Impact of CYP2D6 Polymorphisms on Tamoxifen Treatment in Patients With Retroperitoneal Fibrosis: A First Step Towards Tailored Therapy?

OBJECTIVE: To investigate the influence of CYP2D6 polymorphisms on outcomes and health-related quality of life of patients with retroperitoneal fibrosis (RPF) receiving tamoxifen (TMX). TMX is an effective alternative to corticosteroids for patients with RPF. Conversion of TMX to more potent endoxifen is dependent on enzyme activity of CYP2D6. MATERIALS AND METHODS: CYP2D6 genotyping and phenotype prediction of all patients treated with TMX between 02/2007 and 01/2018 was assessed using multiplex polymerase chain reaction (PCR). Groups were classified by phenotype: extensive (EM) vs poor and intermediate (PM + IM) vs ultrarapid metabolizer (UM). Retrospective evaluation of outcome (including magnetic resonance imaging and positron emission tomography-computed tomography) and health-related quality of life using the SF-36 was performed. RESULTS: A total of 63/194 patients received TMX, 40/63 with complete follow-up were sequenced: Twenty-nine patients with EM phenotype, 8 PM + IM and 3 UM. The median therapy duration was 364.5 days with a mean follow-up of 62.9 months. Seven therapy terminations occurred due to lack of response (17.5%), including all UM patients (P <.001). Magnetic resonance imagings showed a regression of fibrosis for EM and PM + IM in 69% and 62.5% of cases and a progression for UM in 100% (P = .004). In positron emission tomography-computed tomography, glucose utilization of RPF decreased significantly for EM and PM + IM. The physical sum-score of SF-36 improved for EM and PM + IM and decreased for UM (P <.05). The removal of DJ-stents was successful for EM, PM + IM, and UM in 48.3%, 75%, and 0% of cases (P = .0581). CONCLUSION: Contrary to expectations, UM showed the lowest success rate, which concludes that genotyping of RPF-patients may be useful in the sense of a tailored-therapy.

Long-term experience of hyperbaric oxygen therapy for refractory radio- or chemotherapy-induced haemorrhagic cystitis.

BACKGROUND: Radiotherapy and cyclophosphamide-induced haemorrhagic cystitis are rare but severe complications occurring in 3-6% of patients. Hyperbaric oxygen treatment (HBOT) has been demonstrated to be an effective treatment for haematuria not responding to conventional management. Only very few data exist for long-term follow-up after HBOT. METHODS: We retrospectively reviewed 15 patients referred for HBOT for haemorrhagic cystitis (HC). HBOT was performed for 130 min/day at a pressure of 2.4 atmospheres. We evaluated patient demographics, type of radio- and chemotherapy and characteristics of haematuria. The effect of HBOT was defined as complete or partial resolution of hematuria according to the RTOG/EORTC grade and Gray score. RESULTS: A total of 15 patients (12 after radiotherapy, two after chemotherapy and one patient with a combination of both) were treated with a median of 34 HBO treatments. Radiotherapy patients received primary, adjuvant, salvage and HDR radiotherapy (60 - 78 Gy) for prostate, colon or cervical cancer. The patient with combination therapy and both of the chemotherapy patients were treated with cyclophosphamide. First episodes of haematuria occurred at a median of 48 months after completion of initial therapy. The first HBOT was performed at a median of 11 months after the first episode of hematuria. After a median of a 68-month follow-up after HBOT, 80% experienced a complete resolution and two patients suffered a singular new minor haematuria (p < 0.00001). A salvage-cystectomy was necessary in one patient. No adverse effects were documented. CONCLUSIONS: Our experience indicate that HBOT is a safe and effective therapeutic option for treatment-resistant radiogenic and chemotherapy-induced haemorrhagic cystitis. For a better evaluation prospective clinical trials are required.

Tracking Structural Changes in Lipid-based Multicomponent Food Materials due to Oil Migration by Microfocus Small-Angle X-ray Scattering.

One of the major problems in the confectionery industry is chocolate fat blooming, that is, the formation of white defects on the chocolate surface due to fat crystals. Nevertheless, the mechanism responsible for the formation of chocolate fat blooming is not fully understood yet. Chocolate blooming is often related to the migration of lipids to the surface followed by subsequent recrystallization. Here, the migration pathway of oil into a cocoa butter matrix with different dispersed particles was investigated by employing microfocus small-angle X-ray scattering and contact angle measurements. Our results showed that the chocolate powders get wet by the oil during the migration process and that the oil is migrating into the pores within seconds. Subsequently, cocoa butter is dissolved by the oil, and thus, its characteristic crystalline structure is lost. The chemical process provoked by the dissolution is also reflected by microscopical changes of the surface morphology of chocolate model samples after several hours from the addition of oil to the sample. Finally, the surface morphology was investigated before and after oil droplet exposure and compared to that of water exposure, whereby water seems to physically migrate through the particles, namely cocoa powder, sucrose, and milk powder, which dissolve in the presence of water.

Development of a serum-free supplement for primary neuron culture reveals the interplay of selenium and vitamin E in neuronal survival.

Serum-free media require a number of supplements in order to support long-term neuronal survival. Commercially available B27, in combination with Neurobasal medium, supports neuronal survival and suppresses glial proliferation. However, B27 contains many biological antioxidants as well as catalase and superoxide dismutase, eventually demanding the application of unphysiologically high peroxide concentrations in survival assays. Moreover, optimal amounts of selenium (Se) are included in "B27 supplement minus antioxidants", a commercially available supplement used for the study of the role of antioxidants. Hence, Se-dependent enzymes like glutathione peroxidase are maximally expressed when this supplement is used and Se-depletion studies are not possible without changing the medium composition. We have therefore developed a modified serum-free media supplement which allows for free variation of all constituents. Our supplement was comparable to B27 with regard to cell survival and expression of neurochemical markers. Reduction of Se content in the supplement reduced selenoprotein expression and made cortical neurons more sensitive towards challenges with peroxides. Withdrawal from the medium supplement of vitamin E alone did not alter the survival of neurons in response to peroxides, while simultaneous reduction of Se and vitamin E rendered neurons hypersensitive towards peroxide challenge. This finding implied that adequate Se supply of neurons is required to minimize lipid peroxidation. Our medium supplement is easily prepared, inexpensive, and should be applicable to the analysis of survival mechanisms beyond peroxide challenge.

Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration.

Cerebral selenium (Se) deficiency is associated with neurological phenotypes including seizures and ataxia. We wanted to define whether neurons require selenoprotein expression and which selenoproteins are most important, and explore the possible pathomechanism. Therefore, we abrogated the expression of all selenoproteins in neurons by genetic inactivation of the tRNA[Ser](Sec) gene. Cerebral expression of selenoproteins was significantly diminished in the mutants, and histological analysis revealed progressive neurodegeneration. Developing interneurons failed to specifically express parvalbumin (PV) in the mutants. Electrophysiological recordings, before overt cell death, showed normal excitatory transmission, but revealed spontaneous epileptiform activity consistent with seizures in the mutants. In developing cortical neuron cultures, the number of PV(+) neurons was reduced on combined Se and vitamin E deprivation, while other markers, such as calretinin (CR) and GAD67, remained unaffected. Because of the synergism between Se and vitamin E, we analyzed mice lacking neuronal expression of the Se-dependent enzyme glutathione peroxidase 4 (GPx4). Although the number of CR(+) interneurons remained normal in Gpx4-mutant mice, the number of PV(+) interneurons was reduced. Since these mice similarly exhibit seizures and ataxia, we conclude that GPx4 is a selenoenzyme modulating interneuron function and PV expression. Cerebral SE deficiency may thus act via reduced GPx4 expression.-Wirth, E. K., Conrad, M., Winterer, J., Wozny, C., Carlson, B. A., Roth, S., Schmitz, D., Bornkamm, G. W., Coppola, V., Tessarollo, L., Schomburg, L., Köhrle, J., Hatfield, D. L., Schweizer, U. Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration.

Lycopene for advanced hormone refractory prostate cancer: a prospective, open phase II pilot study.

PURPOSE: We investigated the influence of lycopene on the clinical and laboratory course in men with hormone refractory prostate cancer. To our knowledge this study represents the first time that subjective assessments of the course of therapy have been recorded. MATERIAL AND METHODS: We performed a prospective, open phase II pilot study, in which patients with progressive hormone refractory prostate cancer were included. Lycopene supplementation (15 mg) was given daily for 6 months. Followup laboratory tests and clinical examinations were done monthly. Changes to analgesic use and quality of life (European Organisation for Research and Treatment of Cancer QLQ-C30) were measured. The study end point was a significant change in serum prostate specific antigen, clinical progression or the end of the 6-month observation period. RESULTS: A total of 18 patients 64 to 85 years old (median age 73) were enrolled in the study during a 20-month period, of whom 17 could be analyzed. Five of the 17 patients (29%) withdrew from the study prematurely, including 4 of 5 because of prostate specific antigen progression and/or tumor associated complications, and 1 due to an allergic reaction to lycopene. Median prostate specific antigen doubled in 6 months from 42.7 ng/ml (range 13.8 to 521.6) in 17 patients to 96.4 ng/ml (range 13.5 to 1,240) in 12. Stable prostate specific antigen was observed in 5 of 17 patients (29%). None of the patients had a greater than 50% decrease in prostate specific antigen. Patients experienced a slight deterioration in mean health status at the end of the study compared to the outset. However, two-thirds of the patients experienced an improved or unchanged situation regardless of the clinical and biochemical course. CONCLUSIONS: No clinically relevant benefits were shown for patients with advanced stages of the disease.