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Abstract Following the results of the IMpassion130 trial, an early access program (EAP) was opened in France, allowing patients with PD-L1-positive advanced triple negative breast cancer (aTNBC) to receive a combination of paclitaxel and atezolizumab as first line therapy. This EAP was later discontinued when the IMpassion131 trial read out with negative results. We performed a retrospective multicentric analysis in patients who were prospectively enrolled in the French EAP. Efficacy and toxicity data were obtained on 64 patients treated from August 2019 to August 2020 in 10 French cancer centers. Median progression-free survival (PFS) and overall survival (OS) were 4.1 months (95% CI [3.0–5.8]) and 17.9 months (95% CI [12.4–NR]), respectively. The 6-months PFS rate was 28% (95% CI [16–40%]) (N = 18/64), while N = 33/64 patients (52%, 95% CI [38–63%]) experienced a tumor response. Exploratory subgroup analyses retrieved that corticosteroid use at inclusion in the EAP, before treatment initiation, was the only independent unfavorable prognostic factor for PFS (HR 2.7, 95% CI [1.3–5.6]). No new safety signal was observed. This real-life study, unique by its setting (EAP granted by anticipation and later withdrawn), suggests atezolizumab and paclitaxel has a limited efficacy in PD-L1-positive aTNBC, especially in patients receiving corticosteroids as comedication before treatment start.

Abstract Introduction Studies regarding coronavirus disease 2019 (COVID-19) were mainly performed in the initial wave, but some small-scale data points to prognostic differences for patients in successive waves. We therefore aimed to study the impact of time on prognosis of ICU-admitted COVID-19 patients. Method We performed a national retrospective cohort study, including all adult patients hospitalized in French ICUs from March 1, 2020 to June 30, 2021, and identified three surge periods. Primary and secondary outcomes were in-hospital mortality and need for invasive mechanical ventilation, respectively. Results 105,979 critically ill ICU-admitted COVID-19 patients were allocated to the relevant three surge periods. In-hospital mortality for surges 1, 2, and 3 was, respectively, 24%, 27%, and 24%. Invasive mechanical ventilation was the highest level of respiratory support for 42%, 32%, and 31% (p

Abstract Background Immunotherapy alone or in combination has clearly improved the survival of patients with lung cancer. However, it may also be responsible for adverse events impacting these patients' quality of life. The ToxImmune study aims to identify prognostic factors that can help to predict immune‐related adverse events. Methods We included all patients aged 18 years and older who had received at least one dose of immune checkpoint inhibitors, with or without other therapy, between June 2015 and December 2020 and were diagnosed with nonsmall cell lung cancer or small‐cell lung cancer. Patients' baseline demographic characteristics, biological blood markers, and imaging by PET‐scanner were collected from electronic medical records. All adverse events (AEs) and immune‐related AEs (irAEs) were recorded (Common Terminology Criteria For Adverse Events V.5.0). Results Sixty‐four patients were included, of whom 60 (94%) presented at least one irAE. The incidence of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 and grade 3–4 was 34% and 8% respectively. Female sex, Primitive Tumor Standardized Uptake Value Max (SUVmax)

Abstract Background We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425). Methods In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy. Results A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1–2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55–40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4+ PD1+ OX40+ T cells than patients without DCB. Patients with DCB presented also with more DC-LAMP+ dendritic cells, CD3+ T cells and FOXP3+ Tregs in baseline tumor biopsies. For DCB patients, the nintedanib lead-in monotherapy resulted in higher blood CCL3, Tregs and CCR4+ CXCR3+ CXCR5− memory CD4 T cells. After the first pembrolizumab infusion, patients with DCB showed lower IL-6, IL-8, IL-27 plasma levels. Conclusion Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy. Trial registration ClinicalTrials.gov, NCT02856425 . Registered August 4, 2016 — Prospectively registered.

Research aim and purposeThe benefits of Electronic Patient -Reported Outcomes (e-PRO) for telemonitoring are well established, allowing early detection of illnesses and continuous monitoring of patients. The primary objective of the PROTECTY study was to assess the compliance with patient use of the telemonitoring platform Cureety. An exploratory objective was to assess if the first-month health status is a prognostic factor of progression free-survival (PFS) and overall survival (OS) for prostate cancer patient.MethodsThis prospective study was conducted at the Military Hospital Bégin on prostate cancer patients. Patients were allowed to respond to a symptomatology questionnaire based on CTCAE v.5.0, personalized to their pathology and treatment. An algorithm evaluates the health status of the patient based on the reported adverse events, with a classification into 2 different states: Good Health Status (GHS) and Poor Health status (PHS).ResultsSixty-one patients were enrolled between July 1st, 2020 and September 30th, 2021. The median age was 74.0 (range 58.0–94.0). 78% presented a metastatic stage, and the most represented cancer was mHSPC. Overall, 2,457 questionnaires were completed by the patients, 4.0% resulted in a health classification in to monitor or critical state. 87% of patients were classified in the GHS group. The compliance was 72% in the overall population during the first month, 71% in GHS group and 75% in PHS group. The median follow-up was 8 months. PFS at 6 months was 84% in GHS group vs. 57% in PHS group, p = 0.19. OS at 6 months was 98% in GHS group vs. 83% in PHS group, p = 0.31.ConclusionsOur study showed that compliance was satisfactory. The feasibility of remote monitoring for prostate cancer patients means that they should benefit from its implementation. Our study is also the first to assess the correlation between treatment tolerance and survival. The initial results suggest that e-PRO assessment could help identify in the early stages the patients that require further health assessment and potential therapeutic changes. While further follow-up of more patients will be required, our study highlights the importance of e-PRO in cancer patient care.

Abstract Background The first wave of the COVID-19 pandemic confronted healthcare systems around the world with unprecedented organizational challenges, particularly regarding the availability of intensive care unit (ICU) beds. One strategy implemented in France to alleviate healthcare pressure during the first COVID-19 wave was inter-hospital transfers of selected ICU patients from overwhelmed areas towards less saturated ones. At the time, the impact of this transfer strategy on patient mortality was unknown. We aimed to compare in-hospital mortality rates among ICU patients with COVID-19 who were transferred to another healthcare facility and those who remained in the hospital where they were initially admitted to. Method A prospective observational study was performed from 1 March to 21 June 2020. Data regarding hospitalized patients with COVID-19 were collected from the Ministry of Health-affiliated national SI-VIC registry. The primary endpoint was in-hospital mortality. Results In total, 93,351 hospital admissions of COVID-19 patients were registered, of which 18,348 (19.6%) were ICU admissions. Transferred patients (n = 2228) had a lower mortality rate than their non-transferred counterparts (n = 15,303), and the risk decreased with increasing transfer distance (odds ratio (OR) 0.7, 95% CI: 0.6–0.9, p = 0.001 for transfers between 10 and 50 km, and OR 0.3, 95% CI: 0.2–0.4, p 200 km). Mortality decreased overall over the 3-month study period. Conclusions Our study shows that the mortality rates were lower for patients with severe COVID-19 who were transferred between ICUs across regions, or internationally, during the first pandemic wave in France. However, the global mortality rate declined overall during the study. Transferring selected patients with COVID-19 from overwhelmed regions to areas with greater capacity may have improved patient access to ICU care, without compounding the short-term mortality risk of transferred patients.

BackgroundAnti-PD-(L)1 treatment is indicated for patients with mismatch repair-deficient (MMRD) tumors, regardless of tumor origin. However, the response rate is highly heterogeneous across MMRD tumors. The objective of the study is to find a score that predicts anti-PD-(L)1 response in patients with MMRD tumors.MethodsSixty-one patients with various origin of MMRD tumors and treated with anti-PD-(L)1 were retrospectively included in this study. An expert radiologist annotated all tumors present at the baseline and first evaluation CT-scans for all the patients by circumscribing them on their largest axial axis (single slice), allowing us to compute an approximation of their tumor volume. In total, 2120 lesions were annotated, which led to the computation of the total tumor volume for each patient. The RECIST sum of target lesions’ diameters and neutrophile-to-lymphocyte (NLR) were also reported at both examinations. These parameters were determined at baseline and first evaluation and the variation between the first evaluation and baseline was calculated, to determine a comprehensive score for overall survival (OS) and progression-free survival (PFS).ResultsTotal tumor volume at baseline was found to be significantly correlated to the OS (p-value: 0.005) and to the PFS (p-value:

Background Clinical studies have highlighted the efficacy of anti-programmed death 1 (αPD-1) monoclonal antibodies in patients with DNA mismatch repair-deficient (MMRD) tumors. However, the responsiveness of MMRD cancers to αPD-1 therapy is highly heterogeneous, and the origins of this variability remain not fully understood.Methods 4T1 and CT26 mouse tumor cell lines were inactivated for the MMRD gene Msh2, leading to a massive accumulation of mutations after serial passages of cells. Insertions/deletion events and mutation load were evaluated by whole exome sequencing. Mice bearing highly mutated MMRD tumor or parental tumors were treated with αPD-1 and tumor volume was monitored. Immune cell type abundance was dynamically assessed in the tumor microenvironment and the blood by flow cytometry. Neutrophils were depleted in mice using αLY6G antibody, and regulatory T (Treg) cell population was reduced with αCD25 or anti-cytotoxic T-lymphocytes-associated protein 4 (αCTLA-4) antibodies. Patients with MMRD tumors treated with immune checkpoint blockade-based therapy were retrospectively identified and neutrophil-to-lymphocyte ratio (NLR) was evaluated and examined for correlation with clinical benefit.Results By recapitulating mismatch repair deficiency in different mouse tumor models, we revealed that elevated circulating tumor-induced neutrophils (TIN) in hypermutated MMRD tumors hampered response to αPD-1 monotherapy. Importantly, depletion of TIN using αLy-6G antibody reduced Treg cells and restored αPD-1 response. Conversely, targeting Treg cells by αCD25 or αCTLA-4 antibodies limited peripheral TIN accumulation and elicited response in αPD-1-resistant MMRD tumors, highlighting a crosstalk between TIN and Treg cells. Thus, αPD-1+αCTLA-4 combination overcomes TIN-induced resistance to αPD-1 in mice bearing MMRD tumors. Finally, in a cohort of human (high microsatellite instability)/MMRD tumors we revealed that early on-treatment change in the NLR ratio may predict resistance to αPD-1 therapy.Conclusions TIN countered αPD-1 efficacy in MMRD tumors. Since αCTLA-4 could restrict TIN accumulation, αPD-1+αCTLA-4 combination overcomes αPD-1 resistance in hosts with hypermutated MMRD tumors displaying abnormal neutrophil accumulation.

Site‐selective ortho/ipso C−H difunctionalizations of aromatic compounds were designed to afford polyfunctionalized arenes including challenging 1,2,3,4‐tetrasubstituted ones (62 examples, up to 97 % yields). To ensure the excellent regioselectivity of the process while keeping high efficiency, an original strategy based on a "C−H thianthenation/Catellani‐type reaction" sequence was developed starting from simple arenes. Non‐prefunctionalized arenes were first regioselectively converted into the corresponding thianthrenium salts. Then, a palladium‐catalyzed, norbornene (NBE)‐mediated process allowed the synthesis of ipso‐olefinated/ortho‐alkylated polyfunctionalized arenes using a thianthrene as a leaving group (revisited Catellani reaction). Pleasingly, using a commercially available norbornene (NBE) and a unique catalytic system, synthetic challenges known for the Catellani reaction with aryl iodides were smoothly and successfully tackled with the "thianthrenium" approach. The protocol was robust (gram‐scale reaction) and was widely applied to the two‐fold functionalization of various arenes including bio‐active compounds. Moreover, a panel of olefins and alkyl halides as coupling partners was suitable. Pleasingly, the "thianthrenium" strategy was successfully further applied to the incorporation of other groups at the ipso (CN/alkyl/H, aryl) and ortho (alkyl, aryl, amine, thiol) positions, showcasing the generality of the process. [ABSTRACT FROM AUTHOR]

Abstract Background Cancer-related microangiopathic haemolytic anaemia (MAHA) is a rare but life-threatening paraneoplastic syndrome. Only single cases or small series have been reported to date. We set up a retrospective multicentre study focusing on breast cancer-related MAHA. Methods Main inclusion criteria were known diagnosis of breast cancer, presence of schistocytes and either low haptoglobin or cytopenia and absence of any causes of MAHA other than breast cancer, including gemcitabine- or bevacizumab-based treatment. Patient characteristics, treatments and outcome were retrieved from digital medical records. Results Individual data from 54 patients with breast cancer-related MAHA were obtained from 7 centres. Twenty-three (44%) patients had a breast tumour with lobular features, and most primary tumours were low grade (grade I/II, N = 39, 75%). ER+/HER2−, HER2+ and triple-negative phenotypes accounted for N = 33 (69%), N = 7 (15%) and N = 8 (17%) cases, respectively. All patients had stage IV cancer at the time of MAHA diagnosis. Median overall survival (OS) was 28 days (range 0–1035; Q1:10, Q3:186). Independent prognostic factors for early death (≤ 28 days) were PS > 2 (OR = 7.0 [1.6; 31.8]), elevated bilirubin (OR = 6.9 [1.1; 42.6]), haemoglobin

Abstract Background Cancer patients have been reported to be at higher risk of COVID-19 complications and deaths. We report the characteristics and outcome of patients diagnosed with COVID-19 during breast cancer treatment at Institut Curie hospitals (ICH, Paris area, France). Methods An IRB-approved prospective registry was set up at ICH on March 13, 2020, for all breast cancer patients with COVID-19 symptoms or radiologic signs. Registered data included patient history, tumor characteristics and treatments, COVID-19 symptoms, radiological features, and outcome. Data extraction was done on April 25, 2020. COVID-19 patients were defined as those with either a positive RNA test or typical, newly appeared lung CT scan abnormalities. Results Among 15,600 patients actively treated for early or metastatic breast cancer during the last 4 months at ICH, 76 patients with suspected COVID-19 infection were included in the registry and followed. Fifty-nine of these patients were diagnosed with COVID-19 based on viral RNA testing (N = 41) or typical radiologic signs: 37/59 (63%) COVID-19 patients were treated for metastatic breast cancer, and 13/59 (22%) of them were taking corticosteroids daily. Common clinical features mostly consisted of fever and/or cough, while ground-glass opacities were the most common radiologic sign at diagnosis. We found no association between prior radiation therapy fields or extent of radiation therapy sequelae and extent of COVID-19 lung lesions. Twenty-eight of these 59 patients (47%) were hospitalized, and 6 (10%) were transferred to an intensive care unit. At the time of analysis, 45/59 (76%) patients were recovering or had been cured, 10/59 (17%) were still followed, and 4/59 (7%) had died from COVID-19. All 4 patients who died had significant non-cancer comorbidities. In univariate analysis, hypertension and age (> 70) were the two factors associated with a higher risk of intensive care unit admission and/or death. Conclusions This prospective registry analysis suggests that the COVID-19 mortality rate in breast cancer patients depends more on comorbidities than prior radiation therapy or current anti-cancer treatment. Special attention must be paid to comorbidities when estimating the risk of severe COVID-19 in breast cancer patients.

Abstract Background PD(L)1 antibodies (anti‐PD(L)‐1) have been a major breakthrough in several types of cancer. Novel patterns of response and progression have been described with anti‐PD(L)‐1. We aimed at characterizing pseudoprogression (PSPD) among patients with various solid tumor types treated by anti‐PD(L)‐1. Methods All consecutive patients (pts) enrolled in phase 1 trials with advanced solid tumors and lymphomas treated in phase I clinical trials evaluating monotherapy by anti‐PD(L)‐1 at Gustave Roussy were analyzed. We aimed to assess prevalence and outcome of PSPD across tumor types. We also intended to describe potential clinical and pathological factors associated with PSPD. Results A total of 169 patients treated with anti‐PD(L)‐1 were included in the study. Most frequent tumor types included melanoma (n = 57) and non‐small cell lung cancer (n = 19). At first tumor evaluation 77 patients (46%) presented with immune unconfirmed progressive disease. Six patients (8%) experienced PSPD: 2 patients with partial response; 4 patients with stable disease. Increase in target lesions in the first CT‐scan was more frequently associated to PSPD (67% vs 33%; P = .04). Patients with a PSPD had a superior survival when compared to patients progressing (median OS: 10.7 months vs 8.7 months; P = .07). Conclusions A small subset of PSPD patients may experience response after an initial progression. Assessment of the current strategy for immune‐related response evaluations may require further attention.

This study evaluates the influence of a gelatin sponge on adipose-derived stromal cells (ASC). Transcriptomic data revealed that, compared to ASC in a monolayer, a cross-linked porcine gelatin sponge strongly influences the transcriptome of ASC. Wound healing genes were massively regulated, notably with the inflammatory and angiogenic factors. Proteomics on conditioned media showed that gelatin also acted as a concentrator and reservoir of the regenerative ASC secretome. This secretome promoted fibroblast survival and epithelialization, and significantly increased the migration and tubular assembly of endothelial cells within fibronectin. ASC in gelatin on a chick chorioallantoic membrane were more connected to vessels than an empty sponge, confirming an increased angiogenesis in vivo. No tumor formation was observed in immunodeficient nude mice to which an ASC gelatin sponge was transplanted subcutaneously. Finally, ASC in a gelatin sponge prepared from outbred rats accelerated closure and re-vascularization of ischemic wounds in the footpads of rats. In conclusion, we provide here preclinical evidence that a cross-linked porcine gelatin sponge is an optimal carrier to concentrate and increase the regenerative activity of ASC, notably angiogenic. This formulation of ASC represents an optimal, convenient and clinically compliant option for the delivery of ASC on ischemic wounds.

Background: CT lung extent has emerged as a potential risk factor of COVID-19 pneumonia severity with mainly semiquantitative assessment, and outcome was not assessed in the specific oncology setting. The main goal was to evaluate the prognostic role of quantitative assessment of the extent of lung damage for early mortality of patients with COVID-19 pneumonia in cancer patients.Methods: We prospectively included consecutive cancer patients with recent onset of COVID-19 pneumonia assessed by chest CT between March 15, 2020, and April 20, 2020, and followed until May 1, 2020. Demographic, clinical, laboratory test data and imaging findings were recorded. Quantitative chest CT assessment of COVID-19 pneumonia was based on the density distribution of lung lesions using a freely available software recently released (Myrian XP-Lung). The association between extent of lung damage and overall survival was studied by univariate and multivariate Cox analysis. The Uno C-index was used to assess the discriminatory value of the quantitative CT extent of lung damage.Results: Seventy cancer patients with chest CT evidence of COVID-19 were included. After a median follow-up of 25 days, 17 patients (24%) had died. The median quantitative chest CT extent of COVID-19 was 20% (IQR = 14–35, range = 3–59) for non-survivors vs. 10% (IQR = 6–15, range = 2–55) for survivors (p = 0.002). The extent of COVID-19 pneumonia was correlated with inpatient management (p = 0.003) and oxygen therapy requirements (p < 0.001). Independent factors associated with death were performance status (PS) ≥2 (HR = 3.9, 95% CI = [1.1–13.8] p = 0.04) and extent of COVID-19 pneumonia ≥30% (HR = 12.0, 95% CI = [2.2–64.4] p = 0.004). No differences were found regarding the histology of cancer, cancer stage, metastases sites, or type of oncologic treatment between the survivor and non-survivor groups. The cross-validated Uno C-index of the model including PS and extent of COVID-19 pneumonia was 0.83, 95% CI = [0.73–0.93].Conclusions: The quantitative chest CT extent of COVID-19 pneumonia was a strong independent prognostic factor of early inpatient mortality in a population of cancer patients.

Selective one-pot sequential ortho-/meta-C–H functionalizations provided highly desirable polyfunctionalized arenes. Starting from readily available carboxylic acid derivatives, the concomitant formation of C–O and C–halogen bonds was achieved under mild reaction conditions (12 examples, up to 75% yield). The utility of the products was illustrated with post-functionalization reactions and Metiglinid synthesis. [ABSTRACT FROM AUTHOR]

Background: The required duration of antibiotic treatment for prosthetic joint infections (PJI) with debridement and retention of the implant (DAIR procedure) is unknown. Methods: Multicenter retrospective study emphasizing the duration of antibiotic therapy in patients treated with by DAIR. Results: We included 87 hip or knee PJI episodes in 87 patients from three university hospitals in France and Switzerland. All debridements were performed within 3 weeks of symptom onset. After a mean follow-up of 52.1 months, 60 patients with PJI (69%) remained in remission, with no significant difference between hip and knee cases (73.3% vs. 59.3%, 95% confidence interval (CI), 0.20–1.38), or between patients receiving 6 compared with 12 weeks of antibiotic treatment (70.5% vs.67.4%, 95%CI 0.27–2.10, p = 0.60). Methicillin-resistant Staphylococcus aureus was isolated from 13.8% of infections and this was the only variable associated with a poorer outcome (remission in 41.7% vs. 73.3% for those with other pathogens, 95%CI 0.05–0.77, p = 0.02). Conclusions: In patients undergoing DAIR for hip or knee PJI, the likelihood of long-term remission was not significantly different for those receiving 6 versus 12 weeks of antibiotic therapy. Prospective randomized trials are required to confirm this observation.

Objectives: The initial phase of infection of a foot ulcer in a person with diabetes is often categorized as mild. Clinicians usually treat these infections with antimicrobial therapy, often applied topically. Some experts, however, believe that mild diabetic foot ulcer infections will usually heal with local wound care alone, without antimicrobial therapy or dressings. Methods: To evaluate the potential benefit of treatment with a topical antibiotic, we performed a single-center, investigator-blinded pilot study, randomizing (1:1) adult patients with a mild diabetic foot ulcer infection to treatment with a gentamicin–collagen sponge with local care versus local care alone. Systemic antibiotic agents were prohibited. Results: We enrolled a total of 22 patients, 11 in the gentamicin–collagen sponge arm and 11 in the control arm. Overall, at end of therapy, 20 (91%) patients were categorized as achieving clinical cure of infection, and 2 (9%) as significant improvement. At the final study visit, only 12 (56%) of all patients achieved microbiological eradication of all pathogens. There was no difference in either clinical or microbiological outcomes in those who did or did not receive the gentamicin–collagen sponge, which was very well tolerated. Conclusion: The results of this pilot trial suggest that topical antibiotic therapy with gentamicin–collagen sponge, although very well tolerated, does not appear to improve outcomes in mild diabetic foot ulcer infection.