Kaposi's sarcoma and mTOR: a crossroad between viral infection neoangiogenesis and immunosuppression

The incidence of Kaposi's sarcoma (KS) among the recipients of solid organ transplants is about 500 times the rate in the general population, suggesting a role for immunosuppression in the development of the disease. The drugs used for the induction and maintenance of immunosuppression and the length of treatment with these agents influence both the incidence and the type of cancer development. The clinical presentation of KS in transplant recipients is often limited to the skin. The risk of death from KS is related to the form and extent of the lesions. The main approach to managing transplant-associated KS is to reduce or even discontinue immunosuppressive therapy; this strategy carries a risk of acute rejection of the graft. KS is a multicentric tumor composed of endothelium-lined vascular spaces and spindle-shaped cells. Its pathogenesis is unclear. Recent evidence suggests that vascular endothelial growth factor (VEGF) is likely to be a growth factor for KS cells: blocking the interaction between VEGF and Flk-1/KDR can abolish VEGF-induced growth of the tumor. Recently, Sirolimus, a drug used in kidney-transplant recipients, has been suggested to reduce KS progression in transplant recipients. This unexpected effect of the drug confirms previous experimental information on KS pathogenesis and may shed light on an array of molecular mechanisms, modulated by Sirolimus, of potential clinical interest in the transplantation scenario.     

Immunosuppressants and Skin Cancer in Transplant Patients: Focus on Rapamycin

Background. The responsibility of immunosuppressants for the increased risk of skin cancers in organ transplant recipients is widely recognized. Discerning the role of each drug is complicated owing to the fact that most patients generally have combinations of several medications.
Objective. This article will discuss the role of the main immunosuppressants in the pathogenesis of skin cancers.
Methods. This work consists of a review of the most significant publications.
Results. Experimental and clinical studies suggest that corticosteroids, azathioprine, cyclosporine (CsA), and tacrolimus increase the incidence of skin cancer. Each drug may act through two different mechanisms including the impairment of the systemic immunosurveillance and a direct oncogenic effect. CsA was shown to be oncogenic independently of its immunosuppressive effect. By contrast, several works on mice have found that rapamycin inhibits tumor growth while being immunosuppressive. Furthermore, rapamycin was shown to inhibit several UV-induced mechanisms involved in skin carcinogenesis. Preliminary clinical studies have reported a lower incidence of skin malignancy in patients treated with rapamycin compared to CsA from the time of transplantation.
Conclusion. New immunosuppressive strategies for transplant patients with skin cancer are not only based on minimizing immunosuppression. Data suggest that rapamycin could have a protective effect against skin cancer. Further studies are required to assess accurately the efficacy and tolerance of rapamycin in these patients.     

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 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.     

Acitretin for prophylaxis of cutaneous malignancies after cardiac transplantation.

BACKGROUND: Heart transplant recipients have an increased risk of developing actinic keratoses and non-melanotic skin cancers when compared with the general population. Systemic retinoids have been shown to be beneficial in the treatment of such lesions in recipients of other organs, but as of yet the heart transplant model has rarely been studied. In this investigation we describe our experience with the use of acitretin in a group of heart transplant patients. METHODS: Five heart transplant recipients with multiple new skin cancer presentations were treated with acitretin at doses of either 10 or 25 mg/day. Inclusion criteria were based on progressive actinic keratoses, recurrent skin malignancies or continuous lesions despite treatment with appropriate topical therapies. Patients were excluded if they were women of child-bearing age, had severe hepatic or renal impairment or were taking contraindicated medications. RESULTS: Over the treatment period all patients showed a reduction in the number of new non-melanotic skin cancers excised and histologically confirmed. Three patients had a very large reduction and 2 patients had a more moderate reduction in the number of new presentations. All patients had an objective decrease in the number of actinic keratoses. All patients tolerated the drug well with only 1 patient transiently discontinuing the Acitretin due to side effects. No significant alterations in the biochemical tests or serum lipids were reported. CONCLUSIONS: Over the treatment period, low-dose acitretin proved a valuable addition in the long-term strategy of reduction and treatment of non-melanotic skin cancers in heart transplant recipients with multiple skin cancers and actinic keratoses.     

Maintenance immunosuppression: new agents and persistent dilemmas

Since the approval of cyclosporine in 1983, only 3 drugs, mycophenolate mofetil, tacrolimus, and sirolimus, have been approved for maintenance immunosuppression in renal transplant recipients. All 3 agents decrease the incidence of early acute allograft rejection. An increase in intermediate and long-term graft survival has not been shown. However, survival data from these clinical trials should be interpreted with caution because the studies were not designed for this purpose. All 3 drugs have significant, albeit different, safety profiles. It remains to be seen whether, the lower incidence of hypertension and hyperlipidemia seen in tacrolimus-treated patients will reduce the incidence and severity of the cardiovascular disease experienced by renal transplant recipients. Sirolimus causes severe hyperlipidemia, and the long-term consequences both on the pathogenesis of cardiovascular disease and on lipid-associated renal injury have yet to be determined. Tacrolimus and mycophenolate mofetil appear to increase graft survival in pancreas-kidney recipients but their efficacy in another high-risk group, African-American recipients, has not yet been clearly shown. However, the trend toward improved graft survival in African-American recipients treated with tacrolimus is encouraging. Steroid-withdrawal remains a goal in the posttransplant period. The available data from steroid-withdrawal and steroid-avoidance clinical trials are mixed. Steroid withdrawal can be achieved in about 50% of patients on a cyclosporine-based immunosuppression regimen. Steroid-withdrawal under coverage of tacrolimus, mycophenolate mofetil or Neoral (Novartis Pharmaceuticals, East Hanover, NJ) may be more successful than that achieved in patients receiving Sandimmune (Novartis Pharmaceuticals). Further studies are needed in this area.     

P53 Immunohistochemical Expression in Early Posttransplant-Associated Malignant and Premalignant Cutaneous Lesions

Background.  Current evidence suggests that p53 accumulation is critical to the development of skin cancer in the general population. It is possible, however, that the molecular steps involved in transplant-associated and non-transplant-associated skin carcinogenesis may differ.
Objective.  Our purpose was to examine p53 expression in premalignant and malignant skin lesions from renal transplant recipients (RTRs) in their first 3 years of immunosuppression, as well as in equivalent lesions from immunocompetent normal individuals.
Methods.  p53 expression was examined by routine immunohistochemical methods using the anti-p53 monoclonal antibody DO7.
Results.  p53 immunoreactivity was more prevalent in dysplastic epidermal keratoses and cutaneous carcinomas from RTRs than in equivalent lesions from nontransplant controls. Statistical analysis revealed significant differences, however, only in premalignant skin lesions ( p = 0.03).
Conclusion.  This study demonstrates that accumulation of p53 protein is frequently encountered in both premalignant and malignant skin lesions of RTRs, and that this may occur as an early step in transplant-associated skin carcinogenesis.     

Everolimus immunosuppression in de novo heart transplant recipients: What does the evidence tell us now?

The efficacy of everolimus with reduced cyclosporine in de novo heart transplant patients has been demonstrated convincingly in randomized studies. Moreover, everolimus-based immunosuppression in de novo heart transplant recipients has been shown in two randomized trials to reduce the increase in maximal intimal thickness based on intravascular ultrasound, indicating attenuation of cardiac allograft vasculopathy (CAV). Randomized trials of everolimus in de novo heart transplantation have also consistently shown reduced cytomegalovirus infection versus antimetabolite therapy. In maintenance heart transplantation, conversion from calcineurin inhibitors to everolimus has demonstrated a sustained improvement in renal function. In de novo patients, a renal benefit may only be achieved if there is an adequate reduction in exposure to calcineurin inhibitor therapy. Delayed introduction of everolimus may be appropriate in patients at high risk of wound healing complications, e.g. diabetic patients or patients with ventricular assist device. The current evidence base suggests that the most convincing reasons for use of everolimus from the time of heart transplantation are to slow the progression of CAV and to lower the risk of cytomegalovirus infection. A regimen of everolimus with reduced-exposure calcineurin inhibitor and steroids in de novo heart transplant patients represents a welcome addition to the therapeutic armamentarium.     

Malignancy in uremia: dialysis versus transplantation.

The incidence of cancer was compared in 499 dialysis patients and 121 renal transplant recipients. De novo malignancy developed in 15 patients on chronic dialysis (3 per cent) and in 6 transplant recipients (4.9 per cent), a significant increase over the expected number in the age-matched general population. There was no difference in the incidence of cancer in uremic patients on dialysis or after transplantation. A total of 10 dialysis patients (67 per cent) and 1 transplant patient (16 per cent) died of cancer. Neoplasms in the dialysis patients were the common types of mesenchymal tumors, while superficial skin cancers were seen more frequently in the transplant recipients. The differences in tumor types accounted for the higher mortality rate from cancer in the dialysis patients and may reflect different patterns of immunosuppression in these 2 patient populations.     

The Historical Link Between Solid-Organ Transplantation, Immunosuppression, and Skin Cancer

Background. Skin cancers are more common in organ transplant recipients than in the general population.
Objective. The objective of this study was establish the historical link between organ transplantation, immunosuppression, and the development of skin cancer.
Methods. The pertinent literature in cutaneous oncology and transplantation is reviewed.
Results. There is a historical link between organ transplants, immunosuppression, and the subsequent development of skin cancers.
Conclusions. Organ transplant recipients have more skin cancer than those in the general population and this is temporally related to their degree of immunosuppression.     

Systemic strategies for chemoprevention of skin cancers in transplant recipients

BACKGROUND: Solid organ transplant recipients (OTRs) are a growing population at high risk for cutaneous neoplasms, resulting in significant post-transplant morbidity and mortality. Management of malignant and pre-malignant cutaneous lesions in transplant recipients is challenging, making prevention of such neoplasms paramount. The objectives of the present study are to review and analyze systemic strategies for chemoprevention of malignant and pre-malignant cutaneous neoplasms in OTRs. METHODS: MEDLINE and PubMed searches were performed to identify studies with original data quantifying the effects of systemic agents on the development of malignant cutaneous neoplasms in patients with solid organ transplants. RESULTS: We identified nine studies describing 111 transplant recipients that quantified the effects of oral retinoids on cutaneous neoplasms. A majority of the studies found a decrease in the number of malignant and pre-malignant cutaneous lesions in patients treated with systemic retinoids, with several studies noting increased benefit in those patients with multiple previous skin cancers. Multiple studies described a rebound effect, with increased numbers of neoplasms occurring following discontinuation of retinoids. Side effects often limited dosing, but required discontinuation of retinoids in a minority of patients. No studies were identified that adequately quantified the effects of other systemic agents on skin cancer incidence in this population. CONCLUSIONS: Although systemic retinoids are frequently used for chemoprevention of cutaneous malignancies in OTRs, the data supporting their use are composed largely of small uncontrolled case reports and case series. However, the available data suggest that retinoids have chemopreventative effects in this population. Although optimal dosing and indications for initiation of systemic retinoid therapy are not conclusive from the data, it suggests that retinoids are most effective in patients with multiple previous non-melanoma skin cancers. Side effects and beneficial effects were noted across a wide range of doses, suggesting that retinoids should be initiated at a low dose and increased as tolerated to a minimally effective dose. Further investigation through randomized controlled trials is needed to further clarify the tolerability and efficacy of multiple dosing regimens on the incidence of pre-malignant and malignant lesions in transplant recipients. The therapeutic role of other systemic agents in the transplant population has not been established.     

What do we know about the clinical impact of complete withdrawal of immunosuppression in liver transplantation?

The liver is a privileged organ with a lower incidence of rejection than other organs. However, immunosuppressive regimens are still required to control the alloreactive T-lymphocyte response after transplantation. These treatments may lead to severe complications, such as infectious diseases, cancers, cardiovascular diseases, and chronic renal insufficiency. In clinical transplantation, there is increasing evidence that some liver transplant recipients who cease taking immunosuppressive drugs maintain allograft function, suggesting that tolerance is already present. This strategy is feasible in 25% to 33% of liver transplant recipients. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression (IS) withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with it. In preliminary studies, IS withdrawal was safely achieved in selected liver transplant patients, and improved not only kidney function, but also other IS-associated side-effects such as hypercholesterolemia, hyperuricemia, hypertension, and diabetes control. However, longer follow-up periods are needed to confirm the benefits of IS withdrawal in liver transplant patients.     

Dermatopathology of skin cancer in solid organ transplant recipients

Skin cancers occur more frequently in solid organ transplant recipients relative to the general population. Transplant recipients are at particularly high risk of squamous cell carcinoma, with up to a 100-fold increase in the relative risk when compared to the nontransplanted population. This compares with a 10- to 16-fold increase in basal cell carcinoma for renal transplant recipients. An increased incidence of melanoma in transplant patients has also been reported. Other types of skin cancer associated with immunosuppression in transplant patients include Kaposi sarcoma, Merkel cell carcinoma, and posttransplant lymphoproliferative disorder. This review discusses the epidemiology and pertinent pathologic features of each of these tumors. A brief clinical management strategy is outlined. In addition, the contribution of viral induced carcinogenesis with respect to Kaposi sarcoma, Merkel cell carcinoma, and posttransplant lymphoproliferative disorder is discussed.     

Baseline Quality of Life and Anxiety in Solid Organ Transplant Recipients: A Pilot Study

BACKGROUND: Solid organ transplant recipients on high doses of immunosuppression are at increased risk for the development of nonmelanoma skin cancer (NMSC). OBJECTIVE: The objective was to assess the possible factors impacting quality of life (QOL) in solid organ transplant recipients. METHODS: Patients were seen in a dermatology clinic integrated within the transplant center at a university-based hospital. One anxiety questionnaire and three QOL questionnaires were administered to each patient. A regression model was used to determine possible predictors of anxiety and lower QOL. RESULTS: The baseline scores on the QOL instruments and anxiety questionnaire indicate poor organ-specific and general QOL as well as high levels of anxiety. Time since transplant was predictive of lower QOL as measured by Skindex-16 (p<.01). While not significant, number of NMSCs correlated with higher anxiety as measured by the STAI (p=.055). CONCLUSIONS: While transplant patients enjoy longer survival, the quality of the extended life has room for improvement. Future studies will determine how QOL changes over time as these patients develop more numerous and aggressive skin cancers. Intervention with regular screening may not only lessen morbidity associated with skin cancer but may improve overall QOL in the posttransplant period.     

Prostate Cancer Metastatic to the Renal Allograft: A Case Report

Malignancy is a leading cause of morbidity and mortality in organ transplant recipients who receive immunosuppression. Cancers associated with viruses such as nonmelanotic skin cancer and Kaposi sarcoma occur in allograft recipients at rates that far exceed that in the general population. The increased risk and tumor type may depend not only on degree of immune system modulation but also on the type of organ transplanted. In kidney transplant recipients, the risk of cancers such as prostate and breast does not seem to be increased. However, these cancers tend to be advanced and aggressive. The management of these cancers is similar to the general population with the additional consideration for reduction in immunosuppression and conversion to sirolimus. Given the increased survival of both transplanted organs as well as organ recipients along with the increased number of older recipients, the diagnosis of prostate cancer in the older male organ recipient is increasing. The long-term outcomes using current treatment guidelines for prostate cancer in these individuals are not clear. We report a case of known localized prostate cancer in a renal transplant recipient presenting with metastasis diagnosed as tumor infiltration of the allograft. Our patient, upon initial diagnosis of cancer, opted for radiation with eventual androgen-deprivation therapy. This unusual site of prostate cancer spread heightens the need for awareness among providers as well as the need for further studies of the outcomes in these patients undergoing treatments designed using guidelines developed for those with normally functioning immunity.     

Cancer incidence in patients on chronic dialysis and in renal transplant recipients

A markedly increased incidence of cancer in renal transplant recipients is now recognized; to determine if immunosuppression alone may be responsible for this increase in risk, cancer incidence was compared in 709 renal transplant recipients and 317 dialysis patients. Malignancy developed in 19 transplant recipients (2.7%) and in 33 patients on chronic dialysis (10.4%). In our report an excess of skin cancer was observed in the transplant series while tumors of the urinary tract were seen more frequently in patients on dialysis. Transplantation and consecutive immunosuppression does not appear to constitute an additional cancer risk for the uremic patient who is faced with the alternative to undergo chronic dialysis or renal transplantation.     

Malignancy after kidney transplantation: still a challenge

Long-term complications of continuous immunosuppression still remain a serious threat and are currently drawing the attention of transplant physicians. Wimmer et al. show that malignancy occurs approximately fourfold more frequently in renal-transplant recipients than in a normal control population. Besides immunosuppression, viruses probably play an important oncogenic role in transplant recipients. The retrospective analysis by Wimmer et al. suggests that mTOR inhibitors and interleukin-2 receptor antibodies are promising immunosuppressive drugs to reduce the risk of cancer after transplantation. These preliminary results must be confirmed in large, prospective, randomized, controlled trials, with long follow-up, designed to evaluate the incidence of de novo malignancy in transplant recipients.     

Cancer after renal transplantation

PURPOSE OF REVIEW: Prolonged waiting times for renal transplantation, an increase in the average age of recipients, decreased acute rejection rates due to use of newer potent immunosuppressives and improving long-term transplant survival have raised concerns in the transplant community regarding posttransplant cancer. In view of the fact that transplant recipients are living longer, it is of paramount importance that we continue to translate discoveries at the bench to the bedside and document cancers in the posttransplant recipient registries. Analysis of data will help in optimizing patient management. RECENT FINDINGS: Recent evidence indicates that sirolimus is associated with a decreased incidence of posttransplant de-novo cancer and remission of Kaposi's sarcoma and nonmelanoma skin cancer. Mycophenolate mofetil has been shown to have an antiproliferative activity against leukemia and lymphoma and an anti-tumor effect against colon and prostate cancer. Clinically it has been shown to be associated with a reduced incidence of cancers like posttransplant lymphoproliferative disorder. SUMMARY: Appropriate selection of transplant candidates, pretransplant and posttransplant cancer surveillance and judicious evidence-based use of newer immunosuppressants may help reduce the incidence and improve the outcome of posttransplant cancer.     

Maintenance Versus Reduction of Immunosuppression in Renal Transplant Recipients With Aggressive Squamous Cell Carcinoma

Background. There has been a significant increase in skin cancers in transplant patients in recent years. Transplant recipients are also more likely to develop skin cancers that are locally invasive with the potential to metastasize early.
Objectives. This study aimed to determine the effect of significantly reducing or stopping immunosuppressive therapy on prognosis of aggressive squamous cell carcinomas (SCC) in renal transplant recipients (RTRs).
Patients/methods. Retrospective study of nine patients with aggressive SCC identified two groups, one whose immunosuppressive therapy was not altered and the other who had their therapy stopped or significantly reduced.
Results. Aggressive SCC all occurred on the head and neck, with five of the primary tumors originating from the ear. Using a Wilcoxon-Breslow test to compare equality of survivor functions, reducing or stopping immunosuppression was associated with the prolongation of metastatic disease-free survival period (p=0.023).
Conclusions. This nonrandomized pilot study suggests that reduction of immunosuppression in RTRs with aggressive SCC may improve prognosis compared to patients whose immunosuppression is unchanged. Allograft function may continue despite significant reduction of immunosuppression.     

免疫抑制方案的改进对单中心受者移植肾长期存活的影响

目的 探讨免疫抑制方案的调整对移植肾预后的影响.方法 回顾性分析2001年1月1日至2010年12月31日404例肾移植受者的临床资料与随访结果.受者分为早期移植组(260例)和后期移植组(144例).后期改进的免疫抑制方案包括应用小剂量抗胸腺细胞球蛋白(ATG)诱导,术后近期皮质激素快速减量,根据吗替麦考酚酯暴露量调整用药剂量,以及尽可能地减少钙调磷酸酶抑制剂的剂量.比较两组间性别、年龄构成、供肾来源、诱导方案、免疫抑制维持方案、活检证实的急性排斥反应、重症肺部感染发生率及移植后人、肾存活率,COX回归分析上述因素对移植肾存活率的影响.结果 98.3%的受者规则随访,中位随访时间为65个月(1～112个月),7例失访.后期移植组ATG诱导治疗的比例为78.5%,高于早期移植组的31.9%(P<0.01).早期移植组和后期移植组活检证实的急性排斥反应发生率相当,后期移植组重症肺部感染发生率低于早期移植组,后期移植组存活率较早期移植组显著提高.重症肺部感染为影响移植后人、肾存活率的主要因素.结论 后期肾移植疗效较早期有所提高,得益于改进免疫抑制方案后重症肺部感染显著减少,同时未增加活检证实的急性排斥反应的发生率.

Abstract：

Objective To investigate the influence of immunosuppression strategy optimization on the outcomes of the renal transplant recipients in the last decades. Methods Data from 404 renal transplant recipients from Jan. 1st, 2001 to Dec. 31st, 2010 were analyzed retrospectively. The patients were divided into early transplant group (n = 260) and late transplant group (n= 144). The change of immunosuppression strategy included a low dose antithymoglobin (ATG) induction, a quick corticosteroid reduction and mycophenolate mofetil therapeutic monitoring with calcineurin inhibitor minimization. Recipients' gender,age, donor type, induction therapy, immunosuppression regime, occurrences of biopsy-proven acute rejection (BPAR), severe pulmonary infection and patient/allograft survival were compared between groups. A Cox regression model was used to investigate the factors that influenced the allograft survival. Results The follow-up rate was 98. 3 % in this study. The median follow-up period was 65 month (1-112 months). The proportion of ATG induction in late transplant group was significantly higher than in early transplant group (78. 5 % versus 31. 9 %, P<0. 01). The severe pulmonary infection rate was lower in late transplant group, while the BPAR rate was comparable between two groups. The allograft survival rate was significantly higher in late transplant group. Severe pulmonary infection was correlated with patient/allograft survival in Cox regression model. Conclusion The improvement of outcome in renal transplant recipients in our center is related to the optimization of immunosuppression strategy that reduces the severe pulmonary infection rate with no increase in BPAR.