Macintosh-style videolaryngoscope use for tracheal intubation in elective surgical patients revisited: a sub-analysis of the 2022 Cochrane review data.

The Cochrane systematic review and meta-analysis published in 2022 that compared videolaryngoscopy (VL) with direct laryngoscopy (DL) for facilitating tracheal intubation in adults found that all three types of VL device (Macintosh-style, hyper-angulated and channeled) reduced the risk of failed intubation and increased the likelihood of first-pass success. We report the findings of a subgroup re-analysis of the 2022 Cochrane meta-analysis data focusing on the Macintosh-style VL group. This was undertaken to establish whether sufficient evidence exists to guide airway managers in making purchasing decisions for their local institutions based upon individual device-specific performance. This re-analysis confirmed the superiority of Macintosh-style VL over Macintosh DL in elective surgical patients, with similar efficacy demonstrated between the Macintosh-style VL devices examined. Thus, when selecting which VL device(s) to purchase for their hospital, airway managers decisions are likely to remain focused upon issues such as financial costs, portability, cleaning schedules and previous device experience.

Integration of Genetic Testing and Counseling in Patients With Breast Cancer in a Large, Multisite Community-Based Practice.

PURPOSE: Despite data-driven consensus recommendations, there remains significant nonadherence to genetic screening and testing. More than 300,000 patients are diagnosed with breast cancer annually, with one third of these estimated to be eligible for homologous recombination deficiency (HRD)/BRCA testing following National Comprehensive Cancer Network (NCCN) guidelines. Only 35% of eligible patients are referred for genetic counseling. METHODS: The goal of this project was to apply NCCN guidelines for germline genetic testing to all new patients with breast cancer within a large community oncology practice to improve HRD/BRCA testing. Plan-Do-Study-Act methodology was used, and cycles were built on a proven teaching infrastructure. In cycle 1, providers were educated and directed to use electronic health record (EHR) templates in the setting of an initial diagnosis visit and treatment planning. Discreet data fields were created in the EHR during cycle 2 to streamline and automate the process. Appropriate patients were referred to the genetics team for further evaluation, counseling, and testing. Adherence to the plan was maintained and measured using data analytic reports and chart audits. RESULTS: Of the 1,203 patients with breast cancer eligible for inclusion, 1,200 (99%) were screened according to NCCN guidelines. Of the screened patients, 631 (52.5%) met the referral/testing criteria. In total, 585 (92.7%) of the 631 were referred to a genetic specialist. Seven percent had previous referrals. A total of 449 (71%) patients were acceptable to genetics referral while 136 (21.5%) patients refused. CONCLUSION: The implemented methods of education, NCCN guidelines imbedded within provider notes, and discreet data fields in the EHR have proven to be highly effective in screening appropriate patients and ordering subsequent genetic referrals.

Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study.

Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during cycle 1 and improved with premedication and step dosing. Prostate-specific antigen (PSA) and RECIST responses across cohorts were encouraging [49% PSA50; 24% objective response rate (ORR)], with greater frequency at target doses ≥0.75 mg (59% PSA50; 41% ORR). Xaluritamig is a novel immunotherapy for prostate cancer that has shown encouraging results supporting further development. SIGNIFICANCE: Xaluritamig demonstrated encouraging responses (PSA and RECIST) compared with historical established treatments for patients with late-line mCRPC. This study provides proof of concept for T-cell engagers as a potential treatment for prostate cancer, validates STEAP1 as a target, and supports further clinical investigation of xaluritamig in prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Nolan-Stevaux et al., p. 90. This article is featured in Selected Articles from This Issue, p. 5.

Sustainable Integration of US Food and Drug Administration-Approved Biosimilars: Pharmacy- Versus Physician-Driven Change.

PURPOSE: Biosimilars are clinically equivalent to branded products yet cost significantly less. Interchangeability is a US Food and Drug Administration (FDA) designation that allows generic drugs to be substituted for reference drugs at the pharmacy, without a physician's consent. Currently, no oncologic biosimilar has FDA approval for interchangeability. METHODS: Building on pharmacy auto-substitution processes with therapeutic interchange, Plan-Do-Study-Act methodology was used to automate conversions from reference biological products to Pharmacy and Therapeutics-/Physician-approved biosimilars. After establishing the baseline metrics, cycle 1 focused on full staff education (completed July 2020) with systematic pharmacy-driven biosimilar conversion initiated in September 2020 for rituximab, trastuzumab, and bevacizumab. Physician-initiated conversion of Neulasta biosimilar products was encouraged but not mandated. During cycle 2 (May 1, 2021-November 30, 2021), pharmacy-driven Neulasta biosimilar conversion was mandated. In cycle 3 (December 1, 2021-April 30, 2023), stakeholder education was reinforced and the sustainability of conversions was confirmed. RESULTS: Systematic pharmacy-driven conversion to biosimilar products improved over cycles 1 and 2 from baseline: 1.8% to 90.3% for rituximab, 9.2% to 89.7% for trastuzumab, and 20.5% to 96.1% for bevacizumab. Physician-driven biosimilar conversion for Neulasta was lower at 12.7% through April 2021. Pharmacy-driven Neulasta biosimilar conversion was initiated during cycle 2, resulting in a conversion rate of 39.7%. The conversion rates remained sustainable through April 2023. CONCLUSION: Pharmacy-driven auto-substitution of biosimilar products results in rapid and statistically significant biosimilar adoption. The pharmacy-based substitution approach was found to be far more effective than physician-driven substitution. Rapid conversion from branded products to FDA-approved biosimilar is feasible, measurable, and sustainable and can be scaled. Barriers to Neulasta conversion warrant further investigation.

Simple steps towards improving safety in obstetric airway management: A quality improvement project.

BACKGROUND: Guidelines from the Obstetric Anaesthetists' Association and Difficult Airway Society state that 'a videolaryngoscope should be immediately available for all obstetric general anaesthetics'. OBJECTIVE: To report the incidence of videolaryngoscopy use, and other airway management safety interventions, in an obstetric population before and after various quality improvement interventions. DESIGN: Prospective data collection was undertaken over 18 months, divided into three separate 6-month periods: June to November 2019; March to August 2021; January to June 2022. These periods relate to evaluation of specific quality improvement interventions. SETTING: The project was carried out in a large tertiary referral obstetric unit. PATIENTS: We identified 401 pregnant women (> 20 weeks' gestation) and postnatal women (up to 48 h post delivery) undergoing an obstetric surgical procedure under general anaesthesia. INTERVENTIONS: To standardise practice, an intubation checklist was introduced in December 2020 and multidisciplinary staff training in August 2021. MAIN OUTCOME MEASURES: Primary outcome measures were use of a Macintosh-style videolaryngoscope and tracheal intubation success. Secondary outcome measures were use of an intubation checklist; low flow nasal oxygen; and ramped patient positioning. RESULTS: Data from 334 tracheal intubations (83.3% of cases) were recorded. Videolaryngoscope use increased from 60% in 2019, to 88% in 2021, to 94% in 2022. Tracheal intubation was successful in all patients, with 94% first pass success overall and only 0.9% requiring three attempts. Use of secondary outcome measures also increased: low flow nasal oxygen from 48% in 2019 to 90% in 2022; ramped positioning from 95% in 2021 to 97% in 2022; and checklist use from 63% in 2021 to 92% in 2022. CONCLUSIONS: We describe the successful adoption of simple safety measures introduced into routine practice. These comprised videolaryngoscopy, ramped positioning and low flow nasal oxygen. Their introduction was supported by the implementation of an intubation checklist and multidisciplinary team training.

Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib.

Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2- breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.

Closing the Testing Gap: Standardization of Comprehensive Biomarker Testing for Metastatic Non-Small-Cell Lung Cancer in a Large Community Oncology Practice.

PURPOSE: Non-small-cell lung cancer (NSCLC), the leading cause of cancer death in the United States, accounts for 85% of all lung cancer cases. Biomarker testing is an integral part of the care of patients with NSCLC. Despite broad consensus recommendations that all patients with metastatic NSCLC (mNSCLC) undergo comprehensive biomarker testing (comprehensive genomic profiling and PD-L1), testing rates remain suboptimal. METHODS: The primary goal of this project was to apply National Comprehensive Cancer Network (NCCN) guidelines for comprehensive biomarker testing to all new patients with mNSCLC within a large community practice. Plan-Do-Study-Act methodology was used, with cycle 1 focused on provider education and the creation of a mNSCLC initial consult Note (electronic health record template/McKesson iKnowMed G2) and accompanying order set. Staging, template/order set utilization, and comprehensive biomarker testing rates were recorded while workflow processes were monitored. Cycle 2 centered on improved cancer staging, data analytic reporting, auditing, and reeducation. RESULTS: The comprehensive biomarker testing rates increased from a historic rate of 68% to 92.7% during the 1-year intervention period. The template utilization rate was 71% with complete staging (TNM stage and relevant biomarkers) documented in 40%. CONCLUSION: Implementation and standardization of comprehensive biomarker testing of patients with mNSCLC in a large multisite community-based oncology practice is feasible and results in significant improvement in comprehensive biomarker testing and reporting. Establishing reliable and measurable tracking metrics to ensure that these new processes are used and maintained can assist in scaling these processes. Efforts to scale this best practice are planned across the US Oncology Network.

Definitive results of a phase III adjuvant trial comparing six cycles of FEC-100 to four cycles of AC in women with operable node-negative breast cancer: the NSABP B-36 trial (NRG Oncology).

PURPOSE: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy. METHOD: NSABP B-36 was a phase III clinical trial originally designed as a 2 × 2 factorial study comparing 6 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC-100) to 4 cycles of conventional doxorubicin and cyclophosphamide (AC) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS). RESULTS: Between May 2004 and July 2008, 2722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR 1.09; 95% CI 0.92-1.29, p value = 0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR 1.32, 95% CI 1.05-1.66) compared to receptor-negative patients (HR 0.86, 95% CI 0.66-1.11) (treatment-by-receptor status interaction p value = 0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR 1.06; 95% CI 0.84-1.35, p value = 0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group. CONCLUSION: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00087178.

Behavioral and health outcomes from the NRG Oncology/NSABP B-36 trial comparing two different adjuvant therapy regimens for early-stage node-negative breast cancer.

BACKGROUND: The NSABP B-36 compared four cycles of doxorubicin and cyclophosphamide (AC) with six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC-100) in node-negative early-stage breast cancer. A sub-study within B-36, focusing on symptoms, quality of life (QOL), menstrual history (MH), and cardiac function (CF) was conducted. PATIENTS AND METHODS: Patients completed the QOL questionnaire at baseline, during treatment, and every 6 months through 36 months. FACT-B Trial Outcome Index (TOI), symptom severity, and SF-36 Vitality and Physical Functioning (PF) scales scores were compared between the two groups using a mixed model for repeated measures analysis. MH was collected at baseline and subsequently assessed if menstrual bleeding occurred within 12 months prior to randomization. Post-chemotherapy amenorrhea outcome was examined at 18 months and was defined as lack of menses in the preceding year. Logistic regression was used to test for association of amenorrhea and treatment. CF assessment was done at baseline and 12 months. Correlation analysis was used to address associations between changes in baseline and 12-month PF and concurrent CF changes measured by LVEF. RESULTS: FEC-100 patients had statistically significantly lower TOI scores during chemotherapy (P = 0.02) and at 6 months (P < 0.001); lower Vitality score at 6 months (P < 0.01), and lower PF score during the first year than AC patients. There were no statistically significant QOL score differences between the two groups beyond 12 months. No significant differences in symptom severity between the two groups were observed. Rates of amenorrhea were significantly different between FEC-100 and AC (67.4% vs. 59.1%, P < 0.001). There was no association between changes in LVEF and PF (P = 0.38). CONCLUSIONS: Statistically significant QOL differences between the two groups favored AC; however, the magnitude was small and unlikely to be clinically meaningful. There was a clinical and statistically significant difference in risk for amenorrhea, favoring AC. TRIAL REGISTRY: NCT00087178; Date of registration: 07/08/2004.

Midterm Outcomes of Posterior Medial Meniscus Root Tear Repair: A Systematic Review.

BACKGROUND: Whereas there has been growing interest in surgical repair of posterior medial meniscus root tears (PMMRTs), our understanding of the medium- and long-term results of this procedure is still evolving. PURPOSE: To report midterm clinical outcomes from PMMRT repairs. STUDY DESIGN: Systematic review. METHODS: A literature review for this systematic analysis was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We identified studies that reported the results of arthroscopic repair of PMMRTs. Functional and imaging outcomes were reviewed and summarized. RESULTS: In total, 28 studies with a total of 994 patients (83% female) with an overall mean age of 57.1 were included in this review. Clinical outcomes (Lysholm, International Knee Documentation Committee, Hospital for Special Surgery, and Tegner scores) were improved at final follow-up in all studies. Of patients, 49% had radiographic progression of at least 1 grade in the Kellgren-Lawrence scale at a mean follow-up of 4.0 years in 11 studies. Cartilage degeneration had progressed at least 1 grade on magnetic resonance imaging scans in 23% of patients at a mean follow-up of 31.6 months in 4 studies. CONCLUSION: PMMRT repairs provide a functional benefit with consistent improvements in clinical outcome scores. There is some evidence that PMMRT repair slows the progression of osteoarthritis but does not prevent it at midterm follow-up.

Histological findings of tracheal samples from COVID-19 positive critically ill mechanically ventilated patients.

OBJECTIVES: This study examines the histological findings of tracheal tissue samples obtained from COVID-19 positive mechanically ventilated patients, to assess the degree of tracheal inflammation/ulceration present. DESIGN AND PARTICIPANTS: Retrospective single-centre observational cohort study. All patients admitted to Adult Intensive Care Unit (AICU) with COVID-19 infection, requiring mechanical ventilation and surgical tracheostomy between 1 April and 1 May 2020, were included (Group 1). Tracheal windows excised at tracheostomy underwent histological analysis. Comparison was made with: tracheal windows from COVID-19 positive AICU ventilated patients admitted between 1 January and 1 March 2021 (Group 2); tracheal windows from COVID-19 negative AICU ventilated patients (Group 3); and, tracheal autopsy samples from COVID-19 positive patients that died without undergoing prolonged mechanical ventilation (Group 4). RESULTS: Group 1 demonstrated mild/moderate inflammation (tracheitis) in nearly all samples (15/16, 93.8%), with infrequent micro-ulceration (2/16, 12.5%). Group 2 demonstrated similar mild/moderate inflammation in all samples (17/17, 100%), with no ulceration. Histological findings of Groups 1 and 2 COVID-19 positive patients were similar to Group 3 COVID-19 negative patients, which demonstrated mild/moderate inflammation (5/5, 100%), with uncommon superficial erosion (1/5, 20%). Group 4 demonstrated mild chronic inflammation or no significant inflammation, with uncommon micro-ulceration (1/4, 25%). CONCLUSIONS: Severe tracheal inflammation was not demonstrated in mechanically ventilated COVID-19 positive patients at the level of the second/third tracheal rings, at the stage of disease patients underwent tracheostomy. Histological findings were similar between mechanically ventilated COVID-19 positive and negative patients. Tracheal ulceration may be a feature of early or severe COVID-19 disease.

The in vitro and in vivo anti-virulent effect of organic acid mixtures against Eimeria tenella and Eimeria bovis.

Eimeria tenella and Eimeria bovis are complex parasites responsible for the condition of coccidiosis, that invade the animal gastrointestinal intestinal mucosa causing severe diarrhoea, loss of appetite or abortions, with devastating impacts on the farming industry. The negative impacts of these parasitic infections are enhanced by their role in promoting the colonisation of the gut by common foodborne pathogens. The aim of this study was to test the anti-Eimeria efficacy of maltodextrin, sodium chloride, citric acid, sodium citrate, silica, malic acid, citrus extract, and olive extract individually, in vitro and in combination, in vivo. Firstly, in vitro infection models demonstrated that antimicrobials reduced (p < 0.05), both singly and in combination (AG), the ability of E. tenella and E. bovis to infect MDBK and CLEC-213 epithelial cells, and the virulence reduction was similar to that of the anti-coccidial drug Robenidine. Secondly, using an in vivo broiler infection model, we demonstrated that AG reduced (p = 0.001) E. tenella levels in the caeca and excreted faeces, reduced inflammatory oxidative stress, improved the immune response through reduced ROS, increased Mn-SOD and SCFA levels. Levels of IgA and IgM were significantly increased in caecal tissues of broilers that received 0.5% AG and were associated with improved (p < 0.0001) tissue lesion scores. A prophylactic approach increased the anti-parasitic effect in vivo, and results indicated that administration from day 0, 5 and 10 post-hatch reduced tissue lesion scores (p < 0.0001) and parasite excretion levels (p = 0.002). Conclusively, our in vitro and in vivo results demonstrate that the natural antimicrobial mixture (AG) reduced parasitic infections through mechanisms that reduced pathogen virulence and attenuated host inflammatory events.

A Phase 1 Study Evaluating Rovalpituzumab Tesirine in Frontline Treatment of Patients With Extensive-Stage SCLC.

INTRODUCTION: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, a Notch pathway ligand highly expressed on SCLC cells. Rova-T was evaluated alone or in combination with platinum-based chemotherapy (cisplatin or carboplatin combined with etoposide [CE]) in frontline treatment of extensive-stage SCLC. METHODS: One cycle of CE pre-enrollment was permitted (later mandated). The following four cohorts were enrolled: Rova-T monotherapy (0.3 mg/kg, every 6 [q6] wk × 2; cohort 1; n = 4); Rova-T induction (0.3 mg/kg, q6 wk × 2) followed by CE every 21 days (q21) × 4 (cohort 2; n = 5); Rova-T (0.1 or 0.2 mg/kg, q6 wk × 2) overlapping with CE q21 × 4 (cohort 3; n = 14); and Rova-T maintenance (0.3 mg/kg, q6 wk × 2) after CE q21 × 4 (cohort 4; n = 3). RESULTS: A total of 26 patients were dosed (cohort 3: 14; cohorts 1, 2, and 4 combined: 12). Median age was 66 years, and 73% had Eastern Cooperative Oncology Group performance status of 1. In cohort 3, seven patients (50%) had confirmed objective responses, with a median progression-free survival of 5.2 months and median overall survival of 10.3 months. Compared with cohorts 1, 2, and 4 combined, cohort 3 had lower frequency of some Rova-T-related adverse events of special interest, such as pleural effusion (0 versus 33%), pericardial effusion (0 versus 17%), ascites (0 versus 8%), peripheral edema (36% versus 42%), generalized edema (0 versus 8%), pneumonia (7% versus 25%), and hypoalbuminemia (0 versus 17%). CONCLUSIONS: Lower Rova-T doses may be associated with lower incidence of some Rova-T-related adverse events of special interest. Rova-T 0.2 mg/kg plus CE (cohort 3) was tolerable; however, there was no clear efficacy benefit of adding Rova-T to CE.

Impact of Anti-HER2 Treatments Combined With Atezolizumab on the Tumor Immune Microenvironment in Early or Metastatic Breast Cancer: Results From a Phase Ib Study.

BACKGROUND: Despite advances, there continues to be unmet need in breast cancer. Combining anti-programmed death-ligand 1 (PD-L1) cancer immunotherapy atezolizumab with other targeted therapies may enhance T-cell-dependent cytolytic antitumor activity. METHODS: This open-label, phase Ib study evaluated the safety of atezolizumab-based combinations with antibody-dependent cellular cytotoxicity or antibody-drug conjugate (ADC) agents. Patients with unresectable human epidermal growth factor receptor 2-positive (HER2+) locally advanced or metastatic breast cancer (mBC) received atezolizumab with trastuzumab/pertuzumab, atezolizumab with the ADC ado-trastuzumab emtansine (T-DM1), or atezolizumab with trastuzumab/pertuzumab and docetaxel. In an early-breast cancer (eBC) "window of opportunity" study, patients with operable HER2+ locally advanced or inflammatory eBC received neoadjuvant atezolizumab with trastuzumab/pertuzumab or atezolizumab/T-DM1, followed by docetaxel, carboplatin, and trastuzumab/pertuzumab. Exploratory outcomes included tumor response and biomarkers. RESULTS: By March 15, 2019, 73 patients were enrolled. Safety findings were consistent with the treatment components' individual profiles. Objective responses were observed in 2 of 6 and 5 of 14 patients in 2 mBC cohorts receiving atezolizumab/T-DM1 and in 6 of 6 patients with mBC receiving atezolizumab, trastuzumab/pertuzumab, and docetaxel. PD-L1 in immune cells was the only biomarker that increased with atezolizumab/T-DM1. In the window of opportunity cohorts, PD-L1 levels and CD8+ T-cell infiltration increased from baseline in HER2+ eBC tumors receiving atezolizumab with trastuzumab/pertuzumab or T-DM1, irrespective of response. Despite increases in T-cell and B-cell gene signatures with trastuzumab/pertuzumab, but not T-DM1, neither combination promoted T-cell receptor clonal expansion. CONCLUSION: Atezolizumab with antibody-dependent cellular cytotoxicity or ADC agents appears safe and may activate the adaptive immune system of patients with HER2+ eBC tumors more than those with mBC tumors.

Antiviral activity of a novel mixture of natural antimicrobials, in vitro, and in a chicken infection model in vivo.

The aim of this study was to test in vitro the ability of a mixture of citrus extract, maltodextrin, sodium chloride, lactic acid and citric acid (AuraShield L) to inhibit the virulence of infectious bronchitis, Newcastle disease, avian influenza, porcine reproductive and respiratory syndrome (PRRS) and bovine coronavirus viruses. Secondly, in vivo, we have investigated its efficacy against infectious bronchitis using a broiler infection model. In vitro, these antimicrobials had expressed antiviral activity against all five viruses through all phases of the infection process of the host cells. In vivo, the antimicrobial mixture reduced the virus load in the tracheal and lung tissue and significantly reduced the clinical signs of infection and the mortality rate in the experimental group E2 receiving AuraShield L. All these effects were accompanied by a significant reduction in the levels of pro-inflammatory cytokines and an increase in IgA levels and short chain fatty acids (SCFAs) in both trachea and lungs. Our study demonstrated that mixtures of natural antimicrobials, such AuraShield L, can prevent in vitro viral infection of cell cultures. Secondly, in vivo, the efficiency of vaccination was improved by preventing secondary viral infections through a mechanism involving significant increases in SCFA production and increased IgA levels. As a consequence the clinical signs of secondary infections were significantly reduced resulting in recovered production performance and lower mortality rates in the experimental group E2.