Neuroblastoma-induced inhibition of dendritic cell IL-12 production via abrogation of CD40 expression

Background/Purpose

CD40 expression by dendritic cells (DCs) critically regulates their maturation/antitumor activity. CD40-CD40 ligand (CD40L) signaling stimulates DC-mediated IL-12 production/cytotoxicity. Recent studies suggest that neuroblastoma (NB)-derived gangliosides impair DC maturation, IL-12 secretion, and NK/T-cell activity. Neuroblastoma ganglioside-mediated abrogation of CD40 expression by DC and tumor-induced tolerance has not been studied. The purpose of this study is to determine if NB inhibits DC IL-12 production via CD40. The contributory role of the NB-derived ganglioside G_M3 in this process is also examined.

Methods

Dendritic cells were generated from bone marrow of mice injected with saline (control) or murine NB. Control DCs were matured with or without G_M3. Dendritic cells were cocultured with NB cells treated with or without a ganglioside synthesis inhibitor. Dendritic cell groups were analyzed for maturation/costimulatory markers. Control and tumor-derived DC were stimulated with CD40L or Staphylococcus aureus and studied for IL-12 expression.

Results

CD40 expression on DC generated from NB bearing mice decreased by 64% (P < .001). G_M3 down-regulated DC maturation and CD40 expression. Only CD40-dependent IL-12 production was abrogated (60%, P < .01) in DC derived from NB-bearing mice. Dendritic cell capacity to synthesize IL-12 remained intact.

Conclusions

Neuroblastoma-induced inhibition of DC function may result from ganglioside-mediated CD40 signaling deficiency. Strategies to bypass/augment CD40-CD40L signaling may improve current NB immunotherapies.     

Effect of Aspergillus fumigatus and Candida albicans on pro-inflammatory response in cystic fibrosis epithelium

Background

The identification of filamentous fungi and/or yeasts in the airway secretions of individuals with cystic fibrosis (CF) is becoming increasingly prevalent; yet the importance of these organisms in relation to underlying inflammation is poorly defined.

Methods

Cystic fibrosis bronchial epithelial cells (CFBE) and human bronchial epithelial cells (HBE) were co-incubated with Candida albicans whole cells or Aspergillus fumigatus conidia for 24 h prior to the measurement of pro-inflammatory cytokines IL-6 and IL-8 by ELISA.

Results

Treatment of HBE or CFBE with C. albicans whole cells did not alter cytokine secretion. However treatment of CFBE with A. fumigatus conidia resulted in a 1.45-fold increase in IL-6 and a 1.65-fold increase in IL-8 secretion in comparison to basal levels; in contrast there was far less secretion from HBE cells.

Conclusion

Our data indicate that A. fumigatus infection modulates a pro-inflammatory response in CF epithelial cells while C. albicans does not.     

Impact of surgery on immunologic function: comparison between minimally invasive techniques and conventional laparotomy for surgical resection of colorectal tumors

Background

Surgical trauma suppresses host immune function, potentially creating an environment vulnerable to tumor cell growth. This study compared immune function after laparoscopy, minilaparotomy, and conventional colorectal tumor resections.

Methods

Seventy-one patients underwent surgery (20 laparoscopy, 21 minilaparotomy, and 30 conventional). Blood samples were taken before surgery and at 3 hours, 24 hours, and 5 days after surgery. White blood cell constitution was determined using monoclonal antibodies. Levels of TH1 cytokines interferon-γ, tumor necrosis factor-α, and interleukin (IL)-2 and TH2 cytokines IL-10, -4, and -6 were measured in plasma and from supernatants of activated peripheral blood mononuclear cells.

Results

At 5 days after surgery, lymphocyte counts remained low in the conventional and minilaparotomy groups (P = .001 and P = .008) but had resolved in laparoscopic patients. Three-hour postoperative serum IL-6 concentrations were lower in laparoscopic than in conventional patients (P = .028). Production of TH1 cytokines 3 hours after surgery were significantly increased in laparoscopic patients (interferon-γ P = .018, tumor necrosis factor-α P = .011, and IL-2 P = .037).

Conclusions

TH1 lymphocyte function is improved transiently and immune homeostasis restored earlier in patients undergoing laparoscopic colorectal cancer resection, which may influence disease recurrence.     

Intravenous landiolol, a novel β(1)-adrenergic blocker, reduces the minimum alveolar concentration of sevoflurane in women

Study Objective

To investigate the effect of intravenous (IV) landiolol, a novel β₁-adrenergic blocker, on the minimum alveolar concentration (MAC) of sevoflurane in adult women.

Design

Prospective, randomized study.

Setting

University hospital.

Patients

42 ASA physical status 1 and 2 women, aged 24-57 years, who were scheduled to undergo elective abdominal surgery.

Interventions

Anesthesia was induced in all patients by vital capacity rapid inhalation induction of sevoflurane. In the landiolol group, administration of landiolol began when patients took a vital-capacity breath: 0.125 mg/kg/min for one minute and then 0.04 mg/kg/min. Normal saline was administered in the control group.

Measurements

MAC was determined by a technique adapted from the conventional up-down method.

Main Results

The MAC of sevoflurane was 2.2% ± 0.2% in the control group and 1.7% ± 0.2% in the landiolol group, a statistically significant difference (P = 0.0005).

Conclusions

IV landiolol reduces the MAC of sevoflurane in women by approximately 20%.     

Candiduria in renal transplant recipients: incidence, clinical repercussion, and treatment indication

Introduction

The incidence of candiduria in renal transplant recipients is unknown. In clinical practice, the indications for antifungal therapy are not well established. Furthermore, there is the problem of the choice of the antifungal drug since some of them may select resistant Candida species, or interact with immunosuppressive agents or only be used intravenously.

Aim

We sought to study the incidence, clinical repercussions and effectiveness of antifungal treatment to prevent recurrence of candiduria.

Materials and methods

We examined all episodes of Candida-positive urine cultures (>50,000 cfu/mL) in 996 recipients over 2 years. We considered the Candida species, administered treatment, presence of fever, requirement for hospital admission versus outpatient case, occurrence of simultaneous bacterial urinary tract infection (UTI), antibiotic use during the week before candiduria, and presence of an indwelling urinary catheter.

Results

Among 996 subjects, 34 displayed 83 episodes of candiduria, yielding an accumulated incidence of 3.4% after 2 years. The frequency was higher among women (6.3% vs 1.7%, P < .001). Of the 45 outpatient episodes (54.2%), 17 were treated and one required hospitalization (5.9%). Of the 28 nontreated outpatients, two were hospitalized (7.1%, P = .68 vs treated patients). All cases of hospital admission presented simultaneous bacterial UTI, none developed candidemia, and two patients did not receive any antifungal therapy. With respect to the first episodes of each patient (n = 34), 5/11 treated (45.5%) and 4/23 untreated (17.4%) patients developed recurrences (P = .095). Selection of more resistant Candida species was not observed. Fifty cases (60%) were associated with antibiotic therapy and 34 (41%) the presence of a urinary catheter.

Conclusions

It does not seem necessary to treat candiduria in this setting. Antifungal therapy was not associated with either a reduction in recurrence or the appearance of more resistant species in this study. We observed no important clinical repercussions.     

Renal transplantation in old recipients from expanded criteria donors selected by kidney biopsy

Background

In Spain, the number of ideal kidney transplant donors has fallen, with at the same time an increase in the number of older recipients on the waiting list.

Aim

To analyze the results of expanded criteria cadaveric donor kidney transplants into older recipients using grafts selected by kidney biopsy.

Patients and methods

We studied 360 kidney transplant recipients who had been followed to December 2009: 180 in the study group and 180 in a control group composed of younger patients who received grafts from non-expanded criteria donors between 1999 and 2006. A paraffin-embedded kidney biopsy was evaluated by the percentages of sclerosed glomeruli, arteriolar hyalinosis, intimal wall thickening, interstitial fibrosis, and tubular atrophy.

Results

Significant differences were observed in donor age (63.50 ± 5.46 vs 31.90 ± 13.29 years; P < .001) and recipient age (58.40 ± 8.80 vs 40.71 ± 13.23 years; P < .001). Donor renal function was significantly worse among the expanded criteria group (90.80 vs 108.11 mL/min/1.73 m²; P = .006), remaining so over time in the recipient (at 1 year: 42.08 vs 63.71 [P < .001]; at 3 years: 41.25 vs 62.31 [P < .001], and at 7 years: 38.17 vs 64.18 [P < .001]). Censored 7-year graft survivals were 73% versus 87% (P < .001) with similar patient survivals (90.5% vs 95%; P = .39).

Conclusions

Selection of expanded criteria donors by kidney biopsy resulted in good renal function as well as graft and patient survivals at 7 years in older recipients.     

Patients with severe obstructive sleep apnea syndrome and elevated high-sensitivity C-reactive protein need priority treatment

Objective

To evaluate the clinical factors predicting the significantly elevated high-sensitivity C-reactive protein (hs-CRP) concentrations, defined herein as hs-CRP ≥ 3 mg/L, in adult males with untreated obstructive sleep apnea syndrome (OSAS).

Study Design

Cross-sectional study.

Setting

Tertiary referral center.

Subjects and Methods

Sixty-five consecutive male patients with newly diagnosed OSAS were enrolled to receive complete medical history review, physical examination, in-laboratory overnight polysomnography, and hs-CRP test. The patients had no current or history of cardiovascular disease. The patients had a mean age of 38.2 ± 9.9 years, body mass index (BMI) of 27.4 ± 3.5 kg/m², and Epworth Sleepiness Scale (ESS) of 11.3 ± 4.6. The serum levels of hs-CRP were assessed using peripheral venous blood samples.

Results

Twenty-three percent of the overall patients had significantly elevated serum levels of hs-CRP. The increase of hs-CRP correlated fairly with BMI, apnea-hypopnea index (AHI), tonsil size, and ESS (r = 0.450, 0.398, 0.393, and 0.300, respectively; all P ≤ 0.05) after adjustment for conventional coronary heart disease risk factors. However, only the AHI could predict for significantly elevated hs-CRP after stepwise multiple linear regression (R² = 0.251, P < 0.001).

Conclusion

Patients in this study with hs-CRP ≥ 3 mg/L were more prevalent in the severe OSAS group. This observation suggests that the severe OSAS patients need to have their cardiovascular statuses evaluated by use of an hs-CRP screening test.     

Primary gastrointestinal tract lymphoma in the pediatric patient: review of 265 patients from the SEER registry

Objective

The objective of this study is to determine outcomes of pediatric patients with primary gastrointestinal tract lymphoma (PGTL) and the impact of surgery or radiation on survival.

Methods

The Surveillance, Epidemiology, and End Result database was queried from 1973 to 2006 for patients younger than 20 years with PGTL.

Results

265 patients with PGTL were identified. Overall 5- and 10-year survivals were 84% and 83%, respectively. Tumors of the stomach (9%) and rectum/anus (2%) had the worst and best 10-year survivals, respectively (59% vs 100%, P = .023). There was no significant difference in 10-year survival for patients younger than 10 years of age who had surgical extirpation (83% vs 85% no surgery, P = .958) or radiotherapy (76% vs 85% no radiotherapy, P = .532). However, there was a significantly decreased 10-year survival in patients 10 years or older who had surgical extirpation (79% vs 100% no surgery, P = .013) or radiotherapy (49% vs 87% no radiotherapy, P = .001). Under multivariate analysis, tumor location was an independent predictor of improved survival (small bowel, HR 0.21, P = .002; large bowel, HR 0.23, P = .004).

Conclusion

We found no significant survival advantage for surgical extirpation or radiotherapy in patients younger than 10 years with PGTL, whereas either treatment modality was associated with lower survival in patients 10 years or older.     

Utilidad de la tomografía computarizada para el diagnóstico de lesiones intestinales y mesentéricas en el trauma abdominal cerrado

Background

The frequency of bowel and mesenteric injuries is increasing. They are difficult to diagnose and delays in their diagnosis leads to a significantly increased morbidity and mortality. The aim of this study is to evaluate the usefulness of the computed tomography (CT) in the detection of blunt bowel and mesenteric injuries.

Method

Between January 2000 and October 2007, 79 patients with blunt abdominal trauma (60 men and 19 women) were included in our study. They underwent laparotomy after performing the abdominal CT. The CT findings were compared with the findings at laparotomy in order to determine the accuracy of the CT in the detection of bowel and mesenteric injuries.

Results

For the detection of bowel and mesenteric injuries we obtained for the CT: Sensitivity=84.2%, Specificity=75.6%, Positive Predictive Value =76.2%, Negative Predictive Value =83.8%, Positive Probability Value=3.45 and Negative Probability Value =0.21. Accuracy: 79.7%.

Conclusion

The abdominal CT is suitable for detecting bowel and mesenteric injuries following blunt abdominal trauma.     

Intestine as Source of Cytokines and Growth Factors

Background

The activation status of intestinal immune system cells is much higher than that of analogous peripheral cells. Increased serum concentrations of proinflammatory cytokines have been reported in various pathologic conditions; however, the source of these mediators has not been elucidated.

Objective

To assess the role of the human intestine and its lymphatic system in production of growth factors and proinflammatory cytokines.

Material and Methods

Twenty liver transplant recipients and 20 donors were included in the study. Blood samples were obtained from the artery supplying the intestine, the portal vein, and a peripheral vein during liver harvesting in donors and after transplantation in recipients. An enzyme-linked immunosorbent assay was used to assess serum concentrations of IL-6, tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and hepatocyte growth factor (HGF).

Results

In transplant recipients, IL-6 concentration in arterial blood was lower than that in portal blood (P < .049), whereas in donors, there was no significant difference in these concentrations. Neither recipients nor donors demonstrated significant differences in arterial or portal blood concentrations of TNF-α, TGF-β, or HGF.

Conclusions

In healthy human beings, the intestine is not a substantial source of IL-6, TNF-α, TGF-β, or HGF. However, in patients with liver cirrhosis, the intestine is an important source of IL-6 but not of the other studied growth factors and cytokines.     

Effect of age on cervical spine injuries in children after motor vehicle collisions: effectiveness of restraint devices

Purpose

Despite the devastating consequences of cervical spine (C-spine) injury in children after motor vehicle collisions (MVC), the factors leading to the injury and the appropriateness of protective restraints remain undefined. The authors hypothesized that age-related anatomic factors contribute to inadequate restraints and therefore increase injury severity after MVC.

Methods

Data on children (<18 years, 1997 to 2002) admitted to a level 1 pediatric trauma center were prospectively collected and retrospectively reviewed. Those with C-spine injuries caused by MVC were extracted and divided into 2 groups: young (0 to 8 years) and old (9 to 18 years). Statistical comparison was by Student’s t test or Z-test, with P less than .05 accepted as significant.

Results

Of 5,117 trauma admissions, 94 had C-spine injuries with a mean age of 11 ± 5 years, 66% of which were boys. Among 1,124 patients who had sustained MVC there were 27 C-spine injuries (2.4% incidence), of which, 12 were less than 8 and 15 were older than 8 years. Restraint devices were utilized at least as frequently in younger children (young, 58% v. old, 43%; not significant). However, younger children had an increased incidence of permanent cord deficit (young, 57% v. old, 13%; P <.05) and closed head injury (young, 50% v. old, 7%; P <.05) even while wearing restraint devices, suggesting that restraint devices are inadequate or improperly used in younger patients. This is supported by the increased injury severity scores of the younger group (young, 37.7 ± 8.5 v. old, 16.5 ± 4.6; P <.05).

Conclusions

Younger children suffer more sever cervical spine injuries after motor vehicle collisions than their older counterparts, in part because of the inadequacy of currently existing restraint devices. Design modifications to current restraints, including the use of head straps, might improve outcome after MVC in younger patients.     

Long-term symptomatic outcome and radiologic assessment of laparoscopic hiatal hernia repair

Background

The long-term durability of laparoscopic repair of paraesophageal hiatal herniation is uncertain. This study focuses on the long-term symptomatic and radiologic outcome of laparoscopic paraesophageal herniation repair.

Methods

Between 2000 and 2007, 70 patients (49 females, mean age ± standard deviation 60.6 ± 10.9 years) undergoing laparoscopic repair of paraesophageal herniation were studied prospectively. After a mean follow-up of 45.6 ± 23.8 months, symptomatic (65 patients, 93%) and radiologic follow-up (60 patients, 86%) was performed by standardized questionnaires and esophagograms.

Results

The symptomatic outcome was successful in 58 patients (89%), and gastroesophageal anatomy was intact in 42 patients (70%). The addition of a fundoplication was the only significant predictor of an unfavorable radiologic outcome in the univariate analysis (odds ratio .413; 95% confidence interval, .130 to 1.308; P = .125).

Conclusions

The long-term symptomatic outcome of laparoscopic repair of paraesophageal hiatal herniation was favorable in 89% of patients, and 70% had successful anatomic repair. The addition of a fundoplication did not prevent anatomic herniation.     

Ureteral trauma: Patterns and mechanisms of injury of an uncommon condition

Background

Traumatic ureteral injuries are uncommon, thus large series are lacking.

Methods

We performed a retrospective analysis of the National Trauma Data Bank (2002-2006).

Results

Of the 22,706 genitourinary injuries, 582 ureteral injury patients were identified (38.5% blunt, 61.5% penetrating). Patients were 84% male, 38% white, and 37% black (mean age, 31 y). Blunt trauma patients had a median Injury Severity Score of 21.5 versus 16.0 for penetrating injury (P < .001). Mortality rates were 9% blunt, and 6% penetrating (P = .166). Penetrating trauma patients had a higher incidence of bowel injuries (small bowel, 46%; large bowel, 44%) and vascular injuries (38%), whereas blunt trauma patients had a higher incidence of bony pelvic injuries (20%) (P < .001).

Conclusions

Ureteral injuries are uncommon, seen in approximately 3 per 10,000 trauma admissions, and occur more in penetrating than in blunt trauma. The most common associated injury for blunt ureteral trauma is pelvic bone fracture, whereas penetrating ureteral trauma patients have more hollow viscus and vascular injuries.     

Diagnostic evaluation of foreign body aspiration in children: a prospective study

Aim

The aim of this study was to evaluate the yield of clinical symptoms, signs, and radiological studies in the diagnosis of foreign body aspiration (FBA) in children.

Methods

During the 2-year study, we performed on all children admitted to the pediatric department for suspected FBA a protocol that included the following: thorough medical history, physical examination, radiological studies (chest x-ray and fluoroscopy), and rigid bronchoscopy by a senior otolaryngologist. The yield of these measures for the diagnosis of FBA was evaluated.

Results

Foreign bodies were found in 56 (57%) of the 98 children with suspected FBA. Thirty-three (59%) children were boys and 23 (41%) girls (P < .05), with a mean age of 24 months (range, 8-84 months). Main symptoms in the children with FBA were the following: choking (76.8%), prolonged cough (14.3%), dyspnea (3.6%), and nonresolving pneumonia (1.8%). Physical examination, chest x-ray, and fluoroscopy findings were abnormal in 80.4%, 67.9%, and 46.9% of the children with FBA, respectively. The diagnostic yield of physical examination and radiological studies increased 24 hours after the event of FBA. In 45.2% of the children with positive history but with normal findings from physical examination and radiological studies, foreign bodies were found. Of the children with “doubtful” history, physical examination, chest x-ray, and fluoroscopy findings were abnormal in 58%, 38%, and 12.5%, respectively. Foreign bodies were found in 9.5% of these children.

Conclusion

Medical history is the key for the diagnosis of FBA. Choking followed by an acute episode of coughing is the most common presentation of FBA. The yield of physical examination and radiological studies in the diagnosis of FBA is relatively low but is increased when the presentation is delayed and when history is doubtful. If FBA is suspected, bronchoscopy should be performed.     

Despite overall low pediatric head injury mortality, disparities exist between races

Background

To continually improve quality of care, it is important for centers caring for children with head injury to evaluate their overall outcome and that among diverse patient groups.

Methods

Data on children with head injuries were extracted from the National Trauma Data Bank of the American College of Surgeons and our local trauma registry. Unadjusted mortality, as well as stratified analysis and logistic regression modeling, was used to evaluate overall and race-specific mortality.

Results

There were 13,363 children in the National Trauma Data Base and 3111 in our database included. Our overall mortality rate compared favorably with the national data (3.2% vs 6.8%, P < .05). Our local data, however, showed a significant difference in mortality between white and African American (AA) children (2.2% vs 5.3%, P < .05), which was not identified in the national data. After stratification, the disparities by race persisted. Finally, multivariate regression modeling revealed that AA race was an independent predictor of mortality among our patient population, with an odds ratio of 3.1 (95% confidence interval, 1.2-7.8).

Conclusion

Despite excellent outcomes for children with head injuries, we have uncovered unsettling inequities between AA and white children. These findings support the need to evaluate outcomes among specific groups to identify disparities that require further careful investigation.     

Clinicopathologic characteristics and prognosis of young patients with breast cancer

Background

The aim was to describe the clinicopathological features and prognosis of young patients with breast cancer.

Patients and Methods

We reviewed the records of 1478 consecutive patients aged ≤50 years with first diagnosis of invasive breast cancer referred to surgery from January 1999 to March 2005. A total of 174 patients were aged <35 years (group I) and 1304 were aged 35-50 years (group II).

Results

Compared with patients of group II, patients of group I had a higher percentage of tumors classified as estrogen receptors (ER) negative, progesterone receptors (PR) negative, with a Ki-67 labeling index ≥20% of the cells. The 5-year survival of group I was 78.3% as compared with 84.2% for group II (P = 0.006).

Conclusion

Compared with patients aged between 35 and 50 years, patients aged <35 years have a greater chance of having an endocrine-unresponsive tumor and a significantly poor prognosis.     

Preoperative platelet-lymphocyte ratio is an independent significant prognostic marker in resected pancreatic ductal adenocarcinoma

Background

The objective of this study was to investigate whether the preoperative platelet-lymphocyte (P/L) ratio represents a significant prognostic index in resected pancreatic ductal adenocarcinoma.

Methods

A total of 110 patients undergoing pancreatoduodenectomy for pancreatic ductal adenocarcinoma over a 10-year period were identified from a prospectively maintained database.

Results

The preoperative P/L ratio was found to be a more significant prognostic marker (P < .001) than either the lymphocyte count (P = .007) or platelet count (P = .068) on univariate Cox survival analysis. The median overall survival in patients with a P/L ratio of 150 or less (n = 48) was 19.7 months, 13.7 months in those with a P/L ratio of 151 to 300 (n = 43), and 5.8 months in patients with a value of greater than 300 (n = 19) (log-rank, P = .006). The preoperative P/L ratio retained significance on multivariate analysis (P < .001), along with tumor size (P = .010) and lymph node ratio (P = .013).

Conclusions

The preoperative P/L ratio represents a significant independent prognostic index in patients of resected pancreatic adenocarcinoma.     

Survival of severe congenital diaphragmatic hernia has morbid consequences

Background/Purpose

Fetal tracheal occlusion (TO) was developed in an attempt to enhance prenatal lung growth and improve survival in fetuses with severe congenital diaphragmatic hernia (CDH). We conducted a randomized, controlled clinical trial in 24 fetuses with severe left CDH (liver herniated into the thorax and low lung-to-head ratio) to compare survival after endoscopic fetal TO vs standard perinatal care (control) and prospectively followed up the 16 survivors (9 control, 7 TO) to compare neurodevelopmental, respiratory, surgical, growth, and nutritional outcomes.

Methods

At 1 and 2 years old, subjects underwent evaluation consisting of medical and neurological history and physical, developmental testing, nutritional assessment, oxygen saturation and pulmonary function testing, chest radiograph, and echocardiogram. Growth and developmental measures were corrected for prematurity. Data were analyzed by Mann-Whitney rank sum test, Fisher's Exact test, and logistic and linear regression.

Results

Infants with TO were significantly more premature at birth (control vs TO, 37.4 ± 1.0 vs 31.1 ± 1.7 weeks; P < .01). Growth failure (z score for weight <2 SDs below mean) was severe in both groups at 1 year of age (control vs TO, 56% vs 86%; P = .31). There was considerable catch-up growth by age 2 years (growth failure: control vs TO, 22% vs 33%; P = .19). There were no differences in other growth parameters. There were also no differences in neurodevelopmental outcome at 1 and 2 years. Supplemental oxygen at hospital discharge was a significant predictor of worse neurodevelopmental outcome at 1 and 2 years old (P = .05 and P = .02, respectively). Hearing loss requiring amplification has been diagnosed in 44% of the group (control vs TO, 44% vs 43%; P = 1.0).

Conclusions

In this group of infants with severe CDH, there were no differences in outcome at 2 years old despite significant prematurity in the TO group. Oxygen supplementation at hospital discharge identified the most vulnerable group with respect to neurodevelopmental outcome, but all infants had significant growth failure, and hearing impairment is a substantial problem in this population. Severe CDH carries significant risk of chronic morbidity.     

De novo use of everolimus with elimination or minimization of cyclosporine in renal transplant recipients

Background

The purpose of two similarly designed multicenter, prospective, parallel-group, open-label studies was to evaluate early cyclosporine (CsA) elimination versus minimization from an everolimus-CsA-steroid regimen in de novo renal transplant patients.

Methods

Within 24 hours after transplantation, 170 renal transplant patients received everolimus (trough levels 3-8 ng/mL), CsA, and steroids. Those eligible (n = 114) were randomized (1:1) at 3 months to have CsA elimination by month 4 to 6 (±1 week) with everolimus trough levels maintained at 6 to 12 ng/mL or CsA minimization, until 12 months. The randomized population excluded those who discontinued the study prior to randomization due to adverse events, acute rejection episodes of Banff grade IIb/III, or worsening renal function during the month prior to randomization.

Results

At 12 months, the estimated glomerular filtration rate (Nankivell) with CsA elimination was noninferior versus CsA minimization (P < .0001, α-level 0.05; 90% confidence interval 0.6-8.5) by 7 mL/min/1.73 m² (noninferiority margin). Composite efficacy failure was comparable with CsA elimination and CsA minimization (18.9% and 17.5%, respectively, P = 1.000) and no graft loss or death was reported after randomization. Cytomegalovirus infections were rare under everolimus treatment, and no pneumonitis episode was reported.

Conclusion

In our selected randomized study population, immediate initiation of everolimus allowed CsA elimination. Renal function was stable on everolimus-based, CsA-free maintenance regimen without compromising efficacy.