest. From that time more than 60 patients underwent OLT for hepatic tumors, which in most cases were HCC. Our clinical examination was undertaken to analyze the possible influential factors of outcomes for our series of patients who received OLT for HCC. Methods We performed a review of all patients who underwent OLT for HCC at our department from 1996 to October 1, 2013. Disease extent was determined by preoperative computed tomography or magnetic resonance images. All explants were examined and categorized based on tumor number, size, distribution, HCC histologic grade, and vascular invasion. Patients with HCC were classified as having tumors either meeting Milan criteria, beyond Milan criteria but within UCSF criteria, or exceeding UCSF criteria. OLT was performed using standard techniques including orthotopic implantation with cross-clamp technique or with the piggyback technique. Postoperative immunosuppression included a triple drug regimen of calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), and prednisone. mTOR inhibitors have been available since 2004. Results HCC most commonly occurs in the presence of cirrhosis as a result of longstanding chronic liver disease. Most of our patients who underwent OLT for HCC are 56 to 60 years old, and most also had underlying HCV cirrhosis. As of October 1, 2013, 21 of 49 (42.85%) patients had died after OLT for HCC. The main cause was the recurrence of the HCC in 38%, followed by sepsis in 33%, and HCV recurrence in 19%. One death each (4.7% of the total number of deaths) was caused by primary nonfunction of the graft, acute myocardial infarct, and de novo malignancy, respectively. Overall survival for the entire group at 1, 3, and 5 years after transplantation was 73.48%, 65.2%, and 50.08%, respectively. Using pretransplant imaging, 34 tumors (69.3%) were within Milan criteria, 8 (16.3%) were beyond Milan but within UCSF criteria, and 7 (14.3%) exceeded UCSF criteria. Based on explant pathology, 30 tumors (61.2%) were within Milan criteria, 7 (14,3%) were beyond Milan but within UCSF criteria, and 12 (24.3%) exceeded UCSF criteria. New onset, non-HCC malignant tumor developed in 2 cases (4%). There was no significant difference between the surgical techniques or the immunosuppressive strategies. Using the Cox analysis in our series, it can be seen that mortality was higher with tumors exceeding Milan criteria but within UCSF criteria compared with tumors within Milan criteria (Coef. = 0.5749 in Setting 1 and 0.1226 in Setting 2), and even higher with tumors beyond UCSF criteria compared with tumors within Milan criteria (Coef. = 0.7228 in Setting 1 and 0.1456 in Setting 2). Recurrence of the tumor causes higher mortality (Coef. = 1.709 in Setting 1 and 1.0256 in Setting 2). It seems that using an mTOR inhibitor has a beneficial impact on mortality (Coef. = −1.409 in Setting 1). Vascular invasion was associated with higher mortality (Coef. = 0.6581in Setting 1). Higher AFP levels correlated with higher mortality but not significantly (Coef. = 0.0002 in Setting 2). In our series, survival after OLT for HCC was best with tumors within Milan criteria comparing those exceeded Milan criteria (odds ratio = 4.000). Conclusion According to our findings, the Milan criteria are still the safest criteria system; however, slightly expanded criteria do not have significantly worse results. Preoperative imaging methods sometimes show fewer or smaller tumors, and the explant histology reports the exact staging of HCC at the time of OLT. Histological examination especially of the lymphovascular invasion is mandatory to assess the estimated prognosis. Extremely high levels of AFP mean higher risk. HCC recurrence is an important factor on the outcome; therefore, continuous oncologic screening is mandatory. Immunosuppressant agents are chiefly responsible not just for higher risk of recurrence but for higher risk to develop de novo malignancies. Viral serology must be done periodically to catch HCV recurrence in time and begin adequate antiviral therapy. Potentially, mTOR inhibitors could be potent immunosuppressive agents after OLT for HCC due to this antiproliferative effect.

TGF-β1 (transforming growth factor beta 1) is a negative regulator of lymphocytes, inhibiting proliferation and switching on the apoptotic program in normal lymphoid cells. Lymphoma cells often lose their sensitivity to proapoptotic/anti-proliferative regulators such as TGF-β1. Rapamycin can influence both mTOR (mammalian target of rapamycin) and TGF-β signaling, and through these pathways it is able to enhance TGF-β induced anti-proliferative and apoptotic responses. In the present work we investigated the effect of rapamycin and TGF-β1 combination on cell growth and on TGF-β and mTOR signalling events in lymphoma cells. Rapamycin, an inhibitor of mTORC1 (mTOR complex 1) did not elicit apoptosis in lymphoma cells; however, the combination of rapamycin with exogenous TGF-β1 induced apoptosis and restored TGF-β1 dependent apoptotic machinery in several lymphoma cell lines with reduced TGF-β sensitivity in vitro. In parallel, the phosphorylation of p70 ribosomal S6 kinase (p70S6K) and ribosomal S6 protein, targets of mTORC1, was completely eliminated. Knockdown of Smad signalling by Smad4 siRNA had no influence on apoptosis induced by the rapamycin+TGF-β1, suggesting that this effect is independent of Smad signalling. However, apoptosis induction was dependent on early protein phosphatase 2A (PP2A) activity, and in part on caspases. Rapamycin+TGF-β1 induced apoptosis was not completely eliminated by a caspase inhibitor. These results suggest that high mTOR activity contributes to TGF-β resistance and lowering mTORC1 kinase activity may provide a tool in high grade B-cell lymphoma therapy by restoring the sensitivity to normally available regulators such as TGF-β1.

There is a greater risk of malignant tumors developing in kidney transplant patients. Due to this, early detection is of outmost importance, in which screening tests play an important role.We have conducted a survey among renal transplant recipients to assess individual risk factors.Of 530 respondents, 55 developed post-transplantation tumors. Cutaneous tumors (36%) and kidney cancer (16%) were the most frequent. In total, 59% of recipients were over the age of 50, 61.7% were over the normal body-mass index range, 40.3% smoked or used to smoke, and 21.8% had diabetes. Five patients had hepatitis B virus and 11 were hepatitis C virus-positive. Malignancies developed significantly more frequent in men than in women (P = .04). The progressing of age (P = .0001) and the time elapsed after transplantation (P .01) also were associated with a significant increase in the occurrence of post-transplantation tumors.We have created a database to facilitate a more personalized and efficient screening program for immunocompromised patients.

Besides orthotopic liver transplantation (OLT) there is no long-term and effective replacement therapy for severe liver failure. Artificial extracorporeal liver supply devices are able to reduce blood toxin levels, but do not replace any synthetic function of the liver. Molecular adsorbent recirculating system (MARS) is one of the methods that can be used to treat fulminant acute liver failure (ALF) or acute on chronic liver failure (AoCLF). The primary non-function (PNF) of the newly transplanted liver manifests in the clinical settings exactly like acute liver failure. MARS treatment can reduce the severity of complications by eliminating blood toxins, so that it can help hepatic encephalopathy (HE), hepatorenal syndrome (HRS), and the high rate mortality of cerebral herniation. This might serve as a bridging therapy before orthotopic liver retransplantation (reOLT). Three patients after a first liver transplantation became candidate for urgent MARS treatment as a bridging solution prior to reOLT in our center. Authors report these three cases, focusing on indications, MARS sessions, clinical courses, and final outcomes.

The objective of the study was to examine proliferation and apoptosis associated gene expression in the whole sequence parathyroid lesions to reveal specific features of carcinoma. This study was based on surgically removed parathyroid tissues, gene expression analysis was performed both at gene and protein level. First, mRNA isolation was performed from deep-frozen tissue samples, and further apoptosis pathway-specific cDNA macroarray analysis was carried out. The results were validated with real-time PCR. Subsequently, protein expression was analyzed with immunhistochemistry on Tissue Micro Array multi-blocks derived from several paraffin-embedded samples. cDNA macroarrays revealed elevated expression of both pro-apoptotic (FAS receptor, TRAIL ligand, CASPASE8, and −4) and anti-apoptotic (cIAP1, APOLLON) genes in benign proliferative lesions compared to that in normal gland. TMA studies showed overexpression of KI67, P53, SURVIVIN and APOLLON protein and failure of expression of P27, BCL2, BAX, CHROMOGRANIN-A, SYNAPTOPHYSIN, CYCLIND1, FLIP, TRAIL, CK8, CK18, CK19 in parathyroid carcinoma was detected. These alterations in gene expression of the investigated products could be used in differentiation between beningn and malignant proliferative processes of the parathyroid gland. Authors conclude that a series of alterations in gene expression such as overexpression of APOLLON, P53, KI67 and suppression of P27, BCL2, BAX lead to uncontrolled cell proliferation, but still not leading to increased apoptotic activity in parathyroid carcinoma.