Real-world treatment patterns and outcomes among metastatic cutaneous melanoma patients treated with ipilimumab.

BACKGROUND: There is a scarcity of real-world data on treatment patterns and outcomes among advanced melanoma patients treated with immunotherapies including ipilimumab, an anti-CTLA-4 antibody approved since 2011. OBJECTIVE: To evaluate ipilimumab and postipilimumab treatment patterns and outcomes among patients with advanced melanoma in Australia, Germany, Italy and Spain, following regulatory approval. METHODS: Retrospective multicentre, multinational, observational chart review study. Data were extracted from the start of ipilimumab therapy until the end of at least 40 weeks of follow-up, or death. RESULTS: Data from 371 patients (Australia, 103; Germany, 152; Italy, 76; Spain, 40) were analysed. Mean age was 65 years; 62% were male. Eastern Cooperative Oncology Group performance status (ECOG PS) was 0 or 1 for 94%. In 67%, ipilimumab was initially received as second-line or later therapy. Patients received on average 3.4 ipilimumab doses. The ipilimumab-refractory cohort comprised of 226 patients. Of these, 17% in Australia, 47% in Germany, 29% in Italy and 14% in Spain received another antimelanoma treatment after ipilimumab including chemotherapy in 26% and BRAF/other kinase inhibitors in 11%. Ipilimumab-refractory patients who received postipilimumab treatment showed a 40% reduced hazard of dying than those not receiving treatment after ipilimumab (HR 0.60; 95% CI 0.43-0.83), after adjustment for potential confounders. CONCLUSION: During the time observed, ipilimumab was mainly used as second-line or later therapy. A significant proportion of patients received postipilimumab therapy, most of which was chemotherapy. Nevertheless, overall survival following progression on ipilimumab treatment remained poor, highlighting the need for research to develop more effective end-of-life treatment options.

Ultraviolet exposure and risk of melanoma and basal cell carcinoma in Ulm and Dresden, Germany.

BACKGROUND: There is a perpetuating increase in melanoma and basal cell carcinoma (BCC) incidence in Europe. Few studies are evaluating various risk factors for both tumours. OBJECTIVES: This pre-planned additional analysis directly compared occupational and past-time ultraviolet exposure behaviour, and examined the effects of sun sensitivity between melanoma and sporadic BCC, and assessed its importance for the two entities. PATIENTS/METHODS: The study included 503 patients (melanoma, n = 291 and BCC, n = 212), and 329 controls from Germany. In all, 244 (49%) of the cases and 165 (50%) of the controls were male (median age melanoma, 55 years; BCC, 69 years; and controls, 57 years). Selection of important risk factors was performed by backward elimination in a polytomous logistic regression. RESULTS: When directly comparing melanoma and sporadic BCC, actinic elastosis (OR 48.83; 95% CI 17.87, 133.40) and site were associated with a higher risk of melanoma, whereas mountaineering in childhood, sunburn 20 years before diagnosis, farming full time, sunbed use in general, seborrheic keratosis, actinic cheilitis, actinic keratosis and age were associated with a higher risk of sporadic BCC. Gardening 20 years before melanoma, hair colour and solar lentigo were risk factors for both entities. A re-evaluation of the data excluding lentiginous melanoma entities (i.e. acro-lentiginous and lentigo-maligna melanoma) resulted in selection of the same factors. However, compared to controls, atopy evolved as a protective factor for melanoma (OR 0.29; 95% CI 0.15, 0.57) and BCC (OR 0.41; 95% CI 0.17, 0.99), respectively, but was associated with a higher risk of sporadic BCC compared to melanoma. CONCLUSION: The odds for having clinical actinic elastosis was lower in BCC compared to melanoma. In contrast, various factors associated with chronic UV exposure and age had higher odds for sporadic BCC, rather than melanoma. Further research is required to set the context for these findings, especially regarding, atopy in non-lentiginous vs. lentiginous forms of melanoma, and possible molecular pathways involved.

[Caspofungin after solid organ transplantation in Germany: observational study on treatment of invasive fungal infections]. / Caspofungin nach Transplantation solider Organe in Deutschland: Beobachtungsstudie zur Behandlung invasiver Pilzinfektion.

BACKGROUND: This study was a pre-planned country-specific secondary analysis of results in Germany from a multinational multicenter observational study to retrospectively evaluate clinical outcomes with caspofungin in patients with probable and proven invasive fungal infection following solid organ transplantation (SOT). METHODS: Data were retrospectively collected on a single episode of invasive fungal infection (IFI) in patients who had a SOT between January 2004 and June 2007. Effectiveness was reported as the proportion of patients who received at least five doses of caspofungin with a favorable (complete or partial) response. Safety was assessed for patients who received at least one dose of caspofungin. Descriptive statistics were employed for all evaluations. RESULTS: A total of 41 SOT patients (27 male, 14 female; median age 56 years, median APACHE II score at start of caspofungin therapy 23) were enrolled from 5 sites in Germany. Organs transplanted were mainly heart (51%) and liver (46%). Prevalent risk factors for IFI at baseline were use of central venous catheter (37 out of 41 patients, 90%), steroid use (37 out of 41 patients, 90%), recent stay in intensive care (36 out of 41 patients, 88%),and duration of SOT procedure >5 hours (21 out of 41 patients, 51%). Candidiasis was diagnosed in 34 patients (83%) and aspergillosis in 10 patients (24%). The lungs were the most common site of IFI (21 out of 41, 51%). Caspofungin as monotherapy was received by 28 patients (68%); 6 patients (15%) received caspofungin as salvage therapy for IFI, in most cases because they were refractory to prior antifungal drugs. Immunosuppressants were administered with caspofungin in 39 out of 41 patients (95%). In subjects with at least 5 doses of caspofungin (modified intention to treat population) the favorable response rate at the end of caspofungin therapy was 88% overall, 29 out of 33 patients; 95% confidence interval (95%-CI) 72-97%), 86% (19 out of 22 patients) with monotherapy and 91% (10 out of 11 patients) with combination therapy. No (serious) adverse events or drug interactions related to treatment with caspofungin were reported. The overall survival rate was 79% (26 out of 33 patients; 95%-CI 61-91%) at 7 days after completion of caspofungin treatment. CONCLUSION: Caspofungin was found to be an effective treatment of probable and proven invasive fungal infections in patients following SOT in Germany.

Caspofungin for post solid organ transplant invasive fungal disease: results of a retrospective observational study.

OBJECTIVE: This study was designed to determine clinical outcomes with caspofungin in patients with proven or probable invasive fungal infection (IFI) after a solid organ transplant (SOT) procedure. METHODS: In this retrospective observational study, data were collected for a single episode of IFI in patients with an SOT between January 2004 and June 2007. Response was determined by the investigator as favorable (complete or partial) or unfavorable (stable disease or failure) at the end of caspofungin therapy (EOCT). The primary effectiveness population was the proportion of patients who received >or=5 doses of caspofungin (modified all-patients-treated population). Safety was assessed for patients who received >or=1 dose of caspofungin. RESULTS: A total 81 of patients from 13 sites in China, Germany, Italy, and the United Kingdom were enrolled, including 49 (60%) liver, 22 (27%) heart, 5 (6%) lung, 2 (2%) kidney, 2 (2%) liver and kidney, and 1 (1%) pancreas and kidney recipients. Candidiasis was diagnosed in 64/81 patients (79%) and aspergillosis in 22/81 patients (27%). Most patients received caspofungin monotherapy (75%). Caspofungin was given as first-line therapy to 59 (73%) patients. The overall favorable response at EOCT was 87% (58/67; 95% confidence interval [CI]: 76%, 94%), with favorable responses in 88% (43/49; 95% CI: 75%, 95%) of patients receiving caspofungin monotherapy and 83% (15/18; 95% CI: 59%, 96%) of patients receiving combination therapy with caspofungin (modified all-patients-treated population). Response by type of SOT was as follows: liver 87% (39/45), heart 93% (14/15), kidney 100% (5/5), and lung 50% (2/4). An overall survival rate (all-patients-treated) of 69% (56/81; 95% CI: 59%, 79%) was observed at 7 days post EOCT. No serious drug-related adverse events were reported. CONCLUSION: In this study, caspofungin was effective and well tolerated in the treatment of IFIs involving SOT recipients.

The Faces Symbol Test, a newly developed screening instrument to assess cognitive decline related to multiple sclerosis: first results of the Berlin Multi-Centre FST Validation Study.

Reliable, language-independent, short screening instruments to test for cognitive function in patients with multiple sclerosis (MS) remain rare, despite the high number of patients affected by cognitive decline. We developed a new, short screening instrument, the Faces Symbol Test (FST), and compared its diagnostic test characteristics with a composite of the Digit Symbol Substitution Test (DSST) and the Paced Auditory Serial Addition Test (PASAT), in 108 MS patients and 33 healthy controls. An Informant-Report Questionnaire, a Self-Report Questionnaire, and a neurologist's estimation of the Every Day Life Cognitive Status were also applied to the MS patients. The statistical analyses comprised of a receiver operating characteristic analysis for test accuracy and for confounding variables. The PASAT and DSST composite score estimated that 36.5% of the MS patients had cognitive impairment. The FST estimated that 40.7% of the MS patients were cognitively impaired (sensitivity 84%; specificity 85%). The FST, DSST and PASAT results were significantly correlated with the patients' physical impairment, as measured by the Expanded Disability Status Scale (EDSS). The results suggest that the FST might be a culture-free, sensitive, and practical short screening instrument for the detection of cognitive decline in patients with MS, including those in the early stages.

Risk and protective factors for sporadic basal cell carcinoma: results of a two-centre case-control study in southern Germany. Clinical actinic elastosis may be a protective factor.

BACKGROUND: There are very few data regarding sun exposure behaviour of patients with basal cell carcinoma (BCC) in central Europe. OBJECTIVES: A case-control study of patients with sporadic BCC was conducted to assess the risk of occupational and leisure-time sun exposure behaviour, precursor lesions for skin cancer and phenotypic factors on the development of sporadic BCC in Ulm and Dresden, Germany. METHODS: A comparison was made of 213 patients with BCC (128 from Ulm, 85 from Dresden; 103 men and 110 women; median age at diagnosis 69 years) and 411 controls (237 from Ulm, 174 from Dresden; 197 men and 214 women; median age 58 years). Crude odds ratios (ORs) and corresponding 95% confidence intervals for all of 64 possible risk factors revealed strong associations in 33 items. Selection of important risk factors was performed in a multiple logistic regression. RESULTS: For sporadic BCC, an increased risk was shown for persons with actinic cheilitis (OR 7.1), actinic keratosis (OR 2.7) and solar lentigo (OR 2.5). The only phenotypic factor indicating risk of sporadic BCC was hair colour, with a higher risk for red/fair than brown/black hair (OR 4.3). There was an increased risk for persons with BCC in first-degree relatives (OR 5.1) and those with sunburn 20 years before sporadic BCC was diagnosed (OR 3.6). Additionally, occupational ultraviolet (UV) exposure appeared to be a risk factor (OR 2.4). In contrast, clinical actinic elastosis showed a protective effect (OR 0.1). CONCLUSIONS: In contrast to earlier reports, clinical actinic elastosis turned out to be the only protective factor for sporadic BCC. A special relationship between wrinkling and BCC risk could not be shown. For basic research, future work should be aimed at elucidating further the different forms of collagen repair processes after intermittent and/or chronic UV exposure. The data strongly support the recommendation that a change in recreational UV exposure habits in individuals, and sunburn avoidance in particular, are necessary not only because of the increased long-term risk of melanoma, but also because of the risk of other skin cancers such as sporadic BCC.

Outdoor activities in childhood: a protective factor for cutaneous melanoma? Results of a case-control study in 271 matched pairs.

BACKGROUND: A matched case-control study was performed in Munich, Germany, in 1996-97 to evaluate the risk of cutaneous melanoma due to ultraviolet (UV) exposure behaviour in Southern Bavaria, Germany. OBJECTIVES: Patients with cutaneous melanoma and controls were investigated by two physicians using a standardized questionnaire to identify risk factors for the development of melanoma, such as professional and leisure sun exposure behaviour. In each person, a total body examination was performed to detect benign skin alterations, phenotypic characteristics and precursor lesions for skin cancer. PATIENTS/METHODS: A total of 271 melanoma patients and 271 controls were individually matched for residence, age and gender. A multiple conditional logistic regression analysis was performed. RESULTS: Of 56 factors, those risk factors with a strong effect on the development of melanoma were: the existence of melanoma in first degree relatives, solar lentigo, actinic keratosis, actinic cheilitis, skin phototype, immediate skin reaction to UV light at the start of the outdoor season, sunburn in childhood and sun exposure during holidays in sunny areas 20 years before melanoma was diagnosed; outdoor activities in childhood were found to be protective. CONCLUSIONS: Sunburn in childhood and increased sun exposure during annual holidays in sunny areas should be avoided. In contrast, outdoor activities in childhood, including soccer and gardening, should be encouraged because they are associated with a lower risk of melanoma formation.

UVB-induced decrease of p16/CDKN2A expression in skin cancer patients.

The lack of p16 expression has been shown in cultured melanoma cells, however contradictory evidence for p16 expression in melanoma tissues exist. Ultraviolet (UV) C and UVB have been shown to affect p16 expression, which impairs cell cycle regulation in vitro and in vivo. In this study, p16/CDKN2A gene expression was determined by reverse transcription polymerase chain reaction in seven skin cancer patients, in one dysplastic nevus patient and in seven healthy individuals, prior to UVB exposure and at various times after application of one minimal erythema dose (MED). Five of the seven skin cancer patients showed a down-regulation of p16/CDKN2A expression after UVB exposure, while controls remained unaltered. The UVB-induced decline of p16/CDKN2A in skin cancer patients might offer new insights into photocarcinogenesis. The putative sequence of events could start with a down-regulation of p16/CDKN2A expression, which would lead to impaired cell cycle regulation. Altered expression patterns of p16/CDKN2A following UVB exposure could be of value for identifying people with an increased risk of UV-induced skin cancer.

S100 beta is a more reliable tumor marker in peripheral blood for patients with newly occurred melanoma metastases compared with MIA, albumin and lactate-dehydrogenase.

Lactate-dehydroxynase (LDH) has been described as a leading blood parameter in patients with melanoma metastases. However, recent data indicates that levels of S100 as well as melanoma inhibiting activity (MIA) in peripheral blood, correlate with melanoma progression. The aim of this study was to evaluate tumor markers S100, MIA, LDH and albumin in peripheral blood of 373 melanoma patients. 284 patients presented with in-situ or UICC stage I/II, and 89 with stage III/IV (54 tumor-free, 29 with newly occurred metastases). For newly occurred metastases, sensitivity was highest for S100 in peripheral blood (0.86), followed by MIA (0.80), LDH (0.48), and albumin (0.15). Specificity for albumin (0.99) and LDH (0.98) was higher than for S100 (0.91) and MIA (0.62). This data indicate that S100 in peripheral blood as compared to MIA, LDH and albumin appears to be the most appropriate tumor marker for newly occurred melanoma metastases.

Increased blood levels of human S100 in melanoma chick embryo xenografts' circulation.

The chorioallantoic membrane (CAM) of the fertilized egg allows grafting of human melanomas for short-term investigations and offers the opportunity to investigate the behavior of metastasizing cells and the release of S100beta into peripheral blood. Tissue from one primary melanoma as well as cutaneous and subcutaneous metastases of 10 melanoma patients with elevated levels of S100 in the peripheral blood before surgery were transplanted onto the CAM of chick embryos at day 5/6 of development. Grafts were nourished by the host blood supply 2 days after transplantation. Histologically, 3 days after grafting, metastasizing melanoma cells could be found near the vessels of the host membrane, penetrating the endothelial layer and entering the blood system. Growth conditions remained stable for 6 days after transplantation. Blood samples were taken from a larger CAM vessel before collecting the xenografts 5 days after grafting. Measurement of human S100 in peripheral blood was performed in a blinded manner. No negative control showed elevated levels of human S100 protein. Samples deriving from melanoma xenografts contained highly elevated levels of S100 protein in 80% of cases. The data strongly support the concept of graft-host interaction concerning adherence of tumors and extravasation of human melanoma cells.

Coexpression patterns of EGFR, HER2, HER3 and HER4 in non-melanoma skin cancer.

The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR), HER2, HER3 and HER4 are involved in the pathogenesis of multiple human malignant neoplasias. However, their role in the carcinogenesis of basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) remains to be elucidated. In order to further define the role of these RTKs, 56 human skin tissue samples of normal skin, BCC and SCC were studied by conventional and differential and quantitative reverse transcriptase-polymerase chain reaction (rtPCR). EGFR and HER3 were predominantly expressed in the BCCs and SCCs, while HER2 was ubiquitously expressed. HER4 was not expressed in any sample. Since in vitro studies have provided compelling evidence that heterodimer formation of these receptors are associated with different signal transduction processes, coexpression patterns might be decisive for the induction and maintenance of a malignant phenotype. These results confirm this concept: isolated HER2 expression and EGFR/HER2 were predominantly found in normal skin, while HER2/HER3 and the triple expression of EGFR/HER2/HER3 were seen more frequently in the BCCs and SCCs compared with normal skin (50% and 40% compared with 26%, respectively). The activation of HER3, in addition to EGFR and HER2, might therefore be associated with the malignant phenotype. However, due to the small numbers in this study, further confirmation of the patterns is needed.

Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases.

Amplification and overexpression of the c-myc gene have been associated with neoplastic transformation in a plethora of malignant tumours. We applied interphase fluorescence in situ hybridization (FISH) with a locus-specific probe for the c-myc gene (8q24) in combination with a corresponding chromosome 8 alpha-satellite probe to evaluate genetic alterations in 8 primary melanomas and 33 advanced melanomas and compared it to 12 melanocytic nevi, 7 safety margins and 2 cases of normal skin. Additionally, in metaphase spreads of 7 melanoma cell lines a whole chromosome 8 paint probe was used. We investigated the functionality of the c-myc gene by detecting c-myc RNA expression with RT-PCR and c-myc protein by immunohistochemistry. 4/8 primary melanomas and 11/33 melanoma metastases showed additional c-myc signals relative to the centromere of chromosome 8 copy number. None of the nevi, safety margins or normal skin samples demonstrated this gain. In 2/7 melanoma cell lines (C32 and WM 266-4) isochromosome 8q formation with a relative gain of c-myc copies and a loss of 8p was observed. The highest c-myc gene expression compared to GAPDH was found in melanoma metastases (17.5%). Nevi (6.6%) and primary melanomas (5.0%) expressed the c-myc gene on a lower level. 72.7% of the patients with c-myc extra copies had visceral melanoma metastases (UICC IV), patients without c-myc gain in 35.0% only. The collective with additional c-myc copies also expressed the gene on a significantly higher level. These results indicate that a c-myc gain in relation to the centromere 8 copy number might be associated with advanced cutaneous melanoma.

[Improving textile sun protection by regular washing of clothing]. / Verbesserung des textilen Sonnen- schutzes durch regelmässiges Waschen der Kleidung. Ein innovatives Konzept.

The highest priority in the prevention of malignant tumors of the skin is given to the avoidance of sun-induced reddening of the skin and sunburn at any age. The usual recommendation is to keep out of the sun between 11 am and 3 pm, wear a sun-hat and appropriate clothing, and use a sun screen (UV-A and UV-B) that doesn't wash off on exposed skin and when in the water. With regard to the wearing of clothing protecting against UV radiation, compliance must be expected to be low, since just such protective clothing (in particularthick, densely-woven materials) is unsuitable for the summer. Using detergents containing a UV absorber in the home wash, even light summer wear can be made to offer good UV protection.

Calcipotriol vs. tazarotene as combination therapy with narrowband ultraviolet B (311 nm): efficacy in patients with severe psoriasis.

BACKGROUND: Phototherapy has been shown to be one of the most effective treatment modalities for patients with psoriasis. Nevertheless, photocombination therapies capable both of reducing cumulative ultraviolet (UV) doses and of accelerating clearance of skin lesions are important and of high interest. There have been no published studies comparing the effect of narrowband UVB irradiation in combination with topical application of tazarotene vs. calcipotriol. OBJECTIVES: To determine, in a half-side manner, whether a combination of UVB (311 nm) and tazarotene is superior to UVB (311 nm) plus calcipotriol or vice versa. METHODS: Ten patients suffering from widespread symmetrical psoriasis were treated for at least 4 weeks with topical calcipotriol and tazarotene in a half-side distribution. Additionally, the whole body was irradiated with narrowband UVB (311 nm) four times a week. Before treatment and once weekly during therapy a modified Psoriasis Area and Severity Index was estimated for each body half. The total treatment time, number of treatment sessions and cumulative UVB dose necessary for clearance of skin lesions were determined in an observer-blind fashion for each patient. Furthermore, all patients completed a quality of life questionnaire. RESULTS: Clearance of psoriasis was observed after a median of 19 treatment sessions (range 14-28) and a median cumulative UVB dose of 22.98 J cm-2 (range 9.24-58.22) simultaneously for both body halves. On the side treated with topical tazarotene gel, four patients complained of itching and dryness of the skin, and skin irritation was observed in three of them. Six patients preferred the application of tazarotene gel, while four preferred calcipotriol. CONCLUSIONS: Our clinical comparison of narrowband UVB with either topical calcipotriol or topical tazarotene revealed no significant therapeutic difference between both regimens. Although these results need to be confirmed in larger patient groups, we feel that both photocombination therapies can broaden the therapeutic options for moderate to severe psoriasis vulgaris and may reduce the cumulative UVB dose during therapy.

Trauma and melanoma formation: a true association?

BACKGROUND: Little is known about the role of mechanical trauma in the pathogenesis of malignant melanoma. In individual patients, traumatic events have been discussed as a causative factor for the induction of melanoma and diagnosis of melanoma following trauma may raise medico-legal questions. OBJECTIVES: To evaluate the relationship between traumatic single or recurrent events and melanoma characteristics. METHODS: Retrospective questionnaire in 369 melanoma patients. RESULTS: A large number of patients (337 of 369; 91.3%) denied an association between a possible traumatic event and melanoma formation. Thirty-two of 369 patients (8.7%) considered an association of trauma and melanoma formation likely. Of these 32 patients, 22 patients (13 men, nine women) reported a single event, and 10 patients (four men, six women) a persisting irritation. An irritation of a pre-existing melanocytic naevus was reported by two patients with histologically confirmed melanoma on acquired or congenital naevus. CONCLUSIONS: As most of the patients who mentioned a trauma in this study suffered from acral melanoma, or melanoma located on the extremities, a history of trauma should be expected more frequently at these body sites. A review of epidemiological, clinical and scientific research indicates that there seems to be no evidence for single or persistent traumatic events as a causative factor for melanoma formation.