Post-transplant Malignancies Research Articles

The complex existence of γδ T cells following transplantation: the good, the bad and the simply confusing

Gamma delta (γδ) T cells are a highly heterogeneous population of lymphocytes that exhibit innate and adaptive immune properties. Despite comprising the majority of residing lymphocytes in many organs, the role of γδ T cells in transplantation outcomes is under‐researched. γδ T cells can recognise a diverse array of ligands and exert disparate effector functions. As such, they may potentially contribute to both allograft acceptance and rejection, as well as impacting on infection and post‐transplant malignancy. Here, we review the current literature on the role and function of γδ T cells following solid organ and hematopoietic stem cell transplantation.

Pancreaticoduodenectomy in a liver transplant recipient with pancreatic adenosquamous carcinoma.

Introduction: In the literature, malignancy after solid organ transplantation is not rare and well described. The majority of posttransplant malignancies are either related to prolonged immunosuppression or the disease that necessitated transplant. With improvements in clinical condition, patients are experiencing an increase in posttransplant life expectancy. Therefore, the clinical physician will face increasing cases of uncommon malignancies in transplant recipient. The aim of this presentation is to introduce the use of pancreaticoduodenectomy for malignancy in patients who have undergone liver transplantation. Method: A 68-year-old female underwent living donor liver transplantation for liver cirrhosis. Six years post-transplant, she presented with abdominal pain and was diagnosed with a 4.5 x 3 cm pancreatic head mass on computed tomography scan. The mesocolon and superior mesenteric vein were involved by tumor. Result: The patient therefore underwent open pancreaticoduodenectomy with concomitant segmental resection of superior mesenteric vein. The operation time was 11 hours 25 minutes with blood loss of 1550 c.c.. The liver graft had been functioning well without any rejection episode. She recovered uneventfully and was discharged home 37 days after pancreaticoduodenectomy. Conclusion: A major operation such as pancreaticoduodenectomy could still be considered for the patient with previous living donor liver transplantation. Our success experience may encourage physicians facing similar scenarios, particularly the technical challenges and post-operative management.

Incidence and Risk Factors for Second Malignancies after Transplant in Long Term Survivors of Allogeneic Haematopoietic Stem Cell Transplant: A Single Centre Experience

Second malignancies are well recognised complications of haematopoietic stem cell transplantation (HCT). The incidence increases with time after HCT with no evidence of plateau with follow up times of 15-20 years. In this study we have investigated patients over a 37-year period to include all patients transplanted at The Hammersmith hospital since 1979 who survived a minimum of two years after transplant. We aimed to describe the post-transplant malignancies (PTM) that occurred and calculate the cumulative incidence with time.MethodsData was gathered through internal databases and supplemented with case notes with all patients giving consent for their data to be used in clinical studies. Additional information on patients who had died at the time of analysis included review of death certificates for evidence of a second malignancy. If a patient had not been seen within 5 years evidence of death was sought on the NHS Spine and if apparently still alive, the date of last follow up was taken as follow up time. Second malignancies included second solid neoplasms (SSN), non-melanoma skin cancer (NMSC) and leukemias/lymphomas. These were recorded and categorised in accordance with the international classification of disease for oncology (ICD-O).Results697 patients survived a minimum of two years after HCT between 1979-2018, 60% of whom were male. Follow up was prolonged with 20% of our 2-year survivors followed up for more than 20 years. The majority of patient (80%) were aged between 20-50 at time of HCT. (median age 35.6y, range 4-69) with only 7 patients < 10 y at HCT. The most frequent diagnoses were CML (n=463) or AML (n=103). The majority of patients (n=538, 77%) had received TBI, and the most frequently used conditioning was Cyclo-TBI (479 patients, 69%). At the time of analysis, 222 patients had died and of the remaining 475, 107 were lost to follow up.We identified 97 PTM in 87 patients a median of 14.2 years post HCT (range 0.8-35.9 years). These included 58 cases of SSN, 28 cases of NMSC and 11 cases of leukemia or lymphoma. The most frequent SSN were breast (n=12), tongue (n=7), colorectal (n=6), melanoma (n=5), bladder (n=4), thyroid (n=3) and oesophagus (n=3). Of 28 patients with NMSC, 19 developed one or more BCC and 9 developed SCC.The cumulative incidence of PTMs did not plateau with time. Cumulative incidences were as follows with 95% confidence intervals (CI) in parentheses: 4.9% (3.3-7.3) at 10 years, 12.2% (9.1-16.2) at 15 years, 22.5% (17.6-28.9) at 20 years, 39% (30.3-48.4) at 25 years and 53% (41.6-64.1) at 30 years. These data reflected the substantial increases in the CI of SSN and NMSC between these time points. For SSN the cumulative incidence increased from 3% (1.8-5) at 10 years to 37.9% (27.4-49.6) at 30 years; for NMSC the cumulative incidence increased from 1.3% (0.6-2.7) at 10 years 16.6% (9.2-28.2) at 30 years.In multivariate analyses older age (>50) at time of transplant was associated with significantly increased (p<0.01) risk of PTM with a relative risk (RR) of 4.53 (2.1-9.6). On subgroup analysis this was only relevant to SSN where the RR was 5.17 (2.2-12.1). Patient/donor sex combinations other than male patient/male donor were also at increased risk of PTM, RR 1.797 (1.1-2.9), p=0.033, and again this was only significant for SSN (RR 2.11, 1.13-3.93).Discussion and conclusionsIn this predominantly adult study, the cumulative incidence of SSN and NMSC increased substantially with time after HCT beyond a 10-year follow-up period. The risk was increased in patients who were >50 at time of HCT. Prolonged expert follow-up with a high index of suspicion for second malignancy in these patients is recommended to facilitate early diagnosis. DisclosuresApperley:Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Milojkovic:Incyte: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

Treatment Patterns for Patients with Post-Transplant Lymphoproliferative Disorder Who Fail Rituximab after Allogeneic Hematopoietic Stem Cell Transplantation: Findings from a Systematic Literature Review

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized disease after allogeneic hematopoietic stem cell transplantation (HCT) and is one of the most common post-transplant malignancies. In most cases, PTLD is associated with Epstein-Barr Virus (EBV) infection. The management of PTLD remains a challenge, with no approved treatments for patients. Clinical practice treatment guidelines recommend rituximab as first-line therapy for PTLD post-allogeneic HCT; however, treatment options for PTLD patients who fail rituximab are not clearly defined. We conducted a systematic literature review of the published literature to better understand treatment patterns for patients with PTLD who fail rituximab post-allogeneic HCT in a real-world setting.Methods: The systematic literature review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with the scope defined in terms of Population, Intervention Comparators, Outcomes, and Study design (PICOS) criteria. Using extensive search terms for the indication and study designs, studies were identified using key biomedical literature databases: EMBASE, MEDLINE, and Cochrane. The literature search was conducted on July 19, 2018 and included studies published between database inception in January 1, 1959 and July 19, 2018. Relevant congress abstracts published between January 2015 and June 2018 were also identified. The PICOS-based inclusion and exclusion criteria were used to review identified citations. No treatment limitations were imposed to ensure inclusion of all relevant evidence; the study designs were limited to prospective and retrospective observational studies. Case reports were included regardless of sample size. Two independent reviewers screened all citations and full-text articles; any discrepancies were resolved by a third independent reviewer. Data from included studies were extracted into a pre-defined template, and results were summarized using the PRISMA flow diagram.Results: A total of 69 studies were identified that described patients with PTLD post-allogeneic HCT. The majority (61 studies) were retrospective chart reviews, of which 54 studies were single-center studies. Forty-eight studies reported data on treatment of patients with PTLD. Among these, 5 studies included data prior to 2000, 33 studies included data from 2000-2010, and 26 studies included data from 2010-2016. The sample size for PTLD patients was between 1 and 144 patients, with only one study of > 100 patients. First-line therapy in PTLD included rituximab (41 studies), various chemotherapy regimens (15 studies), and lymphocyte infusion (10 studies). Nine studies reported treatment for patients who failed first-line rituximab (13-67% of PTLD patients); the number of patients with second-line treatments ranged from 2-10 across studies. Second-line treatments varied greatly across studies and included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP, n=1); rituximab plus CHOP (R-CHOP, n=1-2); cyclophosphamide, etoposide/cytarabine (VP16/ARA-C, n=1); rituximab plus cyclophosphamide (n=1); rituximab plus high-dose cytarabine (n=1); chemotherapy unspecified (n=2-4), and lymphocyte infusion (n=3-5). Only 2 studies reported treatment outcomes in rituximab-refractory patients. One study (N=62, second-line n=10, median age 49 years) reported no complete or partial remission in the chemotherapy group; 60% had complete remission in the lymphocyte infusion group. The second study (N=12, second-line n=3, mean age 5 years) reported complete remission in 1 patient with lymphocyte infusion as second-line treatment.Conclusions: This systematic literature review demonstrates that data on treatment patterns for PTLD patients who failed rituximab post-allogeneic HCT are limited (9 studies with a sample size ≤ 10). Published data suggest that the percentage of patients who fail rituximab vary greatly (13-67%), there is no consistent standard of care for PTLD patients who fail rituximab, and outcomes are poor. There continues to be a significant unmet need among PTLD patients who fail rituximab, and further studies are needed to better understand rituximab response rates in the real-world setting. DisclosuresXu:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Watson:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Forsythe:Novartis: Consultancy. Barlev:Atara Biotherapeutics, Inc: Employment, Equity Ownership.

Cancer risk after renal transplantation in South Korea: a nationwide population-based study

BackgroundThis study aimed to evaluate patterns of posttransplant malignancies among renal transplant recipients (RTRs) in South Korea using nationwide data.MethodsThe nationwide cohort assessed in this study included RTRs from January 1, 2010, to December 31, 2014. We analyzed cancer incidence during the time course after renal transplantation. Additionally, we calculated standardized incidence ratios (SIRs) to evaluate the risk of malignancies in RTRs.ResultsA total of 1343 RTRs (871 males and 472 females, mean age 48.5 ± 11.6 years) were assessed. Among them, 104 (7.7%) developed malignancies after transplantation, most commonly in the thyroid cancer (23.1%). The SIR for all cancers was 3.54; particularly, the SIRs for renal cancer, myeloma, and non-Hodgkin lymphoma were 16.31, 24.02, and 28.64, respectively. Females showed a higher risk of malignancy than males (SIRs: 4.04 for women and 3.26 for men). The median interval between transplantation and malignancy diagnosis was 27.2 months (range 12.3–54.8 months).ConclusionsRTRs in South Korea demonstrated a high risk of malignancy after transplantation compared with the general population. This indicates that close surveillance and routine screening for cancer in RTRs are needed.

Pulmonary hypertension associated with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a frequent autosomal dominant genetic disorder with a prevalence of 1 in 3000. Pulmonary hypertension (PH) associated with NF1 (PH-NF1) is a rare but severe complication of NF1 and is classified as Group 5 PH, defined as "PH with unclear and/or multifactorial mechanisms". A literature review in PubMed on the association between NF1 and PH identified 18 articles describing 31 cases. PH-NF1 was characterised by a female predominance, an advanced age at diagnosis, an association with parenchymal lung disease in two out of three cases and poor long-term prognosis. NF1 is generally associated with interstitial lung disease but some cases of severe PH without parenchymal lung disease suggest that there could be a specific pulmonary vascular disease. There is no data available on the efficacy of specific pulmonary arterial hypertension treatment in PH-NF1. Therefore, these patients should be evaluated in expert PH centres and referred for lung transplantation at an early stage. As these patients have an increased risk of malignancy, careful assessment of the post-transplant malignancy risk prior to listing for transplantation is necessary. Clinical trials are needed to evaluate promising treatments targeting the RAS-downstream signalling pathways.

Epithelial to Mesenchymal Transition in Endomyocardial Biopsies from Orthotopic Heart Transplant Recipients

Introduction Heart transplant patients are at high risk of organ rejection and require close monitoring with frequent endomyocardial biopsies (EMB), especially during their first post-transplant year. We encountered a hypercellular, atypical endocardial lesion composed of enlarged, pleomorphic cells in a 54-year-old male heart transplant recipient 7.5 months post-transplantation. Our initial impression was post-transplant lymphoproliferative disorder or malignancy. We later identified two additional cases with similar histopathologic findings and hypothesized that these were actually reactive changes or so called epithelial-mesenchymal transition (EMT). EMTs have not been previously reported in EMB from heart transplant recipients and we identified 3 cases in less than a one year time period. Methods For these 3 cases, we further evaluated their clinical history and analyzed the EMB with additional immunostains (CD3, CD68, CD20, PAX-5, Kappa, Lambda, WT1, CK AE1/3, CD34, adenovirus, and EBV) to determine the etiology of the lesions. Right heart EMB are conducted at our institution weekly for the first 8 weeks and then every 3 months thereafter. Results All 3 patients had undergone orthotopic heart transplant replacement 2-7 months prior to having the EMB in which the lesions were observed and received similar induction and immune suppression regimens (MMF and tacrolimus). The IHC stains showed that the atypical-appearing cells were forming a new layer on the endocardial surface and were transitioning from epithelial-like (AE1/3+) to mesenchymal-like (CD34+), and were thus undergoing EMT. Underlying this reactive process was mixed inflammation including macrophages and scattered aggregates of CD3+ T cells; there was no evidence of a lymphoproliferative disorder and EBV was negative. All 3 patients had similar EM findings. Their subsequent biopsies showed similar lesions, although slightly less cellular, with increased fibrosis. Graft function remained normal in all patients. Conclusion The presence of atypical appearing cells on EMB can raise suspicion for rejection or post-transplant lymphoproliferative disorder; however, this appears to often be a reparative process, namely EMT. Similar to reports in kidney transplant patients on tacrolimus, EMT does not seem to play a role in the development of allograft rejection. Due to our small sample size, further investigation is needed.

Interleukin-27 is a potential marker for the onset of post-transplant malignancies.

Malignancies represent the third leading cause of post-transplant mortality worldwide. The main challenge for transplant physicians is a timely diagnosis of this condition. The aim of the study was to identify a soluble diagnostic marker for monitoring the development of post-transplant malignancies. This is a multicentre, observational, perspective, case-control study. We enrolled 47 patients with post-transplant solid neoplasia. As a control group we employed 106 transplant recipients without a history of neoplasia and matched them with cases for the main demographic and clinical features. We investigated the transcriptomic profiles of peripheral blood mononuclear cells from kidney graft recipients with and without post-transplant malignancies enrolled in two of the participating centres, randomly selected from the whole study population. Microarray results were confirmed by quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) in the remaining patients from the same transplant centres and validated in a further independent group enrolled in two different transplant centres. We identified 535 differentially expressed genes comparing patients with and without post-transplant malignancies (fold change ≥2.5; false discovery rate <5%). The cancer pathway was closely related to gene expression data, and one of the most down-regulated genes in this pathway was interleukin-27 (IL-27), a cytokine regulating anti-tumour immunity. Quantitative PCR and ELISA confirmed the microarray data. Interestingly, IL-27 plasma levels were able to discriminate patients with post-transplant neoplasia with a specificity of 80% and a sensitivity of 81%. This observation was confirmed in an independent set of patients from two different transplant centres. Our data suggest that IL-27 may represent a potential immunological marker for the timely identification of post-transplant neoplasia.

Everolimus vs Mycophenolate Mofetil in Combination With Tacrolimus: A Propensity Score-matched Analysis in Liver Transplantation

BackgroundNo trial has investigated the long-term outcome of everolimus (EVR)-incorporating immunosuppression vs tacrolimus (TAC) and mycophenolate mofetil (MMF) after liver transplantation. Materials and MethodsWith a propensity score methodology, 178 recipients on TAC and MMF were compared to 178 patients on TAC and EVR. ResultsAt a median (interquartile range) follow-up of 45 (46.3) months, the probability of treated biopsy-proven acute rejection, graft loss, and death was 36.6% for MMF and 28.1% for EVR (P = .0891). Treated biopsy-proven acute rejection was numerically lower for EVR (3.3% vs 7.3%, P = .09), while adverse events (70.2% vs 58.9%, P = .02) and drug discontinuations (21.3% vs 11.8%, P = .01) were significantly higher with regard to hypercholesterolemia (P = .001), thrombocytopenia (P = .0062), and edema (P = .0107). Patients on MMF showed more hypertension (P = .0315), tremor (P = .0006), cytomegalovirus infection (P = .0165), and malignancies (P = .0175). EVR was associated with lesser deterioration in mean (SD) renal function at the latest follow-up (−2.2 (1.8) vs −5.1 (3.2) mL/min/1.73 m2, t = 3.6, P = .005). ConclusionsThe efficacy of the combination of TAC and EVR is comparable to that of TAC and MMF. Drug discontinuations and adverse events were higher for patients on EVR, but these latter showed less hypertension, cytomegalovirus infection, and renal dysfunction. The observed reduction in posttransplant malignancies for EVR requires longer follow-up to be confirmed.

Cancer Incidence After Kidney Transplantation in Saudi Arabia

In the current era of renal transplantation the patient and graft survival are continuously improving. However there are some factors that are counterbalancing the effect of such success. One such factor is post renal transplant malignancies (PRTxM). The longer the patient survival is with functioning allograft, the higher is the risk of developing malignancy. In this present study we describe our experience of PRTxM among 2981 renal transplants performed in our centre. Material and Methods We performed retrospective analysis of prospectively collected data of 2981 renal transplant performed at King Faisal Specialist Hospital and Research Centre KSA between 1981 and 2016 with a median follow-up period of 153 months. We studied incidence and outcome of PRTxM among these patients. Statistical analysis was carried out using the Statistical Package for the Social Sciences (SPSS 21). Non-variables were analyzed using the T-Test, and variables were analyzed by means of the Fisher exact test and Chi square test. We also analyzed for relative risk ratio among different factors. Survival analysis was conducted using Kaplan-Meier survival graphs and log-rank testing was used where differences in survival were significant. In general, a P value of <0.05 was considered statistically significant for the purpose of our study. Results Overall there was 4.2% (n=125) incidence of post renal transplant malignancies recorded in our patients with equal distribution among pediatric and adult recipients [RR 1.0106; 95% CI 0.5927 to 1.7231; P = 0.96921. The median time from transplant to malignancy was 53 months. Non-cutaneous carcinomas (n=42) were the commonest malignancy followed by PTLD (n=33) [Table I]. The incidence of PTLD was higher in pediatric group as compared to adults [RR 3.4667; 95% CI 1.2050 to 2.4504; P <0.0001]. Likewise the incidence of non-cutaneous carcinoma was higher in adult as compared with pediatric population [RR 2.343; 95% CI 1.2204 to 2.042; P <0.0001]. The overall mortality was 7.45% during the median follow-up period of 153 months. Patients with malignancy had higher mortality rate of 29.24% as compared to 6.64% in non-malignancy group [P= <0.0001] [Figure I] Death with functioning graft (DWFG) was significantly more in malignant group [P=<0.0001]. Conclusion The overall rate of malignancy remain low(4.2%) when compared to the international rat, this is in spite of high rate of follow up. Viral driven cancer were more common when compared to national rates, however non cutaneous carcinoma were comparable to local standardized rate. Mortality was significantly higher with cancer development and PTLD was common among pediatric patients particularly EBV negative.

PO-484 Immunohistochemical analysis of mTORC1 and mTORC2-related proteins in renal cell carcinoma of kidney transplant recipients

IntroductionKidney 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 methodsExpression 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 discussionsIn 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).ConclusionOur 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 ÚNKP-17–3, Bolyai Found of Hungarian Academy Sciences, and Semmelweis University Innovation Found STIA-KF-17.

Analysis of the Incidence and Site of Post-Transplant Cancer in Patients with Pre-Transplant Malignancies

Collaborative Transplant Study. Introduction Patients with a pre-transplant (pre Tx) malignancy were reported to be at an increased risk of developing cancer after kidney transplantation. However, the preferred location of such malignancies was not addressed. Using the CTS database we analyzed the incidence and site of post-transplant (post Tx) malignancies that occurred in patients with different types of pre Tx cancer. Materials and Methods Recipients of first kidney-only transplantations performed between 1984 and 2015 were analyzed for 10-year cancer occurrence. Cancers diagnosed on the day of transplantation were excluded. Using multivariable Cox-regression, the hazard ratio (HR) of post Tx cancer was calculated for 3,948 patients with different types of pre Tx cancer as compared to 263,142 patients without pre Tx cancer (Table 1). Results The location and HR of post Tx cancer in patients with pre Tx genital, urinary, lymphoma or non-melanoma skin cancer (NMCS) are shown in Table 2. All other cancers were merged in the heterogeneous ‘other solid’ category. A strong tendency was observed for the occurrence of post Tx cancer at the pre Tx location. The highest evidence was observed with HR 5.63 for urinary tract cancer in patients with a pre Tx cancer at the same site (P<0.001). Discussion As shown in Table 2, several cancer sites appeared to be linked to each other, e.g. an increased risk of genital cancer was observed also in patients with a pre Tx cancer of the urinary tract (HR=1.69, P=0.015). A dissemination trend was observed in patients with pre Tx lymphomas; due to insufficient case numbers, statistical significance was reached only for the group combining all post Tx cancers without NMSC (HR=2.46, P<0.001). Conclusion Patients with a pre Tx cancer history should be checked regularly for the development of a malignancy after transplantation, especially at the site of the pre Tx cancer. In patients with pre Tx lymphoma, post Tx cancers at various locations are common.

Outcome of Patients With Small Vessel Vasculitis After Renal Transplantation: National Database Analysis.

BackgroundSmall vessel vasculitis commonly affects the kidney and can progress to end-stage renal disease. The goal of this study is to compare outcomes of patients who received a renal transplant as a result of small vessel vasculitis (group A) with those who received kidney transplants because of other causes (group B).MethodsThis is a retrospective analysis of United Network for Organ Sharing registry data for adult primary kidney transplants from January 2000 to December 2014. Group A patients (N = 2196) were compared with a group B (N = 6588); groups were case matched for age, race, sex, donor type, and year of transplant in a 1:3 ratio.ResultsRenal and patient survivals were better in the group A (P < 0.001). New-onset diabetes after transplant developed in 8.3% of the group A and 11.3% of group B (P < 0.001). Seventeen (0.8%) patients in group A developed recurrent disease. Of these, 7 patients had graft failure, 3 of which were due to disease recurrence. Group A patients had significantly higher risk of developing posttransplant solid organ malignancies (11.3% vs 9.3%, P = 0.006) and lymphoproliferative disorder (1.3% vs 0.8%, P = 0.026). Independent predictors of graft failure and patient mortality were recipients' morbid obesity, diabetes, age, and dialysis duration (hazard ratio of 1.7, 1.4, 1.1/10 years, and 1.1/year for graft failure, and 1.7, 1.7, 1.6/10 years and 1.1/year for patient mortality, respectively).ConclusionsRenal transplantation in patients with has favorable long-term graft and patient outcomes with a low disease recurrence rate. However, they may have a higher risk of developing posttransplant malignancies.

Nonmelanoma Skin Cancers in Solid-Organ Transplant Recipients: A Single Center Experience.

Skin cancers are one of the most common malignancies in solid-organ transplant recipients. Increased age and immunosuppressive drug use are risk factors for posttransplant skin malignancies. We evaluated nonmelanocytic skin cancer incidence and development time in transplant patients. We reviewed 1833 patients who received kidney, liver, and heart grafts between 1996 and 2016 at Baskent University. We excluded melanocytic skin cancers, premalignant lesions, and benign skin tumors. Of 1833 patients, 1253 were male (68.4%) and 580 were female (31.6%), composed of 1133 kidney (61.8%), 512 liver (27.9%), and 120 heart recipients (6.5%). Of these, 22 patients (18 kidney/3 liver/1 heart) developed 23 different types of skin cancer. Prevalence of skin cancer was 1.20%. Mean age at presentation was 55.8 years (range, 37-71 y). Average time from transplant to skin malignancy was 6.1 years (range, 1-13 y), with the most common being basal cell carcinoma (43%, 10 cases), followed by squamous cell carcinoma (39%, 9 cases) and Kaposi sarcoma (13%, 3 cases). Tumor sites included head and neck (15 case), trunk (2 cases), lower extremity (2 cases), and upper extremity (2 cases). Neither local recurrence nor distant metastasis was shown. Skin cancer risk is increased in solid-organ transplant recipients versus the general population. Although squamous cell carcinoma is the most common tumor in this patient population, followed by basal cell carcinoma, we found this reversed in our patients. The low prevalence of skin malignancy (1.20%) may be associated with close clinical follow-up to detect premalignant skin lesions and the lowdose immunosuppressive drug regimen. We believe that local recurrence and distant metastasis were absent because we use a wide surgical margin of excision and provide strict follow-up. Routine dermatologic follow-up visits of transplant recipients are recommended to detect and treat early skin cancer and premalignant lesions and thus lower morbidity and mortality.

MTOR Inhibition and Clinical Transplantation: Liver.

The evidence base concerning use of mammalian target of rapamycin (mTOR) inhibitor therapy after liver transplantation is evolving rapidly, clarifying their benefits and disadvantages in different clinical scenarios. The H2304 trial showed that starting everolimus at 1 month posttransplant, with reduced tacrolimus, achieves a sustained improvement in renal function versus standard tacrolimus-based therapy, with at least equivalent immunosuppressive efficacy. Randomized studies evaluating early discontinuation of calcineurin inhibitor (CNI) therapy after introduction of an mTOR inhibitor consistently demonstrated a substantial improvement in renal function versus standard CNI therapy. However, concomitant mycophenolic acid is advisable to avoid an increase in mild biopsy-proven acute rejection, and induction with an interleukin-2 receptor antagonist may also be helpful. High-quality robust data regarding prevention of posttransplant malignancies under mTOR inhibitors is lacking in liver transplantation, although there are some indications of benefit. In maintenance patients, robust data are limited regarding mTOR inhibitor initiation in response to deteriorating renal function or other indications but late conversion (>1 year) appears ineffective. Rates of mTOR inhibitor discontinuation due to adverse events are high, affecting at least a quarter of patients. In conclusion, the evidence base for use of mTOR inhibitors early posttransplant to support CNI reduction now convincingly demonstrates a renal advantage, but adequate adjunctive immunosuppression is essential to preserve efficacy.

Post-transplant malignancies in pediatric liver transplant recipients: Experience of two centers in Turkey.

A liver transplant is the preferred treatment for patients with end-stage liver disease, as it usually results in longterm survival. However, due to the use of chronic immunosuppressive therapy, which is necessary to prevent rejection, de novo cancer is a major risk after transplantation. The aim of this study was to assess the incidence of post-transplant malignancies in children after liver transplantations. The study group consisted of 206 liver transplant recipients, with no history of cancer, including hepatocellular carcinoma, in two liver transplantation centers in Turkey between 1997 and 2015. Data were obtained from patient's data chart. In the study group, de novo cancer was diagnosed in 13 of the 206 patients. Post-transplant lymphoproliferative disease (PTLD) occurred in seven (53.8%) patients and other malignancies in six of the 13 patients. The types of PTLD were as follows: B-cell origin (n=2), Epstein-Barr virus (EBV)-related (n=2), T-cell origin (n=1), and Hodgkin's lymphoma (n=2). EBV DNA was isolated from seven patients, three of whom developed PTLD. The others developed Kaposi's sarcomas, Burkitt's lymphomas, cutaneous large-cell lymphomas, Hodgkin's lymphomas, and liver sarcomas. After transplantation, immunosuppressive treatment is unavoidable, increasing the risk of malignancies. However, a close follow-up and periodic screening can reduce cancer-related mortality and morbidity.

Efficiency of late conversion from mycophenolate mofetil to everolimus in kidney graft recipients with posttransplant malignancy

Malignancy is one of the leading causes of death in recipients with a kidney grafts. The use of proliferative signal inhibitors (PSI) is one of the approaches to solve this problem.Aim: to evaluate the effi cacy and safety of everolimus in combination with reduced dose of calcineurin inhibitors (CNI) in patients with posttransplant malignancy.Materials and methods.62 kidney graft recipients (KGR) with neoplasia were converted from mycophenolate mofetil to everolimus in combination with reduced dose of CNI at 83.5 ± 69.3 months after transplantation. The duration follow-up was 35.5 ± 26.9 month. The effectiveness of management was assessed by patient survival, type of immunosuppression therapy, renal function and proteinuria. The patient survival in PSI group was compared with the survival in the patients in control group (n = 145), who did not receive everolimus.Results.10-year and 15-year patient survival was 92% and 85,7% in patients treated with PSi versus 61.1% and 52.8% in control group (p &lt; 0.0003). Patients survival with everolimus-therapy after 1 year was 86.5%, after 3 year it was 64.2%, and by the end of 5 years the possibility of treatment with everolimus decreased to 50.8%, mainly due to the proteinuria and other adverse events. The recurrence rate of tumors among patients, who was treated with everolimus for 35 (26; 60) months was 13.2%. Creatinine level in serum increased from 0.13 ± 0.04 to 0.15 ± 0.09 mmol during the treatment (p &lt; 0.031), and the daily proteinuria increased from 0.18 ± 0.25 g/day to 0.75 ± 1.63 g/day, p &lt; 0.011.Conclusion.The usage of PSi improves long-term survival of KTR with posttransplant malignancy and demonstrates a relatively low tumors recurrence rate (13.2%) over a period of 35 months. However this treatment is not suitable for many patients and it was stopped in almost half of them due to increasing proteinuria or serious adverse events.

A preliminary study on the expression of human leucocyte antigen G in urothelial carcinoma after renal transplantation

Objective To investigate the expression of human leucocyte antigen G (HLA-G) in urothelial carcinoma after renal transplantation, and to analyse the relationship between HLA-G expression and the various clinical and pathological parameters. Methods 29 patients with urothelium carcinoma after renal transplantation for the first time from January 2005 to June 2016 were selected as the experimental group, the age range was 32-70 years, with an average of (55.5±8.1)years. 29 non-transplanted patients with urothelial carcinoma as the control group 1, the age range was 36-74 years, with an average of (57.9±8.2)years. 15 cases of normal urinary tract epithelial were from cystoscopy biopsy as the control group 2. Immunohistochemical method was used to detect the difference of HLA-G expression between the three groups. The clinical and pathological data of patients with urothelial carcinoma after renal transplantation were analyzed. Results The expression rate of HLA-G was 79.3% (23/32) in patients with urothelial carcinoma after renal transplantation, 37.9% (11/32) in non-transplanted group and 0 (0/15) in normal urinary tract epithelium group. The expression rate of HLA-G in non-transplanted group was significantly higher than that in normal urinary tract epithelium group (P<0.05). The expression rate of HLA-G in patients with urothelial carcinoma after renal transplantation was significantly higher than that in non-transplanted group and normal urinary tract epithelium group (P<0.05). Conclusions HLA-G is associated with the occurrence of urothelial carcinoma after renal transplantation. It may provide a new idea for the prevention and treatment of urinary tract epithelium after renal transplantation. Key words: Human leukocyte antigen G; Renal transplantation; Urothelial carcinoma; Post-transplant malignancy

Evaluation of quantitative changes in regulatory T cells in peripheral blood of kidney transplant recipients with skin cancer after conversion to mTOR inhibitors.

IntroductionImmunosuppressive therapy, necessary for graft survival, has its clinical consequences with an increased risk of developing malignancies being one of them. It seems that the maintenance of a proper balance between cytotoxic and regulatory activity of the immune system may prevent graft rejection, and with a lower risk of cancer.AimTo assess the quantitative changes in regulatory T cells (Tregs) in peripheral blood of kidney transplant recipients with post-transplantation skin neoplasm after conversion to mTOR inhibitors (mTORi) and to assess the incidence of secondary skin cancer in that group of patients.Material and methodsFourteen patients with post-transplant cutaneous malignancies converted to mTORi were included into the study. The control group consisted of eighteen patients maintained on immunosuppressive regimens without mTORi. The level of Tregs with a phenotype defined as CD4lowCD25high was measured before, and 6 months after, mTORi introduction.ResultsIn all cases, 6 months after conversion, a significant decrease in the ratio of CD4+CD25+ to CD4lowCD25high from 6.52 to 4.29 was detected (p = 0.035). One patient converted to mTORi developed subsequent skin cancer, while in the control group, subsequent skin cancer was recognized in eight patients. Moreover, introducing mTORi significantly improved progression-free survival in this group of patients (p = 0.016).ConclusionsIntroducing mTORi to the immunosuppressive regimen resulted in an increase in the number of regulatory cells without increasing the incidence of secondary skin cancer in the investigated group of patients.

Temporal Trends of De Novo Malignancy Development After Heart Transplantation

BackgroundMalignancy is a concern in cardiac transplant recipients, but the temporal trends of de novo malignancy development are unknown. ObjectivesThe goal of this study was to describe the temporal trends of the incidence, types, and predictors of de novo malignancy in cardiac transplant recipients. MethodsThe authors analyzed the temporal trends of post-transplant incidence, types, and predictors of malignancy using 17,587 primary adult heart-only transplant recipients from the International Society for Heart and Lung Transplantation registry. The main study outcomes included the incidence of, types of, and time to de novo malignancy. ResultsThe risk of any de novo solid malignancy between years 1 and 5 after transplantation was 10.7%. The cumulative incidence by malignancy type was: skin cancer (7.0%), non-skin solid cancer (4.0%), and lymphoproliferative disorders (0.9%). There was no temporal difference in the time to development according to malignancy type. However, the cumulative incidence of de novo solid malignancy increased from 2000 to 2005 vs. 2006 to 2011 (10.0% vs. 12.4%; p < 0.0001). Survival in patients after de novo malignancy was markedly lower than in patients without malignancy (p < 0.0001). Older recipients and patients who underwent transplantation in the recent era had a higher risk of de novo malignancy. ConclusionsMore than 10% of adult heart transplant recipients developed de novo malignancy between years 1 and 5 after transplantation, and this outcome was associated with increased mortality. The incidence of post-transplant de novo solid malignancy increased temporally, with the largest increase in skin cancer. Individualized immunosuppression strategies and enhanced cancer screening should be studied to determine whether they can reduce the adverse outcomes of post-transplantation malignancy.