Investigator-initiated Study Research Articles

Reversal of liver failure using a bioartificial liver device implanted with clinical-grade human-induced hepatocytes

Liver resection is the first-line treatment for primary liver cancers, providing the potential for a cure. However, concerns about post-hepatectomy liver failure (PHLF), a leading cause of death following extended liver resection, have restricted the population of eligible patients. Here, we engineered a clinical-grade bioartificial liver (BAL) device employing human-induced hepatocytes (hiHeps) manufactured under GMP conditions. In a porcine PHLF model, the hiHep-BAL treatment showed a remarkable survival benefit. On top of the supportive function, hiHep-BAL treatment restored functions, specifically ammonia detoxification, of the remnant liver and facilitated liver regeneration. Notably, an investigator-initiated study in seven patients with extended liver resection demonstrated that hiHep-BAL treatment was well tolerated and associated with improved liver function and liver regeneration, meeting the primary outcome of safety and feasibility. These encouraging results warrant further testing of hiHep-BAL for PHLF, the success of which would broaden the population of patients eligible for liver resection.

CEFTO-CURE study: CEFTObiprole Clinical Use in Real-lifE – a multi-centre experience in Italy

Ceftobiprole is approved in Europe for treatment of community-acquired pneumonia and non-ventilator-associated hospital-acquired pneumonia (HAP) in adults. Real-world data are limited. This multi-centre, observational, ambispective investigator-initiated study was undertaken in Italy from January 2018 to December 2019 in order to evaluate the use of ceftobiprole in a real-world setting. Overall, 195 patients from 10 centres were evaluated (68% retrospectively). Male sex was prevalent (n=121, 62%). Median age was 67 [interquartile range (IQR) 53-75] years. Median Charlson Comorbidity Index score was 5 (IQR 3-7). The most common indication was pneumonia (151/195, 77%), especially HAP. Other uses were skin and soft tissue infections (5%), endocarditis (4%) and bone infections (4%). Ceftobiprole was usually an empiric choice (65%), in combination with other drugs (66%) and as second-line therapy (58%). A causative agent was found in 39% of cases. A diagnosis of sepsis was made in 59 cases (30%). Success in the clinically evaluable population (excluding 12 cases due to isolation of pathogens outside ceftobiprole's spectrum of activity) was obtained in 79% of cases, with all-cause mortality of 20%. On multi-level analysis, three predictors were positively associated with clinical success: male gender, pneumonia and detection of causal agent. Sepsis was a negative predictor. Nine factors were independently associated, favourably or unfavourably, with fatal outcome. Ceftobiprole is a safe and effective therapeutic choice, even in a real-world setting. More data are needed to establish its efficacy in patients with sepsis.

Clinical Profiles, Outcomes, and Sex Differences of Patients With STEMI: Findings From the NORIN-STEMI Registry

BackgroundLow- and middle-income countries account for most of the global burden of coronary artery disease. There is a paucity of data regarding epidemiology and outcomes for ST-segment elevation myocardial infarction (STEMI) patients in these regions. ObjectivesThe authors studied the contemporary characteristics, practice patterns, outcomes, and sex differences in patients with STEMI in India. MethodsNORIN-STEMI (North India ST-Segment Elevation Myocardial Infarction Registry) is an investigator-initiated prospective cohort study of patients presenting with STEMI at tertiary medical centers in North India. ResultsOf 3,635 participants, 16% were female patients, one-third were <50 years of age, 53% had a history of smoking, 29% hypertension, and 24% diabetes. The median time from symptom onset to coronary angiography was 71 hours; the majority (93%) presented first to a non-percutaneous coronary intervention (PCI)-capable facility. Almost all received aspirin, statin, P2Y12 inhibitors, and heparin on presentation; 66% were treated with PCI (98% femoral access) and 13% received fibrinolytics. The left ventricular ejection fraction was <40% in 46% of patients. The 30-day and 1-year mortality rates were 9% and 11%, respectively. Compared with male patients, female patients were less likely to receive PCI (62% vs 73%; P < 0.0001) and had a more than 2-fold greater 1-year mortality (22% vs 9%; adjusted HR: 2.1; 95% CI: 1.7-2.7; P < 0.001). ConclusionsIn this contemporary registry of patients with STEMI in India, female patients were less likely to receive PCI after STEMI and had a higher 1-year mortality compared with male patients. These findings have important public health implications, and further efforts are required to reduce these gaps.

Abstract 3387: ctDNA dynamics in early stage node negative lung cancers

Abstract Introduction: Patients with early-stage lung cancers have a high risk of relapse and death even after curative surgery. Detection of circulating tumour DNA (ctDNA) in plasma perioperatively is associated with shorter recurrence free survival (RFS). ctDNA-Lung-Detect is an investigator-initiated prospective study of ctDNA detection and association with RFS in patients with early stage non-small cell lung cancer (NSCLC). Methods: Patients with clinically staged T&amp;lt;4cm N0 NSCLC planned for surgical resection at the Princess Margaret/University Health Network underwent ctDNA assessment before and after surgery (~1 month and 1 year). ctDNA minimal residual disease (MRD) was detected using the highly sensitive and specific tumor-informed Residual Disease and Recurrence (RaDaR®, Inivata, Cambridge, UK) assay, which can track up to 48 tumor-specific variants in plasma. Results: Since August 2021, 64 eligible patients were enrolled (Table 1). One had isolated metastasis from a remote non-lung primary and subsequently excluded; another had their preoperative sample missed but was included. Preoperative ctDNA was detected in 15/62 (23.8%) patients and 1/63 (1.6%) post-operatively at the 1-month landmark timepoint (occult N2 disease found at surgery). All but one (93.3%) had ctDNA clearance with surgical resection. Two patients have recurred radiographically and in plasma at 1 year post-operatively, 1/15 with preoperative ctDNA detected (6.7%) and 1/47 without preoperative ctDNA detected (2.1%). Patients with higher T stage, tumor size, squamous histology, and without actionable driver alterations were more likely to have ctDNA detected at any timepoint. Conclusions: In patients with early stage NSCLC (small node negative tumors), 24% have detectable ctDNA pre-operatively. Surgical resection led to ctDNA clearance in 93% of cases. Our results support ongoing testing beyond the initial MRD landmark. Assessment of the impact on RFS post resection is ongoing. Citation Format: Jamie Feng, Tom Waddell, Kazuhiro Yasufuku, Andrew Pierre, Shaf Keshavjee, Jonathan Yeung, Marcelo Cypel, Laura Donahoe, Elliot Wakeam, Marc de Perrot, Jennifer Law, Alexandra Salvarrey, Lisa W. Le, Jennifer Lister, Michael Cabanero, Ming Tsao, Christodoulos Pipinikas, Karen Howarth, Natasha Leighl. ctDNA dynamics in early stage node negative lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3387.

SATISFY-JP, a phase II multicenter open-label study on Satralizumab, an anti-IL-6 receptor antibody, use for the treatment of pulmonary arterial hypertension in patients with an immune-responsive-phenotype: Study protocol.

Pulmonary arterial hypertension (PAH), an intractable disease with a poor prognosis, is commonly treated using pulmonary vasodilators modulating the endothelin, cGMP, and prostacyclin pathway. Since the 2010s, drugs for treating pulmonary hypertension based on mechanisms other than pulmonary vasodilation have been actively developed. However, precision medicine is based on tailoring disease treatment to particular phenotypes by molecular-targeted drugs. Since interleukin-6 (IL-6) is involved in the development of PAH in animal models, and some patients with PAH have elevated IL-6 levels, the cytokine is expected to obtain potentials for therapeutic targeting. Accordingly, we identified a phenotype with elevated cytokine activity of the IL-6 family in the PAH population by combining case data extracted from the Japan Pulmonary Hypertension Registry with a comprehensive analysis of 48 cytokines using artificial intelligence clustering techniques. Including an IL-6 threshold ≥2.73 pg/mL as inclusion criteria for reducing the risk of insufficient efficacy, an investigator-initiated clinical study using satralizumab, a recycling anti-IL6 receptor monoclonal antibody, for patients with an immune-responsive phenotype is underway. This study is intended to test whether use of patient biomarker profile can identify a phenotype responsive to anti-IL6 therapy.

Risk assessment in pulmonary arterial hypertension: A step towards clinical implementation based on the 2022 ESC/ERS pulmonary hypertension guidelines.

Risk assessment in pulmonary arterial hypertension: A step towards clinical implementation based on the 2022 ESC/ERS pulmonary hypertension guidelines.

Epidemiology of unexplained chronic cough in adults: a population-based study.

Unexplained chronic cough accounts for a significant proportion of chronic cough cases in adults, and its persistent phenotype shows female preponderance that is demographically similar to individuals with cough hypersensitivity https://bit.ly/3EwjWVo.

Reduction in the COVID-19 pneumonia case fatality rate by silver nanoparticles: A randomized case study

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has devastated mankind. To date, no approved treatment is available to completely combat this disease. Although many studies reported the potential of silver nanoparticles’ (AgNPs) action mechanism and effect against SARS-CoV-2, this is the first clinical trial that aimed to prove this effect. This open-label, randomized, parallel-group, investigator-initiated study (IIS) was conducted in India from 2021 to 2022 and included 40 patients diagnosed with moderately-severe to severe COVID-19 pneumonia. This study proved a significantly higher survival rates (p < 0.05) and significantly lower number of days until supplemental oxygenation was required (p < 0.0001) for patients receiving intravenous AgNPs in form of AgSept® in addition to the standard COVID-19 treatment. This study highlights the importance of intravenous AgNPs administration in the treatment of virus-induced pneumonia.

Abstract P3-02-07: Combined Chemo-endocrine Therapy Maybe a New Option for HR+/HER2− Advanced Breast Cancer: A Prospective, Single-center Clinical Study of Fulvestrant plus Oral Vinorelbine

Abstract Background Fulvestrant have demonstrated synergistic antitumor effect with chemotherapy regimen. This study evaluates the efficacy and safety of Fulvestrant with Vinorelbine in patients with hormone receptor positive (HR+)/human epidermal growth factor receptor-2-negative (HER2−) recurrent or metastatic breast cancer. Methods In this prospective, single-arm and investigator-initiated clinical study, patients with recurrent or metastatic HR+/HER2− breast cancer after the first line adjuvant endocrine therapy for &amp;gt; 1 year were eligible, in which the subjects of the first line was defined as the patients with recurrence and metastasis after adjuvant endocrine therapy for over 1 year and did not receive treatment for the recurrence and metastasis and the second-line defined as the patients who had disease progression after receiving first-line endocrine therapy or first-line chemotherapy). Patients were administered i.m. Fulvestrant 500mg (day 1 per cycle for 28 days) and oral Vinorelbine (60 mg/m2 on day 1, 8 and 15 of each cycle). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and safety. The Kaplan–Meier method and log-rank test were used to evaluate PFS and OS. Results Total 38 HR+/HER2- advanced breast cancer patients with median follow-up time (25.1 months) were enrolled in, and median PFS [9.86 months (95% CI: 7.2, 23.13)] were discovered. The median PFS of the first-line and the second-line treatment population were 20.73 months (95% CI: 9.82, NR) and 4.27 months (95% CI: 3.68, NR), respectively. The median OS of the intent-to-treat (ITT) and the first-line treatment population were not reached, and the OS of the second-line treatment was 28.2 months (95% CI: 11.5, NR). The ORR of the ITT population was 39.47% (95% CI: 23.93, 55.01). The ORR of the patients receiving first-line and second-line treatments were 44.44% (95% CI: 25.70, 63.19) and 27.27% (95% CI: 0.95, 53.59), respectively. The DCR of ITT population was 92.11% (95% CI: 83.54, 100.00)], and the median DoR was approximately 15.33 months (95% CI: 7.23, 22.54)]. In the safety analysis, most of the adverse events were grade of 1/2, and none of grade 4/5 adverse events were reported. Conclusion This is the first exploratory study of Fulvestrant with oral Vinorelbine regimen in the treatment of HR+/HER2− recurrent and metastatic breast cancer conducted worldwide. The combinative chemo-endocrine therapy was efficacious, safe and promising for patients with HR+/HER2− advanced breast cancer. Citation Format: Xue Wang, Jian Yue, Jiayu Wang, Pin Zhang, Fei Ma, Binghe Xu, Peng Yuan. Combined Chemo-endocrine Therapy Maybe a New Option for HR+/HER2− Advanced Breast Cancer: A Prospective, Single-center Clinical Study of Fulvestrant plus Oral Vinorelbine [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-02-07.

Trial in progress: Phase II study of niraparib and dostarlimab for the treatment of germline or somatic homologous recombination repair mutated metastatic pancreatic cancer.

TPS780 Background: Pancreatic adenocarcinoma is an aggressive malignancy with a limited number of therapeutic options. One subset of patients (up to 15%) carries germline and/or somatic mutations in homologous recombination repair genes, most notably BRCA1, BRCA2 and PALB2 amongst others, that confer sensitivity to PARP inhibition. Combinations of PARP inhibitors with anti-PD1 immunotherapy have shown activity in breast and ovarian cancer and have not yet been thoroughly studied in pancreatic cancer. Methods: We designed a single-arm phase 2 investigator-initiated study utilizing the combination of niraparib, a highly selective PARP inhibitor and a dostarlimab, an anti PD1 antibody, in the subset of pancreatic cancer patients with germline or somatic mutations in BRCA1/2, PALB2, BARD1, RAD51C, or RAD51D. Additional inclusion criteria include metastatic pancreatic adenocarcinoma, receipt of a platinum agent in 1st or 2nd line unless contraindicated, and at least 1 but not more than 2 prior lines of systemic therapy not including maintenance. Prior PARP inhibition is allowed, but not immediately prior to enrollment. Exclusion criteria include active unstable autoimmune disease or prior malignancy requiring active treatment within 2 years. Patients are treated with niraparib 200 mg orally once daily on days 1 through 21 of a 21 day cycle. Dostarlimab is administered IV 500 mg every 3 weeks for the 1st 4 cycles and then 1000 mg IV every 6 weeks subsequently. The primary endpoint of the study is the disease control rate at 12 weeks using standard iRECIST criteria. Twenty patients will be enrolled to ensure 19 evaluable. The design has 80% power to detected improvement in disease control rate from 25-50% with significance level of 0.10. Descriptive factors include gene mutated for inclusion, germline/somatic, and platinum refractoriness. Given the size of the study along with genetic heterogeneity there will be no interim analysis. Patients are being enrolled at 3 Mayo clinic sites in Rochester Minnesota, Phoenix Arizona, Jacksonville Florida. To date, 13 patients have been enrolled across all 3 sites. Full accrual is anticipated by early 2023. Correlative studies include genomic characterization of baseline tumors, assessment of immune infiltration of tumor microenvironment, tumor collection for organoid/xenograft, and serial circulating cell-free DNA and immune biomarkers. Trial Identifiers: NCT04493060, Mayo: MC1841. Supported by Glaxo Smith Kline. Clinical trial information: NCT04493060 .

Comparison of adhesive single-lead cardiac ECG patch device with Holter monitoring for detecting atrial fibrillation after an acute cerebral ischemic event: An interim analysis

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health Malaysia Background Stroke secondary to atrial fibrillation (AF) is common and often associated with higher risk of stroke recurrence. Detection of AF is challenging due to brief unpredictable episodes of AF runs, especially in patients whose admission electrocardiogram (ECG) demonstrates a sinus rhythm. Probability of AF detection may be higher with early initiation of prolonged ECG monitoring. Purpose To compare diagnostic yield of 7-day cardiac ECG patch versus 24-hour Holter monitoring for detecting AF≥30 seconds; to identify predictors of AF in stroke patients; to determine if 7-day cardiac ECG patch results in a change in clinical practice. Methods In this investigator-initiated prospective study with pairwise comparison of 24-hour Holter and 7-day cardiac ECG patch monitoring, 150 patients who were admitted to a tertiary referral centre with acute ischemic stroke (AIS) or transient ischemic attack (TIA) within 1 week, without known AF, and had sinus rhythm in the admission 12-lead ECG were enrolled. Each patient underwent simultaneous 24-hour Holter and 7-day cardiac ECG patch monitoring. Routine transthoracic echocardiography was performed on each patient to assess cardiac function and exclude intracardiac thrombus. Results There were 102 (68.0%) male patients. 12 (8.0%) patients had underlying history of coronary artery disease; 26 (17.3%) had recurrent stroke or TIA. On admission, median NIH Stroke scale was 4; 18 (12.0%) patients had thrombolysis with alteplase. On transthoracic echocardiography, none had intracardiac thrombus. Both Holter and cardiac ECG patch monitoring were initiated simultaneously at median 2 days after index stroke event. Of 150 patients, 17 (11.3%) detected AF ≥30 seconds. Of these 17 patients, 7 (4.7%) had AF detected within the first 24 hours on both Holter and cardiac ECG patch; 10 (6.7%) were detected after 24 hours on cardiac ECG patch only. Number needed to screen to detect one AF was 6. Compliance to 7-day cardiac ECG patch monitoring was 81.3%. There was no significant difference in age among patients with and without AF. Although left atrium (LA) was not found to be dilated in patients with AF, LA volume index was significantly higher (28.3±15.9 vs 21.8±8.5, p=0.018) and LA emptying fraction (LAEF) was significantly lower (38.0%±30.2 vs 52.6%±16.7, p=0.007). The prolonged 7-day cardiac ECG monitoring patch resulted in 1.5-fold increase in prescription of anticoagulation therapy. Conclusions A 7-day cardiac ECG patch monitoring detected more patients with AF ≥30 seconds than 24-hour Holter monitoring and resulted in increase in prescription of anticoagulation therapy. Higher LA volume index and lower LA emptying fraction were predictors of AF in patients with a recent stroke.

Ocrelizumab concentration and antidrug antibodies are associated with B-cell count in multiple sclerosis

BackgroundThe majority of patients with multiple sclerosis on ocrelizumab have B-cell depletion after standard interval dosing of 26 weeks. With B-cell-guided dosing patients receive their next dose when B-cell repopulation...

Herombopag promotes platelet engraftment and decreases platelet transfusion after allogeneic hematopoietic stem cell transplantation.

The delayed platelet engraftment associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a common complication and often results in increased transplant-related complications. A single-center, prospective, investigator-initiated pilot study was conducted to explore whether herombopag, a second generation thrombopoietin-receptor agonist, would promote platelet engraftment after allo-HSCT. Between 2/2022 and 06/2022, 17 individuals (median age 39; range 15-58 years) with hematological malignancies were enrolled. Herombopag was given for a median of 22 (range 14-61) days at a dose of 7.5mg/d. The median time to neutrophil >500/μl was 11 (range 9-19) days. The median time to platelet >20 000/μl and >50 000/μl was 13 (range 8-22), and 20 (range 14-45) days, respectively. Compared with historical controls, the cumulative incidence of platelet engraftment after HSCT was significantly higher in the herombopag group (>20 000/μl at day +21, 88% vs 65%, p=.003; >50 000/μl at day +30, 65% vs. 43%, p=.001). Herombopag also reduced the units of platelet transfusion within 30 days post-SCT (3.6 ± 2.5 vs. 5.4 ± 3.2U, p=.01). In conclusion, it seems likely that herombopag could enhance platelet engraftment after allo-HSCT.

O03 Rapid Infection Diagnostics in Cirrhosis (RIDiC): a novel molecular-based approach to address the ever increasing challenge of antimicrobial resistant infections in decompensated cirrhosis and acute-on-chronic liver failure

Abstract Background Global prevalence of MDR infections in cirrhotic patients has risen to 34% and associates with worsening clinical trajectory and mortality (Fernandez J et al. 2019). A major unmet need in addressing the challenge of antimicrobial resistance (AMR) in cirrhosis is rapid pathogen diagnosis and antimicrobial resistance (AMR) (Patel VC et al. 2019). These can facilitate selection of more effective antibiotic therapy, reducing selection for MDR organisms. The Curetis Unyvero™ platform (CUp) employs multiplex PCR technology for pathogen and AMR gene detection from multiple bodily tissues and fluids requiring minimal pre- processing. The investigator-initiated pilot study aimed to assess the utility of this platform for hospitalized cirrhotic patients. Methods Ascitic fluid, bronchoalveolar lavage (BAL) and blood culture samples were obtained from hospitalized cirrhotic patients with acute decompensation (AD) or acute-on-chronic liver failure (ACLF), in whom there was clinical suspicion of infection. Samples were tested using the IAI (intra-abdominal infection) panel, HPN (hospital pneumonia) panel and BCU (blood culture) panel based on sample type available. Results were not shared with clinicians for decision-making. Data were compared with standard microbiology diagnostics. Results 31 samples from 21 patients were tested: ascites (25), BAL (4), blood culture (2). Time to positive culture result of all samples was reduced with CUp compared with standard microbiology (4.59 versus 73.5 h). CUp showed 100% specificity (12/12) and detected the same organism in 100% of cases (10/12). In 6 samples, CUp identified pathogens which were consistent with clinical evidence of spontaneous bacterial peritonitis and previous positive isolates which standard microbiological diagnostics failed to identify. AMR genes identified by the CUp correlated with AMR patterns reported by standard diagnostics in 100% (5/5) of cases. In 2 patients, broad-spectrum antibiotic therapy continued although the CUp supported infection resolution. Four patients in whom CUp screening was negative continued to receive antibiotics whilst awaiting negative standard cultures that arrived 72 h later. CUp did not identify an Aspergillus species in one BAL sample as this is not part of the BAL panel. Conclusions These preliminary data suggest CUp results are compatible with standard laboratory diagnostics. The CUp may be utilized for earlier infection diagnosis and improve the targeting and de-escalation of antimicrobial therapy in AD and ACLF. These are crucial components in enhancing antibiotic stewardship strategies and to reduce MDR infections (Figure 1). Further work is however required to evaluate cost implications, validation and impact on clinical outcomes and mortality in cirrhosis.

Acute Effects of Insulin Infusion on Kidney Hemodynamic Function in People With Type 2 Diabetes and Normal Kidney Function

Acute Effects of Insulin Infusion on Kidney Hemodynamic Function in People With Type 2 Diabetes and Normal Kidney Function

Ability of patients with acute ischemic stroke to recall given information on intravenous thrombolysis: Results of a prospective multicenter study.

Intravenous thrombolysis (IVT) is an on label treatment for selected patients with acute ischemic stroke (AIS). As major bleeding or allergic shock may occur, the need to ensure patients' informed consent for IVT is a matter of debate. Prospective investigator-initiated multi-center observational study to assess the ability of AIS patients to recall information, provided by a physician during a standardized educational talk (SET) on IVT use. The recall of 20 pre-defined items was assessed in AIS after 60-90 min (n = 93) or 23-25 h (n = 40) after SET. About 40 patients with subacute stroke, 40 non-stroke patients, and 23 relatives of AIS patients served as controls, and were surveyed 60-90 min after SET. Within 60-90 min after SET, AIS patients (median age 70 years, 31% female, median NIHSS score on admission 3 points) who were considered capable to provide informed consent recalled 55% (IQR 40%-66.7%) of the provided SET items. In multivariable linear regression analysis recapitulation by AIS patients was associated with their educational level (β = 6.497, p < 0.001), self-reported excitement level (β = 1.879, p = 0.011) and NIHSS score on admission (β = -1.186, p = 0.001). Patients with subacute stroke (70 years, 40% female, median NIHSS = 2) recalled 70% (IQR 55.7%-83.6%), non-stroke patients (75 years, 40% female) 70% (IQR 60%-78.7%), and AIS relatives (58 years, 83% female) 70% (IQR 60%-85%). Compared to subacute stroke patients, AIS patients less often recalled the frequency of IVT-related bleeding (21% vs 43%), allergic shock (15% vs 39%), and bleeding-related morbidity and mortality (44% vs 78%). AIS patients recalled 50% (IQR 42.3%-67.5%) of the provided items 23-25 h after SET. AIS patients eligible for IVT remember about half of all SET-items after 60-90 min or 23-25 h, respectively. The fact that the recapitulation of IVT-associated risks is particularly poor should be given special consideration.

The Outcome of Ultrathin-Strut Biodegradable Polymer-Coated Sirolimus-Eluting Stents in Coronary Artery Disease Patients - A Feasibility Study.

Drug-eluting coronary stents with ultrathin struts and biodegradable polymers have been shown to reduce inflammation, neointimal proliferation, and thrombus formation, leading to less early and late complications in patients with coronary artery disease as compared to thinner strut and durable polymer second-generation stents. In Oman, currently, second-generation stents are used for all patients. The purpose of this feasibility study was to evaluate the clinical safety and performance of ultrathin-strut (60 μm) biodegradable polymer-coated sirolimus-eluting stents in an all-comers patient population. This was a prospective, observational, single-center, and single-arm investigator-initiated study from August 2018 to August 2019. Inclusion criteria: 18 years of age, patients with symptomatic coronary artery disease indicated for percutaneous coronary intervention, and stenting of at least one coronary lesion. All patients were followed clinically or telephonically at 12 months after the index procedure. A total of 88 patients were recruited in the study, but 10 patients were lost to follow-up and hence excluded from the analysis. The overall mean age was 63 ± 13 years and 78% were males. The main comorbid conditions were hypertension (58%), diabetes mellitus (49%), and hyperlipidemia (26%). Fifty-three percent presented with unstable angina or non-ST elevation myocardial infarction (MI), 10% with ST elevation MI, recent MI 16%, 18% with stable angina, and 1.3% in cardiogenic shock. The mean left ventricular ejection fraction of the cohort was 46 ± 14%. Angiographically, Type A lesions were seen in 25%, Type B in 32%, and Type C in 42%. Left anterior descending stenting was done in 44%, right coronary artery in 32%, left circumflex artery in 14%, left main in 5%, and graft stenting in 4%. Device success was 96%. Procedural success was seen in 97% of patients. At 1-year follow-up, 93% were asymptomatic; overall device-oriented clinical events were 6.8% including cardiac death in 2.7%, target-vessel MI in 2.7%, and target-lesion revascularization in 1.3% which all occurred in uncontrolled diabetic patients. At index admission and 1 year, ultrathin-strut biodegradable polymer-coated sirolimus-eluting stent study showed low device-related adverse clinical events which are comparable to published data for the second-generation stents. This feasibility study shows that these stents can be used in all types of stent-indicated patients with added advantages of biodegradable polymer and ultrathin struts. In addition, measures to prevent, diagnose, and control diabetes need to be taken in Oman as this cohort of patients develop ST after stenting.

A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial of olanzapine plus triple antiemetic regimen for the prevention of multiday highly emetogenic chemotherapy-induced nausea and vomiting (OFFER study).

Evidence supports prophylactic use of olanzapine for the treatment of chemotherapy-induced nausea and vomiting (CINV). However, most studies to date have focused on patients with single-day highly emetogenic chemotherapy (HEC). Currently, administration of antiemetic therapies for nausea and vomiting induced by multiday chemotherapy regimens remains a challenge. In this study, we evaluated the efficacy of olanzapine combined with triple antiemetic therapy for the prevention of CINV in patients receiving multiday chemotherapy. We performed a randomized, double-blind, placebo-controlled phase 3 trial in 22 hospitals. Eligible patients were between 18 and 75 years old, were diagnosed with malignant solid tumors, and they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. All the study participants were scheduled to be treated with chemotherapy regimens containing 3-day cisplatin (3-day total dose ≥75mg/m2). Randomization was computer generated and stratified by gender and chemotherapy treatment history. Allocation was done via an interactive web response system. Enrolled patients were randomly assigned 1:1 to receive either 5mg olanzapine or placebo orally before bedtime for 5 days combined with intravenous fosaprepitant (150mg) 1h before the administration of cisplatin on day 1, ondansetron hydrochloride intravenously, and dexamethasone orally 30min before cisplatin from days 1 to 3. Dexamethasone was also administered at the same time on days 4 and 5. The primary endpoint was the proportion of subjects with complete response (no vomiting and no rescue therapy) within the overall phase (days 1-8) after starting chemotherapy. Baseline plasma concentrations of P-substance and 5-HT were measured for exploratory analysis. This study was registered at ClinicalTrials.gov, number NCT04536558. Between December 2020 and September 2021, 349 patients with malignant solid tumors were enrolled in the study, with 175 participants randomly assigned to receive olanzapine and 174 participants assigned to receive placebo. The proportion of patients who achieved a complete response in the overall phase was significantly higher in the olanzapine group than in the placebo group (69% vs. 58%, P=0.031). A complete response benefit was observed in the olanzapine group versus the placebo group in almost all the subgroups. Four factors were considered significantly associated with complete response in multivariable analysis: treatment group, gender, baseline plasma concentration of 5-HT, and prior radiotherapy. All the reported adverse events associated with olanzapine administration were grades 1 and2. Olanzapine (5mg) combined with fosaprepitant, ondansetron, and dexamethasone was better than triple antiemetic therapy alone for patients receiving multiday chemotherapy regimens. Based on these results, the four-drug combination should be recommended as the best antiemetic regimen given to patients receiving multiday cisplatin-based chemotherapy and baseline plasma concentration of 5-HT may be used to identify individuals who are prone to CINV. However, all these findings need to be further validated in future studies. Jiangsu Hansoh Pharmaceutical Group Co., Ltd. provided research grant and study drugs for this investigator-initiated study.

Variability of fractional exhaled nitric oxide is associated with the risk and aetiology of COPD exacerbations.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are heterogeneous in aetiology and accelerate disease progression. Here, we aimed to investigate the association of fractional exhaled nitric oxide (FeNO) and its variability with AECOPD of different aetiology. FeNO was determined in 2157 visits (1697 stable, 133 AECOPD and 327 follow-up) of 421 COPD patients from the PREVENT study, an investigator-initiated, longitudinal and interventional study, who were on daily treatment with inhaled corticosteroids/long-acting β2-agonists. Longitudinal measurements of FeNO revealed an intra-subject variability of FeNO that was significantly higher in exacerbators compared to non-exacerbators (p< 0.001) and positively associated with the number of AECOPD. As FeNO variability increased, the probability of patients to remain AECOPD-free decreased. In patients included in the highest FeNO variability quartile (≥15.0ppb) the probability to remain free of AECOPD was only 35% as compared to 80% for patients included in the lowest FeNO variability quartile (0.50-4.39 ppb). The change of FeNO from the last stable visit to AECOPD was positively associated with the probability of viral infections and this association was stronger in current smokers than ex-smokers. In contrast, the change in FeNO from the last stable visit to an AECOPD visit was inversely associated with the probability of bacterial infections in ex-smokers but not in current smokers. FeNO variability was associated with the risk and aetiology of AECOPD differentially in current and ex-smokers.

Five-year remission without disease progression in a patient with relapsed/refractory multiple myeloma with extramedullary disease treated with LCAR-B38M chimeric antigen receptor T cells in the LEGEND-2 study: acase report.

Multiple myeloma remains incurable despite treatment advancements over the last 20years. LCAR-B38M Cells in Treating Relapsed/Refractory Multiple Myeloma was a phase 1, first-in-human, investigator-initiated study in relapsed/refractory multiple myeloma conducted at four sites in China. The study used LCAR-B38M chimeric antigen receptor-T cells expressing two B-cell maturation antigen-targeting single-domain antibodies designed to confer avidity, and a CD3ζ signaling domain with a 4-1BB costimulatory domain to optimize T-cell activation and proliferation. This chimeric antigen receptor construct is identical to ciltacabtagene autoleucel. In the LEGEND-2 study (n = 57, Xi'an site), overall response rate was 88%; median (95% CI) progression-free survival and overall survival were 19.9 (9.6-31.0) and 36.1 (26.4-not evaluable) months, respectively; and median follow-up was 25months. This case study reports on a patient with relapsed/refractory multiple myeloma (λ light chain type) who was treated with LCAR-B38M chimeric antigen receptor T cells in the LEGEND-2 study (Xi'an site); he had received five prior lines of treatment and had extensive extramedullary lesions. The patient, a 56-year-old Asian male, received cyclophosphamide (500mg daily × 3days) as lymphodepletion therapy and a total dose of 0.5 × 106 chimeric antigen receptor + T cells/kg split into three infusions (days 1, 24, and 84 from June to August 2016). He experienced grade 2 cytokine release syndrome after the first infusion; all symptoms resolved with treatment. No cytokine release syndrome occurred following the second and third infusions. His λ light chain levels decreased and normalized 20days after the first infusion, and extramedullary lesions were healed as of January 2018. He has sustained remission for 5years and received no other multiple myeloma treatments after LCAR-B38M chimeric antigen receptor T cell infusion. As of 30 October 2020, the patient is still progression-free and has maintained minimal residual disease-negative (10-4) complete response status for 52months. This case provides support that treatment with LCAR-B38M chimeric antigen receptor T cells can result in long-term disease remission of 5 or more years without disease progression in a heavily pretreated patient with extensive extramedullary disease and no other treatment options.