Wyniki leczenia wemurafenibem chorych na zaawansowanego czerniaka w ramach programu lekowego w Polsce

Introduction. Melanoma is a heterogeneous group of tumours with poor prognosis if the disease is metastatic. More than half of patients with melanoma of the skin have detectable mutations in the BRAF gene. Vemurafenib is the BRAF kinase inhibitor used in the treatment of patients with advanced melanoma with the BRAF mutation. This improves time to progression-free survival and overall survival in patients with this diagnosis. The aim of the study was to analyse the results of treatment and safety of vemurafenib in patients treated during the Polish drug programme. Materials and methods .Between October 2013 and April 2015 a total of 189 patients were treated, 90 women and 99 men, who had previously been diagnosed with unresectable/metastatic melanoma with BRAF V600 mutation. Patients received vemurafenib in 960 mg dose twice per day. The estimated progression-free survival, overall survival and adverse events were assessed. For the survival analysis the Kaplan-Meier method and log-rank test (log-rank) for multi-factor analysis were used. Results. In the first evaluation of the effectiveness of treatment, 8 patients (4.3%) had a complete response, 75 patients (39.7%) partial response, 62 patients (32.8%) had stable disease, and 44 patients (23.2%) had progression of the disease. The disease was controlled in 76.7% of patients. After progression during the therapy with vemurafenib 27% of the patients received subsequent lines of systemic therapy. Twenty-eight patients received chemotherapy and 22 patients immunotherapy with ipilimumab. During the last analysis dated 5 September 2015, the median observation time for still living patients was 8 months (range 3–26). Median progression-free survival was 6.7 months. The median overall survival was 12 months. 146 patients (77%) had adverse events, mostly in the form of dermal toxicity of Grades 1 and 2. Thirty-two patients (17%) presented with side effects of the 3rd and 4th grades of toxicity. Two patients had to stop the treatment due to the toxicity. There were no deaths reported due to the toxicity of treatment. Conclusions. The multicentre analysis confirmed the efficacy and safety of vemurafenib in routine clinical practice in a heterogeneous group of advanced melanomas with BRAF mutation. We confirmed the importance of the known prognostic factors for overall survival in this group of patients, such as lactate dehydogenaze activity (LDH) and ECOG performance status. The current survival of patients with the metastatic melanomas with BRAF mutations are longer than those observed in historical groups.  Wstęp. Czerniak należy do heterogennej grupy nowotworów o bardzo złym rokowaniu w przypadku rozsiewu choroby. U ponad połowy chorych na czerniaka skóry stwierdza się obecność mutacji w obrębie genu BRAF. Wemurafenib jest inhibitorem kinazy BRAF stosowanym w leczeniu chorych na zaawansowanego czerniaka z mutacją BRAF, który poprawia u nich czas przeżycia wolny od progresji choroby oraz przeżycia całkowitego. Celem pracy jest analiza wyników leczenia oraz bezpieczeństwa terapii wemurafenibem u chorych leczonych w ramach programu lekowego w Polsce. Materiały i metody. W okresie od października 2013 do kwietnia 2015 roku leczonych było 189 chorych (90 kobiet i 99 mężczyzn) z rozpoznaniem nieresekcyjnego/przerzutowego czerniaka z mutacją BRAF V600. Chorzy otrzymywali wemurafenib w dawce wyjściowej 960 mg dwa razy na dobę. Oceniano czas wolny od progresji choroby, czas przeżycia całkowitego oraz monitorowano działania niepożądane. Do analizy przeżycia użyto metody Kaplana-Meiera oraz testu logarytmicznego rang (log-rank) dla analiz dwuczynnikowych. Wyniki. W pierwszej ocenie skuteczności leczenia u 8 chorych (4,3%) stwierdzono całkowitą odpowiedź, u 75 chorych (39,7%) częściową odpowiedź, u 62 chorych (32,8%) stabilizację choroby, a u 44 chorych (23,2%) progresję choroby. Kontrolę choroby wykazano u 76,7% chorych. Po progresji w trakcie terapii wemurafenibem 27% chorych otrzymało kolejne linie leczenia systemowego — 28 chorych chemioterapię, 22 chorych ipilimumab. Podczas ostatniej analizy z dnia 5 września 2015 mediana czasu obserwacji dla żyjących chorych wyniosła 8 miesięcy (zakres 3–26). Mediana przeżycia wolnego od progresji wyniosła 6,7 miesiąca. Mediana czasu całkowitego przeżycia wyniosła 12 miesięcy. U 146 chorych (77%) stwierdzono działania niepożądane, głównie pod postacią toksyczności skórnej w stopniu 1. i 2., u 32 chorych (17%) objawy uboczne w 3.–4. stopniu toksyczności. U dwóch chorych zakończono leczenie z powodu toksyczności. Nie było zgonów spowodowanych toksycznością leczenia. Wnioski. Przeprowadzona analiza wieloośrodkowa potwierdziła skuteczność i bezpieczeństwo leczenia wemurafenibem w rutynowej praktyce klinicznej w heterogennej grupie zaawansowanych czerniaków z obecnością mutacji BRAF. Potwierdzono wagę znanych czynników prognostycznych dla całkowitego przeżycia w tej grupie chorych, takich jak aktywność dehydrogenazy mleczanowej (LDH) i wyjściowy stan sprawności wg ECOG. Obecne przeżycia chorych w grupie przerzutowych czerniaków z mutacją BRAF są dłuższe niż obserwowane w próbach historycznych.

Interakcje fluorków z wybranymi składnikami diety i farmakoterapeutykami - rola stresu oksydacyjnego

Wykaz publikacji będących przedmiotem rozprawy habilitacyjnej s. 7

Metabolic syndrome in peri - and postmenopausal women performing intellectual work

Introduction Metabolic Syndrome is a set of interrelated risk factors for the emergence and progression of cardiovascular disease and diabetes, such as central obesity (abdominal), elevated blood pressure and disorders of carbohydrate and lipid metabolism. Peri- and postmenopausal women are particularly at risk of developing MS, by aging and the loss of protective effect of estrogen on the body, additionally by intellectual work associated with a sedentary lifestyle and job stress. The aim of our study was to analyze the frequency of MS and its criteria in perimenopausal and postmenopausal women doing intellectual work, as well as selected factors on which metabolic syndrome depend. Material and methods The study group consist of 300 women aged 44–66 working intellectually. Research methods used: metabolic syndrome’s criteria, Greene Climacteric Scale, body fat accumulation, medical interview. Statistical methods used: logistic regression analysis, analysis of variance, χ2 test of stochastic independence. Results The MS was diagnosed in about ¼ of the women in perimenopausal and postmenopausal period working intelectually, in most of them abdominal obesity ( ¾ ), in more than a half hypertension, in every sixth hypertriglyceridemia, in every seventh hyperglycemia and in every tenth low HDL-C. Prevalence of MS and its criteria was correlated with BMI, body fat accumulation and parity. Prevalence of arterial hypertension was associated with the severity of menopausal symptoms and lack of physical activity. Conclusions Prevalence of MS and some of its criteria depended on BMI, body fat accumulation, parity, severity of menopausal symptoms and lack of physical activity, whereas did not depend on: age between 44-66, educational level, marital status or HRT taking

The polymorphism of estrogen receptor α is important for metabolic consequences associated with menopause

Menopause is associated with multiple health and metabolic consequences resulting from the decrease in estrogens level. Women at postmenopausal age are burdened with a higher risk of cardiovascular diseases, and the main cause of mortality in this group is ischemic heart disease. Estrogen deficiency is related, among other things, with frequent occurrence of dislipidemia, cessation of the beneficial effect of estrogens on the vascular wall, increase in body weight characterized by unfavourable redistribution of fatty tissue, with an increased amount of visceral fat and reduction of so-called non-fatty body mass. Estrogens exert an effect on metabolism, mainly through the genomic mechanism. The presence of α and β estrogen receptors was found in many tissues and organs. Recently, attention was paid to the fact that the effect of estrogens action on tissues and organs may depend not only on distribution, but also on their polymorphic types. The article presents the latest approach to the problem of metabolic consequences resulting from menopause, according to the possessed α estrogen receptor polymorphism (ERα).Genes encoding for ERα have many polymorphic variants, the most important of which from the clinical aspect are two single nucleotide polymorphisms (SNPs) – Xba1 and PvuII. The review of literature indicates that ERα polymorphisms are of great importance with respect to the effect of estrogens on the functioning of the body of a woman after menopause, and may imply the development of many pathological states, including the prevention or development of metabolic disorders. Identifying ERα polymorphisms may be useful in case of estrogen therapy for menopausal women who may benefit from it

Two Novel Pathogenic Variants Confirm RMND1 Causative Role in Perrault Syndrome with Renal Involvement

RMND1 (required for meiotic nuclear division 1 homolog) pathogenic variants are known to cause combined oxidative phosphorylation deficiency (COXPD11), a severe multisystem disorder. In one patient, a homozygous RMND1 pathogenic variant, with an established role in COXPD11, was associated with a Perrault-like syndrome. We performed a thorough clinical investigation and applied a targeted multigene hearing loss panel to reveal the cause of hearing loss, ovarian dysfunction (two cardinal features of Perrault syndrome) and chronic kidney disease in two adult female siblings. Two compound heterozygous missense variants, c.583G>A (p.Gly195Arg) and c.818A>C (p.Tyr273Ser), not previously associated with disease, were identified in RMND1 in both patients, and their segregation with disease was confirmed in family members. The patients have no neurological or intellectual impairment, and nephrological evaluation predicts a benign course of kidney disease. Our study presents the mildest, so far reported, RMND1-related phenotype and delivers the first independent confirmation that RMND1 is causally involved in the development of Perrault syndrome with renal involvement. This highlights the importance of including RMND1 to the list of Perrault syndrome causative factors and provides new insight into the clinical manifestation of RMND1 deficiency

Cardiovascular diseases, metabolic syndrome and health behaviours of postmenopausal women working in agriculture

Introduction: The objective of the study was to examine the impact of occurrence of cardiovascular diseases (CVDs) and metabolic syndrome (MS) diagnoses on the frequency of health behaviours in postmenopausal women working in agriculture. Material and methods: Eight hundred and ten postmenopausal women living in rural areas and working in agriculture, aged 46–70 and at least 12 months from the last menstrual period, were examined. Analysis of variance with multiple comparison tests was used to compare the Inventory of Health Behaviours among the women with and without CVDs and MS. Results: The frequency of some health behaviours, mainly health practices, is higher in postmenopausal women working in agriculture with CVDs or MS than in those without CVDs or MS (p = 0.045). Women with such disorders more often limit their physical effort (p = 0.029), try to be less overworked (p < 0.001) and to take more rest, (p = 0.027) more often limit consumption of animal fat and sugar (p = 0.024), more regularly visit physicians (p = 0.003) and more often take seriously recommendations concerning their health. However, an insufficient frequency of health behaviours was observed among both the healthy women and those with metabolic disorders and CVDs. One third of all the examined women had a high frequency of health behaviours, one third had an average frequency and one third had a low frequency; hence actions should be taken to improve the situation. Conclusions : Postmenopausal women working in agriculture more often perform beneficial health behaviours if they have MS and CVDs diagnosed in comparison to healthy women

Are cognitive functions in post-menopausal women related with the contents of macro- and micro-components in the diet?

[b]The objective[/b] of the study was an evaluation of the relationship between the level of cognitive functions and contents of micro- and macro-components in the diet of postmenopausal women. A group of 402 women was recruited to the study. The inclusion criteria were: minimum two years after the last menstruation, FSH concentration 30 U/ml and no dementia signs on the Montreal Cognitive Assessment (MoCA). A computerized battery of the Central Nervous System Vital Signs (CNS VS) test was used to diagnose cognitive functions. The dietary questionnaire was evaluated based on observation of a seven-day diet. The data obtained were introduced into the database and analyzed using computer software DIETICIAN. Statistical analysis was performed using statistical software STATISTICA. [b]Results[/b]. The results of the study concerning diet unequivocally indicate a very poor quality of diet in the group of postmenopausal women examined. The daily diet had a too high energetic value. The women consumed an excessive amount of total fat, including definitely too much monounsaturated fatty acids, and insufficient polyunsaturated fatty acids. The dietary intake of sodium and phosphorus was too high, whereas deficiencies were observed in the consumption of iron, copper, potassium, calcium, magnesium and zinc. No significant correlations were found in the analysis of cognitive functions according to the energetic value of daily diet and contents of macro- and micro-components. The results concerning verbal memory significantly depended on the daily intake of polyunsaturated fatty acids. Women who consumed polyunsaturated fatty acids below the daily normal or normal level obtained significantly higher results in verbal memory

Increased Levels of RANTES in Induced Sputum of Chronic Asthma but Not in Seasonal Grass Pollen-Induced Rhinitis

Backgroud: Allergic rhinitis is one of risk factors for development of allergic asthma. Meth­ods: 9 patients with asthma, 16 patients with seasonal allergic rhinitis (SAR) due to grass or rye pollen sensiti­zation and 17 healthy control subjects were recruited to the study. SAR patients were identified by history, skin­prick test, specific lgE and positive nasal allergen challenge. Every subject underwent the methacholine bronchial provocation test and sputum induction. Levels of RANTES were measured in supernatant of induced sputum. Results: Increased percentage of eosinophils in induced sputum in asthma compared to control group (p = 0.01) but not in SAR patients compared to healthy subjects (p = 0.13) were found. Similarly, asthmatic patients (p = 0.01) but not SAR patients had increased levels of RANTES in sputum compared to healthy subjects. Conclusion: Increased levels of RANTES in induced sputum of patients with chronic asthma but not in SAR patients indicate that RANTES is important in pathogenesis of chronic airway inflammation