Biological aggressiveness of prostate cancer in the Finnish screening trial

Prostate cancer aggressiveness was evaluated based on pathologic characterization of cases detected in the Finnish prostate cancer screening trial. The trial population consists of 80,458 men aged 55–67 years. A total of 32,000 men were randomized to the screening arm. The remaining 48,000 men formed the control arm. The interval cases and cancers among nonparticipants and in the control arm were identified from the Finnish Cancer Registry. Random samples were selected from screen‐detected cases (126 of 543 in the first and 133 of 508 in the second round) and control arm cancers (133 out of 863), in addition to all 92 interval cancers and 106 cases among nonparticipants. All the biopsies were regraded according to the Gleason system. The expression of the proliferation antigen Ki‐67 was determined in 479 cases (72%). More than half of the tumors diagnosed in the first round of screening were high‐grade cancers (Gleason 7 or higher). In the second round, the proportion of low‐grade cancers increased from 47% to 70%. Cancers in the screening arm were more commonly focal and fewer bilateral cancers were detected. The cancers among nonparticipants were the most aggressive group. The aggressiveness of the interval cancers was between the cancers detected in the first and the second round. Our results indicate that prostate cancers detected through screening are less biologically aggressive. This was most notable after the first screening round. Nonparticipants had more aggressive cancers. © 2008 Wiley‐Liss, Inc.     

Late new morbidity in survivors of adolescent and young-adulthood brain tumors in Finland: a registry-based study

Background

Brain tumors (BTs) in adolescence and young adulthood (AYA) differ from those in childhood or late adulthood. However, research concerning late effects in this particular survivor group is limited. This study evaluates late morbidity of survivors diagnosed in AYAs.

Methods

We identified from the Finnish Cancer Registry all survivors diagnosed with BT at the ages 16–24 years between 1970 and 2004 (N = 315) and used data from the Hospital Discharge Registry to evaluate their late (≥5 y after diagnosis) morbidity requiring treatment in a specialized health care setting. A sibling cohort of BT patients diagnosed before the age of 25 years was used as a comparison cohort (N = 3615).

Results

The AYA BT survivors had an increased risk for late-appearing endocrine diseases (HR, 2.9; 95% CI, 1.1–8.0), psychiatric disorders (HR, 2.0; 95% CI, 1.2–3.2), diseases of the nervous system (HR, 9; 95% CI, 6.6–14.0), disorders of vision/hearing loss (HR, 3.6; 95% CI, 1.5–8.5), diseases of the circulatory system (HR, 4.9; 95% CI, 2.9–8.1), and diseases of the kidney (HR, 5.9; 95% CI, 2.5–14.1). Survivors with irradiation had an increased risk for diseases of the nervous system compared with non-irradiated survivors (HR, 3.3; 95% CI, 1.8–6.2). The cumulative prevalence for most of the diagnoses remained significantly increased for survivors even 20 years after cancer diagnosis.

Conclusions

The AYA BT survivors have an increased risk of morbidity for multiple new outcomes for ≥5 years after their primary diagnosis. This emphasizes the need for structured late-effect follow-up for this patient group.     

Urinary and blood manganese in occupationally nonexposed populations and in manual metal are welders of mild steel

Summary To obtain reference values for blood and serum manganese levels, blood specimens were collected from 29 men and 36 women. Mn in blood showed a normal distribution; its upper 97.5% limit in blood was 0.38 mol/l. Mn in serum showed a skewed distribution, which did not differ from the normal one after logarithmic transformation. The respective reference limit was 19 nmol/l. In both specimens, the levels of Mn were significantly lower in men than in women. To obtain reference values for Mn in urine, midday urine specimens were collected from 58 men and 96 women. Mn in urine also showed a skewed distribution, and the upper 97.5% limit was 38 nmol/l. The levels of Mn in blood and urine were statistically significantly higher in manual metal arc (MMA) welders of mild steel (MS) than in the reference populations. Five MMA/MS welders were subjected to a further study in which the ambient intramask Mn levels and urinary Mn excretion were monitored throughout a full working week. For two welders the correlation of Mn in urine specimens voided in the afternoon was good with the before noon Mn concentrations in the hygienic measurements; for the rest the correlation was minimal. Mn in diurnal urine specimens collected in six portions showed fluctuation if specific gravity or creatinine in urine was used to standardize for the urinary flow, but it was less evident for urinary Mn excretion rate. Our results seem to indicate that the measurement of Mn in urine or blood may be used for monitoring Mn exposure in MMA/MS welders only at the group level.These results were presented in part at the 2nd COMTOX meeting, held in Montreal in 1983     

Atypical idiopathic inflammatory demyelinating lesions: prognostic implications and relation to multiple sclerosis

Atypical lesions of a presumably idiopathic inflammatory demyelinating origin present quite variably and may pose diagnostic problems. The subsequent clinical course is also uncertain. We, therefore, wanted to clarify if atypical idiopathic inflammatory demyelinating lesions (AIIDLs) can be classified according to previously suggested radiologic characteristics and how this classification relates to prognosis. Searching the databases of eight tertiary referral centres we identified 90 adult patients (61 women, 29 men; mean age 34 years) with ≥1 AIIDL. We collected their demographic, clinical and magnetic resonance imaging data and obtained follow-up (FU) information on 77 of these patients over a mean duration of 4 years. The AIIDLs presented as a single lesion in 72 (80 %) patients and exhibited an infiltrative (n = 35), megacystic (n = 16), Baló (n = 10) or ring-like (n = 16) lesion appearance in 77 (86 %) patients. Additional multiple sclerosis (MS)-typical lesions existed in 48 (53 %) patients. During FU, a further clinical attack occurred rarely (23–35 % of patients) except for patients with ring-like AIIDLs (62 %). Further attacks were also significantly more often in patients with coexisting MS-typical lesions (41 vs. 10 %, p < 0.005). New AIIDLs developed in six (7 %), and new MS-typical lesions in 29 (42 %) patients. Our findings confirm the previously reported subtypes of AIIDLs. Most types confer a relatively low risk of further clinical attacks, except for ring-like lesions and the combination with MS-typical lesions.     

Real-world evidence data on the monoclonal antibody erenumab in migraine prevention: perspectives of treating physicians in Germany

BackgroundErenumab, the first-in-class fully human monoclonal antibody targeting the calcitonin gene-related peptide receptor, was shown to be efficacious and safe for the prophylactic treatment of migraine in adults in randomized clinical trials. Large-scale, real-world evidence in multi-centre settings is still needed to confirm these results. Erenumab patient profiles outside clinical trials and physicians’ treatment patterns, as well as data from patients treated in Germany, a severely impacted population, are not published yet.MethodsTELESCOPE was a multi-centre survey gathering real-world data from 45 German headache centres between July 2019 and December 2019. The project consisted of two parts. In the first part, treating physicians shared their experiences on current erenumab treatment with regard to patient profiles, treatment patterns and treatment responses. In the second part, a retrospective chart review was conducted of 542 migraine patients treated with erenumab for at least three months. Treatment responses focused on various aspects of patients’ quality of life.ResultsThe analysis of 542 patients’ charts revealed that three-month treatment with erenumab significantly reduced monthly headaches, migraine and acute medication days. Furthermore, headache intensity and frequency were reduced in over 75 % and accompanying aura in 35 % of patients. The clinical global impression scale revealed a general improvement in 91 % of patients. According to the treating physicians’ professional judgement, 83 % of patients responded to erenumab and 80 % were satisfied with the treatment. Physicians evaluated restricted quality of life, the number of monthly migraine days and previous, prophylactic treatments as the main components of the current patient profile for monoclonal antibody recipients. Based on the assessment of physicians, erenumab reduced migraine symptoms in 65 % and increased quality of life in more than 75 % of their patients.ConclusionsTELESCOPE confirms positive treatment responses with erenumab shown in clinical trials in a real-world multi-centre setting. The results show consistently positive experiences of physicians utilizing erenumab in clinical practice and underline that therapy with this monoclonal antibody is effective in migraine patients, particular in those, who have failed several prophylactic therapies.     

Einstellungen zur (resektiven) Epilepsiechirurgie

Clinical Epileptology - Ziel der resektiven Epilepsiechirurgie ist Anfallsfreiheit, die „number needed to treat“ beträgt&nbsp;2. Die Resektion führt – im Vergleich...     

Pathogenicity of IgG subclass autoantibodies to type VII collagen: Induction of dermal–epidermal separation

In different autoimmune diseases, tissue damage is mediated by the Fc portion of autoantibodies. These include autoimmunity to type VII collagen, a major hemidesmosomal skin constituent, where autoantibodies activate both complement and leukocytes, leading to separation within the dermal–epidermal junction. Fc-dependent effector functions differ among IgG subclasses. To elucidate the still controversial role of IgG subclasses in the pathogenesis of autoimmunity to type VII collagen, we generated a unique set of V gene-matched recombinant chimeric anti-type VII collagen autoantibodies of the four human IgG subclasses. Binding specificities and avidities of all four autoantibodies were comparable. Using ex vivo models, our results demonstrate that a monoclonal autoantibody is sufficient to activate complement and to induce dermal–epidermal separation. However, only IgG1 and IgG3, but not IgG2 and IgG4 against type VII collagen, were pathogenic in our ex vivo model systems. To our knowledge, this is the first time that a full-length recombinant disease-related human autoantibody has been investigated. Our results demonstrate the usefulness of recombinant antibody technology to dissect the contribution of F(ab′)₂ and Fc portions of autoantibodies to their biological effects. These findings may eventually contribute to novel diagnostic tools for monitoring disease and to the development of more specific therapies in autoantibody-mediated diseases, i.e. the generation of subclass-specific adsorbers, used for extracorporal immunoapheresis, or the shifting of the autoimmune response to production of non-pathogenic autoantibodies.     

Cell-to-cell contact of human monocytes with infected arterial smooth-muscle cells enhances growth of Chlamydia pneumoniae

Chlamydia pneumoniae can infect arterial cells. It has been shown that coculture of human monocytes (U937) and endothelial cells promotes infection of C. pneumoniae in endothelial cells and that the enhancement was mediated by a soluble factor (insulin-like growth factor 2) secreted by monocytes. In this study, it is shown that coculture of monocytes with C. pneumoniae enhances infection of C. pneumoniae in arterial smooth-muscle cells 5.3-fold at a monocyte-to-smooth-muscle cell ratio of 5. However, unlike endothelial cells, no enhancement was observed if monocytes were placed in cell culture inserts or if conditioned medium from monocyte cultures was used, which suggests that cell-to-cell contact is critical. The addition of mannose 6-phosphate or octyl glucoside, a nonionic detergent containing a sugar group, to cocultures inhibited the enhancement. These findings suggest that the monocyte-smooth-muscle cell interaction may be mediated by mannose 6-phosphate receptors present on monocytes.