[Electrochemotherapy in metastatic melanoma]. / Elektrokemoterápia áttétes melanomában.

INTRODUCTION: In metastatic melanoma, despite the increased survival rates with new innovative therapies, therapeutic response is still quite heterogenous, not always durable. In the case of oligoprogression, several additional therapeutic modalities are available such as electrochemotherapy in the local treatment of cutaneous or subcutaneous metastases. OBJECTIVE: Analysis of our experiences with electrochemotherapy in patients with metastatic melanoma. METHOD AND RESULTS: 23 patients with metastatic melanoma (10 male and 13 female) were treated with electrochemotherapy, between 2016 and 2021 in our Institute. Median age was 74.5 years. The location of metastases varied. 13 of our patients (57%) had metastases on the lower limbs, in 5 cases (22%) metastases were located in the head and neck region, in 4 cases (17%) on the upper limbs, and one (4%) patient received electrochemotherapy for metastases located on the chest. Prior to electrochemotherapy, 7 patients (30%) received chemotherapy, 6 patients (26%) were treated with immunotherapy and 2 patients (9%) received targeted therapy, while electrochemotherapy was first-line treatment for 8 patients (35%). Complete remission was achieved in 12 cases (52%), and partial remission in 6 cases (26%). In 1 case (4%) stable disease was observed, and in 4 patients (35%) progression was detected. We continued the previous systemic therapy which was effective in other localizations after the electrochemotherapy in 8 patients (35%) and in the case of 4 patients (17%) no further systemic therapy was needed. Side effects were observed in 8 patients (35%), 1 had severity of G3. CONCLUSION: Electrochemotherapy in melanoma results in effective local tumor control, improved quality of life, and survival advantage in most of the patients, with tolerable side effects. Orv Hetil. 2023; 164(35): 1381-1386.

Therapeutic and Adverse Effect of Anti-PD1 Immunotherapy in Melanoma: A Retrospective, Single-Institute Study of 222 Patients.

BACKGROUND: The introduction of immuno- and targeted therapeutic modalities meant a breakthrough step in the therapy of melanoma. As a checkpoint inhibitor, the more effective and less toxic anti-PD1 therapy followed an anti-CTLA4 approach. METHODS: From our patient pool, 222 advanced melanoma cases were selected, where anti-PD1 (pembrolizumab, nivolumab) therapy was initiated between March 2015 and December 2020. During our retrospective analysis, the efficacy and safety of the therapy were assessed. RESULTS: The median follow-up was 16 months (interval: 0-64 months), and 150 patients (67.6%) received therapy in the first line, while second and third line therapy was performed among 72 patients (32.4%) for the median of 7.0 months (0-60). In 50 cases, BRAF mutations were detected. Ninety-six patients showed objective response (11.3% CR, 32.0% PR). The median PFS was 10.0 months (0-60), and the median OS was 23.0 months (0-64). Autoimmune side effects were found in 79 patients (35.5%); grade 3 occurred in 6.3% of the cases, while 1 patient died due to fulminant pneumonitis (0.25%). CONCLUSION: Although the range of immunotherapeutic options is getting wider, in the management of melanoma patients, anti-PD1 monotherapy remains an important, effective, and safe method. However, significant correlation was found between the immune-related side effects and therapeutic efficacy.

Atezolizumab for the treatment of advanced recurrent basal cell carcinoma and urothelial carcinoma of bladder: a case report.

BACKGROUND: The use of checkpoint inhibitors has become increasingly important in the treatment of different cancers, including advanced muscle-invasive urothelial cancer and even in basal cell carcinoma. We present the case of a patient with advanced basal cell carcinoma and metastatic muscle-invasive urothelial cancer, who was treated with the programmed death-ligand 1 inhibitor, atezolizumab for both cancers. CASE PRESENTATION: A 72-year-old Caucasian female patient, with a history of smoking without any comorbidities developed periocular basal cell carcinoma, which was surgically removed but relapsed 4 years later. Surgical excision was carried out twice, but with positive margins, therefore definitive radiotherapy was given. Subsequently, the patient developed non-muscle-invasive papillary urothelial carcinoma, which was removed by transurethral resection. Follow-up was irregular owing to the patient's inadequate compliance, and within 2 years, the patient's cancer relapsed and histology confirmed muscle-invasive urothelial carcinoma. Definitive radiochemotherapy was not accepted by the patient. Meanwhile, the patient's basal cell carcinoma had also progressed, despite receiving vismodegib therapy. Therefore, the patient was administered epirubicin-cisplatin. Having reached the maximum cumulative dose of epirubicin, treatment with this chemotherapeutic agent could not be continued. The patient developed bladder cancer metastasis in her left suprainguinal lymph nodes. Owing to the presence of both types of tumors, programmed death-ligand 1 inhibitor atezolizumab treatment was chosen. In just over 1 year, the patient received 17 cycles of atezolizumab altogether, which was tolerated well without any adverse or side effects. Follow-up imaging scans indicated complete remission of the metastatic bladder cancer and stable disease of the basal cell carcinoma. The patient subsequently passed away in hospital due to a complication of COVID-19 infection. CONCLUSIONS: Our patient attained stable disease in advanced basal cell carcinoma and complete remission in metastatic muscle-invasive urothelial cancer after receiving programmed death-ligand 1 inhibitor, atezolizumab, therapy. To our knowledge, this is the first paper to report the use of programmed death-ligand 1 inhibitor, atezolizumab, as treatment for advanced basal cell carcinoma. This case may also be of interest for clinicians when treating patients with two synchronous cancers.

The Role of Stereotactic Radiotherapy in the Management of Melanoma, A Retrospective Single Institute Preliminary Study of 30 Patients.

Cutaneous melanoma is the third most common type of skin cancer in the world. The incidence of melanoma is increasing in most countries, however, mortality seems to be slowly decreasing. The treatment of advanced cutaneous melanoma changed radically since 2011. The new therapeutic modalities, such as immuno- and targeted therapies give a chance to successfully reach more prolonged progression-free survival (PFS) and overall survival (OS) in patients with metastatic melanoma. Despite the great therapeutic benefit, most patients eventually develop resistance to these therapies, and the disease will progress. In some cases oligoprogression develops. In those cases local therapy, such as stereotactic radiotherapy can make it possible to continue the previously applied effective medical treatment for the benefit of patients. In our study of a total of 30 patients-20 of them received pre-treatment with systemic medical therapy-received stereotactic radiotherapy using various systems, in the National Institute of Oncology, Hungary, Budapest. We managed to prolong the systemic therapy for 12.5 months median period with the assistance of CyberKnife technique. Therapy related adverse events were mostly tolerable with only 3% of Grade 3 toxicity. We concluded that stereotactic radiotherapy and stereotactic radiosurgery, are safe, and effective therapeutic modalities for regional tumor control in cases of oligoprogression.

[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.

[Actual points of melanoma management]. / Néhány aktuális kérdés melanómában.

The development of the therapy of advanced melanoma resulted in significant improvement of disease outcome; over 6 years of median survival was reached in the CheckMate 067 study. The new therapeutic modalities are already implemented in the clinical practice according to the current guidelines, however some diagnostic and therapeutic questions are still unresolved. We aimed to highlight the topic of therapeutic options for BRAF mutated melanomas, the role of PD-L1 ligand examination, the adequate therapy of oligoprogression, and the current indication of sentinel lymph node biopsy.

[COVID-19 and melanoma: a single center retrospective cohort study from Hungary]. / Covid-19 és a melanóma: egy év tapasztalatai az Országos Onkológiai Intézetben.

COVID-19 pandemic affected the diagnosis and management of many diseases, including the most vulnerable group of patients with cancer. In this retrospective survey we evaluated the course of disease of patients treated for melanoma, who got infected with COVID-19 virus between March 2020 and April 2021. 382 patients had been treated for advanced melanoma in our center in this time period. 24 of them had been infected with coronavirus. Six of them suffered in stage III melanoma, the remaining 18 patients had stage IV disease. 14, 5 and 4 of the infected patients had been administered with checkpoint inhibitor, targeted therapy and chemotherapy, respectively. Seven (29%) patients died in COVID-19 infection, in a median of 12 days. None of our patients who had been vaccinated at least one time, had severe symptoms. As a conclusion, the mortality of COVID-19 infection was significantly higher among our melanoma patients compared to the age-standardized mortality rate in Hungary.

HLA Class I Downregulation in Progressing Metastases of Melanoma Patients Treated With Ipilimumab.

Characterization of the molecular mechanisms underlying antitumor immune responses and immune escape mechanisms has resulted in the development of more effective immunotherapeutic strategies, including immune checkpoint inhibitor (ICI) therapy. ICIs can induce durable responses in patients with advanced cancer in a wide range of cancer types, however, the majority of the patients fail to respond to this therapy or develop resistance in the course of the treatment. Information about the molecular mechanisms underlying primary and acquired resistance is limited. Although HLA class I molecules are crucial in the recognition of tumor antigens by cytotoxic T lymphocytes, only a few studies have investigated the role of their expression level on malignant cells in ICI resistance. To address this topic, utilizing immunohistochemical staining with monoclonal antibodies (mAbs) we analyzed HLA class I expression level in pre-treatment and post-treatment tumor samples from melanoma patients treated with ipilimumab. Twenty-nine metastases removed from six patients were available for the study, including 18 pre-treatment and 11 post-treatment lesions. Compared to metastases excised before ipilimumab therapy, post-treatment lesions displayed a significantly lower HLA class I expression level on melanoma cells; HLA class I downregulation was most marked in progressing metastases from nonresponding patients. We also evaluated the level of infiltration by CD8+ T cells and NK cells but did not find consistent changes between pre- and post-treatment samples. Our results indicate the potential role of HLA class I downregulation as a mechanism of ICI resistance.

Súlyos Covid-19-fertozés disszeminált melanómás betegnél, immunterápiát követoen.

The COVID-19 pandemic has created significant barriers to the treatment of cancer patients requiring regular hospitalisation, as coronavirus infection significantly increases the risk of serious and even fatal complications. In our case report, a middle-aged patient with advanced melanoma has developed immune-mediated pancreatitis after more than a year of pembrolizumab treatment. After changing the therapy, the patient was diagnosed with coronavirus infection, which led to nearly a month of hospitalisation and rehabilitation, thus suspending active oncotherapeutical treatment. Thanks to professional medical care, our patient successfully recovered from the severe COVID-19 pneumonia caused by the infection, even in the absence of a coronavirus vaccine. After recovery, he received two Pfizer- BioNTech vaccines in August and September 2021, and a follow-up CT scan showed almost complete remission. Given the patient's lack of complaints and the absence of tumours other than two residual pulmonary nodules, he was observed afterwards. Our patient was in a serious condition before the vaccines were introduced, but has recovered thanks to professional medical care.

Role of the anatomic site in the association of HLA class I antigen expression level in metastases with clinical response to ipilimumab therapy in patients with melanoma.

BACKGROUND: The clinical response to immune checkpoint inhibitors (ICIs) in only part of the treated patients, in conjunction with the potentially serious side effects associated with this type of therapy, has emphasized the need to identify biomarkers to select patients who may benefit from ICI treatment. The aim of our study was to test human leukocyte antigen (HLA) class I and II expression in melanoma metastases as potential biomarkers of response to ipilimumab and survival in patients with metastatic melanoma, since these molecules play a crucial role in the interactions of malignant cells with host's immune system. MATERIALS AND METHODS: HLA class I and II antigen expression level in pretreatment surgical tissue samples (50 lymph node and 35 cutaneous or subcutaneous metastases) from 30 patients was analyzed by immunohistochemical staining with monoclonal antibodies. Expression levels were correlated to intratumoral density of lymphocytes expressing cluster of differentiation (CD)8, CD45RO, CD4, forkhead box P3 (FOXP3) and/or programmed cell death protein 1 (PD-1), to clinical response to treatment, and to patients' survival. RESULTS: HLA class I antigen expression level in lymph node metastases, but not in cutaneous or subcutaneous metastases was significantly correlated to density of CD8+ and CD45RO+ T cells and of lymphocytes expressing PD-1, as well as to clinical response and to patients' survival. CONCLUSIONS: Our results corroborate the role of HLA class I expression level (alone or in combination with T-cell density values) as a predictive biomarker of response to ipilimumab in patients with melanoma. In addition, our results show that this association is influenced by the anatomic site of the metastasis used to measure the HLA class I antigen expression level.

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.

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.

Challenging tumour immunological techniques that help to track cancer stem cells in malignant melanomas and other solid tumours.

AIM OF THE STUDY: The arsenal of questions and answers about the minor cancer initiating cancer stem cell (CSC) population put responsible for cancer invasiveness and metastases, has left with an unsolved puzzle. Specific aims of a complex project were partly focused on revealing new biomarkers of cancer. We designed and set up novel techniques to facilitate the detection of cancerous cells. MATERIALS AND METHODS: As a novel approach, we investigated B cells infiltrating breast carcinomas and melanomas (TIL-B) in terms of their tumour antigen binding potential. By developing the TIL-B phage display technology we provide here a new technology for the specific detection of highly tumour-associated antigens. Single chain Fv (scFv) antibody fragment phage ELISA, immunofluorescence (IF) FACS analysis, chamber slide technique with IF confocal laser microscopy and immunohistochemistry (IHC) in paraffin-embedded tissue sections were set up and standardized. RESULTS: We showed strong tumour-associated disialylated glycosphingolipid expression levels on various cancer cells using scFv antibody fragments, generated previously by uniquely invasive breast carcinoma TIL-B phage display library technology. CONCLUSIONS: We report herein a novel strategy to obtain antibody fragments of human origin that recognise tumour-associated ganglioside antigens. Our investigations have the power to detect privileged molecules in cancer progression, invasiveness, and metastases. The technical achievements of this study are being harnessed for early diagnostics and effective cancer therapeutics.

Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy.

Monoclonal antibodies targeting immune checkpoints are gaining ground in the treatment of melanoma and other cancers, and considerable effort is made to identify biomarkers predicting the efficacy of these therapies. Our retrospective study was performed on surgical tissue samples (52 lymph nodes and 34 cutaneous/subcutaneous metastases) from 30 patients with metastatic melanoma treated with ipilimumab. Using a panel of 11 antibodies against different immune cell types, intratumoral immune cell densities were determined and evaluated in relation to response to ipilimumab treatment and disease outcome. For most markers studied, median immune cell densities were at least two times higher in lymph node metastases compared to skin/subcutaneous ones; therefore, the prognostic and predictive associations of immune cell infiltration were evaluated separately in the two groups of metastases as well as in all samples as a whole. Higher prevalence of several immune cell types was seen in lymph node metastases of the responders compared to non-responders, particularly FOXP3+ cells and CD8+ T lymphocytes. In subcutaneous or cutaneous metastases, on the other hand, significant difference could be observed only in the case of CD16 and CD68. Associations of labeled cell densities with survival were also found for most cell types studied in nodal metastases, and for CD16+ and CD68+ cells in skin/s.c. metastatic cases. Our results corroborate the previous findings suggesting an association between an immunologically active tumor microenvironment and response to ipilimumab treatment, and propose new potential biomarkers for predicting treatment efficacy and disease outcome.

[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.

The novel panel assay to define tumor-associated antigen-binding antibodies in patients with metastatic melanomas may have diagnostic value.

We aim to harness the natural humoral immune response by various technologies to get novel biomarkers. A complex antibody analysis in sera and in the tumor microenvironment leads to reveal tumor-specific antibodies. More strategies were introduced to select the most effective one to identify potential tumor antigen-binding capacity of the host. Epstein-Barr virus transformation and cloning with limiting dilution assay, magnetic cell sorting and antibody phage display with further methodological improvements were used in epithelial and neuroectodermal cancers. Column-purified sera of patient with melanoma were tested by immunofluorescence assay, while sera of further melanoma patients were processed for membrane-binding enzyme-linked immunosorbent assay. Some supernatants of selected B cell clones and purified antibodies showed considerable cancer cell binding capacity by immunofluorescence FACS analysis and confocal laser microscopy. Our native tumor cell membrane preparations helped to test soluble scFv and patients' sera for tumor binder antibodies. A complex tumor immunological study was introduced for patients with melanoma (ethical permission: ETT TUKEB 16462-02/2010); peripheral blood (n = 57) and surgically removed primary or metastatic tumors (n = 44) were gathered and processed at cellular immunological level. The technological developments proved to be important steps forward to the next antibody profile analyses at DNA sequence level. Cancer cell binding of patient-derived antibodies and natural immunoglobulin preparations of pooled plasma product intravenous immunoglobulins support the importance of natural human antibodies. Important cancer diagnostics and novel anticancer strategies are going to be built on these tools.

[Unblocking antitumor immune response: novel possibilities for the immunotherapy of melanoma]. / Az immunválasz "akadálymentesítése": újabb lehetõségek a melanóma immunterápiájában.

Recent advances in tumor immunology, a better understanding of mechanisms regulating the immune response has led to experimental and clinical testing of a novel type of immunotherapeutics: antibodies blocking negative regulatory mechanisms of T-cell activation [corrected]. The application of the CTLA-4 antagonist ipilimumab, the prototype of this new class of immune stimulating agents, represents the first treatment that resulted in significant prolongation of the survival of metastatic melanoma patients in randomized, controlled trial, leading to the approval of its use for the therapy of these patients in 2011. Together with the BRAF inhibitor vemurafenib, which was also approved in 2011, ipilimumab has changed the standard therapy of metastatic melanoma, and also paved the way for other agents aiming at influencing immune regulating molecules, of which antibodies blocking the PD-1 pathway also showed promising clinical activity. According to clinical experience collected so far, these agents induce objective tumor response in a relatively small proportion of patients, with a characteristic response kinetics frequently showing delayed activity, but resulting in durable remission in a considerable proportion of the responding patients. On the other hand, antitumor activity is frequently accompanied by significant toxicity. The spectrum of side effects is different from that of conventional therapies, and a large part of them is caused by the enhanced systemic immune activity. In order to spare non-responding patients of the severe side effects and to increase response rate, the search for biomarkers that could help in identifying patients likely to react to the treatment represents an important focus of studies. Furthermore, development of combinations with other immunotherapeutic modalities, chemo- or targeted therapies may further increase the efficiency of immunomodulatory antibodies.

[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.

[Epidemiology of malignant melanoma (Clinical experience at the National Institute of Oncology in Hungary)]. / A melanoma malignum epidemiológiája (Klinikai tapasztalatok az Országos Onkológiai Intézetben).

UNLABELLED: The National Cancer Registry, which has been running since 1999 in Hungary, supplies more and more precise data about the growing incidence of malignant melanoma although nationwide melanoma database currently does not exist. As in the National Institute of Oncology a notable percentage of patients (20-25%) were treated with newly diagnosed melanoma, conclusions may be drawn for the efficacy of primary prevention for the whole country. METHODS: The recent study compares the data of patients presented in the Institute with cutaneous malignant melanoma in 1998 and ten years later, in 2008. The histology parameters of tumors were also analyzed. The two groups were compared according to age, gender, localization and histology parameters (histological types Breslow and Clark numbers). In case of continuous variables the Mann-Whitney test were used to determine significant differences. Categorical variables were checked by χ2 test. RESULTS: 149 and 377 cutaneous melanomas were diagnosed in 1998 and in 2008, respectively, which accounts for 153% increase in ten years. The mean age of patients was 56.3 and 57.2 years in 1998 and in 2008, respectively. The per cent of males was 43% in 1998 and 49% in 2008. Trunk was the most frequent localization in both years: 39% and 46%, then lower limbs (28% and 22%), upper limbs (21% and 18%) and the head and neck region (12% and 14%). Superficial melanoma was found the most frequent histological type (52 and 54%) followed by nodular melanoma (31% and 23%). Rate of in situ melanoma changed from 10% to 15%. The mean of Breslow numbers was 2.2 mm in 1998 and 1.6 mm in 2008, the difference was highly significant (p = 0.0002). Clark numbers were also decreasing, although the difference was not significant (p = 0.08). The majority of patients were presented with Clark III depth melanoma in both years (38% and 32%). CONCLUSIONS: It seems that forces emphasizing the importance of early recognition in medical education and in media are not futile considering that principally the early diagnosis can improve the melanoma's prognosis - which is represented mainly by Breslow tumor depth.