Chronic Use Of Immunosuppressants Research Articles

Etiology, risk factors and management of hypertension post liver transplantation.

Cardiovascular events are one of the most important causes of morbidity and mortality in the long-term follow-up of liver transplant recipients. Hypertension is a significant cardiovascular risk factor that occurs frequently after pediatric liver transplantation. Chronic use of immunosuppressants - mainly calcineurin inhibitors - plays a major role in the development of post-transplant hypertension and circadian disturbances such as flattening of the nocturnal blood pressure dip. This requires special attention in children given the long timeframe during which immunosuppressive therapy is necessary. Careful and structured blood pressure monitoring and adequate treatment of hypertension are essential to optimize the quality of life and life expectancy of pediatric liver transplant patients. However, evidence-based guidelines for monitoring and management of post-transplant hypertension and its complications are lacking. We conducted a comprehensive review of the current knowledge and practices concerning post-transplant hypertension. The databases Pubmed, Embase, Web of Science and Google Scholar were scanned with the following keywords: pediatric liver transplantation, immunosuppression, tacrolimus, cardiovascular effects, hypertension, heart function, kidney function, circadian rhythm, mechanism, monitoring, and management. In this review, we describe the incidence and etiology of hypertension in pediatric liver transplant recipients, the underlying mechanisms and characteristics of calcineurin inhibitor-induced hypertension, and the consequences of and risk factors for post-transplant hypertension. We hereby present an overview of the current practices in blood pressure monitoring and antihypertensive treatment as well as an algorithm for the evaluation and management of hypertension post liver transplantation. Finally, we discuss knowledge gaps and suggestions for future research.

Sex-specific analysis of clinical features and outcomes in staphylococcal periprosthetic joint infections managed with two-stage exchange arthroplasty.

Background: Differences in susceptibility and response to infection between males and females are well established. Despite this, sex-specific analyses are under-reported in the medical literature, and there is a paucity of literature looking at differences between male and female patients with periprosthetic joint infection (PJI). Whether there are sex-specific differences in presentation, treatment tolerability, and outcomes in PJI has not been widely evaluated. Methods: We undertook a retrospective case-matched analysis of patients with staphylococcal PJI managed with two-stage exchange arthroplasty. To control for differences other than sex which may influence outcome or presentation, males and females were matched for age group, causative organism category (coagulase-negative staphylococci vs. Staphylococcus aureus), and joint involved (hip vs. knee). Results: We identified 156patients in 78pairs of males and females who were successfully matched. There were no significant baseline differences by sex, except for greater use of chronic immunosuppression among females (16.4 % vs. 4.1 %; ). We did not detect any statistically significant differences in outcomes between the two groups. Among the 156 matched patients, 16 recurrent infections occurred during a median follow-up time of 2.9 (IQR 1.5-5.3) years. The 3-year cumulative incidence of relapse was 16.1 % for females, compared with 8.8 % for males ( ). Conclusions: Success rates for PJI treated with two-stage exchange arthroplasty are high, consistent with previously reported literature. This retrospective case-matched study did not detect a significant difference in outcome between males and females with staphylococcal PJI who underwent two-stage exchange arthroplasty.

990. Sex-Specific Analysis of Clinical Features and Outcomes in Staphylococcal Periprosthetic Joint Infections Managed with Two-Stage Exchange Arthroplasty

Abstract Background There are anatomical, pharmacokinetic, and joint biomechanical differences between males and females. Whether these differences result in differing presentation, treatment tolerability and outcomes in periprosthetic joint infection (PJI) has not been widely evaluated. Methods We undertook a retrospective case matched study of patients with staphylococcal PJI managed with two-stage exchange arthroplasty. In order to control for differences other than sex which may influence outcome or presentation, males and females were case-matched for age, causative organism (Coagulase-negative staphylococci vs Staphylococcus aureus) and joint involved. The two matched groups were analyzed for differences in duration of symptoms, inflammatory markers, duration of hospital stay, antimicrobial side effects, post-operative complications and recurrence rate. Recurrence of infection was defined as per Musculoskeletal Infection Society criteria for PJI and included both relapse with original microorganism or with an additional organism. Results 78 pairs of males and females with staphylococcal PJI were successfully matched. There were no significant baseline differences by sex, except for greater use of chronic immunosuppression among females (16.7% vs. 4.1%; p=0.012). Clinical characteristics and outcomes of the patients are summarized in table 1. We did not detect a statistically significant between the outcomes of the two groups. Overall, 16 recurrent infections occurred during a median follow-up time of 2.9 (IQR: 1.5 - 5.3) years. The 3-year cumulative incidence of treatment failure depicted in figure 1 was 16.1% for females, compared with 8.8% for males (p=0.434). Conclusion Success rates for PJI treated with two-stage exchange arthroplasty are high consistent with previously reported literature. A larger cohort of patients may be required to detect differences in relapse rates. This study included only staphylococcal PJI and was thus unable to evaluate the differences in microbiology of PJI between males and females, which could also impact outcomes. This retrospective case-matched study did not detect any significant differences in outcomes between males and females with staphylococcal PJI who underwent two stage exchange arthroplasty. Disclosures Gina A. Suh, M.D., Adaptive Phage Therapeutics (APT): Grant/Research Support|Adaptive Phage Therapeutics (APT): Dr. Suh received grants and has an equity and royalty-bearing know-how agreement with Adaptive Phage Therapeutics but is unrelated to project Aaron J. Tande, M.D., Uptodate: Dr Tande has received an honorarium from Uptodate for medical writing unrelated to this project.

Increased perioperative complication rates in patients with solid organ transplants following rotator cuff repair.

Rotator cuff repair is the second most common soft tissue procedure performed in orthopedics. Additionally, an increasing percentage of the population has received a solid organ transplant (SOT). The chronic use of immunosuppressants as well as a high prevalence of medical comorbidities in this population are both important risk factors when considering surgical intervention. The purpose of this study is to determine the demographic profile, comorbidity profile, and perioperative complication rate of SOT patients undergoing inpatient rotator cuff repair surgery compared to nontransplanted patients. The Nationwide Inpatient Sample (NIS) database was queried from years 2002-2017 to identify all patients who underwent inpatient rotator cuff repair (n = 144,528 weighted). This group was further divided into SOT (n = 286 weighted) and nontransplant (n = 144,242 weighted) cohorts. Demographic and comorbidity analyses were performed between these groups. Additionally, a matched cohort of nontransplanted patients controlled for the year of procedure, age, sex, race, income, and hospital region was created in a 1:1 ratio to the SOT group (n = 286 each) for perioperative complication rate analysis. Compared to nontransplanted patients, SOT patients were more likely to have at least 1 significant medical comorbidity (98% vs. 69%, P < .001), had a higher number of total comorbidities (3.1 vs. 1.4, P < .001), and had a higher Charlson-Deyo Comorbidity Index (2.6 vs. 0.54, P < .001). Compared to the matched cohort, SOT patients experienced longer hospital stays (2.9 vs. 1.8 days, P < .001), higher surgery costs ($12,031 vs. $8476, P < .001), and were more likely to experience a perioperative complication (24% vs. 3%, P < .001) with an odds ratio of 7.7 (95% confidence interval: 3.9-15.1). Compared with nontransplanted patients, SOT patients undergoing rotator cuff repair had a significantly higher comorbidity index, longer hospital stays, costlier surgeries, and were >7 times more likely to experience a perioperative complication. With nearly a quarter of all SOT patients experiencing a perioperative complication following rotator cuff repair, careful consideration for surgery as well as increased postoperative surveillance should be considered in this unique population.

Carcinoma Camouflage

Question: A 74-year-old woman with compensated Child-Pugh A cirrhosis (Model for End-Stage Liver Disease score of 8) secondary to autoimmune hepatitis on azathioprine monotherapy was evaluated for abdominal bloating and intermittent right upper quadrant abdominal pain. She endorsed a 5-lb unintentional weight loss over the past 4 months associated with anorexia. On physical examination, she was well-appearing with a soft abdomen and no abdominal tenderness, distension, or ascites. The pertinent serology revealed an aspartate aminotransferase of 76 U/L, a total protein of 8.3 g/dL, albumin of 3.4 g/dL, hemoglobin of 12.2 g/dL, white blood cells of 3.1 × 109/L, platelets of 96,000, lactate dehydrogenase of 290 U/L, and alpha fetoprotein of 4.25 ng/mL. An abdominal ultrasound examination revealed a new hypoechoic lesion measuring 2.5 cm × 2 cm × 1.5 cm with minimal flow by Doppler. Triple phase magnetic resonance imaging (MRI) of the liver revealed a lobular 3.5 cm × 3.0 cm mass in hepatic segments 2 and 3 (Figures A and B, red arrows) as well as a 3.9 cm × 3.1 cm mass in segment 7, each T1 hypointense and T2 hyperintense with peripheral enhancement and washout including marked diffusion restriction favoring multifocal hepatocellular carcinoma with an atypical enhancement pattern. Imaging was negative for extrahepatic disease. Outside of the Milan criteria, the patient was referred to surgical oncology for further evaluation and management. The mass in segment 3 seemed to be larger via intraoperative ultrasound examination (5 cm) and was therefore resected. The mass in segment 7 underwent microwave ablation to preserve the liver parenchyma. Pathology revealed a sheetlike proliferation of large, pleomorphic, atypical vesicular lymphoid cells (Figure C) with mitotic figures and apoptotic bodies (Figure D). Immunohistologic staining was diffusely and strongly positive for CD20 (Figure E), CD10, and BCL6. Workup for viral serologies was negative (hepatitis B virus, hepatitis C virus, HIV, and Epstein–Barr virus stain from liver tissue). What is the next step in evaluation and management? What is the most likely diagnosis? Look on page 1942 for the answer and see the Gastroenterology website (www.gastrojournal.org/) for more information on submitting your favorite image to Clinical Challenges and images in GI. A referral to hematology/oncology was made for the initiation of rituximab-based chemotherapy. This patient has diffuse large B-cell lymphoma (DLBCL), germinal center B-cell type. The pathology from the resected liver segments revealed DLBCL, germinal center B-cell subtype, without double or triple-hit features after fluorescence in situ hybridization analysis. Positron emission tomography with computed tomography scans confirmed no evidence of active disease and final staging was deemed to be stage IEA with a National Comprehensive Cancer Network International Prognostic Index score of 4 (high to intermediate) secondary to age, extranodal disease, and elevated lactate dehydrogenase. Three short cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) was recommended. Echocardiogram revealed a normal ejection fraction. Unfortunately, she developed neutropenic fever during cycle 1 with extended spectrum beta lactamase urinary tract infection, urinary retention, and anasarca requiring granulocyte colony stimulating factor, antibiotics, and adjustment of diuretics. Additional chemotherapy was not advised, and she will follow-up with positron emission tomography with computed tomography scans in 2 months. DLBCL is the most common aggressive non-Hodgkin lymphoma (NHL).1Shibata J. Kurahashi S. Naito T. et al.Diffuse large B cell lymphoma primarily presenting as acute liver failure in a surviving patient.J Community Hosp Intern Med Perspect. 2019; 9: 135-139Crossref PubMed Google Scholar DLBCL may manifest as a primary hepatic lymphoma (PHL) in the late stage of disease. PHL is exceedingly rare, estimated to be present in 0.4% of extranodal NHL and 0.016% of all NHL cases.2Zhang K.J. Chen S. Chen J.L. et al.Complete response to comprehensive treatment of a primary hepatic diffuse large b cell lymphoma: a case report.Oncol Lett. 2015; 9: 1557-1660Crossref PubMed Scopus (3) Google Scholar Contributing factors include chronic viral infections (hepatitis B and C, Epstein–Barr virus, HIV), cirrhosis, autoimmune disease, and chronic use of immunosuppressants. R-CHOP is the gold standard of therapy. Chronic azathioprine use increases the risk of lymphoma; however, the association with PHL has not been reported. Imaging characteristics suggestive of PHL on MRI may consist of signal restriction in the diffusion-weighted imaging and a lower apparent diffusion coefficient.3Colagrande S. Calistri L. Grazzini G. et al.MRI features of primary hepatic lymphoma.Abdom Radiol. 2018; 43: 2277-2287Crossref PubMed Scopus (17) Google Scholar Clinicians should consider hepatic lymphoma in cirrhotic patients if there is a history of autoimmune disease, immunosuppressant use such as azathioprine, atypical enhancement pattern on MRI, and a normal alpha fetoprotein.

Recombinogenic, genotoxic, and cytotoxic effects of azathioprine using in vivo assays

ABSTRACT Azathioprine (Aza) is a purine antimetabolite immunosuppressant that is widely employed for immunosuppressive therapy in post-transplant recipients or patients with autoimmune diseases. Chronic use of immunosuppressants might produce several side effects, including a high rate of neoplasms in these patients. Considering that genotoxic effects are associated with an increased risk of developing cancer, the aim of this study was to examine the recombinogenic, genotoxic, and cytotoxic effects of Aza using Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster, as well as comet and micronucleus assays in mouse bone marrow cells. Further, the adverse effects of Aza were determined in mouse hepatic and renal tissues using histopathological analysis. Data demonstrated that Aza induced significant increased genotoxicity in D. melanogaster and mouse bone marrow cells at all concentrations tested. Homologous recombination was the predominant genotoxic event noted for the first time to be initiated by Aza in SMART. In histopathological analysis, Aza did not show any marked toxic activity in mouse hepatic and renal tissues. Therefore, the high rate of neoplasms reported in patients with long-term use of Aza may be attributed, at least partially, to the genotoxic action of this drug.

Multidisciplinary management of anal intraepithelial neoplasia and rate of progression to cancer: A retrospective cohort study

PurposeTo describe the regional burden of AIN and rate of progression to cancer in patients managed in specialist and non-specialist clinic settings. MethodsPatients with a histopathological diagnosis of AIN between 1994 and 2018 were retrospectively identified. Clinicopathological characteristics including high-risk status (chronic immunosuppressant use or HIV positive), number and type of biopsy (punch/excision) and histopathological findings were recorded. The relationship between clinicopathological characteristics and progression to cancer was assessed using logistic regression. ResultsOf 250 patients identified, 207 were eligible for inclusion: 144 from the specialist and 63 from the non-specialist clinic. Patients in the specialist clinic were younger (<40 years 31% vs 19%, p = 0.007), more likely to be male (34% vs 16%, p = 0.008) and HIV positive (15% vs 2%, p = 0.012). Patients in the non-specialist clinic were less likely to have AIN3 on initial pathology (68% vs 79%, p = 0.074) and were more often followed up for less than 36 months (46% vs 28%, p = 0.134). The rate of progression to cancer was 17% in the whole cohort (20% vs 10%, p = 0.061). On multivariate analysis, increasing age (OR 3.02, 95%CI 1.58–5.78, p < 0.001), high risk status (OR 3.53, 95% CI 1.43–8.74, p = 0.006) and increasing number of excisions (OR 4.88, 95%CI 2.15–11.07, p < 0.001) were related to progression to cancer. ConclusionThe specialist clinic provides a structured approach to the follow up of high-risk status patients with AIN. Frequent monitoring with specialist assessments including high resolution anoscopy in a higher volume clinic are required due to the increased risk of progression to anal cancer.

Perforator Free Flap Coverage of Chronic Lower Extremity Ulcers in Patients With Autoimmune Diseases Under Immunosuppression.

Objectives. Lower extremity ulcers are quite common in patients with autoimmune diseases. Due to chronic use of immunosuppressants, these wounds may develop into deeper wounds resulting in exposure of bone or tendon, which in turn may require free tissue transfers for coverage. The author reviewed perforator free flap transfers performed in this group of patients and analyzed the results. Methods. A retrospective review was performed on all patients who underwent perforator free flap transfer for coverage of lower extremity ulcers without trauma, over a 10-year period. Patient demographics, administered immunosuppressants, and flap and donor site complications were analyzed. Results. Twenty-two perforator free flap transfers were performed in patients with autoimmune diseases, including 18 thoracodorsal perforator flaps, 2 anterolateral thigh flaps, and 2 deep inferior epigastric artery flaps. There was no total flap loss, but there was a high rate of partial flap necrosis (40.9%) and wound dehiscence (40.9%). Intake of corticosteroids was significantly associated with postoperative complications (P < .05). Conclusion. As partial loss of flap and wound dehiscence is much more common in this group of patients, treatment may take longer, and a fully informed consent should be obtained preoperatively. Surgeons should not avoid performing perforator free flap transfers in patients with autoimmune diseases under immunosuppression; instead, much more preparation and caution are required.

Patient-related risk factors for unplanned 30-day readmission following total knee arthroplasty: a narrative literature review.

Osteoarthritis is a debilitating condition as well as a growing global health problem, and total knee arthroplasty (TKA) is an effective treatment for advanced disease. Unplanned 30-day hospital readmission is an indicator of complications, which is a significant financial burden on healthcare systems. We reviewed the literature to better understand the patient-related factors associated with unplanned 30-day readmission following TKA. MEDLINE and EMBASE were searched for studies reporting on patient-related risk factors for unplanned 30-day readmission following primary or revision TKA for any indication. The impact of specific medical comorbidities on increasing the risk of 30-day readmission following TKA is quite well established. The following comorbidities are strongly associated with readmission: bleeding disorder, diabetes, chronic kidney disease and dialysis, chronic immunosuppressant use and history of cancer. Other significant comorbidities include: dementia; depression; haematological (coagulopathy and anaemia), cardiovascular (atrial fibrillation, cardiovascular disease, coronary artery disease and congestive heart failure), respiratory (chronic obstructive pulmonary disease) and liver diseases; and cerebrovascular accident/transient ischaemic attack (but only in revision TKA patients). The influence of variation in sex, age and body mass index each demonstrate a more complex pattern. A systematic review and meta-analysis is required to quantify the impact of the various patient-related factors on 30-day readmission following TKA. Clinicians can use this information in preoperative decision-making.

Recommendations for photoprotection in pediatric rheumatology patients.

Patients seen at pediatric rheumatology are at increased risk of immediate and long-term consequences from sun exposure. The objective of this review is to build awareness of the need of sun protection in pediatric rheumatology patients. Sun exposure can lead to disease exacerbations in many rheumatic diseases. There is well documented literature linking the chronic use of immunosuppressants with long-term risk of skin cancer. Although there is a lack of literature in pediatric rheumatology addressing the need of sun protection in this patient population, the young age of patients, the nature of their disease and the treatments they receive, make them a high-risk population for the effects of the sun. Sun protection recommendations are outlined in the following manuscript, backed up by the rationale and biology of why it is important for pediatric rheumatology patients to be protected from the sun. The information reviewed in this article should be part of the education that all pediatric rheumatology patients should receive as part of their care.

Chronic immunosuppressant use in colorectal cancer patients worsens postoperative morbidity and mortality through septic complications in a propensity-matched analysis.

Chronic immunosuppressant use increases the risk of septic complications after colectomy; however, adverse effects on other organ systems remain poorly understood. The aim of this study was to evaluate the multisystem organ effect(s) of chronic immunosuppressant(s) in colorectal cancer patients. This was a retrospective study. The American College of Surgeons National Surgical Quality Improvement database (2005-2012) was queried. The primary end-points were 30-day mortality and 30-day morbidity after colectomy in patients on chronic immunosuppressant(s) compared to a non-immunosuppressant cohort. In total, 50766 patients were identified, with 1203 (2.4%) taking chronic immunosuppressant(s). After propensity matching, 1197 patients in each cohort were evaluated with no differences seen in age, body mass index, male sex, wound classification, emergency case status, the presence of preoperative sepsis or operative time. On outcome analysis, 30-day mortality (5.7% vs 3.4%, P<0.001) and 30-day overall morbidity (35.4% vs 29.0%, P=0.001) were higher in patients on chronic immunosuppressant(s). Septic complications (10.6% vs 7.9%, P=0.02) and surgical site infections (15.3% vs 12.3%, P=0.03) were elevated with chronic immunosuppressant(s). There were no differences in cardiovascular, pulmonary, renal or neurological complications. Chronic immunosuppressant patients demonstrated longer total hospital stay (11.4±11.7 vs 9.5±9.4days, P<0.001) and postoperative length of stay (9.4±9.2 vs 8.1±7.6days, P<0.001). The limitation was that this was a retrospective study using a clinical dataset. In this study, immunosuppressant use is associated with worsened infective complications, without contributing to organ-specific complications following colectomy. Significant thought should be given to anastomosis vs stoma creation to possibly prevent worsened morbidity and mortality. Future study is required to determine specific pathways for risk reduction.

PD-L1-engineered pancreatic islet grafts overcome rejection in allogeneic recipients

Abstract The use of chronic immunosuppression is a major hurdle for clinical islet transplantation as a curative modality for the treatment of type 1 diabetes. T effector cells (Teffs) are a main culprit of allograft rejection, and their pathogenic response is kept in check by CD4+CD25+FoxP3+ T regulatory cells (Tregs). The PD-1/PD-L1 immune checkpoint pathway plays an important role in the Teff/Treg balance with demonstrated clinical efficacy in cancer immunotherapy. This study was designed to assess the immunoregulatory function of PD-L1 in preventing allogeneic islet graft rejection. A chimeric protein (SA-PD-L1) containing the extracellular portion of PD-L1 fused to a modified form of core streptavidin was generated. SA-PD-L1 protein was expressed in insect cells and purified. The protein was functional as it enhanced TGF-beta-induced conversion of Teffs into Tregs and suppressed the proliferation of Teffs in response to alloantigens. Importantly, SA-PD-L1 was transiently displayed on the surface of biotinylated islets, and such engineered islets survived for over 100 days in allogeneic recipients treated with a short course (15 days) of low dose rapamycin. In marked contrast, unmodified islets under the same rapamycin regimen were rejected within 20 days. SA-PD-L1-engineered islets without rapamycin, although showing prolonged survival, were eventually rejected within 40 days. These results provide strong proof-of-efficacy and feasibility for the use of SA-PD-L1 protein as an immunomodulator to promote allogeneic islet graft survival in the absence of continued immunosuppression.

Short-Term Perioperative Outcomes and Complications in Chronic Immunosuppressant Users following Total Hip Arthroplasty

AbstractAs the rate of total hip arthroplasties (THA) being performed continues to increase, orthopaedic surgeons are likely to operate on patients who use systemic immunosuppressants for a variety of ailments. It may be necessary to continue these medications perioperatively, and it has been reported that they may affect post-operative outcomes. The authors proposed the following questions: (1) Are perioperative outcomes (i.e., operative time, lengths-of-stay, and discharge disposition) affected by chronic immunosuppressant use during THA, and (2) does chronic immunosuppressant use increase the rate of complications within 30-days of THA? The American College of Surgeons National Surgical Quality Improvement Program database was used to identify all THAs from 2008 to 2014. Only osteoarthritis diagnoses were included, and any emergency or concurrent surgeries were excluded. The authors identified 64,796 cases that met the inclusion/exclusion criteria. Prior to surgery, 1,900 patients used chronic immunosuppressants, while 62,896 patients did not use immunosuppressants. Lengths-of-stay, operative time, discharge destination, and 30-day complication rates were the measured perioperative outcomes. To determine significant outcome differences between cohorts, univariate analysis was applied. Next, multivariate regression analysis helped determine if immunosuppressant use independently increased the risk for the measured outcomes and complications. Chronic immunosuppressant users were at higher risk of certain adverse perioperative outcomes and short-term complications. Compared with the control group, immunosuppressant users were more likely to be discharged to a non-home facility (odds ratio [OR]: 1.16; 95% confidence interval [CI]: 1.03–1.31). These patients also had greater rates of septic shock (OR: 2.88; 95% CI: 1.08–7.67) and 30-day readmission (OR: 1.37; 95% CI: 1.10–1.70). Chronic immunosuppressant use leads to higher rates of complications and adverse outcomes following THA. Adverse outcomes related to immunosuppressant use included higher rates of non-home discharge. Complications related to immunosuppressant use included septic shock and 30-day readmission.

Novel technologies to engineer graft for tolerance induction.

Conquering allograft rejection remains an elusive goal in spite of recent breakthroughs in the field of immunosuppression. Much of the problem lies in the toxicity and side-effects of long-term use of systemic immunosuppressant drugs, which are sometimes ineffective in controlling rejection, but also hinder establishment of transplant tolerance. In this review, we discuss novel technologies that use grafts engineered with immunomodulatory molecules as a means of inducing tolerance. Several recent studies have demonstrated the feasibility of engineering cells, tissues, or solid organ grafts with immunoregulatory biologics to achieve long termgraft survival without the use of chronic immunosuppression. This approach was shown to primarily change the ratio of T effector versus CD4+CD25+FoxP3+ T regulatory cells within the graft microenvironment in favor of attaining localized tolerance induction and maintenance. Localized immunomodulation using biologic-engineered allografts represent a new paradigm for achieving long-term graft survival in the absence of chronic use of immunosuppression. The manipulation of the graft, rather than the recipient, not only ensures short- and long-term safety by minimizing the adverse effects of immunosuppression, but also allows retention of immune competency critical for the ability of the recipient to fight infections and cancer.

From Kidney Transplants to Vascularized Composite Allografts: The Role of the Plastic Surgeon in Transplantation

In 1954, plastic surgeon Dr Joseph Murray performed the first successful organ transplant between identical twins. Today solid organ transplants are performed routinely and offer a curative option for patients with end stage organ failure. For his pioneering work in transplantation biology, Dr Murray remains the only plastic surgeon to have been awarded the Nobel Prize in Medicine.The success of modern day transplants has allowed transplantation to be applied more broadly. In particular, vascularized composite allografts (VCAs), including face and hand transplants, have emerged over the past 15 y. These have been used for reconstruction of patients with extensive disfigurements. Despite these great successes, the use of chronic immunosuppression by transplant recipients is accompanied by the risk of malignancy, organ toxicity and infection. Current research efforts by transplant physicians and plastic surgeons are aimed at reducing and subsequently eliminating the burden of life-long immunosuppression.Thi...

Expansion of CMV-Mediated NKG2C+ NK Cells Associates with the Development of Specific De Novo Malignancies in Liver-Transplanted Patients

Solid cancers are a major adverse outcome of orthotopic liver transplantation (OLT). Although the use of chronic immunosuppression is known to play a role in T cell impairment, recent insights into the specificities of NK cells led us to reassess the potential modulation of this innate immune cell compartment after transplantation. Our extensive phenotypic and functional study reveals that the development of specific de novo noncutaneous tumors post-OLT is linked to unusual NK cell subsets with maturation defects and to uncommon cytokine production associated with the development of specific cancers. Remarkably, in CMV(+) patients, the development de novo head/neck or colorectal tumors is linked to an aberrant expansion of NK cells expressing NKG2C and a high level of intracellular TNF-α, which impact on their polyfunctional capacities. In contrast, NK cells from patients diagnosed with genitourinary tumors possessed a standard immature signature, including high expression of NKG2A and a robust production of IFN-γ. Taken together, our results suggest that under an immunosuppressive environment, the interplay between the modulation of NK repertoire and CMV status may greatly hamper the spectrum of immune surveillance and thus favor outgrowth and the development of specific de novo tumors after OLT.

Long-term follow-up of patients with severe ANCA-associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear

Patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV) requiring dialysis at diagnosis are at risk for developing end-stage renal disease (ESRD) or dying. Short-term results of a trial comparing plasma exchange (PLEX) to intravenous methylprednisolone (IV MeP) suggested PLEX improved renal recovery. Here we conducted long-term follow-up to see if this trend persisted. A total of 137 patients with newly diagnosed AAV and a serum creatinine over 500 μmol/l or requiring dialysis were randomized such that 69 received PLEX and 68 received IV MeP in addition to cyclophosphamide and oral glucocorticoids. The patients were followed for a median of 3.95 years. In each group there were 35 deaths, while 23 PLEX and 33 IV MeP patients developed ESRD. The hazard ratio for PLEX compared to IV MeP for the primary composite outcome of death or ESRD was 0.81 (95% confidence interval 0.53-1.23). The hazard ratio for all-cause death was 1.08 with a subhazard ratio for ESRD of 0.64 (95% confidence interval 0.40-1.05). Thus, although short-term results with PLEX are encouraging, the long-term benefits remain unclear. Further research is required to determine the role of PLEX in AAV. Given the poor outcomes of patients with severe AAV, improved treatment is urgently needed.

1392P - Increased Incidence of Renal Cell Carcinoma (RCC) Among Melanoma Patients

ABSTRACT Purpose There is scant evidence for an increased risk for developing RCC among melanoma patients (pts), and evidence for possible risk factors for the association between melanoma and RCC is lacking. We examined the risk of developing both melanoma and RCC, and also the possible risk factors. Methods We searched our institutional tumor registry for pts with a diagnosis of melanoma and RCC. We used summary statistics to describe the population of pts and calculate total person-years at risk for RCC. We computed standardized incidence ratios (SIRs), which is the ratio of the observed to the expected number of pts with RCC among pts with melanoma using the Cohort Analysis for Genetic Epidemiology program. The expected number of pts with RCC was determined from SEER data. The 95% confidence intervals (CI) for the SIRs were determined by assuming a Poisson distribution for the observed number of RCC. SIRs were also calculated for subsets of the data according to race and gender. Results Between 1980 and 2005, we identified 15,482 pts with a diagnosis of melanoma: 59% were male and 94% were white. Among these pts, 114 (0.7%) pts had a diagnosis of RCC either before or after the diagnosis of melanoma. The mean age of RCC presentation was 59.4 years. The total person-years at risk for RCC were 886,506. We observed a significant excess of RCC (SIR = 1.64, 95% CI = 1.37-1.95) among our cohort of melanoma pts. This excess of RCC was also significant among white pts (SIR = 1.64, 95% CI = 1.36-1.92) and among both genders. None of the 114 pts with a diagnosis of both melanoma and RCC had a concomitant diagnosis of immunocompromised disease nor received chronic immunosuppressive drugs. Only 17% of the pts received radiation or chemotherapy for melanoma. Conclusions There is an increase risk of RCC among melanoma pts. Neither preexisting immunocompromised condition nor the chronic use of immunosuppressants were risk factors for developing both malignancies. Group Observed Expected SIR (95% CI) for development of RCC All (n = 15482) 114 69.53 1.64 (1.37-1.95) Gender M (n = 9072) F (n = 6410) 81 33 54.85 14.67 1.48 (1.19-1.82) 2.25 (1.61-3.08) Ethnicity White (n = 14580) Non-White (n = 902) 109 5 66.37 3.15 1.64 (1.36-1.96) 1.59 (0.70-3.25) Disclosure All authors have declared no conflicts of interest.

Long-term tolerance after transplantation of mismatched vascularized composite allografts without the use of chronic immunosuppression

Long-term tolerance after transplantation of mismatched vascularized composite allografts without the use of chronic immunosuppression

Decreased NKp46 and NKG2D and elevated PD‐1 are associated with altered NK‐cell function in pediatric transplant patients with PTLD

Post-transplantation lymphoproliferative disorders (PTLD) are life-threatening complications of organ transplantation caused by EBV infection and the use of chronic immunosuppression. While T-cell impairment is known to play a critical role in the immunopathogenesis of EBV complications post-transplantation, the role of NK cells is still under investigation. Here, we have characterized NK-cell phenotype and function in peripheral blood from asymptomatic pediatric thoracic transplant patients, patients with PTLD, and healthy controls. Overall, asymptomatic pediatric solid organ transplant (Tx) patients presented significant expansion of the CD56(bright) CD16(±) subset and displayed effective NK-cell function, while PTLD patients accumulated CD56(dim) CD16(-) and CD56(-) CD16(+) NK-cell subsets. In addition, NK cells from PTLD patients down-regulated NKp46 and NKG2D, and significantly up-regulated PD-1. These phenotypic changes were associated with NK functional impairment, resembling cellular exhaustion. Disrupting PD-1 inhibitory pathway improved IFN-γ release, but did not enhance cytotoxicity in PTLD patients, suggesting that these defects were partially PD-1 independent. Our results indicate the important role of NK cells during EBV surveillance post-transplantation, with implications for the immunopathogenesis of EBV complications, and suggest that monitoring NK cells in transplant patients may hold clinical value.