Quality of life in the follow-up of uveal melanoma patients after enucleation in comparison to CyberKnife treatment.

PURPOSE: To compare quality of life (QoL) in patients with uveal melanoma after enucleation and stereotactic radiosurgery to that in an age-matched patient collective. METHODS: QoL was assessed in a cross-sectional survey and compared among 32 uveal melanoma patients after enucleation, 48 patients after stereotactic radiosurgery (CyberKnife(®); Accuray(®) Incorporated, Sunnyvale, CA, USA), and an age-matched control group of 35 patients, using the SF-12 Health Survey. Statistical analysis was performed with Fisher's exact test, Student's t test, one-way ANOVA analysis, Wilcoxon rank-sum (Mann-Whitney test), and ordered logistic regression for multivariate analysis. RESULTS: There was no significant difference in QoL between patients treated by stereotactic radiosurgery and the age-matched control group. After enucleation, patients presented significantly lower values in Physical Functioning (PF), Role Physical (RP), and Role Emotional (RE) compared to the radiosurgery and control group. To control for the overall QoL lowering effect of visual loss, the QoL of the patients who underwent enucleation was compared with the QoL of patients suffering severe functional loss after CyberKnife radiosurgery in a subgroup analysis, which showed no statistically significant difference. The number of comorbidities had a significant impact on QoL in multivariate analysis. CONCLUSIONS: Superior performance in PF, RP, and RE suggests that CyberKnife represents a suitable first-line therapy for uveal melanoma. In cases with painful amaurosis or vast tumor recurrence, enucleation can be performed with an acceptable QoL outcome.

High-dose intravenous vitamin C is not associated with an increase of pro-oxidative biomarkers.

OBJECTIVE: High-dose vitamin C therapy might mediate beneficial clinical effects by counteracting reactive oxygen species. However, concerns are raised whether this approach might provoke diametrical (ie pro-oxidative) effects. The objective was to determine ascorbyl free radical (AFR) concentrations and potential variables of pro-oxidative damage. DESIGN: Crossover study; six healthy males received daily infusions of 750 or 7500 mg vitamin C for six consecutive days. Fasting concentrations of vitamin C and AFR were determined daily. On day 1, concentrations of vitamin C and AFR were measured at 0.25, 0.5, 1, 2, 4 and 8 h post infusion. Plasma concentrations of thiobarbituric acid-reactive substances (TBARS), tocopherol and urine concentrations of 8-oxoguanosine were determined on days 1 and 6. RESULTS: Kinetic studies on day 1 showed that concentrations of vitamin C and AFR displayed parallel dose- and time-dependent kinetics and elimination was highly efficient. Vitamin C and AFR fasting concentrations on days 2-6 were slightly above the baseline, suggesting new, stable steady states. TBARS decreased in both groups, whereas tocopherol and 8-oxoguanosine concentrations remained unchanged. CONCLUSION: Kinetics of AFR largely depend on plasma vitamin C concentrations and AFR is eliminated efficiently. Our data do not support induction of pro-oxidative effects in healthy volunteers given intravenous high-dose vitamin C. SPONSORSHIP: Pascoe Pharmazeutische Präparate GmbH, Giessen, Germany.

Carotenoids are decreased in biopsies from colorectal adenomas.

UNLABELLED: A lower intake of carotenoids is associated with an increased risk of colorectal cancer. In order to take advantage of the chemopreventive properties of carotenoids, it is necessary to determine carotenoid concentration at the target tissue. As early stages in the adenoma-carcinoma sequence of colorectal cancer might be susceptible to chemoprevention, we sought to determine carotenoid concentrations in biopsies from colorectal adenomas. METHODS: Biopsies from colorectal adenomas and non-involved mucosa were taken from seven patients. For controls, biopsies were obtained from the ascending and descending colon of patients without polyps (n = 5). Concentration of carotenoids (alpha-, beta-carotene, lutein, lycopene, zeaxanthin, beta-cryptoxanthin) were determined by optimizing gradient HPLC-analysis. Results are expressed as pmol/microg DNA. RESULTS: Except for alpha-carotene, all carotenoids could reliably be detected in all specimens. In control patients carotenoid concentrations were highest in the ascending colon, being followed by the descending colon and non-involved mucosa from polyp-carriers. In colorectal adenomas all carotenoids were significantly reduced as compared to-non-involved mucosa (beta-carotene: 0.37 vs 0.19, P<0.03; lycopene: 0.34 vs 0.21, P<0.06, beta-cryptoxanthin: 0.14 vs 0.09, P<0.03, zeaxanthin: 0.18 vs 0.09, P<0.02; lutein: 0.18 vs 0.13,P <0.02). CONCLUSION: All carotenoids investigated are reduced in colorectal adenomas, suggesting that mucosal carotenoids could serve as biomarkers for predisposition to colorectal cancer. Moreover, anti-tumor activity exerted by carotenoids is limited due to mucosal depletion. We speculate that supplementation of a larger array of carotenoids might be beneficial for patients with colorectal adenoma.

[Acquired hemophilia A after an early abortion]. / Erworbene Hämophilie A nach Frühabort.

HISTORY: A 30-year-old woman was referred to our clinic because she had developed recurrent spontaneous hematomas of both calves within the last 2 months. 6 months earlier the patient had developed an ovarian hyperstimulation syndrome after ovarian stimulation treatment and intrauterine insemination. Shortly afterwards a missed abortion (8 (th) week) had been diagnosed. A curettage was carried out. INVESTIGATIONS: Routine coagulation tests confirmed a prolongation of aPTT to 90 s and a lupus anticoagulant. A high-titre factor VIII inhibitor (56 Bethesda units) was identified. TREATMENT AND COURSE: Given these facts an acquired post-partum hemophilia was diagnosed. The patient was treated with prednisolone and immunoglobulins. The aPTT shortened to normal values. The factor VIII inhibitor and lupus anticoagulant disappeared. There were no further hematomas. CONCLUSIONS: The simultaneous occurrence of antibodies in an altered immune state such as pregnancy is well known. In our case, acquired factor VIII inhibitor was found after an early abortion. Treatment with steroids and immunoglobulines led to the disappearance of factor VIII inhibitor and lupus anticoagulant.

Inhalation of aerosolized vitamin a: reversibility of metaplasia and dysplasia of human respiratory epithelia -- a prospective pilot study.

The objective of this preliminary uncontrolled study was twofold: First, to assess the feasibility of retinyl palmitate inhalation and second, to analyze the changes of metaplastic lesions of the respiratory epithelium (metaplasia or dysplasia) following retinyl palmitate inhalation. The response to a daily dose of 18.000 I.U. retinyl palmitate by inhalation over a period of 3 month was assessed in 11 subjects (9 smokers, 2 ex-smokers). Using white-light bronchoscopy combined with autofluorescence bronchoscopy, bronchial biopsies were taken before and after a 3 month-period. The biopsy samples were evaluated blind by a referee lung pathologist. The overall response rate (remission or partial remission) was 56% (95% CI 0.30 0.79; p<0.05). These data suggest that inhalation of retinyl esters could be a promising therapeutical approach for chemoprevention of lung cancer. Vitamin A; chemoprevention; lung cancer; squamous metaplasia; dysplasia; retinoids

Meta-analysis: efficacy of therapeutic regimens in ongoing variceal bleeding.

BACKGROUND AND STUDY AIMS: Variceal bleeding is a major cause of mortality in liver cirrhosis. Therapeutic options include medical (vasoconstrictive/vasoactive drugs) and endoscopic (sclerotherapy/ligation) treatments. Most studies evaluating acute esophageal bleeding have included patients with both ongoing and recent bleeding. Therefore therapeutic efficacy in ongoing bleeding may not have been adequately determined in these studies. A meta-analysis was performed for two reasons: first to compare directly the various treatments in the case of ongoing bleeding, as this would not be accomplished by a single trial, and secondly, to determine the success rates of each treatment option based on a larger number of patients. METHODS: An extensive Medline search identified 13 randomized controlled trials with precise statements of the number of patients with ongoing bleeding and their clinical outcomes. All studies followed a similar design and a Q test excluded heterogeneity of the studies. Data were pooled and cumulative success rates were calculated. RESULTS: Ligation appeared to be the most effective treatment (91.0 %, 95 % CI 82.4-96.3 %); it was significantly more successful than vasoconstrictive treatment (vasopressin/terlipressin 68.7 %, 61.7-75.2 %; P < 0.002, chi-squared-test) or vasoactive treatment (somatostatin/octreotide, 75.9 %, 68.1-82.6 %; P < 0.02) treatment, but was not statistically better than sclerotherapy (81.1 %, 71.7-88.4 %). The latter therapy was not statistically superior to medical treatment options. Calculations of estimated true effects, which take into account the weight of each study, rendered similar results. CONCLUSION: Ligation is the most effective treatment option. No significant difference was found between the efficacy of sclerotherapy and treatment with somatostatin or octreotide.

A modified system to evaluate the potency of anti-oxidative compounds in different cell types in vitro.

Common assays for evaluation of antioxidative capacity of different compounds are usually performed in cell-free systems. By this approach, cell-specific regulatory mechanisms upon distinct stimuli are not taken into account. Therefore, there is a need to measure anti-oxidative capacity in a cellular setting. - We now developed a valid method that provides monitoring of anti-oxidative capacities of compounds in different cell types. Oxidative stress, induced by 100 microM H subset2O subset2 in human microvascular endothelial cells (HMEC-1), was quantified by the generation of oxidized, fluorescent C-DCF from C-H subset2DCF-DA/AM. As DCF-production could be almost completely blocked by diethyldithiocarbamate (DEDTC), which inhibits intracellular Cu/Zn superoxide dismutase (SOD), mainly intracellular production of C-DCF was assumed. Preincubation with alpha-tocopherol resulted in a dose-dependent reduction of both spontaneous and H subset2O subset2-induced C-DCF-production (maximal inhibition by 41.6% at 75 microM). A synergistic effect was observed with co-incubation with vitamin C (maximal inhibition 46.8% at 10 microM vitamin C and 50 microM alpha-tocopherol). In this way compounds with different modes of action and subcellular localization can be evaluated concomitantly in respect of their anti-oxidative capacities. As this method was established on 24- and 48-well plates in other cell lines (Caco-2, HFP-1), too, screening of a large array of antioxidative compounds in different cell lines can be performed.

[Angina abdominalis: duplex ultrasound diagnosis and percutaneous revascularization]. / Angina abdominalis: duplexsonographische Diagnostik und perkutane Revaskularisierung.

Intestinal ischemia is still a challenge for clinicians and requires a close interdisciplinary cooperation between internist, surgeon and radiologist. In the last years the diagnosis and therapy, classically invasive and surgical, was supplemented by duplex ultrasound and percutaneous techniques like angioplasty and stenting. A 56 year-old man from Greece presented with epigastric pain, which was intensified by food ingestion. These symptoms were caused by a stenosis of the superior mesenteric artery, which was diagnosed by duplex sonography and angiography. No blood flow was detected in the inferior mesenteric and the celiac artery. Occlusion of one internal carotid artery made the patient a poor candidate for surgery. Therefore an interventional approach was chosen. A good result was achieved by angioplasty and stent implantation. On the day after the intervention oral food intake was possible without any pain. 18 months after the intervention the patient was free of abdominal symptoms. Therapy of mesenteric ischemia by percutaneous angioplasty and stenting is published only in case-reports and small series. Therefore the indication is mainly restricted to patients with a high risk for a surgical intervention.

[Chronic HIV- and chronic HBV infection with hematuria and proteinuria]. / Chronische HIV- und chronische HBV-Infektion mit Erythrozyturie und Proteinurie.

HISTORY AND CLINICAL FINDINGS: A medical examination, undertaken in an apparently healthy 30-year-old man because of his occupational exposure to chemicals, revealed haematuria and proteinuria. Physical examination was unremarkable except for oral hair-leukoplakia and swelling of the cervical, supraclavicular, axillary and inguinal lymph nodes. INVESTIGATIONS: Examination of the urine demonstrated selective glomerular proteins (1.5 g/24 h) and dysmorphic erythrocytes. SGOT and SGPT activities were raised (73 and 129 IU/l, respectively). Active hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) infections were demonstrated virologically. The CD4+ count in blood was reduced to 200 cells/microliter. Renal biopsy showed an IgA nephropathy. TREATMENT AND COURSE: Antiretroviral treatment with zidovudine and lamivudine were started. SGOT and SGPT activities and HIV load fell steadily, while CD4+ cell count rose markedly. Renal functions have remained stable during the past 6 months. CONCLUSION: Signs of glomerular damage are not unusual in systemic diseases, tumors or infections (Hepatitis B and HIV in this case) and they may be the first manifestations of the underlying disease.

Successful treatment with ganciclovir of a HIV endstage patient with adrenal insufficiency.

We report on a 31-year-old AIDS patient who presented with rapid progressive fatigue, weakness, weight loss and hyperpigmentation. Endoscopy showed an ulcerous CMV gastritis with the histological hallmarks of this disease. In addition, laboratory tests revealed the constellation of an adrenal insufficiency with low plasma levels of sodium and increased levels of potassium and ACTH. After initiation of ganciclovir treatment, the CMV gastritis healed and the electrolyte abnormalities were resolved within 2 weeks. We assume that a CMV adrenalitis was treated in a reversible stage. The literature on CMV adrenalitis is reviewed to support this conclusion.

Single dose, dose-escalating trial with fozivudine tidoxil (BM 21.1290).

BACKGROUND AND OBJECTIVES: In vitro and in vivo experimental data for fozivudine tidoxil [BM21.1290 (FZD) an ether-lipid conjugate of zidovudine] have shown better efficacy, no myelotoxicity and better tolerability compared with zidovudine. Therefore, the objectives of our study were to evaluate the safety of FZD in patients with human immunodeficiency virus (HIV) infection and to establish basic pharmacokinetic data. PATIENTS AND METHODS: In a Phase I dose-escalating trial, seven different single dose applications were studied in 39 patients: 50, 100, 300, 600, 900, 1200 and 1800 mg in capsule and tablet formulations. Inclusion criteria were HIV infection, CD4 count > 100 cells/mm3 and informed consent. Exclusion criteria were active opportunistic manifestations, concomitant zidovudine therapy and neutropenia (< 750 neutrophils/mm3). Safety parameters, 24 h plasma levels and urinary excretion were determined. RESULTS: The tolerance of FZD was excellent up to single doses of 1800 mg. In only one case, a single episode of loose stool was reproducible in a second treatment period and was therefore considered to be a probable drug-related event. In an amendment to the trial, a tablet formulation of FZD did not induce diarrhoea in this patient. FZD was available in measurable concentrations after 2 to 4 h. Maximum concentrations were reached after 4 to 8 h. After normalization for a dose of 100 mg/patient, the mean AUC was 8.6 mg x h/l and the mean Cmax was 1.13 mg/l; t1/2 was 3.78 h. Interestingly, plasma concentrations of zidovudine and zidovudine glucuronide were much lower than with equimolar zidovudine doses. CONCLUSIONS: The zidovudine conjugate FZD is safe and well tolerated at the seven doses tested. Phase II trials are warranted.

Tumor necrosis factor-alpha- and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on insulin signaling.

Inhibition of insulin receptor signaling by high glucose levels and by TNF-alpha was recently observed in different cell systems. The aim of the present study was to characterize the mechanism of TNF-alpha-induced insulin receptor inhibition and to compare the consequences of TNF-alpha- and hyperglycemia-induced insulin receptor inhibition for signal transduction downstream from the IR. TNF-alpha (0.5-10 nM) and high glucose (25 mM) showed similar rapid kinetics of inhibition (5-10 min, > 50%) of insulin receptor autophosphorylation in NIH3T3 cells overexpressing the human insulin receptor. TNF-alpha effects were completely prevented by the phosphotyrosine phosphatase (PTPase) inhibitors orthovanadate (40 microM) and phenylarsenoxide (35 microM), but they were unaffected by the protein kinase C (PKC) inhibitor H7 (0.1 mM), the phosphatidylinositol-3 kinase inhibitor wortmannin (5 microM), and the thiazolidindione troglitazone (CS045) (2 microgram/ml). In contrast, glucose effects were prevented by PKC inhibitors and CS045 but unaffected by PTPase inhibitors and wortmannin. To assess effects on downstream signaling, tyrosine phosphorylation of the following substrate proteins of the insulin receptor was determined: insulin receptor substrate-1, the coupling protein Shc, focal adhesion kinase (FAK125), and unidentified proteins of 130 kD, 60 kD. Hyperglycemia (25 mM glucose) and TNF-alpha showed analogous (> 50% inhibition) effects on tyrosine phosphorylation of insulin receptor substrate-1, Shc, p60, and p44, whereas opposite effects were observed for tyrosine phosphorylation of FAK125, which is dephosphorylated after insulin stimulation. Whereas TNF-alpha did not prevent insulin-induced dephosphorylation of FAK125, 25 mM glucose blocked this insulin effect completely. In summary, the data suggest that TNF-alpha and high glucose modulate insulin receptor-signaling through different mechanisms: (a) TNF-alpha modulates insulin receptor signals by PTPase activation, whereas glucose acts through activation of PKC. (b) Differences in modulation of the insulin receptor signaling cascade are found with TNF-alpha and high glucose: Hyperglycemia-induced insulin receptor inhibition blocks both insulin receptor-dependent tyrosine phosphorylation and dephosphorylation of insulin receptor substrate proteins. In contrast, TNF-alpha blocks only substrate phosphorylation, and it does not block insulin-induced substrate dephosphorylation. The different effects on FAK125 regulation allow the speculation that long-term cell effects related to FAK125 activity might develop in a different way in hyperglycemia- and TNF-alpha-dependent insulin resistance.