Potentially advanced malignancies detected by screening for prostate carcinoma after an interval of 4 years

BACKGROUND: At the Rotterdam branch of the European Randomized Study of Screening for Prostate Cancer, a cohort of 19,970 men ages 55-75 years is screened at an interval of 4 years. Screening includes systematic sextant needle biopsy for men with elevated prostate-specific antigen (PSA) levels and/or positive findings on digital rectal examination or transrectal ultrasound. Detection during the second screening round of a large number of high-grade (Gleason Grade 4 or 5) malignancies and/or a large number of malignancies in general could be considered the result of a failure to identify these malignancies at an early stage, during prevalence screening. METHODS: Men diagnosed during the second screening round with potentially advanced carcinoma (PAC), characterized by a biopsy Gleason score of 7 (4 + 3, or 3 + 4 with > 30% malignant involvement) or a biopsy Gleason score of 8-10, were identified. Clinical data, including PSA values on prevalence screening, biopsy history, clinical stage, and follow-up data, were retrieved for these patients. Tumor features were further analyzed in radical prostatectomy specimens. RESULTS: During the second screening round, 503 malignancies, including 30 (6.0%) with features of PAC on diagnostic biopsy, were detected in 11,210 patients. Curative treatment was offered to 26 patients. Prostatectomy demonstrated the presence of organ-confined disease in 11 of 12 specimens, and tumor volume ranged from 0.11-7.93 cm3 (median, 1.05 cm3). PSA failure was noted in 6 of 22 patients who were offered curative therapy. CONCLUSIONS: PAC is a rare finding in the second round of screening after a 4-year interval, and a substantial proportion of PAC cases detected in the second screening round represent organ-confined disease. The findings of the current study suggest that the screening protocol used is sufficiently effective for detecting > 95% of malignancies before they develop features that would make them incurable.     

Localization of orexins and their receptors in the rat olfactory system: possible modulation of olfactory perception by a neuropeptide synthetized centrally or locally

Orexin-A and -B, also known as hypocretins, are two neuropeptides acting on feeding and sleep. They are specific ligands for two different receptors belonging to the G-protein coupled receptors family. Orexin fibers and orexin receptor neurons have been previously described in the forebrain olfactory system. Using immunocytochemistry, we showed that both orexin-A and -B as well as their receptors were present at different levels of the olfactory system, from the nasal mucosa to nuclei of the amygdala. A punctuated staining for orexins and their receptors was detected at the apical part of the olfactory epithelium; in the lamina propria of the mucosa, the staining was localized around olfactory nerves. At the ultrastructural level, olfactory neurons and supporting cells were found immunoreactive for orexins and their receptors. The labeling was localized in dendritic knobs and cilia of neurons, in the apical part and microvilli of supporting cells. The finding of immunolabeled cisternae of reticulum strongly suggests a local synthesis of both peptides and receptors, confirmed by RT-PCR experiments. In forebrain and amygdala regions, we detected numerous orexin fibers. Orexin receptors were present in mitral-tufted cells of the bulb and in many neuronal perikarya in the anterior olfactory nuclei, piriform cortex and amygdala nuclei. Altogether, these results show that orexins and their receptors are present at all levels of the olfactory system, from cilia where odors bind to their receptors to central regions where integration of olfactory signals occurs. They suggest a possible modulation of olfactory perception by these neuropeptides.     

TP53 and ovarian cancer

Ovarian cancer represents the fourth most frequent type of cancer among females and is the leading cause of death from gynecological cancer in the western world. This review describes gene alterations in ovarian cancer. Specific emphasis is placed on genetic alterations and the prevalence of TP53 (p53) gene alterations in the distinct biological ovarian tumors (benign, borderline, and malignant) and histological subtypes (serous, mucinous, endometrioid, clear cell), as well as in BRCA1-associated hereditary ovarian cancer. Although multi-modality treatment regimens, including cytoreductive surgery and cisplatin-containing combination chemotherapy, have usefully prolonged survival, the overall cure rate of the disease has not changed dramatically. Ovarian cancer is difficult to eradicate completely by surgery and many patients have only a partial response to postoperative chemotherapy and/or many will develop chemotherapy resistance. All these important factors contribute to the poor prognosis of ovarian cancer patients. In this review, the putative prognostic or predictive value of TP53 in ovarian cancer is addressed.     

Pancreatic haemangioma in infancy: the place of radiology

Pancreatic haemangiomas in infants are rare. Seven cases have been reported in the literature to date. We report two new cases. One of our cases had antenatal diagnosis and was associated with atypical portal vein thrombosis. The diagnosis was obtained by percutaneous biopsy without complication. For both cases, regression was observed without treatment.     

Ruling out clinically suspected pulmonary embolism by assessment of clinical probability and D-dimer levels: a management study

D-dimer test combined with clinical probability assessment has been proposed as the first step in the diagnostic work-up of patients with suspected pulmonary embolism (PE). In a prospective management study we investigated the safety and efficiency of excluding PE by a normal D-dimer combined with a low or moderate clinical probability. Of the 202 study patients this combination ruled out PE in 64 (32%) patients. The 3-month thromboembolic risk in these patients was 0% (95% CI, 0.0-5.6%). The prevalence of PE in the entire cohort was 29% (59 patients), whereas in the low, moderate and high clinical probability groups this was 25%, 26% and 50%, respectively. We conclude that ruling out suspected PE by a normal D-dimer combined with a low or moderate clinical probability appears to be a safe and efficient strategy. The accuracy of the clinical probability assessment is modest.     

Respiratory insufficiency in desminopathy patients caused by introduction of proline residues in desmin c-terminal alpha-helical segment

Mutations in desmin gene have been identified in patients with cardiac and skeletal myopathy characterized by intracytoplasmic accumulation of desmin-reactive deposits and electron-dense granular aggregates. We characterized two new desminopathy families with unusual features of adult-onset, slowly progressive, diffuse skeletal myopathy and respiratory insufficiency. Progressive reduction of respiratory muscle strength became clinically detectable between the 3rd and the 8th years of illness and led to recurrent chest infections and death in one of the patients. Novel mutations, A357P and L370P, predicted to introduce proline residue into a highly conserved alpha-helical region of desmin, were identified. Proline is known to disrupt the alpha-helix. In addition, the A357P mutation distorts a unique stutter sequence that is considered to be critically important for proper filament assembly. Functional assessment in two cell-lines, one of which does and the other of which does not constitutively produce type III intermediate filaments, demonstrated the inability of mutant desmin carrying either the A357P or the L370P mutation to polymerize and form an intracellular filamentous network. The results of this study indicate that respiratory insufficiency is an intrinsic feature of disease associated with specific desmin mutations; in some patients, respiratory weakness may present as a dominant clinical manifestation and a major cause of disability and death.     

Cognitive impairment in SCA-19

The autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of neurodegenerative disorders characterised by progressive cerebellar dysfunction in combination with various associated features. Since 1993, ADCAs have been increasingly characterised in terms of their genetic mutation and are currently referred to as spinocerebellar ataxias (SCAs). The discovery of genetic abnormalities offers the opportunity to study the possible interaction between the identified gene mutation and cognitive function. In this study, we focus on the neuropsychological abnormalities in a Dutch ADCA family, in which a new locus was recently identified (SCA-19). The family members showed frontal-executive dysfunction, with global cognitive impairment occurring in some of the more severely affected patients. Interestingly, the neuropsychological profile of this new family seems to overlap that of individuals with various other SCAs. Apparently, similar pattern of neuronal degeneration in various SCA subtypes accounts for the neuropsychological dysfunction, which is thus not genotype specific.