Post-transplant Malignancies Research Articles

Incidence, Site and Risk Factor of Post-Transplant Malignancies–Analysis of 771 Renal Transplant Recipients for 40 Years in Japanese Single Center

Incidence, Site and Risk Factor of Post-Transplant Malignancies–Analysis of 771 Renal Transplant Recipients for 40 Years in Japanese Single Center

Effect of immunosuppressive drugs on DNA repair in human peripheral blood mononuclear cells

IntroductionCancer is a major cause of mortality among transplant recipients. Immunosuppressive treatment is a modifiable factor contributing to this phenomenon. Cyclosporine in kidney transplant recipients was associated with reduced UV-induced DNA repair by peripheral blood mononuclear cells (PBMC) and increased cancer rate. H2O2 is a common cellular reactive oxygen species (ROS), which induces DNA damage followed by DNA repair. AimTo investigate the effect of currently used immunosuppressive drugs on DNA repair. MethodsH2O2-induced DNA repair by human PBMC was tested in vitro in the presence of the calcineurin inhibitors (CNI) cyclosporine and tacrolimus, mycophenolic acid (MPA), and the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus, at low to high non-toxic concentrations. The effect of combination therapy at maintenance levels was also tested. ResultsCyclosporine and tacrolimus suppressed DNA repair throughout the tested dose range. In contrast, MPA, sirolimus and everolimus did so only at the high doses. Maintenance doses of a combination of tacrolimus and MPA, the most frequent treatment regimen, reduced DNA repair, while MPA with sirolimus or everolimus did not. ConclusionIn an attempt to reduce the risk of post-transplantation malignancy, treatment protocols may be modified by reducing CNI dose.

Malignancies after renal transplantation in Taiwan: a nationwide population-based study

Renal transplantation has been regarded as the treatment of choice for end-stage renal disease. Renal transplantation increases the risk of cancers due to long-term immunosuppression. The types of post-transplantation malignancies may vary among different geographic regions and ethnic populations. To date, large population-based studies of post-transplantation malignancies in Asian renal transplant recipients (RTRs) have rarely been reported. To investigate the patterns of post-transplantation malignancies in Chinese RTRs, we performed a nationwide population-based cohort study between 1997 and 2008 based on data from the National Health Insurance Database in Taiwan. Patterns of cancer incidence in RTRs were compared with those of the general population using standardized incidence ratios (SIRs). Among the 4716 RTRs (2475 males and 2241 females; mean age 44.1 ± 12.4 years) and 22 556 person-years of observation, 320 post-transplant cancers were diagnosed. The SIR of all cancers was 3.75 (95% confidence interval 3.36-4.18). Women had a higher risk than men for the development of malignancies (SIR 5.04 for women and SIR 2.88 for men). Renal, bladder and liver cancers were the most common cancers, with SIRs of 44.29, 42.89 and 5.07, respectively. When stratified by age, RTRs of young age at transplant (<20 years) had the highest risk of post-transplantation malignancies. This study demonstrates different patterns of malignancies after renal transplantation in Chinese RTRs, with higher incidences of kidney and bladder cancers. Physicians should be more vigilant in examining RTRs for post-transplantation malignancies especially in younger patients.

The efficacy and safety of second allogeneic hematopoietic stem cell transplantation for post-transplant hematologic malignancies relapse

To investigate the safety and efficacy of second allogeneic hematopoietic stem cell transplantation for the relapsed hematologic malignancies. The data of 25 relapsed patients received the second allogeneic transplantation as a salvage therapy in Institute of Hematology Peking University between October 1999 and March 2010 were analyzed retrospectively. Twenty-four patients relapsed at 8.8 (1 - 55) months after the first transplantation, except one received the second transplantation as prophylaxis therapy. They received the second transplantation after 3 (0.3 - 20) months' therapy. The median time between the 2 transplants was 10.6 (0.6 - 59.0) months. Most of the patients were given the conditioning regimen including total body irradiation (TBI, 700 - 779 cGy) or modified busulfan and cyclophosphamide (BUCY, BU 12 mg). All patients survived more than 30 days and achieved sustained white blood cell engraftment. Sinus obstructive syndrome, irradiation dermatitis and acute myocardial infraction were occurred in 3 patients and recoverable. Until January 31 in 2011, with a median observation period of 9.1 (2.0 - 131.1) months, 8 patients had been living with a overall survival (OS) of 30.9%. Twelve patients relapsed at a median 4.4 months and 10 died of it. The other 7 patients died of transplant related complications. The non-relapsed mortality was 35.1%. The disease status at the 2nd transplantation was the only factor which effected the OS (P = 0.009). The second allogeneic transplantation is a viable option for patients relapsing after the first transplantation. Reduced intensive conditioning regimen ensures the graft engraftment and reduces transplant related toxicity.

Walking on the Molecular Pathway: m-TOR Inhibition in the Liver Transplant Setting

Hepatocellular carcinoma (HCC) is a major problem worldwide, representing the fifth most common tumor among the general population (1). Several molecular pathways seem to be involved in HCC growth and progression, realizing an intricate mechanism of proliferative and angiogenetic stimulation and inhibiting apoptosis. The recent identification of these molecular pathways has improved our knowledge of HCC tumorigenesis and has setted up a more specific approach to HCC treatment. However, since non advanced HCC is one of the most common indications for liver transplantation, the recent novelties in pharmacologic inhibition of HCC growth mechanisms have opened new interesting opportunities in recipients' immunosuppressive treatment. M-TOR inhibitors belong to the group of rapamycine analogues, are used as second line immunosuppressive drugs and capable to inhibit one of the most active molecular pathways in HCC cells: the m-TOR pathway. In this review, we explain the mechanism and the molecular elements involved, up- and downstream, in m-TOR activation, providing an overview of the other features of HCC tumorigenesis too. Moreover, we describe the effects of m-TOR inhibition on HCC cells in vitro and in animal models, as well as on liver transplant recipients at risk of or with a manifest tumor recurrence and on de novo post-transplant malignancies. Finally, we discuss the possible efficacy of a proper combined therapy, well tolerated by patients and active against multiple molecular targets, to obtain a synergistic effect on the tumor mass with the greatest benefit for patients' survival and quality of life.

Malignancies after kidney transplantation: a 40-year single-center experience in Korea

Cancer is a well-recognized complication of kidney transplantation (KT), but nearly almost all data have come from Western countries. The aim of this study was to determine the incidence, type, and risk factors of malignancy after KT in Korea. The 1695 patients who underwent KT between 1969 and 2009 were studied retrospectively. Results were compared with a cohort of patients without cancer from the same center. During the follow-up period, 136 of 1695 patients developed 141 post-transplant malignancies (PTM). The cumulative incidence of cancer at 1, 5, 10, 20, and 30 years was 0.64%, 2.42%, 7.89%, 21.49%, and 66.35% respectively. Stomach cancer was the most common PTM. Risk of Kaposi sarcoma, malignant lymphoma, skin cancer, cervical cancer, and renal cell carcinoma was more than 10-times higher in KT recipients. Multivariate logistic regression analysis showed that cancers were clearly associated with recipients' age, recipients' gender, duration of graft function and follow-up period. Our data suggest that most malignancies develop more frequently after KT, but the incidence of individual cancer is different from Western countries. A more vigorous cancer surveillance program should be adapted to risk associated with transplant recipients, especially older, female or long-term follow-up recipients or those with functioning grafts.

Post-transplant malignancy: reducing the risk in kidney transplant recipients

Introduction: The growing and aging of the end-stage kidney disease population, and improvements in short-term kidney transplant outcomes, have increased the number of patients receiving and living with kidney transplants who are at risk for the long-term complications of transplantation. Cancer has become a major cause of death following kidney transplantation, increasing the need to better understand the risk of post-transplant malignancy and to adapt patient management to minimize that risk.Areas covered: This paper reviews the scope of the problem of post-transplant malignancy, its pathogenesis, and strategies for prevention, with attention to the impact of various immunosuppressive strategies. A Medline search was conducted, reviewing English-language publications from 1948 to February 2011.Expert opinion: Post-transplant malignancy, one of the most common causes of death following transplantation, is linked to both modifiable and non-modifiable risk factors. The current armamentarium of pharmacotherapy and the possibilities for immunologic monitoring in the future hold the potential for tailoring post-transplant care to minimize the risk of post-transplant malignancy without sacrificing graft survival to optimize outcomes following transplantation.

De novo malignancy is associated with renal transplant tourism

Despite the objections to transplant tourism raised by the transplant community, many patients continue travel to other countries to receive commercial transplants. To evaluate some long-term complications, we reviewed medical records of 215 Taiwanese patients (touring group) who received commercial cadaveric renal transplants in China and compared them with those of 321 transplant recipients receiving domestic cadaveric renal transplants (domestic group) over the same 20-year period. Ten years after transplant, the graft and patient survival rates of the touring group were 55 and 81.5%, respectively, compared with 60 and 89.3%, respectively, of the domestic group. The difference between the two groups was not statistically significant. The 10-year cumulative cancer incidence of the touring group (21.5%) was significantly higher than that of the domestic group (6.8%). Univariate and multivariate stepwise regression analyses (excluding time on immunosuppression, an uncontrollable factor) indicated that transplant tourism was associated with significantly higher cancer incidence. Older age at transplantation was associated with a significantly increased cancer risk; however, the risk of de novo malignancy significantly decreased with longer graft survival. Thus, renal transplant tourism may be associated with a higher risk of post-transplant malignancy, especially in patients of older age at transplantation.

Risk factors of lung, head and neck, esophageal, and kidney and urinary tract carcinomas after liver transplantation: The effect of smoking withdrawal

Liver transplant recipients have an increased risk of malignancy. Smoking is related to some of the most frequent causes of posttransplant malignancy. The incidence and risk factors for the development of neoplasia related to smoking (head and neck, lung, esophageal, and kidney and urinary tract carcinomas) were studied in 339 liver transplant recipients. Risk factors for the development of smoking-related neoplasia were also studied in 135 patients who had a history of smoking so that it could be determined whether smoking withdrawal was associated with a lower risk of malignancy. After a mean follow-up of 7.5 years, 26 patients were diagnosed with 29 smoking-related malignancies. The 5- and 10-year actuarial rates were 5% and 13%, respectively. In multivariate analysis, smoking and older age were independently associated with a higher risk of malignancy. In the smoker subgroup, the variables related to a higher risk of malignancy were active smoking and older age. In conclusion, smoking withdrawal after liver transplantation may have a protective effect against the development of neoplasia.

81 Early vs. Delayed EVERolimus in De Novo HEART Transplant Recipients

Purpose Multicenter clinical trials showed that everolimus (EVE) associated with low dose cyclosporine (CSA) is superior to azathioprine and equivalent to mycophenolate (MMF) in preventing myocardial acute rejection in de novo heart recipients. In addition, data from randomized and non-randomized studies suggest that EVE may have ancillary properties that may favorably impact long-term survival, by reducing the progression of allograft vasculopathy, the incidence of cytomegalovirus infection, and the onset of post-transplant malignancies. Nonetheless, EVE safety profile still needs to be optimized in particular in the early post-surgery phase, because of a worsening renal function when used with full-dose CSA, and because EVE anti-proliferative properties may delay surgical wound healing and increase the risk for pleural and pericardial effusions. The purpose of this 6-month, controlled, randomized study in de novo heart transplant patients is to compare the occurrence of a composite safety enpoint between a strategy based on delayed introduction of EVE – with MMF as a 4 to 6 weeks bridge in the post-transplant period – and EVE started within post-operative day 5. EVE start dose is adjusted according with some patients' characteristics potentially associated with EVE-related adverse events. This study is sponsored by Novartis Farma Italy and is registered at clinicaltrials.gov ( NCT 01017029 ). Methods and Materials The primary study enpoint is the 6-month composite cumulative incidence of wound healing complications related to initial transplant surgery, pleural/pericardial effusions and occurrence of acute renal insufficiency, defined as GFR ≤ 30/ml/min/1.73m 2 . Results This study has been designed to compare the safety of two EVE strategies of administration that differ from what has been tested in the clinical trials conducted since now. Thus, for patients safety purposes, in the study design we anticipated a pre-specified interim analysis when at least 60 randomized patients completed the first 3-months of follow-up. Conclusions The interim analysis will be completed in January 2011.

Ex vivo gene transfer for improved adoptive immunotherapy of cancer

Adoptive immunotherapy is an appealing approach to cancer treatment, with the potential for more precise targeting and reduced toxicity. While early clinical trial data using adoptive T cells against post-transplant virus-associated hematologic malignancies, lymphoma and melanoma have been promising, treating other solid tumors has proven to be more challenging. Adoptive lymphocytes have been genetically modified in many ways to improve activity and circumvent tumor evasion, including transfer of transgenic T-cell receptors and chimeric antigen receptors to redirect T cell and natural killer cell antigen specificity. Gene transfer may also allow expression of homeostatic cytokines or their receptors to overcome the lack of stimulatory signals or expression of dominant-negative receptors for inhibitory cytokines to compensate for an immunosuppressive tumor milieu. In addition, suicide genes can install a 'safety switch' on adoptively transferred cells to allow ablation if necessary. Although further refinement and validation are necessary, these genetic modification strategies offer hope for significant improvements in cancer immunotherapy.

Current Approaches to Skin Cancer Management in Organ Transplant Recipients

Approximately 225,000 people are living with organ transplants in the United States. Organ transplant recipients have a greater risk of developing skin cancer, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma, with an approximately 250 times greater incidence of squamous cell carcinoma in certain transplant recipients, compared with the general population. Because skin cancers are the most common posttransplant malignancy, the resultant morbidity and mortality in these high-risk patients is quite significant.

Old Male Living Renal Transplant Recipients More Likely to Be at Risk for Colorectal Cancer

Background The development of posttransplant malignancy is a well-recognized complication of kidney transplantation due to immunosuppressive therapy. The literature on colorectal malignancy in living renal transplant recipients are limited; most of the data have been collected from deceased donor cases. As living kidney donation is now growing, we sought to define the characteristics and pattern of gastrointestinal malignancy among this group. Methods This cross-sectional, multicenter study analyzed the incidence and characteristics of colorectal malignancy among 17 patients with gastrointestinal malignancy after living donor renal transplantation between 1985 and 2009 in Iran. We observed a new-onset, biopsy-proven colorectal malignancy in eight patients of mean age 49.6 ± 10.3 years (range = 27–60) at transplantation time and a mean age of 61.1 ± 8.6 years (range = 53.4–78.6) at cancer diagnosis. Results The cumulative incidence rate of colorectal malignancy of 0.03% was restricted to the male gender (100%), all of whom had functioning grafts. The mean period from transplantation to diagnosis was 99.7 ± 10.4 months (range = 5–284). The majority of the recipients were aged more than 50 years ( n = 5) and the most frequent immunosuppressive drug was azathioprine ( n = 5); none had received antithymocyte globulin/antilymphocyte globulin. It was mostly a late-onset malignancy with 50% of recipients presenting beyond 5 years from transplantation. They were followed for a mean of 9.2 ± 2.4 (range = 6–12) months after cancer diagnosis with three patients having succumbed within 9 months. Conclusion Due to the long latency after transplantation and the poor outcomes of colorectal malignancy these patients require long-term screening tests for early detection and due to their poor outcomes a new therapeutic approach.

Case Presentation: Regression of Kaposi’s Sarcoma in a Sudanese kidney Transplant Recipient after Conversion to Sirolimus: a Focus on a Common Clinical Problem

Introduction: Post-transplant malignancy is an increasing problem among patients receiving solid organ transplant worldwide. It has been related to recipient morbidity and mortality. Kaposi's sarcoma (KS) is a relatively common malignancy after kidney and solid organ transplantation, accounting for the majority of malignancies among those patients in developing countries. Case report: We report a 56-year-old male who underwent pre-emptive kidney transplantation on July 2010 from a live related donor (LRD), his son, with an HLA mismatch of three antigens. Induction with Basiliximab (Simulect) was given at the time of transplantation and the patient was then maintained on prednisolone, cyclosporine and azathioprine. He had an episode of acute rejection treated with pulses of methyl prednisolone. Three months after transplantation he presented with Kaposi’s sarcoma of the skin, the diagnosis of which was confirmed by histological examination. Immunosuppressant medication was switched to sirolimus and mycophenolate mofetil. He showed good response within two months of treatment with regression of the skin lesions and improvement of his renal function. Conclusion: Kaposi sarcoma can occur shortly after transplantation in men of African descent. This report confirms earlier reports about the beneficial effect of sirolimus in regression of KS lesions. Keywords: Kaposi’s sarcoma; Kidney Transplantation; Sirolimus; Sudan

Immune functional assay for immunosuppressive management in post-transplant malignancy

Immunosuppression management in post-transplant malignancy is challenging because of a lack of objective immunologic assessment tools. The ImmuKnow assay measures the ATP level from CD4 T cells, quantifying cell-mediated immunity and providing an insight into the immune status of transplant recipients. Its potential use in patients with post-transplant de novo malignancy was evaluated. Thirteen adult transplant patients with de novo malignancy were divided into survivors (n = 9) and non-survivors (n = 4) after malignancy treatment. Tacrolimus and the ImmuKnow levels were monitored before, during, and after malignancy treatment. The ImmuKnow level in non-survivors group was significantly lower before and after malignancy treatment compared to survivors group (p = 0.013 and 0.0014 respectively). In survivor group, the ImmuKnow level was significantly decreased during malignancy treatment (p = 0.019) but recovered to the initial level after the treatment. However, in non-survivor group, the ImmuKnow level remained suppressed throughout the observed period despite a reduction in immunosuppressive drug levels. The ImmuKnow assay can be an objective means evaluating immune status of patients with de novo malignancy. The ImmuKnow assay can express the degree of immune suppression induced by chemotherapeutic or radiation therapy and may be a useful tool in optimizing the timing of re-introduction of immunosuppression after malignancy treatment.

Thymic Hyperplasia after Lung Transplantation Imitating Posttransplant Lymphoproliferative Disorder

Thymic hyperplasia is usually associated with the treatment of malignant tumours and is sometimes linked with endocrine diseases. For the first time, we report a case of thymic hyperplasia in a patient 2 years after bilateral lung transplantation. Contrast-enhanced chest CT scan was highly suspicious for a posttransplant lymphoma or thymoma. Therefore, the patient received total thymectomy. Excised specimens were sent to the Department of Pathology. Unexpectedly, the histological examination revealed hyperplastic thymic tissue without evidence for a posttransplant lymphoproliferative disorder or malignancy.

NK/T-cell lymphoma in a renal transplant recipient and review of literature

T-cell lymphomas, particularly NK/T-cell lymphomas are rare post transplantation malignancies. Only a few cases have been described. These tumors behave aggressively and the outcome is poor. We present here a case of NK/T-cell lymphoma who presented to us with an orbital swelling 9 years after renal transplantation, along with the review of literature. To the best of our knowledge, this is the first case of NK/T-cell lymphoma post-renal transplantation reported from India.

The role of mTOR inhibition in renal transplant immune suppression

AbstractThe mammalian target of rapamycin inhibitors (mTOR‐Is) sirolimus and everolimus represent a class of proliferation signal inhibitors with a wide spectrum of activities, including suppression of T‐cell proliferation and reduction of tumor growth. In solid‐organ transplantation, mTOR inhibitors are an option for maintenance immune suppression due to their relative lack of nephrotoxicity compared with the current backbone of most regimens, the calcineurin inhibitors (CNIs). This property, in conjunction with their unique pharmacology, allows mTOR‐Is to be used as an adjunct or alternative to CNIs. Earlier studies of their use in de novo renal transplantation have delineated potential strategies for use of this class of drugs in groups of patients in whom mTOR inhibition may be useful. From recent kidney studies it appears that the time for introduction of mTOR‐I therapy may be prior to the development of proteinuria or significant graft deterioration. Consideration should also be given to the use of mTOR‐Is in patients with or at high risk of post‐transplant malignancy. Due to potential toxicities, knowledge of the adverse effects and pharmacokinetic profiles of mTOR‐Is is necessary for proper management of patients receiving these agents.

Urological De Novo Malignancy After Kidney Transplantation: A Case for the Urologist

The development of de novo malignancies is a well-known complication after renal transplantation. With increasing donor and recipient age the risk of post-transplant malignancy including genitourinary cancers is increasing. Thus, urologists have an increasing likelihood of treating these cases. We report our experience with the management of urological de novo malignancies after renal transplantation. Urological de novo malignancies developed in 29 of 802 patients after renal transplantation between 1988 and 2009. Data were analyzed for tumor incidence, treatment, followup and possible factors contributing to tumor development. Patients had renal cell carcinoma (12 at a median of 46.5 months after renal transplantation), transitional cell carcinoma (6 bladder cases at 35 months, 2 renal pelvis cases at 37.5 months), carcinoma of the prostate (7 at 69 months) and seminoma (2 at 41.5 months). No treatment related graft losses occurred. Of 3 cases of renal cell carcinoma developing in the graft 2 were treated with nephron sparing surgery. Urological post-transplant malignancies are an increasing problem for urologists. Regular surveillance after renal transplantation is mandatory to detect early occurrence of de novo malignancies and standard urological treatment principles can be applied. Nonfunctioning native kidneys with suspicious lesions should be removed early. Radical pelvic surgery after renal transplantation and nephron sparing procedures in the graft can be a challenge even for the experienced urologist, and require surgical versatility.

Posttraumatic stress disorder and depression in heart transplantation recipients: the relationship with outcome and adherence to medical treatment

Objective There is growing evidence of the importance of psychiatric risk factors for predicting the outcome of heart transplantation (HT) recipients. The aim of our study was to investigate the role of major depression and posttraumatic stress disorder (PTSD) in the prediction of the outcome of HT in a consecutive sample of 107 recipients. Method All subjects of the study underwent a structured diagnostic interview for assessing the presence of pretransplant and posttransplant major depression and transplantation-related PTSD 1 to 5 years after HT. The adherence to medical treatment was assessed some months after the structured interview. The medical outcome (acute rejections, cancer, mortality) was followed up for 8 years on average after the interview, using a prospective design. Results Estimated frequency of psychiatric diagnoses after HT was 12% for transplantation-related PTSD and 41% for major depression. The presence of an episode of major depression prior to HT is a significant independent risk factor for posttransplant malignancies. Age, posttransplant malignancies and poor adherence are significant predictors of mortality in the survival analyses. Conclusions The present study highlights the importance of the assessment of psychosocial variables and psychiatric diagnoses before and after transplantation in HT recipients. Our findings have important clinical implications and require replication with larger samples.