Clinical Pharmacology and Interplay of Immune Checkpoint Agents: A Yin-Yang Balance.

T cells have a central role in immune system balance. When activated, they may lead to autoimmune diseases. When too anergic, they contribute to infection spread and cancer proliferation. Immune checkpoint proteins regulate T cell function, including cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) and its ligand (PD-L1). These nodes of self-tolerance may be exploited pharmacologically to downregulate (CTLA-4 agonists) and activate [CTLA-4 and PD-1/PD-L1 antagonists, also called immune checkpoint inhibitors (ICIs)] the immune system.CTLA-4 agonists are used to treat rheumatologic immune disorders and graft rejection. CTLA-4, PD-1, and PD-L1 antagonists are approved for multiple cancer types and are being investigated for chronic viral infections. Notably, ICIs may be associated with immune-related adverse events (irAEs), which can be highly morbid or fatal. CTLA-4 agonism has been a promising method to reverse such life-threatening irAEs. Herein, we review the clinical pharmacology of these immune checkpoint agents with a focus on their interplay in human diseases.

Evaluation of supportive care needs, sexuality and quality of life in phase 1 trials: a prospective monocentric study.

PURPOSE: Patients enrolled in oncology phase 1 trials (ph1) usually have advanced heavily pre-treated cancers with few therapeutic options. Quality of life (QoL) is one of the key cancer-treatment outcome measures, especially in ph1, and sexuality is an important part of Qol but rarely explored. This prospective study aims to assess supportive care needs, QoL and sexuality in ph1. METHODS: Between September 2020 and June 2021, we prospectively recruited patients enrolled in ph1 at Gustave Roussy in France. Supportive care needs, QoL (EORTC QLQ-C30) and sexuality (female sexual function index for women, male sexual health questionnaire [MSHQ] for men) were assessed at baseline, one, three and 5 months. We performed multivariate analyses to identify associations between clinical characteristics, QoL and quality of sexual life over time. RESULTS: At baseline, we analyzed 187 patients (45% women (n = 84) and 55% men (n = 103)). Patients expressed the need for consultations in pain management, nutrition, psychology and sexology in 28%, 26%, 19% and 9%, respectively. Lower global QoL was independently associated with Royal Marsden Hospital score (p = 0.012), urogenital location tumor (p = 0.021), elevated CRP levels (p = 0.014) and pain intensity (p = 0.005). Ninety-two percent of women had sexual dysfunction. In men, a lower MSHQ score was independently associated with urogenital location tumor (p = 0.021), ECOG Performance Status (p = 0.006), comorbidity at risk (p = 0.024) and pain intensity (p = 0.004). CONCLUSIONS: There are significant needs for supportive care in ph1, especially in some subgroups of patients. New models of care should be developed to improve early phase pathways.

Late phase 1 studies: concepts and outcomes.

Over the past two decades, targeted therapies have become cornerstone treatments for numerous cancers with oncogene addiction. Unfortunately, their effectiveness reduces over time and most patients who receive targeted therapies relapse within 12 months. The emergence of drug-resistance mechanisms in tumours paved the way for next-generation inhibitors. However, insufficient concentration of targeted therapy is a frequent but poorly explored mechanism of treatment failure. Additionally, the maximum tolerated dose (MTD) is not always reached in phase studies, and the recommended phase 2 dose is mostly based on benefit-risk ratio and pharmacokinetic considerations, which could result in a suboptimal dose. This scenario has led us to propose a new concept in clinical drug development: the late phase 1 study. The primary goal of this type of trial is to define an alternative MTD of a drug in patients who are chronically exposed and had an initial benefit from targeted therapy but subsequently progressed without an identified resistance alteration. Intrapatient dose escalation might increase drug concentration and restore drug activity or efficacy.

The Effect of Concomitant Proton Pump Inhibitor and Cabozantinib on the Outcomes of Patients with Metastatic Renal Cell Carcinoma.

INTRODUCTION: Cabozantinib is an oral tyrosine kinase inhibitor that is approved for the treatment of metastatic renal cell carcinoma (mRCC). Cabozantinib is a weak base that exhibits a pH-dependent solubility profile in vitro which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPIs). The purpose of this study was to investigate whether PPI use has an impact on the efficacy, safety, and residual concentration (Ctrough) of cabozantinib in patients with mRCC. MATERIALS AND METHODS: This is a retrospective review of a prospectively collected electronic database of patients with mRCC who received cabozantinib at Gustave Roussy between February 2014 and December 2018. The Kaplan-Meier method was used for survival analysis and the Cox proportional-hazard model for uni- and multivariate analysis. In parallel, we conducted a pharmacokinetic study of cabozantinib in a distinct cohort of 50 mRCC patients, in which cabozantinib Ctrough was assayed using a validated tandem mass spectrometry-liquid chromatography method. RESULTS: We identified 99 patients treated with cabozantinib, including 43 patients being PPI users. With a median follow-up of 30.3 months, PPI users showed similar progression-free survival and overall survival outcomes compared with PPI nonusers. Similarly, the incidence of adverse events was not significantly different between the PPI users and nonusers, although PPI users required dose reductions more often. In the independent pharmacokinetic cohort, of whom 21 received PPI concomitantly, Ctrough was similar between the two groups. CONCLUSION: In line with the pharmacologic data, the concomitant use of PPI does not significantly impact the efficacy or safety of cabozantinib in patients with mRCC. IMPLICATIONS FOR PRACTICE: Drug interactions, especially between targeted therapies and proton pump inhibitors (PPI), were shown to potentially impact the outcomes of cancer patients. Cabozantinib, a current therapeutic standard in metastatic renal cell carcinoma (mRCC), exhibits a pH-dependent solubility profile, which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPI). At the present time, there is no evidence regarding the effect of PPIs on cabozantinib's efficacy and safety in patients with mRCC. This study found that the concomitant use of PPI during cabozantinib treatment in mRCC patients does not appear to impact the residual concentration, efficacy, and safety of cabozantinib in a real-life context.

Preliminary experience of the concurrent use of radiosurgery and T-DM1 for brain metastases in HER2-positive metastatic breast cancer.

This is preliminary study assessing the efficacy and safety of concurrent use of radiation therapy (RT) and T-DM1 for the treatment of brain metastases (BM) in patients with HER2-positive metastatic breast cancer (BC). We retrospectively studied 12 patients treated for BM at the Institut Curie in 2014-2015 with T-DM1 and concurrent (4) or sequential (8) radiosurgery with or without whole brain irradiation. The following variables were studied: local control, clinical and radiological response as well as early and late side effects. The mean age of the population was 38 years at the time of diagnosis of BC and 46 years at of BM. All patients were with good PS. The response rate of the concurrent treatment group was 75 % with 1 complete response, 1 partial response, one stable disease and 1 progression. Comparatively, the response rate in the sequential group was as follows: two complete responses, two partial responses, six cases of stable disease and two cases of local progression. No patient experienced interruption of irradiation because of side effects. About 50 % of patients were asymptomatic after treatment. Radiation necrosis was observed in 50 % of patients in the concurrent group and 28.6 % of patients in the sequential group with a similar rate of oedema in the two groups. We found that the combination of T-DM1 and radiosurgery was feasible but can increase the incidence of radiation necrosis. Larger prospective studies with longer follow-up are needed to more clearly evaluate this association.

Management of Pain Medication in Patients With a History of Bariatric Surgery: A Systematic Review.

CONTEXT: Obesity prevalence is persistently increasing worldwide. Among surgical therapeutic procedures, bypass surgery and sleeve gastrectomy have shown the best results regarding weight loss, prevention, and treatment of secondary complications. However, these surgeries are associated with an increased risk of malabsorption and metabolic changes that could further affect the pharmacokinetics of drugs. On the other hand, patients with a history of such surgeries are more likely to experience pain and request analgesic initiation or adaptation. The question of how to manage pain medication in these patients is challenging due to their narrow therapeutic indexes. OBJECTIVES: To summarize the current literature on the impact of bariatric surgery on the subsequent pharmacokinetics of analgesics and propose a multidisciplinary therapeutic attitude to optimize pain management in these patients. METHODS: We conducted a systematic review that included all pharmacological studies published after 2000. RESULTS: Unexpectedly, these surgeries seem to increase the bioavailability of drugs by long-term improvement of hepatic function. Yet, the medical community drastically lacks robust guidelines for pain management in those patients. This systematic review aims to bring together pharmacological studies related to the use of pain treatments in patients who underwent bypass surgery or sleeve gastrectomy. CONCLUSIONS: Caution should be exercised regarding the risk of overdose in every circumstance: treatment initiation, change of doses, or change of molecule. More prospective trials comparing the pharmacokinetics of medications in obese patients with and without prior bariatric surgery are needed.

A Score to Predict the Clinical Usefulness of Therapeutic Drug Monitoring: Application to Oral Molecular Targeted Therapies in Cancer.

Therapeutic drug monitoring (TDM) involves measuring and interpreting drug concentrations in biological fluids to adjust drug dosages. In onco-hematology, TDM guidelines for oral molecular targeted therapies (oMTTs) are varied. This study evaluates a quantitative approach with a score to predict the clinical usefulness of TDM for oMTTs. We identified key parameters for an oMTT's suitability for TDM from standard TDM recommendations. We gathered oMTT pharmacological data, which covered exposure variability (considering pharmacokinetic (PK) impact of food and proton pump inhibitors), technical intricacy (PK linearity and active metabolites), efficacy (exposure-response relationship), and safety (maximum tolerated dose, and exposure-safety relationship). To assess the validity and the relevance of the score and define relevant thresholds, we evaluated molecules with prospective validation or strong recommendations for TDM, both in oncology and in other fields. By September 1, 2021, the US Food and Drug Administration (FDA) approved 67 oMTTs for onco-hematological indications. Scores ranged from 15 (acalabrutinib) to 80 (sunitinib) with an average of 48.3 and a standard deviation of 15.6. Top scorers included sunitinib, sorafenib, cabozantinib, nilotinib, and abemaciclib. Based on scores, drugs were categorized into low (< 40), intermediate (≥ 40 and < 60), and high (≥ 60) relevance for TDM. Notably, negative controls generally scored around or under 40, whereas positive controls had a high score across different indications. In this work, we propose a quantitative and reproducible score to compare the potential usefulness of TDM for oMTTs. Future guidelines should prioritize the TDM for molecules with the highest score.

Reactions and adverse events induced by T-cell engagers as anti-cancer immunotherapies, a comprehensive review.

T-cell engagers (TCE) are cancer immunotherapies that have recently demonstrated meaningful benefit for patients with hematological malignancies and solid tumors. The anticipated widespread use of T cell engagers poses implementation challenges and highlights the need for guidance to anticipate, mitigate, and manage adverse events. By mobilizing T-cells directly at the contact of tumor cells, TCE mount an obligatory and immediate anti-tumor immune response that could result in diverse reactions and adverse events. Cytokine release syndrome (CRS) is the most common reaction and is largely confined to the first drug administrations during step-up dosage. Cytokine release syndrome should be distinguished from infusion related reaction by clinical symptoms, timing to occurrence, pathophysiological aspects, and clinical management. Other common reactions and adverse events with TCE are immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), infections, tumor flare reaction and cytopenias. The toxicity profiles of TCE and CAR-T cells have commonalities and distinctions that we sum-up in this review. As compared with CAR-T cells, TCE are responsible for less frequently severe CRS or ICANS. This review recapitulates terminology, pathophysiology, severity grading system and management of reactions and adverse events related to TCE.

Antibody drug conjugates in older patients: State of the art.

More than half of cancer cases occur in patients aged 65 years or older. The efficacy and safety of antibody drug conjugates (ADCs) in older patients remains an unclear subject as available evidence is limited. Geriatric population is underrepresented in clinical trials. Consequently, most of our knowledge regarding innovative therapeutics was studied on a younger population. In this review of published literature, we report the available information on efficacy, safety and pharmacokinetics of FDA approved ADCs for hematologic malignancies and solid tumors in the geriatric population. We explore the results of clinical trials dedicated for older individuals as well as subgroup analyses of the geriatric population in major trials evaluating these drugs. Available data suggest a similar efficacy in older adults as compared to general population. However, older patients might be prone to a higher rate of adverse events in incidence with a potential impact on quality of life. We lack data to support primary dose reductions or schedule modifications in this category of patients. No pharmacokinetic differences were reported between age groups. It is crucial to encourage the development of clinical trials dedicated to older patients with geriatric parameters (G8 score, G-CODE…) so that results can be more representative of this population outside of clinical trials.

Genomic landscape of liquid biopsy mutations in TP53 and DNA damage genes in cancer patients.

Next-generation sequencing (NGS) assays based on plasma cell-free DNA (cfDNA) are increasingly used for clinical trials inclusion. Their optimized limit of detection applied to a large number of genes leads to the identification of mutations not confirmed in tissue. It becomes essential to describe the characteristics and consequences of these liquid biopsy-only mutations. In the STING protocol (Gustave Roussy, NCT04932525), 542 patients with advanced solid cancer had cfDNA-based and tissue-based NGS analysis (performed by FoundationOne® Liquid CDx and FoundationOne CDx™, respectively). Mutations identified in the liquid biopsy but not in the paired tissue were considered as liquid biopsy-only mutations irrespective of their variant allelic frequency (VAF). Out of 542 patients, 281 (51.8%) harbored at least one liquid biopsy-only mutation. These patients were significantly older, and more heavily pretreated. Liquid biopsy-only mutations occurring in TP53, and in DDR genes (ATM, CHEK2, ATR, BRCA2, and BRCA1) accounted for 90.8% of all the mutations. The median VAF of these mutations was generally low (0.37% and 0.40% for TP53 and DDR genes respectively). The variant type repartition depended on the gene. Liquid biopsy-only mutations affected hotspot in TP53 codon 273, 125, 195, 176, 237 or 280 and ATM codon 2891 and 3008. In a subset of 37 patients, 75.0%, 53.5% and 83.3% of the liquid biopsy-only mutations occurring respectively in ATM, TP53, and CHEK2 were confirmed in the matching whole blood sample. Although liquid biopsy-only mutations makes the interpretation of liquid biopsy results more complex, they have distinct characteristics making them more easily identifiable.

Radiological patterns of tumour progression in patients treated with a combination of immune checkpoint blockers and antiangiogenic drugs.

BACKGROUND: Immune checkpoint blockers (ICBs) in combination with antiangiogenic drugs showed synergistic efficacy in several tumour types. New patterns of progression have recently been defined upon treatment with ICB alone including atypical responses such as pseudoprogression (PsPD), dissociated response and hyperprogressive disease (HPD). This study aimed to describe the patterns of response observed in patients treated with combination ICB with antiangiogenic drugs. METHODS: We conducted a monocentric retrospective analysis of patients (pts) enrolled in phase I trials at Gustave Roussy assessing the combination of ICB and antiangiogenic drugs. Radiological CT scans were centrally reviewed by a senior radiologist according to iRECIST criteria including progressive disease (PD), partial response (PR) and stable disease (SD). HPD was defined as a progression at the first evaluation with a delta tumour growth rate exceeding 50%. PsPD was defined as initial progression followed by stabilisation or decrease of tumour size, DisR as a concomitant size decrease in some tumour lesions and size increase in others. Both PsPD and DisR are defined as atypical responses. Overall response rate included PR and complete response (CR) and disease control rate included PR, CR and SD. RESULTS: Between December 2016 and June 2020, 111 pts were included. The median follow up was 12.8 months (11.3-15.1). The most common tumour types were lung and pleura (20%), kidney (18%) and bladder (17%). The overall response rate and disease control rate were 21.6% (n = 24) and 59% (n = 65), respectively. Twenty-one patients (19%) experienced PD as the best response. PsPD, DisR and HPD were observed in 4 (3.6%), 11 (9.9%) and 7 (6.3%) pts, respectively. DisR and PsPD were associated with longer iProgression Free Survival (median: 6.9 and 18.9 months, respectively) and iOverall Survival (median: 28.4 and 31.1 months, respectively) than a median of SD in immune progression-free survival (median: 4.2 months) and immune overall survival (median: 12.7 months). CONCLUSION: Patients treated with ICBs and antiangiogenic agents display atypical responses. Survival might be longer in patients with DisR responses and PsPD disease than patients with HPD, PD and SD.

Next-Generation Sequencing on Circulating Tumor DNA in Advanced Solid Cancer: Swiss Army Knife for the Molecular Tumor Board? A Review of the Literature Focused on FDA Approved Test.

FDA-approved next-generation sequencing assays based on cell-free DNA offers new opportunities in a molecular-tumor-board context thanks to the noninvasiveness of liquid biopsy, the diversity of analyzed parameters and the short turnaround time. It gives the opportunity to study the heterogeneity of the tumor, to elucidate complex resistance mechanisms and to adapt treatment strategies. However, lowering the limit of detection and increasing the panels' size raise new questions in terms of detection of incidental germline alterations, occult malignancies and clonal hematopoiesis of indeterminate potential mutations. In this review, after a technological discussion and description of the common problematics encountered, we establish recommendations in properly using these FDA-approved tests in a molecular-tumor-board context.

PALLIA 10 score in phase I cancer studies.

OBJECTIVE: Phase I clinical trials usually include patients with advanced disease who have failed standard therapies and should benefit from early palliative care. We try to assess whether PALLIA 10, a score developed in France to help identify patients who might benefit from a palliative care referral, could be used in a phase I department trial. METHODS: We assessed PALLIA 10 score and other prognostic factors in patients enrolled in phase I trials at Gustave Roussy Cancer Center prospectively during two periods of time (cohort 1 (C1) and 2 (C2)). A double-blind assessment of the PALLIA 10 score was done in C2 by a palliative care specialist and a nurse. RESULTS: From 1 July 2018 to 1 November 2018 (C1) and from 1 December 2020 to 16 April 2021 (C2), 86 patients were assessed in C1 and 302 in C2. Median PALLIA 10 was very low in both cohorts (median 1, range 1-5 in C1 and 1-8 in C2). On C1 and C2, 12% and 5% of patients had a dedicated palliative consultation. In C2, assessment of PALLIA 10 score was significantly different between palliative care physician (median 5, range 3-8), phase I physician (median 1, range 1-6) and phase I nurse (median 3, range 1-8) (p<0.001). CONCLUSION: Median PALLIA 10 score was low when assessed by the phase I physician, which suggests the need for a better tool and appropriate clinician's education to implement early palliative care in clinical practice and trials.

Implementing the European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets in a Comprehensive Profiling Program: Impact on Precision Medicine Oncology.

PURPOSE: To facilitate implementation of precision medicine in clinical management of cancer, the European Society of Medical Oncology proposed in 2018 a new scale to harmonize and standardize the reporting and interpretation of clinically relevant genomics data (ESMO Scale of Actionability of molecular Targets [ESCAT]). This study aims to characterize the clinical impact of matching targetable genomic alterations (GAs) in patients with advanced cancer according to ESCAT. MATERIAL AND METHODS: Analysis of next-generation sequencing results from 552 patients is included in two prospective precision medicine studies at Gustave Roussy. End points included objective response rates, progression-free survival, and overall survival according to ESCAT. RESULTS: Molecular data from 516 patients were available and discussed within a Molecular Tumor Board. The most common tumor types were GI (n = 164; 30%), lung (n = 137; 25%), and urologic tumors (n = 68; 13%). Overall, 379 GAs were considered as actionable targets according to ESCAT in 348 (67%) patients. In 31 (6%) patients, two concomitant actionable targets were identified. On the basis of ESCAT, GAs were considered to be classified as tier I in 120 patients (29%), II in 25 patients (5%), III in 80 patients (16%), and IV in 153 patients (30%). A total of 136 patients (27%) received a matched therapy. ESCAT was significantly associated with objective response rates and clinical benefit rates. The median progression-free survival was 6.5 months (95% CI, 4.2 to 8.9), 3 months (95% CI, 1 to not available), 3 months (95% CI, 2.2 to 3.8), and 4 months (95% CI, 2.8 to 6.3) for ESCAT I, II, III, and IV, respectively (P = .0125). CONCLUSION: Implementation of ESCAT classification for clinical decision making by Molecular Tumor Board is feasible and useful to better tailor therapies in patients with cancer.

The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals.

Vaccination against coronavirus disease 2019 (COVID-19) relies on the in-depth understanding of protective immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We characterized the polarity and specificity of memory T cells directed against SARS-CoV-2 viral lysates and peptides to determine correlates with spontaneous, virus-elicited, or vaccine-induced protection against COVID-19 in disease-free and cancer-bearing individuals. A disbalance between type 1 and 2 cytokine release was associated with high susceptibility to COVID-19. Individuals susceptible to infection exhibited a specific deficit in the T helper 1/T cytotoxic 1 (Th1/Tc1) peptide repertoire affecting the receptor binding domain of the spike protein (S1-RBD), a hotspot of viral mutations. Current vaccines triggered Th1/Tc1 responses in only a fraction of all subject categories, more effectively against the original sequence of S1-RBD than that from viral variants. We speculate that the next generation of vaccines should elicit Th1/Tc1 T-cell responses against the S1-RBD domain of emerging viral variants. SIGNIFICANCE: This study prospectively analyzed virus-specific T-cell correlates of protection against COVID-19 in healthy and cancer-bearing individuals. A disbalance between Th1/Th2 recall responses conferred susceptibility to COVID-19 in both populations, coinciding with selective defects in Th1 recognition of the receptor binding domain of spike. See related commentary by McGary and Vardhana, p. 892. This article is highlighted in the In This Issue feature, p. 873.

Potential cytochrome P450-mediated pharmacokinetic interactions between herbs, food, and dietary supplements and cancer treatments.

Herbs, food and dietary supplements (HFDS), can interact significantly with anticancer drug treatments via cytochrome p450 isoforms (CYP) CYP3A4, CYP2D6, CYP1A2, and CYP2C8. The objective of this review was to assess the influence of HFDS compounds on these cytochromes. Interactions with CYP activities were searched for 189 herbs and food products, 72 dietary supplements in Web of Knowledge® databases. Analyses were made from 140 of 3125 clinical trials and 236 of 3374 in vitro, animal model studies or case reports. 18 trials were found to report direct interactions between 9 HFDS with 8 anticancer drugs. 21 HFDS were found to interact with CYP3A4, a major metabolic pathway for many anticancer drugs. All 261 HFDS were classified for their interaction with the main cytochromes P450 involved in the metabolism of anticancer drugs. We provided an easy-to-use colour-coded table to easily match potential interactions between 261 HFDS and 117 anticancer drugs.

[Impact of the use of systemic corticosteroid therapy on the effectiveness of immune checkpoint inhibitors]. / Impact de l'utilisation de la corticothérapie systémique sur l'efficacité des inhibiteurs de points de contrôle immunitaire.

Immunotherapy, which consists in using molecules targeting the immune system, has existed for many years in oncology (vaccines, interleukins, monoclonal antibodies) but has recently expanded due to the development of immune checkpoint inhibitors. These monoclonal antibodies help to restore the immunity against cancer by specifically targeting some immune checkpoints such as CTLA-4, PD-1 and PD-L1. Furthermore, in oncology, it is common to use systemic corticosteroids in the management of symptoms linked to the natural history of the disease (pain, spinal cord compression, cerebral edema) and toxicities linked to anticancer treatment. The impact of corticosteroids on the efficacy of immune checkpoint inhibitors is still poorly understood and they should be used cautiously. According to previously published studies, there seems to be a deleterious effect of corticosteroid therapy on the efficacy of immune checkpoint inhibitors when administered before or at the initiation of immunotherapy, while this effect does not seem present when corticosteroids are administered to patients already undergoing immunotherapy. The aim of this work is to analyze the existing data evaluating the impact of corticosteroid use of on the efficacy of immune checkpoint inhibitors.

[Intercontinental Multidisciplinary Oncology Videoconferencing between the South Pacific and the French mainland: Results after one year and 323 cases of rare or complex cancers discussed]. / RCP Pacifique : bilan après un an et 323 cancers rares et/ou complexes discutés.

INTRODUCTION: Overseas France represents 18 % of French territory and is home to 4 % of its population for whom there is unequal treatment in the field of rare/complex cancer. AIM: To report our experience of intercontinental multidisciplinary videoconferencing between the French mainland and Pacific territories. METHODS: Every other friday, three centers located in Papeete, Nouméa and Paris-Villejuif connected between 6:30 AM and 8:00 AM GMT to discuss cases of rare/complex cancers. RESULTS: Between November 2019 and December 2020, 323 presentations implicating 233 patients involved sarcoma (n=93), digestive pathology (n=60), neuroendocrine tumors (n=35), urology (n=24), gynecology (n=24), neurology (n=16), thyroid pathology (n=14), dermatology (n=14), senology (n=11), hematology (n=11), ENT pathology (n=10), pathology thoracic (n=10) and pediatrics (n=1). Of the 233 patients, 134 (57.5 %) living in New Caledonia and 99 (42.5 %) in French Polynesia, 117 (50.5 %) had metastatic disease. 39 patients (16.7 %) were transferred to French mainland (EVASAN), for surgery (n=25), vectorized radiotherapy (n=7), biopsy (n=5), chemotherapy (n=1) or inclusion in a clinical trial (n=1). 195 patients (83.7 %) were treated at home, 15 (6.4 %) are still awaiting a decision and 4 (1.7 %) lost to follow-up. CONCLUSION: The use of videoconferencing to discuss rare/complex cancer cases was effective in guaranteeing French overseas population access to innovative therapies and clinical trials, limiting the need for intercontinental transfer to 16.7 %.

Circulating acetylated polyamines correlate with Covid-19 severity in cancer patients.

Cancer patients are particularly susceptible to the development of severe Covid-19, prompting us to investigate the serum metabolome of 204 cancer patients enrolled in the ONCOVID trial. We previously described that the immunosuppressive tryptophan/kynurenine metabolite anthranilic acid correlates with poor prognosis in non-cancer patients. In cancer patients, we observed an elevation of anthranilic acid at baseline (without Covid-19 diagnosis) and no further increase with mild or severe Covid-19. We found that, in cancer patients, Covid-19 severity was associated with the depletion of two bacterial metabolites, indole-3-proprionate and 3-phenylproprionate, that both positively correlated with the levels of several inflammatory cytokines. Most importantly, we observed that the levels of acetylated polyamines (in particular N1-acetylspermidine, N1,N8-diacetylspermidine and N1,N12-diacetylspermine), alone or in aggregate, were elevated in severe Covid-19 cancer patients requiring hospitalization as compared to uninfected cancer patients or cancer patients with mild Covid-19. N1-acetylspermidine and N1,N8-diacetylspermidine were also increased in patients exhibiting prolonged viral shedding (>40 days). An abundant literature indicates that such acetylated polyamines increase in the serum from patients with cancer, cardiovascular disease or neurodegeneration, associated with poor prognosis. Our present work supports the contention that acetylated polyamines are associated with severe Covid-19, both in the general population and in patients with malignant disease. Severe Covid-19 is characterized by a specific metabolomic signature suggestive of the overactivation of spermine/spermidine N1-acetyl transferase-1 (SAT1), which catalyzes the first step of polyamine catabolism.

Intercontinental Multidisciplinary Oncology Videoconferencing for Rare and Complex Cancer: An Alternative to Systematic Transfer.

PURPOSE: To report our experience of intercontinental multidisciplinary oncology videoconferencing between the French mainland and South Pacific to discuss rare and/or complex cancer cases. METHODS: On the first and third Friday of each month, all participants connected between 6:30 am and 8:00 am GMT to discuss using a web conference service. RESULTS: Between November 2019 and April 2020, 99 cases concerning 78 patients were discussed. Oncology subspecialties required were sarcoma (n = 36), digestive (n = 29), dermatology (n = 5), gynecology (n = 5), breast (n = 5), urology (n = 5), hematology (n = 5), ENT (n = 3), thoracic (n = 3), thyroid (n = 2), and pediatric (n = 1). Median patient age was 58 years, 41 were female (53%), 37 were male (47%), and 43 had a metastatic disease (55%). Following discussion, 16 patients (21%) were transferred to the French mainland. Reasons for transfer were requirement for complex surgery (n = 11) and need for specialized diagnostic biopsy (n = 5). Fifty-six patients were treated locally, with systemic chemotherapy (n = 36), surveillance (n = 8), surgery (n = 8), radiotherapy (n = 3), or endoscopy (n = 1). Direct benefits for patients treated in their local facility included strategy changes (surveillance or surgery contraindication, n = 9), targeted therapy decision (n = 14), immunotherapy decision (n = 9), and diagnostic or metastatic status corrections (n = 4). Six patients are still awaiting decision. CONCLUSION: Using real-time intercontinental multidisciplinary oncology videoconferencing to discuss complex or rare cancer cases is reliable and effective for decision making. This concept helped to limit to 21% the need for transfers to the mainland.