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Background: In EDTA-induced pseudothrombopenia, citrate or MgSO4 are recommended for platelet counting. Pre-analytical conditions are poorly defined for tubes containing MgSO4 or citrate. In this study, we analyzed the impact of agitation of these tubes on platelet counts. Methods: K2EDTA, citrate, and MgSO4 tubes from 70 patients were gently agitated on a wheel rotating at 20 rpm. Platelets were analyzed on the Sysmex XN analyzer at different times, and the percentage of platelet deviation from T0 was assessed and compared with the desirable bias of the EFLM. Results: at 180 min in fluorescence, the relative variation of platelets after shaking is 1.17% for K2EDTA, −29.76% for citrate, and −33.18% for MgSO4, while for unshaken MgSO4 platelets the variation is −1.3%. The reduction in platelet numbers when citrate or MgSO4 tubes are shaken is linked to the appearance of platelet clusters. Conclusions: agitation of MgSO4 and especially citrate tubes led to a decrease in platelet counts due to the formation of platelet aggregates; on the other hand, platelet counts on EDTA are virtually stable. During transport, we recommend putting sodium citrate and MgSO4 tubes in an upright position and avoiding shaking them to avoid giving an erroneous platelet result. [ABSTRACT FROM AUTHOR]

A joint modeling framework was developed using data from 75 patients of early amcenestrant phase I–II AMEERA‐1‐2 dose escalation and expansion cohorts. A semi‐mechanistic tumor growth inhibition (TGI) model was developed. It accounts for the dynamics of sensitive and resistant tumor cells, an exposure‐driven effect on tumor proliferation of sensitive cells, and a delay in the initiation of treatment effect to describe the time course of target lesion tumor size (TS) data. Individual treatment exposure overtime was introduced in the model using concentrations predicted by a population pharmacokinetic model of amcenestrant. This joint modeling framework integrated complex RECISTv1.1 criteria information, linked TS metrics to progression‐free survival (PFS), and was externally evaluated using the randomized phase II trial AMEERA‐3. We demonstrated that the instantaneous rate of change in TS (TS slope) was an important predictor of PFS and the developed joint model was able to predict well the PFS of amcenestrant phase II monotherapy trial using only early phase I–II data. This provides a good modeling and simulation tool to inform early development decisions. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study performed on Sysmex XN is to compare platelet values on citrate and MgSO4 (TBX) in patients with K2EDTA‐induced platelet clusters and to identify platelet biases of these matrices compared to K2EDTA. Methods: Sixty patients with K2EDTA‐induced platelet clusters were re‐sampled with K2EDTA, citrate and TBX. Platelet results were then compared, and smears were analysed for clumping. Platelet results from 120 patients without K2EDTA‐induced platelet clusters were compared between K2 EDTA, citrate, and MgSO4 with impedance and fluorescence modes. Biases from regressions were analysed. Results: Out of the 60 patients with K2EDTA‐induced platelet clusters, none showed platelet clusters with MgSO4 whereas 50% still showed clusters with citrate. Among those without platelet clusters on citrate, the mean relative difference between (citrate‐ MgSO4)/MgSO4 was −12.7% in impedance and −9.8% in fluorescence. Among the 120 patients without K2EDTA‐induced platelet clusters, in fluorescence the mean relative bias with respect to K2EDTA was −2.06% for MgSO4 and −10.3% for Citrate. For the MgSO4 versus K2 EDTA regressions, the maximum absolute values of the 95% CI of the relative biases at 150 × 109/L (5.45%) and 450 × 109/L (3.56%) were below the desirable analytical objectives of the EFLM. Conclusion: In patients with K2EDTA‐induced platelet clusters, MgSO4 is preferable to citrate. MgSO4 provides a bias with XN in fluorescence when compared to EDTA which is within analytical tolerance. [ABSTRACT FROM AUTHOR]

AMEERA-1 is a Phase 1/2 open-label single-arm study evaluating once-daily (QD) amcenestrant, an orally bioavailable selective estrogen receptor (ER) degrader, in postmenopausal women with ER+/HER2− advanced breast cancer (NCT03284957), who were mostly heavily pretreated (including targeted therapies and fulvestrant). In the dose escalation phase (Part A: n = 16), patients received amcenestrant 20-600 mg QD. Based on absence of dose-limiting toxicities, paired functional 18F-fluoroestradiol positron emission tomography, and pharmacokinetics, 400 mg QD was selected as recommended Phase 2 dose (RP2D) for the dose expansion phase (Part B: n = 49). No Grade ≥3 treatment-related adverse events or clinically significant cardiac/eye toxicities were reported. The Part B primary endpoint, confirmed objective response rate (ORR) was 3/45 at the interim analysis and 5/46 (10.9%) at the final analysis. The overall clinical benefit rate (CBR) was 13/46 (28.3%). CBRs among patients with baseline wild-type and mutated ESR1 were 9/26 (34.6%) and 4/19 (21.1%), respectively. Paired tumor biopsy and cell-free DNA analyses revealed ER inhibition and degradation, and a reduction in detectable ESR1 mutations, including Y537S. In conclusion, amcenestrant at RP2D of 400 mg QD for monotherapy is well-tolerated with no dose-limiting toxicities, and demonstrates preliminary antitumor activity irrespective of baseline ESR1 mutation status. There is a need for potent and non-toxic estrogen receptor (ER) antagonists to overcome the limitations of existing endocrine therapies. Here the authors report the results from Arm 1 of the Phase 1/2 study (AMEERA-1) among postmenopausal women with ER+/HER2− advanced breast cancer, which evaluates the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of amcenestrant administered as monotherapy. [ABSTRACT FROM AUTHOR]

Background: For estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC), the current standard first-line treatment includes an aromatase inhibitor in combination with a cyclin-dependent kinase 4/6 inhibitor. When resistance occurs, often related to the occurrence of ESR1 mutations, selective estrogen receptor modulators or degraders (SERDs) may be used, alone or in combination regimens. Amcenestrant (SAR439859), an optimized oral SERD, has shown clinical antitumor activity in combination with palbociclib in patients with ER+/HER2– ABC and, as monotherapy, in patients with and without ESR1 mutations. Here, we describe the study design of AMEERA-5, an ongoing, prospective, phase 3, randomized, double-blind, multinational study comparing the efficacy and safety of amcenestrant plus palbociclib versus letrozole plus palbociclib in patients with advanced (locoregional recurrent or metastatic) ER+/HER2– breast cancer. Methods: Patients are pre-/postmenopausal women and men with no prior systemic therapy for ABC. The planned enrollment is 1066 patients. Patients are randomized 1:1 to either amcenestrant 200 mg plus palbociclib 125 mg or letrozole 2.5 mg plus palbociclib 125 mg. Amcenestrant, letrozole, and their matching placebos are taken once daily continuously; palbociclib is taken once daily for 21 days, followed by 7 days off-treatment for a 28-day cycle. Treatment continues until disease progression, unacceptable toxicity, or decision to stop treatment. Pre-/perimenopausal women and men receive goserelin subcutaneously. Randomization is stratified by de novo metastatic disease, menopausal status, and visceral metastases. The primary endpoint is progression-free survival. The key secondary endpoint is overall survival; others are safety, pharmacokinetics, and quality of life. Conclusions: AMEERA-5 is evaluating the efficacy and safety of amcenestrant in combination with palbociclib as first-line therapy in pre-/postmenopausal women and men with ER+/HER2– ABC. ClinicalTrials Identifier: NCT04478266. [ABSTRACT FROM AUTHOR]

Novel technologies are needed to facilitate large-scale detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific antibodies in human blood samples. Such technologies are essential to support seroprevalence studies and vaccine clinical trials, and to monitor quality and duration of immunity. We developed a microfluidic nanoimmunoassay (NIA) for the detection of anti-SARS-CoV-2 IgG antibodies in 1,024 samples per device. The method achieved a specificity of 100% and a sensitivity of 98% based on the analysis of 289 human serum samples. To eliminate the need for venipuncture, we developed low-cost, ultralow-volume whole blood sampling methods based on two commercial devices and repurposed a blood glucose test strip. The glucose test strip permits the collection, shipment, and analysis of 0.6 μL of whole blood easily obtainable from a simple finger prick. The NIA platform achieves high throughput, high sensitivity, and specificity based on the analysis of 289 human serum samples, and negligible reagent consumption. We furthermore demonstrate the possibility to combine NIA with decentralized and simple approaches to blood sample collection. We expect this technology to be applicable to current and future SARS-CoV-2 related serological studies and to protein biomarker analysis in general. [ABSTRACT FROM AUTHOR]

In 208 children seeking medical care, the seropositivity rate of anti–SARS-CoV-2 IgG antibodies was 8.7%, suggesting an infection rate similar to that observed in adults but >100-fold the incidence of RT-PCR–confirmed pediatric cases. Compared with the gold-standard combined ELISA + immunofluorescence, the MEDsan IgG rapid diagnostic test performed accurately. [ABSTRACT FROM AUTHOR]

An antigen binding fragment (BFab) derived from a tumor-associated mucin 1–sialoglycotope antigen (CA6) targeting antibody (huDS6) was engineered. We synthesized a companion diagnostic positron emission tomography (PET) tracer by radiolabeling BFab with [64Cu] to measure CA6 expression on cancer tissues prior to anti-human CA6 (huDS6-DM4 antibody-drug conjugate) therapy for ovarian and breast cancer patients. After chemotherapy, the ovarian patient received PET scan with 18F-2-fluoro-2-deoxyglucose ([18F]FDG: 10 mCi), followed by [64Cu]-DOTA-BFab ([64Cu]BFab; 5.5 mCi) 1 week later for PET scanning of CA6 expression and subsequent surgery. The breast cancer patient was treated with chemotherapy before primary tumor resection and subsequent [18F]FDG-PET scan. 4 weeks later the patient received of [64Cu]BFab (11.7 mCi) for CA6 PET scan. Whole body [18F]FDG-PET of the breast cancer patient indicated FDG-avid tumor metastases to the liver, bilateral hila and thoracic spine, but no uptake was observed for the ovarian patient. Each patient was also imaged by PET/CT with [64Cu]BFab at 1 and 24 hours after tracer administration. The [64Cu]BFab tracer was well tolerated by both patients without adverse effects, and no significant tracer uptake was observed in both patients. Immunohistochemistry (IHC) data indicated CA6 expressions were weak to intermediate and matched with the [64Cu]BFab-PET signals. [ABSTRACT FROM AUTHOR]

Aims: To validate the diagnostic accuracy of the Augurix SARS‐CoV‐2 IgM/IgG rapid immunoassay diagnostic test (RDT) for COVID‐19. Methods: In this unmatched 1:1 case‐control study, blood samples from 46 real‐time RT‐PCR–confirmed SARS‐CoV‐2 hospitalized cases and 45 healthy donors (negative controls) were studied. Diagnostic accuracy of the IgG RDT was assessed against both an in‐house recombinant spike‐expressing immunofluorescence assay (rIFA), as an established reference method (primary endpoint), and the Euroimmun SARS‐CoV‐2 IgG enzyme‐linked immunosorbent assays (ELISA) (secondary endpoint). Results: COVID‐19 patients were more likely to be male (61% vs 20%; P =.0001) and older (median 66 vs 47 years old; P <.001) than controls. Whole blood IgG‐RDT results showed 86% and 93% overall Kendall concordance with rIFA and IgG ELISA, respectively. IgG RDT performances were similar between plasma and whole blood. Overall, RDT sensitivity was 88% (95% confidence interval [95%CI]: 70‐96), specificity 98% (95%CI: 90‐100), PPV 97% (95%CI: 80‐100) and NPV 94% (95%CI: 84‐98). The IgG‐RDT carried out from 0 to 6 days, 7 to 14 days and > 14 days after the SARS‐CoV‐2 RT‐PCR test displayed 30%, 73% and 100% positivity rates in the COVID‐19 group, respectively. When considering samples taken >14 days after RT‐PCR diagnosis, NPV was 100% (95%CI:90‐100), and PPV was 100% (95%CI:72‐100). Conclusions: The Augurix IgG‐RDT done in whole blood displays a high diagnostic accuracy for SARS‐CoV‐2 IgG in high COVID‐19 prevalence settings, where its use could be considered in the absence of routine diagnostic serology facilities. [ABSTRACT FROM AUTHOR]

A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) is the source of a current pandemic (COVID-19) with devastating consequences in public health and economic stability. Using a peptide array to map the antibody response of plasma from healing patients (12) and heathy patients (6), we identified three immunodominant linear epitopes, two of which correspond to key proteolytic sites on the spike protein (S1/S2 and S2') known to be critical for cellular entry. We show biochemical evidence that plasma positive for the epitope adjacent to the S1/S2 cleavage site inhibits furin-mediated proteolysis of spike. [ABSTRACT FROM AUTHOR]

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OBJECTIVE: To compare the inhibitory effect of a novel proton pump inhibitor (PPI), tenatoprazole 40 mg once daily, with esomeprazole 40 mg once daily on intragastric acidity. METHODS: A randomized, investigator-blind, two-way, crossover study was conducted in 30 healthy Helicobacter pylori negative male volunteers. Tenatoprazole 40 mg or esomeprazole 40 mg was administered once daily for 7 consecutive days with a 4-wk washout period between treatments. Ambulatory 24-h intragastric pH was recorded at baseline, after 7 days' treatment, and 3 and 5 days after treatment was stopped. RESULTS: At presumed steady-state (day 7), median 24-h pH values were 5.02 and 4.79 for tenatoprazole and esomeprazole, respectively. There was a significant difference between tenatoprazole and esomeprazole during the nocturnal period when mean pH was 4.64 ± 0.67 versus 3.61 ± 0.90, respectively ( p < 0.0001), as well as a significantly higher mean percentage of time with pH >4 on tenatoprazole (72.5 ± 14.9 vs 62.2 ± 13.6, p < 0.0001). The effect of tenatoprazole was still present 5 days after treatment withdrawal especially during the night-time. The mean area under the plasma concentration–time curve and elimination half-time was significantly higher in the tenatoprazole group as compared with the esomeprazole group. CONCLUSION: Tenatoprazole 40 mg daily provides a prolonged duration of acid suppression and a shorter nocturnal acid breakthrough in healthy volunteers, even after stopping the drug. Thus, tenatoprazole may provide greater clinical efficacy for patients in whom a once daily PPI is ineffective. Further studies are indicated. (Am J Gastroenterol 2005;100:1–8) [ABSTRACT FROM AUTHOR]

Background: Comparative data of SARS-CoV-2 IgM/IgG serology rapid diagnostic tests (RDTs) is scarce. We thus performed a head-to-head comparison of three RDTs. Methods: In this unmatched case-control study, blood samples from 41 RT-PCR-confirmed COVID-19 cases and 50 negative controls were studied. The diagnostic accuracy of three commercially available COVID-19 RDTs: NTBIO (RDT-A), Orient-Gene (RDT-B), and MEDsan (RDT-C), against both a recombinant spike-expressing immunofluorescence assay (rIFA) and Euroimmun IgG ELISA, was assessed. RDT results concordant with the reference methods, and between whole blood and plasma, were established by the Kendall coefficient. Results: COVID-19 cases' median time from RT-PCR to serology was 22 days (interquartile range (IQR) 13–31 days). Whole-blood IgG detection with RDT-A, -B, and -C showed 0.93, 0.83, and 0.98 concordance with rIFA. Against rIFA, RDT-A sensitivity (SN) was 92% (95% CI: 78–98) and specificity (SP) 100% (95% CI: 91–100), RDT-B showed 87% SN (95% CI: 72–95) and 98% SP (95% CI: 88–100), and RDT-C 100% SN (95% CI: 88–100) and 98% SP (95% CI: 88–100). Against ELISA, SN and SP were above 90% for all three RDTs. Conclusions: RDT-A and RDT-C displayed IgG detection SN and SP above 90% in whole blood. These RDTs could be considered in the absence of routine diagnostic serology facilities. [ABSTRACT FROM AUTHOR]