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Vladeta Ajdacic-Gross,1 Ana Buadze,1 En-Young N Wagner,2 Mario Müller,1 Erich Seifritz,1 Setareh Ranjbar,3 Jennifer Glaus,4 Enrique Castelao,3 Marie-Pierre F Strippoli,3 Caroline L Vandeleur,3 Martin Preisig,3 Roland von Känel2 1Department of Adult Psychiatry and Psychotherapy, Psychiatric University Clinic Zurich and University of Zurich, Zurich, Switzerland; 2Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital Zurich and University of Zurich, Zurich, Switzerland; 3Department of Psychiatry, Psychiatric Epidemiology and Psychopathology Research Center, Lausanne University Hospital and University of Lausanne, Prilly, Switzerland; 4Department of Psychiatry, Service of Child and Adolescent Psychiatry, Lausanne University Hospital and University of Lausanne, Lausanne, SwitzerlandCorrespondence: Vladeta Ajdacic-Gross, Department of Adult Psychiatry and Psychotherapy, Psychiatric University Clinic Zurich and University of Zurich, PO Box 2019, CH-8032, Zürich, Switzerland, Tel +41 79 921 36 80, Email vladeta.ajdacic-gross@uzh.chAbstract: Previous research has unveiled an intriguing positive association between the AB blood group and mental disorders in general. In this study, we compared ABO blood groups with five major groups of mental disorders to attain a higher level of specificity. The analyses were conducted using data from the CoLaus|PsyCoLaus study (N=5111). They revealed that the AB blood group exhibited a positive association with both neurodevelopmental disorders (RR 2.29, CI 1.38– 3.82) and substance use disorders (RR 2.25, CI 1.38– 3.65) after adjusting for sex and childhood adversities. These associations could be replicated with respect to the familial aggregation of neurodevelopmental and substance use disorders. Large databases are needed to achieve more detailed results related to specific disorders.Plain Language Summary: Prior research has shown an interesting link between the AB blood group and mental disorders. In our study, we used data from a large Swiss population-based epidemiological cohort study to learn more about this connection. We examined the relationship between ABO blood groups and five major groups of mental disorders: neurodevelopmental, early onset anxiety, later onset anxiety, mood, and substance use disorders. Our analyses revealed associations between the AB blood group and neurodevelopmental and substance use disorders. The findings point to an unknown immunological mechanism that may play a role in the development of neurodevelopmental and substance use disorders.Keywords: ABO blood groups, neurodevelopmental disorders, substance use disorders, familial aggregation

Current therapies show limited efficacy against peritoneal metastases (PM) from pancreatic cancer. Pressurized intra-peritoneal aerosol chemotherapy (PIPAC) has emerged as a novel intraperitoneal drug delivery method. Recently, a dose-escalation study identified the safe dose of Nabpaclitaxel for PIPAC administration, an ideal intraperitoneal chemotherapy agent against pancreatic cancer. Combining systemic NabPaclitaxel-Gemcitabine with NabPaclitaxel-PIPAC may enhance disease control in pancreatic cancer patients with PM.

Abstract Background Risk stratification and treatment benefit prediction models are urgent to improve negative sentinel lymph node (SLN-) melanoma patient selection, thus avoiding costly and toxic treatments in patients at low risk of recurrence. To this end, the application of artificial intelligence (AI) could help clinicians to better calculate the recurrence risk and choose whether to perform adjuvant therapy. Methods We made use of AI to predict recurrence-free status (RFS) within 2-years from diagnosis in 94 SLN- melanoma patients. In detail, we detected quantitative imaging information from H&E slides of a cohort of 71 SLN- melanoma patients, who registered at Istituto Tumori “Giovanni Paolo II” in Bari, Italy (investigational cohort, IC). For each slide, two expert pathologists firstly annotated two Regions of Interest (ROIs) containing tumor cells alone (TUMOR ROI) or with infiltrating cells (TUMOR + INF ROI). In correspondence of the two kinds of ROIs, two AI-based models were developed to extract information directly from the tiles in which each ROI was automatically divided. This information was then used to predict RFS. Performances of the models were computed according to a 5-fold cross validation scheme. We further validated the prediction power of the two models on an independent external validation cohort of 23 SLN- melanoma patients (validation cohort, VC). Results The TUMOR ROIs have revealed more informative than the TUMOR + INF ROIs. An Area Under the Curve (AUC) value of 79.1% and 62.3%, a sensitivity value of 81.2% and 76.9%, a specificity value of 70.0% and 43.3%, an accuracy value of 73.2% and 53.4%, were achieved on the TUMOR and TUMOR + INF ROIs extracted for the IC cohort, respectively. An AUC value of 76.5% and 65.2%, a sensitivity value of 66.7% and 41.6%, a specificity value of 70.0% and 55.9%, an accuracy value of 70.0% and 56.5%, were achieved on the TUMOR and TUMOR + INF ROIs extracted for the VC cohort, respectively. Conclusions Our approach represents a first effort to develop a non-invasive prognostic method to better define the recurrence risk and improve the management of SLN- melanoma patients.

Purpose Tildrakizumab is a selective inhibitor of IL-23 approved for the treatment of moderate-to-severe plaque psoriasis in two dosages. We conducted a 16-week multicenter retrospective study to compare the effectiveness and safety of tildrakizumab 200 mg versus tildrakizumab 100 mg in patients with a high disease burden or high body weight.Materials and methods Our retrospective study included 134 patients treated with tildrakizumab 200 mg and 364 patients treated with tildrakizumab 100 mg from 28 Italian Dermatology Units affected by moderate-to-severe plaque psoriasis. The patients had a body weight above 90 kg or a high disease burden (Psoriasis Area and Severity Index [PASI] ≥ 16 or the involvement of difficult-to-treat areas). We evaluated the effectiveness of tildrakizumab at the week-16 visit in terms of PASI90, PASI100 and absolute PASI ≤ 2.Results After 16 weeks of treatment with tildrakizumab 200 mg, PASI90 was reached by 57.5% of patients and PASI100 by 39.6% of patients. At the same time point, 34.3% and 24.2% of patients treated with tildrakizumab 100 mg achieved PASI90 and PASI100, respectively.Conclusions Our data suggest that tildrakizumab 200 mg has better effectiveness than tildrakizumab 100 mg in patients with a body weight ≥ 90 kg and a high disease burden.

Glycolytic metabolism generates energy and intermediates for biomass production. Tumor-associated glycolysis is upregulated compared to normal tissues in response to tumor cell-autonomous or non-autonomous stimuli. The consequences of this upregulation are twofold. First, the metabolic effects of glycolysis become predominant over those mediated by oxidative metabolism. Second, overexpressed components of the glycolytic pathway (i.e. enzymes or metabolites) acquire new functions unrelated to their metabolic effects and which are referred to as “moonlighting” functions. These functions include induction of mutations and other tumor-initiating events, effects on cancer stem cells, induction of increased expression and/or activity of oncoproteins, epigenetic and transcriptional modifications, bypassing of senescence and induction of proliferation, promotion of DNA damage repair and prevention of DNA damage, antiapoptotic effects, inhibition of drug influx or increase of drug efflux. Upregulated metabolic functions and acquisition of new, non-metabolic functions lead to biological effects that support tumorigenesis: promotion of tumor initiation, stimulation of tumor cell proliferation and primary tumor growth, induction of epithelial-mesenchymal transition, autophagy and metastasis, immunosuppressive effects, induction of drug resistance and effects on tumor accessory cells. These effects have negative consequences on the prognosis of tumor patients. On these grounds, it does not come to surprise that tumor-associated glycolysis has become a target of interest in antitumor drug discovery. So far, however, clinical results with glycolysis inhibitors have fallen short of expectations. In this review we propose approaches that may allow to bypass some of the difficulties that have been encountered so far with the therapeutic use of glycolysis inhibitors.

Given the association of Epstein-Barr virus (EBV) with subjective perception of fatigue and demyelination in clinical conditions, the question about potential subclinical effects in the adult general population remains open. We investigate the association between individuals’ EBV immune response and perceived fatigue in a community dwelling cohort (n = 864, age 62 ± 10 years old; 49% women) while monitoring brain tissue properties. Fatigue levels are assessed with the established fatigue severity scale, the EBNA-1 and VCA p18 immunoglobulin G (IgG) chronic response – with multiplex serology and the estimates of local brain volume, myelin content, and axonal density - using relaxometry- and multi-shell diffusion-based magnetic resonance imaging (MRI). In our analysis we adjust for the effects of demographic and cardiovascular risk factors, sleep apnea, depression, and polygenic risk score for multiple sclerosis. We demonstrate that EBNA-1 IgG levels are positively associated with perceived levels of fatigue, whilst VCA p18 IgG levels show a positive correlation with myelin content and a negative one with an estimate of axonal g-ratio in male participants. In the context of EBVs immune response, the polygenic risk for multiple sclerosis is not associated with increased fatigue levels, brain myelination or atrophy. Our findings bring empirical evidence about the potential role of EBVs chronic immune response in perceived fatigue and hint towards a protective role of myelination specific for men. They underscore the added value of advanced assessment of brain tissue microstructure in uncovering the mechanisms behind frequent fatigue complaints associated with EBV infection and multiple sclerosis.

Circular Economy (CE) is considered a possible solution to mitigate the environmental externalities of the tourism industry, with a view to more sustainable tourism by reducing environmental, social, and economic burdens in an integrated holistic approach. Moreover, the role of CE in tourism is highlighted by the possibility of achieving all sustainable development goals (SDGs) directly and indirectly using the links that connect SDG 12 with the others.From this point of view, this literature review was aimed at discussing the key strategies of CE applied to the tourism industry, focussing on the widespread problems of single-use plastic, excess food, and water consumption. The environmental and socio-economic benefits deriving from the application of the CE principles to waste management will be shown, by contributing to meeting all the SDGs. Many strategies have been proposed to make tourism circular and sustainable, and research revealed that those are mainly based on the concepts of reduce, reuse, recycle, and recover.This article confirmed the importance of – and the need for - research on CE in the tourism sector; further, by contributing to expanding research in this content area, it can stimulate the development and application of solutions that make the industry more efficient and resilient. This study was also conceived to raise the awareness of tourism stakeholders on the importance of CE to mitigate the negative externalities of the sector.

IntroductionThe management of cancer patients follows a Diagnostic Therapeutic and Care Pathway (PDTA) approach, aimed at achieving the optimal balance between care and quality of life. To support this process, precision medicine and innovative technologies [e.g., next-generation sequencing (NGS)] allow rapid identification of genetic-molecular alterations useful for the design of PDTA-approved therapies. If the standard approach proves inadequate, the Molecular Tumor Board (MTB), a group comprising specialists from diverse disciplines, can step in to evaluate a broader molecular profile, proposing potential therapies beyond evidence levels I–II or considering enrolment in clinical trials. Our aim is to analyze the role of the MTB in the entire management of patients in our institute and its impact on the strategy of personalized medicine, particularly when all approved treatments have failed.Materials and methodsIn alignment with European and national guidelines, a panel of clinicians and preclinical specialists from our institution was defined as the MTB core team. We designed and approved a procedure for the operation of this multidisciplinary group, which is the only one operating in the Puglia region.Results and discussionIn 29 months (2021–2023), we discussed and analyzed 93 patients. A total of 44% presented pathogenic alterations, of which 40.4% were potentially actionable. Only 11 patients were proposed for enrollment in clinical trials, treatment with off-label drugs, or AIFA (the Italian pharmaceutical agency for drugs)—5% funding. Our process indicators, time to analysis, and number of patient cases discussed are in line with the median data of other European institutions. Such findings underscore both the importance and usefulness of the integration of an MTB process into the care of oncology patients.

Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multiple studies demonstrated that the aberrant activation of Hedgehog signaling is a driver of BCC development, and its blockade represents a potential therapeutic target. In Italy, clinicians can prescribe Hedgehog inhibitors (HhIs) Vismodegib and Sonidegib. To highlight the treatment choice of clinicians, we conducted an online survey between November 1 and November 18, 2020 with 33 Italian clinicians from 27 reference hospitals, in which each participant received an anonymous survey consisting of two multiple-choice questions on clinical efficacy and safety profile of Sonidegib and Vismodegib. Respondents reported their opinions on which efficacy and tolerability data of the pivotal phase-II BOLT trial were more relevant in the treatment choice of patients with locally advanced BCC (laBCC). This survey shows that overall response rate (ORR) and the duration of response (DoR) are the most expected across dermatologists and oncologists. The different pharmacokinetic profile of the two HhIs are behind their diverse toxicity spectrum, dose and schedule modification seem to address the choice between vismodegib and sonidegib among dermato-oncology prescribers.

IntroductionGastric cancer (GC) is the fourth leading cause of cancer-related death worldwide with limited therapeutic options. The aim of this study was to analyze the value of adding surgery to the first-line treatment in patients with oligometastatic GC (OGC).MethodsThis retrospective study included patients with OGC who underwent induction chemotherapy followed by surgery of both primary tumor and synchronous metastasis between April 2012 and April 2022. Endpoints were overall survival (OS) and relapse-free survival (RFS) analyzed by the Kaplan–Meier method. Prognostic factors were assessed with the Cox model.ResultsData from 39 patients were collected. All cases were referred to our multidisciplinary tumor board (MTB) to evaluate the feasibility of radical surgery. After a median follow-up of 33.6 months (mo.), median OS was 26.6 mo. (95% CI 23.8–29.4) and median RFS was 10.6 mo. (95% CI 6.3–14.8). Pathologic response according to the Mandard criteria (TRG 1–3, not reached versus 20.5 mo. for TRG 4–5; HR 0.23, p=0.019), PS ECOG ≤ 1 (26.7 mo. for PS ≤ 1 versus 11.2 mo. for PS >1; HR 0.3, p=0.022) and a low metastatic burden (26.7 mo. for single site versus 12.9 mo. for ≥2 sites; HR 0.34, p=0.039) were related to good prognosis. No major intraoperative complications nor surgery-related deaths occurred in our series.DiscussionA sequential strategy of preoperative chemotherapy and radical surgical excision of both primary tumor and metastases was demonstrated to significantly improve OS and RFS. Multidisciplinary evaluation is mandatory to identify patients who could benefit from this strategy.

Abstract Aims Blood glucose control is central to the management of diabetes, and continuous glucose monitoring (CGM) improves glycemic control. We aimed to describe the perspectives of people with diabetes using CGM. Materials and methods We performed a systematic review of qualitative studies. Results Fifty‐four studies involving 1845 participants were included. Six themes were identified: gaining control and convenience (reducing pain and time, safeguarding against complications, achieving stricter glucose levels, and sharing responsibility with family); motivating self‐management (fostering ownership, and increasing awareness of glycemic control); providing reassurance and freedom (attaining peace of mind, and restoring social participation); developing confidence (encouraged by the endorsement of others, gaining operational skills, customizing settings for ease of use, and trust in the device); burdened with device complexities (bewildered by unfamiliar technology, reluctant to rely on algorithms, overwhelmed by data, frustrated with malfunctioning and inaccuracy, distressed by alerts, and bulkiness of machines interfering with lifestyle); and excluded by barriers to access (constrained by cost, lack of suppliers). Conclusions CGM can improve self‐management and confidence in patients managing diabetes. However, the technical issues, uncertainty in readings, and cost may limit the uptake. Education and training from the health professionals may help to reduce the practical and psychological burden for better patient outcomes.

(1) Background/Objectives: Nail psoriasis (NP) is a chronic and difficult-to-treat disease, which causes significant social stigma and impairs the patients’ quality of life. Moreover, nail psoriasis is a true therapeutic challenge for clinicians. The presence of nail psoriasis can be part of a severe form of psoriasis and can have predictive value for the development of psoriatic arthritis. Our real-world-evidence multicenter study aims to evaluate the efficacy of bimekizumab in nail psoriasis. (2) Methods: A retrospective analysis of a multicenter observational study included 834 patients affected by moderate-to-severe psoriasis, in 33 Dermatologic Units in Italy, treated with bimekizumab from December 2022 to September 2023. Clinimetric assessments were based on Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), and Physician’s Global Assessment of Fingernail Psoriasis (PGA-F) for the severity of nail psoriasis at 0, 12, 24, and 36 weeks. (3) Results: Psoriatic nail involvement was present in 27.95% of patients. The percentage of patients who achieved a complete clearance of NP in terms of PGA-F 0 was 31.7%, 57%, and 88.5% at week 4, 16, and 36, respectively. PASI 100 was achieved by 32.03% of patients at week 4, by 61.8% at week 16, and by 78.92% of patients at week 36. The mean baseline PASI was 16.24. The mean DLQI values for the entire group of patients at baseline, at week 4, at week 16, and at week 36 were 14.62, 3.02, 0.83, and 0.5, respectively. (4) Conclusions: Therapies that promote the healing of both the skin and nails in a short time can also ensure a lower risk of subsequently developing arthritis which is disabling over time. Bimekizumab proved to be particularly effective to treat NP, with a fast response in terms of complete clearance, with over 88.5% of patients free from NP after 36 weeks. The findings of our real-world study showed that patients with moderate-to-severe PsO and concomitant NP had significantly faster and more substantial improvements in NP up to 36 weeks with respect to previous research findings. Considering the rapid healing of the nail, the dual inhibition of IL17 A and F might have a great value in re-establishing the dysregulation of keratin 17 at the nail level.

Abstract Background Clinical drawback in checkpoint inhibitors immunotherapy (ICI) of metastatic melanoma (MM) is monitoring clinical benefit. Soluble forms of PD1(sPD1) and PD-L1(sPD-L1) and extracellular vesicles (EVs) expressing PD1 and PD-L1 have recently emerged as predictive biomarkers of response. As factors released in the blood, EVs and soluble forms could be relevant in monitoring treatment efficacy and adaptive resistance to ICI. Methods We used pre-therapy plasma samples of 110 MM patients and longitudinal samples of 46 patients. Elisa assay and flow cytometry (FCM) were used to measure sPD-L1 and sPD1 concentrations and the percentage of PD1+ EVs and PD-L1+ EVs, released from tumor and immune cells in patients subsets. Transwell assays were conducted to investigate the impact of EVs of each patient subset on MM cells invasion and interaction between tumor cells and macrophages or dendritic cells. Viability assays were performed to assess EVs effect on MM cells and organoids sensitivity to anti-PD1. FCM was used to investigate immunosuppressive markers in EVs and immune cells. Results The concentrations of sPD1 and sPD-L1 in pre-treatment and longitudinal samples did not correlate with anti-PD1 response, instead only tumor-derived PD1+ EVs decreased in long responders while increased during disease progression in responders. Notably, we observed reduction of T cell derived EVs expressing LAG3+ and PD1+ in long responders and their increase in responders experiencing progression. By investigating the impact of EVs on disease progression, we found that those isolated from non-responders and from patients with progression disease accelerated tumor cells invasiveness and migration towards macrophages, while EVs of long responders reduced the metastatic potential of MM cells and neo-angiogenesis. Additionally, the EVs of non-responders and of progression disease patients subset reduced the sensitivity of MM cells and organoids of responder to anti-PD1 and the recruitment of dendritic cells, while the EVs of progression disease subset skewed macrophages to express higher level of PDL-1. Conclusion Collectively, we suggest that the detection of tumor-derived PD1 + EVs may represent a useful tool for monitoring the response to anti-PD1 and a role for EVs shed by tumor and immune cells in promoting tumor progression and immune dysfunction. Graphical Abstract

BackgroundDesmoplastic melanoma (DM) is a rare subtype of melanoma characterized by high immunogenicity which makes it particularly suitable for immune checkpoint inhibitors (ICIs) treatment.Case presentationWe report the case of a 53-year-old man with metastatic DM successfully treated with the combination of anti-CTLA-4 and anti-PD-1 antibodies, who developed serious immune-related adverse events (irAEs). The primary tumor was characterized by absent PD-L1 expression and no-brisk lymphocytes infiltration. NGS showed absence of BRAF mutation, a high tumor mutational burden, and an UV-induced DNA damage signature. Metastatic lesions regressed rapidly after few cycles of ICIs until complete response, however the patient developed serious irAEs including hypothyroidism, adrenal deficiency, and acute interstitial nephritis which led to the definitive suspension of treatment. Currently, the patient has normal renal functionality and no disease relapse after 26 months from starting immunotherapy, and after 9 months from its definitive suspension.ConclusionEfficacy and toxicity are two sides of the same coin of high sensitivity to ICIs in DM. For this reason, these patients should be closely monitored during ICIs therapy to promptly identify serious side effects and to correctly manage them.

IntroductionTrisomy 21 (T21), which causes Down syndrome (DS), is the most common chromosomal aneuploidy in humankind and includes different clinical comorbidities, among which the alteration of the immune system has a heavy impact on patient’s lives. A molecule with an important role in immune response is zinc and it is known that its concentration is significantly lower in children with T21. Different hypotheses were made about this metabolic alteration and one of the reasons might be the overexpression of superoxide dismutase 1 (SOD1) gene, as zinc is part of the SOD1 active enzymatic center.MethodsThe aim of our work is to explore if there is a linear correlation between zinc level and immune cell levels measured in a total of 217 blood samples from subjects with T21. Furthermore, transcriptome map analyses were performed using Transcriptome Mapper (TRAM) software to investigate whether a difference in gene expression is detectable between subjects with T21 and euploid control group in tissues and cells involved in the immune response such as lymphoblastoid cells, thymus and white blood cells.ResultsOur results have confirmed the literature data stating that the blood zinc level in subjects with T21 is lower compared to the general population; in addition, we report that the T21/control zinc concentration ratio is 2:3, consistent with a chromosomal dosage effect due to the presence of three copies of chromosome 21. The transcriptome map analyses showed an alteration of some gene’s expression which might explain low levels of zinc in the blood.DiscussionOur data suggest that zinc level is not associated with the levels of immunity cells or proteins analyzed themselves and rather the main role of this ion might be played in altering immune cell function.

Abstract The presentation will focus on long-term weight changes in patients with major depressive disorder who use antidepressants. Research studying weight change over periods of more than 12 months is scarce and the effects of depressive episodes and antidepressants on weight changes have rarely been assessed simultaneously. Using data of a prospective population-based CoLaus|PsyCoLaus study, data on the associations of antidepressant use prior to baseline and during a 5.5-year follow-up with changes in adiposity markers and multiple adjustments including for the effects of depressive episodes will be presented. The cohort included 2479 randomly selected 35 to 66 year-old white residents (mean age 49.9 years, 53.3% women) of an urban area who accepted the physical and psychiatric evaluations at baseline and follow-up (76.8% participation at the follow-up). Diagnostic information on mental disorders, treatment use including psychotropic drugs was elicited using a semi-structured interview. Independently of the effect of antidepressants used during the follow-up and the effects of depressive episodes, the number of any antidepressant compounds used prior to baseline was associated with lower increase of body mass index (BMI), whereas the use of antidepressants during the follow-up was associated with steeper increase in BMI and waist circumference. Within AD classes, the use of tricyclic AD (TCA) and selective serotonin reuptake inhibitor (SSRI) prior to baseline was associated with lower increase, the use of SSRI during follow-up was associated with steeper increases in BMI. Similarly, the use of SSRI prior to baseline was associated with lower increase, the use of TCA and SSRI during the follow-up was associated with steeper increase in waist circumference. Finally, the use of SSRI during follow-up was also associated with steeper increase in fat mass. The findings support unfavorable obesogenic effects of sustained treatment not only with TCAs but also with SSRIs, suggesting that the benefit of long-term administration of these AD classes should be carefully weighed against the potential risk of weight gain. Disclosure of Interest None Declared