Primary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma.

The application of mammalian target of rapamycin inhibition (mTORi) as primary prophylactic therapy to optimize T cell effector function while preserving allograft tolerance remains challenging. Here, we present a comprehensive two-step therapeutic approach in a male patient with metastatic cutaneous squamous cell carcinoma and heart transplantation followed with concomitant longitudinal analysis of systemic immunologic changes. In the first step, calcineurin inhibitor/ mycophenolic acid is replaced by the mTORi everolimus to achieve an improved effector T cell status with increased cytotoxic activity (perforin, granzyme), enhanced proliferation (Ki67) and upregulated activation markers (CD38, CD69). In the second step, talimogene laherparepvec (T-VEC) injection further enhances effector function by switching CD4 and CD8 cells from central memory to effector memory profiles, enhancing Th1 responses, and boosting cytotoxic and proliferative activities. In addition, cytokine release (IL-6, IL-18, sCD25, CCL-2, CCL-4) is enhanced and the frequency of circulating regulatory T cells is increased. Notably, no histologic signs of allograft rejection are observed in consecutive end-myocardial biopsies. These findings provide valuable insights into the dynamics of T cell activation and differentiation and suggest that timely initiation of mTORi-based primary prophylaxis may provide a dual benefit of revitalizing T cell function while maintaining allograft tolerance.

[Emotional and physical aftereffects of cancer Utility and impact of a rehabilitation program]. / Séquelles émotionnelles et physiques du cancer. Utilité et impact d'un programme de réadaptation.

An increasing number of people are surviving cancer in Switzerland : 163,450 people were still alive in 2006 after a cancer diagnosis less than ten years prior, compared to 210,350 in 2016. However, most have to cope with debilitating emotional and physical aftereffects. A new 12-week rehabilitation program aims to restore patients' abilities. It consists of group-led therapies: adapted physical activity, psycho-oncology, dietetics, management of cognitive disorders, and integrative medicine. The first 116 patients who benefited from the program reported a general reduction in symptoms at the end of the program, an improvement that lasts even after 9 months, although fatigue and mood become concerning again. Some express a desire for post-rehabilitation follow-up.

De plus en plus de personnes survivent au cancer en Suisse : 163 450 personnes étaient encore en vie après un diagnostic de cancer remontant à moins de dix ans en 2006, contre 210 350 en 2016. La plupart doivent toutefois faire face à des séquelles émotionnelles et physiques invalidantes. Un nouveau programme de réadaptation de 12 semaines vise à restaurer les capacités des patients. Il est composé de thérapies menées en groupe : activité physique adaptée, psycho-oncologie, diététique, gestion des troubles cognitifs et médecine intégrative. Les 116 premiers patients bénéficiaires expriment une diminution générale des symptômes à l'issue du programme, une amélioration qui perdure après 9 mois, même si la fatigue et le moral redeviennent préoccupants. Certains expriment le souhait d'un suivi post-réadaptation.

Modeling tumor size dynamics based on real-world electronic health records and image data in advanced melanoma patients receiving immunotherapy.

The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer therapy but only a fraction of patients benefits from this therapy. Model-informed drug development can be used to assess prognostic and predictive clinical factors or biomarkers associated with treatment response. Most pharmacometric models have thus far been developed using data from randomized clinical trials, and further studies are needed to translate their findings into the real-world setting. We developed a tumor growth inhibition model based on real-world clinical and imaging data in a population of 91 advanced melanoma patients receiving ICIs (i.e., ipilimumab, nivolumab, and pembrolizumab). Drug effect was modeled as an ON/OFF treatment effect, with a tumor killing rate constant identical for the three drugs. Significant and clinically relevant covariate effects of albumin, neutrophil to lymphocyte ratio, and Eastern Cooperative Oncology Group (ECOG) performance status were identified on the baseline tumor volume parameter, as well as NRAS mutation on tumor growth rate constant using standard pharmacometric approaches. In a population subgroup (n = 38), we had the opportunity to conduct an exploratory analysis of image-based covariates (i.e., radiomics features), by combining machine learning and conventional pharmacometric covariate selection approaches. Overall, we demonstrated an innovative pipeline for longitudinal analyses of clinical and imaging RWD with a high-dimensional covariate selection method that enabled the identification of factors associated with tumor dynamics. This study also provides a proof of concept for using radiomics features as model covariates.

Semiautomated Pipeline to Quantify Tumor Evolution From Real-World Positron Emission Tomography/Computed Tomography Imaging.

PURPOSE: A semiautomated pipeline for the collection and curation of free-text and imaging real-world data (RWD) was developed to quantify cancer treatment outcomes in large-scale retrospective real-world studies. The objectives of this article are to illustrate the challenges of RWD extraction, to demonstrate approaches for quality assurance, and to showcase the potential of RWD for precision oncology. METHODS: We collected data from patients with advanced melanoma receiving immune checkpoint inhibitors at the Lausanne University Hospital. Cohort selection relied on semantically annotated electronic health records and was validated using process mining. The selected imaging examinations were segmented using an automatic commercial software prototype. A postprocessing algorithm enabled longitudinal lesion identification across imaging time points and consensus malignancy status prediction. Resulting data quality was evaluated against expert-annotated ground-truth and clinical outcomes obtained from radiology reports. RESULTS: The cohort included 108 patients with melanoma and 465 imaging examinations (median, 3; range, 1-15 per patient). Process mining was used to assess clinical data quality and revealed the diversity of care pathways encountered in a real-world setting. Longitudinal postprocessing greatly improved the consistency of image-derived data compared with single time point segmentation results (classification precision increased from 53% to 86%). Image-derived progression-free survival resulting from postprocessing was comparable with the manually curated clinical reference (median survival of 286 v 336 days, P = .89). CONCLUSION: We presented a general pipeline for the collection and curation of text- and image-based RWD, together with specific strategies to improve reliability. We showed that the resulting disease progression measures match reference clinical assessments at the cohort level, indicating that this strategy has the potential to unlock large amounts of actionable retrospective real-world evidence from clinical records.

[Is ketogenic diet effective against cancer ?] / Le régime cétogène : efficace contre le cancer ?

The ketogenic diet, which consists of reduced carbohydrate intake and increased fat intake, is a recognized treatment option for children with intractable epilepsy. This diet is now receiving renewed interest from physicians and researchers because of its potential therapeutic effect in other diseases, such as neurodegenerative diseases, metabolic syndrome or cancer. Since cancer is one of the major public health challenges, complementary approaches to improve the efficacy of standard anti-cancer therapies are the subject of much research. This article reviews the place of the ketogenic diet as a complementary therapy in cancer, the scientific evidence and possible practical aspects of such an approach.

Le régime cétogène vise à réduire l'apport nutritionnel d'hydrates de carbone en augmentant les lipides. Ce régime est une option thérapeutique reconnue, en particulier chez les enfants souffrant d'épilepsie réfractaire. Il fait aujourd'hui l'objet d'un regain d'intérêt de la part des médecins et des chercheurs, en raison de son potentiel effet thérapeutique dans d'autres pathologies comme certaines maladies neurodégénératives, le syndrome métabolique ou même le cancer. Le cancer étant l'un des grands défis de santé publique, les approches complémentaires pour améliorer l'efficacité des thérapies anticancéreuses standards font l'objet de nombreuses recherches. Cet article fait le point sur la place du régime cétogène comme thérapie complémentaire dans le cancer, les évidences scientifiques et les éventuels aspects pratiques d'une telle approche.

[Management of brain metastases in 2022]. / Prise en charge des métastases cérébrales en 2022.

Brain metastases (BM) are a common occurrence of systemic cancers. Technical improvements in neuroimaging offer additional tools for an early detection of BM, to target them precisely and differentiate these lesions from other cerebral pathologies. The therapeutic tools have also evolved from neurosurgery and whole brain therapy to include stereotactic radiosurgery, targeted and immune therapies. Given the numerous treatment options available, a multidisciplinary approach is essential to offer the patient a personalized approach to optimize the sequence and combination of treatments to offer the best outcome possible. This article aims to review key elements of diagnosis, risk stratification and modern treatment paradigms in the diagnosis and management of BM.

Les métastases cérébrales (MC) sont une manifestation fréquente des cancers systémiques. Les améliorations des techniques de radiologie offrent des options supplémentaires pour détecter de manière précoce les MC, les cibler avec précision et les différencier d'autres pathologies. Les outils thérapeutiques se sont également élargis pour inclure des techniques de radiothérapie stéréotaxiques, des thérapies ciblées et des immunothérapies. Au vu des nombreuses options de traitement pour les patients souffrant de MC, une approche multidisciplinaire doit impérativement être favorisée pour personnaliser le traitement de chaque patient et améliorer le pronostic. Cet article décrit les éléments clés du diagnostic, de la stratification du risque et les paradigmes modernes de la prise en charge et des traitements des patients avec MC.

Physical approaches to treat glioblastoma.

PURPOSE OF REVIEW: Glioblastoma (GBM) patients have a poor prognosis despite the use of modern synergistic multimodal treatment strategies, with a progression-free survival estimated at 7-8 months, a median survival of 14-16 months and 5-year overall survival of 9.8%. RECENT FINDINGS: Physical methods hold the promise to act synergistically with classical treatments to improve the outcome of GBM patients. Fluorescent guided surgery with 5-aminolevulinic acid and tumor-treating fields therapy have already shown positive results in randomized phase III trials and have been incorporated in the standard management. Other techniques such as photodynamic therapy (PDT) and focused ultrasound, often combined whit microbubbles, are reaching clinical development. SUMMARY: Several clinical trials to evaluate the feasibility and efficacy of ultrasound devices to disrupt the blood-brain barrier are ongoing. PDT enables the creation of a safety margin or treatment of non-resecable tumors. However, randomized trials are urgently required to validate the efficacy of these promising approaches. We aim to critically review physical approaches to treat GBM, focusing on available clinical trial data.

Neurological Adverse Events Associated with Immune Checkpoint Inhibitors: Diagnosis and Management.

PURPOSE OF REVIEW: Immune checkpoint inhibitors represent a major step forward in the field of oncologic immunotherapy these last years and have significantly increased survival of cancer patients in an ever-growing number of indications. These agents block specific immune checkpoint molecules (programmed cell death protein 1 and its ligand as well as cytotoxic T-lymphocyte-associated antigen 4) that normally downregulate the immune response. These new agents show a specific range of adverse effects induced by abnormal immunologic activation. RECENT FINDINGS: Many different neurologic adverse events have been described, including encephalitis, myelopathy, aseptic meningitis, meningoradiculitis, Guillain-Barré-like syndrome, peripheral neuropathy (including mononeuropathy, mononeuritis multiplex, and polyneuropathy) as well as myasthenic syndrome. Immune checkpoint inhibitors have shown promising results in cancer but can possibly induce autoimmune disorders. Although rare, neurological adverse events require prompt recognition and treatment to avoid substantial morbidity.

[Palliative care for glioblastoma]. / Prise en charge palliative des glioblastomes.

Patients with glioblastoma have a limited life expectancy and an impaired quality of life and they should be offered palliative care soon after the diagnosis is established. Still, only a quarter of patients aged over 65 return home or medical institution after completing treatments. Home care must be promoted by coordinating assistance and care, combining disciplines such as physiotherapy and ergotherapy, medical and nursing care and psychosocial support. Patients are at risk of mood, personality and behavioural disorders. Limited awareness of these troubles and their physical limitations alter their capacity of rehabilitation and social relationships. Isolation of relatives, exhaustion and misunderstandings should be prevented. The therapeutic goals should be discussed and determined upstream to anticipate difficulties and questions concerning end of life.