Molecular and Clinicopathological Biomarkers in the Neoadjuvant Treatment of Patients with Advanced Resectable Melanoma.

Neoadjuvant systemic therapy is emerging as the best medical practice in patients with resectable stage III melanoma. As different regimens are expected to become available in this approach, the improved optimization of treatment strategies is required. Personalization of care in each individual patient-by precisely determining the disease-related risk and the most efficient therapeutic approach-is expected to minimize disease recurrence, but also the incidence of treatment-related adverse events and the extent of surgical intervention. This can be achieved through validation and clinical application of predictive and prognostic biomarkers. For immune checkpoint inhibitors, there are no validated predictive biomarkers until now. Promising predictive molecular biomarkers for neoadjuvant immunotherapy are tumor mutational burden and the interferon-gamma pathway expression signature. Pathological response to neoadjuvant treatment is a biomarker of a favorable prognosis and surrogate endpoint for recurrence-free survival in clinical trials. Despite the reliability of these biomarkers, risk stratification and response prediction in the neoadjuvant setting are still unsatisfactory and represent a critical knowledge gap, limiting the development of optimized personalized strategies in everyday practice.

Development and validation of the Substance Use Protective Strategies Scale (SUPSS) among Polish young adults using various psychoactive substances.

Research supports protective behavioral strategies (PBS) as effective in reducing substance use, intoxication, and/or related risks/harms. However, despite the predominance of polysubstance use and common co-occurrence of different substance use disorders (SUDs), previous PBS research has been limited in terms of substance-specific measurement. This study sought to develop and validate a measure of PBS that is not substance-specific. Building from initial pilot work, we tested the psychometric properties of the Substance Use Protective Strategies Scale (SUPSS) in a large sample of young adults (N = 7325, aged 18-30), who reported using multiple psychoactive substances (other than alcohol and nicotine), recruited via social media in Poland. By splitting the sample, we conducted exploratory (n = 3709) and confirmatory factor analysis (n = 3614), which supported a 4-factor structure with 19 items (7 items dropped): Preparation for use (α = 0.66), Manner of use (α = 0.85), Additional concerns (α = 0.74), and Setting (α = 0.62). Configural, metric and scalar invariance were supported across sex, age, and user status for most substance types (cannabis, dissociatives, etc.). Further, the SUPSS factors were strongly associated with substance-related harms (R-squared = 0.495) and SUD symptoms (DUDIT, R-squared = 0.570). Our model fit was adequate (but not excellent), and two subscales had low internal consistency, highlighting the need for further improvement of the SUPSS. Despite its limitations, we found the SUPSS to have strong psychometric properties and it holds promise to enhance PBS research and harm reduction-oriented interventions.

Resilience Through Harm Reduction? Protective Behavioral Strategies as a Factor of Resilience Among Polish Young Adults Using Various Psychoactive Substances.

Resiliency theory might provide a conceptual framework for understanding why adverse substance-related consequences vary considerably among young adults using psychoactive substances. Protective behavioral strategies (PBS) are behaviors that reduce substance use and related consequences. Despite such suggestions, to date no research has explicitly treated PBS as resilience factors. The purpose of this study was to examine compensatory and protective models of resilience among young adults using various substances. Data were obtained from an online questionnaire distributed through online social networks. Participants were Polish young adults (18-30 years old; M = 22, SD = 3.6; about 30% female and 1.3% non-binary; N = 7253), who reported using substances, other than alcohol or nicotine, in the last 12 months. After controlling for sociodemographics, hierarchical regression analyses of both substance-related harms and SUDs indicated the main effects of risk and protective factors, and the interaction between substance use and PBS. The models explained about 50% and 52% of the dependent variables variance, respectively. The results of this cross-sectional study provide support for both compensatory and protective models of resilience. This presents a rationale for recognizing PBS use as resilience factors that help young adults reduce substance-related harms. Theoretical discussion and practical implications are provided.

Use of medicines to alleviate negative emotional states among adolescents attending Special Education Centres.

Introduction: Substantial research evidence indicates that adolescents commonly use a variety of pharmaceuticals. Studies in this area carried out so far in Poland have focused on youth attending mainstream schools. However, there is a lack of research covering adolescents residing in special education centres (SEC). The purpose of the study was to assess the prevalence of medicine use for negative emotional states (nervousness, difficulties in falling asleep, and depressive mood), and to identify factors associated with the use of the aforementioned medications by SEC youth. Materials and methods: The study was conducted in 2018 on a random nationwide sample of SEC adolescents aged 12-19 (N = 1730). The logistic regression analyses included sociodemographic variables, as well as factors related to the participant's individual characteristics and to their social environment. Results: Medicine use for negative emotional states was confirmed by about 24%-30% of respondents. The prevalence of these medicine use among SEC youth was significantly higher than among adolescents from mainstream schools. The individual risk factors associated with medicine use were gender (female), current mental and somatic health problems, past suicide attempts and psychoactive substances use while self-control turned out to be protective factor. Among factors related to the respondents' social environment, positive relationships with peers were significant protective factor. Conclusions: Preventive measures aimed at SEC youth should be focused on improving positive relationships with peers and developing self-control. Educational programs for youth, their parents and SEC staff to develop knowledge and skills regarding safe medicines intake would also be useful.

Long-term clinical evidence of comparable efficacy and toxicity of nivolumab and pembrolizumab in advanced melanoma treatment.

Pembrolizumab and nivolumab (anty-PD-1 antibody) are commonly used for the treatment of melanoma patients. However, their efficacy and safety have never been directly compared, leaving little guidance for clinicians to select the best therapy. The study included patients with inoperable or metastatic melanoma treated in first line with anti-PD-1 immunotherapy (nivolumab or pembrolizumab). In total 1037 patients were enrolled in the study, 455 (44%) patients were treated with pembrolizumab and 582 (56%) with nivolumab. The estimated median overall survival (OS) in the pembrolizumab and nivolumab groups was 17.4 and 20.0 months [ P = 0.2323; hazard ratio (HR), 1.1; 95% confidence interval (CI), 0.94-1.28], respectively, whereas the median progression-free survival (PFS) was 5.6 and 7.5 months ( P = 0.0941; HR, 1.13; 95% CI, 0.98-1.29), respectively. The estimated 2- and 3-year OS in the pembrolizumab and nivolumab groups were 42/34% and 47/37%, respectively, and the PFS was 25/21% and 29/23%, respectively. There were 391 (49%) immune-related adverse events (irAEs) of any grade during treatment, including 133 (42%) related to pembrolizumab treatment and 258 (53%) to nivolumab treatment. A total of 72 (9.6%) irAEs were in G3 or G4, including during pembrolizumab 29 (9%) and nivolumab 48 (11%). There were no differences in OS, PFS and overall response rates between nivolumab and pembrolizumab therapy in previously untreated patients with advanced/metastatic melanoma. There were no differences in the frequency of G1/G2 or G3/G4 irAEs. The choice of treatment should be based on the preferences of the patient and the clinician.

Long Term Results and Prognostic Biomarkers for Anti-PD1 Immunotherapy Used after BRAFi/MEKi Combination in Advanced Cutaneous Melanoma Patients.

(1) Background: BRAFi/MEKi are usually offered as a first line treatment for patients requiring rapid response; with elevated lactate dehydrogenase (LDH) activity, large tumor burden, and with brain metastases. The efficacy of second line therapies after BRAFi/MEKI failure is now well defined. (2) Methods: Patients treated with first line target BRAFi/MEKi therapy (vemurafenib plus cobimetinib, dabrafenib plus trametinib or encorafenib plus binimetinib); and for the second line treatment immunotherapy with programmed cell death 1 (PD-1) checkpoint inhibitors (nivolumab or pembrolizumab) with at least one cycle of second line were analyzed for survival and prognostic biomarkers. (3) Results: There were no statistically significant differences in ORR between the treatment groups with nivolumab and pembrolizumab, as well as median progression free-survival (PSF) and overall survival (OS) since the initiation of second line therapy; on nivolumab OS was 6.6 months, and on pembrolizumab 5.0 months. The greatest clinical benefit with second line immunotherapy was observed in patients with LDH ≤ ULN and <3 organ sites with metastasis at baseline. Longer OS was also noted in patients with time to PD >6 months in first line (slow progression). (4) Conclusions: Second line anti-PD1 immunotherapy is effective in BRAF-mutated melanoma patients after BRAFi/MEKi therapy failure.

Long-Term Outcomes of Targeted Therapy after First-Line Immunotherapy in BRAF-Mutated Advanced Cutaneous Melanoma Patients-Real-World Evidence.

BACKGROUND: Currently, limited data on targeted therapy and immunotherapy sequencing in patients with BRAF-mutant melanoma is available. Targeted therapy and immunotherapy are expected to be comparable in terms of overall survival (OS) when used as second-line therapies; therefore, understanding the characteristics of patients who completed sequential treatment is needed. METHODS: The primary objective of this study was to analyze the efficacy of BRAFi/MEKi activity as second-line therapy in patients with advanced melanoma. We also aimed to describe the clinical characteristics of patients with advanced melanoma who were treated sequentially with immunotherapy and targeted therapy. We enrolled 97 patients treated between 1st December 2015 and 31st December 2020 with first-line immunotherapy with programmed cell death 1 (PD-1) checkpoint inhibitors; and for the second-line treatment with at least one cycle of BRAFi/MEKi therapy with follow-up through 31 January 2022. RESULTS: Median OS since first-line treatment initiation was 19.9 months and 12.8 months since initiation of BRAFi/MEKi treatment. All BRAFi/MRKi combinations were similarly effective. Median progression free survival (PFS) was 7.5 months since initiation of any BRAFi/MEKi treatment. CONCLUSIONS: BRAFi/MEKi therapy is effective in the second-line in advanced and metastatic melanoma patients. For the first time, the efficacy of all BRAFi/MEKi combinations as second-line therapy is shown.

Risk and protective factors associated with internalizing and externalizing mental health problems among 13-15-year-old youth. / Czynniki ryzyka i chroniace zwiazane z internalizacyjnymi i eksternalizacyjnymi problemami zdrowia psychicznego 13-15-letniej mlodziezy.

OBJECTIVES: The main aim of the research was to identify factors associated with the occurrence of mental health problems in adolescents. METHODS: The study group consisted of elementary and junior high school students from Ilawa aged 13-15 years (N=574). The self-administered, anonymous questionnaire had been completed during school lessons. Two groups of mental health problems were included in the study: internalizing (depressive symptoms and emotional problems) and externalizing (use of psychoactive substances, aggressive behavior, delinquency), as well as a number of psychosocial factors (parental support and control, school bonding, peer influence, victimization, leisure activities). Hierarchical logistic regression models with Wald statistics were used to identify risk and protective factors. RESULTS: Parental support and control appeared to be universal protective factors that reduce the risk of both internalizing and externalizing problems. On the other hand, being a victim of peer violence and spending a lot of time on e-contacts appeared to be risk factors for both groups of adolescent mental health problems. In addition, sex, negative peer influences, school bonding, and use of computer / video games were important factors in the regression models. CONCLUSIONS: Prevention of mental health problems should be directed to education of parents in the skills of support and monitoring adolescents, strengthening the bonding to school and resilience to the negative influences of peer company.

Mental health of Warsaw middle school students. Mokotow Study 2004-2016. / Zdrowie psychiczne warszawskich gimnazjalistów. Badania mokotowskie 2004­2016.

OBJECTIVES: The aim of the study was to estimate the prevalence of mental health problems in subpopulation of Warsaw adolescents and to identify trends in 2004-2016. METHODS: The cross-sectional study, conducted every four years, covered the third grade Warsaw middle school students from three Warsaw districts: Mokotów, Ursynów and Wilanów. Sample was randomly selected with the adjustment for cluster selection. The self-administered questionnaire had been completed during school lessons. Indicators were related to following problems: (1) internalizing (symptoms of depression measured by the shortened CES-D scale and other emotional problems, based on subjective assessment); (2) externalizing - coexistence of two out of three types of behaviors (psychoactive substances abuse, being perpetrator of violence and delinquent behavior); (3) mixed. RESULTS: In 2016, 42% of youth exhibited symptoms of mental health disorders. These problems more often affected girls (48%) than boys (36%). Between 2008 and 2016, the percentage of young people experiencing internalizing problems increased significantly. This was due to the increase in the prevalence of depressive symptoms. At the same time, there was a significant decrease in the percentage of young people demonstrating externalizing problems. The last result was a consequence of the decrease in substance abuse and violence. CONCLUSIONS: Growing prevalence of internalizing problems, depressive symptoms and other emotional problems among teenagers indicates an urgent need to develop or adapt effective prevention programs and to improve the access to psychological and psychiatric support.

Efficacy of Neoadjuvant Targeted Therapy for Borderline Resectable III B-D or IV Stage BRAF V600 Mutation-Positive Melanoma.

Neoadjuvant therapy for locally advanced disease or potentially resectable metastatic melanoma is expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment as it is for sarcoma, breast, rectal, esophageal, or gastric cancers. Patients with locoregional recurrence after initial surgery and those with advanced regional lymphatic metastases are at a high risk of relapse and melanoma-related death. There is an unmet clinical need to improve the outcomes for such patients. Patients with resectable bulky stage III or resectable stage IV histologically confirmed melanoma were enrolled and received standard-dose BRAFi/MEKi for at least 12 weeks before feasible resection of the pre-therapy target and then received at least for the next 40 weeks further BRAFi/MEKi. Of these patients, 37 were treated with dabrafenib and trametinib, three were treated with vemurafenib and cobimetinib, five with vemurafenib, and one with dabrafenib alone. All patients underwent surgery with 78% microscopically margin-negative resection (R0) resection. Ten patients achieved a complete pathological response. In patients with a major pathological response with no, or less than 10%, viable cells in the tumor, median disease free survival and progression free survival were significantly longer than in patients with a minor pathological response. No patient discontinued neoadjuvant BRAFi/MEKi due to toxicity. BRAFi/MEKi pre-treatment did not result in any new specific complications of surgery. Fourteen patients experienced disease recurrence or progression during post-operative treatment. We confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of melanoma. Pathological response to neoadjuvant treatment may be considered as a surrogate biomarker of disease recurrence.

Drinking and alcohol-related problems among at-risk adolescents: The role of protective behavioral strategies.

INTRODUCTION: Protective Behavioral Strategies (PBS) are an alcohol-specific cognitive-behavioral strategies that may be employed before, during and/or after drinking, in order to reduce alcohol consumption and related consequences, particularly in the at-risk populations. Previous research on PBS was limited to North American college students. The purpose of this study was to examine the role of PBS use in a sample of Polish adolescents attending Special Educational Centers (SEC). METHOD: Data were collected from a nationwide sample of 12-19 year-old (Mean = 15.8; SD = 1.22) students attending SEC in Poland (N = 1585; about 33% female). The self-administered anonymous questionnaires were completed on-site in the SEC. PBS were measured by the authors adaptation of the PBSS-20. Alcohol-related problems were assessed by the Polish adaptation of the measures used in the MINI-KID tool. Alcohol use was measured by a single question on drinking frequency. These two latter variables were measured in the past year timeframe. Hierarchical regression models were used to test the main and interaction effects of employing PBS (total and subscales scores) on alcohol-related problems, after adjusting for demographics (gender, family composition and type of SEC) and alcohol use. RESULTS: The majority (about 94%) of study participants reported employment of some PBS. Regression analyses indicated that PBS use was associated with reduced risk of alcohol use and alcohol-related problems. We found that PBS significantly moderated the relationship between alcohol use and alcohol-related problems, for PBS total scale (F-change (1,1555) = 15.96, p < .001) and one of the PBS subscale: Limiting/Stopping Drinking (F-change (1,1555) = 4.80, p < .029). Findings were discussed within the results of PBS literature and resilience theory framework. CONCLUSION: The use of PBS helps to reduce alcohol-related problems among adolescents attending SEC. Implementation of tailored interventions that teach PBS among vulnerable adolescents may be an effective way to strengthen adolescent self-protection, reduce risky alcohol use and related negative consequences.

Alcohol and Cigarette Use Among Warsaw Adolescents: Factors Associated With Risk and Resilience.

BACKGROUND: Youth in Poland are at notable risk for substance use. Guided by resiliency theory, we examine if developmental risk and promotive factors are associated with substance abuse risk. OBJECTIVES: We examined the association between adolescent cigarette and alcohol use and related risk and promotive factors including maternal support, neighbors' informal social control, friends' acceptance of substance use, and alcohol and cigarette use by nonparental adults. METHOD: Data were collected from a random sample of 13- to 14-year-old students attending Warsaw middle schools (N = 3029). We used hierarchical regression models and examined compensatory and protective models of resilience, controlling for sociodemograhic factors. RESULTS: Our results indicated that friends' acceptance of substance use and perceived drug use among nonparental adults was associated with increased risk cigarette and alcohol use among youth. We found that maternal support moderated the relationship between friends' acceptance of substance use and cigarette use (protective model of resilience). Thus, mother support buffered the negative effects of friends' acceptance of substance use on youths' cigarette use. Neighbor's informal social control and maternal support were associated with reduced risk of alcohol use (compensatory model of resilience). CONCLUSION: Collectively, results of the study support compensatory and protective models of resilience in a large representative sample of Warsaw adolescents.

Inadequate Models of Adolescent Substance Use Prevention: Looking for Options to Promote Pro-Social Change and Engagement.

In the adolescent substance use prevention two competing models can be found: negative and positive. The negative model is entirely focused on risks and problems that young people should avoid. The positive model goes beyond that problem-oriented perspective and calls for positive youth growth and development. Both models of prevention seems to be inadequate to address effectively the challenging problem of adolescent substance use associated consequences. Both models are in fact flawed, but in different ways. Old, negative model neglects the power of individual strengths and ecological developmental assets, while new, positive model is often instrumentally used by politicians and other stakeholders for completely different goals than an informed, science-based prevention. As a result many substance use prevention programs implemented at schools and in communities are neither theoretically nor empirically informed. In order to address these flaws, the model of balanced prevention was outlined. It posits that triple well informed efforts are needed to achieve both specific substance use prevention goals and youth personal/social development. These efforts include protection building, risks reducing and individual assets development support. The proposed model is an ongoing work in progress. It can be considered as an encouragement for international dialogue to build a balanced conceptual foundation for adolescent substance use prevention.

International note: prevailing with extracurricular activities in an alcohol-dominated environment: sex differences in resilience among middle school youth.

Extracurricular involvement creates an outlet for adolescents to gain skills and resources that assist them in overcoming certain risks. Resiliency theory is applied to study the promotive effects of extracurricular activity involvement as this may help Polish youth overcome risks for alcohol use. Our data include 2903, 13 and 14 year old Polish adolescents. We use regression analysis to test the main and interaction effects of extracurricular involvement after adjusting for demographics and social influences. Sex differences are examined within the resilience framework. We found protective effects of extracurricular involvement for males, but only a compensatory effect for females. Implications for future research and intervention are discussed.

[Theory of resilience. Key conceptual constructs and chosen issues]. / Koncepcja resilience. Kluczowe pojecia i wybrane zagadnienia.

The aim of this article is to familiarize readers with key conceptual constructs related to resilience theory. This theory explains the phenomenon of children's and adolescents' positive adaptation despite various adverse life conditions and traumatic events. The resilience theory emphasizes the importance (relevance) of positive factors and mechanisms for child and adolescent development. Thus, it could be very useful for developing primary prevention and mental health promotion programmes among children and youth. This article is based on a review of publications written by significant resiliency researchers: M Rutter, N. Garmezy, E. Werner, S. Luthar, A. Sameroff, K. Kumpfer, A. Masten, M. Zimmerman, D. Cicchetti. More than 20 articles and book chapters published during the past 25 years were taken into consideration. They were chosen from the electronic database available at the University of Michigan and SAMSHA, and publications available in Poland. Several resilience definitions are mentioned, indicating the interactive and dynamic process of positive adaptation. These definitions encompass the impact of both risk and positive factors (and their interaction) on the individual's behavior, competence and health. The key conceptual constructs such as risk, risk factors, positive factors, resilience models and mechanisms are described in this article. The differences between the risk and protective mechanism are also presented. The difficulties related to operationalization of the key resilience constructs in empirical research are discussed. Common difficulties are related for example to clear criteria for risk and positive adaptation, and for risk group selection.

The effects of cumulative risks and promotive factors on urban adolescent alcohol and other drug use: a longitudinal study of resiliency.

Resiliency theory provides a conceptual framework for studying why some youth exposed to risk factors do not develop the negative behaviors they predict. The purpose of this study was to test compensatory and protective models of resiliency in a longitudinal sample of urban adolescents (80% African American). The data were from Years 1 (9th grade) and 4 (12th grade). The study examined effects of cumulative risk and promotive factors on adolescent polydrug use including alcohol, tobacco and marijuana. Cumulative measures of risk/promotive factors represented individual characteristics, peer influence, and parental/familial influences. After controlling for demographics, results of multiple regression of polydrug use support the compensatory model of resiliency both cross-sectionally and longitudinally. Promotive factors were also found to have compensatory effects on change in adolescent polydrug use. The protective model of resiliency evidenced cross-sectionally was not supported in longitudinal analysis. The findings support resiliency theory and the use of cumulative risk/promotive measures in resiliency research. Implications focused on utilizing multiple assets and resources in prevention programming are discussed.

[Trends in cigarette smoking among Warsaw teenagers: the Mokotów study 1984-2000]. / Ttrendy w paleniu papierosów przez 15-letnia mlodziez. Badania mokotowskie 1984-2000.

UNLABELLED: Since mid 1980s self-report anonymous surveys were repeated in all types of secondary schools in Mokotów - the biggest district of Warsaw. The study was aimed at trends and patterns in teenagers' substance use including cigarette smoking. Between 1984-2000 there were five surveys utilizing the same procedure and instruments and targeted at 15 years old students. The number of students participating in these five surveys ranged from 2000 to 3900. RESULTS: Between 1988-2000 total cigarette use had increased from about 26% to 36%. This increase was mainly influenced by the shift in daily smoking rates - from about 10% in 1988 to nearly 18% in 2000. These changes were stronger among girls. In this period the rates of female daily smoking had increased nearly three times and reached about 18% in 2000. As a result in 2000 smoking rates became similar (daily smoking) or were even higher among girls if total smoking was considered. Systematic growth in cigarette use among girls observed since 1988 reflects general changes in health-related behaviour of teen-age girls. Growing smoking rates among 15 year old students were in contrast with decreasing tendencies observed among their parents. Between 1984 and 2000 the group of students having both nonsmoking parents increased about 10%. Results of multivariable logistic regression confirmed that alcohol use and company of drug taking peers are the most prominent risk factors for smoking among the 15 year olds. Other significant risk factors were connected with school career (poor academic achievement and type of secondary school) and family patterns (regularly smoking parents). The relationship between these factors and teenager smoking was stable during the years covered by the Mokotów study. CONCLUSIONS: Cigarette smoking among Warsaw teenagers increased significantly in the past decade, which consistent with the general increase in psychoactive substance use among youth in Poland. This process can be considered as a real challenge for teachers and physicians working with youth.