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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

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

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

PURPOSE: Patients with cancer are presumed to be more vulnerable to COVID-19. We evaluated a screening strategy combining chest computed tomography (CT) and reverse-transcription polymerase chain reaction (RT-PCR) for patients treated with radiation therapy at our cancer center located in a COVID-19 French hotspot during the first wave of the pandemic. METHODS AND MATERIALS: Chest CT images were proposed during radiation therapy CT simulation. Images were reviewed by an expert radiologist according to the COVID-19 Reporting and Data System classification. Nasal swabs with RT-PCR assay were initially proposed in cases of suspicious imaging or clinical context and were eventually integrated into the systematic screening. A dedicated radiation therapy workflow was proposed for COVID-19 patients to limit the risk of contamination. RESULTS: From March 18, 2020 to May 1, 2020, 480 patients were screened by chest CT, and 313 patients had both chest CT and RT-PCR (65%). The cumulative incidence of COVID-19 was 5.4% (95% confidence interval [CI], 3.6-7.8; 26 of 480 patients). Diagnosis of COVID-19 was made before radiation therapy for 22 patients (84.6%) and during RT for 4 patients (15.3%). Chest CT directly aided the diagnosis of 7 cases in which the initial RT-PCR was negative or not feasible, out of a total of 480 patients (1.5%) and 517 chest CT acquisitions. Four patients with COVID-19 at the time of the chest CT screening had a false negative CT. Sensitivity and specificity of chest CT screening in patients with both RT-PCR and chest CT testing were estimated at 0.82 (95% CI, 0.60-0.95) and 0.98 (95% CI, 0.96-0.99), respectively. Adaptation of the radiation therapy treatment was made for all patients, with 7 postponed treatments (median: 5 days; interquartile range, 1.5-14.8). CONCLUSIONS: The benefit of systematic use of chest CT screening during CT simulation for patients undergoing radiation therapy during the COVID-19 pandemic seemed limited.

Purpose The Gustave Roussy Cancer Institute implemented a patient-reported outcome platform (CAPRI-COVID) for cancer patients with coronavirus disease 2019 (COVID-19) to quarantine patients at home while ensuring monitoring of COVID-related symptoms and securing the care pathway. In this study, we described the CAPRI-COVID intervention, evaluated its use, and presented results of the tracking indicators with a focus on the nurse navigators’ (NNs) activities and the experience of patients. Methods Data of 130 cancer patients with COVID-19 diagnosed from March 23 to June 5, 2020, were collected. Six COVID-related symptoms were monitored daily, either by the patient via the CAPRI mobile application (CAPRI App) or by NNs via telemonitoring. In the cases of worsening or new-onset symptoms, an automated alert was sent to the platform, and NNs could immediately consult an emergency physician for future course of action. Results All 130 patients (median age: 59 years; 59.2% female) were monitored during the study period. There were no deaths or admissions to the intensive care unit attributable to COVID-19; 7.8% of patients were hospitalized (excluding scheduled hospitalization), and 17.1% were admitted to the emergency department at least once during the monitoring period. NNs carried out 1412 regular monitoring calls (average of 10.9 calls per patient), while 55% of the patients downloaded the CAPRI App. Conclusions Most patients monitored with CAPRI-COVID were quarantined during the first wave of the pandemic. In addition to the CAPRI App, which helped limit phone calls, NNs played an essential role in patient management.

The SARS-COV-2 pandemic has put pressure on intensive care units, so that identifying predictors of disease severity is a priority. We collect 58 clinical and biological variables, and chest CT scan data, from 1003 coronavirus-infected patients from two French hospitals. We train a deep learning model based on CT scans to predict severity. We then construct the multimodal AI-severity score that includes 5 clinical and biological variables (age, sex, oxygenation, urea, platelet) in addition to the deep learning model. We show that neural network analysis of CT-scans brings unique prognosis information, although it is correlated with other markers of severity (oxygenation, LDH, and CRP) explaining the measurable but limited 0.03 increase of AUC obtained when adding CT-scan information to clinical variables. Here, we show that when comparing AI-severity with 11 existing severity scores, we find significantly improved prognosis performance; AI-severity can therefore rapidly become a reference scoring approach., The SARS-COV-2 pandemic has put pressure on intensive care units, so that predicting severe deterioration early is a priority. Here, the authors develop a multimodal severity score including clinical and imaging features that has significantly improved prognostic performance in two validation datasets compared to previous scores.

Patients with cancer are presumed to be at increased risk of severe COVID-19 outcomes due to underlying malignancy and treatment-induced immunosuppression. Of the first 178 patients managed for COVID-19 at the Gustave Roussy Cancer Centre, 125 (70.2%) were hospitalized, 47 (26.4%) developed clinical worsening and 31 (17.4%) died. An age of over 70 years, smoking status, metastatic disease, cytotoxic chemotherapy and an Eastern Cooperative Oncology Group score of ≥2 at the last visit were the strongest determinants of increased risk of death. In multivariable analysis, the Eastern Cooperative Oncology Group score remained the only predictor of death. In contrast, immunotherapy, hormone therapy and targeted therapy did not increase clinical worsening or death risk. Biomarker studies found that C-reactive protein and lactate dehydrogenase levels were significantly associated with an increased risk of clinical worsening, while C-reactive protein and D-dimer levels were associated with an increased risk of death. COVID-19 management impacted the oncological treatment strategy, inducing a median 20 d delay in 41% of patients and adaptation of the therapeutic strategy in 30% of patients. Barlesi and colleagues describe the determinants of severe COVID-19 outcomes in patients with cancer managed at the Gustave Roussy Cancer Centre.

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

Optimal vaccination and immunotherapy against coronavirus disease COVID-19 relies on the in-depth comprehension of immune responses determining the individual susceptibility to be infected by SARS-CoV-2 and to develop severe disease. We characterized the polarity and specificity of circulating SARS-CoV-2-specific T cell responses against whole virus lysates or 186 unique peptides derived from the SARS-CoV-2 or SARS-CoV-1 ORFeome on 296 cancer-bearing and 86 cancer-free individuals who were either from the pre-COVID-19 era (67 individuals) or contemporary COVID-19-free (237 individuals) or who developed COVID-19 (78 individuals) in 2020/21. The ratio between the prototypic T helper 1 (TH1) cytokine, interleukin-2, and the prototypic T helper 2 (TH2) cytokine, interleukin-5 (IL-5), released from SARS-CoV-2-specific memory T cells measured in early 2020, among SARS-CoV-2-negative persons, was associated with the susceptibility of these individuals to develop PCR-detectable SARS-CoV-2 infection in late 2020 or 2021. Of note, T cells from individuals who recovered after SARS-CoV-2 re-infection spontaneously produced elevated levels of IL-5 and secreted the immunosuppressive TH2 cytokine interleukin-10 in response to SARS-CoV-2 lysate, suggesting that TH2 responses to SARS-CoV-2 are inadequate. Moreover, individuals susceptible to SARS-CoV-2 infection exhibited a deficit in the TH1 peptide repertoire affecting the highly mutated receptor binding domain (RBD) amino acids (331-525) of the spike protein. Finally, current vaccines successfully triggered anti-RBD specific TH1 responses in 88% healthy subjects that were negative prior to immunization. These findings indicate that COVID-19 protection relies on TH1 cell immunity against SARS-CoV-2 S1-RBD which in turn likely drives the phylogenetic escape of the virus. The next generation of COVID-19 vaccines should elicit high-avidity TH1 (rather than TH2)-like T cell responses against the RBD domain of current and emerging viral variants.

Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus-host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and non-cancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer, 89% COVID-19+), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Chronic viral RNA carriers exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of non-conventional monocytes and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T helper cells, and non-naive Granzyme B+ FasL+, EomehighTCF-1high, PD-1+CD8+ Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.

Background: The coronavirus disease (COVID-19) pandemic has caused 180,000 confirmed cases in France with more than 28, 000 deaths as of May 19 A large part of COVID-19 patients seem asymptomatic and cancer patients may be more vulnerable We evaluated a screening strategy combining chest computed tomography (CT) and PCR for patients treated with radiotherapy (RT) Methods: A screening strategy was organized from March 18, in our RT department An inspiratory breath hold chest acquisition was proposed during the CT simulation for RT Images was reviewed by a radiologist according to the CO-RADS classification A nasal swab with a polymerase chain reaction (PCR) assay was proposed by the radiation oncologist in case of evocative imaging or clinical context For patients who were already undergoing RT at this time, a PCR was proposed in case of evocative symptoms and before concomitant chemotherapy Results: From March 18 to May 1, 2020, 507 CT simulation were performed for 449 patients, including 445 chest acquisition 237 of the chest CT (53%) showed lung abnormalities, of which 34 (8%) were COVID-19 compatible (CO-RADS ≥ 3) 102 patients were tested by PCR after the chest CT 24 of the 449 (5 3%) patients were considered as COVID-19 patients: 19 had positive PCR, and five were considered positive on the basis of imaging despite PCR-negative PCR Four of the patients (17%) were diagnosed during RT: 3 on routine screening before chemoradiotherapy, and one on symptoms Four patients needed several PCR for the diagnosis of COVID-19 with six confirmed false negative PCR (Sensitivity (Se)= 76 % (19/25)) Three PCR positive patients had no evocative lung images (Se = 84%) During this period, an additional 169 patients whose CT simulation was prior to March 18, were also undergoing RT Among them, six patients (3 6%) were diagnosed with COVID-19 by PCR during RT, performed for symptoms in 4 cases and on screening for the other 2 Of the 30 COVID-19 patients, only 8 (27%) had symptoms at the time of diagnosis Twelve patients (40%) reported no symptoms and benefited from screening Conclusions: This study confirms the high proportion of asymptomatic patients with COVID-19 and suggests the value of screening by CT and PCR during COVID-19 pandemics Legal entity responsible for the study: The authors Funding: Has not received any funding Disclosure: R Sun: Travel/Accommodation/Expenses: AstraZeneca E Deutsch: Advisory/Consultancy: Roche, BMS, Boehringer, Astrazeneca, Lilly Amgen and Merck-Serono All other authors have declared no conflicts of interest

Background: The current COVID-19 pandemic has raised a major challenge to healthcare systems Deployment of telehealth solutions can help maintaining continuity of care while limiting pts' and healthcare workers’ exposure with the virus In this context, Gustave Roussy Cancer Institute has implemented a pts reported outcome platform (CAPRI-COVID) to improve monitoring and effective management of COVID-19 positive pts with cancer Methods: CAPRI-COVID consists in a mobile application (CAPRI App) and a telephone platform with a dedicated call number, the entire procedure being managed by four NNs After an initial assessment by the NNs, remote monitoring of 6 COVID-related symptoms were collected daily, either by the patient via the CAPRI App or by NNs during a phone call In case of worsening or emerging symptoms, an automated alert was sent to the platform;NN assessed the clinical condition and could ask for a medical advice if necessary The monitoring period was 14 days (with at least 2 days with complete regression of symptoms) Each intervention performed by NNs was tracked on the platform, as well as pts-reported data This analysis presents the data collected via the platform from March 23 to May 4 2020 Results: Overall, 116 COVID-positive pts have completed the monitoring period (median age: 58 5 years, 21-90;56 9% female) 54 3% were monitored after hospitalization for COVID-19, 37 1% after RT-PCR screening (symptomatic pts) and 8 6% for systematic screening prior to surgery There were no deaths or admissions to intensive care unit 7 8% of pts were hospitalized (excluding scheduled hospitalization) NNs conducted an average of 9 9 calls per patient Of 53 events requiring a medical opinion, 50 9% resulted in a visit to the emergency room 41 4% of pts downloaded the CAPRI App, and completed the tracking data on average 1 1 times per day Conclusions: CAPRI-COVID enabled to keep the majority of pts at home, and helped to ensure secure pts’ pathways during this epidemic NNs play an essential role in addition with the use of CAPRI App which helped limiting phone calls and focusing on the management of complex pts Ongoing analyses are exploring actions of NNs and pts’ experience Legal entity responsible for the study: Gustave Roussy Funding: Has not received any funding Disclosure: O Mir: Honoraria (self), Travel/Accommodation/Expenses: Amgen;Honoraria (self), Honoraria (institution): AstraZeneca;Honoraria (self), Research grant/Funding (institution): Bayer;Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines;Honoraria (self): Bristol-Myers Squibb;Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eli Lilly;Honoraria (self), Honoraria (institution), Advisory/Consultancy, Shareholder/Stockholder/Stock options: Ipsen;Honoraria (self): Lundbeck;Honoraria (self): MSD;Honoraria (self), Honoraria (institution): Novartis;Honoraria (self), Honoraria (institution), Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer;Honoraria (self), Honoraria (institution), Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche;Honoraria (self), Speaker Bureau/Expert testimony: Servier;Honoraria (self): Vifor Pharma;Shareholder/Stockholder/Stock options: Amplitude Surgical;Honoraria (self), Shareholder/Stockholder/Stock options: Transgene;Honoraria (institution): PharmaMar F Scotte: Honoraria (self): CIO Roche;Honoraria (self): MSD;Honoraria (self): Pierre fabre Oncology;Honoraria (self): Leo Pharma;Honoraria (self): BMS;Honoraria (self): Pfizer;Honoraria (self): Mundi Pharma;Honoraria (self): Mylan All other authors have declared no conflicts of interest

Patients with cancer are presumed to be at increased risk of severe COVID-19 outcomes due to underlying malignancy and treatment-induced immunosuppression. Of the first 178 patients managed for COVID-19 at the Gustave Roussy Cancer Centre, 125 (70.2%) were hospitalized, 47 (26.4%) developed clinical worsening and 31 (17.4%) died. An age of over 70 years, smoking status, metastatic disease, cytotoxic chemotherapy and an Eastern Cooperative Oncology Group score of ≥2 at the last visit were the strongest determinants of increased risk of death. In multivariable analysis, the Eastern Cooperative Oncology Group score remained the only predictor of death. In contrast, immunotherapy, hormone therapy and targeted therapy did not increase clinical worsening or death risk. Biomarker studies found that C-reactive protein and lactate dehydrogenase levels were significantly associated with an increased risk of clinical worsening, while C-reactive protein and D-dimer levels were associated with an increased risk of death. COVID-19 management impacted the oncological treatment strategy, inducing a median 20 d delay in 41% of patients and adaptation of the therapeutic strategy in 30% of patients.

With 15% of severe cases among hospitalized patients​, the SARS-COV-2 pandemic has put tremendous pressure on Intensive Care Units, and made the identification of early predictors of future severity a public health priority. We collected​ ​ clinical and biological data, as well as CT scan images and radiology reports from 1,003 coronavirus-infected patients from two French hospitals. Radiologists' manual CT annotations were also available. We first identified 11 clinical variables and 3 types of radiologist-reported features significantly associated with prognosis. Next, focusing on the CT images, we trained deep learning models to automatically segment the scans and reproduce radiologists' annotations. We also built CT image-based deep learning models that predicted future severity better than models based on the radiologists' scan reports. Finally, we showed that including CT scan features alongside the clinical and biological data yielded more accurate predictions than using clinical and biological data alone. These findings show that CT scans provide insightful early predictors of future severity.

Malnutrition is frequently observed in oncology. The consequences on patient survival, chemotherapy toxicities and quality of life need to be identified and treated appropriately. A set of tools are available that enable clinicians to diagnose and detect malnutrition. Each tool must consider three items: the patient's current nutritional status, reduced food intake and the characteristics of the underlying disease. The parameters and thresholds used to detect malnutrition differ according to the objective pursued. It can be economic, increasing the reimbursement of hospital stays, it can help define prognostic risk groups or its purpose can be to initiate nutritional treatment. Recent data support the assessment of parameters such as inflammatory markers, decreased muscle mass (i.e. sarcopenia) whose diagnosis is associated with a worse outcome and the quantification of food intake with simplified methods. The benefit for the patient of detecting malnutrition will be the initiation of a nutritional treatment when its efficacy has been demonstrated. A case in point is the nutritional support provided to malnourished patients before surgery with benefits in terms of mortality and morbidity and in certain head and neck cancer situations where nutritional support is systematically implemented. It is probably relevant to detect and initiate treatment early in order to promote muscle anabolism.

Eggerthella lenta is increasingly found in patients with severe comorbidities. Because oncologic patients are exposed to emerging pathogens, we aimed to describe the factors associated with E. lenta bacteremia in this immunosuppressed population. Oncology patients with blood cultures positive for E. lenta were retrospectively recorded from 2009 to 2015. Socio-demographic and medical/biological data as well as potential risk factors and mortality were recorded and analyzed. Twenty-three patients were included. Gastro intestinal (GI) and gynecological cancers were reported in 12/23 (52%) and 7/23 cases (30%), respectively. Eleven/23 patients (48%) had metastatics lesions and 6/23 (26%) had peritoneal carcinomatosis. No associated tissue infection was found in 14/23 cases (61%). Blood cultures yielded at least one other species in addition to E. lenta in 10/23 cases (43%). Mortality associated with E. lenta bacteremia was 22% (5/23). E. lenta bacteremia often occurred in patients with advanced cancer disease without documented infection. In most of the cases, intestinal obstruction and/or isolated fever were the only recorded symptoms. In these cases, the damages of intestinal barrier induced by the cancer and/or its specific treatments may be the cause of bacterial translocation.

Background: The SARS-CoV-2 outbreak in Paris’ region significantly affected Gustave Roussy cancer center. Here, we report the Gustave Roussy experience during the SARS-CoV-2 outbreak. This outbreak has led to a rapid reorganization of cancer patients’ (pts) management, with two concurrent objectives. First, protect cancer pts, who may experience more severe form of the disease, from being infected by the SARS-CoV-2. Second, protect cancer pts from losing the chance to receive optimal, if not standard, cancer care. Methods: Cancer pts with suspected SARS-CoV-2 infection were admitted at Gustave Roussy starting March, 12th. Screening indications have been adapted over the time. All the COVID19 pts positively tested and managed at Gustave Roussy between March 14th (1st positive case) and April 15th have been included in a redcap database. Pts and underlying oncological and COVID19 diseases characteristics have been collected. Cancer and COVID-19 managements, and outcomes have been assessed. The primary endpoint of this analysis was the clinical deterioration, defined as the need for O2 supplementation of 6l/min or more, or death of any cause. Results: Overall, 7,251 cancer pts were managed at Gustave Roussy during this period of time, with 3616 being hospitalized. Based on our testing strategy, 1302 pts have been tested with 12% of them found positive for SARS-CoV-2. Among the first 137 cancer pts diagnosed with SARS-CoV-2, most cases were female (58%) with a median age of 61 years, including 36 pts (26%) ≥ 70 years. Most frequent underlying cancers were solid tumors (115) including breast (23), GI (18), head and neck (17), GU (17), GYN (17) malignancies or hemopathies (22). At time of COVID diagnosis, 79 pts (58%) had metastatic/active cancer and 56 pts (41%) were considered in remission/treated with curative intent. The diagnosis of SARS-CoV-2 infection was made by RT-PCR or thoracic CT scan alone in 93.4% and 6.6% of the cases, respectively. The majority of the pts was hospitalized (75%) and treated with HCQ/AZI (40; 30%) with inclusion in the ONCOVID trial (EudraCT: 2020-01250-21), IL-6 inhibitor (10), antiviral (6) or steroids (13). Fifteen pts were admitted in ICU (11%). Clinical deterioration occurred in 34 pts (24.8%) and was associated with hematological underlying disease, CRP at diagnosis of COVID19 >50 and the use of cytotoxic chemotherapy within Conclusions: Globally, the rate of the SARS-CoV-2 infection in our cancer patients’ population does not seem to be higher compared to the global population. We have not found evidence that COVID19 is more lethal or aggressive in cancer patients that underwent usual SARS-Cov-2 treatment. We believe that adequate testing and protective measures, along with the low rate of SARS-cov-2-treatment-related adverse events (5.5%), justify an optimal management of the cancer patients’ underlying tumor. Citation Format: Fabrice Barlesi, Stéphanie Foulon, Arnauld Bayle, Bertrand Gachot, Fanny Pommeret, Christophe Willekens, Annabelle Stoclin, Mansouria Merad, Franck GriscelliI, Jean-Baptise Micol, Roger Sun, Thomas Nihouarn, Corinne Balleygier, Fabrice André, Florian Scotte, Benjamin Besse, Jean-Charles Soria, Laurence Albiges. Outcome of cancer patients infected with COVID-19, including toxicity of cancer treatments [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT403.

Background The risk of pharmacokinetic interaction is important in HIV-infected cancer patients receiving concomitantly highly active antiretroviral therapy (HAART) and anti-cancer systemic treatments. We aimed to evaluate the safety profile of raltegravir-based HAART in cancer patients receiving multi-kinase inhibitors (MKIs). Patients and Methods We conducted a retrospective medical record review of adult, HIV-infected cancer patients treated in our institutions from January 2010 to December 2015. Patients eligible for the present analysis were those receiving a raltegravir-based HAART at the time of the initiation of a MKI for the treatment of advanced solid tumors. Treatment-related toxicity, virological outcomes and pharmacokinetic profile of MKIs were examined. Results Twelve patients (7 males, median age 55 years) were identified. Seven had sarcoma/GIST, 3 had hepatocellular carcinoma, one had pancreatic neuroendocrine tumor, and one had NSCLC. Patients received the following MKIs: imatinib (n = 3), sorafenib (n = 3), pazopanib (n = 3), sunitinib (n = 2) and erlotinib (n = 1). The mean CD4+ count at baseline was 929 cells/mm3, and 860 cells/mm3 after completion of MKI treatment. In all patients, HIV viral loads remained below the limit of detection (40 copies/ mm3) during the whole MKI treatment. No virological failure occurred. No unexpected or serious adverse event related either to raltegravir-based HAART or to MKIs was observed. The trough plasma concentrations of MKIs were assessed in 8 patients, and were found normal in all but one case (not related to raltegravir-based HAART). Conclusions The present data represent the first documentation of the concomitant use of raltegravir-containing HAART and MKIs in HIV-infected adult patients with advanced non-AIDS defining malignancies, with a reassuring safety profile.

Resume Introduction La neutropenie febrile (NF) est une complication severe de la chimiotherapie. Si l’hospitalisation est recommandee pour les patients avec une NF a haut risque (HR) de complications, la prise en charge des NF a faible risque reste mal codifiee. Methodes Etude prospective observationnelle chez les patients avec une tumeur solide consultant aux urgences pour un episode de NF. Les donnees demographiques, cliniques, biologiques, le score de MASCC et les couts ont ete collectes. Resultats Cent trente-sept episodes de NF survenus chez 128patients ont ete analyses. L’hospitalisation de ces patients a ete decidee sur des parametres clinicobiologiques: 26NF (19%) ont ete pris en charge en ambulatoire strict (tous ces patients avaient un MASCC ≥ 21); 111 (81%) ont ete hospitalises: 37episodes ont ete consideres a risque eleve de complications (tous avaient un MASCC Conclusion Cette etude a permis de montrer certaines limites au score de MASCC (groupe RI). Certains patients hospitalises selon nos criteres clinicobiologiques avec un score de MASCC les classant a HR n’ont pas presente de complications. Malgre les limites methodologiques, notre etude a permis l’evaluation des couts et des difficultes du choix des prises en charge de la NF post-chimiotherapie

Better pathophysiological understanding of PTTM could result in specific targeted therapies and improve prognosishttp://ow.ly/U93wg

Malnutrition is frequently observed in oncology. The consequences on patient survival, chemotherapy toxicities and quality of life need to be identified and treated appropriately. A set of tools are available that enable clinicians to diagnose and detect malnutrition. Each tool must consider three items: the patient's current nutritional status, reduced food intake and the characteristics of the underlying disease. The parameters and thresholds used to detect malnutrition differ according to the objective pursued. It can be economic, increasing the reimbursement of hospital stays, it can help define prognostic risk groups or its purpose can be to initiate nutritional treatment. Recent data support the assessment of parameters such as inflammatory markers, decreased muscle mass (i.e. sarcopenia) whose diagnosis is associated with a worse outcome and the quantification of food intake with simplified methods. The benefit for the patient of detecting malnutrition will be the initiation of a nutritional treatment when its efficacy has been demonstrated. A case in point is the nutritional support provided to malnourished patients before surgery with benefits in terms of mortality and morbidity and in certain head and neck cancer situations where nutritional support is systematically implemented. It is probably relevant to detect and initiate treatment early in order to promote muscle anabolism.

The function of the NF-E2 transcription factor, a p45/small Maf heterodimer, was analyzed in the erythroleukemia cell lines MEL and CB3. In contrast to MEL cells, CB3 cells are null for p45 and thus express only extremely low levels of adult globin transcripts upon induction by agents promoting erythroid differentiation. We investigated the response of erythroleukemia cells to hemin treatment. Hemin rapidly induces beta-globin gene transcript levels in MEL cells, but not in CB3 cells. Stable expression of the large p45 NF-E2 subunit in CB3 cells restores hemin mediated beta-globin gene transcription, suggesting that the presence of a functional NF-E2 is required for strong induction of beta-globin mRNA levels by hemin in erythroleukemia cells. We performed mutagenesis of two potential heme-regulatory motifs (HRMs) in p45 NF-E2 and found that the mutated versions are expressed and can still recognize a NF-E2 DNA binding element. In addition, we showed that p45 NF-E2 HRM mutants are able to restore beta-globin gene transcription in CB3 cells upon induction by hemin. Our results suggest that globin gene activation by heme appears to be independent of the putative HRMs in the p45 subunit of the NF-E2 transcription factor.

Febrile neutropenia (FN) is a severe chemotherapy side effect. Hospitalization is recommended for FN episode of high-risk (HR) of complications. Management of FN at lower risk of complications remains unclear.This is a prospective observation study in patients with solid tumors admitted to the emergency department FN. Collected data included demographics, clinical, biological, therapeutic costs, MASCC score and complications.Hundred and thirty-seven consecutive FN were recorded in 128 patients. Twenty-six FN (19%) were managed at home (all of them had a MASCC score ≥ 21); 111 (81%) were treated at hospital of which 37 NF were at HR of complications based on clinical and biological parameters (all of them had a MASCC score21) and for 74 of them the admission could be discussed (MASCC20 or ≥ 20). This group of patients was considerate with intermediate risk (IR). All IR patients were treated with the same antibiotics than outpatients, i.e. ceftriaxone in 36 cases (49%) or amoxicillin/clavulanic acid and ciprofloxacin in 38 cases (51%). For these 74 cases, any severe complication was recorded. Antibiotics were adapted for only 12% of these patients according to bacteriology results.This study showed the limits of the MASCC score. We did not observe any severe complications in patients admitted to the hospital according to clinical and biological parameters and with the high risk score MASCC. This study had some methodological bias but it allowed us to estimate the cost of the different ways of management and the difficulties to decide the hospitalization in FN.

In patients who are receiving prolonged antiretroviral treatment (ART), HIV can persist within a small pool of long-lived resting memory CD4+ T cells infected with integrated latent virus. This latent reservoir involves distinct memory subsets. Here we provide results that suggest a progressive reduction of the size of the blood latent reservoir around a core of less-differentiated memory subsets (central memory and stem cell-like memory (TSCM) CD4+ T cells). This process appears to be driven by the differences in initial sizes and decay rates between latently infected memory subsets. Our results also suggest an extreme stability of the TSCM sub-reservoir, the size of which is directly related to cumulative plasma virus exposure before the onset of ART, stressing the importance of early initiation of effective ART. The presence of these intrinsic dynamics within the latent reservoir may have implications for the design of optimal HIV therapeutic purging strategies., HIV can persist in CD4+ T cells of patients receiving long-term antiretroviral therapy. Here the authors show the presence of intrinsic dynamics that progressively contract the latent HIV reservoir around a core of less-differentiated CD4 T-cell memory subsets.

In Parkinson's disease (PD), dopaminergic cell death in the substantia nigra was associated with a profound glutathione (GSH) decrease and a mitochondrial dysfunction. The fall in GSH concentration seemed to appear before the mitochondrial impairment and the cellular death, suggesting that a link may exist between these events. The relationships between GSH depletion, reactive oxygen species (ROS) production, mitochondrial dysfunction and the mode of cell death in neuronal cells remain to be resolved and will provide important insights into the etiology of Parkinson's disease. An approach to determine the role of GSH in the mitochondrial function and in neurodegeneration was to create a selective depletion of GSH in a neuronal cell line in culture (NS20Y) by inhibiting its biosynthesis with L-buthionine-(S,R)-sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase. This treatment led to a nearly complete GSH depletion after 24 hr and induced cellular death via an apoptotic pathway after 5 days of BSO treatment. By using the reactive oxygen species-sensitive probe 2',7'-dichlorofluorescin, we observed that the rapid GSH depletion was accompanied, early in the process, by a strong and transient intracellular increase in reactive oxygen species evidenced after 1 hr with BSO, culminating after 3 hr when the GSH level decreased to 30% of normal. GSH depletion induced a loss of mitochondrial function after 48 hr of BSO treatment. In particular, the activities of complexes I, II and IV of the respiratory chain were decreased by 32, 70 and 65%, respectively as compared to controls. These results showed the crucial role of GSH for maintaining the integrity of mitochondrial function in neuronal cells. Oxidative stress and mitochondrial impairment, preceding DNA fragmentation, could be early events in the apoptotic process induced by GSH depletion. Our data are consistent with the hypothesis that GSH depletion could contribute to neuronal apoptosis in Parkinson's disease through oxidative stress and mitochondrial dysfunction.

Defenses against free radical damage were determined in red blood cells and plasma from 40 patients with dementia of the Alzheimer-type (DAT) and 34 aged control subjects with normal cognitive function. No crude significant difference in erythrocyte copper-zinc superoxide dismutase (E-CuZnSOD), seleno-dependent glutathione peroxidase (E-GSH-Px), glutathione reductase (E-GSSG-RD) activities, and selenium (Se) concentration was found between DAT cases and control subjects. The peroxidation products evaluated in plasma by the thiobarbituric-reactive material (TBARS) were at the same level in the DAT group as compared to controls. In the DAT group, plasma GSH-Px (P-GSH-Px) activity and plasma Se (P-Se) were negatively correlated with age (r = -0.58; p < 0.001 and r = -0.63; p < 0.001 respectively). Moreover, erythrocyte GSH-Px activity and Se were also negatively correlated with age (r = -0.40; p < 0.01 and r = -0.46; p < 0.01, respectively). No significant correlation with age was observed in the controls. When controlling for age, a significant increase for P-GSH-Px activity and P-Se was observed in DAT patients as compared to controls. These significant differences mostly appeared in DAT subjects under 80 years. Some correlations were only observed in the DAT group such as P-GSH-Px and E-GSH-Px (r = +0.68; p < 0.001); P-GSH-Px and E-Se (r = +0.79; p < 0.001). Correlations between P-GSH-Px and P-Se, E-GSH-Px and P-Se, and P-Se with E-Se are greater in the DAT group (r = +0.84; p < 0.001; r = +0.76; p < 0.001 and r = 0.75; p < 0.001) than in the control group (r = 0.54, pI < 0.01; r = 0.43, p < 0.01 and r = +0.34, p < 0.05 respectively). The fact that first -- a significant increase in P-GSH-Px and P-Se, second -- some modifications in the relationships between antioxidant parameters, and third -- age-dependent decreases of glutathione-peroxidase activities and their cofactor, appeared only in the DAT group suggest that DAT is associated with an oxidative stress due to an imbalance between reactive oxygen species and the peripheral antioxidant opposing forces.

A profound imbalance between oxidants and antioxidants has been suggested in uremic patients on maintenance hemodialysis. However, the respective influence of uremia and dialysis procedure has not been evaluated. Circulating levels of copper-zinc superoxide dismutase (CuZn SOD), glutathione peroxidase (GSH-Px), and reductase (GSSG-Rd), total GSH and GSSG were determined in a large cohort of 233 uremic patients including 185 undialyzed patients with mild to severe chronic renal failure, and 48 patients treated by peritoneal dialysis or hemodialysis. Compared to controls, erythrocyte GSH-Px and GSSG-Rd activities were significantly increased at the mild stage of chronic uremia (p < .001), whereas erythrocyte CuZn SOD activity was unchanged, total level of GSH and plasma GSH-Px activity were significantly decreased, and GSSG level and GSSG-Rd activity were unchanged. Positive Spearman rank correlations were observed between creatinine clearance and plasma levels of GSH-Px (r = .65, p < .001), selenium (r = .47, p < .001), and GSH (r = .41, p < .001). Alterations in antioxidant systems gradually increased with the degree of renal failure, further rose in patients on peritoneal dialysis and culminated in hemodialysis patients in whom an almost complete abolishment of GSH-Px activity was observed. In conclusion, such disturbances in antioxidant systems that occur from the early stage of chronic uremia and are exacerbated by dialysis provide additional evidence for a resulting oxidative stress that could contribute to the development of accelerated atherosclerosis and other long-term complications in uremic patients.

International audience; The neuroprotective potential of the nerve growth factor (NGF) against permanent ischemic brain damage has been investigated in vivo using NGF-transgenic (tg) mice. The expression of the transgene is driven by part of the promoter of the proto-oncogene c-fos, which belongs to the first set of genes activated after brain ischemic insult. Wild-type (wt) mice and tg mice were subjected to permanent focal ischemia induced by electrocoagulation of the middle cerebral artery. Twenty four hours (h) after the ischemic shock, when compared to wt, tg mice displayed a 40% reduction of the infarcted area, which lasted up to 1 week. However, infarcted brain areas were similar in wt and tg mice within the first hours post-occlusion, indicating that NGF acted to block the progression of neuronal damage. Kinetics of NGF synthesis assessed by ELISA was in good agreement with the observed neuroprotective effect, since NGF content peaked 6 h post-ischemia. This was further correlated with the time-course of c-Fos immunoreactivity, detectable only from 6 h post-ischemia. The neuroprotective effect of NGF involved the impairment of apoptotic cell death, as evidenced by a marked decrease of the number of apoptotic profiles inside the ischemic zone in tg mice. These results underline the potential of c-fos-NGF-tg mice to study in vivo the molecular and cellular mechanisms of the NGF-induced neuroprotective effect against ischemic damage.

Oxidative stress may play an important role in the pathogenesis of brain injuries associated with aging and neurodegenerative disorders such as Down’s syndrome, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Brain contain several antioxidant enzymes, most importantly, superoxide dismutases (MnSOD and CuZnSOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R) and catalase. The tripeptide reduced glutathione (GSH) serves as one of the major endogenous antioxidants in protecting mammalian cells against oxidative stress. GSH has a role not only as a substrate for GSH-Px to break down hydrogen peroxide and lipid peroxides but also as free radical scavenger. The individual contribution of these antioxidants in neuronal protection remains unknown and requires elucidation. A first approach to this question was to establish a comprehensive profile of the brain antioxidant defense potential during aging in control mice. A second approach was to use genetic manipulations to construct transgenic mice that overexpress CuZnSOD. These constructed transgenic mice which exhibit increased CuZnSOD activity in the brain would provide a suitable model to further investigate the role of an increased CuZnSOD activity in neuronal aging and Alzheimer-like neuropathology in Down syndrome. A third strategy in assessing the role of a particular antioxidant in brain fonction was to use metabolic manipulations to deplete brain GSH levels with electrophiles that conjugate with GSH in the presence of glutathione S-transferases, such as diethylmaleate (DEM), and to correlate this depletion with brain injury or susceptibility to oxidative stress. Obtention of such a variation of a particular antioxidant in the brain and neurobiological consequences will be evaluated and discussed.

Murine erythroleukemia (MEL) cells provide a valuable model to study the molecular events leading to erythroid differentiation. Maturing erythroid cells synthesize large quantities of hemoglobin, a process requiring the coordinated synthesis of heme and globin. Here, we investigated the role of the ERK and p38 mitogen-activated protein kinase (MAPK) signaling pathways in the differentiation of MEL cells. We determined the effect of the MEK1/2 inhibitor U0126 that blocks the ERK1/2 pathway, and the p38 inhibitor SB202190 on the differentiation potential of MEL cells induced by hexamethylene bisacetamide (HMBA). We found that treatment of HMBA induced MEL cells with the ERK1/2 pathway inhibitor U0126 results in higher hemoglobin levels. Using a fluorometric assay, we determined that intracellular heme levels also increased. Immunoblot studies showed an increase in globin protein levels. In contrast, treatment of MEL cells with the p38 inhibitor SB202190 has the opposite effect, leading to decreased amounts of heme and hemoglobin. In addition, inhibition of the p38 pathways results in lower transferrin receptor levels. Our results suggest that the ERK1/2 and p38 pathways play antagonistic roles in HMBA induced erythroid differentiation in MEL cells. This data also provides a novel link between MAPK signaling and the regulation of heme biosynthesis and iron uptake in erythroid cells.

Murine erythroleukemia (MEL) cells provide a valuable model to study the molecular events leading to erythroid differentiation. Maturing erythroid cells synthesize large quantitities of hemoglobin, a process requiring the coordinated synthesis of heme and globin. Here, we investigated the role of the ERK and p38 mitogen-activated protein kinase (MAPK) signaling pathways in chemically induced differentiating MEL cells. We showed that treatment of DMSO- or HMBA-induced MEL cells with the MEK1/2 inhibitor UO126, blocking the ERK pathway, results in the increase of beta-globin and 5-aminolevulinate synthase-2 (ALAS-2) transcript levels. We found that addition of the p38 inhibitor SB203580 has the opposite effect, leading to decreased beta-globin and ALAS-2 mRNA levels. The regulation on the transcript level correlated with increased or decreased hemoglobin levels in the presence of MEK1/2 and p38 inhibitors, respectively. Our results suggest that the ERK and p38 pathways play antagonistic roles in DMSO- and HMBA induced erythroid differentiation in MEL cells. This data also provide a novel link between MAPK signaling and the regulation of intracellular heme levels, as ERK and p38 MAPK signaling cascades appear to differentially regulate one of the key enzymes of the heme biosynthesis pathway.

Introduction et but de l’etude L’epidemie a coronavirus 2019 (COVID-19) est a l’origine de 179000 cas confirmes en France depuis fin janvier et plus de 27000 deces en date du 15 mai. Les patients atteints de cancers semblent etre plus vulnerables a la COVID-19. En outre, plus de la moitie des patients atteints de COVID-19 semblent etre asymptomatiques. Ainsi, les strategies de depistage pourraient etre utiles pour assurer la continuite des soins ainsi que la securite des patients et des personnels soignants. Nous rapportons ici les resultats preliminaires d’une strategie de depistage systematique par scanographie thoracique et polymerase chain reaction (PCR) pour les patients recevant une radiotherapie. Materiel et methodes Une acquisition thoracique en inspiration bloquee etait proposee lors de la scanographie dosimetrique des patients recevant une radiotherapie. L’imagerie etait relue par un radiologue et classee selon le COVID-19 Reporting and Data System (Co-RADS). Une PCR de depistage du severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, responsable de la COVID-19) sur un prelevement nasopharynge etait proposee par l’oncologue radiotherapeute en cas d’anomalie sur l’imagerie, ou de contexte clinique evocateur. Les donnees relatives a la survenue d’une COVID-19 en cours de radiotherapie ont aussi ete recueillies afin d’estimer l’incidence des cas de COVID-19 dans le service de radiotherapie. Resultats et analyse statistique Du 18 mars au 1er mai 2020, 507 scanographies dosimetriques ont ete realisees dans le service, dont 445 avec une coupe thoracique, pour un total de 449 patients. En tout, 237 scanographies (soit 53 %) presentaient des images pulmonaires anormales, dont 34 (soit 8 %) etaient compatibles avec la COVID-19 (grade 3 ou plus selon la classification Co-RADS). Cent-deux patients ont ete testes par PCR apres la scanographie thoracique. Dix-neuf patients sur les 449 ayant eu une scanographie dosimetrique durant cette periode ont ete confirmes comme infectes par le SARS-CoV-2 par PCR, et cinq ont ete consideres atteints sur la base de l’imagerie malgre des PCR negatives, soit une incidence de 5,3 % (24 cas sur 449) sur la periode. Le diagnostic de COVID-19 etait connu chez huit de ces 24 patients (soit 33 %) avant la radiotherapie, dont quatre avaient toujours une PCR positive lors de la scanographie dosimetrique, a distance de la premiere PCR positive connue (8j, 36j, 40j, 56, respectivement). Quatre cas (soit 17 %) ont ete diagnostiques en cours de radiotherapie, dont trois par depistage systematique avant la chimioradiotherapie, et un seul selon les symptomes. Durant cette periode, 169 autres patients en cours de traitement ont eu leur scanographie de radiotherapie avant le 18 mars et n’ont pas eu d’acquisition thoracique systematique. Parmi eux, six cas d’infection par le SARS-CoV-2 (soit 3,6 %) ont ete diagnostiques par PCR en cours de radiotherapie, realisee pour des symptomes dans quatre cas et par depistage systematique pour les deux autres. En tout, sur les 30 patients atteints de COVID-19, seulement huit (soit 27 %) avaient des symptomes lors de la PCR, et dix (soit 33 %) ont rapporte un antecedent de symptomes evocateurs. Douze patients (soit 40 %) n’ont rapporte aucun symptome et ont ainsi beneficie du depistage. Deux deces (soit 7 %) imputables a la COVID-19 ont ete a deplorer. Conclusion Cette etude confirme la part importante de patients asymptomatiques atteints de COVID-19 et suggere l’interet d’un depistage systematique par scanographie et PCR.