A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Gemcitabine-based adjuvant chemotherapy in subtypes of ampullary adenocarcinoma: international propensity score-matched cohort study.

BACKGROUND: Whether patients who undergo resection of ampullary adenocarcinoma have a survival benefit from adjuvant chemotherapy is currently unknown. The aim of this study was to compare survival between patients with and without adjuvant chemotherapy after resection of ampullary adenocarcinoma in a propensity score-matched analysis. METHODS: An international multicentre cohort study was conducted, including patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma between 2006 and 2017, in 13 centres in six countries. Propensity scores were used to match patients who received adjuvant chemotherapy with those who did not, in the entire cohort and in two subgroups (pancreatobiliary/mixed and intestinal subtypes). Survival was assessed using the Kaplan-Meier method and Cox regression analyses. RESULTS: Overall, 1163 patients underwent pancreatoduodenectomy for ampullary adenocarcinoma. After excluding 187 patients, median survival in the remaining 976 patients was 67 (95 per cent c.i. 56 to 78) months. A total of 520 patients (53·3 per cent) received adjuvant chemotherapy. In a propensity score-matched cohort (194 patients in each group), survival was better among patients who received adjuvant chemotherapy than in those who did not (median survival not reached versus 60 months respectively; P = 0·051). A survival benefit was seen in patients with the pancreatobiliary/mixed subtype; median survival was not reached in patients receiving adjuvant chemotherapy and 32 months in the group without chemotherapy (P = 0·020). Patients with the intestinal subtype did not show any survival benefit from adjuvant chemotherapy. CONCLUSION: Patients with resected ampullary adenocarcinoma may benefit from gemcitabine-based adjuvant chemotherapy, but this effect may be reserved for those with the pancreatobiliary and/or mixed subtype.

ANTECEDENTES: Actualmente se desconoce si la quimioterapia adyuvante ofrece un beneficio en la supervivencia de los pacientes que se someten a resección de un adenocarcinoma ampular. El objetivo de este estudio fue comparar la supervivencia mediante la concordancia estimada por emparejamiento por puntaje de propensión, entre pacientes con y sin quimioterapia adyuvante después de la resección de un adenocarcinoma ampular. MÉTODOS: Se realizó un estudio internacional de cohortes multicéntrico, que incluyó a los pacientes que se sometieron a una duodenopancreatectomía por adenocarcinoma ampular (2006-2017) en 13 centros de seis países. Los puntajes de propensión se usaron para emparejar a los pacientes que recibieron quimioterapia adyuvante con los que no; tanto en la cohorte completa como en dos subgrupos (subtipo pancreaticobiliar / mixto e intestinal). La supervivencia se evaluó utilizando el método de Kaplan-Meier y las regresiones de Cox. RESULTADOS: En total, 1.163 pacientes fueron sometidos a una duodenopancreatectomía por adenocarcinoma ampular. Después de excluir a 179 pacientes, la mediana de supervivencia de los 976 pacientes restantes fue de 67 meses (i.c. del 95%, 56-78), de los cuales un total de 520 pacientes (53%) recibieron quimioterapia adyuvante. En una cohorte de emparejamiento por puntaje de propensión (194 versus 194 pacientes), la mediana de supervivencia fue mejor en los pacientes tratados con quimioterapia adyuvante en comparación con aquellos sin quimioterapia adyuvante (no se alcanzó la mediana de supervivencia versus 60 meses, respectivamente; P = 0,051). En el subtipo pancreaticobiliar/mixto se observó un beneficio en la supervivencia; no se alcanzó la mediana de supervivencia en pacientes que recibieron quimioterapia adyuvante versus 32 meses en el grupo sin quimioterapia, P = 0,020. El subtipo intestinal no mostró beneficio en la supervivencia de la quimioterapia adyuvante. CONCLUSIÓN: Los pacientes con adenocarcinoma ampular resecado pueden beneficiarse de la quimioterapia adyuvante basada en gemcitabina, pero este efecto podría reservarse para aquellos pacientes con subtipo de tumor pancreaticobiliar y/o mixto.

Systematic review of clinical prediction models for survival after surgery for resectable pancreatic cancer.

BACKGROUND: As more therapeutic options for pancreatic cancer are becoming available, there is a need to improve outcome prediction to support shared decision-making. A systematic evaluation of prediction models in resectable pancreatic cancer is lacking. METHODS: This systematic review followed the CHARMS and PRISMA guidelines. PubMed, Embase and Cochrane Library databases were searched up to 11 October 2017. Studies reporting development or validation of models predicting survival in resectable pancreatic cancer were included. Models without performance measures, reviews, abstracts or more than 10 per cent of patients not undergoing resection in postoperative models were excluded. Studies were appraised critically. RESULTS: After screening 4403 studies, 22 (44 319 patients) were included. There were 19 model development/update studies and three validation studies, altogether concerning 21 individual models. Two studies were deemed at low risk of bias. Eight models were developed for the preoperative setting and 13 for the postoperative setting. Most frequently included parameters were differentiation grade (11 of 21 models), nodal status (8 of 21) and serum albumin (7 of 21). Treatment-related variables were included in three models. The C-statistic/area under the curve values ranged from 0·57 to 0·90. Based on study design, validation methods and the availability of web-based calculators, two models were identified as the most promising. CONCLUSION: Although a large number of prediction models for resectable pancreatic cancer have been reported, most are at high risk of bias and have not been validated externally. This overview of prognostic factors provided practical recommendations that could help in designing easily applicable prediction models to support shared decision-making.

Defining the molecular pathology of pancreatic body and tail adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas. METHODS: Detailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study. RESULTS: Clinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole-genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial-to-mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer. CONCLUSION: PDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.

Management of an acute catecholamine-induced cardiomyopathy and circulatory collapse: a multidisciplinary approach.

A phaeochromocytoma (PC) is a rare, catecholamine-secreting neuroendocrine tumour arising from the adrenal medulla. Presenting symptoms of this rare tumour are highly variable but life-threatening multiorgan dysfunction can occur secondary to catecholamine-induced hypertension or hypotension and subsequent cardiovascular collapse. High levels of circulating catecholamines can induce an acute stress cardiomyopathy, also known as Takotsubo cardiomyopathy. Recent studies have focused on early diagnosis and estimation of the prevalence of acute stress cardiomyopathy in patients with PC, but very little is reported about management of these complex cases. Here, we report the case of a 38-year-old lady who presented with an acute Takotsubo or stress cardiomyopathy and catecholamine crisis, caused by an occult left-sided 5 cm PC. The initial presenting crisis manifested with symptoms of severe headache and abdominal pain, triggered by a respiratory tract infection. On admission to hospital, the patient rapidly deteriorated, developing respiratory failure, cardiogenic shock and subsequent cardiovascular collapse due to further exacerbation of the catecholamine crisis caused by a combination of opiates and intravenous corticosteroid. An echocardiogram revealed left ventricular apical hypokinesia and ballooning, with an estimated left ventricular ejection fraction of 10-15%. Herein, we outline the early stabilisation period, preoperative optimisation and intraoperative management, providing anecdotal guidance for the management of this rare life-threatening complication of PC. LEARNING POINTS: A diagnosis of phaeochromocytoma should be considered in patients presenting with acute cardiomyopathy or cardiogenic shock without a clear ischaemic or valvular aetiology.Catecholamine crisis is a life-threatening medical emergency that requires cross-disciplinary expertise and management to ensure the best clinical outcome.After initial resuscitation, treatment of acute catecholamine-induced stress cardiomyopathy requires careful introduction of alpha-blockade followed by beta-blockade if necessary to manage ß-receptor-mediated tachycardia.Prolonged α-adrenergic receptor stimulation by high levels of circulating catecholamines precipitates arterial vasoconstriction and intravascular volume contraction, which can further exacerbate hypotension. Invasive pressure monitoring can aid management of intravascular volume in these complex patients.

Gene-expression profiling to predict responsiveness to immunotherapy.

Recent clinical successes with immunotherapy have resulted in expanding indications for cancer therapy. To enhance antitumor immune responses, and to better choose specific strategies matched to patient and tumor characteristics, genomic-driven precision immunotherapy will be necessary. Herein, we explore the role that tumor gene-expression profiling (GEP) may have in the prediction of an immunotherapeutic response. Genetic markers associated with response to immunotherapy are addressed as they pertain to the tumor genomic landscape, the extent of DNA damage, tumor mutational load and tumor-specific neoantigens. Furthermore, genetic markers associated with resistance to checkpoint blockade and relapse are reviewed. Finally, the utility of GEP to identify new tumor types for immunotherapy and implications for combinatorial strategies are summarized.

Serum amylase and C-reactive protein in risk stratification of pancreas-specific complications after pancreaticoduodenectomy.

BACKGROUND: Pancreas-specific complications (PSCs), comprising postoperative pancreatic fistula, haemorrhage and intra-abdominal collections, are drivers of morbidity and mortality after pancreaticoduodenectomy (PD). A serum amylase concentration of 130 units/l or more on postoperative day (POD) 0 has been shown to be an objective surrogate of pancreatic texture, a determinant of PSCs. This study evaluated serial measurements of C-reactive protein (CRP) to refine PSC risk stratification. METHODS: Consecutive patients undergoing PD between 2008 and 2014, with vascular resection if required and without preoperative chemoradiotherapy, had serum investigations from the day before operation until discharge. Receiver operating characteristic (ROC) curve analysis was used to identify a threshold value of serum CRP with clinically relevant PSCs for up to 30 days after discharge as outcome measure. RESULTS: Of 230 patients, 95 (41·3 per cent) experienced a clinically relevant PSC. A serum CRP level of 180 mg/l or higher on POD 2 was associated with PSCs, prolonged critical care stay and relaparotomy (all P < 0·050). Patients with a serum amylase concentration of 130 units/l or more on POD 0 who developed a serum CRP level of at least 180 mg/l on POD 2 had a higher incidence of morbidity. Patients were stratified into high-, intermediate- and low-risk groups using these markers. The low-risk category was associated with a negative predictive value of 86·5 per cent for development of clinically relevant PSCs. There were no deaths among 52 patients in the low-risk group, but seven deaths among 79 (9 per cent) in the high-risk group. CONCLUSION: A serum amylase level below 130 units/l on POD 0 combined with a serum CRP level under 180 mg/l on POD 2 constitutes a low-risk profile following PD, and may help identify patients suitable for early discharge.

When one becomes more: minimum renal artery length in laparoscopic live donor nephrectomy.

BACKGROUND: Laparoscopic donor nephrectomy may convert short main arteries into multiple arteries, increasing the technical challenge of implantation. We evaluated our experience to identify factors predictive of multiple arteries after laparoscopic nephrectomy. METHODS: All laparoscopic nephrectomies from the start of our program in November 2002 until June 2013 were studied, and preoperative imaging reviewed for donor artery length and multiplicity together with operative findings. RESULTS: A total of 287 consecutive laparoscopic live donor nephrectomies (64 right and 223 left nephrectomies) were studied. Renal artery length was measured from preoperative donor magnetic resonance or computed tomography angiogram and nephrectomy performed using a laparoscopic stapling device. Nine left kidneys with a single artery (6, 7, 9, 10, 11, 12, 13, 14, and 16 mm in length) and five right kidneys with a single artery (5, 13, 15, 20, and 26 mm) on imaging resulted in multiple renal arteries at implantation. Complex renal vein anatomy was associated with multiple arteries following retrieval. CONCLUSION: A main renal artery length of more than 16 mm on the left and 26 mm on the right is unlikely to result in multiple arteries to implant. The possibility of multiple arteries should be borne in mind when the donor renal artery is short.

Outcome after surgical resection for duodenal adenocarcinoma in the UK.

BACKGROUND: Factors influencing long-term outcome after surgical resection for duodenal adenocarcinoma are unclear. METHODS: A prospectively created database was reviewed for patients undergoing surgery for duodenal adenocarcinoma in six UK hepatopancreaticobiliary centres from 2000 to 2013. Factors influencing overall survival and disease-free survival (DFS) were identified by regression analysis. RESULTS: Resection with curative intent was performed in 150 (84·3 per cent) of 178 patients. The postoperative morbidity rate for these patients was 40·0 per cent and the in-hospital mortality rate was 3·3 per cent. Patients who underwent resection had a better median survival than those who had a palliative surgical procedure (84 versus 8 months; P < 0·001). The 1-, 3- and 5-year overall survival rates for patients who underwent resection were 83·9, 66·7 and 51·2 per cent respectively. Median DFS was 53 months, and 1- and 3-year DFS rates were 80·8 and 56·5 per cent respectively. Multivariable analysis revealed that node status (hazard ratio 1·73, 95 per cent c.i. 1·07 to 2·79; P = 0·006) and lymphovascular invasion (hazard ratio 3·49, 1·83 to 6·64; P = 0·003) were associated with overall survival. CONCLUSION: Resection of duodenal adenocarcinoma in specialist centres is associated with good long-term survival. Lymphovascular invasion and nodal metastases are independent prognostic indicators.

Pancreatic cancer genomics: where can the science take us?

The incidence of pancreatic ductal adenocarcinoma (PDAC) is steadily increasing and the annual death-to-incidence ratio approaches one. This is a figure that has not changed for several decades. Surgery remains the only chance of cure; however, only less than 20% of patients are amenable to operative resection. Despite successful surgical resection, the majority of the patients still succumb to recurrent metastatic disease. Therefore, there is an urgent need to develop novel therapeutic strategies and to better select patients for current therapies. In this review, we will discuss current management by highlighting the landmark clinical trials that have shaped current care. We will then discuss the challenges of therapeutic development using the current randomized-controlled trial paradigm when confronted with the molecular heterogeneity of PDAC. Finally, we will discuss strategies that may help to shape the management of PDAC in the near future.

Adult small intestinal and multivisceral transplantation: lessons through the "retrospecto-scope" at a single UK centre from 1991 to 2013.

The first intestinal transplantation in the United Kingdom was performed in Cambridge in 1991. Thirty-eight intestinal transplantations have since been performed in 35 patients. All deaths in the first postoperative month related to hemorrhage, in 2 cases to severe portal hypertension (SPH) and poor venous access in 2. We have modified our practice to reduce the bleeding risk with SPH. Loss of venous access can be avoided by timely referral. Rejection was implicated in 3/14 deaths all dying of sepsis. Cytomegalovirus disease resulted in 2 deaths; we try to avoid CMV-positive donors giving to CMV-negative recipients. Three deaths were related to psychiatric illness, which led to loss of graft in 2 others. Three patients were retransplanted (2 rejections and 1 infarction) and all remain alive. Most patients (10/13) experienced a fall in body weight in the first postoperative year after SB/MV transplantation. Body weight fell by as much as 25%. As transplantation resulted in a net gain in small bowel in most cases, the postoperative loss of native body weight may be underestimated. Interestingly this was not associated with a significant fall in midarm circumference or handgrip strength. Long-term nutrition can be maintained with oral intake in the majority of patients post-SBT. There is improvement in handgrip strength post-transplant. Transplantation does not significantly alter weight, albumin, or other common anthropometric markers. Despite these problems, our 5-year survival results remain relatively good at 73% in the cohort from 1991, 79% from 2003, and 80% from 2008. We consider that deployment of strategies learned from our experiences has improved outcomes.

Prothrombotic disorders in a cohort of 25 patients undergoing transplantation: investigation and management implications.

BACKGROUND: Many patients referred for intestinal transplantation have a history of thrombosis. We undertook an analysis of transplanted patients to describe the history and frequency of thrombosis, clinical course, and management strategies used. RESULTS: Twenty-five patients underwent transplantation of intestine containing blocks between 2007 and 2012; 20 of 25 are still alive. Five of 25 patients were transplanted with history of portomesenteric thrombosis, 6 of 25 had experienced loss of venous access due to thrombosis, and 6 of 25 had history of mesenteric ischemia. Pretransplantation, 16 of 25 patients were anticoagulated. Thrombophilia screens identified 3 of 16 patients who were JAK2 positive, 1 of 25 who had antithrombin deficiency, and 1 of 25 who had a factor V Leiden heterozygote. Post-transplantation, of all 16 patients who were anticoagulated pretransplantation and continued postoperatively, 1 of 16 infarcted their small bowel graft and 4 of 16 developed a further venous thrombosis despite anticoagulation. Of the 9 without a previous history of thrombosis, 1 had a pulmonary embolus more than a decade after transplantation and another had an upper limb deep vein thrombosis associated with a line. Both were then anticoagulated. Seven of 25 are not anticoagulated, although they are administered antiplatelet prophylaxis. Postoperative bleeding complications of anticoagulation occurred in 3 patients. After a subarachnoid hemorrhage in 1 of those 3 patients, anticoagulation was stopped. The other 2 patients bled during ileal biopsy, and both remain on low molecular weight heparin treatment. CONCLUSION: Those with identifiable thrombophilic tendency and a history of venous or arterial thrombosis are considered to be at high risk for recurrent thrombosis. Those without such a history could be considered low risk. Our practice is to anticoagulate all high-risk individuals before and after transplantation and offer antiplatelet prophylaxis to low-risk patients as the risk of anticoagulation probably outweighs the risk of thrombosis for them. Early input from hematologists is vital in the management of high-risk patients, particularly those who thrombose when anticoagulated.

A national survey of attitudes to research in Scottish General Surgery Trainees.

INTRODUCTION: Given the importance placed on awareness and participation in research by Speciality and Training organisations, we sought to survey Scottish trainee attitudes to exposure to research practice during training and research in or out of programme. METHODS: An online survey was distributed to core and specialist trainees in general surgery in Scotland. RESULTS: Over a 4-month period, 108 trainees (75 ST/SPRs and 33 CTs) completed the survey. In their current post, most were aware of ongoing research projects (77%) and 55% were aware of trial recruitment. Only 47% attend regular journal clubs. Most believe that they are expected to present (89%) and publish (82%) during training. Most (59%) thought that participation in research is well supported. 57% were advised to undertake time out of programme research, mostly by consultants (48%) and training committee (36%). Of the 57 with time out of programme research experience, most did so in early training (37%) or between ST3-5 (47%). 28 out of the 36 (78%) without a national training number secured one after starting research. Most undertook research in a local academic unit (80%) funded by small grants (47%) or internally (33%). Most research (69%) was clinically orientated (13/55 clinical, 25/55 translational). 56% of those completing time out of programme research obtained an MD or PhD. About 91% thought that research was relevant to a surgical career. CONCLUSIONS: Most trainees believe that research is an important part of training. Generally, most trainees are exposed to research practices including trial recruitment. However, <50% attend regular journal clubs, a pertinent point, given the current 'exit exam' includes the assessment of critical appraisal skills.

Exploiting inflammation for therapeutic gain in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC.

Cambridge-Miami score for intestinal transplantation preoperative risk assessment: initial development and validation.

INTRODUCTION: Preoperative quantification of survival after transplantation would assist in assessing patients. We have developed a preliminary preoperative scoring system, called the Cambridge-Miami (CaMi) score, for transplantation of the small intestine either alone or as a composite graft. METHODS: The score combines putative risk factors for early-, medium-, and long-term survival. Factors included were loss of venous access and impairment of organs or systems not corrected by transplantation. Each factor was scored 0-3. A score of 3 indicated comorbidity approaching a contraindication for transplantation, that which might lead to but was not currently an adverse risk factor scored 1, and that presenting a definite but moderate increase in risk scored 2. The preoperative scores of 20 patients who had received intestinal transplants either isolated or as part of a cluster graft, who had either been followed up postoperatively for at least 10 years, or died within 10 years were compared with their survivals. RESULTS: Postoperative survival and CaMi score inversely correlated when analysed using Spearman test (r(s) = -0.82; P = .0001). A score of <3 associated with survival > or =3 years (12/12 patients) and >3 with survival of <6 months (4/4). Patient Kaplan-Meier (KM) survival curves for patients grouped according to CaMi score became significantly different from group 0 to group 3. Using this as a threshold score patients grouped as either >2 or <3 had significantly different survival rates (log-rank; P = .0001), KM median survival hazard ratio (HR) = 6, and rate of death KM HR = 5. Receiver-operator characteristics indicate a high degree of accuracy for prediction of death with an area under the curve (C statistic) at 3 years of 0.98, at 5 years of 0.82, and at 10 years of 0.65. CONCLUSION: This initial validation suggested that the preoperative CaMi score predicted postoperative survival.

Similar lipid profile but improved long-term outcomes with sirolimus after cyclosporine withdrawal compared to sirolimus with continuous cyclosporine.

Renal transplant recipients show an increased risk of cardiovascular disease compared with a nontransplant population. Herein we have shown an analysis of a randomized controlled trial wherein 525 patients receiving a first or second (9.7%) renal allograft from a deceased (89.1%), a living-related (7.8%), or a living-unrelated donor (3.1%) received sirolimus (SRL), cyclosporine (CsA), and steroids (ST) at the time of transplantation with randomization at 3 months after transplantation of 430 eligible patients to continue on SRL-CsA-ST or to have CsA withdrawn with increased SRL trough targets (SRL-ST group). Graft survival, patient survival, and renal function at 5 years were analyzed by average fasting total cholesterol (200 mg/dL) and triglyceride (240 mg/dL) subgroups. At 5 years, total, high-density lipoprotein (HDL), and low-density lipoprotein [LDL] cholesterol and triglyceride values were similar between the groups. Statins ( approximately 80% of patients of both groups) were most effective to lower cholesterol ( approximately 50 mg/dL; P < .001; both groups), and fibrates ( approximately 25% of patients of both groups) were most effective to decrease triglycerides ( approximately 100 mg/dL; P < .001; both groups). Renal function and blood pressure were significantly better with SRL-ST. Hypercholesterolemia and hypertriglyceridemia were associated with reduced graft survival, patient survival, and calculated GFR, but the only significant difference was lower graft survival among SRL-CsA-ST patients with hypertriglyceridemia. Cardiovascular-related deaths were reported in 3.7% and 2.8% of patients in the SRL-CsA-ST and SRL-ST groups, respectively. In conclusion, when compared with continuous SRL-CsA-ST, CsA withdrawal at 3 months followed by SRL-ST significantly improved glomerular filtration rate (GFR) and blood pressure without a further increase in lipid parameters or an incidence of untoward effects from hyperlipidemia, despite a 2-fold higher SRL exposure.