Forkhead box M1 (FOXM1) transcription factor is a key oncogenic driver of aggressive human meningioma progression.

AIMS: Aggressive meningioma remains incurable with neither chemo- nor targeted therapies proven effective, largely due to unidentified genetic alterations and/or aberrant oncogenic pathways driving the disease progression. In this study, we examined the expression and function of Forkhead box M1 (FOXM1) transcription factor during meningioma progression. METHODS: Human meningioma samples (n = 101) were collected, followed by Western blotting, quantitative PCR, immunohistochemical and progression-free survival (PFS) analyses. For in vitro assays, FOXM1 was overexpressed or knocked-down in benign (SF4433 and SF4068) or malignant (SF3061 and IOMM-Lee) human meningioma cell lines respectively. For in vivo studies, siomycin A (a FOXM1 inhibitor)-pretreated or control IOMM-Lee cells were implanted subcutaneously in nude mice. RESULTS: FOXM1 expression was increased in higher grades of meningioma and correlated with the mitotic index in the tumour tissue. Moreover, FOXM1 was increased in recurrent meningioma compared with the matched primary lesions. The patients who had higher FOXM1 expression had shorter PFS. In the subsequent in vitro assays, knockdown of FOXM1 in malignant meningioma cell lines resulted in decreased tumour cell proliferation, angiogenesis and invasion, potentially via regulation of ß-catenin, cyclin D1, p21, interleukin-8, vascular endothelial growth factor-A, PLAU, and epithelial-to-mesenchymal transition-related genes, whereas overexpression of FOXM1 in benign meningioma cell lines had the opposite effects. Last, suppression of FOXM1 using a pharmacological inhibitor, siomycin A, decreased tumour growth in an in vivo mouse model. CONCLUSIONS: Our data demonstrate that FOXM1 is a key transcription factor regulating oncogenic signalling pathways in meningioma progression, and a promising therapeutic target for aggressive meningioma.

Comparative outcomes of robot-assisted minimally invasive versus open esophagectomy in patients with esophageal squamous cell carcinoma: a propensity score-weighted analysis.

Robots are increasingly used in minimally invasive surgery. We evaluated the clinical benefits of robot-assisted minimally invasive esophagectomy (RAMIE) in comparison with the conventional open esophageal surgery. From 2012 to 2016, 371 patients with esophageal squamous cell carcinoma underwent an Ivor Lewis or McKeown procedure at our institution. Of these, 130 patients underwent laparoscopic gastric conduit formation followed by RAMIE, whereas 241 patients underwent conventional esophageal surgery, including laparotomy and open esophagectomy (OE). We compared the short- and long-term clinical outcomes of these patients using the propensity score-based inverse probability of treatment weighting technique (IPTW). Among the early outcomes, the OE group showed a higher incidence of pneumonia (P = 0.035) and a higher requirement for vasopressors (P = 0.001). Regarding the long-term outcomes, all-cause mortality was significantly higher (P = 0.001) and disease-free survival was lower (P = 0.006) in the OE group. Wound-related problems also occurred more frequently in the OE group (P = 0.020) during the long-term follow-up. There was no statistical intergroup difference in the recurrence rates (P = 0.191). The Cox proportional-hazard analysis demonstrated that wound problems (HR 0.16, 95% CI 0.02-0.57; P = 0.017), pneumonia (HR 0.23, 95% CI 0.06-0.68; P = 0.019), and use of vasopressors (HR 0.14, 95% CI 0.08-0.25; P = 0.001) were independent predictors of mortality. RAMIE could be a better surgical option for selected patients with esophageal squamous cell carcinoma.

LKB1 deficiency enhances sensitivity to energetic stress induced by erlotinib treatment in non-small-cell lung cancer (NSCLC) cells.

The tumor suppressor serine/threonine kinase 11 (STK11 or LKB1) is mutated in 20-30% of patients with non-small-cell lung cancer (NSCLC). Loss of LKB1-adenosine monophosphate-activated protein kinase (AMPK) signaling confers sensitivity to metabolic inhibition or stress-induced mitochondrial insults. We tested the hypothesis that loss of LKB1 sensitizes NSCLC cells to energetic stress induced by treatment with erlotinib. LKB1-deficient cells exhibited enhanced sensitivity to erlotinib in vitro and in vivo that was associated with alterations in energy metabolism and mitochondrial dysfunction. Loss of LKB1 expression altered the cellular response to erlotinib treatment, resulting in impaired ATP homeostasis and an increase in reactive oxygen species. Furthermore, erlotinib selectively blocked mammalian target of rapamycin signaling, inhibited cell growth and activated apoptosis in LKB1-deficient cells. Erlotinib treatment also induced AMPK activation despite loss of LKB1 expression, which was partially reduced by the application of a calcium/calmodulin-dependent protein kinase kinase 2 inhibitor (STO-609) or calcium chelator (BAPTA-AM). These findings may have significant implications for the design of novel NSCLC treatments that target dysregulated metabolic and signaling pathways in LKB1-deficient tumors.

Evaluation of 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in rat models with hepatocellular carcinoma with liver cirrhosis.

Liver cirrhosis is a predominant risk factor for hepatocellular carcinoma (HCC). However, the exact mechanism of the progression from cirrhosis to cancer remains unclear. The uptake of 2-[(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG) is widely used as a marker of increased glucose metabolism to monitor the progression of cancer with positron emission tomography (PET)/computed tomography (CT). Here we investigated the feasibility of using (18)F-FDG PET/CT in the diethylnitrosamine (DEN) mediated experimental hepatocellular carcinoma model. Rats received weekly intraperitoneal injections of DEN for 16 weeks for induction of HCC. We recorded starting from 0 days or 0 weeks after the last DEN injection. The weight and survival rate of rats were then measured. Also, an (18)F-FDG PET scan and serum analysis were performed at minus 2, 0, plus 2, and plus 4 weeks after the last DEN injection. The body weight of rats was maintained between 350 g and 370 g during 14 and 20 weeks, and the rats were euthanized at 35 days after the last DEN injection. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphate (ALP) were significantly higher at zero weeks after the last DEN injection. The (18)F-FDG uptake for the quantitative evaluation of HCC was done by measuring the region of interest (ROI). At minus two weeks after the last DEN injection, the ROI of rats had significantly increased compared to the normal group, in a time-dependent manner. These results suggest that FDG uptake serves as a good screening test to evaluate the feasibility of DEN-induced HCC.

Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of ß-catenin activation of the DKK1 promoter in prostate cancer.

Prostate cancer (PCa)bone metastases are unique in that majority of them induce excessive mineralized bone matrix, through undefined mechanisms, as opposed to most other cancers that induce bone resorption. Parathyroid hormone-related protein (PTHrP) is produced by PCa cells and intermittent PTHrP exposure has bone anabolic effects, suggesting that PTHrP could contribute to the excess bone mineralization. Wnts are bone-productive factors produced by PCa cells, and the Wnt inhibitor Dickkopfs-1 (DKK1) has been shown to promote PCa progression. These findings, in conjunction with the observation that PTHrP expression increases and DKK1 expression decreases as PCa progresses, led to the hypothesis that PTHrP could be a negative regulator of DKK1 expression in PCa cells and, hence, allow the osteoblastic activity of Wnts to be realized. To test this, we first demonstrated that PTHrP downregulated DKK1 mRNA and protein expression. We then found through multiple mutated DKK1 promoter assays that PTHrP, through c-Jun activation, downregulated the DKK1 promoter through a transcription factor (TCF) response element site. Furthermore, chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that PTHrP mediated this effect through inducing c-Jun to bind to a transcriptional activator complex consisting of ß-catenin, which binds the most proximal DKK1 promoter, the TCF response element. Together, these results demonstrate a novel signaling linkage between PTHrP and Wnt signaling pathways that results in downregulation of a Wnt inhibitor allowing for Wnt activity that could contribute the osteoblastic nature of PCa.

Comparison of clinical outcomes after conservative and surgical treatment of isolated anastomotic leaks after esophagectomy for esophageal cancer.

The clinical course and outcome of isolated anastomotic leaks (IALs) after esophagectomy are significantly different from those of necrotic leaks. The purpose of this study was to investigate the clinical features, diagnosis, treatment, and long-term outcome in patients with IALs after esophagectomy with reconstruction for esophageal cancer. A total of 663 patients underwent esophagectomy with esophageal reconstruction because of esophageal cancer between 2000 and 2010 at the Seoul Asan Medical Center. IALs occurred in 23 patients (3.5%). All patients with IAL were male, with a median age of 61 years. Patients with IAL were divided into three groups based on their clinical course. group A comprised patients who had definite clinical symptoms and/or signs indicating mediastinal contamination or leak before routine contrast esophagography was performed. Groups B and C comprised patients who had no definite clinical symptoms and/or signs of leaks before the routine contrast examination. Furthermore, group B contained those patients who resumed oral intake because no leak was found in the routine contrast examination and was diagnosed some days after resuming oral intake. Group C contained those patients who kept fasting because the leak was found in the routine contrast examination. The median follow-up period was 30 months. The mean time to closure of the IAL was 70.1 ± 96.0 days (range 4-364). There was a 72.7% overall closure rate within 60 days. By univariate analysis, the mean time to closure of the IAL was found to be significantly longer for group A patients or in cases where the patients had an uncontained leak, leukocytosis, or empyema. However, there was no statistically significant differences in age, neoadjuvant treatment, site of anastomosis (cervical vs. thoracic), fever, or treatment of the leak. By multivariate analysis, group A was found to be an independent predictive factor for the time to closure of the IAL. Repeat contrast studies revealed no anastomotic leaks in 18 patients and the formation of contained fistula in four cases (excluding one patient who died in hospital). The four patients with a contained fistula showed no clinical symptoms or signs, and tolerated resumed oral intake. IALs were resolved in most cases with low leak-related mortality, and resolution of the leaks occurred within 2 months in the majority of patients.

Long-term results of thoracoscopic thymectomy for thymoma without myasthenia gravis.

OBJECTIVE: To compare the feasibility and safety of thoracoscopic thymectomy with conventional sternotomy thymectomy for thymoma without myasthenia gravis. METHODS: Data from 70 patients diagnosed with thymoma, who underwent thoracoscopic thymectomy (n = 25, Group T) or sternotomy thymectomy (n = 45, Group S) between March 2002 and March 2008, were retrospectively evaluated. RESULTS: Mean follow-up durations were 78.0 ± 21.9 months and 70.0 ± 23.6 months in Groups T and S, respectively. No deaths occurred in Group T; seven deaths occurred in Group S, all > 1 month post follow-up. Durations of chest intubation and hospitalization were significantly shorter in Group T than in Group S. No significant between-group difference in the incidence of operative complications was observed. Tumour recurrence-free rates at 5 and 7 years postsurgery were 96% (both years) in Group T and 95% (both years) in Group S. CONCLUSIONS: Long-term follow-up indicates that thoracoscopic thymectomy for thymoma without myasthenia gravis is effective and is well tolerated, and associated with low rates of operative complications and recurrence.

Donor evaluation for lung transplantation in Korea.

Lung transplantation for end-stage lung disease results in prolonged survival and improved pulmonary function. However, the shortage of donor lungs has been a major limiting factor in Korea. We sought to investigate the number and utilization of donor lungs by the five institutions performing LTx in Korea, retrospectively reviewing outcomes of organs registered in the Korean Network for Organ Sharing from January to December, 2010. Lungs were offered from 270 brain-dead patients (189 males and 81 females) of mean age of 45.2 ± 14.2 years (range, 12 to 77 years). The most common cause of brain death was hemorrhage (n = 219, 81%). Only 18 (6.7%) donor lungs were used, which was low compared with kidney (93.3%), liver (86.3%), heart (26.7%), and pancreas (11.1%) use. The mean age of donors of transplanted lungs was 35.7 years (range, 14 to 51 years) compared with 45.9 years for other organs (P = .003). The characteristics of utilized donor lungs were: mean partial pressure of oxygen (PaO(2)), 300.9 mm Hg; mean smoking history, as 2.7 pack-years; and mean body mass index, 21.2 kg/m(2). The causes of refusal were medical ineligibility (n = 129) including poor PaO(2), abnormal chest x-ray, long smoking history, older age (n = 46), no properly matched recipient (n = 46), unknown (n = 17), and family withdrawal (n = 14). Only 8 (33.3%) were transplanted from standard criteria and 10 from the lungs that did not satisfy these criteria. An efficient utilization system is needed to improve lung transplantations.

Reconstructive endovascular treatment of fusiform or ultrawide-neck circumferential aneurysms with multiple overlapping enterprise stents and coiling.

BACKGROUND AND PURPOSE: Fusiform aneurysms and ultrawide-neck circumferential aneurysms are still some of the most challenging lesions. The aim of this study was to investigate the efficacy and feasibility of the use of multiple overlapping Enterprise stents with coiling for the treatment of fusiform or ultrawide-neck circumferential aneurysms. MATERIALS AND METHODS: Twelve consecutive patients (9 men and 3 women; mean age, 56 years) with fusiform (n = 5) or ultrawide-neck circumferential (n = 7) aneurysms were treated with 2-3 overlapping Enterprise stents and coiling. The feasibility of this procedure and the clinical and angiographic outcomes of this technique were retrospectively evaluated. RESULTS: All patients were successfully treated by using this technique without any complications. Posttreatment angiographic results revealed grade 4 occlusion of the aneurysm in 6, grade 3 in 4, and grade 2 in 2 patients. Clinical follow-up was performed in all patients (mean, 16 months; range, 5-24 months). Nine patients had an mRS score of 0. Two had an mRS score of 1, one of whom had an initial mRS score of 2 due to the mass effect of a giant aneurysm; the other had a recurrent aneurysm presenting with SAH 5 years after clipping. Angiographic follow-up was performed in 10 patients at 6-20 months posttreatment. Nine had stable or improved occlusion, while 1 had a minor recurrence. CONCLUSIONS: In this small series, multiple overlapping Enterprise stents with coiling were a feasible and effective option for the treatment of fusiform and ultrawide-neck circumferential aneurysms. Further experience and follow-up are required to document the long-term efficacy of this treatment.

Vaginal and pelvic recurrence rates based on vaginal cuff length in patients with cervical cancer who underwent radical hysterectomies.

AIMS: The objective of this study was to determine the association of vaginal cuff length (VCL) with vaginal and pelvic recurrence rates in patients with cervical cancer who underwent radical hysterectomies. MATERIALS AND METHODS: The clinicopathologic characteristics were collected from the medical records of 280 patients with cervical cancer who underwent radical hysterectomies. The association of VCL with 3-year vaginal and pelvic recurrence rates was determined using a Z-test. The association of VCL with other clinicopathologic characteristics was also determined. RESULTS: The VCL was not associated with 3-year vaginal and pelvic recurrence rates. The 3-year vaginal recurrence rate was 0%-2% and the 3-year pelvic recurrence rate was 7%-8%, independent of VCL. The VCL and the age of patients had an inverse relationship. However, the VCL was not associated with histologic type, FIGO stage, clinical tumor size, tumor size in the surgical specimen, depth of invasion, lymphovascular space invasion, parametrial involvement, lymph node involvement, and adjuvant therapy. One-hundred ninety of 280 patients (68%) underwent adjuvant therapies following radical hysterectomies. CONCLUSION: Although it is limited by the high rate of adjuvant therapy, the current study suggested that the VCL following radical hysterectomy in patients with cervical cancer was not associated with vaginal and pelvic recurrence rates.

Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99].

BACKGROUND: The second-line chemotherapeutic treatment for metastatic urothelial cancer (UC) after failure of cisplatin-based first-line therapy needs to be improved. Based on encouraging phase II data of gemcitabine and paclitaxel (Taxol) (GP), this trial was designed to compare a short-term (arm A) versus a prolonged (arm B) second-line combination chemotherapy of GP. PATIENTS AND METHODS: Of 102 randomized patients, 96 were eligible for analysis. Primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rates (ORR) and toxicity. RESULTS: Neither OS [arm A: 7.8 (95% CI: 4.2-11.4), arm B: 8.0 (95% CI: 4.9-11.1) months] and PFS [arm A: 4.0 (95% CI: 0-8.0), arm B: 3.1 (95% CI: 1.9-4.2) months] nor ORR (arm A: 37.5%, arm B: 41.5%) were significantly different. On prolonged treatment, more patients experienced severe anemia (arm A: 6.7% versus arm B: 26.7% grade III/IV anemia; P = 0.011). In six patients, treatment was stopped during the first cycle due to disease progression or toxicity. Two patients died due to treatment-related toxic effects. CONCLUSION: Due to rapid tumor progression and toxicity at this dosage and schedule in a multicenter setting, it was not feasible to deliver a prolonged regimen. However, a high response rate of ∼40% makes GP a promising second-line treatment option for patients with metastatic UC.

Branched oligomerization of cell-permeable peptides markedly enhances the transduction efficiency of adenovirus into mesenchymal stem cells.

Cell-permeable peptides (CPPs) promote the transduction of nonpermissive cells by recombinant adenovirus (rAd) to improve the therapeutic efficacy of rAd. In this study, branched oligomerization of CPPs significantly enhanced the transduction of human mesenchymal stem cells (MSCs) by rAd in a CPP type-independent manner. In particular, tetrameric CPPs increased transduction efficiency at 3000-5000-fold lower concentrations than did monomeric CPPs. Although branched oligomerization of CPPs also increases cytotoxicity, optimal concentrations of tetrameric CPPs required for maximum transduction are at least 300-1000-fold lower than those causing 50% cytotoxicity. Furthermore, although only approximately 60% of MSCs were maximally transduced at 500 muM of monomeric CPPs, >95% of MSCs were transduced with 0.1 muM of tetrameric CPPs. Tetrameric CPPs also significantly increased the formation and net surface charge of CPP/rAd complexes, as well as the binding of rAd to cell membranes at a greater degree than did monomeric CPPs, followed by rapid internalization into MSCs. In a critical-size calvarial defect model, the inclusion of tetrameric CPPs in ex vivo transduction of rAd expressing bone morphogenetic protein 2 into MSCs promoted highly mineralized bone formation. In addition, MSCs that were transduced with rAd expressing brain-derived neurotrophic factor in the presence of tetrameric CPPs improved functional recovery in a spinal cord injury model. These results demonstrated the potential for tetrameric CPPs to provide an innovative tool for MSC-based gene therapy and for in vitro gene delivery to MSCs.

Prognostic significance of histological grade in clear-cell carcinoma of the ovary: a retrospective study of Korean Gynecologic Oncology Group.

BACKGROUND: This study was to investigate the prognostic significance of clinicopathologic characteristics in patients with clear-cell carcinoma (CCC) of the ovary. MATERIALS AND METHODS: Two hundred and one patients with CCC of the ovary were registered in the Korean Gynecologic Oncology Group. The Korean Gynecologic Pathology Study Group reviewed the pathological slides centrally, using a universal grading system. The prognostic significances of clinicopathologic factors were evaluated by multivariate analysis. RESULTS: Most of the patients were diagnosed at an early stage (stage I, 61.3%), and the overall 5-year survival rate was 57%. Early-stage disease showed a favorable prognosis, but advanced diseases showed poor prognosis. Stage of disease was the only significant prognostic factor on multivariate analysis (P < 0.001). However, universal grade and residual tumor also showed prognostic significance on the forward stepwise likelihood ratio test. There was no survival difference observed between patients treated with paclitaxel-based and those treated with platinum-based combination chemotherapy. CONCLUSIONS: The stage, residual tumor, and universal grade were significant prognostic factors in patients with CCC of the ovary. The universal grading system is applicable in determining prognosis of CCC of the ovary. Further clinical trials for optimal chemotherapy are in need.

Src family kinases as mediators of endothelial permeability: effects on inflammation and metastasis.

Src family kinases (SFKs) are signaling enzymes that have long been recognized to regulate critical cellular processes such as proliferation, survival, migration, and metastasis. Recently, considerable work has elucidated mechanisms by which SFKs regulate normal and pathologic processes in vascular biology, including endothelial cell proliferation and permeability. Further, when inappropriately activated, SFKs promote pathologic inflammatory processes and tumor metastasis, in part through their effects on the regulation of endothelial monolayer permeability. In this review, we discuss the roles of aberrantly activated SFKs in mediating endothelial permeability in the context of inflammatory states and tumor cell metastasis. We further summarize recent efforts to translate Src-specific inhibitors into therapy for systemic inflammatory conditions and numerous solid organ cancers.

Clinical outcome and ischemic complication after treatment of anterior choroidal artery aneurysm: comparison between surgical clipping and endovascular coiling.

BACKGROUND AND PURPOSE: Although coiling has been favorably comparable with clipping for treatment of most intracranial aneurysms, there is a controversy on which modality is safer for anterior choroidal artery (AchoA) aneurysm. We retrospectively evaluated the clinical outcomes and treatment-related complications after surgical clipping and endovascular coiling of AchoA aneurysms. MATERIALS AND METHODS: Seventy-three AchoA aneurysms were recruited from 1895 intracranial aneurysms, which were treated either by surgical clipping or by endovascular coiling in 4 institutions between May 1999 and December 2006. The AchoA aneurysms were dichotomized according to the modality of treatment, the coil group (37 patients; 38 aneurysms) and the clip group (35 patients; 35 aneurysms). Clinical outcomes and incidence of treatment-related complications between 2 groups and the factors influencing the clinical outcomes were evaluated. RESULTS: There was no rebleeding in both groups during follow-up, for 4-72 months (mean, 27 months) in the coil group and for 3-84 months (mean, 34 months) in the clip group. In the coil group, 31 patients (83.8%) had favorable outcome (modified Rankin Scale score [mRS], 0-3). In the clip group, 31 patients (88.6%) had favorable outcome. The complication of coiling was transient contralateral hemiparesis in 2 patients, who recovered completely. The complications of clipping were permanent contralateral hemiparesis due to AchoA infarction in 4 patients and third-nerve palsy in 1 patient. Hunt and Hess grade 4 or 5 and AchoA infarction were significantly correlated with poor outcome (mRS, < or =4). Clipping had significantly higher incidence of AchoA infarction than coiling (P < .05). CONCLUSION: Coiling of AchoA aneurysms appears comparable with clipping in clinical outcome and prevention of rebleeding, with significantly lower incidence of AchoA infarction than clipping.

Detection and molecular characterization of calf diarrhoea bovine coronaviruses circulating in South Korea during 2004-2005.

Although the widespread occurrence of calf diarrhoea (CD) bovine coronavirus (BCoV) infections have been reported in most cattle producing countries, only the genetic differences in the BCoVs from American and Canadian isolates and/or strains have been identified and compared. Hence, it is unclear if the BCoVs circulating in the other countries have distinct genetic characteristics. The aim of this study was to determine the prevalence and genetic diversity of CD BCoVs based on the deduced amino acid (aa) sequences of the spike (S) and haemagglutinin/esterase (HE) proteins in South Korea. RT-PCR and nested PCR using the primer pairs specific to the nucleocapsid gene, BCoVs detected the BCoVs in 56 (15.6%) of 359 diarrhoeic faecal samples. Phylogenetic analysis of the entire S gene indicated that 10 Korean CD BCoV strains clustered with other Korean BCoV strains with different clinical forms but were different from the American and Canadian BCoV strains. Moreover, the phylogenetic data of the aa sequences of the HE gene revealed all the Korean CD strains to be distinct from the other Korean BCoV strains with different clinical forms. These results suggest that the Korean BCoVs cause endemic infections in diarrhoeic calves in Jeonnam province and have taken a different evolutionary pathway from the BCoVs in other countries. Moreover, the different BCoV strains are circulating in the different clinical forms in South Korea. These results also suggest that vaccines against the BCoVs can be developed with each Korean BCoV in different clinical forms.

Exploratory calcineurin inhibitor-free regimens in living-related kidney transplant recipients.

Chronic allograft nephropathy is among the major causes of graft loss even in low-risk kidney transplant recipients and correlates with acute nephrotoxic events during the first year post-transplant. Therefore, calcineurin inhibitor-free regimens may improve patient and graft survival among recipients of living-related kidney transplants. To confirm this hypothesis, we evaluated the efficacy and safety of two calcineurin inhibitor-free regimens in 92 low-risk recipients of one-haplotype living-related kidney transplants. Immunosuppression consisted of tacrolimus, azathioprine and prednisone (group I, GI, N = 38), 2 doses of daclizumab, mycophenolate mofetil (MMF), and prednisone (GII, N = 33) and 2 doses of daclizumab, MMF, sirolimus and prednisone (GIII, N = 21). At 12 months, treatment failure (biopsy-confirmed acute rejection, graft loss or death) was higher in GII compared to GIII and GI (54.5 vs 24.0 vs 13.1%, P < 0.01, respectively). In patients of black ethnicity the incidence of acute rejection was 25 vs 83.3 vs 20% (P = 0.055), respectively. Patient and graft survival was comparable. There were no differences in mean creatinine or calculated creatinine clearance at 12 months. Overall incidence of post-transplant diabetes mellitus (3.3%) and cytomegalovirus disease (4.3%) was similar in all groups. Further development of effective calcineurin inhibitor-free regimens should exclude patients of black ethnicity and may need full-induction therapy, perhaps with depleting agents, and concentration-controlled use of sirolimus and MMF.

Exploratory calcineurin inhibitor-free regimens in living-related kidney transplant recipients

Chronic allograft nephropathy is among the major causes of graft loss even in low-risk kidney transplant recipients and correlates with acute nephrotoxic events during the first year post-transplant. Therefore, calcineurin inhibitor-free regimens may improve patient and graft survival among recipients of living-related kidney transplants. To confirm this hypothesis, we evaluated the efficacy and safety of two calcineurin inhibitor-free regimens in 92 low-risk recipients of one-haplotype living-related kidney transplants. Immunosuppression consisted of tacrolimus, azathioprine and prednisone (group I, GI, N = 38), 2 doses of daclizumab, mycophenolate mofetil (MMF), and prednisone (GII, N = 33) and 2 doses of daclizumab, MMF, sirolimus and prednisone (GIII, N = 21). At 12 months, treatment failure (biopsy-confirmed acute rejection, graft loss or death) was higher in GII compared to GIII and GI (54.5 vs 24.0 vs 13.1 percent, P < 0.01, respectively). In patients of black ethnicity the incidence of acute rejection was 25 vs 83.3 vs 20 percent (P = 0.055), respectively. Patient and graft survival was comparable. There were no differences in mean creatinine or calculated creatinine clearance at 12 months. Overall incidence of post-transplant diabetes mellitus (3.3 percent) and cytomegalovirus disease (4.3 percent) was similar in all groups. Further development of effective calcineurin inhibitor-free regimens should exclude patients of black ethnicity and may need full-induction therapy, perhaps with depleting agents, and concentration-controlled use of sirolimus and MMF.