Simultaneous endometrioid ovarian and uterine carcinoma diagnosed after an in vitro fertilization procedure--case report and review of the literature

BACKGROUND: The presence of simultaneous carcinomas involving both the ovary and uterus is relatively uncommon, while the possible link between fertility drugs and carcinogenesis still remains controversial. CASE: The case of a 40-year-old patient with simultaneous aggressive endometrioid carcinoma of the ovary and uterus a few months after the sixth attempt of in vitro fertilization is presented. The patient had de novo lung disease at surgery and diffuse metastatic spread to adjacent bone, subcutaneous tissue and the central nervous system (CNS) soon after a spectacular response to the primary paclitaxel/carboplatinum chemotherapy and while on maintenance and second-line chemotherapy, respectively. CONCLUSION: The fulminating course of our patient might in part be attributed to the existence of advanced disease at presentation. Definite conclusions about the possible association with the previously performed assisted reproduction cannot be drawn but close clinical surveillance of such patients before, during and after infertility treatment is strongly warranted.     

Diagnosis of rejection in renal allograft biopsies using the presence of activated and proliferating cells

Forty cyclosporine-treated renal allograft biopsies were stained with anti-Tac, a monoclonal antibody (MoAb) against interleukin 2 receptor (CD25), anti-transferrin receptor MoAb, and Ki67 MoAb (a proliferating cell marker), using a method of gold enhancement of the diaminobenzidine reaction product, in order to study the utility of these markers to differentiate rejection from other causes of graft dysfunction. Biopsies were selected on the basis of availability of sufficient frozen material and optical microscopy diagnosis, and only biopsies that showed acute cellular rejection and biopsies that did not show any sign of rejection (cyclosporine toxicity or a stable graft) were studied. In addition biopsies were stained with a panel of monoclonal antibodies reacting with CD45, CD3, CD4, CD8, EBM11 (a monocyte-macrophage marker), HLA-DR, DP, and DQ, using the usual indirect immunoperoxidase method. The clinical diagnosis (rejection versus no rejection) was made in ignorance of the biopsy findings. In 17 of 18 (94%) episodes of rejection, anti-Tac and anti-transferrin receptor-positive cells, and in 15 of 18 rejection episodes (83%), proliferating cells, were found in the interstitium. Anti-Tac-positive cells were never found in the 11 biopsies diagnosed as no rejection, and only in two a few anti-transferrin receptor-positive cells were present. The proportion of activated and proliferating cells in rejection episodes, expressed as the percentage of CD45-positive cells were: anti-Tac MoAb 4.1 +/- 2.9%, anti-transferrin receptor MoAb 6.9 +/- 3.9%, and Ki-67 MoAb 6.3 +/- 4.8%. There was a positive correlation between the total number of infiltrating cells and the number of cells stained with anti-Tac (r = 0.75, P less than 0.005), anti-transferrin receptor MoAb (r = 0.84, P less than 0.0001), and Ki-67 (r = 0.50, P less than 0.05). The episodes of rejection that took place when cyclosporine levels were high had fewer 1L-2R-bearing cells in the interstitium than those that took place when cyclosporine levels were low (r = 0.47, P less than 0.05). We conclude that during rejection the presence of activated and proliferating cells is a consistent finding, and that these markers could be useful in differentiating between rejection and other causes of graft dysfunction as well as in grading the severity of rejection.     

Autonomic antecedents to variant angina exacerbation after beta-blockade withdrawal

We describe a patient with nonsignificant coronary artery disease who experienced variant angina after beta -blockade withdrawal. Standard therapy with nifedipine and nitrates aimed at suppressing symptoms and typical transient ST-segment elevations was superseded by the reinstitution of metoprolol. The autonomic alternations before and after readministration of metoprolol were analyzed by time and spectral indices of heart rate variability (HRV). Metoprolol reduced the HRV and reversed the low-frequency/high-frequency power ratio toward a more physiological autonomic balance. We conclude that the reinstitution of beta -blocker acted protectively by preventing surges of sympathetic activity on an underlying basis of parasympathetic predominance.     

Gemcitabine and docetaxel as first-line treatment for advanced urothelial carcinoma: a phase II study

The purpose of the study was to investigate the toxicity and efficacy of the combination of gemcitabine and docetaxel in untreated advanced urothelial carcinoma. Patients with previously untreated, locally advanced/recurrent or metastatic urothelial carcinoma stage-IV disease were eligible. Patients with Performance status: PS ECOG >3 or age >75 years or creatinine clearance <50 ml min(-1) were excluded. Study treatment consisted of docetaxel 75 mg m(-2) (day 8) and gemcitabine 1000 mg m(-2) (days 1+8), every 21 days for a total of six to nine cycles. A total of 31 patients with urothelial bladder cancer, 25 men and six women, aged 42-74 (median 64) years were enrolled. The majority of patients had a good PS (51.6%; PS 0). In all, 15 (48.3%) patients had locally advanced or recurrent disease only and 16 (54.8%) presented with distant metastatic spread, with multiple site involvement in 22.5%. Toxicity was primarily haematologic, and the most frequent grade 3-4 toxicities were anaemia 11 (6.7%) thrombocytopenia eight (4.9%), and neutropenia 45 (27.6%), with 10 (6.1%) episodes of febrile neutropenia. No toxic deaths occurred. A number of patients had some cardiovascular morbidity (38.7%). Nonhaematological toxicities except alopecia (29 patients) were mild. Overall response rate was 51.6%, including four complete responses (12.9%) and 12 partial responses (38.7%), while a further five patients had disease stabilisation (s.d. 16.1%). The median time to progression was 8 months (95% CI 5.1-9.2 months) and the median overall survival was 15 months (95% CI 11.2-18.5 months), with 1-year survival rate of 60%. In conclusion, this schedule of gemcitabine and docetaxel is very active and well tolerated as a first-line treatment for advanced/relapsing or metastatic urothelial carcinoma. Although its relative efficacy and tolerance as compared to classic MVAC should be assessed in a phase III setting, the favourable toxicity profile of this regimen may offer an interesting alternative, particularly in patients with compromised renal function or cardiovascular disease.     

Cellular localization and functional significance of CYP3A4 in the human epileptic brain

Purpose: Compelling evidence supports the presence of P450 enzymes (CYPs) in the central nervous system (CNS). However, little information is available on the localization and function of CYPs in the drug‐resistant epileptic brain. We have evaluated the pattern of expression of the specific enzyme CYP3A4 and studied its co‐localization with MDR1. We also determined whether an association exists between CYP3A4 expression and cell survival. Methods: Brain specimens were obtained from eight patients undergoing resection to relieve drug‐resistant seizures or to remove a cavernous angioma. Each specimen was partitioned for either immunostaining or primary culture of human endothelial cells and astrocytes. Immunostaining was performed using anti‐CYP3A4, MDR1, GFAP, or NeuN antibodies. High performance liquid chromatography–ultraviolet (HPLC‐UV) analysis was used to quantify carbamazepine (CBZ) metabolism by these cells. CYP3A4 expression was correlated to DAPI) condensation, a marker of cell viability. Human embryonic kidney (HEK) cells were transfected with 4′,6‐diamidino‐2‐phenylindole (CYP3A4 to further evaluate the link between CYP3A4 levels, CBZ metabolism, and cell viability. Key Findings: CYP3A4 was expressed by blood–brain barrier (BBB) endothelial cells and by the majority of neurons (75 ± 10%). Fluorescent immunostaining showed coexpression of CYP3A4 and MDR1 in endothelial cells and neurons. CYP3A4 expression inversely correlated with DAPI nuclear condensation. CYP3A4 overexpression in HEK cells conferred resistance to cytotoxic levels of carbamazepine. CYP3A4 levels positively correlated with the amount of CBZ metabolized. Significance: CYP3A4 brain expression is not only associated with drug metabolism but may also represent a cytoprotective mechanism. Coexpression of CYP3A4 and MDR1 may be involved in cell survival in the diseased brain.     

Cognitive reserve and its relevance for the prevention and diagnosis of dementia

Progressive brain damage is undoubtedly the main cause of clinical symptoms of dementia in neurodegenerative disorders such as Alzheimer's disease. However, the association between brain damage and cognitive symptoms is not linear. Certain interindividual differences such as a good school education or a greater brain volume are associated with a higher resilience against brain damage that is usually referred to as cognitive reserve (CR). Individuals with high CR have a diminished risk for dementia and both active and passive concepts for this phenomenon are discussed. In the concept of passive CR, peculiarities of brain structure such as higher synapse or neuron counts are regarded as buffers against brain damage. Symptoms of dementia do not occur until a certain threshold of damage is passed. In addition to the passive concepts, active mechanisms are also discussed that are associated with the ability to maintain a certain level of cognitive performance in the face of progressive neurodegeneration for a longer period. In subjects with healthy cognitive function, these active mechanisms contribute to the adaptation of brain activity when task difficulty level is increased. Confronted with progressive neurodegeneration, these active mechanisms help to compensate for brain damage. Individuals with higher CR show more efficient activation for solving the same task, which helps them to preserve normal levels of cognitive performance for a longer period.     

Effect of dark chocolate on arterial function in healthy individuals: Cocoa instead of ambrosia?

Cocoa has been consumed for at least 2500 years, and for long time it has been regarded as a medicine. Arterial function is of paramount importance for the proper function and integrity of the cardiovascular system. Dark chocolate and flavonoid-rich cocoa have beneficial acute and shortterm effects on endothelial function and wave reflections in normal individuals, in adults with cardiovascular risk factors, and in patients with coronary artery disease. Furthermore, dark chocolate and flavonoid-rich cocoa may have a blood pressure-lowering effect. These effects can be attributed to flavonoids and are mainly mediated through increased nitric oxide bioavailability. Further research is needed to demonstrate whether these effects of chocolate on arterial function are translated into clinical benefit.     

AE9C90CB: a novel, bladder-selective muscarinic receptor antagonist for the treatment of overactive bladder

Background and purpose:

AE9C90CB (N- [(1R, 5S, 6R)-3-azabicyclo [3.1.0] hex-6-ylmethyl]-2-hydroxy-N-methyl-2, 2-diphenylacetamide), a novel muscarinic receptor antagonist, was synthesized for the treatment of overactive bladder. Here we describe the in vitro and in vivo profiles of AE9C90CB for action in bladder over salivary gland and compare it with four agents already in clinical use (tolterodine, oxybutynin, solifenacin and darifenacin).

Experimental approach:

Radioligand binding assay and isolated tissue-based functional assay were used to evaluate affinity, potency, and receptor subtype selectivity of compounds. Inhibition of carbachol-induced increase in intravesicular pressure and salivary secretion were measured in anaesthetized rabbits to assess the functional selectivity.

Key results:

In vitro radioligand binding study using human recombinant muscarinic receptors showed that AE9C90CB had greater affinity for M₃ muscarinic receptors with pKi of 9.90 ± 0.11 and was 20-fold more selective for M₃ than for M₂ muscarinic receptors. AE9C90CB exhibited an unsurmountable antagonism on rat bladder strips (pK_B, 9.13 ± 0.12). In anaesthetized rabbits after intravenous administration, AE9C90CB dose dependently inhibited carbachol-induced increase in intravesicular pressure and salivary secretion, and exhibited functional selectivity for urinary bladder over salivary gland which was ninefold better than that of oxybutynin.

Conclusions and implications:

We have identified AE9C90CB, a compound exhibiting moderate selectivity for M₃ over M₂ receptors but greater selectivity for urinary bladder over salivary gland than oxybutynin, tolterodine, solifenacin and darifenacin. Therefore, AE9C90CB may be a promising compound for the treatment of overactive bladder with reduced potential to cause dry mouth than currently available antimuscarinic drugs.