iDermatoPath - a novel software tool for mitosis detection in H&E-stained tissue sections of malignant melanoma.

BACKGROUND: Malignant Melanoma (MM) is characterized by a growing incidence and a high malignant potential. Besides well-defined prognostic factors such as tumour thickness and ulceration, the Mitotic Rate (MR) was included in the AJCC recommendations for diagnosis and treatment of MM. In daily routine, the identification of a single mitosis can be difficult on haematoxylin and eosin slides alone. Several studies showed a big inter- and intra-individual variability in detecting the MR in MM even by very experienced investigators, thus raising the question for a computer-assisted method. OBJECTIVE: The objective was to develop a software system for mitosis detection in MM on H&E slides based on machine learning for diagnostic support. METHODS: We developed a computer-aided staging support system based on image analysis and machine learning on the basis of 59 MM specimens. Our approach automatically detects tumour regions, identifies mitotic nuclei and classifies them with respect to their diagnostic relevance. A convenient user interface enables the investigator to browse through the proposed mitoses for fast and efficient diagnosing. RESULTS: A quantitative evaluation on manually labelled ground truth data revealed that the tumour region detection yields a medium spatial overlap index (dice coefficient) of 0.72. For the mitosis detection, we obtained high accuracies of above 83%. CONCLUSION: On the technical side, the developed iDermatoPath software tool provides a novel approach for mitosis detection in MM, which can be further improved using more training data such as dermatopathologist annotations. On the practical side, a first evaluation of the clinical utility was positive, albeit this approach provides most benefit for difficult cases in a research setting. Assuming all slides to be digitally processed and reported in the near future, this method could become a helpful additional tool for the pathologist.

Outcome of empirical or targeted antifungal therapy after antifungal prophylaxis in febrile neutropenia.

Azole prophylaxis has been shown to be effective in preventing invasive fungal infections (IFIs) and increasing survival in patients with prolonged neutropenia after myelosuppressive chemotherapy for haematological malignancies. Similarly, empirical antifungal therapy for persistent neutropenic fever has been shown to reduce IFI-related mortality. However, to date, there is little information with regard to the outcome of patients who receive both strategies. Here, we present our retrospective data on three cohorts of patients receiving empirical or targeted antifungal therapy after different antifungal prophylaxis regimens. All records from patients who received myelosuppressive induction chemotherapy for acute myelogenous leukemia (AML) in our centre from 2004-2010 were analysed. From 2004-2006, itraconazole was used as antifungal prophylaxis; for the first 6 months in 2007, local polyenes and from mid-2007 till 2010, posaconazole. Data of 315 courses of chemotherapy in 211 patients were analysed. Antifungal therapy (empirical or targeted, time point and antifungal agent at the physician's discretion) was initiated in 50/174 (29 %), 7/18 (39 %) and 34/123 courses (28 %, p = 0.615) in the itra cohort, the cohort without systemic prophylaxis and the posa cohort, respectively, and was effective in 24/50 (48 %), 5/7 (71 %) and 22/34 courses (65 %, p = 0.221), respectively. IFI occurred in 25/174 (14 %), 4/18 (22 %) and 16/123 (13 %) courses, respectively (p = 0.580). IFI-related survival was not different in the three cohorts. Antifungal treatment in patients with AML who received azole prophylaxis resulted in the expected efficacy-importantly, prior posaconazole prophylaxis did not render subsequent antifungal treatment less effective than prior itraconazole prophylaxis.

[Comparison of rehabilitation between in-hospital geriatric departments and geriatric out-of-hospital rehabilitation facilities. Analysis of routine data using the example of femur fractures]. / Vergleich der geriatrischen frührehabilitativen Komplexbehandlung und der geriatrischen Anschlussrehabilitation. Routinedatenanalyse am Beispiel der Femurfraktur.

AIM OF THE STUDY: The goal of this study was to compare two types of rehabilitation for geriatric patients with femoral fracture in Germany, i.e. care in geriatric hospital departments (§109 SGB V) and care in geriatric out-of-hospital rehabilitation facilities (§111 SGB V). METHODS: Based on claims data of the AOK ("Allgemeine Ortskrankenkasse"=local insurance fund) insurants with a documented hospital stay with discharge diagnosis fracture of the femur in 2007 (n=25,954) were included and allocated to the respective form of rehabilitative health care via the OPS (German procedure classification for inpatient procedures) procedure 8-550 (§109, n=2028) or via admission to a geriatric rehabilitation unit (§111, n=4061). Excess costs (costs in the first year after fracture--costs in the previous year), risk of rehospitalization due to femoral fracture, and risk of death during the 1-year follow-up were compared using multivariate regression analyses. RESULTS: No significant differences were observed related to the outcomes rehospitalization due to femoral fracture and death. However, slight but significantly higher excess costs were observed in the health care type §109 (compared to §111) in patients with low excess costs. Moreover, insured members treated according to health care type §109 were more often receiving long-term care. CONCLUSION: Further analyses including qualitative endpoints, e.g., achievements of rehabilitation aims, are warranted.

[Rehabilitation in geriatric patients after ischemic stroke--a comparison of 2 organisational systems in Germany using claims data of a statutory health insurance fund]. / Rehabilitation geriatrischer Patienten nach Schlaganfall--Ein Vergleich zweier Versorgungssysteme in Deutschland anhand von Routinedaten der gesetzlichen Krankenkasse.

UNLABELLED: Due to historical aspects in some federal states in Germany rehabilitation of geriatric patients is organized in geriatric departments in hospitals (§ 109 SGB V). In other states rehabilitation of these patients is mainly realized in geriatric rehabilitation facilities outside hospital care after approval by the health insurance (§ 111 SGB V). Thus, it is of interest to compare both types of health care with respect to differences in population characteristics, resource utilization and outcome parameters (i.e., excess costs, rehospitalization, fracture risk and mortality) using a common geriatric indication, the ischemic stroke, as an example. METHODS: Claims data of the AOK (Local Health Care Fund) from seven federal states in Germany were used. Insured persons with a documented hospital stay with discharge diagnosis cerebral infarction/stroke (ICD-10 I63, I64, below denoted by "ischemic stroke") in 2007 (N=39,887) were included and allocated to the respective form of rehabilitative health care via the OPS (German procedure classification for inpatient procedures) procedure 8-550 (§ 109, N=1,272) or via admission to a geriatric rehabilitation unit within 1 month after hospital discharge (§ 111, N=2,200). All direct costs were ascertained and presented with and without costs of long-term care. Excess costs were calculated as the difference of costs between the first year after insult and the costs in the previous year. Excess costs in the 2 types of care were compared using multivariate quantile regression analysis. Risk of hospitalization (due to ischemic stroke or fracture) and risk of death in a 1-year follow-up was analysed using multivariate cox regression. RESULTS: Insured members treated according to health care type § 109 were somewhat older (mean: 81 vs. 80 years of age), more frequently female (72 vs. 67%), more often receiving long-term care (27 vs. 19%) and had more often documented sequelae after insult (>=4 diseases 39 vs. 28%). No significant differences in excess costs between both types of care were observed (quantile regression: 25%-percentile-comparison: p=0.49 and 0.11; median-comparison: p=0.99 and 0.13; 75%-percentile-comparison: p=0.13 and 0.30, with and without costs of long-term care, respectively). Moreover, no significant differences were observed related to the outcomes 'rehospitalization due to ischemic stroke' (hazard ratio - HR [95% confidence interval - CI])=1.12 [0.85-1.48], p=0.43) and death (HR [95% CI]=1.03 [0.88-1.20], p=0.75) in the multivariate model (reference: health care type § 111). Insured members in health care type § 109 had a significant lower risk of rehospitalization due to fracture (HR [95% CI]=0.61 [0.40-0.93], p=0.02). CONCLUSION: According to health care type § 109 and § 111, geriatric patients differ in certain characteristics such as gender, statutory care and documented sequelae after insult. Except for the outcome 'fracture', no significant differences between both types of care have been observed in the selected outcomes. Primary studies with more differentiated data collection may focus on specific treatment and on aims and achievements of rehabilitation.

Polymorphism Thr160Thr in SRD5A1, involved in the progesterone metabolism, modifies postmenopausal breast cancer risk associated with menopausal hormone therapy.

Menopausal hormone therapy (MHT) is associated with an increased breast cancer risk in postmenopausal women, with combined estrogen-progestagen therapy posing a greater risk than estrogen monotherapy. However, few studies focused on potential effect modification of MHT-associated breast cancer risk by genetic polymorphisms in the progesterone metabolism. We assessed effect modification of MHT use by five coding single nucleotide polymorphisms (SNPs) in the progesterone metabolizing enzymes AKR1C3 (rs7741), AKR1C4 (rs3829125, rs17134592), and SRD5A1 (rs248793, rs3736316) using a two-center population-based case-control study from Germany with 2,502 postmenopausal breast cancer patients and 4,833 matched controls. An empirical-Bayes procedure that tests for interaction using a weighted combination of the prospective and the retrospective case-control estimators as well as standard prospective logistic regression were applied to assess multiplicative statistical interaction between polymorphisms and duration of MHT use with regard to breast cancer risk assuming a log-additive mode of inheritance. No genetic marginal effects were observed. Breast cancer risk associated with duration of combined therapy was significantly modified by SRD5A1_rs3736316, showing a reduced risk elevation in carriers of the minor allele (p (interaction,empirical-Bayes) = 0.006 using the empirical-Bayes method, p (interaction,logistic regression) = 0.013 using logistic regression). The risk associated with duration of use of monotherapy was increased by AKR1C3_rs7741 in minor allele carriers (p (interaction,empirical-Bayes) = 0.083, p (interaction,logistic regression) = 0.029) and decreased in minor allele carriers of two SNPs in AKR1C4 (rs3829125: p (interaction,empirical-Bayes) = 0.07, p (interaction,logistic regression) = 0.021; rs17134592: p (interaction,empirical-Bayes) = 0.101, p (interaction,logistic regression) = 0.038). After Bonferroni correction for multiple testing only SRD5A1_rs3736316 assessed using the empirical-Bayes method remained significant. Postmenopausal breast cancer risk associated with combined therapy may be modified by genetic variation in SRD5A1. Further well-powered studies are, however, required to replicate our finding.

Characterization of infectious bursal disease viruses isolated in 2007 from Delmarva commercial broiler chickens.

A study was performed in 2007 to isolate and characterize infectious bursal disease viruses (IBDVs) in commercial broilers grown in the Delmarva (DMV) Peninsula region of the United States. Bursae of Fabricius were collected weekly from 1 to 4 wk of age from broilers on 10 farms with a history of poor performance. Microscopic pathology was used to determine the infectious bursal disease (IBD) status of the broilers. Bursae from 1- and 2-wk-old broilers did not show IBD microscopic lesions. Moreover, broilers on 1 of the 10 farms were IBD lesion free at 3 and 4 wk of age. However, 3 of 9 and 9 of 9 farms yielded broilers with IBD-affected bursae from 3- and 4-wk-old commercial broilers, respectively. Ten IBDV isolates were recovered from 3 of 3 lesion-positive bursal pools at 3 wk of age and 7 of 9 lesion-positive bursal pools at 4 wk of age. Analysis of the viral protein (VP) 2 genes identified all isolates as serotype 1 Delaware (Del) variant viruses. Five field isolates, each representing different molecular clades of the Delaware variant viruses, were selected for further study. Experimental infection of specific-pathogen-free white leghorn chickens with isolates DMV/4813/07, DMV/4947/07, DMV/4955/07, DMV/5038/07, and DMV/5041/07 produced gross and microscopic pathology of the bursa consistent with Delaware variant infection. Monoclonal antibody testing showed DMV/4813/07, DMV/4947/07, DMV/ 4955/07, and DMV/5041/07 to be similar to previous recognized variant viruses. However, DMV/5038/07 was found to be unreactive with the monoclonal antibodies that typically recognize reference strains STC, Del E, GLS, RS593, and AL2. In a challenge of immunity study, 10-day-old progeny from breeders immunized with a commercially available inactivated IBDV vaccine containing the Del E and classic strains were protected to a lesser degree against isolate DMV/5038/07 compared to Del E challenge based on microscopic lesion scores (P < 0.01) of the bursa. This result suggests the virus is antigenically different from the Del E strain contained in the vaccine. Collectively, the monoclonal antibody and progeny challenge of immunity findings suggest DMV/5038/07 is antigenically different from the Del E strain contained in the vaccine.

Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk.

BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

Resistance exercise and lipoproteins in postmenopausal women.

The specific aims of this study were to quantify the effects of 12 weeks of resistance training, as well as a single session of resistance exercise on lipids and lipoproteins in obese, postmenopausal women. 21 obese, postmenopausal women, not on hormone replacement therapy (age=65.9 ± 0.5 yr; BMI=32.7 ± 0.8 kg/m(2)), were randomly assigned to control (n=12) and exercise (n=9) groups matched for age and BMI. For 12 weeks, 3 days/week, the exercise group performed 10 whole body resistance exercises (3 sets at 8-RM). Fasting (10 h) blood samples were collected immediately prior to and 24 h after the first and last exercise and control session. Serum was assayed for concentrations of total cholesterol, triglycerides, LDL-C, HDL-C, HDL 2-C, HDL 3-C, non-HDL-C and TC:HDL and LDL:HDL ratios. The exercise group exhibited a significant (P<0.01) improvement in muscular strength, but no change in BMI, body mass or body composition post-training. Total cholesterol, LDL-C and non-HDL-C were significantly (P<0.05) lower in the exercise compared to the control group following the 12 weeks of resistance training. Whole body resistance training provides obese, postmenopausal women a non-pharmacological approach for the reduction of lipid and lipoprotein-cholesterol concentrations.

[Mixed tumor of the skin]. / Mischtumor der Haut.

An 81-year-old woman presented with a skin-colored, slowly growing tumor on her right lower eyelid. The diagnosis of mixed tumor of the skin was confirmed after excision and histologic examination of the tissue, which demonstrated a characteristic histology and immunohistochemistry. The mixed tumor of the skin is a usually benign neoplasm believed to originate in sweat glands. It is composed of epithelial cells set in a mesenchymal matrix, showing apocrine differentiation. Immunohistochemical staining is positive for cytokeratin, CEA, EMA and S100.

Quality of life in localised malignant melanoma.

BACKGROUND: The incidence of melanoma is still increasing in fair-skinned populations. At least 80% of patients have localised disease and expect a 5-year relative survival of >90%. PATIENTS AND METHODS: In 2003-2004, disease-free patients with localised melanoma were recruited from the Munich Cancer Registry to answer quality-of-life (QoL) questionnaires 2 years after treatment. RESULTS: A response rate of 72% was achieved from a total of 1085 distributed questionnaires. Hundred and seventeen questionnaires had to be excluded because of updated information about secondary tumour and progression events. Thus, questionnaires from 664 patients were evaluated. QoL scores in melanoma patients were essentially similar to those of a general population. Differences were detected between women and men concerning emotional and sexual functioning. Age and number of comorbidities were the strongest factors influencing most all aspects of QoL. Fifty percent of patients referred to deficits in communication with their doctors. CONCLUSIONS: Patients who overcome melanoma do not necessarily have a reduced QoL. Strategies used by these melanoma patients resulted in similar levels of coping as previous studies in comparable general populations. Nevertheless, doctor-patient communication was correlated with emotional and social functioning and should be emphasised in treatment and care of melanoma patients.

Successful ultraviolet A1 phototherapy in the treatment of localized scleroderma: a retrospective and prospective study.

BACKGROUND: Ultraviolet (UV) A1 phototherapy is an effective anti-inflammatory treatment modality that influences fibroblast functions. OBJECTIVES: To document the effects of UVA1 treatment in patients with localized scleroderma (LS) in a retrospective study (at least 6 months after UVA1 treatment) and in a prospective study before and immediately after medium-dose UVA1 irradiation. METHODS: In total, 30 patients (retrospective study n = 17, prospective study n = 13) with LS receiving UVA1 phototherapy five times weekly (for 3-6 weeks) were investigated. Improvement was documented using standardized questionnaires and clinical evaluation (using modified Rodnan skin score, Cutometer and 7.5-MHz ultrasound measurements). Levels of collagen I and collagen III metabolites were measured in serum and urine. RESULTS: In the retrospective study, medium-dose UVA1 phototherapy had been performed 6 months-3 years earlier (cumulative dose 750-1400 J cm(-2); mean + or - SD number of irradiations 19.3 + or - 3.8). Fourteen of 17 patients (82%) reported an improvement in symptoms following UVA1 therapy. In the prospective study, skin elasticity increased in 77% of the patients following medium-dose UVA1 phototherapy (cumulative dose 750-1250 J cm(-2); mean + or - SD number of irradiations 20.8 + or - 4.0). 7.5-MHz ultrasound measurements showed a mean reduction of lesional skin thickness of 13% compared with skin thickness before UVA1 phototherapy. The ratio of deoxypyridinoline to creatinine was significantly elevated in about two-thirds of the patients. CONCLUSIONS: This open study showed a positive short- and long-term efficacy of UVA1 phototherapy in patients with LS, with a reduction in sclerotic plaques, an increase in skin elasticity and a reduction of lesional skin thickness. UVA1 phototherapy had a significant effect on collagen metabolism. UVA1 phototherapy can be regarded as a safe treatment modality for patients with LS.

The Bacterial Connection between the Oral Cavity and the Gut Diseases.

More than 100 trillion symbiotic microorganisms constitutively colonize throughout the human body, including the oral cavity, the skin, and the gastrointestinal tract. The oral cavity harbors one of the most diverse and abundant microbial communities within the human body, second to the community that resides in the gastrointestinal tract, and is composed of >770 bacterial species. Advances in sequencing technologies help define the precise microbial landscape in our bodies. Environmental and functional differences render the composition of resident microbiota largely distinct between the mouth and the gut and lead to the development of unique microbial ecosystems in the 2 mucosal sites. However, it is apparent that there may be a microbial connection between these 2 mucosal sites in the context of disease pathogenesis. Accumulating evidence indicates that resident oral bacteria can translocate to the gastrointestinal tract through hematogenous and enteral routes. The dissemination of oral microbes to the gut may exacerbate various gastrointestinal diseases, including irritable bowel syndrome, inflammatory bowel disease, and colorectal cancer. However, the precise role that oral microbes play in the extraoral organs, including the gut, remains elusive. Here, we review the recent findings on the dissemination of oral bacteria to the gastrointestinal tract and their possible contribution to the pathogenesis of gastrointestinal diseases. Although little is known about the mechanisms of ectopic colonization of the gut by oral bacteria, we also discuss the potential factors that allow the oral bacteria to colonize the gut.

[Reticular erythematous plaques]. / Netzförmig angeordnete erythematöse Plaques.

Reticular erythematous mucinosis (REM) syndrome primarily affects young women; the skin lesions usually appear on the chest and upper back. REM is diagnosed on the basis of the clinical picture and histological findings. REM syndrome is often associated with lupus erythematosus tumidus. Both diseases respond well to treatment with chloroquin. Topical tacrolimus and the use of a pulsed dye laser have fewer side effects and have also proved to be effective.

The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement.

OBJECTIVE: Systemic sclerosis (SSc) is a rare, heterogeneous disease, which affects different organs and therefore requires interdisciplinary diagnostic and therapeutic management. To improve the detection and follow-up of patients presenting with different disease manifestations, an interdisciplinary registry was founded with contributions from different subspecialties involved in the care of patients with SSc. METHODS: A questionnaire was developed to collect a core set of clinical data to determine the current disease status. Patients were grouped into five descriptive disease subsets, i.e. lcSSc, dcSSc, SSc sine scleroderma, overlap-syndrome and UCTD with scleroderma features. RESULTS: Of the 1483 patients, 45.5% of patients had lcSSc and 32.7% dcSSc. Overlap syndrome was diagnosed in 10.9% of patients, while 8.8% had an undifferentiated form. SSc sine scleroderma was present in 1.5% of patients. Organ involvement was markedly different between subsets; pulmonary fibrosis for instance was significantly more frequent in dcSSc (56.1%) than in overlap syndrome (30.6%) or lcSSc (20.8%). Pulmonary hypertension was more common in dcSSc (18.5%) compared with lcSSc (14.9%), overlap syndrome (8.2%) and undifferentiated disease (4.1%). Musculoskeletal involvement was typical for overlap syndromes (67.6%). A family history of rheumatic disease was reported in 17.2% of patients and was associated with early disease onset (P < 0.005). CONCLUSION: In this nationwide register, a descriptive classification of patients with disease manifestations characteristic of SSc in five groups allows to include a broader spectrum of patients with features of SSc.

Photodynamic therapy induces less pain in patients treated with methyl aminolevulinate compared to aminolevulinic acid.

Photodynamic therapy (PDT) with topical application of either aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) is increasingly used for the treatment of actinic keratoses (AKs). Although PDT is a well-tolerated treatment, pain is the most severe side effect. Sixty-nine patients (mean age 69 years, 61 male, 8 female) suffering from multiple AKs on the scalp (field cancerization) were included in the study. PDT treatment was performed, using red light (Waldmann PDT 1200) with a light dose of 100 J/cm2 delivered at a dose rate of 160 mW/cm2. Either ALA or MAL were used as photosensitizer. Patients were asked to rate their pain on a scale from 0 to 10 (0 = no pain, 10 = unbearable pain). Upon reaching a score of 10 treatment was discontinued. Comparison of ALA and MAL in patients with AK revealed that MAL induced less pain than ALA. While 14% of the patients treated with MAL discontinued treatment before reaching the required light dose of 100 J/cm2, the number of patients treated with ALA who discontinued treatment reached 54%. PDT using MAL appears to be a better tolerated treatment for multiple AKs on the scalp compared to ALA-PDT. Differences in selectivity for tumor cells and transport of ALA in peripheral neurons may play a role.

Melanoma-inhibiting activity, a novel serum marker for progression of malignant melanoma.

Melanoma-inhibiting activity (MIA) was isolated previously as a small soluble protein secreted from malignant melanoma cell lines in vitro. In vivo, highly restricted expression patterns in melanocytic tumors were identified. We therefore quantitated serum levels of MIA protein by means of a nonradioactive ELISA and investigated whether MIA provides a clinically useful parameter in patients with malignant melanomas. Here, we report enhanced MIA serum levels in 13 and 23% of patients with stage I and II disease, respectively, and in 100% with stage III or IV disease. Compared with S-100 and soluble intercellular adhesion molecule 1 serum levels in these patients, MIA was the most sensitive marker. Response to therapy in stage IV disease correlated with changes in MIA serum levels. Measuring repeatedly sera of 350 patients with a history of stage I or II melanoma during follow-up, we detected 32 patients developing positive MIA values. At the time of serum analysis, 15 of them had developed metastases, and one presented with metastatic disease 6 months later. In contrast, none of the patients with normal MIA serum levels developed metastases during the follow-up period of 6-12 months. In conclusion, MIA represents a novel serum marker for systemic malignant melanoma revealing the highest sensitivity and specificity among currently available markers. Useful clinical applications include staging of primary melanomas, detection of progression from localized to metastatic disease during follow-up, and monitoring therapy of advanced melanomas.