Pediatric renal transplantation with mycophenolate mofetil-based immunosuppression without induction: results after three years

BACKGROUND: Mycophenolate mofetil (MMF)-based immunosuppression has reduced the acute rejection rate in adults and in children in the early posttransplantation period. Three-year posttransplantation results have been reported for adults but not for children thus far. In the present open-labeled study, patients 18 years old and younger were evaluated prospectively for up to 3 years after renal transplantation (RTX). METHODS: Eighty-six patients receiving MMF in combination with cyclosporine and prednisone without induction were evaluated for patient survival, transplant survival, renal function, arterial blood pressure, adverse events, and opportunistic infections. These patients were compared with a historic control group (n=54) receiving azathioprine (AZA) instead of MMF. RESULTS: Patient survival after 3 years was 98.8% in the MMF group and 94.4% in the AZA group (NS). Intent-to-treat analysis of graft survival demonstrated superiority for MMF (98% vs. 80%; P<0.001). Cumulative acute rejection episodes occurred in 47% of patients in the MMF group versus 61% in the AZA group (P<0.05). Renal function was not significantly different, neither after 3 years nor in the long-term calculation. Antihypertensive medication was administered to 73% to 84% of patients, similar in both groups. Opportunistic infections were recorded only for MMF. Infection rates were comparable to those reported in adults. CONCLUSIONS: These results suggest that MMF is safe and beneficial as a longer term maintenance immunosuppressive drug in children and adolescents.     

Calgranulins in cystic fluid and serum from patients with ovarian carcinomas

Ovarian cancer remains still associated with poor prognosis because it is diagnosed predominantly at advanced stages. Ovarian-specific tumor markers do not yet exist for early detection of the disease. At the search of diagnostic markers for ovarian cancer, proteomic-based approaches have focused on novel investigations of neoplastic processes in tumor patients. Cystic fluids of malignant and benign ovarian tumors and serum from the corresponding patients were collected and processed for two-dimensional gel electrophoresis. Proteins were visualized on the gels by silver staining. At the low molecular mass level between 10 and 20 kDa, selected protein spots were additionally processed for nanospray mass spectrometry and partial amino acid sequencing. For protein identification, the sequencing results were compared with computer information from a protein data bank. Protein patterns from cystic fluids of ovarian carcinomas differed significantly from those of benign cysts and revealed additional polypeptides at low molecular mass level between 10 and 20 kDa. Protein patterns from serum of patients with malignant ovarian tumors also contained additional polypeptides between 10 and 20 kDa that were not detected in serum from patients with benign cysts. The additional proteins in serum were present in similar electrophoretic positions compared with those found in the cystic fluid of the corresponding ovarian carcinomas. Protein spots in the range of 10-20 kDa were selected for partial amino acid sequencing. Two protein spots were identified as calgranulin A and three spots as calgranulin B. Either both proteins or only calgranulin A or B were present in cystic fluid from ovarian carcinomas and serum of the corresponding patients. These two proteins were absent or not detectable in fluid from benign ovarian cysts and in serum from those patients. Our investigations concerning protein patterns in cystic fluid of malignant and benign ovarian tumors provide new information about alterations in protein synthesis linked to neoplastic events of the ovary. With the proteomic strategy, new tumor markers are characterized and may serve for diagnostic purposes of patients with ovarian cancer.     

Barrett’s esophagus and Barrett’s carcinoma

The alarming rise in the incidence of esophageal adenocarcinomas in the Western world has focused interest on so-called Barrett’s esophagus. Barrett’s esophagus is characterized by specialized intestinal epithelium replacing the normal squamous epithelium in the distal esophagus and is considered a consequence of long-lasting and severe gastroesophageal reflux disease. A metaplasia-dysplasia-carcinoma sequence links Barrett’s esophagus with adenocarcinoma of the distal esophagus (Barrett’s cancer). Despite intensive research, many questions concerning the pathogenesis, diagnosis, and treatment of Barrett’s esophagus and associated adenocarcinoma are still unanswered. Based on current data, the malignant progression of Barrett’s esophagus cannot be substantially prevented by medical or surgical therapy for reflux. Although no firm data are available to show that surveillance strategies can reduce overall mortality from Barrett’s cancer, early detection and cure are possible. Management of Barrett’s esophagus and carcinoma is reviewed with reference to the sequence of disease from metaplasia to carcinoma.     

Human SP-A and a pharmacy-grade porcine lung surfactant extract can be reconstituted into tubular myelin--a comparative structural study of alveolar surfactants using cryo-transmission electron microscopy

Cryo-transmission electron microscopy (cryo-TEM) is a rather artefact-free method, well suited to study the alveolar surfactant system. A pharmacy grade porcine lung surfactant extract (HL-10) was mixed with human SP-A and Ringer's solution (for calcium ions), and it was shown by cryo-TEM that the tubular myelin (TM) type of structure was reconstituted. These aggregates were associated to liposomal aggregates, and resulted in macroscopic phase-separation. This phase showed a weak birefringence in the polarising microscope, which is characteristic for a liquid-crystalline type of structure. TM from rabbit lung lavage was also examined, and showed the same periodic arrangement of bilayers as alveolar surface layer from freshly cut rabbit lungs deposited directly on the cryo-TEM grids. The distance between the bilayers of TM was 40-50 nm, and an electron dense material, assumed to be SP-A, was sometimes seen to occur periodically along the bilayers, oriented perpendicularly to the tubuli. The results are consistent with the surface-phase model of the alveolar lining.     

Electro-otolithography: new insight into benign paroxysmal positioning vertigo

Early vestibular evoked potentials were recorded with an extratympanic electrode. The recording principle was adding responses that were phase-locked to a recording frequency. The recording frequency was empirically determined to match harmonically an individual response frequency, thus allowing averaging. This new technique was evaluated in benign paroxysmal positioning vertigo. Normal data were obtained from 12 patients without vestibulocochlear symptoms and were compared with data from 18 symptomatic patients with diagnoses of benign paroxysmal positioning vertigo. All symptomatic patients were treated with a canalith repositioning maneuver, and all responded, in that they no longer had attacks of vertigo. Of the five patients who could be reassessed, all five no longer had attacks of vertigo, but three complained of persisting postural imbalance. Repeat electro-otolithography results continued to be abnormal in these patients, whereas in the remaining two patients responses were normal, consistent with the treatment outcome. The results suggest that electro-otolithography is a valuable addition to the otoneurological test battery. Successful canalith repositioning can abolish attacks of vertigo, although not necessarily a persisting imbalance, which patients frequently describe as a temporary and momentary instability. This is most likely related to a remaining otolithic deficit.     

Bladder substitution in women

Bladder substitution in women with transitional cell carcinoma (TCC) is not a universally accepted procedure. There are many concerns, one of which is the potential risk of metachronous and synchronous urethral transitional cell carcinoma involvement. Another concern is that voiding dysfunction may be more frequent than in male patients. The numbers of female patients who have had this procedure are still small, and follow-up data are relatively brief. Thus, the true role for orthotopic bladder substitution in the female is still being evaluated. This paper reviews the data on this type of surgery in women, with emphasis on urethral TCC risk and on voiding dysfunction. Early results from a number of institutions are encouraging, particularly in correctly selected patients. Based on more than 15 years experience in an albeit small number of patients, we believe that if there is a functional external sphincter and tumor margins can be safely cleared, this form of surgery offers patients the best opportunity to preserve quality of life following cystectomy.     

Inflammatory response after phacoemulsification treated with 0.5% prednisolone acetate or vehicle

Purpose  To compare the inflammatory response after phacoemulsification and intraocular lens implantation, using postoperative treatment with 0.5% prednisolone acetate eye drops or vehicle. Design  A multi-center randomized double-masked vehicle-controlled, parallel group phase IV study. Methods  Sixty-two eyes of 62 patients undergoing phacoemulsification were examined at five German university eye hospitals (Mainz, Heidelberg, Bonn, Erlangen, Frankfurt/Main). Patients received either 0.5% prednisolone acetate eye drops (group 1) or vehicle eye drop solution (group 2) four times a day until day 2, then open-label treatment with 0.5% prednisolone acetate eye drops four times a day continued until day 14 for all patients. Postoperative inflammation was evaluated by using laser flare photometry. Secondary efficacy variables included visual acuity, intraocular pressure, corneal edema, bulbar conjunctival hyperemia and ocular discomfort. Results  In group 1, median flare rose from 7.4 photon counts/ms preoperatively to 31.0 photon counts/ms at day 1. In group 2, the flare increased from 8.6 photon counts/ms preoperatively to 30.5 photon counts/ms at day 1. The differences between the groups were not statistically significant. At day 3, flare measures were reduced in group 1 but remained fairly unchanged in group 2 (20.8 photon counts/ms vs 32.6 photon counts/ms), which was statistically significant (p = 0.0055). At day 14, photon counts were comparable in both groups (13.0 photon counts/ms vs 11.4 photon counts/ms), respectively. Both groups were comparable regarding secondary efficacy variables. Conclusions  0.5% prednisolone acetate appeared to be significantly more effective as vehicle in controlling intraocular inflammation after phacoemulsification; both groups had a similar safety profile. Clinical Trials.gov Identifier: NCT00170729     

Vascular hyperpermeability as a hallmark of phacomatoses: is the etiology angiogenesis comparable with mechanisms seen in inflammatory pathways? Part I: historical observations and clinical perspectives on the etiology of increased CSF protein levels,CSF clotting,and communicating hydrocephalus: a comprehensive review

Phacomatoses are a special group of familial hamartomatous syndromes with unique neuro-cutaneous manifestations as well as disease characteristic tumors. Neurofibromatosis 2 (NF2) and tuberous sclerosis complex (TSC) are representatives of this family. Vestibular schwannoma (VS) and subependymal giant cell tumor (SGCT) are two of the most common intracranial tumors associated with NF2 and TSC, respectively. These tumors can present with obstructive hydrocephalus due to their location adjacent to or in the ventricles. However, both tumors are also known to have a unique association with an elevated protein concentration in the cerebrospinal fluid (CSF), sometimes in association with non-obstructive (communicating) hydrocephalus (HCP), the causality of which has been unclear. Furthermore, SGCTs have repeatedly been shown to have a predisposition for CSF clotting, causing debilitating obstructions and recurrent malfunctions in shunted patients. However, the exact relation between high protein levels and spontaneous clotting of the CSF is not clear, nor is the mechanism understood by which CSF may clot in SGCTs. Elevated protein levels in the CSF are thought to be caused by increased vascular permeability and dysregulation of the blood–brain barrier. The two presumed underlying pathophysiologic mechanisms for that, in the context of tumorigenesis, are angiogenesis and inflammation. Both mechanisms are correlated to the Pi3K/Akt/mTOR pathway which is a major tumorigenesis pathway in nearly all phacomatoses. In this review, we discuss the influence of angiogenesis and inflammation on vascular permeability in VSs and SGCTs at the phenotypic level as well as their possible genetic and molecular determinants. Part I describes the historical perspectives and clinical aspects of the relationship between vascular permeability, abnormal CSF protein levels, clotting of the CSF, and communicating HCP. Part II describes different cellular and molecular pathways involved in angiogenesis and inflammation in these two tumors and the correlation between inflammation and coagulation. Interestingly, while increased angiogenesis can be observed in both VS and SGCT, inflammatory processes seem more prominent in SGCT. Both pathologies are characterized by different subgroups of tumor-associated macrophages (TAM): the pro-inflammatory, M1 type is predominating in SGCTs while pro-angiogenetic, M2 type is predominating in VSs. We suggest that lack of NF2 protein in VS and lack of TSC1/2 proteins in SGCT determine this fundamental difference between the two tumor types, by defining the predominant TAM type. Since inflammatory reactions and coagulation processes are tightly connected, a “pro-inflammatory state” of SGCT can be used to explain the observed associated enhanced CSF clotting process. These distinct cellular and molecular differences may have direct therapeutic implications on tumors that are unique to certain phacomatoses or those with similar genetics.