Autoimmune hypophysitis secondary to therapy with immune checkpoint inhibitors: Four cases describing the clinical heterogeneity of central endocrine dysfunction.

INTRODUCTION: Immune checkpoint inhibitors are becoming increasingly important in oncology. Immune-related adverse events, including autoimmune hypophysitis, have been reported before. CASE REPORT: We present a case series of three males and one female, suffering from either malignant melanoma or renal cell carcinoma, who developed hypophysitis under Nivolumab and/or Ipilimumab. A wide range of clinical manifestations from asymptomatic hypophysitis, headache, general weakness, loss of appetite, visual field impairment, and confusion to acute life-threatening Addison crisis was observed.Management and outcome: All patients received corticosteroids. Immune checkpoint inhibitors were discontinued in three cases until resolution of symptoms. DISCUSSION: The objective of our report is to raise the awareness of physicians, regarding this rare clinical entity, which may become life-threatening, if not promptly recognized and properly treated.

Open-label, multicenter, single-arm phase II DeCOG-study of ipilimumab in pretreated patients with different subtypes of metastatic melanoma.

BACKGROUND: Ipilimumab is an approved immunotherapy that has shown an overall survival benefit in patients with cutaneous metastatic melanoma in two phase III trials. As results of registrational trials might not answer all questions regarding safety and efficacy of ipilimumab in patients with advanced melanoma seen in daily clinical practice, the Dermatologic Cooperative Oncology Group conducted a phase II study to assess the efficacy and safety of ipilimumab in patients with different subtypes of metastatic melanoma. PATIENTS AND METHODS: We undertook a multicenter phase II study in melanoma patients irrespective of location of the primary melanoma. Here we present data on patients with pretreated metastatic cutaneous, mucosal and occult melanoma who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months. RESULTS: 103 pretreated patients received at least one dose of ipilimumab, including 83 cutaneous, seven mucosal and 13 occult melanomas. 1-year OS rates for cutaneous, mucosal and occult melanoma were 38 %, 14 % and 27 %, respectively. Median OS was 6.8 months (95 % CI 5.3-9.9) for cutaneous, 9.6 months (95 % CI 1.6-11.1) for mucosal, and 9.9 months (lower 95 % CI 2.3, upper 95 % CI non-existent) for occult melanoma. Overall response rates for cutaneous, mucosal and occult melanoma were 16 %, 17 % and 11 %, respectively. Eleven patients had partial response (16 %) and ten patients experienced stable disease (14 %), none achieved a complete response. Treatment-related AEs were observed in 71 patients (69 %), including 20 grade 3-4 events (19 %). No new and unexpected safety findings were noted. CONCLUSIONS: Ipilimumab is a treatment option for pretreated patients with advanced cutaneous melanoma seen in daily routine. Toxicity was manageable when treated as per protocol-specific guidelines. TRIAL REGISTRATION: Clinical Trials.gov NCT01355120.

S1 guideline: microscopically controlled surgery (MCS).

When using procedures that enable complete examination of surgical margins (3D histology), microscopically controlled surgery (MCS) represents a safe and proven method to confirm R0 resection of infiltrating tumors, especially at problematic sites, while preserving the adjacent tissue. This allows for excellent or good aesthetic results that are superior (cryosurgery, short-range irradiation) or equivalent (PDT) to nonsurgical and less safe procedures (PDT).

DRG benchmarking: analysis of service structures and -differences in dermatology departments.

BACKGROUND: In the context of DRG-based hospital funding, the analysis of services provided in dermatologic inpatient care is highly relevant. We analyzed and compared clinical service structures and varieties in dermatologic hospitals through a benchmarking technique. METHODS: For this multicenter cross-sectional study, routine data from 46 German dermatologic clinics and departments were collected, processed, and analyzed. In total, 95 257 data sets from 2011 were available. The data were grouped according to the G-DRG-system 2013 version. RESULTS: The average length of stay for all cases was 6.3 days (DRG "inliers": 5.7 days), and average patient age was 52 years. In total, 55 % of all cases were grouped to medical, 45 % to surgical DRGs. 71 % of all hospitals provide services within or close to this average value (± 10 %). No association was found between the number of hospital beds and the variety of clinical services provided in our sample. We found huge varieties in several parameters assessing the coding quality. CONCLUSIONS: The results reflect the heterogeneous reality in German inpatient dermatology. The varieties in dermatologic service range still depend on patient-related factors as well as infrastructural conditions and the resources available at each site.

Patterns of care and follow-up care of patients with uveal melanoma in German-speaking countries: a multinational survey of the German Dermatologic Cooperative Oncology Group (DeCOG).

PURPOSE: Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting. METHODS: A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated. RESULTS: 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures. CONCLUSION: Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.

Microscopically controlled surgery (MCS).

To confirm a local R0 resection of tumors with infiltrative growth at problem sites and for sparing of tissue, microscopically controlled surgery represents a safe and proven method, particularly when there are no gaps between the tissue taken at the incision margins.

Erythema multiforme majus (Fuchs syndrome) associated with Mycoplasma pneumoniae infection in two patients.

In Germany Fuchs syndrome is used to describe a variant of erythema multiforme majus which mainly involves the mucosal surfaces. As the skin may be completely unaffected, it is an under-recognized diagnosis and often difficult to confirm. Clinical features involve erythema, erosions and ulcerations of the oral mucosa. In most cases there is severe conjunctivitis and sometimes the genital mucosa is involved. Most cases of Fuchs syndrome are triggered by infections; herpes simplex virus and Mycoplasma pneumoniae are the most common causes. We describe two women presenting with Fuchs syndrome after respiratory illness caused by Mycoplasma pneumoniae.

Purpura fulminans secondary to respiratory infection.

Purpura fulminans features the sudden onset of large rapidly-spreading areas of hemorrhagic skin necrosis. This is followed by a disseminated intravascular coagulopathy with consecutive consumption of anticoagulant factors. Patients with severe disease in whom therapy is delayed often develop shock with a poor prognosis.The mortality rate is about 30-40%. An elderly women developed purpura fulminans after a respiratory infection. Prompt diagnosis before shock symptoms had started was instrumental in producing a favorable clinical course.

Development of lengths of stay and DRG cost weights in dermatology from 2003 to 2006.

BACKGROUND: The G-DRG per case payments are calculated annually on the basis of present output and cost data provided from German hospitals. The economic valuation of dermatology-related DRGs depends largely on inpatients' length of stay. At present, longitudinal analyses of dermatologic hospital data considering the development of length of stay under DRG conditions are not available. METHODS: A multicenter, longitudinal study of clinical data from hospitals with different care levels was performed (n = 23). Frequent and relevant dermatologic diagnoses were grouped and analyzed over a time period of four years (2003-2006). The development of lengths of stay and of G-DRG cost weights were studied in detail. Descriptive statistical methods were applied. RESULTS: After introduction of DRG, the data reveal a) reduction of length of stay in inpatient dermatology and b) after an initial abrupt rise, DRG valuation of dermatologic groups moderately decreased over time. Both trends changed most rapidly in the early years but reached a stable niveau in 2006. The study furthermore points out that not only length of stay, but also other type of costs influence DRG calculations. CONCLUSIONS: German dermatology reflects the international trend showing reductions of length of stay after introduction of a DRG-based hospital funding system. The DRG calculation and valuation of inpatient services depend on the duration of hospital stay. However, increasing per diem costs resulting from higher performances of every inpatient bed day are also taken into account. Further reduction of length of stay must not threaten the quality of inpatient care in dermatology.

G-DRG Version 2009: new developments.

The update of the G-DRG system for the year 2009 has been successfully negotiated. Like in the past years, changes are minimal and not dramatic, but they significantly enhance the quality of the DRG system. Once again, the German DRG system demonstrates its versatility and reliability for clinical reimbursement purposes. In the field of dermatology, several improvements or enhancements can be identified; the average case mix index that declined in the past years should now rise by 0.5 percent for 2009. Oncology cases are affected especially by this increase. Some refinements advanced for several years by the German Dermatologic Society (DDG) have been recognized --complex therapies like vacuum wound therapy, isolation due to multi-resistant infections and multiple primary tumors now have better cost weights. Although there still remain some minor problems like reimbursement of cost-intensive treatments, German dermatology is in summary very well prepared for the year 2009.

Light chain multiple myeloma with cutaneous AL amyloidosis.

Cutaneous AL amyloidosis is one complication of multiple myeloma. In our patient, painful sclerotic skin changes on the extremities and macroglossia were the presenting features which led to a more detailed investigation and the diagnosis of multiple myeloma. Histological examination revealed cutaneous deposits of amyloid which were positive with Congo red stain and had an apple green color in polarized light.

Treatment modalities for allergic reactions in pigmented tattoos.

Decorative tattoos have become very popular. As a result, a higher number of hypersensitivity reactions are seen, caused by the mostly undeclared tattoo dyes. If local and intralesional therapy with corticosteroids is not effective, total excision was formerly considered the best approach. Selective laser therapy offers an alternative approach for removing the offending pigment. Case reports are used to illustrate the individual treatment options for removal of tattoos.

[G-DRG version 2007: a short overview]. / G-DRG Version 2007: Ein kurzer Uberblick.

Just as in the year before, the structure and regulations of the new GDRG version 2007 was successfully agreed on a mutual basis by the national self-governing bodies in the German health care system. Although some problems in high-specialized medicine or day clinic care will remain, the current developments demonstrate once more the learning aptitude of the G-DRG-system. Some beneficial and major changes have been made in 2007, but most of them do not touch dermatology. Additional procedure-based payments have been introduced in 2007 including the parenteral administration of such expensive agents as etanercept and itraconazole. A statistical analysis of cost weights of the year 2006 versus 2007 for two university clinics suggests that in dermatology, the increasing complexity of the G-DRG system partly leads to lower cost weights. Overall in 2007 a remarkable increase of complexity and differentiation throughout the DRG-system can be identified as well as a careful expansion of procedure-based payments.

Varying Mutational Alterations in Multiple Primary Melanomas.

In melanoma, the mitogen-activated protein (MAP) kinase pathway plays a crucial oncogenic role. Recent studies identified additional genetic alterations, eg, TERT-promoter mutations. Up to 8% of melanoma patients present with multiple primary melanomas (MPMs). The pathogenesis is not fully understood, and data on the genetic diversity of MPMs are limited. To identify putative diagnostic and therapeutic consequences, we assessed the mutational status of the BRAF and NRAS genes and TERT promoter in patients with MPMs. The study cohort consisted of 96 patients with 237 malignant melanomas. The BRAF, NRAS, and TERT-promoter genotypes were assessed in all MPMs and were correlated with patients' clinicopathological characteristics. BRAF mutations were found in 84 melanomas (35.4%), NRAS mutations, in 33 (14.0%); and TERT-promoter mutations, in 112 (47.3%). Mutation patterns were concordant between first and subsequent primary tumors in 23.9% of patients and were discordant in 61.4% of patients. The genetic alterations were partially different in 14.7% of patients. By Cox regression analysis, only the NRAS mutation had a significant negative prognostic impact on time to progression to stage III (P = 0.016) and on distant metastasis-free survival (P = 0.032). In the majority of primary melanomas in patients with MPMs, BRAF, NRAS, and TERT-promoter genotypes were discordant. Thus, molecular testing for targeted therapy should be performed on metastatic tissue and not on primary tumors.

Phase II DeCOG-study of ipilimumab in pretreated and treatment-naïve patients with metastatic uveal melanoma.

PURPOSE: Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM. PATIENTS AND METHODS: We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months. RESULTS: Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7-8.1), median progression-free survival 2.8 months (95% CI 2.5-2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3-4 events (36%). One drug-related death due to pancytopenia was observed. CONCLUSIONS: Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT01355120.

Aplasia cutis congenita in two siblings.

We report on two siblings with aplasia cutis congenita (ACC). This rare congenital malformation is characterized by a local defect of epidermis, dermis, and subcutaneous tissues occurring predominantly on the vertex of the scalp. Patient A (a boy) was born with a parietooccipital 4 x 4 cm scalp defect, that healed under conservative treatment with scar formation within three months. At the age of three years we started with serial excisions of the affected area. In patient B (a girl) two 1.5 x 1.5 cm midline scalp defects were noted at birth. After primary conservative treatment we performed an excision at the age of three years. Both children were born at term following normal pregnancy and delivery. Neither physical nor psychomotor retardation nor any other associated abnormality was found in these cases. Two younger brothers were born without any skin defects or other anomalies. There is no unifying theory on the pathogenesis of ACC. Traumatic, vascular, teratogenic, and genetic factors are discussed as initial steps in etiopathogenesis. In this family the occurrence of ACC in two siblings of either sex, with unaffected parents, may suggest an autosomal recessive mode of transmission. However autosomal dominant inheritance with germline mosaicism in one parent can not be excluded.