Circulating inflammatory proteins associate with response to immune checkpoint inhibition therapy in patients with advanced melanoma.

BACKGROUND: Inflammation can modulate tumour growth and progression, and influence clinical response to treatment. We investigated the potential of circulating inflammatory proteins for response stratification of immune checkpoint inhibitor (ICI) therapy for advanced melanoma. METHODS: Study subjects were 87 patients with unresectable stage III or IV cutaneous melanoma from the multiple centres across the United Kingdom (UK) and the Netherlands (NL) who received ipilimumab, nivolumab, or pembrolizumab, or a combination of ipilimumab and nivolumab. Serum samples were collected before and during ICI therapy at follow-up visits scheduled every third week over a 12-week period. We performed targeted quantification of 92 proteins involved in inflammation and tested for association of their pre-treatment and on-treatment levels, as well as longitudinal changes, with overall response rate, progression-free survival, and overall survival. FINDINGS: We observed consistently higher pre-treatment levels of interleukin-6 (IL-6), hepatocyte growth factor (HGF), and monocyte chemotactic protein 2 (MCP-2), in non-responders compared to responders (meta-analysis p=3.31 × 10-4, 2.29 × 10-4, and 1.02 × 10-3, respectively). Patients' stratification according to the median value of IL-6, HGF, and MCP-2 highlighted a cumulative negative effect of pre-treatment levels of the three proteins on response (p=1.13 × 10-2), with overall response rate among patients presenting with combined elevated IL-6, HGF, and MCP-2 levels being three-fold lower (26.7%) compared to patients with none of the three proteins elevated (80.0%, p=9.22 × 10-3). Longitudinal data analysis showed that on-treatment changes in circulating inflammatory proteins are not correlated with response. INTERPRETATION: Our findings are in line with an increasing body of evidence that the pro-inflammatory cytokine IL-6 can influence response to ICI in advanced melanoma, and further support a role of circulating HGF and MCP-2 levels as prognostic biomarkers as suggested by previous smaller studies. Inflammatory proteins may serve as predictive biomarkers of ICI response and valuable targets for combination therapy. FUNDING: This work was supported by the Seerave Foundation and Dutch Cancer Society.

Setting the scene - a future 'epidemic' of immune-related adverse events in association with checkpoint inhibitor therapy.

Cancer immune therapy with checkpoint inhibitors (CPIs) has changed the landscape of treatment for a growing number of indications. These drugs are associated with a specific mechanism of action that has profound implications for both immunology and inflammatory disease. This article looks to set the scene covering the history of CPI therapy to date and outlining the likely future developments.

Measurement of psychosocial health in medical students: Validation of the Jefferson Medical College's Questionnaire in Mexico

The greater the psychosocial health, the greater is the well-being and the capacity for adaptation and overcoming problems and common life frustrations in family, relationships, and work. Medical students and practicing physicians, in comparison with the general population and that of other professions, are exposed to academic and professional stress and therefore are vulnerable to psychosocial health problems and certain specific dysfunctions that may compromise their physical, mental, and social health. In the field of psychosocial research in medical education, the key issue is to find relevant and psychometrically sound measures. The Jefferson Medical College's Psychosocial Questionnaire contains abridged versions of nine personality tests, as well as questions about respondents' relationships with parents in the first five years of life and with classmates in the early schooling. The scales in the questionnaire have shown satisfactory internal consistency reliability and construct validity through factor analysis. To our knowledge, in Mexico, there is not a specific questionnaire that measures psychosocial profile in a non-clinical population such as medical students. The present study adapted and translated the questionnaire from English to Spanish in order to evaluate its validity and reliability in Mexican medical students, to further learn its predictive validity of academic performance. In this study, we compared the factor structure in Mexico to the results obtained in the United States research. Implications for predicting academic and clinical performance of medical students and physicians were discussed. Study participants consisted of 3,603 matriculates at the Escuela de Medicina de la Universidad Autónoma de Nuevo León (Mexico). Psychosocial measures included Loneliness, Test anxiety, General anxiety, Self-esteem, Extroversion, External locus of control, Neuroticism, Depression, Stressful life events, Perceptions of early relationships with mother and father, Peer relationships and Perception of health, used by researchers at Jefferson Medical College in the United States. The items were translated into Spanish and back translated from Spanish to English, following the guidelines for adaptation of instruments for psychological evaluation. The questionnaire was administered in the third month after admission of the students to the Medicine School in the students' usual classrooms, on a schedule and day set aside for it according to the school's administration program. They were assured of the strict confidentiality of the test scores and of the individual data. Dimensionality of 40 items of the eight brief psychosocial scales was assessed with factor analysis using the principal components extraction method and orthogonal rotation; the Depression Scale was not included in the factorial analysis because it was not shortened for the present study. Correlation coefficients and internal consistencies were calculated for all the scales. Unidimensionality and construct validity were confirmed for measures of Loneliness, Test anxiety, General anxiety, Self-esteem, and Extroversion. The pattern and direction of the scale correlations with external criterion measures supported the concurrent validity of some of the measures. Also, the magnitude and direction of the inter-scale correlations supported the convergent and discriminant validities with the exception of the External locus of control and Neuroticism scales. The results supported the psychometric properties of the scales useful for providing information for medical educators and mental health professionals in early detection of psychosocial problems. It is important to mention that in spite of frequent talk about the importance of health among college students, few schools of Medicine in Mexico and in Latin America actually promote empirical research and support detect problems and develop solutions once they are identified. The mental health professionals should be responsible for sharing their understanding. They are capable of helping faculty for optimizing mental health through allocation of educational and remedial resources when designing academic programs in agreement with necessities of their students.

Como la literatura consigna, los estudiantes y profesionales de la Medicina en comparación con la población general y de otras carreras conforman una población que resulta vulnerable frente a los trastornos de salud psicosocial. En la investigación psicosocial de la educación médica un punto clave corresponde a la identificación de medidas relevantes con cualidades psicométricas. En el presente trabajo se analiza la validez y confiabilidad de un conjunto de escalas psicosociales aplicadas a 3.603 alumnos de la Facultad de Medicina de la Universidad Autónoma de Nuevo León (México). Las escalas administradas fueron: Soledad, Ansiedad ante los exámenes, Ansiedad general, Autoestima, Extroversión, Locus de control externo, Neuroticismo, Depresión, Eventos estresantes en la vida, Percepción de relaciones tempranas con los padres y amigos y Percepción de estado de salud general. Estas escalas fueron propuestas por investigadores de la Escuela de Medicina de Jefferson (Estados Unidos). Se confirmó la unidimensionalidad y la validez de constructo de las mediciones de Soledad, Ansiedad ante los exámenes, Ansiedad general, Autoestima y Extroversión. Así también, la magnitud y dirección de las correlaciones interescalas apoyaron la validez convergente y discriminante, con excepción de Locus de control externo y Neuroticismo. Los resultados confirman las propiedades psicométricas de las escalas, las cuales son útiles para proveer información a los educadores médicos y a profesionales de la salud mental en la detección temprana de problemas psicosociales quienes en conjunto pueden coadyuvar en la optimización de la salud mental de los estudiantes de escuelas de Medicina a través de programas académicos acordes a sus necesidades.