[BRAF-MEK inhibitor therapy in melanoma]. / BRAF-MEK gátló terápiával elért eredményeink 118, metasztatikus melanómában szenvedo betegnél az Országos Onkológiai Intézetben.

We investigated the efficacy and safety of vemurafenib+cobimetinib (V+C) and dabrafenib+trametinib (D+T) based on real-life data. From 2015 and 2018 we have selected 118 BRAF-mutated metastatic melanoma patients, treated with V+C and D+T in our institute. We retrospectively analyzed the overall response rate (ORR), the progression-free survival (PFS), the overall survival (OS) and the adverse events of the therapies. The median follow-up time was 18 months (3-43) with V+C and 12 months (3-43) with D+T. The median PFS was 8 months in the V+C and 8.5 months in the D+T group. Median OS was 18 months in V+C group and 12 months with D+T. The ORR was revealed to be 82% in D+T group and 76% in V+C group. Each combination displayed a slightly different safety profile. In our retrospective analysis both BRAF-MEK inhibitor combination therapies showed favorable efficacy with a slightly different spectrum of toxicity profile.

Epileptic Seizure Provoked by Bone Metastasis of Chronic Lymphoid Leukemia and Merkel Cell Carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare primary neuroendocrine cutaneous tumor, rarely metastasizing to the brain. Chronic lymphoid leukemia (CLL) is a disease predisposing to MCC. According to previous reports, headache and focal neurological deficits suggest disease progression to the brain. We present a patient with MCC whose seizure was not elicited by a cerebral metastasis, but by bone metastases compressing the brain. Case Presentation. A 62-year-old female patient had a history of CLL. A lesion with the appearance of an atheroma was removed from the right upper arm. Histology confirmed the diagnosis of MCC. She was admitted to the neurology department with her first GM seizure. The cranial MRI/MRA showed bone metastases in the right parietal and both frontal areas, compressing the brain. Flow cytometry of CSF did not reveal metastasis of MCC. CONCLUSIONS: The case history of the patient was unique even among the rare cases of MCC with neurological involvement. The seizure was not elicited by a cerebral metastasis, but by bone metastases compressing the brain. In addition to patient history, clinical presentation and radiological findings enabled a suspected diagnosis of skull metastasis of MCC compressing the brain, causing symptomatic epileptic seizures.

Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab.

Ipilimumab was the first immunotherapy approved for metastatic melanoma in decades and is currently registered as a second-line treatment. However, new immunotherapies, in combination with ipilimumab, offer even better clinical outcomes for patients compared with single-agent treatments, at the expense of improved toxicity. The aim of this study was to evaluate the feasibility of ipilimumab outside the clinical trials and to identify survival predictors for treatment benefit. Data were collected on 47 advanced melanoma patients treated with ipilimumab between 2010 and 2015 at a single center. Association of clinical characteristics (including primary tumor characteristics), serum lactate dehydrogenase (LDH), erythrocyte sedimentation rate, absolute eosinophil, lymphocyte, and neutrophil count, neutrophil/lymphocyte and eosinophil/lymphocyte ratio with toxicity and clinical outcome were assessed using univariate and multivariate analysis. Median progression-free survival at a median follow-up of 10 months was 2.7 months and median overall survival was 9.8 months. Objective response was observed in 17% of patients and the disease control rate at week 24 was 40%. The 1- and 2-year survival rates documented were 40 and 28%, respectively. Significant association between high LDH level (>1.5× upper limit of normal) and decreased overall survival was demonstrated in uni- and multivariate analysis (hazard ratio [HR]: 3.554, 95% CI: 1.225-10.306, p = 0.019). Neither biomarkers nor clinical outcome were associated with toxicity. Using baseline serum LDH to identify patients most likely to benefit from ipilimumab therapy could serve as a simple and inexpensive biomarker of clinical outcome.

[Mucosal melanoma primary and metastatic cases with urogenital localization in our department]. / Urogenitalis lokalizációjú mucosamelanoma primer és áttétes esetei klinikánkon.

INTRODUCTION: Both primary and metastatic cases of mucosal melanoma in urogenital localization are rare tumors. Only 4-5% of all primary melanomas do not arise from the skin. Extracutaneous melanomas have a complex clinical presentation, but these aggressive tumors have a poor prognosis. MATERIALS AND METHOD: In our department, we found 7 patients with malignant melanoma of the genitourinary tract in the past few years. The 7 cases were: primary amelanotic melanoma of the female urethra, a primary melanoma of the bladder, two primary melanomas of the penis, a metastatic melanoma of the urethra and another to the testis and a metastatic melanoma of the bladder with melanuria. We retrospectively analyzed the available data to describe the presentation, management, and clinical outcome of the patients. RESULTS: In the three inoperative cases, palliative, urologic surgical procedures and systemic antitumor therapy were performed. Two of the four primary urogenital tumors were localized to the penis. In one case, local recurrence developed after surgical treatment, but with a radical, repeated surgery, the patient has been asymptomatic for a year and a half. In the other, neglected case, the penis melanoma spread through the urethra and the inguinal lymph nodes two years after radical surgery and inguinal block dissection. In the female primary urethral melanoma case, the first histological study reported a primary mesenchymal tumor, and the recurrent tumor that occurred one and a half years later showed melanoma diagnosis. Radical surgery performed because of urethral involvement resulted in a 5-year asymptomatic state, followed by local recurrence and distant metastasis. In the fourth case of a primary bladder melanoma, the rapid progression of the disease and the BRAF positivity of the tumor suggested that not the firstly diagnosed bladder melanoma was the primary tumor. CONCLUSION: The occurrence of urinary tract melanoma is very rare and its discovery happens often in a disseminated state, so the expected prognosis of the cases is also poor. The most important factors for increasing therapeutic efficacy are early diagnosis and radical surgical intervention. Tumors appearing in different localizations require different urological surgical approaches. The literature recommendations for treatment are not uniform. Their prognosis is worse compared to the cutaneous melanoma, which may be due to clinical and pathological diagnostic difficulties. The latest targeted and immunotherapeutic agents can significantly improve the survival of metastatic patients. Orv Hetil. 2019; 160(10): 378-385.

Efficacy of Vemurafenib Treatment in 43 Metastatic Melanoma Patients with BRAF Mutation. Single-Institute Retrospective Analysis, Early Real-Life Survival Data.

BRAF inhibitor vemurafenib achieved improved overall survival over chemotherapy and have been approved by the FDA and EMA for the treatment of BRAF-mutated metastatic melanoma. The aim of our retrospective analysis was to determine the efficacy and safety of vemurafenib therapy for BRAF mutated metastatic melanoma and subsequently to prove the clinical benefit for the studied 43 patients, based on real-life data. From November 2012 to October 2015 we have selected 43 BRAF mutated, metastatic melanoma patients, treated with vemurafenib. The median follow-up time was 15.9 months. We evaluated progression free survival (PFS), overall survival (OS) and toxicities. According to the AJCC staging system 70% of the patients had stage M1c metastasis, including 6 with stable brain metastasis. Objective responses were noted in 51.1%, the disease control rate was achieved in 79% of the patients. Complete responses were attained by 5 patients (11.6%). Median PFS was 6.48 (95% CI:4.8-15.0) months, median OS was 11.47 (95% CI:8.08-NA) months. We found significant association between LDH level and OS in univariate (p = 0.000613) and multivariate analysis (p = 0.0168). The most common adverse events (AEs) included follicular hyperkeratosis, rash, arthralgia and photosensitivity. Grade 3 AEs, such as cutaneous squamous-cell carcinoma, QTcB interval prolongation, rash, arthralgia were reported in 7 patients (17%). We had no Grade 4 side effects. Similar to the previously published data our analysis confirms the improved survival with vemurafenib treatment (11.47 months) in patients with BRAF V600 mutation. Vemurafenib therapy was well tolerated, the AE profile was almost consistent with the previously reported data of randomised clinical trials.

[Treatment of metastatic progression following the synchronous occurrence of cutaneous and ocular primary melanomas]. / Metasztatikus progresszió kezelése primer cutan és ocularis melanoma szinkrón elofordulását követoen.

The incidence rates of cutaneous melanoma in non-Hispanic whites show an increasing tendency with age. While uveal melanoma in general is a rare disease, representing only 4% of all melanomas with an incidence rate of 0.6 per 100 000, it is still the most frequent malignancy of the eye. Synchronous occurrence of ocular and cutaneous melanoma is an exceptional rarity, due to the distinct genetic background of the diseases. We report the case of a 80-year-old man who underwent total excision of a cutaneous melanoma in 2008. In 2013, he was diagnosed with uveal melanoma as part of a routine work-up for reduced vision. The uveal melanoma was treated by brachytherapy. In 2015, liver metastases were suspected by routine ultrasonography. Core biopsy was carried out, and the histology confirmed melanoma metastases. The molecular analysis of the cutaneous lesion showed gain of function mutation of the BRAF V600 K gene, while we found a wild-type BRAF gene in the metastatic lesion. Based on the recommendation of the oncoteam, hepatic intra-arterial Epirubicin-Platidiam therapy was introduced. He received 11 doses of intra-arterial chemotherapy (IAC), in 21 cycles. IAC was well tolerated without any catheter-related complications or toxicities. Partial regression of the hepatic metastases were documented in February 2016. After completing the eleventh cycle of intrahepatic chemotherapy, the disease remained in complete remission for over a year. The parallel occurrence of cutaneous and ocular melanoma is rare, however, the metastatic progression in such cases make the selection of optimal medical therapy challenging. The distinct genetic background of two melanoma types may help the identification of the source of the metastatic lesions, in order to guide the treatment decisions. Orv Hetil. 2018; 159(16): 642-647.

[Psychological aspects of immunotherapies in the treatment of malignant melanoma]. / Immunterápiák pszichológiai vonatkozásai a melanoma komplex és multidiszciplináris kezelésében.

Psychological problems may arise in connection with oncomedical treatments in three ways: 1. acute and/or 2. chronic ways, as well as 3. co-morbid psychiatric diseases that already exist must also be taken into account. Immunotherapies have the most common and also clinically relevant psychological side effects. Fatigue, anhedonia, social isolation, psychomotor slowness is reported during treatment. Anti-CTLA-4 antibody (ipilimumab) immunotherapy can present one of the most modern opportunities for adequate treatment for patients having distant metastasis or unresectable tumour. In relation to immunotherapies, acute psychological side effects (acute stress) emerging during treatments develop in a way that can mostly be linked to environmental factors, e.g. notification of diagnosis, hospitalisation, progression, deterioration in quality of life, imminent dates of control. Crisis is a temporary and threatening condition that endangers psychological balance. In such conditions, enhanced psychological vulnerability must be taken into account and doctors play a key role in the rapid recognition of the condition. Chronic psychological problems, which may arise from the depressogenic effect of the applied treatment or originated from a pre-melanoma psychiatric condition, may exceed the diagnostic and psychotherapeutic competences of a clinical psychologist. Even in case of a well-defined depressogenic biological mechanism such as the activation of the pro-inflammatory cytokine pathway, positive environmental effects can reduce symptoms and thus increase compliance. Side effects can be treated successfully using psychotherapeutic methods and/or psychiatric medicines. The application of routinely used complex psychosocial screening packages can provide the easiest method to identify worsening psychological condition during immunotherapy and give rapid feedback to the oncologist and the patient. Team work is of particular importance in a situation like this as it requires complex, interdisciplinary and high-level professional collaboration. Multidisciplinarity is the basic framework for modern tumour therapy where, under the guidance of oncologists, the work of specialist nurses, social workers, physiotherapists, dieticians and last but not least psychiatrists/psychologists are indispensable and play a significant role.

Social support decreases depressogenic effect of low-dose interferon alpha treatment in melanoma patients.

OBJECTIVE: The most frequent serious psychological side effect of immune therapies is depression. In the present study, we tested whether social support, as a positive environmental effect, is able to moderate depression or anxiety symptoms in melanoma patients during adjuvant low-dose interferon treatment. METHODS: Hundred and twenty-seven melanoma patients with negative psychiatric history were included in our longitudinal study and followed up for one year. Depression and anxiety symptoms were measured six times during treatment: at baseline, at 1st, 3rd, 6th, 9th and 12th month of the therapy. In addition, social support was investigated with the Social Dimension Scale. RESULTS: Depressive symptoms significantly increased during the 12-month follow-up period (p<0.001). However, social support significantly moderated the depressogenic effect of low-dose interferon treatment (p<0.001). Patients with better social support showed attenuated increase of depression. Anxiety showed no significant changes during the low-dose interferon treatment (p=0.230). Social support had no moderating effect on anxiety symptoms (p=0.745) during the follow up. DISCUSSION: Our data provide evidence that social support and interferon alpha treatment significantly interact in the development of depression. In addition, our study emphasises that enhancement of social support can reduce depressogenic side effects and increase compliance during adjuvant interferon treatment, and thus, psychological screening and psychooncological counselling should be incorporated in the treatment protocol.

Psychological changes in melanoma patients during ipilimumab treatment compared to low-dose interferon alpha therapy-a follow-up study of first experiences.

Immuntherapies are frequently accompanied by psychological side effects. Our goals were to detect the changes of psychological factors (depression, anxiety) among melanoma patients during ipilimumab treatment. Ten ipilimumab treated melanoma patients (Group 1.) and 18 low-dose interferon-alpha treated patients (Group 2.) were compared. In our longitudinal study we measured depression (Zung Self-Rating Depression Scale) and anxiety (State-Trait Anxiety Inventory, STAI). Psychological status was tested four times: in every 3 week during ipilimumab treatment according to the relevant treatment protocol and at baseline, 1st, 3rd and 6th month of interferon therapy. No significant differences were detected at different timepoints in the level of depression or in the anxiety scale in Group 1. However significant increase of depression was found in Group 2 during the 6 months of the study. Increased levels of anxiety were found in the second timepoint in both treatment groups. This increase was only temporary and the level of anxiety returned to the baseline. In our sample no measurable psychological differences were detectable during the 12 weeks treatment period of ipilimumab. Ipilimumab seems to have fewer psychological side-effects compared to other immune therapies.

[The importance of fine needle aspiration cytology in the management of recurrent and metastatic melanoma]. / Az aspirációs citológia jelentosége a recidiváló és metasztatizáló melanoma diagnosztikájában.

UNLABELLED: Fine needle aspiration cytology is a widely accepted, reliable diagnostic modality for the early detection of metastases. OBJECTIVE: Quality assurance analysis of fine needle aspiration cytology in melanoma patients. METHOD: A total of 194 biopsies performed in 142 melanoma patients were analyzed retrospectively. RESULTS: 138 (71.13%) cutaneous or subcutaneous nodules and 56 (28.87%) palpable lymph nodes were studied. 87 (44.85%) true positive, 92 (47.42%) true negative, 3 (1.55%) false positive and 12 (6.19%) false negative cytology results were found. High sensitivity (87.89%), specificity (96.84%) and diagnostic accuracy (93.72%) were confirmed. DISCUSSION: The quality assurance of fine needle aspiration biopsy in these patients with recurrent and metastatic melanoma meets the international requirements.