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Liquid biopsy, the detection of tumor-related DNA in the peripheral blood, is currently the best available technological tool to improve clinical decision making in precision oncology. 1 Liquid biopsy currently has enough analytic and clinical validity to be implemented in routine practice for advanced disease genotyping to predict the benefit of targeted drugs. An additional great promise of the measurement of circulating tumor DNA (ctDNA) has been its use for the detection of the so-called minimal residual disease, particularly after surgical therapy to remove primary tumors, as a predictor of residual disease and relapse and as an indicator of poor prognosis. 2,3 . . .

Emergence of acquired resistance limits the efficacy of the anti-EGFR therapies cetuximab and panitumumab in metastatic colorectal cancer. In the last decade, preclinical and clinical cohort studies have uncovered genomic alterations that confer a selective advantage to tumor cells under EGFR blockade, mainly downstream re-activation of RAS-MEK signaling and mutations in the extracellular domain of EGFR (EGFR-ECD). Liquid biopsies (genotyping of ctDNA) have been established as an excellent tool to easily monitor the dynamics of genomic alterations resistance in the blood of patients and to select patients for rechallenge with anti-EGFR therapies. Accordingly, several clinical trials have shown clinical benefit of rechallenge with anti-EGFR therapy in genomically-selected patients using ctDNA. However, alternative mechanisms underpinning resistance beyond genomics -mainly related to the tumor microenvironment-have been unveiled, specifically relevant in patients receiving chemotherapy-based multi-drug treatment in first line. This review explores the complexity of the multifaceted mechanisms that mediate secondary resistance to anti-EGFR therapies and potential therapeutic strategies to circumvent acquired resistance.

Blockade of the epidermal growth factor receptor (EGFR) with the monoclonal antibodies cetuximab or panitumumab is effective in a subset of colorectal cancers (CRCs), but the emergence of resistance limits the efficacy of these therapeutic agents. At relapse, the majority of patients develop RAS mutations, while a subset acquires EGFR extracellular domain (ECD) mutations. Here we find that patients who experience greater and longer responses to EGFR blockade preferentially develop EGFR ECD mutations, while RAS mutations emerge more frequently in patients with smaller tumour shrinkage and shorter progression-free survival. In circulating cell-free tumour DNA of patients treated with anti-EGFR antibodies, RAS mutations emerge earlier than EGFR ECD variants. Subclonal RAS but not EGFR ECD mutations are present in CRC samples obtained before exposure to EGFR blockade. These data indicate that clonal evolution of drug-resistant cells is associated with the clinical outcome of CRC patients treated with anti-EGFR antibodies. Some colorectal cancer patients respond well to treatment with anti-EGFR antibodies, however response is almost invariably followed by acquired resistance. Here, the authors show that patients with shorter responses acquire RAS mutations, while those relapsing later preferentially develop mutations in the extracellular domain of EGFR .

Immune checkpoints inhibitors (ICIs) have been a breakthrough, with unique response and survival patterns compared with chemotherapy for patients with advanced Mismatch Repair-deficient/Microsatellite instable (dMMR/MSI) colorectal cancer, but have shown disappointing results in Mismatch Repair-proficient/Microsatellite stable (pMMR/MSS) colorectal cancer. As up to 50% of patients harboring dMMR/MSI advanced cancers will ultimately progress after PD-1 blockade, biomarkers are needed to predict response/resistance to immunotherapy and to select patients for immunomodulating combination therapies. Patients with pMMR/MSS colorectal cancer present with distinct immune profiles compared to dMMR/MSI tumors, giving evidence of different immune escape mechanisms, which could be overcome through individualized immunotherapeutic strategies. In this review we discuss the latest developments in the field of immunotherapy for dMMR/MSI and pMMR/MSS colorectal cancers, and unresolved questions and considerations concerning the use of ICI therapies in this population. Future immunomodulation strategies based on biomarker selection (tumor mutational burden, Immunoscore®, mutational profile) are discussed.

Peritoneal carcinomatosis (PC) represents a challenge in the management of metastatic colorectal cancer (mCRC) because of the difficulties in diagnosis, tumor burden assessment, and in selecting the optimal treatments. A critical limitation is the lack of robust prognostic and predictive biomarkers, largely relying on serum markers (e.g., carcinoembryonic antigen) or the peritoneal carcinomatosis index (PCI) for disease extent. Circulating tumor DNA (ctDNA)—genomic fragments shed by tumor cells into the bloodstream—is now recommended by international guidelines for mCRC management. Its potential extends to PC, where it may enhance diagnostic, therapeutic, and follow-up strategies. However, PC from CRC (PC-CRC) is associated with lower ctDNA levels and detection rates compared to other metastatic sites, posing a challenge for its clinical utility. To address these limitations, peritoneal fluid analysis has emerged as a promising alternative, with peritoneal tumor DNA (ptDNA) detected at higher concentrations in this anatomical space. Integrating ctDNA and ptDNA may offer a deeper understanding of PC-CRC biology and provide more precise tools for managing this complex disease. This approach has the potential to revolutionize the treatment paradigm for PC-CRC, bringing precision medicine even to this subgroup of patients traditionally associated with poor outcomes. This review aims to evaluate the diagnostic, prognostic, and therapeutic implications of ctDNA and ptDNA in PC-CRC, highlighting current limitations and future directions.

Currently, the standard treatment for patients with localized colorectal cancer (CRC) includes surgical resection followed by adjuvant chemotherapy based on clinicopathological features. Recurrence risk stratification in those patients is of utmost importance to guide clinicians to avoid both under- and overtreatment. Recently, the concept of minimal residual disease (MRD) has emerged as the detection of circulating tumor DNA (ctDNA) carrying tumor-specific genomic or epigenomic alterations in the bloodstream of patients after surgery. Emerging studies described how the detection of MRD is a powerful prognostic biomarker to identify patients at higher risk of recurrence and who will potentially benefit the most from a systemic adjuvant treatment. Based on that unprecedented finding, several clinical trials involving stage II and III CRC patients are ongoing evaluating the impact of ctDNA guided treatment by escalating or deescalating adjuvant chemotherapy based on ctDNA MRD detection. This review provides a critical overview of current perspectives of liquid biopsy in early-stage CRC including technical, biological, and clinical key points, as well as ongoing ctDNA-based clinical trials that ultimately aim to improve clinical outcomes of patients with CRC.

Self-criticism has been considered as a transdiagnostic dimension that contributes to the development of several mental health difficulties. Moreover, there is a significant association between self-criticism and emotion regulation difficulties. Of special interest are two variables, related to emotion dysregulation, that have garnered significant attention in recent years: emotional overproduction and the perseveration of negative emotions. By contrast, increased self-compassion has been proposed as a protective mechanism of mental health symptoms, specifically depression. The present study used Structural Equation Modeling (SEM) to investigate the relationship between self-criticism, self-compassion, and depressive symptoms, while considering emotional overproduction and perseveration of negative emotions as mediating variables. A cross-sectional design was used. The sample consisted of 453 participants who completed measures of self-criticism, self-compassion, depressive symptoms, emotional overproduction, and perseveration of negative emotions. Results indicate that emotional overproduction mediates the relationship between self-criticism and depressive symptoms. Additionally, both emotional overproduction and the perseveration of negative emotions mediate the negative association between self-compassion and depressive symptoms. Therefore, developing self-compassion may diminish the negative impact of self-criticism on depressive symptoms through these two variables. In conclusion, this study deepens our understanding of the mechanism by which self-compassion can mitigate mental health problems such as depressive symptoms.

Recently, there has been growing scientific interest in studying states of selflessness, where there is no sense of self as the immediate subject of experience. Preliminary findings suggest that this state is associated with increased positive emotions and a sense of connection with the world and all living beings. Given its potential benefits, various practices have been developed to induce or cultivate selflessness, including meditation and psychedelic drugs. However, there is a pressing need to explore alternative cost-effective and non-pharmacological approaches to overcome the limitations of these methods. In this regard, Virtual Reality (VR) presents a promising method capable of creating experiences that may be risky, costly, or otherwise unfeasible in the real world. The present study aims to examine whether a multi-person numadelic VR experience could induce a state of selflessness and to investigate its impact on affect, mystical experiences, and peak experiences. A total of 56 volunteers participated in a VR session and completed several self-report questionnaires before, immediately after, and one week following the experience. Preliminary findings suggest that a single multi-person VR experience can engender selflessness and enhance interpersonal connectedness. Additionally, it increases low-arousal positive affect and warmth, and generates mystical and peak experiences in a notable subset of participants. The experience is also widely accepted, with participants reporting few adverse effects. By providing a new research method for accessing selflessness, this study paves the way for further exploration in this field and contributes to a deeper understanding of this complex psychological experience.

Background: Anti-PD-1-based immunotherapy has improved outcomes in stage IIB to IV resected melanoma patients in clinical trials. However, little is known about real-world outcomes, prognostic factors and patterns of relapse. Methods: This is a retrospective multicenter observational study including patients with resected melanoma treated with subsequent anti-PD-1-based adjuvant immunotherapy. Data on clinical and demographic characteristics, delivered treatment, prognostic factors, time and pattern of relapse were collected. Results: We included 245 patients from eight centers; 4% of patients were at stage IIB-C, 80% at stage IIIA-D and 16% at stage IV. Recurrence-free survival (RFS) rates at 18 and 36 months were 60% and 48%, respectively, with a median RFS of 33.7 months. Prognostic factors associated with recurrence were melanoma primary site (HR 2.64, 95% CI 1.15–6.01) and starting adjuvant therapy more than 12 weeks after the last resection (HR 1.68, 95% CI 1.13–2.5); presence of serious immune-related adverse events was associated with better RFS (HR 0.4, 95% CI 0.19–0.87). Early relapses accounted for 63% of the total recurrences, with a higher number of metastatic sites (18%); in contrast, late relapses presented more frequently with brain metastases (20%). Conclusions: In our patients with resected melanoma who underwent anti-PD-1-based adjuvant immunotherapy, survival outcomes were worse than those reported in clinical trials. Primary melanoma site and time interval between the last resection and the start of adjuvant therapy were associated with survival.

O Estágio Profissionalizante, como o nome indica, tem como principal objetivo a profissionalização do estudante de Medicina, através do contacto com especialidades basilares, constituindo uma etapa essencial na formação pré-graduada. Os estágios que o compõem detêm, na sua maioria, um caráter mais prático, em comparação com anos anteriores. Assim, existe oportunidade de desenvolver competências clínicas, técnicas, comunicacionais e éticas e aplicá-las de forma supervisionada, competências estas que serão essenciais na prática profissional futura. Tendo por base os documentos O Licenciado Médico em Portugal1 e The Tuning Project2 , delineei os seguintes objetivos transversais: 1) Consolidar conhecimentos teóricos e saber aplicá-los na prática; 2) Aperfeiçoar o raciocínio clínico para as patologias mais prevalentes, com correta colheita de anamnese e exame objetivo, sabendo hierarquizar as hipóteses diagnósticas, quais os exames e abordagem terapêutica mais adequados e reconhecer situações de urgência; 3) Praticar gestos e procedimentos médicos adequados à fase de formação prégraduada; 4) Saber aplicar conceitos de prevenção e promoção de saúde; 5) Agir de acordo com o Modelo Biopsicossocial na abordagem de doentes, tendo sempre em conta as suas crenças, desejos, atitudes e comportamentos; 6) Aprimorar a comunicação com os doentes e familiares, para que esta seja feita de forma empática e eficaz, reconhecendo a individualidade de cada situação e investindo na construção da relação-médico doente; 7) Reconhecer a importância do trabalho em equipa, articulando os cuidados com os restantes profissionais de saúde; 8) Demonstrar capacidade de autoaprendizagem e interesse no desenvolvimento das minhas competências pessoais e clínicas, trabalhando a minha confiança.