Study of "de novo" malignancies among greek renal transplant recipients

The incidence of malignancy was estimated in 1055 renal transplant recipients, engrafted between 1983 and 2001 including 611 grafts from living and 444 from cadaveric donors. The meoplasms were 22 skin cancers, 18 Kaposi's sarcomas, 10 lymphomas nine non-Hodgkin's and one Hodgkin's lymphoma) and 24 visceral carcinomas. Skin cancers were completely excised. Patients with Kaposi sarcoma were treated by tapering the immunosuppression with cessation of cyclosporine. In addition, four patients received chemotherapy, and one of them received local radiotherapy. All patients with lymphomas were treated by cessation of calcineurin inhibitors with modulation of the immunosuppression to levels that were safe for the graft. Furthermore, five patients underwent first line chemotherapy, two patients radiotherapy and two patients, surgical removal of the tumor. The patients with visceral tumors were treated surgically with excision of the lesions when possible, without severe modification of the immunosuppressive regimen. Chemotherapy or radiotherapy was added accordingly. Disease-related mortality rate in patients with skin cancer was 4.5%; in Kaposi's Sarcoma cases 11.11%; in lymphomas 50%; and in all the other instances, 45.8%. This study shows the increased incidence of certain malignancies in transplant recipients, illustrating the importance of cancer surveillance following kidney transplantation. A substantial reduction or even cessation of immunosuppressive therapy may be necessary to achieve patient survival.     

The Incidence of Tumours in Renal Transplant Recipients with Long-Term Immunosuppressive Therapy

INTRODUCTION: The incidence of cancers after renal transplantation is significantly higher than in population that have not undergone transplantation. It is increased by a long-term survival of functional graft requiring long-term immunosuppressive therapy. MATERIAL AND METHODS: Since 1972, 620 renal transplantations have been performed for different causes of end stage renal disease. The authors report a group of 18 renal transplant patients (2.9%) who had cancer. Patients with malignancies are reviewed according to their age, sex, type of immunosuppression, interval between transplantation and the diagnosis of cancer, method of treatment and survival. RESULTS: All patients received cadaver kidneys, and secondary transplantation was performed in two patients. Five patients received conventional immunosuppression--azathioprine with prednisone, another 13 patients received cyclosporine with prednisone and/or azathioprine. In 13 males and 5 females (mean age 46.1 years) the malignant disease developed about 62.4 months after renal transplantation. Six patients had epithelial skin cancers (four of them had squamous cell carcinomas and two basal cell carcinomas). Two patients had breast cancer, colorectal carcinoma, renal cell carcinoma and bladder cancer, respectively, one patient had gastric cancer, thyroid carcinoma, carcinoma of tonsilla, and monocytic leukaemia with blastic transformation, respectively. The average survival of patients with malignancies was 20.3 months. Of 17 patients with cancer, 13 underwent surgical treatment, four patients with advanced disease received radiotherapy, hormonal treatment or only symptomatic therapy. In one patient the malignant disease was only discovered at autopsy. Five patients died of progressive malignant disease, four of intercurrent disease. Nine (50%) patients are alive, with no evidence of disease (NED), 31.9 months in average following the diagnosis of malignancy. Three patients returned to dialysis treatment, other 6 patients live with well functioning graft. CONCLUSIONS: In patients surviving long time after kidney transplantation the possibility of development of malignant disease should be considered. Preventive evaluation should guarantee early detection of cancer. Appropriate treatment, without cessation of immunosuppressive therapy, is indicated with the intention to prolong the patients' life with a functional graft and without dialysis treatment.     

Anticancer effect of sirolimus in renal allograft recipients with de novo malignancies

The inhibition of mTOR is a target for anticancer drugs in posttransplant malignancies. The influence of conversion to sirolimus after malignancy diagnosis was investigated on patient and renal allograft survivals. The 20 renal allograft recipients (4 women, 16 men) of ages 26 to 73 years (mean, 59 years) developed malignancies within 6 to 172 months (mean, 53 months) after transplantation. Three patients developed posttransplant lymphoproliferative disease (PTLD); four, Kaposi sarcoma, three, lung cancer; two, malignant melanoma; two, breast cancer; two, renal cell carcinoma; one, Merkel cell carcinoma; one, cutaneous T-cell lymphoma; one, larynx cancer; and one, gingival cancer. After tumor diagnosis, calcineurin inhibitors, azathioprine, or mycophenolate mofetil (MMF) were discontinued abruptly and sirolimus introduced (2 mg/d; target trough level, 4.0 to 8.0 ng/mL). Prednisone was maintained. The observation time of sirolimus therapy was 4 to 48 months (mean, 14 months). Two patients with PTLD (large B-cell lymphoma) and four with Kaposi sarcoma had full regressions. Eleven patients (larynx cancer, melanoma, breast cancer, T-cell lymphoma, renal cell carcinoma, Merkel cell carcinoma, and skin lymphoma) in addition to sirolimus therapy, underwent oncologic treatment, namely, surgery and/or chemotherapy. Six patients died from disseminated malignancy 4 to 9 months after conversion. One patient with T-cell lymphoma lost his graft; in the remaining patients, serum creatinine level was stable. In conclusion, Conversion to sirolimus resulted in regression of large B-cell lymphoma and Kaposi sarcoma. In patients with advanced or disseminated malignancy, the tumors progressed. Graft function was preserved after conversion to sirolimus.     

A comparison of prednisolone and methylprednisolone for renal transplantation

A large difference in immunosuppressive potency between methylprednisolone and prednisolone has been suggested in vitro . However, the selection of the best glucocorticoid for renal transplantation has been seldom considered so far. Thus, the present study was undertaken to compare therapeutic efficacy between prednisolone and methylprednisolone in renal transplantation. We studied 42 renal transplant recipients who were operated on between 1990 and 1994. The patients were divided into two treatment groups: a methylprednisolone/cyclosporine group (n=19) and a prednisolone/cyclosporine group (n=23). Clinical outcome and drug side effects were compared retrospectively between the treatment groups 24–84 months after transplantation. The overall graft survival time in patients treated with methylprednisolone/cyclosporine was superior to that in patients treated with prednisolone/cyclosporine (p<0.05). Among the recipients from cadaver donors, 5/16 (31.3%) treated with prednisolone required nephrectomy, whereas none of the 10 patients treated with methylprednisolone received nephrectomy (p<0.01). An examination of the recipients from living related donors revealed that serum creatinine levels 24–36 months after operation were significantly lower in the methylprednisolone group (p<0.05). Cyclosporine trough levels and glucocorticoid side effects were similar between the treatment groups. The results raised the possibility that methylprednisolone is superior to prednisolone when combined with cyclosporine for maintenance immunosuppressive therapy in renal transplantation.     

Impaired phosphate handling of renal allografts is aggravated under rapamycin-based immunosuppression.

BACKGROUND: Impaired phosphate handling of the renal allograft is a common problem and of multifactorial origin. The aim of the study was to elucidate whether a rapamycin- or a mycophenolate-based immunosuppressive therapy aggravates the renal phosphate leak in kidney transplant recipients. METHODS: Renal phosphate handling was determined in thirty-eight cadaveric allograft recipients, with good renal function at 8, 12, 20 and 28 weeks after transplantation. Nineteen patients (group 1) received triple immunosuppression with rapamycin, cyclosporine and prednisolone, nineteen other transplant recipients received mycophenolate mofetil, cyclosporine and prednisolone immunosuppression (group 2), and six healthy subjects (group 3) served as controls. After 12 weeks of stable graft function, group 1 patients were divided further into two subgroups. Ten patients were kept on their immunosuppressive regimen (group 1A), whereas the remaining nine randomly chosen subjects had their cyclosporine withdrawn; they were thus maintained on a dual immunosuppression regimen with prednisolone and a higher dosage of rapamycin (group 1B). RESULTS: Renal phosphate reabsorption was significantly lower in group 1 at 8 and 12 weeks after transplantation as compared with groups 2 and 3. At 20 weeks after transplantation, patients with rapamycin-based immunosuppression (groups 1A and 1B) continued to exhibit hypophosphataemia and impaired renal phosphate handling. Group 1B had the lowest TmP/ GFR compared with all groups. At 28 weeks, renal phosphate reabsorption and plasma phosphate levels were no longer different between patient groups and controls. CONCLUSION: These data suggest that rapamycin-based immunosuppression prolongs the phosphate leak of the allografted kidney, leading to low serum phosphate levels during the first weeks after transplantation.     

Case of adult mumps infection after renal transplantation

Viruses are the most common cause of opportunistic infections, important complications of transplantation. Mumps infection in renal transplant recipients is uncommon. This report focused on a 23-year-old woman who received immunosuppressive therapy based on tacrolimus, prednisolone, and mycophenolate mofetil for renal transplantation. Sixteen months after transplantation, she was admitted with pain and swelling in both infra-auricular areas. Laboratory findings demonstrated positive mumps IgM and IgG antibodies and an increased serum amylase level. Computed tomography revealed both parotid glands to be diffusely enlarged. After the diagnosis of mumps parotitis, the patient's immunosuppression was reduced and the clinical course was satisfactory.     

Immunosuppressive therapy and Kaposi's sarcoma after kidney transplantation

Immunosuppressive therapy for organ transplant recipients is complicated by high rates of malignant diseases, one of which is Kaposi's sarcoma (KS). Between November 1975 and March 2003, 1425 patients underwent renal transplantation at our center, including the 1095 most recent procedures. Fifty-two malignancies were observed in 50 patients (4.7%), including 16 cases of KS. The 16 recipients comprised 6 men and 10 women of mean age 39 +/- 9 years (range 10 to 62 years). At the time of KS diagnosis, 14 recipients were receiving cyclosporine, azathioprine, and prednisolone, and the other 2 azathioprine and prednisolone. The mean time from transplantation to diagnosis was 24 +/- 15.2 months (range 8 to 74 months). One recipient showed a lymphoma concomitant with KS. Seven patients had lesions limited to the skin, 5 had the skin and gastrointestinal tract disease, and 4 had disseminated disease. After KS was confirmed, the first-line treatment was cyclosporine and azathioprine withdrawal with tapering of prednisolone. The tumors were managed by appropriate surgical and/or medical therapy. At the time of this presentation, 9 individuals are alive, 4 with normal renal function. Five patients lost their grafts due to chronic rejection. We found that the combination of immunosuppressive drug withdrawal and chemotherapy is effective in patients with limited disease, but the results are poor in cases of generalized disease.     

肾移植受者术后发生恶性肿瘤的分析(附19例报道)

目的 了解肾移植术后恶性肿瘤的发病情况、类型及治疗效果。方法 回顾性分析1977-1999年同种肾移植术1286次/1132人,术后肿瘤的发生情况和免疫抑制剂使用情况。结果 共发生恶性肿瘤19例,发生率1.67%,分别发生于移植术后5-126个月,平均57个月。其中泌尿系肿瘤11例,肝癌、肺癌各2例,胃癌、乙状结肠癌,乳腺癌,恶性淋巴瘤各1例,13例行手术治疗,现存活10例,平均存活期20个月,7例属肿瘤病变晚期,短期内死亡,1例死于感染引起的中毒性休克,1例死于肝功能衰竭。结论 肾移植术后恶性肿瘤的发生率明显提高,以泌尿系肿瘤最常见,治疗上应争取尽早手术切除肿瘤。     

Cyclophosphamide in renal transplantation

Success in renal transplantation is now largely dependent on safe and effective immunosuppression. Nonspecific immunosuppression by chemical agents continues to be the mainstay of clinical immunosuppression. Azathioprine and prednisolone have remained the two main drugs used in combination in standard immunosuppressive therapy in renal transplantation for many years. Although cyclophosphamide (CP) was tried in the early years of transplantation, enthusiasm for its use was dampened by the advent of newer agents. We have analyzed our experience with 29 recipients of living-related donor (LRD) renal allotransplantation on cyclophosphamide therapy. Cyclophosphamide is a safe and effective alternative to azathioprine in clinical renal allotransplantation. Due to its easy availability and the fact that it is a cheaper alternative to azathioprine and cyclosporine, it is more significant for developing countries.     

Malignancy after renal transplantation: incidence and role of type of immunosuppression

Background Cancer, particularly skin cancer and lymphoma, is a complication of posttrans-plantation immunosuppression. We investigated the characteristics of cancers in our renal transplant population, the role of type of immunosuppression on cancer incidence, and whether newer, more potent immunosuppressive agents produce cancers sooner after transplantation. Methods The charts of patients who developed cancer after renal transplantation between 1958 and 2000 were reviewed. Statistical analyses were performed with the mid-P version of Fisher's exact test for 2×2 tables for incidence comparison of cancer and with Student'st-test for differences between mean times to cancer. Results Between 1958 and 2000, 924 transplantations in 760 patients were performed. We found a cancer incidence of 12.2%. The most frequent cancers were skin and genitourinary. The overall mortality was 54%. We found an increased incidence of cancer in the group of patients in the cyclosporine era and for patients ≥45 years at transplantation. Cancer did not develop sooner in the cyclosporine group. Conclusions The distribution of types of cancer was similar to that reported in the literature. The mortality rate was high. The incidence of cancer was higher in the cyclosporine era in patients ≥45 years at transplantation. Presented at the Society of Surgical Oncology Meeting, Washington, DC, March 2001.     

Urological malignancy after renal transplantation

Immunosuppression in solid-organ recipients is associated with a greater risk of de novo malignancy after transplantation; herein we report the UK transplant registry (UKTR) database of urological cancer after renal transplantation in the UK transplant population. From September 1999 to January 2006 there were 10,847 kidney recipients with at least one period of follow-up reported after a kidney transplant (mean age at transplantation 42.4 years, sd 15.5; 6685 male, 61.6%, and 4162 female, 38.3%). The recipients represent a homogenous group who received different immunosuppression regimens. Skin cancer was excluded from the study. Unfortunately, the UKTR does not collect information about the presence or absence of cancer, either at registration onto the transplant waiting list or at transplantation. In all, 214 (1.9%) patients were reported to have a subsequent urological malignancy diagnosed among the 10,847 recipients. The UKTR was used to identify patients who developed urological malignancies after renal transplantation, which is a challenging event after solid-organ transplantation. Regular surveillance to diagnose early occurrence and adjustment of immunosuppression might be beneficial. In the presence of metastatic disease, chemotherapy treatment with adjustment or cessation of immunosuppressive therapy is required.     

The janus face of immunosuppression - de novo malignancy after renal transplantation: the experience of the Transplantation Center Munich

After decades of successful organ transplantation clinicians continue to be troubled by the increasing incidence of cancers under maintenance immunosuppression. In this study, we examined rates of malignancies in 2419 renal transplant recipients transplanted in our institution between 1978 and 2005. In renal transplant recipients the cumulative incidence of cancer after 25 years was 49.3% for all tumors and 39.7% excluding non-melanoma skin cancers, compared with 21% for a normal sex- and age-matched population. The most frequent tumors observed were non-melanoma skin cancers (20.5%), kidney cancers (12.0%), and cancers of the pharynx, larynx, or oral cavity (8.2%). The general increase of cancer risk was 4.3-fold. Independent risk factors for the development of a tumor were male gender, older recipient age, the presence of preformed antibodies before transplantation, and the time on immunosuppression. Interestingly, the use of IL-2-receptor antagonists significantly reduced the tumor risk of transplant recipients. The tumor risk between immunosuppressive drugs typically used for maintenance immunosuppression was not significantly different. However, mammalian target of rapamycin (mTOR) inhibitor-based immunosuppressive protocols showed a clear tendency for lower malignancy rates. De novo malignancies following renal transplantation represent a serious problem endangering the prognosis of otherwise successfully transplanted patients. Future studies will have to address whether optimized immunosuppressive regimens including mTOR-inhibitors are capable of reducing the incidence or preventing the development of posttransplant malignancies.     

Sirolimus and mycophenolate mofetil as calcineurin inhibitor-free immunosuppression in a cardiac transplant patient with chronic renal failure.

Chronic renal failure triggered by calcineurin inhibitor (CNI)-based immunosuppression is a common complication after cardiac transplantation. Sirolimus and mycophenolate mofetil (MMF) are 2 newer immunosuppressive agents with no documented nephrotoxic side effects. This case report describes a patient with ongoing chronic renal failure 10 months after cardiac transplantation on cyclosporine-based immunosuppressive therapy. Conversion of the immunosuppressive regimen from cyclosporine to sirolimus and MMF resulted in freedom from acute rejection, excellent cardiac graft function and consistently improved renal function. This case illustrates the beneficial potential of sirolimus and MMF as CNI-free and safe long-term immunosuppression in a patient with chronic renal failure after heart transplantation.     

Rapid development of an immunoblastic lymphoma and death in children following cadaveric renal transplantation.

We report on three children who underwent cadaveric renal transplantation and subsequently developed an immunoblastic lymphoma, leading to death in two patients. The development of the lymphoma occurred following a multi-drug immunosuppression regimen ending with monoclonal antilymphocyte (OKT3) treatment for biopsy-proven cellular and vascular acute rejection. These patients represent three of 11 children who received OKT3 treatment for rejection in the last 18 months at this institution. Following the diagnosis of lymphoma, all three patients were treated by transplant nephrectomy, cessation of immunosuppression, and administration of intravenous acyclovir. The first two patients died at 4 days and 4 weeks, respectively, after the definitive diagnosis was made with widespread metastatic disease. The remaining child is a short-term survivor (13 months), free of demonstrable malignancy. Multidrug regimens for immunosuppression have a profound effects on T cell function. These effects, when combined with a primary infection by the Epstein-Barr virus, are implicated in the rapid development of the lymphomas and are responsible for the death of these two children.     

A new model of corneal transplantation in the miniature pig: efficacy of immunosuppressive treatment

Corneal allograft rejection is frequently studied in small rodent or rabbit models. To study mechanisms of rejection in a model that more closely mimics transplantation in humans, we performed orthotopic corneal transplantation in the miniature pig using a 7-mm diameter donor graft. Four groups of recipients were studied: 1) untreated naive, 2) untreated vascularized (high risk), 3) high-risk grafts treated by topical application of prednisolone, or 4) high-risk grafts treated with a combined systemic immunosuppression regime of oral prednisone, cyclosporine A, and mycophenolate mofetil. Both the clinical features and histological assessment of corneal graft rejection showed close similarities to graft rejection in humans. Interestingly, preliminary results indicated that topical steroid treatment was superior to systemic immunosuppression in significantly promoting graft survival. Thus, corneal transplantation in the pig represents an animal model most closely resembling corneal grafting in humans, and offers possibilities for testing various clinically applicable immunosuppressive treatments.     

Incidence of Upper Aerodigestive Tract Cancer After Liver Transplantation for Alcoholic Cirrhosis: A 10-Year Experience in an Italian Center

Introduction

The aim of this study was to evaluate the incidence, clinical characteristics, treatment, and outcome of de novo tumors (DNT) of the upper aerodigestive tract in patients with alcoholic cirrhosis after orthotopic liver transplantation (OLT).

Methods

Among 225 consecutive OLT performed between January 2002 and January 2012, a total of 205 patients received a first liver allograft. Eleven (4.9%) patients developed DNT (lung, pancreas, bowel, esophagus, larynx, tongue, tonsil, and lymphoma). Among these, we observed 5 patients with DNT of the upper aerodigestive tract.

Results

The 5 patients with DNT of the upper aerodigestive tract underwent OLT for alcoholic cirrhosis. There were 4 men and 1 woman with a mean age at transplantation of 47 years. The mean period of alcohol abuse was 90 months. The tumors occurred after a mean post-transplantation time of 39 months. The immunosuppressive regimen included Tacrolimus, mTOR, mycophenolate mofetil (MMF), and low-dose steroids. We observed 2 cases of squamous cell carcinoma of the esophagus, 1 case of tonsillar cancer, 1 case of larynx carcinoma, and 1 case of tongue carcinoma. All patients underwent surgical excision. After surgery, 4 patients received chemotherapy and 2 patients radiotherapy. At present, among the 5 patients with DNT of the upper aerodigestive tract, only 2 are alive without disease and 1 is alive with a local recurrence.

Conclusion

The incidence of DNT of the upper aerodigestive tract after OLT is higher among patients receiving a transplant for alcoholic cirrhosis. This could be due to an additional effect of post-transplantation immunosuppression in patients exposed to alcohol before transplantation. We suggest a careful post-transplantation follow-up and more attention to improve early diagnosis.     

Sirolimus: a potent new immunosuppressant for liver transplantation

BACKGROUND: Sirolimus (rapamycin) is a new immunosuppressant that appears to be synergistic with cyclosporine in kidney transplantation, but with a different side-effect profile. This pilot study evaluated sirolimus in liver transplantation. METHODS: Patients undergoing orthotopic liver transplantation for primary tumors (8), and later for nonmalignant disease (7), received one of three sirolimus-based immunosuppressive regimens. Protocol A comprised sirolimus, microemulsion cyclosporine (target whole blood concentration: 100 ng/ml), and prednisolone; protocol B omitted prednisolone; and protocol C was sirolimus alone. By 3 months after transplantation, all patients were receiving sirolimus as monotherapy. RESULTS: Fifteen patients were treated with a follow-up of 117-806 days. Rejection was more common on monotherapy than double therapy, and absent on triple therapy. The drug was generally well tolerated, with only three patients discontinuing sirolimus: one for hyperlipidemia, one for pneumocystis pneumonia, and one for inability to tolerate the taste of the drug. Two patients discontinued cyclosporine early, both as a result of neurological complications; they continued on sirolimus monotherapy. Five patients died; one suffered a cardiac arrest, and four died from sepsis in association with graft-versus-host disease, recurrent tumor, a paralyzed right hemidiaphragm, and primary nonfunction. CONCLUSIONS: Sirolimus combined with cyclosporine provided potent immunosuppression of liver allografts, and sirolimus monotherapy was adequate and well tolerated as maintenance therapy. Side effects of sirolimus over the short period of follow-up were uncommon and reversible with dose reduction or cessation of therapy.     

6例心脏移植围手术期的处理

目的总结6例心脏移植围手术期处理经验。方法6例晚期心肌病患者接受同种体原位心脏移植术。围术期免疫抑制剂采用赛尼哌诱导方案。维持治疗为环孢素A＋吗替麦考酚酯（或硫唑嘌呤）＋泼尼松三联方案,术后保持低水平的中心静脉压。随访23～30个月,平均（25．6＋4．2）个月。结果6例受者均存活。1例因牙髓感染并发败血症致胸部伤口延期愈合．1例出现硬膜外血肿、脑疝形成行开颅手术。所有患者围术期及随访期间受者均无急性排斥反应、移植物功能不全、肝肾功能不全等并发症。结论围术期适当强度的免疫抑制治疗,合理应用强心利尿,密切监测血流动力学和重视受者的个体化治疗是防治心脏移植术后并发症的有效方法。     

Living related renal transplantation for end-stage renal disease after liver transplantation from a brain-dead donor

We report a case in which a living related renal transplantation was successfully performed for end-stage renal disease that had progressed after a liver transplantation from a brain-dead donor for liver cirrhosis associated with type C hepatitis. Because the transplanted liver function had been excellent with the use of tacrolimus and mycophenolate mofetil, the same immunosuppressive agents with prednisolone were employed for the renal transplantation. Both grafts are functioning well without recurrence of hepatitis at 10 months after the renal transplantation. From our experience, renal transplantation should not be contraindicated even if the patient has undergone liver transplantation or has hepatitis C viral infection.