Two corticosteroid-free regimens-tacrolimus monotherapy after basiliximab administration and tacrolimus/mycophenolate mofetil-in comparison with a standard triple regimen in renal transplantation: results of the Atlas study

BACKGROUND: The side effects associated with corticosteroids have led to efforts to minimize their use in renal transplant patients. In this study we compared two corticosteroid-free tacrolimus-based regimens with a standard triple therapy. METHODS: This was a 6-month, phase III, open-label, parallel-group, multicenter study. The total analysis set comprised 451 patients, randomized (1:1:1) to receive tacrolimus (Tac) monotherapy following basiliximab (Bas) administration (n=153), Tac/mycophenolate mofetil (MMF) (n=151), or, Tac/MMF/corticosteroids triple therapy as a control (n=147). RESULTS: The study was completed by 91.2% (triple therapy), 94.7% (Tac/MMF), and 82.4% (Bas/Tac) of patients. Patient baseline characteristics were similar in all groups. The incidences of biopsy-proven acute rejection were 8.2% (triple therapy), 30.5% (Tac/MMF), and 26.1% (Bas/Tac), p<0.001 (multiple test for comparison with triple therapy); Bas/Tac vs. Tac/MMF, p=ns. The incidences of corticosteroid-resistant acute rejection were 2.0%, 4.0%, and 5.2%, p=ns. Graft survival (95.9%, 96.7%, and 94.7%, p=ns) and patient survival (100%, 99.3%, and 99.3%, p=ns) were similar in all groups. Median serum creatinine at month 6 was 123.0 micromol/L (triple therapy), 134.7 micromol/L (Tac/MMF) and 135.8 micromol/L (Bas/Tac). The overall safety profiles were similar; differences (p<0.05) were reported for anaemia (24.5% vs. 12.6% vs. 14.5%), diarrhoea (12.9% vs. 17.9% vs. 5.9%), and leukopenia (7.5% vs. 18.5% vs. 5.9%) for the triple therapy, Tac/MMF, and Bas/Tac group, respectively. The incidences of new-onset diabetes mellitus were 4.6%, 7.1%, and 1.4%, respectively. CONCLUSION: Corticosteroid-free immunosuppression was feasible with the Bas/Tac and the Tac/MMF regimens. Both corticosteroid-free regimens were equally effective in preventing acute rejection, with the Bas/Tac therapy offering some safety benefits.     

Juxtacondylar Approach in Temporal Paraganglioma Surgery: When and Why?

As it became clear that patients with paraganglioma (PGL) syndromes had a higher risk of multifocal tumors, we changed our surgical strategy to avoid the possibility of bilateral cranial nerve paralysis. The juxtacondylar approach offers advantages for some jugular foramen tumors, including types C and D temporal PGLs. This approach allows exposure of the jugular foramen without skeletonizing or transposing the facial nerve. It improves the surgeon's ability to distinguish between the pars vascularis and the pars nervosa at the jugular foramen, and it helps to save functioning of the lower cranial nerves. There is already considerable experience using the juxtacondylar approach for patients suffering from schwannomas and meningiomas involving the jugular foramen. Some limitations have been noted for using the juxtacondylar approach with jugular PGLs that are related to their vascular nature. In this article we demonstrate its use for the management of eight patients with locally advanced temporal PGLs and how it can be combined with an infratemporal fossa approach.     

Conversion to sirolimus of patients with chronic allograft nephropathy—a retrospective analysis of outcome and influencing factors

Purpose

The purpose of this study was to analyse the outcome and its influencing factors in patients whose therapy was converted from calcineurin inhibitors (CNI) to sirolimus (SRL) due to chronic allograft nephropathy (CAN).

Materials and methods

Therapies of 78 patients (44 men) with CAN from three European transplant centres were converted from CNI therapy to SRL and followed 24 months. Slopes for creatinine clearance before and after conversion were calculated. Influencing factors were analysed by a multivariance analysis.

Results

The slope of the creatinine clearance improved significantly (?0.90 vs. ?0.34 ml min^?1 month^?1; p?<?0.01). In patients whose therapy was converted from cyclosporine A (CyA) to SRL, the slope improved significantly, whereas conversion from Tacrolimus (Tac) to SRL did not affect the slope. The benefit was more pronounced in (1) patients with low or moderate baseline creatinine clearance, (2) patients receiving SRL after conversion without additional mycophenolate mofetil and (3) patients with low or moderate proteinuria.

Conclusion

Conversion from CyA to SRL but not from Tac to CRL is associated with a reduced loss of renal allograft function in patients with CAN.     

Tumour volume delineation in prostate cancer assessed by [11C]choline PET/CT: validation with surgical specimens

Purpose

PET has been proven to be helpful in the delineation of gross tumour volume (GTV) for external radiation therapy in several tumour entities. The aim of this study was to determine if [¹¹C]choline PET could be used to localize the carcinomatous tissue within the prostate in order to specifically target this area for example with high-precision radiation therapy.

Methods

Included in this prospective study were 20 patients with histological proven prostate carcinoma who underwent [¹¹C]choline PET/CT before radical prostatectomy. After surgical resection, specimens were fixed and cut into 5-mm step sections. In each section the area of the carcinoma was delineated manually by an experienced pathologist and digitalized, and the histopathological tumour volume was calculated. Shrinkage due to resection and fixation was corrected using in-vivo and ex-vivo CT data of the prostate. Histopathological tumour location and size were compared with the choline PET data. Different segmentation algorithms were applied to the PET data to segment the intraprostatic lesion volume.

Results

A total of 28 carcinomatous lesions were identified on histopathology. Only 13 (46 %) of these lesions had corresponding focal choline uptake. In the remaining lesions, no PET uptake (2 lesions) or diffuse uptake not corresponding to the area of the carcinoma (13 lesions) was found. In the patients with corresponding PET lesions, no suitable SUV threshold (neither absolute nor relative) was found for GTV segmentation to fit the volume to the histological tumour volume.

Conclusion

The choline uptake pattern corresponded to the histological localization of prostate cancer in fewer than 50 % of lesions. Even when corresponding visual choline uptake was found, this uptake was highly variable between patients. Therefore SUV thresholding with standard algorithms did not lead to satisfying results with respect to defining tumour tissue in the prostate.     

Effekte einer niedrig dosierten Co-60-Bestrahlung auf den Verlauf einer aseptischen Arthritis am Kniegelenk des Kaninchens

Purpose

Numerous clinical observations demonstrate the efficacy of low radiation doses in the treatment of painful osteoarthritis. Experimental investigations remain scarce. We investigated the effects of locally daily 5 times 1.0 Gy 60-Co irradiation on an artificially induced aseptic gonarthritis in rabbits.

Material and Methods

Three separate experiments (EV) were performed (10 rabbits per experiment, 5 treated/5 controls; duration: EV1: 18 days; EV2: 6 days; EV3: 29 days). An aseptic arthritis in the right knee joint of rabbits was induced by intraarticular injection of 0.5 ml papain solution (3%, 30,000 USP/mg) on day 0. The arthritic knee joint of the anesthesized animals was irradiated daily from day 1 to 5 with 5 times 1.0 Gy. The controls were sham-irradiated under the same conditions. The time course of arthritis in treated animals and sham-treated controls was evaluated by clinical laboratory-chemical and histological criteria. The clinical investigation was performed daily, the puncture of the kneejoints was carried out several times in EV1, and at the end of experiments in EV2 and EV3. At the end of the observation period, animals were killed and the knee joints excised for histological analysis.

Results

The intraarticular injection of papain caused a peracute inflammatory response in all animals. After 1 week the chronical stage was reached, and the experimental arthritis resolved slowly within several weeks. Local irradiation accelerated the decrease of inflammatory joint swelling, being significant by day 4. On day 6 the volume of synovial fluid in irradiated knee-joints was significantly smaller. The morphometric data indicated a reduction in thickness of synovial membrane, a decrease in number of synovial cell layers, and a decrease in distance between capillaries and the synovial membrane surface following irradiation of arthritic joints. Due to considerable individual variability, the morphometric data partially did not reach statistically significance.

Conclusion

The experiments provide evidence for an antiphlogistic effect of irradiation with 5 times 1.0 Gy in vivo. They support the clinical observations of the efficacy of anti-inflammatory radiotherapy.     

Prophylaxis of Heterotopic Ossification in Patients Sedated after Polytrauma

BACKGROUND AND PURPOSE: Heterotopic ossification (HO) often follows acetabular fractures after multitrauma. Irradiation is a mean for prophylaxis. We established a standard procedure in our hospital for patients under sedation, when obtaining informed consent for HO prophylaxis is impossible. PATIENTS AND METHODS: We reviewed current scientific evidence, calculated the risks of radiation and presented the ethical and legal framework. The subject was scrutinised by an interdisciplinary panel. RESULTS: Irradiation is the most effective means for prophylaxis and has few adverse effects in adult patients with fractures of the acetabulum. The lifetime risk of radiation-induced cancer or infertility are insignificant. CONCLUSIONS: Informed consent for irradiation should be obtained before operation whenever possible. When this cannot be done prophylaxis can be postponed for a maximum of 3 days in order to obtain consent. If the patient is not able to communicate within this period, prophylactic irradiation should be given after consulting the relatives. The patient must be informed as soon as possible.     

Diagnostic impact of 18F-FDG PET–CT evaluating solid pancreatic lesions versus endosonography, endoscopic retrograde cholangio-pancreatography with intraductal ultrasonography and abdominal ultrasound

Purpose  This prospective single-centre phase II trial assessed the diagnostic impact of ¹⁸F-FDG PET–CT in the evaluation of solid pancreatic lesions (∅ ≥10 mm) compared to endosonography (EUS), endoscopic retrograde cholangio-pancreatography (ERCP) with intraductal ultrasound (IDUS), abdominal ultrasound (US) and histopathological reference. Methods  Forty-six patients (32 men/14 women, ∅ 61.7 years) with suspected pancreatic neoplasms underwent PET–CT with contrast-enhanced biphasic multi-detector CT of the upper abdomen followed by a diagnostic work-up with EUS, ERCP with IDUS and US within 3 weeks. PET–CT data sets were analysed by two expert readers in a consensus reading. Histology from surgery, biopsy/fine-needle aspiration and/or clinical follow-up ≥12 months served as standard of reference. Results  Twenty-seven pancreatic malignancies were histopathologically proven; 19 patients had benign diseases: 36/46 lesions (78%) were detected in the head of the pancreas, 7/46 and 3/46 in the body and tail region, respectively. Sensitivity and specificity of PET–CT were 89% and 74%, respectively; positive predictive value (PPV) and negative predictive value (NPV) were 83% and 82%, respectively. Sensitivity (81–89%), specificity (74–88%), PPV (83–90%) and NPV (77–82%) achieved by EUS, ERCP and US were not significantly different. PET analysis revealed significantly higher maximum mean standardised uptake values (SUV_max 6.5 ± 4.6) in patients with pancreatic malignancy (benign lesions: SUV_max 4.2 ± 1.5; p < 0.05). PET–CT revealed cervical lymphonodal metastasis from occult bronchogenic carcinoma and a tubular colon adenoma with intermediate dysplasia on polypectomy, respectively. Conclusions   ¹⁸F-FDG PET–CT achieves a comparably high diagnostic impact evaluating small solid pancreatic lesions versus conventional reference imaging modalities. Additional clinical diagnoses are derived from concomitant whole-body PET–CT imaging. Verena Schick and Christiane Franzius contributed equally to this work.     

Liver transplantation in a subject with familial hypercholesterolemia carrying the homozygous p.W577R LDL-receptor gene mutation

Mutations within the low density lipoprotein (LDL)-receptor gene result in familial hypercholesterolemia, an autosomal dominant inherited disease. Clinical homozygous affected subjects die of premature coronary artery disease as early as in early childhood. We identified a girl at the age of five yr with clinical homozygous familial hypercholesterolemia presenting with achilles tendon xanthomas and arcus lipoides. Her total cholesterol reached up to 1050 mg/dL. Molecular characterization of the LDL-receptor gene revealed a homozygous p.W577R mutation. Despite intensive treatment interventions with the combination of diet, statins, colestipol, and LDL-apheresis, the patient developed symptomatic coronary artery disease at the age of 16 yr. Subsequently, orthotopic liver transplantation was performed to cure the defective LDL-receptor gene. Clinical follow-up for almost nine yr post-transplantation revealed excellent liver function, normal liver enzymes, normal LDL-cholesterol, and regression of both tendon xanthomas and symptomatic coronary artery disease. In conclusion, liver transplantation can effectively reduce LDL-cholesterol in a familial hypercholesterolemia recipient with subsequent regression of xanthomas and atherosclerosis. Timing is extremely important in these exceptional cases to exclude the demand for heart transplantation due to severe coronary artery disease. In addition, the identification of the LDL-receptor as etiology of clinical homozygous hypercholesterolemia is a prerequisite once liver transplantation is considered as therapeutic option.