Iron Parameters in Patients Treated with Roxadustat for Anemia of Chronic Kidney Disease.

Roxadustat is a novel agent with a distinct mechanism of action compared to erythropoiesis-stimulating agents (ESAs) and a potentially different combination of effects on iron parameters. This narrative review describes the effects of roxadustat on iron parameters and on hemoglobin levels in the context of iron supplementation in patients with anemia of non-dialysis-dependent (NDD) or dialysis-dependent (DD) chronic kidney disease (CKD). Roxadustat use was associated with a greater reduction in serum ferritin levels than seen with ESAs and an increase in serum iron levels compared to a decrease with ESAs. Decreases in transferrin saturation in patients treated with roxadustat were relatively small and, in the case of patients with NDD CKD, not observed by Week 52. These changes reflect the concomitant increases in both serum iron and total iron-binding capacity. Compared to placebo and an ESA, roxadustat improved iron availability and increased erythropoiesis while requiring less intravenous iron use. Hepcidin levels generally decreased in patients who received roxadustat compared to baseline values in all CKD populations; these decreases appear to be more robust with roxadustat than with an ESA or placebo. The mechanisms behind the effects of roxadustat and ESAs on iron availability and stores and erythropoiesis appear to differ and should be considered holistically when treating anemia of CKD.

Safety of Roxadustat Versus Erythropoiesis-Stimulating Agents in Patients with Anemia of Non-dialysis-Dependent or Incident-to-Dialysis Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies.

INTRODUCTION: This study was conducted to elucidate the safety of roxadustat, an oral medication, in patients with non-dialysis-dependent (NDD) or incident dialysis dialysis-dependent (ID-DD) chronic kidney disease (CKD). METHODS: Safety results from four phase 3, randomized, open-label studies comparing roxadustat to an erythropoiesis-stimulating agent (ESA) in men and women with NDD or ID-DD CKD with anemia were pooled and evaluated. Endpoints were time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), all-cause mortality, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8- and 1.3-margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized. RESULTS: In total, 2142 patients were evaluated (1083 roxadustat; 1059 ESA). Roxadustat was comparable to ESA for risk of MACE (HR 0.79, 95% CI 0.61-1.02), MACE+ (HR 0.78, 95% CI 0.62-0.98), and all-cause mortality (HR 0.78, 95% CI 0.57-1.05). TEAEs were comparable between roxadustat and ESA groups, including any TEAE [incidence rate per 100 (IR/100) patient-exposure years 56.1 vs. 53.5], TEAEs leading to study drug discontinuation (IR/100 patient-exposure years 6.7 vs. 5.1), and TEAEs leading to death (IR/100 patient-exposure years 6.9 vs. 7.4). CONCLUSION: There was no evidence of increased risk of cardiovascular events or mortality with roxadustat compared with ESA in patients with anemia who have NDD or ID-DD CKD. Although TEAEs occurred commonly in both the roxadustat and ESA groups, patients infrequently discontinued the study drug because of an adverse event. CLINICAL TRIAL REGISTRATION NUMBERS: DOLOMITES, 1517-CL-0610 [NCT02021318]; HIMALAYAS, FGCL-4592-063 [NCT02052310]; SIERRAS, FGCL-4592-064 [NCT02273726]; and ROCKIES, D5740C00002 [NCT02174731].

Roxadustat for the Maintenance Treatment of Anemia in Patients with End-Stage Kidney Disease on Stable Dialysis: A European Phase 3, Randomized, Open-Label, Active-Controlled Study (PYRENEES).

INTRODUCTION: Roxadustat is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for the treatment of anemia of chronic kidney disease (CKD). This European, phase 3, randomized, open-label, active-controlled study investigated efficacy and safety of roxadustat in patients with end-stage kidney disease on dialysis for at least 4 months. METHODS: Patients were randomized to switch from an erythropoiesis-stimulating agent (ESA) (epoetin alfa or darbepoetin alfa) to roxadustat three times/week or to continue their previous ESA. Roxadustat and ESA doses were adjusted to maintain hemoglobin within 10.0-12.0 g/dL during the treatment period (day 1 up to 52-104 weeks). Primary endpoints were hemoglobin change from baseline (CFB) to the average of weeks 28-36 without rescue therapy and hemoglobin CFB to the average of weeks 28-52 regardless of rescue therapy. Treatment-emergent adverse events (TEAEs) were assessed descriptively. RESULTS: Of 1081 screened patients, 836 were randomized and received treatment (roxadustat, n = 415; ESA, n = 421). The least squares means (95% CI) of the treatment difference (roxadustat - ESA) for hemoglobin CFB to weeks 28-36 (without rescue therapy) and CFB to weeks 28-52 (regardless of rescue therapy) were 0.235 (0.132, 0.339) g/dL and 0.171 (0.082, 0.261) g/dL, respectively, demonstrating non-inferiority of roxadustat to ESA (non-inferiority margin of - 0.75 g/dL). The proportions of patients who achieved target hemoglobin without rescue therapy during weeks 28-36 were 84.2% (roxadustat) and 82.4% (ESA). Roxadustat was superior to ESA in decreasing LDL cholesterol from baseline to the average of weeks 12-28. Serious TEAEs occurred in 50.7% (roxadustat) and 45.0% (ESA) of patients. Common TEAEs in both treatment groups included hypertension, arteriovenous fistula thrombosis, headache, and diarrhea. CONCLUSION: Roxadustat was non-inferior to ESAs in maintaining hemoglobin levels in this cohort of patients with anemia of CKD on dialysis for at least 4 months who were previously treated with ESAs. Observed TEAEs were consistent with previous studies.

Efficacy and Cardiovascular Safety of Roxadustat in Dialysis-Dependent Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies.

INTRODUCTION: This integrated phase 3 analysis examined efficacy and cardiovascular safety for roxadustat vs erythropoiesis-stimulating agents (ESAs) in dialysis-dependent patients. METHODS: Efficacy and safety results from four phase 3, randomized, open-label studies comparing roxadustat to ESAs (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES) in dialysis-dependent patients with anemia of chronic kidney disease (CKD) were evaluated by study, pooled population and in two subgroups: incident dialysis and stable dialysis. The primary efficacy endpoint per study was hemoglobin change from baseline (CFB) to weeks 28-36 using least-squares mean difference (LSMD) without rescue therapy. Pooled safety endpoints included time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality [ACM]) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8 and 1.3 margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized. RESULTS: In total, 4714 patients were randomized (2354 roxadustat; 2360 ESA). Hemoglobin CFB to weeks 28-36 achieved non-inferiority for roxadustat vs ESA in each study. Roxadustat was non-inferior to ESA for risks for MACE and MACE+ in the entire cohort (MACE: HR 1.09, 95% CI 0.95-1.26; MACE+ : HR 0.98, 95% CI 0.86-1.11) and similar to the incident dialysis and stable dialysis subgroups; ACM results were consistent with MACE and MACE+ (HR 1.13, 95% CI 0.95-1.34). TEAEs were generally comparable between groups. CONCLUSION: Roxadustat improved hemoglobin similarly to ESA while demonstrating comparable cardiovascular and overall safety profiles in a wide spectrum of dialysis-dependent patients with anemia of CKD. Roxadustat represents an oral alternative to ESAs for achieving a target hemoglobin for anemia of CKD in dialysis-dependent patients.

Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, open-label, active-controlled study (DOLOMITES).

BACKGROUND: Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for treatment of anaemia of chronic kidney disease (CKD). METHODS: This randomized, open-label, active-controlled Phase 3 study compared roxadustat versus darbepoetin alfa (DA) in non-dialysis-dependent (NDD) CKD patients with anaemia for ≤104 weeks. Doses were titrated to correct and maintain haemoglobin (Hb) within 10.0-12.0 g/dL. The primary endpoint was Hb response in the full analysis set, defined as Hb ≥11.0 g/dL and Hb change from baseline (BL; CFB) ≥1.0 g/dL in patients with BL Hb >8.0 g/dL or CFB ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL during the first 24 weeks of treatment without rescue therapy (non-inferiority margin, -15%). Key secondary endpoints included change in low-density lipoprotein (LDL), time to first intravenous (IV) iron use, change in mean arterial pressure (MAP) and time to hypertension occurrence. Adverse events were assessed. RESULTS: Of 616 randomized patients (roxadustat, 323; DA, 293), 424 completed treatment (roxadustat, 215; DA, 209). Hb response with roxadustat was non-inferior to DA (roxadustat: 256/286, 89.5% versus DA: 213/273, 78.0%, difference 11.51%, 95% confidence interval 5.66-17.36%). Roxadustat maintained Hb for up to 2 years. Roxadustat was non-inferior to DA for change in MAP and time to occurrence of hypertension and superior for change in LDL and time to first IV iron use. Safety profiles were comparable between groups. Findings suggest that there was no difference between groups regarding the composite endpoints major adverse cardiovascular events (MACEs) and MACE+ [MACE: 0.81 (0.52-1.25), P = 0.339; MACE+: 0.90 (0.61-1.32), P = 0.583]. CONCLUSIONS: Roxadustat is a viable option to treat anaemia in NDD CKD patients maintaining Hb levels for up to 104 weeks.

Twenty-Eight Cases of Extraocular Sebaceous Carcinoma: A Correlative Clinicopathological and Immunohistochemical Analysis of Extraocular Sebaceous Carcinomas and Benign Sebaceous Gland Tumors.

ABSTRACT: Extraocular sebaceous carcinoma (ESC) is a rare appendiceal skin tumor. In contrast to ocular sebaceous carcinoma, information about the exact cellular architecture of these lesions is scarce and the histogenesis of ESC is unknown. Here, we extend our previous study and investigate 28 extraocular carcinomas in comparison to 54 benign sebaceous tumors and 8 cases of normal sebaceous glands using a broad spectrum of antibodies against p63, several keratins, adipophilin, EMA, Ki67, androgen receptor, and mismatch repair proteins. This observational study demonstrates that p63- and K5/14-positive basaloid cells are key cells in normal sebaceous gland and in all sebaceous tumors and that these basaloid cells give rise to EMA+, adipophilin+ sebocytes, and K5/14+, K7±, K10± ductal structures. Finally, about half of ESC is associated with superficial in situ neoplasia, which provides evidence that at least part of these carcinomas arises from flat superficial in situ carcinoma. In contrast to the normal sebaceous gland, about half of all sebaceous tumors lack keratin K7. MMR protein IHC-profiles role will be discussed.

Factors affecting the doses of roxadustat vs darbepoetin alfa for anemia treatment in hemodialysis patients.

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). Emerging evidence suggests that roxadustat may be beneficial for patients who inadequately respond to erythropoiesis-stimulating agents (ESAs). This post-hoc analysis of a Japanese, double-blind, randomized, phase 3 study in hemodialysis-dependent CKD patients treated with traditional ESAs assessed the impact of factors associated with ESA hyporesponsiveness on roxadustat and darbepoetin alfa (DA) doses required to maintain target hemoglobin. Endpoints included mean of average doses of roxadustat and DA per administration in the last 6 weeks (AAD/6W) by prior ESA-resistance index (ERI), iron repletion (transferrin saturation; ferritin), and high-sensitivity C-reactive protein (hs-CRP). Of 415 enrolled patients, 303 were randomized (roxadustat, n = 151; DA, n = 152). Weight-adjusted AAD/6W increased with increasing ERI for roxadustat (ERI <3.3, 0.89 mg/kg; ERI ≥8.4, 1.51 mg/kg) and DA (ERI <3.3, 0.26 µg/kg; ERI ≥8.4, 0.91 µg/kg); the weight-adjusted AAD/6W relative to within-arm mean AAD/6W showed a trend toward increased DA doses for the ERI ≥8.4 category (P = .089). AAD/6W remained stable for roxadustat but increased for DA with decreasing baseline iron repletion markers. The relationship between roxadustat doses and end of treatment (EoT) hs-CRP was not significant (estimated slope, -0.494; P = .814); a trend toward increased DA doses was observed with increasing EoT hs-CRP (estimated slope, 2.973; P = .075). Roxadustat doses required to maintain target hemoglobin appear to be less affected by factors that underlie ESA hyporesponsiveness, relative to DA; roxadustat may be beneficial for patients hyporesponsive to ESAs.

Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan.

BACKGROUND: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for dialysis-dependent CKD anemia. METHODS: This phase 3, 24-week, double-blind, double-dummy study evaluated roxadustat's noninferiority to darbepoetin alfa for hemodialysis-dependent CKD anemia. We randomly assigned Japanese patients to oral roxadustat three times weekly or to darbepoetin alfa injections once weekly, titrating doses to maintain hemoglobin between 10-12 g/dl. The primary end point was change of average hemoglobin from baseline to weeks 18-24 (∆Hb18-24). Secondary end points were average hemoglobin and proportion of patients with hemoglobin between 10-12 g/dl (maintenance rate) at weeks 18-24, and iron parameters. Safety assessments included treatment-emergent adverse events and adjudicated ophthalmologic findings. RESULTS: We randomly assigned 303 patients to roxadustat (n=151) or darbepoetin alfa (n=152). The difference between roxadustat and darbepoetin alfa in ∆Hb18-24 was -0.02 g/dl (95% confidence interval, -0.18 to 0.15), confirming roxadustat's noninferiority to darbepoetin alfa. Average hemoglobin at weeks 18-24 with roxadustat was 10.99 g/dl (95% confidence interval: 10.88 to 11.10), confirming its efficacy. Among patients with one or more hemoglobin value during weeks 18-24, the maintenance rate was 95.2% with roxadustat and 91.3% with darbepoetin alfa. Serum iron, ferritin, and transferrin saturation remained clinically stable with roxadustat; transferrin and total iron binding capacity increased through week 4 before stabilizing. Common treatment-emergent adverse events were nasopharyngitis, shunt stenosis, diarrhea, contusion, and vomiting. The proportion of patients with new or worsening retinal hemorrhage was 32.4% with roxadustat and 36.6% with darbepoetin alfa. We observed no clinically meaningful changes in retinal thickness groups. CONCLUSIONS: Roxadustat maintained hemoglobin within 10-12 g/dl in patients on hemodialysis and was noninferior to darbepoetin alfa. Treatment-emergent adverse events were consistent with previous reports. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: A Study of Intermittent Oral Dosing of ASP1517 in Hemodialysis Chronic Kidney Disease Patients with Anemia, NCT02952092 (ClinicalTrials.gov).

A Phase 3, Multicenter, Randomized, Two-Arm, Open-Label Study of Intermittent Oral Dosing of Roxadustat for the Treatment of Anemia in Japanese Erythropoiesis-Stimulating Agent-Naïve Chronic Kidney Disease Patients Not on Dialysis.

INTRODUCTION: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia in Japan for patients with dialysis-dependent (DD) chronic kidney disease (CKD). OBJECTIVE: Multicenter, randomized, open-label, noncomparative, phase 3 study to evaluate roxadustat for anemia of non-dialysis-dependent (NDD) CKD in Japan. METHODS: Erythropoiesis stimulating agent (ESA)-naïve NDD-CKD patients were randomized to roxadustat (initial dose, 50 or 70 mg 3 times weekly), titrated to maintain hemoglobin (Hb) within 10.0-12.0 g/dL, for ≤24 weeks. Patients with either transferrin saturation of ≥5% or serum ferritin of ≥30 ng/mL during the screening period were eligible. Endpoints included response rate (proportion of patients achieving Hb ≥10.0 or ≥10.5 g/dL and Hb increase ≥1.0 g/dL from baseline) at end of treatment; average Hb (weeks 18-24); change of average Hb from baseline to weeks 18-24; maintenance rate (proportion of patients achieving Hb 10.0-12.0 g/dL at weeks 18-24); rate of rise (RoR) of Hb from weeks 0-4, discontinuation, or dose adjustment. Adverse events were monitored throughout the study. RESULTS: Of 135 patients who provided informed consent, 100 were randomized and 99 received roxadustat (50 mg, n = 49; 70 mg, n = 50). The mean (SD) dose of roxadustat per intake at week 22 was 36.3 (22.7) mg in the roxadustat 50 mg group and 36.8 (16.0) mg in the roxadustat 70 mg group. Prior medications included oral iron therapy (20.2%) and intravenous iron therapy (1.0%). Overall response rate (95% CI) was 97.0% (91.4, 99.4; Hb ≥10.0 g/dL) and 94.9% (88.6, 98.3; Hb ≥10.5 g/dL). Mean (SD) Hb (weeks 18-24) was 11.17 (0.62) g/dL. Mean (SD) change of Hb from baseline (weeks 18-24) was 1.34 (0.86) g/dL. Maintenance rate (95% CI) was 88.8% (80.3, 94.5) among patients with ≥1 Hb measurement during weeks 18-24. Mean (SD) RoR of Hb was 0.291 (0.197) g/dL/week (50 mg) and 0.373 (0.235) g/dL/week (70 mg). Nasopharyngitis and hypertension were the most common adverse events. CONCLUSION: Roxadustat increased and maintained Hb in ESA-naïve, partially iron-depleted NDD-CKD patients with anemia.

Oral roxadustat three times weekly in ESA-naïve and ESA-converted patients with anemia of chronic kidney disease on hemodialysis: Results from two phase 3 studies.

Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for anemia of dialysis-dependent chronic kidney disease (CKD). Japanese hemodialysis patients with anemia of CKD previously naïve to, or converted from, erythropoiesis-stimulating agents (ESAs) were enrolled in two open-label, noncomparative studies of titrated oral roxadustat administered three times weekly. ESA-naïve patients (n = 75) were randomized to roxadustat (initial dose, 50 or 70 mg) for 24 weeks; ESA-converted patients (n = 164) were assigned to roxadustat (initial dose, 70 or 100 mg based on prior ESA dose) for 52 weeks. Efficacy outcomes included average hemoglobin (Hb, weeks 18-24 or 46-52), change of Hb from baseline to weeks 18 to 24 (ΔHb18-24 ) or weeks 46 to 52 (ΔHb46-52 ), and maintenance rate (proportion of patients who achieved average Hb of 10.0-12.0 g/dL for weeks 18-24 or weeks 46-52). Treatment-emergent adverse events (TEAEs) were monitored. Mean (SD) Hb was 10.93 (0.79) g/dL (weeks 18-24) (ESA-Naïve Study), and 10.93 (0.69; weeks 18-24) g/dL and 11.11 (0.67; weeks 46-52) g/dL (ESA-Converted Study). Mean (SD) ΔHb18-24 was 2.26 (1.02) g/dL (ESA-Naïve Study) and -0.03 (0.90) g/dL (ESA-Converted Study); mean (SD) ΔHb46-52 was 0.12 (0.83) g/dL (ESA-Converted Study). The overall maintenance rate was 73.0% (54/74) (ESA-Naïve Study) (weeks 18-24), and 79.1% (129/163; weeks 18-24) and 71.2% (116/163; weeks 46-52) (ESA-Converted Study). Nasopharyngitis was the most common TEAE. Two deaths, considered unrelated to roxadustat, occurred in the ESA-Converted Study. Roxadustat effectively corrected and maintained Hb, regardless of previous ESA treatment, in Japanese anemic CKD patients on hemodialysis.

Spatial analysis of p63, K5 and K7 defines two groups of progenitor cells that differentially contribute to the maintenance of normal sebaceous glands, extraocular sebaceous carcinoma and benign sebaceous tumors.

The histogenesis of extraocular sebaceous carcinomas is - in contrast to ocular sebaceous carcinomas - unclear, and information about the exact cellular architecture of these lesions and even of the normal sebaceous gland is still scarce. This study attempts to elucidate the histogenesis of sebaceous tumors, using multicolor immunofluorescence stainings to analyze 21 cases of sebaceous tumors (six each of extraocular sebaceous carcinoma, sebaceous adenoma and sebaceoma, and three cases of steatocystomas) and eight cases of normal sebaceous glands for p63, several keratins, androgen receptor, adipophilin, epithelial membrane antigen (EMA) and Ki-67. The data of this observational study provide evidence for the existence of two subpopulations of progenitors in normal sebaceous glands: (i) p63+ K5+ progenitors which generate the K10+ luminal cells of sebaceous ducts; and (ii) p63+ K5+ K7+ progenitors which finally generate K7+ adipophilin+ EMA+ sebocytes. Without exception, all types of sebaceous tumors contained p63+ K5+ cells. Furthermore, these tumors showed a cellular hierarchy and differentiation to adipophilin+ and/or EMA+ mature sebocytes and to K10+ ductal cells through intermediary cells. Notably, a considerable number of sebaceous tumors lack the K7 pathway of cell maintenance in the normal sebaceous lobule. Based on our data, we propose a cellular algorithmic model of the hierarchy of normal sebaceous glands and of sebocytic tumors in which p63+ K5+ cells play a major role.

[Association of Health Insurance and Socio-economic Factors with Health Care for Malignant Melanoma]. / Assoziation von Krankenversicherung und soziodemografischen Faktoren mit der Versorgung maligner Melanome.

Objective: To analyze the relationship between socio-demographic and regional factors, health insurance status and clinical features of malignant melanoma (MM). Methods: Primary data from a nationwide dermato-histopathologic laboratory on all consecutive excisions with proven diagnosis of MM over the 5-year period 2009-2013 were analyzed regarding tumor-specific and socioeconomic characteristics. The tumor depth (Breslow index) being a predictor of invasive MM progression and mortality was defined as a major indicator for early detection and intervention, thus reflecting quality of health care. Results: N=4 840 histologically verified MM samples from 4 583 patients were analyzed; of these, 2 537 (52.4%) were invasive MM. The tumor depth, which was 1.09 mm on average, increased with age from 1.00 mm in the lowest to 1.56 mm in the highest age group, p<0.001). Controlled for age and sex, the members of agricultural health insurances (LKK) and of German local public health insurances (AOK) showed significantly increased tumor depths (1.67 resp. 1.20 mm). The lowest average levels were found in members of the substitute health funds (e. g. Barmer GEK 0.93 mm) and in privately insured persons (0.99 mm). Based on a regional 4-step classification, there was a gradient in MM depth from more populated to more rural areas, ranging from 1.05 mm in nucleated cities to 1.22 in small rural communities. Distribution of MM locations varied significantly by health insurance: The highest proportion of MM in the head/neck area was seen in members of the agricultural (52.3%) and of the local public health insurances (30.2%) vs. 18.5% in patients from the substitute health funds. In contrast, MM located on the trunk and lower extremities was more prevalent in private, substitute and company health insurance funds. Conclusion: Age, gender and health insurance status are relevant determinants of MM health care and progression risk in Germany. Prevention and early detection programs by health insurances should take this into account.

Mitotic rate in primary melanoma: interobserver and intraobserver reliability, analyzed using H&E sections and immunohistochemistry.

BACKGROUND: In 2009, the AJCC issued a revised melanoma staging system. In addition to tumor thickness and ulceration, the mitotic rate was introduced as the third major prognostic parameter for the classification of primary cutaneous melanoma. Given that, according to the 2009 AJCC classification, the detection of one or more dermal tumor mitoses leads to an upstaging - from stage Ia to Ib - of melanomas with a tumor thickness of ≤ 1.0 mm, we set out to investigate the reproducibility of this new parameter. METHODS: In order to assess interobserver reliability, 17 dermatopathologists und pathologists - all well versed in the diagnosis of cutaneous melanoma - analyzed the mitotic rate in 15 thin primary cutaneous melanomas (mean tumor thickness 0.91 mm) using identical slides. Mitotic rates were determined on H&E and phosphohistone H3 (Ser10)-stained samples. Without knowledge of their previous assessment, five of the aforementioned examiners reevaluated the samples after more than one year in order to ascertain intraobserver reliability. RESULTS: Interobserver reliability of the mitotic rate in thin primary melanomas is disappointing and independent of whether H&E or immunohistochemically stained samples are used (kappa value: 0.088 [H&E], 0.154 [IH], respectively). Kappa values improved to 0.345 (H&E) and 0.403 (IH) when using a cutoff of 0/1 vs. 2+ mitoses. Similarly unsatisfactory, kappa values for intraobserver reliability ranged from 0.18 and 0.348, depending on the individual examiner. DISCUSSION: Given the unsatisfactory reproducibility and large variations in assessing the mitotic rate, it remains a matter of debate whether this diagnostic parameter should play a role in therapeutic decisions.

Mitoserate beim primären Melanom: Interobserver- und Intraobserver-Reproduzierbarkeit am HE-Schnitt und in der Immunhistologie.

HINTERGRUND: Die Melanomklassifikation wurde 2009 durch die AJCC revidiert. Für die Klassifizierung primärer Melanome wurde als dritte Größe neben Tumordicke und Ulzeration die Angabe der Mitoserate neu eingeführt. Gemäß der AJCC-2009-Klassifikation des Melanoms führt der Nachweis nur einer oder mehrerer dermaler Tumormitosen bei Melanomen ≤ 1,0 mm Tumordicke zu einer Umgruppierung des Tumors von T1a nach T1b. Dies erklärt, wie wichtig die Frage nach der Reproduzierbarkeit dieses neuen Parameters ist. METHODEN: Zur Prüfung der Interobserver-Reproduzierbarkeit der Mitoserate haben 17 Dermatopathologen und Pathologen, die in der Befundung des kutanen Melanoms sehr erfahren sind, die Mitoserate in 15 dünnen Melanomen mit einer mittleren Tumordicke von 0,91 mm an demselben Tumorschnitt bestimmt. Die Mitoserate wurde am HE-Schnitt und immunhistologisch (IH) mittels des mitosespezifischen Antikörpers Phospho-Histon-H3 (Ser10) bestimmt. Fünf Befunder wiederholten die Bestimmung nach mehr als einem Jahr ohne Kenntnis ihres Vorbefundes zur Ermittlung der Intraobserver-Reproduzierbarkeit. ERGEBNISSE: Die Interobserver-Reproduzierbarkeit der Mitoserate bei dünnen Melanomen ist unbefriedigend und unabhängig davon, ob die Mitoserate am HE-Schnitt oder am immungefärbten Schnitt bestimmt wird (κ-Werte: 0,088 [HE] bzw. 0,154 [IH]). Bei einer Diskriminationsschwelle von 0/1 vs. 2+ Mitosen verbesserte sich der κ-Wert auf 0,345 (HE) bzw. 0,403 (IH). Die Intraobserver-Reproduzierbarkeit lag mit κ-Werten zwischen 0,18 und 0,348 je nach Befunder ebenfalls im unbefriedigenden Bereich. DISKUSSION: Wegen der unbefriedigenden Reproduzierbarkeit und der großen Variation der Befunde zur Mitoserate bleibt es zweifelhaft, ob dieser Befund als Grundlage für Therapieentscheidungen herangezogen werden kann.

Health care characteristics of basal cell carcinoma in Germany: the role of insurance status and socio-demographic factors.

BACKGROUND: In Germany population-based data on health care of basal cell carcinoma (BCC) are rare. OBJECTIVE: To analyze the relationship between socio-demographic and regional factors, health insurance status and clinical features of BCC. METHODS: Data base was from a nationwide dermatopathology laboratory. All consecutive excisions from 2010 were analyzed regarding tumor-specific and socioeconomic characteristics of BCC. RESULTS: 9,467 histologically verified BCC derived from 7,116 patients (54.1 % male, mean age 70 years) were analyzed. 33 % of patients had multiple tumors. The average vertical depth of invasion of BCC was 1.27 mm. It was increased significantly (p ≤ 0.001) in men (1.33 mm vs. 1.19 mm in women) and in persons over 70 years of age (1.36 mm vs. 1.14 mm). Controlled for age and sex, members of agricultural health-insurances (LKK) and of German local public health insurances (AOK) showed the highest tumor depths (1.45 mm resp.1.42 mm). The lowest depths (1.17 mm) were found in insurees of the substitute health funds (Ersatzkassen) (p ≤ 0.001). Vertical depth of invasion was significantly increased for patients living in rural counties (1.34 mm) compared to patients from urban areas (1.21 mm). Furthermore, the distribution of BCC locations varied by type of health insurance. CONCLUSIONS: Area of residence, health insurance status, age and gender are relevant determinants of BCC health care in Germany. Prevention programs and activities to improve early detection by health insurances should take this into account.

German psoriasis registry PsoBest: objectives, methodology and baseline data.

BACKGROUND: The German psoriasis registry PsoBest records the long-term efficacy, safety, patient benefit and treatment regimens of psoriasis. PATIENTS AND METHODS: Patients with moderate or severe psoriasis are included in PsoBest when treatment with a conventional systemic agent or biologic is started for the first time. Observation time is five years. Standardized physician and patient case report forms are obtained every three to six months. Baseline data of patients included by 31 December 2012 are presented and compared to the national health care study PsoHealth 2007 (n = 2,009). RESULTS: 602 dermatology practices and clinics have been registered and 199 have recruited n = 2,556 patients (63 % by practices, 37 % by clinics). Initially, n = 808 received biologics (316 adalimumab, 34 efalizumab, 209 etanercept, 75 infliximab, 22 golimumab, 152 ustekinumab) and n = 1,651 conventional systemic therapy (928 fumaric acid esters, 518 methotrexate, 161 cyclosporine A, 191 other drugs or UV treatment). Compared to PsoHealth, patients in PsoBest had on average a higher disease severity (PASI 14.7 vs. 10.1; DLQI 11.0 vs. 7.5; EQ-5D VAS 54.0 vs. 64.5), shorter disease duration (18.2 vs. 21.3 yrs.), lower age (47.3 vs. 51.5), higher rates of psoriatic arthritis (20.5 vs. 19.1 %) and nail psoriasis (55.0 vs. 35.6 %). On average patients receiving biologics were younger, more often male and had higher disease severity and comorbidity. CONCLUSIONS: Patients in PsoBest represent patients with a high burden of disease.

Skin cancer screening in Germany - perception by the public.

BACKGROUND: In 2008, community skin cancer screening (cSCS) was introduced into routine care of the German statutory health insurances (SHI). In the meantime, more than 13 million individuals have been screened. To date, no data are available on the perception of cSCS by the general public. AIM: Evaluation of public perception of cSCS in Germany. PATIENTS AND METHODS: From 10 to 17th March 2011, a phone survey on a population-based sample of n = 1 014 German adults with SHI status was conducted by the Forsa Institute, including 12 questions on the use, knowledge and attitude regarding cSCS. RESULTS: Of the interviewees 48 % were concerned about skin cancer, 29 % of all persons and 31 % of those eligible had already undergone cSCS. Of these, a major proportion (80 %) had been screened by dermatologists. Of the interviewees 75 % would (again) consult a dermatologist for the next cSCS, and less than 10 % would consult the general practitioner. Although about 93 % considered health screenings useful, only 44 % were informed about the legal right to undergo free cSCS after the age of 35. CONCLUSIONS: In Germany cSCS is highly accepted in the community. Leading care providers are the dermatologists. Knowledge about the right to free cSCS needs better public propagation.

Routine skin cancer screening in Germany: four years of experience from the dermatologists' perspective.

BACKGROUND: In 2008, routine skin cancer screening (rSCS) was introduced into routine care for persons ≥35 years in Germany. To date, about 95% of approximately 3,500 office-based dermatologists participate in this program paid by the statutory health insurances. OBJECTIVE: To evaluate German rSCS from the dermatologists' perspective. METHODS: Since 2009, every year standardized questionnaires were sent nationwide to about 2,000 dermatologists, once yearly addressing the actual patients, screenings and treatments, the personal experiences and the dermatologists' attitudes towards rSCS. Descriptive data analysis from 2009, 2010 and 2011 was performed. RESULTS: The average dermatologist -performed 1,380/1,364/1,348 screenings annually (2009/ 2010/2011), with a mean remuneration of EUR 21.50/22.10/ 21.93. 32.9/46.6/53.3% of the dermatologists were rather or very satisfied with rSCS, and a rising number of dermatologists (69.4/80.0/83.1%) perceived a better quality of health care for skin cancer since 2008. CONCLUSION: rSCS is widely accepted by German dermatologists and is conducted with increasing frequency.