Sex related differences in therapy and outcome of patients with intermittent claudication in a real-world cohort.

BACKGROUND AND AIMS: The prevalence of lower extremity artery disease (LEAD) is increasing worldwide and sex-related differences are a current matter of debate. METHODS: We analysed claims data on unselected patients with in-patient treatment for LEAD with intermittent claudication (IC; Rutherford grade 1-3) from 01.01.2014 to 31.12.2015. Data files included diagnostic and procedural information from two years before index, and a five-year follow-up. RESULTS: Our analysis comprised 42,197 IC patients, thereof 28,520 (68%) male. Male patients were younger (median: 66.4 years vs. 72.6 years) but presented with higher frequency of cardiovascular risk factors such as diabetes (40% female vs. 46% male), atrial fibrillation (13% vs. 17%), chronic coronary syndrome (41% vs. 53%), chronic heart failure (23% vs. 27%), or chronic kidney disease (29% vs. 32%; all p < 0.001; age adjusted). Revascularisation applied in 80% of patients, thereof endovascular approach predominantly in female and surgery in male patients. Concomitant pharmacotherapy with statins (74% at 2 years) and platelet inhibitors (75% respectively) were long lasting below guideline recommendation, under-use being more pronounced in women. Two years after index, one-third of IC patients had subsequent revascularisation, one-quarter progressed to chronic limb threatening ischemia (CLTI), and 2% underwent amputation. Male sex was an independent risk factor for long-term mortality (female HR 0.75; 95%-CI 0.72-0.79; p < 0.001) and CLTI (female HR 0.89; 95%-CI 0.86-0.92; p < 0.001) during follow-up. CONCLUSIONS: The majority of in-patient treated patients for IC are male, presenting with worse cardiovascular risk profiles. In view of a general under-supply with statins and platelet inhibitors, women received somewhat less often preventive medication. Despite low LEAD stages at index, serious prognosis was observed in the long term. Particularly male patients were at high risk for all-cause mortality and the combined endpoint CLTI and death.

Characteristics, risk factors and treatment reality in livedoid vasculopathy - a multicentre analysis.

BACKGROUND: Livedoid vasculopathy (LV) is a rare cutaneous thrombotic disease. It is characterized by occlusion of dermal vessels resulting in livedo racemosa, ulceration and atrophie blanche. Clear guidelines for diagnosis and treatment are missing. OBJECTIVE: The purpose of this study was to better characterize epidemiology, clinical appearance and treatment reality of LV in a well-defined patient cohort. METHODS: The cohort was allocated within a prospective, multicentre, phase IIa trial that investigated the effect of rivaroxaban in LV. RESULTS: Analysis of 27 patients revealed that LV patients had an increased Body Mass Index (BMI; 11/27), hypertension (19/27) and increased levels of lipoprotein (a) (5/12) and homocysteine (10/12) in the blood. The female-to-male ratio was 2.1 : 1, and the median age was 53.0 years [interquartile range (IQR) 40.5-68]. Investigation of the clinical appearance found that 82% of patients had livedo racemosa, and the ankle region was most likely to be affected by ulceration (56-70%). The analysis of patient treatment history showed that heparin was most effective (12/17), while anti-inflammatory regimens were, although often used (17/24), not effective (0/17). CONCLUSION: We add clinical clues for a data supported diagnosis of LV, and we provide evidence that anticoagulants should be administered in monotherapy first line (EudraCT number 2012-000108-13-DE).

Facet tropism and facet joint orientation: risk factors for the development of early biochemical alterations of lumbar intervertebral discs.

OBJECTIVE: To assess the glycosaminoglycan (GAG) content of lumbar intervertebral discs (IVD) in healthy volunteers with facet tropism (FT) and sagittal facet joint (FJ) orientation using glycosaminoglycan chemical exchange saturation transfer imaging (gagCEST). METHOD: Seventy-five lumbar IVDs of twenty-five young, healthy volunteers without any history of lumbar spine pathologies (13 female; 12 male; mean age: 28.0 ± 4.4 years; range: 21-35 years) were examined with a 3T MRI scanner. Orientation of FT and FJ were assessed for L3/4, L4/5 and L5/S1 using standard T2 weighted images. Biochemical gagCEST imaging was used to determine the GAG content of each nucleus pulposus (NP) and annulus fibrosus (AF). RESULTS: Significantly higher gagCEST values of NP were found in volunteers without FT and normal FJ orientation compared to volunteers with FT and sagittal FJ orientation >45° (P < 0.0001). GagCEST values were significantly higher in volunteers without FT compared to volunteers with moderate or severe FT (moderate FT: P < 0.0001; severe FT: P = 0.0033). Volunteers with normal FJ orientation showed significantly higher gagCEST values compared to those with sagittal FJ orientation >45° (P < 0.001). We found a significant, negative correlation between gagCEST values and higher angels in sagittal FJ orientation (rho = -0.459; P < 0.0001). CONCLUSION: GagCEST analysis indicated lower GAG values of NP in young volunteers with FT and sagittal orientated FJ, indicating that FT and sagittal orientation of the FJ represent risk factors for the development of early biochemical alterations of lumbar IVDs.

Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia.

DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.

[Modern study designs and analysis methods in clinical research]. / Moderne Studiendesigns und Analysemethoden in der klinischen Forschung.

BACKGROUND: Progress in the field of medical research requires further development of clinical trial methodology to overcome the challenges resulting from small patient populations and restricted resources. METHODS: Classical single-stage designs with fixed sample sizes do not allow for interim analyses or design modifications. In contrast, adaptive designs adhere to established quality criteria while providing flexibility when conducting a clinical trial. In the face of new discoveries or information collected in the course of a trial, sample size adjustment, the selection of the target population and further design modifications can be performed. This enhances the chance of success of a clinical trial. Besides adaptive designs, classical approaches may be replaced or complemented by Bayesian methods. In a Bayesian approach prior knowledge can be efficiently included and hence the amount of information utilized in statistical analyses is increased. Furthermore, Bayes procedures allow the results of a statistical evaluation to be displayed very clearly. CONCLUSION: Modern approaches, such as adaptive designs and Bayesian designs overcome the challenges in clinical research due to enhanced flexibility and efficiency. In addition, both approaches can be combined.

Interleukin-6 in two-stage revision arthroplasty: what is the threshold value to exclude persistent infection before re-implanatation?

The purpose of this study was to evaluate whether the serum level of interleukin 6 (IL-6) could be used to identify the persistence of infection after the first stage of a two-stage revision for periprosthetic joint infection. Between 2010 and 2011, we prospectively studied 55 patients (23 men, 32 women; mean age 69.5 years; 36 to 86) with a periprosthetic joint infection. Bacteria were identified in two intra-operative tissue samples during re-implantation in 16 patients. These cases were classified as representing persistent infection. To calculate a precise cut-off value which could be used in everyday clinical practice, a 3 x 2 contingency table was constructed and manually defined. We found that a serum IL-6 ≥ 13 pg/mL can be regarded as indicating infection: its positive-predictive value is 90.9%. A serum IL-6 ≤ 8 pg/mL can be regarded as indicating an absence of infection: its negative predictive value is 92.1%. The serum IL-6 level seems to be a reasonable marker for identifying persistent infection after the first stage of a revision joint arthroplasty and before attempting re-implantation.

Feasibility of intensive multimodal therapy in infants affected by rhabdoid tumors - experience of the EU-RHAB registry.

Rhabdoid tumors mainly affect infants and other very young children with a marked vulnerability towards intensive therapy such as invasive surgery, high dose chemotherapy (HDCT) and dose intense radiotherapy. Radiotherapy (RT) is a promising option in rhabdoid tumors but its application in infants remains controversial. Neurocognitive and vascular side effects occur even long after completion of therapy. Therapeutic recommendations suggested by the European Rhabdoid Registry including RT, high dose chemotherapy (HDCT) and methotrexate (MTX) were developed by a consensus committee. Unique to our EU-RHAB database is the ability to analyze data of 64 of 81 registered infants (under one year of age) separate from older children. 20 (age at diagnoses 2-12 months) of these had received radiotherapy. To our knowledge, this is the first report specifically analyzing treatment data of infants suffering from malignant rhabdoid tumors. Our results suggest that radiotherapy significantly increases the mean survival time as well as the 3 year overall survival in infants. We detected a doubling of survival times in infants who received RT. Overall, our results suggest that infants benefit from RT with tolerable acute side effects. Severe long term sequelae likely due to intraventricular MTX and/or RT were reported in 4 patients (leukoencephalopathy). No differences in chemotherapy-related toxicity were observed between infants and children. We suggest that a nihilistic therapeutic approach towards young infants is not warranted and that RT may not be a priori rejected as a therapeutic option in infants.

The randomized shortened dental arch study: oral health-related quality of life.

OBJECTIVES: Although the shortened dental arch (SDA) concept is a widely accepted strategy to avoid overtreatment, little is known on its impact on oral health-related quality of life (OHRQoL). This multicenter randomized controlled trial aimed to investigate the OHRQoL for removable partial dental prostheses (RPDP) with molar replacement versus the SDA concept. MATERIAL AND METHODS: In both groups, missing anterior teeth were replaced with fixed dental prosthesis. Two hundred fifteen patients with bilateral molar loss in at least one jaw were included. The Oral Health Impact Profile (OHIP-49) was completed before; 6 weeks (baseline), 6 months, and 12 months after treatment; and thereafter annually until 5 years. RESULTS: Of the initial cohort, 81 patients were assigned to the RPDP group and 71 to the SDA group (age, 34 to 86 years). Before treatment, the median OHIP score was similar in both groups (RPDP, 38.0; SDA, 40.0; n.s.). Results indicate marked improvements in OHRQoL in both groups between pretreatment and baseline (RPDP, 27.0; SDA, 19.0; p ≤ 0.0001) which continued in the RPDP group until the 1-year follow-up (p = 0.0002). These significant reductions in OHIP scores are reflected in its subscales. No further differences were seen within and between groups during the remainder observation period. CONCLUSION: Both treatments show a significant improvement in OHRQoL which continued in the RPDP group until the 1-year follow-up. No significant differences were seen between groups. CLINICAL RELEVANCE: For improving OHRQoL, it is not necessary to replace missing molars with a RPDP.

Peace of mind for patients with differentiated thyroid cancer?

UNLABELLED: Differentiated thyroid carcinomas (DTC) have an excellent prognosis, with 10-year overall survival rates over 90%. In addition, DTC patients benefit from their lifelong medical surveillance. The AIM of the study was to compare the patients' overall survival with that of a matched general population. PATIENTS AND METHODS: We have analyzed 1497 consecutive patients with DTC, who underwent radioiodine therapy in Münster, Germany, according to international standards. We classified our patients according to the current 7th edition of the UICC (Union Internationale Contre le Cancer) classification and we compared the overall survival of the patients with the expected survival based on age and sex of the general population as provided by the Federal Statistical Office, Germany. RESULTS: There were no significant differences in overall survival rates between DTC patients of the cohort in stages I to IVa compared to the expected survival based on age and sex of the general population. However, patients in stage IVc showed a significantly worse overall survival rate using the log-rank test (p < 0.0001). CONCLUSION: Patients with DTC showed excellent overall survival rates in stages I, II, III and IVa. All patients, except for those in stage IVc (M1 ≥ 45 years), had overall survival rates similar to the general population.

CD34(+) lineage specific donor cell chimerism for the diagnosis and treatment of impending relapse of AML or myelodysplastic syndrome after allo-SCT.

After allo-SCT, analysis of CD34(+) lineage-specific donor cell chimerism (DCC) is a sensitive method for monitoring minimal residual disease in patients with AML or myelodysplastic syndrome (MDS) with CD34 expression. To substantiate evidence of whether immune interventions in patients with impending relapse, defined by incomplete lineage-specific DCC, may prevent hematological relapse, we performed a retrospective nested case control study. Unsorted and lineage-specific DCC were measured in 134 patients. Forty-three patients had an incomplete CD34(+)-DCC with no other evidence of relapse. After immediate tapering of immunosuppressive treatment (30 patients) and/or infusion of donor lymphocytes (10 patients), 21 patients remained in remission (conversion to complete lineage-specific DCC) and 22 relapsed. Relapse-free survival at 3 years of the 91 patients with stable DCC and of the 43 patients with incomplete DCC was 74% (95% confidence interval (CI), 64-83%) and 40% (95% CI, 24-58%), respectively. OS rates were 79% (95% CI, 70-88%) and 52% (95% CI, 35-69%), respectively. These results, with 49% of patients with impending relapse successfully treated with immune intervention, highly suggest that analysis of CD34(+)-DCC is an important tool for monitoring and the management of AML and MDS patients after allo-SCT.

NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR-ABL-positive mice.

Although BCR-ABL+ stem cells in chronic myeloid leukemia (CML) resist elimination by targeted pharmacotherapy in most patients, immunological graft-versus-leukemia effects can cure the disease. Besides cytotoxic T cells, natural killer (NK) cells may have a role in immune control of CML. Here, we explored the functionality of NK cells in CML patients and in a transgenic inducible BCR-ABL mouse model. Compared with controls, NK-cell proportions among lymphocytes were decreased at diagnosis of CML and did not recover during imatinib-induced remission for 10-34 months. Functional experiments revealed limited in vitro expansion of NK cells from CML patients and a reduced degranulation response to K562 target cells both at diagnosis and during imatinib therapy. Consistent with the results in human CML, relative numbers of NK1.1+ NK cells were reduced following induction of BCR-ABL expression in mice, and the defects persisted after BCR-ABL reversion. Moreover, target-induced degranulation by expanded BCR-ABL+ NK cells was compromised. We conclude that CML is associated with quantitative and functional defects within the NK-cell compartment, which is reproduced by induced BCR-ABL expression in mice. Further work will aim at identifying the mechanisms of NK-cell deficiency in CML and at developing strategies to exploit NK cells for immunotherapy.

Long-term safety of intramuscular gene transfer of non-viral FGF1 for peripheral artery disease.

Peripheral artery disease is a progressive disease. Primary ischemic leg symptoms are muscle fatigue, discomfort or pain during ambulation, known as intermittent claudication. The most severe manifestation of peripheral artery disease is critical limb ischemia (CLI). The long-term safety of gene therapy in peripheral artery disease remains unclear. This four center peripheral artery disease registry was designed to evaluate the long-term safety of the intramuscular non-viral fibroblast growth factor-1 (NV1FGF), a plasmid-based angiogenic gene for local expression of fibroblast growth factor-1 versus placebo in patients with peripheral artery disease who had been included in five different phase I and II trials. Here we report a 3-year follow-up in patients suffering from CLI or intermittent claudication. There were 93 evaluable patients, 72 of them in Fontaine stage IV (47 NV1FGF versus 25 placebo) and 21 patients in Fontaine stage IIb peripheral artery disease (15 NV1FGF versus 6 placebo). Safety parameters included rates of non-fatal myocardial infarction (MI), stroke, death, cancer, retinopathy and renal dysfunction. At 3 years, in 93 patients included this registry, there was no increase in retinopathy or renal dysfunction associated with delivery of this angiogenic factor. There was also no difference in the number of strokes, MI or deaths, respectively, for NV1FGF versus placebo. In the CLI group, new cancer occurred in two patients in the NV1FGF group. Conclusions that can be drawn from this relatively small patient group are limited because of the number of patients followed and can only be restricted to safety. Yet, data presented may be valuable concerning rates in cancer, retinopathy, MI or strokes following angiogenesis gene therapy in the absence of any long-term data in angiogenesis gene therapy. It may take several years until data from larger patient populations will become available.

BRAF-KIAA1549 fusion transcripts are less frequent in pilocytic astrocytomas diagnosed in adults.

AIM: Duplication of 7q34 resulting in generation of BRAF-KIAA1549 fusion transcripts is a characteristic event in pilocytic astrocytoma that may also aid distinction from diffuse astrocytic tumours. As data on BRAF-KIAA1549 fusion transcript status remain mainly limited to children, we aimed to examine the diagnostic value of BRAF-KIAA1549 fusion transcripts across all age groups. METHODS: BRAF-KIAA1549 fusion transcript status was examined using reverse transcription polymerase chain reaction on formalin-fixed paraffin-embedded samples of 105 primary pilocytic astrocytomas [median patient age: 17 years (1-74 years)]. RESULTS: Informative results (distinct wildtype BRAF bands detectable) were obtained in 105/124 cases (85%). Fusion transcripts were detected in 53 of cases (51%). They were more often encountered in tumours of infratentorial location [42/67 (63%) vs. 11/38 (29%)] and comprised KIAA1549-Ex16_BRAF-Ex9 (32 cases), KIAA1549-Ex15_BRAF-Ex9 (14 cases) and KIAA1549-Ex16_BRAF-Ex11 (seven cases). Fusion transcripts were present in 79% of tumours diagnosed in the first decade of life, but only in 51% of patients aged 11-20 years, 42% of patients aged 21-30 years, 30% of patients aged 31-40 years and 7% of patients older than 40 years. On multivariate logistic regression analysis, the association of fusion transcript status and age was confirmed adjusting for tumour location (P = 0.006). CONCLUSIONS: The frequency of BRAF-KIAA1549 fusion transcripts is significantly lower in adult patients with pilocytic astrocytoma, weakening the sensitivity of this specific diagnostic marker in that age group.

The randomized shortened dental arch study: tooth loss.

The evidence concerning the management of shortened dental arch (SDA) cases is sparse. This multi-center study was aimed at generating data on outcomes and survival rates for two common treatments, removable dental prostheses (RDP) for molar replacement or no replacement (SDA). The hypothesis was that the treatments lead to different incidences of tooth loss. We included 215 patients with complete molar loss in one jaw. Molars were either replaced by RDP or not replaced, according to the SDA concept. First tooth loss after treatment was the primary outcome measure. This event occurred in 13 patients in the RDP group and nine patients in the SDA group. The respective Kaplan-Meier survival rates at 38 months were 0.83 (95% CI: 0.74-0.91) in the RDP group and 0.86 (95% CI: 0.78-0.95) in the SDA group, the difference being non-significant.

Prediction of lymph node metastases in NSCLC. Three dimensional anatomical parameters do not substitute FDG-PET-CT.

PURPOSE: To distinguish between benign and malignant mediastinal lymph nodes in patients with NSCLC by comparing 2D and semi-automated 3D measurements in FDG-PET-CT. PATIENTS, MATERIAL, METHODS: FDG-PET-CT was performed in 46 patients prior to therapy. 299 mediastinal lymph-nodes were evaluated independently by two radiologists, both manually and by semi-automatic segmentation software. Longest-axial-diameter (LAD), shortest-axial-diameter (SAD), maximal-3D-diameter, elongation and volume were obtained. FDG-PET-CT and clinical/FDG-PET-CT follow up examinations and/or histology served as the reference standard. Statistical analysis encompassed intra-class-correlation-coefficients and receiver-operator-characteristics-curves (ROC). RESULTS: The standard of reference revealed involvement in 87 (29%) of 299 lymph nodes. Manually and semi-automatically measured 2D parameters (LAD and SAD) showed a good correlation with mean intraclass coefficients of .80 and .72, respectively. Semi-automated prediction revealed the highest areas-under-the-ROC-curve for volume (.75, 95%CI: .69-81) and SAD (.75, 95%CI: .70-.81). AUC for LAD and maximal-3D diameter were about .68. Substantially lower accuracies were found for elongation (.57, 95%CI: .50-.64). CONCLUSION: Optimized semi-automated three dimensional parameters by CT cannot approximate reported data on FDG-PET-CT for lymph node assessment in NSCLC. SAD remains the most accurate and at the same time simple to achieve anatomical criterion for definition of NSCLC target lesions.

The questionable association of vitamin E supplementation and mortality--inconsistent results of different meta-analytic approaches.

Medical research suggests benefits of vitamin E supplementation in treatment or prevention of cardiovascular disease, inflammatory joint diseases and cancer. Regardless of these benefits in a recently published meta analysis the authors drew the conclusion that high dose supplementation may cause a slight increase in mortality of the treated patients. The purpose of the present paper is to re-analyse the association of vitamin E supplementation and mortality. By means of augmented data sources as well as additional methodological approaches the results of the above mentioned meta analysis is to be either confirmed or called into question. In the above mentioned meta analysis 19 clinical trials comprising a total of 135967 participants were included. The dosages of vitamin E supplementation ranged from 16.5 to 2000 IU/d. In the present paper this data source was augmented and 10 additional trials were included (2495 additional participants receiving vitamin E doses from 136 to 5000 IU/d). Moreover in 2 of the originally included trials updated results of mortality at longer periods of follow-up were available. The present paper yields contradictory results regarding the association of vitamin E supplementation and mortality. Hierarchical logistic regression analyses confirm the former results showing an increased mortality of patients receiving high dose vitamin E. Furthermore a traditional methodological approach of meta-regression was applied to the same data source. Contrary to the former result it showed that the increased mortality odds ratio in certain trials is not due to the higher dose of vitamin E supplementation. Rather it can be explained by a higher proportion of male patients that were included in these trials compared to other trials. The causal relationship of vitamin E supplementation and increased mortality is questionable. Different methodological approaches of meta analysis yield contradictory results. Thus none of these results can be regarded to supply evidence in a statistical sense. In particular high dose vitamin E supplementation can not be regarded proved to increase mortality.

Prognostic relevance of angiogenesis in stage III NSCLC receiving multimodality treatment.

Compelling evidence indicates that microvessel density (MVD) is a prognostic marker in early nonsmall cell lung cancer (NSCLC). However, its role in lymph node metastases in stage III NSCLC receiving multimodality treatment is unknown. Lymph nodes of 142 patients with stage III NSCLC, treated in a trial of the German Lung Cancer Cooperative group, were evaluated for MVD. Median follow-up was 7.39 yrs. MVD was correlated with demographic and tumour-related variables and survival. MVD (median 33.9) did not correlate with survival. However, in multimodality-treated stage IIIA patients receiving tumour resection with negative margins (R0), those with a high MVD had significantly prolonged overall survival with a median of 4.96 yrs compared with 1.99 yrs for those with low MVD (p = 0.041). Cox regression analysis revealed that MVD was a prognostic factor in R0-resected stage IIIA (hazard ratio 0.417). Furthermore, a significant correlation of MVD to stage was observed, with significantly lower MVD in stage IIIA than IIIB (p = 0.0062), and a significant correlation of MVD to histological subtype was observed, with adenocarcinoma revealing the highest scores (p = 0.0001). Increased angiogenesis within lymph node metastases is a prognostic indicator for better survival in NSCLC patients. Thus, measurement of MVD might be useful in selecting patients for future neoadjuvant treatment decisions.

Comparison of patients with and without digital ulcers in systemic sclerosis: detection of possible risk factors.

BACKGROUND: Digital ulcers (DU) are a major complication in the course of systemic sclerosis (SSc). In recent years, efficacious, but expensive therapies (e.g. iloprost, sildenafil, bosentan) have been shown to improve healing or to reduce the recurrence of DU. For optimal management it would be useful to identify the risk factors for DU. Such statistical analyses have been rare because they require a high number of patients. OBJECTIVES: To identify potential risk factors for DU in patients with SSc. METHODS: We used the registry of the German Network for Systemic Scleroderma and evaluated the data of 1881 patients included by August 2007. We assessed potential risk factors for DU by comparing patients with (24.1%) and without active DU at time of entry (75.9%). RESULTS: Multivariate analysis revealed that male sex, presence of pulmonary arterial hypertension (PAH), involvement of the oesophagus, diffuse skin sclerosis (only when PAH was present), anti-Scl70 antibodies, young age at onset of Raynaud's phenomenon (RP), and elevated erythrocyte sedimentation rate (ESR) significantly impacted on the appearance of DU. Certain combinations increased the patients' probability of presenting with DU, with the highest probability (88%) for male patients with early onset of RP, ESR>30 mm h(-1), anti-Scl70 antibodies and PAH. Patients with DU developed RP, skin sclerosis and organ involvement approximately 2-3 years earlier than patients without DU. CONCLUSIONS: The results reveal possible risk factors for the occurrence of DU in SSc. As DU are prone to local complications, prophylactic vasoactive treatment for patients presenting with these factors may be justified.

Ichthyosis vulgaris: novel FLG mutations in the German population and high presence of CD1a+ cells in the epidermis of the atopic subgroup.

BACKGROUND: Ichthyosis vulgaris (IV) is a genetic disorder with a prevalence of 1:250-1000 caused by filaggrin (FLG) mutations, which also predispose to atopic diseases. OBJECTIVES: To study the genotype/phenotype relationship in IV and to analyse whether the suggested skin barrier defect is associated with differences of epidermal dendritic cells. PATIENTS/METHODS: We evaluated a cohort of 26 German patients with IV, established an IV severity score and analysed epidermal ultrastructure, histology, filaggrin and CD1a antigens. Mutations were screened by restriction enzyme analysis. Particular sequencing techniques allowed the complete FLG analysis to reveal novel mutations. RESULTS: The combined null allele frequency of R501X and 2282del4 was 67.3%. Patients also showed the mutations S3247X and R2447X as well as five novel FLG mutations: 424del17 and 621del4 (profilaggrin S100 domain), 2974delGA (repeat 2), R3766X (repeat 10(1)) and E4265X (repeat 10(2)). Their combined allele frequency in controls was <0.7%. No mutation was found in one IV patient, all in all approximately 27% were heterozygous, and the majority (approximately 69%) showed two null alleles. The IV severity score and ultrastructure showed a significant correlation with genotypes. Interestingly, CD1a cell counts showed a significant difference between nonatopic and atopic IV patients both with eczema and without eczema. CONCLUSIONS: We confirm that the mutations R501X and 2282del4 represent the most frequent genetic cause in German IV patients. The novel mutations are probably population and family specific. The observed differences of CD1a cells support the hypothesis that there is a barrier defect that predisposes to atopic manifestations, possibly independent of atopic eczema.

[DiaPat urine test for prostate cancer. Predictive value for results of transrectal ultrasound-guided prostate biopsies]. / DiaPat-Prostatakarzinom-Urintest. Vorhersagekraft für das Ergebnis transrektal-sonographisch gesteuerter Prostatabiopsien.

BACKGROUND: A novel urine test for early detection of prostate cancer (PCA), distributed and marketed by the company DiaPat, is advertised by the statement "correct analysis in 9 of 10 cases." PATIENTS AND METHODS: The test separates urinary polypeptides by means of capillary electrophoresis and characterizes the peptides in a time-of-flight mass spectrometer. The DiaPat test was performed on the urine of 18 men prior to multiple ultrasound-guided prostate biopsies. RESULTS: Sixteen of the 18 samples met the requirements for sample quality as established by the manufacturer. Eight of these 16 urine samples had been collected from patients in whom biopsies consecutively detected PCA; the remaining eight patients had benign biopsy results. Among the eight patients with detected PCA, the urine test yielded a low probability for PCA in three cases and a high probability in five. Within the group of eight patients with benign biopsy results, the urine test predicted a high probability for PCA in five men and a low probability in three. For the given PCA incidence of 50% within the investigated population, the DiaPat test correctly predicted biopsy results in one half of the population, whereas prediction in the remaining half was incorrect. CONCLUSION: Unless reliable validation of the DiaPat urine test for PCA is available, no clinical consequences should be drawn from the test results.