Immune checkpoint inhibitors, endocrine adverse events, and outcomes of melanoma

Objective: Immune checkpoint inhibitors (ICI) can cause endocrine adverse events. However, endocrine AEs could be related to better treatment outcomes. Our aim was to investigate whether this holds true in a real-world setting of metastatic melanoma patients. Design: A retrospective single-institution study. Methods: We included 140 consecutive metastatic melanoma patients treated with ICI between January 2012 and May 2019. We assessed the endocrine toxicity and the best possible treatment outcomes from electronic patient records, including laboratory parameters and radiological images. Results: Of the treated patients, 21 patients (15%) were treated with ipilimumab, 46 (33%) with nivolumab, 67 (48%) with pembrolizumab, and 6 (4%) with combination therapy (ipilimumab + nivolumab). Endocrine AEs appeared in 29% (41/140) patients. Three patients had two different endocrine AEs. Thyroid disorders were the most common: 26% (36/140), followed by hypophysitis: 4% (5/140). Three subjects (2%, 3/140) were diagnosed with autoimmune diabetes. Three patients had to terminate treatment due to endocrine toxicity. Radiological manifestations of endocrine AEs were found in 16 patients (39%, 16/41). Endocrine toxicity was associated with significantly better treatment outcomes. Median progression-free survival (8.1 months, range 5.1-11.1 months vs 2.7 months, range 2.4-3.0 months, P < 0.001), and median overall survival (47.5 months, range 15.5-79.5 months vs 23.7 months, range 15.3-32.1 months, P = 0.035) were longer for patients experiencing endocrine AEs. Conclusions: The higher number of endocrine AEs suggest that regular laboratory monitoring aids in AE detection. Endocrine AEs in metastatic melanoma may correlate with better treatment outcomes.Peer reviewe

Previous radiotherapy improves treatment responses and causes a trend toward longer time to progression among patients with immune checkpoint inhibitor-related adverse events

Background: Immune-related adverse events (irAEs) are frequently encountered by patients during immune checkpoint inhibitor (ICI) treatment and are associated with better treatment outcomes. The sequencing of radiotherapy (RT) and ICIs is widely used in current clinical practice, but its effect on survival has remained unclear. Methods: In a real-world multicenter study including 521 patients who received ICI treatment for metastatic or locally advanced cancer, RT schedules and timing, irAEs, time to progression, overall survival, and treatment responses were retrospectively reviewed. Results: Patients who received previous RT and developed irAE (RT +/AE +) had the best overall response rate (ORR 44.0%). The ORR was 40.1% in the RT −/AE + group, 26.7% in the RT −/AE − group and 18.3% in the RT + /AE − group (p < 0.001). There was a significantly longer time to progression (TTP) in the RT + /AE + group compared to the RT −/AE − and RT + /AE − groups (log rank p = 0.001 and p < 0.001, respectively), but the trend toward longer TTP in the RT + /AE + group did not reach statistical significance in pairwise comparison to that in the RT −/AE + group. Preceding RT timing and intent had no statistically significant effect on TTP. In a multivariate model, ECOG = 0 and occurrence of irAEs remained independent positive prognostic factors for TTP (HR 0.737; 95% CI 0.582–0.935; p = 0.012, and HR 0.620; 95% CI 0.499–0.769; p < 0.001, respectively). Conclusions: Better ORR and a trend toward longer TTP were demonstrated for patients with RT preceding ICI treatment and development of irAEs, which suggests that RT may boost the therapeutic effect of immunotherapy in patients with metastatic cancers.Peer reviewe

Mistä on pienet tytöt ja pojat tehty? : sukupuolisensitiivisyys ja sen hyödyt varhaiskasvatuksessa

Opinnäytetyössä tarkastellaan sukupuolisensitiivisyyttä sekä sen hyötyjä varhaiskasvatuksessa kirjallisuuskatsauksen muodossa. Tavoitteena oli selvittää, millaisena sukupuolisensitiivinen varhaiskasvatus näyttäytyy kotimaisen sekä kansainvälisen kirjallisuuden ja tutkimustyön kautta. Tavoitteena oli tuoda myös tieteellistä tutkimustietoa paljon keskustelua ja mielipiteitä herättävästä, pinnalla olevasta aiheesta. Opinnäytetyön avulla pyrittiin tuottamaan tietoa sukupuolisensitiivisen varhaiskasvatuksen hyödyistä sekä tuomaan sukupuolisensitiivistä varhaiskasvatusta enemmän näkyväksi. Käsitteenä sukupuolisensitiivinen varhaiskasvatus on lapsen kohtaamista yksilönä, ilman häneen kohdistettuja oletuksia sukupuolesta. Sukupuolisensitiivinen varhaiskasvatus antaa tilaa ja tukea lapsen itsensä toteuttamiselle, sukupuolirajojen ylittämisen kokeilemiselle sekä näin ollen kokonaisvaltaiselle kehitykselle. Sukupuolisensitiivinen varhaiskasvatus rakentuu lapsen kehityksen tukemisen, sukupuolistereotypioiden ja -roolien sekä sukupuolittuneiden käytäntöjen purkamisen ympärille. Avainasemassa ovat myös valtakunnalliset toimintaohjeet sekä kasvattajan rooli ja asenne aihetta kohtaan. Ympäristö, oppimateriaalit ja vuorovaikutus ovat osa sukupuolisensitiivistä varhaiskasvatusta. On osoittautunut, että sukupuolisensitiivinen varhaiskasvatus vaikuttaa myönteisesti muun muassa lapsen sukupuoli-identiteetin kehittymiseen sekä eheän minäkuvan muodostumiseen. Sukupuolisensitiivinen varhaiskasvatus on ehkäisemässä kiusaamista sekä edistämässä tasa-arvoa ja yhdenvertaisuutta. Sillä on todettu myös olevan myönteisiä vaikutuksia lapsen tulevaisuuteen, kun tarkastellaan esimerkiksi mielenterveyttä ja työelämää.This thesis examines gender sensitivity and its benefits in early childhood education in the form of a literature review. The aim was to find out what gender-sensitive early childhood education looks like through domestic and international literature and research work. The aim was also to bring scientific research know-ledge into a subject that provokes debate and exchange of opinions. The thesis was used to provide information about the benefits of gender-sensitive early childhood education, as well as bringing gender-sensitive early childhood education into greater prominence. The concept of gender-sensitive early childhood education is about viewing a child as an individual, without any assumptions about gender directed at them. Gender-sensitive early childhood education provides space and support for the child's self-fulfillment, experimenting with gender boundaries, as well as, consequently, holistic development. Gender-sensitive early childhood education is built around support for child development, gender stereotypes and roles, and dismantling gendered practices. Nationwide policy guidelines and the role and attitude of the guardian to the subject are also key. Environment, learning materials, and interactions are part of gender-sensitive early childhood education. Based on the conducted literature review, it can be concluded that gender-sensitive early childhood education has a positive effect on the development of a child's gender identity, as well as the formation of an integral self-image. Gender-sensitive early education is to prevent bullying and promote equality and equality. It has also been found to have positive effects on a child's future when looking at issues such as mental health and work life

Antibiotic Treatment is an Independent Poor Risk Factor in NSCLC But Not in Melanoma Patients Who had Received Anti-PD-1/L1 Monotherapy

Peer reviewe

Viral molecular mimicry influences the antitumor immune response in murine and human melanoma

Molecular mimicry is one of the leading mechanisms by which infectious agents can induce autoimmunity. Whether a similar mechanism triggers an antitumor immune response is unexplored, and the role of antiviral T cells infiltrating the tumor has remained anecdotal. To address these questions, we first developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes. Using peptides identified by this tool, we demonstrated that, in mice, preexisting immunity toward specific viral epitopes enhanced the efficacy of cancer immunotherapy via molecular mimicry in different settings. To understand whether this mechanism could partly explain immunotherapy responsiveness in humans, we analyzed a cohort of patients with melanoma undergoing anti-PD1 treatment who had a high IgG titer for cytomegalovirus (CMV). In this cohort of patients, we showed that high levels of CMV-specific antibodies were associated with prolonged progression-free survival and found that, in some cases, peripheral blood mononuclear cells (PBMC) could cross-react with both melanoma and CMV homologous peptides. Finally, T-cell receptor sequencing revealed expansion of the same CD8þ T-cell clones when PBMCs were expanded with tumor or homologous viral peptides. In conclusion, we have demonstrated that preexisting immunity and molecular mimicry could influence the response to immunotherapies. In addition, we have developed a free online tool that can identify tumor antigens and neoantigens highly similar to pathogen antigens to exploit molecular mimicry and cross-reactive T cells in cancer vaccine development.publishedVersionPeer reviewe

Previous radiotherapy improves treatment responses and causes a trend toward longer time to progression among patients with immune checkpoint inhibitor-related adverse events

Abstract Background: Immune-related adverse events (irAEs) are frequently encountered by patients during immune checkpoint inhibitor (ICI) treatment and are associated with better treatment outcomes. The sequencing of radiotherapy (RT) and ICIs is widely used in current clinical practice, but its effect on survival has remained unclear. Methods: In a real-world multicenter study including 521 patients who received ICI treatment for metastatic or locally advanced cancer, RT schedules and timing, irAEs, time to progression, overall survival, and treatment responses were retrospectively reviewed. Results: Patients who received previous RT and developed irAE (RT +/AE +) had the best overall response rate (ORR 44.0%). The ORR was 40.1% in the RT −/AE + group, 26.7% in the RT −/AE − group and 18.3% in the RT + /AE − group (p &lt; 0.001). There was a significantly longer time to progression (TTP) in the RT + /AE + group compared to the RT −/AE − and RT + /AE − groups (log rank p = 0.001 and p &lt; 0.001, respectively), but the trend toward longer TTP in the RT + /AE + group did not reach statistical significance in pairwise comparison to that in the RT −/AE + group. Preceding RT timing and intent had no statistically significant effect on TTP. In a multivariate model, ECOG = 0 and occurrence of irAEs remained independent positive prognostic factors for TTP (HR 0.737; 95% CI 0.582–0.935; p = 0.012, and HR 0.620; 95% CI 0.499–0.769; p &lt; 0.001, respectively). Conclusions: Better ORR and a trend toward longer TTP were demonstrated for patients with RT preceding ICI treatment and development of irAEs, which suggests that RT may boost the therapeutic effect of immunotherapy in patients with metastatic cancers