Oligometastatic disease has been proposed as an intermediate state between localised and systemically metastasised disease. In the absence of randomised phase 3 trials, early clinical studies show ...improved survival when radical local therapy is added to standard systemic therapy for oligometastatic disease. However, since no biomarker for the identification of patients with true oligometastatic disease is clinically available, the diagnosis of oligometastatic disease is based solely on imaging findings. A small number of metastases on imaging could represent different clinical scenarios, which are associated with different prognoses and might require different treatment strategies. 20 international experts including 19 members of the European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer OligoCare project developed a comprehensive system for characterisation and classification of oligometastatic disease. We first did a systematic review of the literature to identify inclusion and exclusion criteria of prospective interventional oligometastatic disease clinical trials. Next, we used a Delphi consensus process to select a total of 17 oligometastatic disease characterisation factors that should be assessed in all patients treated with radical local therapy for oligometastatic disease, both within and outside of clinical trials. Using a second round of the Delphi method, we established a decision tree for oligometastatic disease classification together with a nomenclature. We agreed oligometastatic disease as the overall umbrella term. A history of polymetastatic disease before diagnosis of oligometastatic disease was used as the criterion to differentiate between induced oligometastatic disease (previous history of polymetastatic disease) and genuine oligometastatic disease (no history of polymetastatic disease). We further subclassified genuine oligometastatic disease into repeat oligometastatic disease (previous history of oligometastatic disease) and de-novo oligometastatic disease (first time diagnosis of oligometastatic disease). In de-novo oligometastatic disease, we differentiated between synchronous and metachronous oligometastatic disease. We did a final subclassification into oligorecurrence, oligoprogression, and oligopersistence, considering whether oligometastatic disease is diagnosed during a treatment-free interval or during active systemic therapy and whether or not an oligometastatic lesion is progressing on current imaging. This oligometastatic disease classification and nomenclature needs to be prospectively evaluated by the OligoCare study.
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Immune checkpoint inhibitors (ICIs) have improved cancer prognosis but have not been evaluated specifically in sarcomatoid carcinoma (SC), a rare lung cancer subtype with poor prognosis. As such, our ...study sought to retrospectively assess the efficacy of ICI in SC.
All consecutive patients with centrally confirmed SC treated using ICI as a second-line treatment or beyond between 2011 and 2017 were enrolled. Programmed death-ligand 1 (PD-L1) tumor expression was assessed using immunohistochemistry (SP263 clone) and the tumor mutational burden (TMB) with the Foundation One panel. TMB was considered high if it was greater than or equal to 10 mutations per megabase.
Overall, 37 patients with SC were evaluated, predominantly men (73%) with a median age of 63.2 years (36.8–79.7) and who were current or former smokers (94.6%). Immunotherapy (nivolumab, 86.5% of cases) was given as a second-line treatment in 54% of the patients and as third-line treatment or beyond in 46% of the patients. The objective response rate was 40.5% and disease control rate was 64.8%, regardless of PD-L1 status. Median overall survival was 12.7 months (range: 0.3–45.7). One-third of patients exhibited early progression. The median PD-L1 expression was 70% (0–100). There was a trend toward higher PD-L1 expression in responsive diseases, with an objective response rate of 58.8% in patients with PD-L1+ and 0% in the one patient with PD-L1- (p = 0.44). The median TMB was 18 (4–39) mutations per megabase, with 87.5% of the cases displaying a high TMB. There was a trend toward higher TMB in responders versus stable or progressive diseases (p = 0.2).
Patients with SC exhibited high response rates and prolonged overall survival under ICI treatment. These data support the prospective investigation of ICI in patients with SC who are under first-line treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The olfactory mucosa, where the first step of odor detection occurs, is a privileged pathway for environmental toxicants and pathogens toward the central nervous system. Indeed, some pathogens can ...infect olfactory sensory neurons including their axons projecting to the olfactory bulb allowing them to bypass the blood–brain barrier and reach the central nervous system (CNS) through the so‐called olfactory pathway. The respiratory syncytial virus (RSV) is a major respiratory tract pathogen but there is growing evidence that RSV may lead to CNS impairments. However, the mechanisms involved in RSV entering into the CNS have been poorly described. In this study, we wanted to explore the capacity of RSV to reach the CNS via the olfactory pathway and to better characterize RSV cellular tropism in the nasal cavity. We first explored the distribution of RSV infectious sites in the nasal cavity by in vivo bioluminescence imaging and a tissue clearing protocol combined with deep‐tissue imaging and 3D image analyses. This whole tissue characterization was confirmed with immunohistochemistry and molecular biology approaches. Together, our results provide a novel 3D atlas of mouse nasal cavity anatomy and show that RSV can infect olfactory sensory neurons giving access to the central nervous system by entering the olfactory bulb.
Cover Image for this issue: doi: 10.1111/jnc.14765.
While the respiratory syncytium virus (RSV) is mainly known for its damaged in the respiratory tract, it could also impact the central nervous system. We explored globally the impact of RSV in the mouse nasal cavity and showed that RSV can infect olfactory sensory neurons giving access to the central nervous system by entering the olfactory bulb. Our study also provides a 3D atlas of the nasal cavity in mice giving tools to improve our understanding of virus tropism in the upper respiratory tract.
Cover Image for this issue: 10.1111/jnc.14765.
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Objective
To describe the efficacy and safety of biologics for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA).
Methods
A retrospective European collaborative study was ...conducted in patients with EGPA who received treatment with biologics for refractory and/or relapsing disease.
Results
Among the 147 patients with EGPA included in the study, 63 received rituximab (RTX), 51 received mepolizumab (MEPO), and 33 received omalizumab (OMA). At the time of inclusion, the median Birmingham Vasculitis Activity Score (BVAS) was 8.5 (interquartile range IQR 5–13) in the RTX group, while the median BVAS in the OMA group was 2 (IQR 1–4.5) and the median BVAS in the MEPO group was 2 (IQR 1–5). In patients receiving RTX, the median BVAS declined both at 6 months (median 1, IQR 0–4.5) and at 12 months (median 0, IQR 0–2), and the frequency of remission, partial response, treatment failure, and stopping treatment due to adverse events was 49%, 24%, 24%, and 3%, respectively. For the treatment of glucocorticoid (GC)–dependent asthma, patients who received MEPO had a much better GC‐sparing effect and overall response than did patients who received OMA. The frequency of remission, partial response, treatment failure, and stopping treatment due to adverse events was 15%, 33%, 48%, and 4%, respectively, in the OMA group and 78%, 10%, 8%, and 4%, respectively, in the MEPO group. Remission rates at 12 months were 76% and 82% among patients receiving MEPO at a doses of 100 mg and 300 mg, respectively.
Conclusion
These results suggest that RTX could be effective in treating relapses of EGPA vasculitis. MEPO is highly effective with a good safety profile in patients with GC‐dependent asthma. Our data suggest that 100 mg MEPO monthly could be an acceptable dosage for first‐line therapy in selected instances of EGPA, recognizing, however, that this has not been compared to the validated dosage of 300 mg monthly.
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Human serum albumin (HSA) has been used for a long time as a resuscitation fluid in critically ill patients. It is known to exert several important physiological and pharmacological functions. Among ...them, the antioxidant properties seem to be of paramount importance as they may be implied in the potential beneficial effects that have been observed in the critical care and hepatological settings. The specific antioxidant functions of the protein are closely related to its structure. Indeed, they are due to its multiple ligand-binding capacities and free radical-trapping properties. The HSA molecule can undergo various structural changes modifying its conformation and hence its binding properties and redox state. Such chemical modifications can occur during bioprocesses and storage conditions of the commercial HSA solutions, resulting in heterogeneous solutions for infusion. In this review, we explore the mechanisms that are responsible for the specific antioxidant properties of HSA in its native form, chemically modified forms, and commercial formulations. To conclude, we discuss the implication of this recent literature for future clinical trials using albumin as a drug and for elucidating the effects of HSA infusion in critically ill patients.
SARS-CoV-2 is a coronavirus causing a globalized outbreak called COVID-19. SARS-CoV-2 transmission is associated with inhalation of contaminated respiratory droplets and could causes severe ...complications. Until today several “waves” of infections have been observed despite implementation of strict health policies. Decisions for such sanitary measures are based on population health monitoring. Unfortunately, for COVID-19, a significant proportion of individuals are asymptomatic but play a role in the virus transmission.
To overcome these limitations, several strategies were developed including genome quantification in wastewater that could allow monitoring of the health status of population, since shedding of SARS-CoV-2 in patient stool is frequent. Wastewater-based epidemiology (WBE) was established and several countries implemented this approach to allow COVID-19 outbreak monitoring. In France, the OBEPINE project performed a quantitative analysis of SARS-CoV-2 in raw wastewater samples collected from major wastewater treatment plants (WWTP) since March 2020.
In the greater Paris area 1101 samples (507 for five WWTP and 594 for sewer) were collected. This 16 months monitoring allows us to observe the outbreak dynamics. Comparison of WBE indicators with health data lead to several important observation; the good level of correlation with incidence rates, the average 3 days lead time, and the sensitivity (WBE change when incidence is > to 7/100000 inhabitants). We also compared the local monitoring (city level) with the regional monitoring, to help cluster identification.
Moreover, variants of concern (VOC) emerged due to the selection pressure. We developed a specific RT-qPCR method targeting the deletion H69-V70 in the spike protein, using this deletion as a proxy of the B.1.1.7 presence in the wastewater. With this data we demonstrate the predominant role played by this strain in the third wave.
All these results allow a better description and understanding of the pandemic and highlight the role of such WBE indicators.
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•Genome quantification of pathogens in wastewater allow monitoring of the health status of population.•Bi weekly sampling allows description of WBE indicators lag with incidence and sensibility at the regional or local level.•RT qPCR tools, targeting specific mutations allow dynamic monitoring of VOC in wastewater and population.•Variant monitoring in Wastewater demonstrates the important role played by some strains in the third wave.
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We studied the existence, localization and attentional modulation of gamma-band oscillatory activity (30–130 Hz) in the human intracranial region. Two areas known to play a key role in visual object ...processing: the lateral occipital (LO) cortex and the fusiform gyrus. These areas consistently displayed large gamma oscillations during visual stimulus encoding, while other extrastriate areas remained systematically silent, across 14 patients and 291 recording sites scattered throughout extrastriate visual cortex. The lateral extent of the responsive regions was small, in the range of 5 mm. Induced gamma oscillations and evoked potentials were not systematically co-localized. LO and the fusiform gyrus displayed markedly different patterns of attentional modulation. In the fusiform gyrus, attention enhanced stimulus-driven gamma oscillations. In LO, attention increased the baseline level of gamma oscillations during the expectation period preceding the stimulus. Subsequent gamma oscillations produced by attended stimuli were smaller than those produced by unattended, irrelevant stimuli. Attentional modulations of gamma oscillations in LO and the fusiform gyrus were thus very different, both in their time-course (preparatory period and/or stimulus processing) and direction of modulation (increase or decrease). Our results thus suggest that the functional role of gamma oscillations depends on the area in which they occur.
The introduction of novel agents has led to major improvements in clinical outcomes for patients with multiple myeloma. To shorten evaluation times for new treatments, health agencies are currently ...examining minimal residual disease (MRD) as a surrogate end point in clinical trials. We assessed the prognostic value of MRD, measured during maintenance therapy by next-generation sequencing (NGS). MRD negativity was defined as the absence of tumor plasma cell within 1 000 000 bone marrow cells (<10−6). Data were analyzed from a recent clinical trial that evaluated the role of transplantation in newly diagnosed myeloma patients treated with lenalidomide, bortezomib, and dexamethasone (RVD). MRD negativity was achieved at least once during maintenance in 127 patients (25%). At the start of maintenance therapy, MRD was a strong prognostic factor for both progression-free survival (adjusted hazard ratio, 0.22; 95% confidence interval, 0.15-0.34; P < .001) and overall survival (adjusted hazard ratio, 0.24; 95% confidence interval, 0.11-0.54; P = .001). Patients who were MRD negative had a higher probability of prolonged progression-free survival than patients with detectable residual disease, regardless of treatment group (RVD vs transplant), cytogenetic risk profile, or International Staging System disease stage at diagnosis. These results were similar after completion of maintenance therapy. Our findings confirm the value of MRD status, as determined by NGS, as a prognostic biomarker in multiple myeloma, and suggest that this approach could be used to adapt treatment strategies in future clinical trials.
•MRD using NGS-identified patients with an excellent outcome in multiple myeloma.•MRD should be assessed in every prospective trial, and is a candidate to become a primary end point.
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Aim
To investigate the association between routine use of dipeptidyl peptidase‐4 (DPP‐4) inhibitors and the severity of coronavirus disease 2019 (COVID‐19) infection in patient with type 2 diabetes ...in a large multicentric study.
Materials and Methods
This study was a secondary analysis of the CORONADO study on 2449 patients with type 2 diabetes (T2D) hospitalized for COVID‐19 in 68 French centres. The composite primary endpoint combined tracheal intubation for mechanical ventilation and death within 7 days of admission. Stabilized weights were computed for patients based on propensity score (DPP‐4 inhibitors users vs. non‐users) and were used in multivariable logistic regression models to estimate the average treatment effect in the treated as inverse probability of treatment weighting (IPTW).
Results
Five hundred and ninety‐six participants were under DPP‐4 inhibitors before admission to hospital (24.3%). The primary outcome occurred at similar rates in users and non‐users of DPP‐4 inhibitors (27.7% vs. 28.6%; p = .68). In propensity analysis, the IPTW‐adjusted models showed no significant association between the use of DPP‐4 inhibitors and the primary outcome by Day 7 (OR 95% CI: 0.95 0.77–1.17) or Day 28 (OR 95% CI: 0.96 0.78–1.17). Similar neutral findings were found between use of DPP‐4 inhibitors and the risk of tracheal intubation and death.
Conclusions
These data support the safety of DPP‐4 inhibitors for diabetes management during the COVID‐19 pandemic and they should not be discontinued.
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