Enrollment Criteria Research Articles

Clinical phenotyping of severe Mycoplasma pneumoniae pneumonia in children

Objective: To investigate and summarize pediatric patients with severe Mycoplasma pneumoniae pneumonia (MPP) presenting with varied clinical and chest imaging features in order to guide the individualized treatment. Methods: This was a retrospective cohort study. Medical records of clinical, imaging and laboratory data of 505 patients with MPP who were admitted to the Department Ⅱ of Respirology Center, Beijing Children's Hospital, Capital Medical University from January 2016 to October 2023 and met the enrollment criteria were included. They were divided into severe group and non-severe group according to whether lower airway obliterans was developed. The clinical and chest imaging features of the two groups were analyzed. Those severe cases with single lobe ≥2/3 consolidation (lobar consolidation) were further divided into subtype lung-necrosis and subtype non-lung-necrosis based on whether lung necrosis was developed. Comparison on the clinical manifestations, bronchoscopic findings, whole blood C-reactive protein (CRP) and other inflammatory indicators between the two subtypes was performed. Comparisons between two groups were achieved using independent-sample t-test, nonparametric test or chi-square test. Univariate receiver operating characteristic (ROC) curve analyses were performed on the indicators such as CRP of the two subtypes. Results: Of the 505 cases, 254 were male and 251 were female. The age of the onset was (8.2±2.9) years. There were 233 severe cases, among whom 206 were with lobar consolidation and 27 with diffuse bronchiolitis. The other 272 belonged to non-severe cases, with patchy, cloudy infiltrations or single lobe <2/3 uneven consolidation or localized bronchiolitis. Of the 206 cases (88.4%) severe cases with lobar consolidation, 88 harbored subtype lung-necrosis and 118 harbored subtype non-lung-necrosis. All 206 cases (100.0%) presented with persistent high fever, among whom 203 cases (98.5%) presented with inflammatory secretion obstruction and plastic bronchitis under bronchoscopy. Of those 88 cases with subtype lung-necrosis, there were 42 cases (47.7%) with dyspnea and 39 cases (44.3%) with moderate to massive amount of pleural effusion. There were 35 cases (39.8%) diagnosed with lung embolism during the disease course, of which other 34 cases (38.6%) were highly suspected. Extensive airway mucosal necrosis was observed in 46 cases (52.3%), and the level of their whole blood CRP was significantly higher than that of subtype non-lung-necrosis (131.5 (91.0, 180.0) vs. 25.5 (12.0, 43.1) mg/L, U=334.00, P<0.001). They were regarded as subtype "lung consolidation-atelectasis-necrosis". Of those 118 cases with subtype non-lung-necrosis, 27 cases (22.9%) presented with dyspnea and none were with moderate to massive amount of pleural effusion. Sixty-five cases (55.1%) presented with plastic bronchitis and localized airway mucosal necrosis was observed in 32 cases (27.1%). They were deemed as subtype "lung consolidation-atelectasis". ROC curve analyses revealed that whole blood CRP of 67.5 mg/L on the 6-10 th day of disease course exhibited a sensitivity of 0.96, a specificity of 0.89, and an area under the curve of 0.97 for distinguishing between these two subtypes among those with lobar consolidation. Conclusions: Pediatric patients with severe MPP present with lobar consolidation or diffuse bronchiolitis on chest imaging. Those with lobar consolidation harbor 2 subtypes as "lung consolidation-atelectasis-necrosis" and "lung consolidation-atelectasis". Whole blood CRP of 67.5 mg/L can be applied as an early discriminating indicator to discriminate between these two subtypes.

High level of gamma-glutamyltransferase is a possible risk factor for psoriasis: A nationwide population-based cohort study.

Background Gamma-glutamyl transferase (GGT) has been associated with coronary heart disease, diabetes mellitus, and hypertension, but its association with psoriasis has not yet been elucidated. Aims We conducted this study to determine the association between the risk of psoriasis and the serum GGT. Methods We conducted a nationwide population-based study. A total of 9,939,350 people met the enrolment criteria. The study population was classified into four groups based on GGT levels and the risk of psoriasis was calculated for each group. Results The incidence rates of psoriasis per 1,000 person-years were 2.96105 and 3.68577 in the lowest and highest GGT groups, respectively. After adjusting for age, sex, income, diabetes mellitus, hypertension, dyslipidemia, smoking, alcohol intake, exercise, and body mass index, the highest GGT group showed a significantly increased risk of developing psoriasis (hazard ratio: 1.057, 95% confidence interval: 1.044-1.07). This risk of psoriasis was significantly higher among the old age group (hazard ratio: 1.162, 95% confidence interval: 1.128-1.197) and women (hazard ratio: 1.14, 95% confidence interval: 1.117-1.164). Limitations The limitations of this study included the retrospective design, International Classification of Diseases code-based diagnosis, small hazard ratio, and non-availability of data on covariates. Conclusion The GGT level was found to be an independent risk factor for developing psoriasis.

Empagliflozin’s role in reducing ventricular repolarization heterogeneity: insights into cardiovascular mortality decline from the EMPATHY-HEART trial

BackgroundThe incidence of myocardial infarction (MI) and sudden cardiac death (SCD) is significantly higher in individuals with Type 2 Diabetes Mellitus (T2DM) than in the general population. Strategies for the prevention of fatal arrhythmias are often insufficient, highlighting the need for additional non-invasive diagnostic tools. The T-wave heterogeneity (TWH) index measures variations in ventricular repolarization and has emerged as a promising predictor for severe ventricular arrhythmias. Although the EMPA-REG trial reported reduced cardiovascular mortality with empagliflozin, the underlying mechanisms remain unclear. This study investigates the potential of empagliflozin in mitigating cardiac electrical instability in patients with T2DM and coronary heart disease (CHD) by examining changes in TWH.MethodsParticipants were adult outpatients with T2DM and CHD who exhibited TWH > 80 µV at baseline. They received a 25 mg daily dose of empagliflozin and were evaluated clinically including electrocardiogram (ECG) measurements at baseline and after 4 weeks. TWH was computed from leads V4, V5, and V6 using a validated technique. The primary study outcome was a significant (p < 0.05) change in TWH following empagliflozin administration.ResultsAn initial review of 6,000 medical records pinpointed 800 patients for TWH evaluation. Of these, 412 exhibited TWH above 80 µV, with 97 completing clinical assessments and 90 meeting the criteria for high cardiovascular risk enrollment. Empagliflozin adherence exceeded 80%, resulting in notable reductions in blood pressure without affecting heart rate. Side effects were generally mild, with 13.3% experiencing Level 1 hypoglycemia, alongside infrequent urinary and genital infections. The treatment consistently reduced mean TWH from 116 to 103 µV (p = 0.01).ConclusionsThe EMPATHY-HEART trial preliminarily suggests that empagliflozin decreases heterogeneity in ventricular repolarization among patients with T2DM and CHD. This reduction in TWH may provide insight into the mechanism behind the decreased cardiovascular mortality observed in previous trials, potentially offering a therapeutic pathway to mitigate the risk of severe arrhythmias in this population.Trial registrationNCT: 04117763.

Identification of severely injured children at very low risk of emergent surgery: A national trauma registry study

ObjectiveThe number of pediatric trauma patients requiring surgical interventions has been steadily decreasing allowing for a judicious approach to immediately available resources. This study aimed to derive and validate a prediction rule that reliably identifies injured children who are at very low risk for requiring emergency surgery upon emergency department (ED) arrival. MethodsA retrospective cohort study of data included in the Israeli National Trauma Registry from January 1, 2011, through December 31, 2020, was conducted. We included children aged 0–14 years who presented to EDs from the scene of injury and were hospitalized. We excluded patients transferred between facilities or with isolated burns. The primary outcome was emergency operative intervention (EOI) performed within one hour of ED arrival. We tested mechanism, GCS, heart rate, and blood pressure as candidate predictors. We then randomized patients to two cohorts, derived and internally validated a prediction rule. ResultsDuring the study period, 83,859 children met enrollment criteria. The median age was 6 years (IQR 2–10) and 56,867 (67.8 %) were male; 75,450 (90.0 %) sustained blunt trauma. One hundred sixty-nine (0.20 %) children underwent EOI. In the derivation and validation cohorts, 34,138 (81.4 %) and 34,271 (81.7 %) patients, were classified as low risk based on blunt trauma mechanism, normal GCS (15), and low-risk heart rate (according to age). Of those, 8 (0.02 %) and 13 (0.04 %) required an EOI, respectively. In the validation cohort, the prediction rule for EOI had a sensitivity of 84 % (95 % CI 75–91), a specificity of 82 % (95 % CI 81–82), and a negative predictive value of 99.96 % (95 % CI 99.94–99.98). Among children with an Injury Severity Score>15, the sensitivity was 87 % (95 % CI 77–94), the specificity of 57 % (95 % CI 54–59), and the negative predictive value was 98.97 % (95 % CI 98.13–99.44). ConclusionsA limited set of physiologic parameters, readily available at hospital admission can effectively identify injured children at very low risk for emergent surgery. For these children, immediate deployment of surgical resources may not be necessary.

Worldwide cohort study of 46, XY differences/disorders of sex development genetic diagnoses: geographic and ethnic differences in variants.

Differences/disorders of sex development (DSDs) in individuals with a 46, XY karyotype are a group of congenital disorders that manifest as male gonadal hypoplasia or abnormalities of the external genitalia. Approximately 50% of patients with 46, XY DSDs cannot obtain a molecular diagnosis. The aims of this paper were to review the most common causative genes and rare genes in patients with 46, XY DSDs, analyze global molecular diagnostic cohorts for the prevalence and geographic distribution of causative genes, and identify the factors affecting cohort detection results. Although the spectrum of genetic variants varies across regions and the severity of the clinical phenotype varies across patients, next-generation sequencing (NGS), the most commonly used detection method, can still reveal genetic variants and aid in diagnosis. A comparison of the detection rates of various sequencing modalities revealed that whole-exome sequencing (WES) facilitates a greater rate of molecular diagnosis of the disease than panel sequencing. Whole-genome sequencing (WGS), third-generation sequencing, and algorithm advancements will contribute to the improvement of detection efficiency. The most commonly mutated genes associated with androgen synthesis and action are AR, SR5A2, and HSD17B3, and the most commonly mutated genes involved in gonadal formation are NR5A1 and MAP3K1. Detection results are affected by differences in enrollment criteria and sequencing technologies.

Rapid Development of a Registry to Accelerate COVID-19 Vaccine Clinical Trials.

The unprecedented scientific response to the SARS-Cov-2 pandemic in 2020 required the rapid development and activation of extensive clinical trial networks to study vaccines and therapeutics. The COVID-19 Prevention Network (CoVPN) coordinated hundreds of sites conducting phase 2 and 3 clinical trials of vaccines and antibody therapeutics. To facilitate these clinical trials, the CoVPN Volunteer Screening Registry (VSR) was created to collect volunteer information at scale, identify volunteers at risk of COVID-19 who met enrollment criteria, distribute candidates across clinical trial sites, and enable monitoring of volunteering and enrollment progress. We developed a secure database to support three primary web-based interfaces: a national volunteer questionnaire intake form, a clinical trial site portal, and an Administrative Portal. The Site Portal supported filters based on volunteer attributes, visual analytics, enrollment status tracking, geographic search, and clinical risk prediction. The Administrative Portal supported oversight and development with pre-specified reports aggregated by geography, trial, and trial site; charts of volunteer rates over time; volunteer risk score calculation; and dynamic, user-defined reports. Over 650,000 volunteers joined the VSR, and 1094 users were trained to utilize the system. The VSR played a key role in recruitment for the Moderna, Oxford-AstraZeneca, Janssen, and Novavax vaccine clinical trials, provided support to the Pfizer and Sanofi vaccine and prophylactic antibody clinical trials, and enhanced the diversity of trial participants. Clinical trial sites selected 166,729 volunteer records for follow-up screening, and of these 47·7% represented groups prioritized for increased enrollment. Despite the unprecedented urgency of its development, the system maintained 99·99% uptime. The success of the VSR demonstrates that information tools can be rapidly yet safely developed through a public-private partnership and integrated into a distributed and accelerated clinical trial setting. We further summarize the requirements, design, and development of the system, and discuss lessons learned for future pandemic preparedness.

Current trends in lung cancer brain metastases trials.

e14006 Background: Brain metastases are the predominant central nervous system malignancy, primarily originating from lung cancer. In the era of precision medicine, enhanced control of extracranial disease is increasing the incidence of brain metastases, underscoring their status as a growing unmet need in modern Neurooncology. Methods: On December 12, 2023, we searched ClinicalTrials.gov for interventional and therapeutic clinical trials focusing on lung cancer brain metastases (LCBM). We gathered information on trial characteristics, including phase, study design, primary and secondary endpoints, status, enrollment criteria, size, duration, and results. Subsequently, the collected data was subjected to systematic analysis. Results: Among 198 identified trials, the majority were in early phases: 12% in phase I, 6% in phase I/II, and 60% in phase II. Only 27% of trials in phase II &amp; II/III were randomized, with 92% lacking blinding. Trials were concentrated in North America (36%) and Asia/Africa/Australia (33%), predominantly targeting non-small cell lung cancer (NSCLC) (82%). Patients with leptomeningeal metastases were included in only about 10.5% of the trials. Out of 44 completed trials, only 21 resulted in published original articles. Termination occurred in 38 trials, primarily due to insufficient participant enrollment. Tyrosine kinase inhibitors emerged as promising treatments for brain parenchymal and leptomeningeal NSCLC metastases. Conclusions: This study highlights critical deficiencies in LCBM trials, ranging from inadequate trial numbers and recruitment difficulties to the overwhelming focus on NSCLC trials, insufficient randomization and blinding, and a marked scarcity of trials involving patients with leptomeningeal metastases. Addressing these issues is pivotal for advancing the understanding and treatment of LCBM.

A phase 1b/2 study of pivekimab sunirine (PVEK, IMGN632) in combination with venetoclax/azacitidine for patients with newly diagnosed CD123-positive acute myeloid leukemia.

TPS6585 Background: Despite improved outcomes with azacitidine (AZA) and venetoclax (VEN) in newly diagnosed (ND) unfit acute myeloid leukemia (AML), only a subset of patients (pts) respond (CR 37%; CR/CRi 66%) and long-term survival remains inadequate (mOS &lt;15m, DiNardo NEJM 2020). The measurable residual disease (MRD)-negative rate was 41% in AZA-VEN treated pts in VIALE-A which was associated with improved survival (Pratz JCO 2022). CD123 is expressed on the majority of AML blasts and leukemic stem cells while minimally expressed on normal hematopoietic stem cells (Kovtun Blood Adv 2018). Pivekimab sunirine (PVEK, IMGN632) is an antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The IGN payload alkylates DNA and causes single strand breaks without crosslinking. IGNs are designed to have high potency against tumor cells, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads. Clinical data from the first 50 pts in the dose expansion cohorts 1 and 2 with ND AML demonstrated a 76% (22/29) MRD negativity rate (by flow cytometry, negativity threshold &lt;0.1%) (Daver ASH 2023), supporting the continued enrollment of the PVEK+AZA+VEN triplet and further evaluation of the regimen’s antileukemia activity and safety in consideration of potential registration-enabling trials. Methods: This is an open-label, multicenter, phase 1b/2 study of PVEK administered in a combination with AZA+VEN in pts with ND CD123-positive (CD123+ by flow cytometry or IHC) AML, with no prior treatment with hypomethylating agents (HMA). Pts will receive the recommended phase 2 dose of PVEK 0.045 mg/kg IV as a &lt; 30-minute outpatient infusion on day 7, AZA 75 mg/m2 SC or IV daily on days 1 to 7, and VEN 400 mg PO daily for up to 28 days in a 28-day cycle. During cycle 1, a bone marrow evaluation at or around day 21 is required to inform VEN dose duration. Current eligibility criteria for continued enrollment of AML patients unfit for intensive chemotherapy include age ≥ 75 years old, or age &lt; 75 years old with ECOG 2-3, or at least one defined comorbidity. The primary study objectives are to assess antileukemia clinical activity (composite CR [complete remission] rate, overall response rate, duration of remission) and MRD-negativity rates. Key secondary objectives are safety and tolerability, pharmacokinetics and immunogenicity. The PVEK+AZA+VEN triplet in pts with ND unfit AML is currently enrolling across sites in France, Germany, Italy, Spain, UK and USA. Clinical trial information: NCT04086264 .

Research protocol for an observational health data analysis to assess the applicability of randomized controlled trials focusing on newly diagnosed metastatic prostate cancer using real-world data: PIONEER IMI’s “big data for better outcomes” program

Background: Metastatic prostate cancer (PCa) constitutes ~5% of all new PCa diagnoses in Western countries. For most cases, primary consideration should be given to systemic therapies as the first-line approach based on evidence from randomized controlled trials (RCTs). Despite the importance of RCTs as the pinnacle of evidence in modern medicine, concerns have been raised about their applicability to real-life scenarios. These trials often feature participants who are younger with better performance statuses and prognoses compared to their real-world counterparts. The PIONEER project falls under the Innovative Medicine Initiative’s (IMI) “Big Data for Better Outcomes” initiative, aimed at revolutionizing PCa care in Europe. The central focus lies in improving cancer-related outcomes, enhancing health system efficiency, and elevating the quality of health and social care. This study endeavours to evaluate the generalizability of RCT findings concerning newly diagnosed metastatic PCa. Methods: A systematic review of the literature will be conducted to compile patient characteristics from RCTs addressing this subject within the past decade. To create a real-world benchmark, patients with recently diagnosed metastatic PCa from a network of population-based databases will serve as a comparison group. The objective is to assess the applicability of RCT results in two ways. First, a comparison will be made between the characteristics of patients with newly diagnosed metastatic PCa enroled in RCTs and those with the same condition included in our databases which might represent the real-world setting. Second, an evaluation will be undertaken to determine the proportion of real-world patients with newly diagnosed metastatic PCa who meet the criteria for RCT enrolment. This study will rely on extensive observational data, primarily sourced from population-based registries, electronic health records, and insurance claims data. The study cohort is established upon routinely gathered healthcare data, meticulously mapped to the Observational Medical Outcomes Partnership Common Data Model.

Similarities and differences of lung cancer (LC) multidisciplinary teams (MDTs) in China compared to Europe and Canada.

e13562 Background: LC MDTs involve a collaborative approach where specialists work together to analyze individual cases, discuss treatment options, and tailor comprehensive care plans for patients. Implementing MDTs can be challenging, especially for developing countries with limited resources and high disease burden. China, with approximately 820,000 new patients with lung cancer in 2020 accounting for 37% of the total number in the world, bears the responsibility of treating the largest lung cancer patient population worldwide. The global MDT Aid Program (MAP) in LC has been including China to gather insights on the challenges, best practices, similarities, and differences of China LC MDT processes compared to other countries, so as to improve the outcome and cost-efficiency of global MDTs. Methods: In this study, we learned about the status, best practices, challenges of LC MDT development in China through virtual semi-structured healthcare professional (HCP) interviews, on-site masterclasses, and internal data sharing with 3 Chinese leading hospitals in LC - Guangdong Provincial People’s Hospital, West China Hospital and Xiangya Hospital. Similarities and differences were gathered based on previous MAP experience and insights from HCP discussions in LC across the Netherlands, Italy, Spain, Switzerland, Denmark, Norway, and Canada. To build a global collaboration on LC MDTs, three international knowledge exchange (IKE) sessions were organised to include China and all participating countries. Results: We identified seven main differences between China, Europe and Canada, including the enrolment criteria of patients in MDT that China MDTs focus on challenging cases such as resistance to multi-lines of therapy, multiple primary lung cancer and stage III lung cancer, while Europe and Canada MDTs mainly for routine patients. Other differences include setup and composition of MDT teams, digitalization of MDTs, incentives and reimbursement for MDT attendance, cross-institutional patient referral to the MDT, time spent per patient, patient follow-up after MDT discussion. Similarities identified include the MDT development model from both hospital and national level, experience sharing to educate junior physicians, hospital willingness to learn at global level, and challenges of high pressure with limited medical resources. Best practices of leveraging innovative digital capabilities to improve MDT efficiency and to support decision-making have been shared by China participants during the IKEs. Conclusions: Global collaboration to identify synergies within LC MDT communities can help China and other regions learn from each other and share China expertise in large-volume data-based practices globally. Alongside China’s rapid development of digital health, the digitalization of MDTs is likely to follow.

Disparities in gynecologic oncology clinical trial availability in the United States: A state-level analysis.

e23128 Background: Disparities in minority participation in gynecologic cancer clinical trials is well documented. FDA guidance stipulates geographic informed analyses to reduce barriers to trial participation. We performed a geographical analyses of gynecologic cancer clinical trials in the United States relative to racial distribution and social vulnerability indices to identify areas of increased need. Methods: We performed a cross-sectional analysis of NIH ClinicalTrials.gov by retrieving all trials first posted 1/1/2013 through to 1/10/2024. We searched for ovarian, uterine, cervical, endometrial, vaginal/vulvar and gynecological cancer. We reviewed enrollment criteria to exclude non-gynecological cancers (1643 trials) or non-invasive gynecological conditions (224 trials). We aggregated census data, state-level total population size, percent Non-Hispanic White (NHW), and the FEMA Expected Annual Loss per state as a measure of social vulnerability. Using R statistical software (v 4.3.1), we measured the association between these variables and the number of gynecological trials per 100,000 persons using Pearson’s correlation. Results: We identified 3,428 trials, filtered down to 1,561 invasive cancer trials. The most common trials were ovarian (911, 58.3%) and cervical (438, 28.0%), followed by endometrial (385, 24.6%), uterine (158, 10.1%), vulva-vaginal (78, 4.99%), and 7.62% genetic-based. Texas had the highest number of trials (501) followed by California (454) and New York (427). The state with the highest population-adjusted number of trials was South Dakota (8.57 trials per 100,000 persons), followed by Rhode Island at 8.38 per 100,000 persons. California, Mississippi, and Puerto Rico had the lowest number of trials per 100,000 persons with 1.148, 0.979, 0.466 respectively. States/territories with greater than 4 trials per 100,000 were comprised of populations that were &gt; 50% NHW. The correlation between the state-level percentage of NHW in 2020 and the number of trials per 100,000 persons was p = 0.057 indicating that there was a correlation between Whiteness at the state-level and trial availability. We found that states with higher FEMA expected annual loss had lower numbers of gynecological trials per 100,000 persons (p &lt; 0.001). Conclusions: We found a disparity in the geographical distribution of trials available for gynecological cancers that was correlated with racial disparities and social vulnerability. Efforts to increase decentralization of trials and improve access and availability of gynecologic cancer clinical trials are necessary to increase equity for minority representation in clinical trials at the national level.

Safety and preliminary efficacy of EIK1001 in combination with atezolizumab in participants with advanced solid tumors.

2618 Background: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response; however, not all patients benefit and some become refractory. EIK1001 is a Toll-like receptor (TLR)7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity provides another pathway, distinct from effects on checkpoint proteins, to enhance antitumor T-cell activity alone or in combination with ICIs. Methods: Study BDB001-102 was a Phase 1, open-label, dose-escalation/expansion study of EIK1001 combined with atezolizumab (comb Rx). Enrollment criteria included participants (pts) ≥ age 18 with confirmed, RECIST-measurable advanced solid tumors. Primary study objectives included safety and tolerability, and secondary objectives included evaluation of dose-limiting toxicities, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy by RECIST 1.1. During dose escalation, pts received a range of doses of EIK1001 (QW IV) in combination with atezolizumab (1200 mg Q3W). Results: Forty-one pts (median age 65 years [range = 32 to 79]) with multiple, distinct histological tumor types and a median of 3 prior Rx regimens were enrolled. Overall, a total of 28/41 (68.3%) receiving EIK1001 + atezolizumab experienced a treatment-related adverse event (TRAE). Of these, 4/41 (9.8%) experienced a ≥ Grade 3 TRAE, including fatigue, nausea, hyponatremia, and lymphedema. Only 1/41 (2.4%) experienced manageable cytokine release syndrome. There were no deaths due to TRAEs. Of the efficacy-evaluable pts (n = 37), complete response (CR) or partial response (PR) was observed for 3/37 (8.1%). Disease control (including CR, PR, or stable disease) was observed in 19/37 (51.4%). The median duration of response (DOR) was 13 months (range = 10 to 27). One responder was PD-L1 negative yet had a &gt; 12-month DOR; another had a history of prior anti-PD-1 Rx yet experienced a 10-month DOR on comb Rx. EIK1001 PK was linear and dose-proportional, and was not affected by combination with atezolizumab. Conclusions: Overall, EIK1001 was well-tolerated with a manageable safety profile and showed encouraging preliminary efficacy across several tumor types in combination with atezolizumab. Responses were observed even in pts not anticipated to respond to atezolizumab monotherapy. Further development of EIK1001 is underway. Clinical trial information: NCT04196530 .

Safety and preliminary efficacy of EIK1001 in combination with pembrolizumab in participants with advanced solid tumors.

2521 Background: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response; however, not all patients benefit and some become refractory. EIK1001 is a Toll-like receptor (TLR)7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity provides another pathway, distinct from effects on checkpoint proteins, to enhance antitumor T-cell activity alone or in combination with ICIs. Methods: Study BDB001-101 was a Phase 1, open-label, dose-escalation/expansion study of EIK1001 as either monotherapy (mono Rx; previously reported) or combined with pembrolizumab (comb Rx). Enrollment criteria included participants (pts) ≥ age 18 with confirmed, RECIST-measurable advanced solid tumors. Primary study objectives included safety and tolerability, and secondary objectives included evaluation of dose-limiting toxicities, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy by RECIST 1.1. During comb Rx dose escalation, pts received a range of doses of EIK1001 (QW IV) in combination with pembrolizumab (200 mg Q3W). Results: Fifty-one pts (median age 67 [range 33 to 86]) with multiple, distinct histological tumor types and with a median of 3 prior Rx regimens were enrolled. Overall, a total of 42/51 (82.4%) comb Rx pts experienced a treatment-related adverse event (TRAE). A total of 9/51 (17.7%) experienced a ≥ Grade 3 TRAE, including fatigue, cytokine release syndrome (CRS), hemiparesis, hypertension, joint range of motion reduced, muscular weakness, pancreatitis, rash (maculopapular), skin plaque, and stomatitis. Overall, 5/51 (9.8%) experienced manageable CRS, with only 1 discontinuation due to CRS. There were no deaths due to TRAEs. Of the efficacy-evaluable pts (n = 50), complete response (CR) or partial response (PR) was observed for 7/50 (14.0%), including 3 CR and 4 PR. Disease control (including CR, PR, or stable disease) was observed in 24/50 (48.0%). The median duration of response was 10 months (range = 4 to 32 months). Responses were observed in pts with prior anti-PD-1 exposure as well as in those with low or negative PD-L1 tumor expression. EIK1001 PK was linear and dose-proportional, and combination with pembrolizumab did not affect EIK1001 PK. Conclusions: Overall, EIK1001 was well-tolerated with a manageable safety profile and showed encouraging preliminary efficacy across several tumor types in combination with pembrolizumab. Responses were observed even in heavily pretreated patients not anticipated to respond to pembrolizumab monotherapy. Further development of EIK1001 is underway. Clinical trial information: NCT03486301 .

A phase I clinical study to evaluate the safety, tolerability, immunogenicity, pharmacokinetics and preliminary efficacy of SCB-219M in patients with chemotherapy-induced thrombocytopenia (CIT): An interim analysis.

e15015 Background: CIT is a serious, chemotherapy-associated complication observed in a wide range of cancer patients with various types of cancer. Incidence of CIT can occur in about 15-25% of patients undergoing standard chemotherapy regiments with platinum, taxane and/or gemcitabine-based regimen. CIT can lead to chemotherapy dose delay or dose reduction, and potentially bleeding events. Currently, there is no FDA-approved therapy for CIT. SCB-219M, a thrombopoietin receptor agonist (TPO-RA) mimetic bispecific Fc-fusion protein produced from CHO cells can efficiently raise PLT count under normal and pathological conditions in laboratory animals. Methods: This is a single-arm, multi-center, open-label, dose escalation Phase Ia clinical study to evaluate the safety, tolerability, and immunogenicity, PK profile and preliminary efficacy of a single ascending dose of SCB-219M administered one day after a chemotherapy in prior CIT patients with malignant solid tumors and lymphoma. The study design of accelerated titration combined with "3 + 3" is used, and the number of subjects planned to enroll is 12 to be assigned to 4 cohorts with 2, 6, 10 and 15 mg/kg subcu administration of SCB-219M, respectively. Enrollment criteria include episode of CIT experienced (&lt;75 × 109/L in PLT count) in prior cycle of chemotherapies and PLT count has recovered to &gt;75 × 109/L prior to initiation of this study . The chemotherapy regimen allowed include either mono or combination chemotherapy (including targeted therapy and/or immunotherapy). The observation period of dose-limiting toxicities (DLTs) is 21 days. Chemotherapy is planned at each study site. There will be no change in the planned dose or frequency of chemotherapy in the study. Results: As of Dec 20, 2023, 9 prior CIT patients including 3 at 15 mg/kg were enrolled. SCB-219M was well tolerated. There were no SAEs or AESIs (Adverse Event of Special Interest) observed. DLT was not reached. A favorable PK profile, in particular in serum availability (AUC) and half-life (T1/2) was obtained. All 9 prior CIT patients in the study maintained PLT counts &gt;75 x 109/L from 1-week following chemotherapies with a single dose of SCB-219M, and durable responses experienced through at least 3 weeks. Conclusions: In this interim analysis, drug safety, PK profile and durable efficacy are expected to support SCB-219M dosing interval of ≥2-weeks or a single dosing regimen within a chemotherapy cycle. Accordingly, a Phase Ib trial evaluating repeated dosing of SCB-219M is planned to initiate in 2024. Clinical trial information: NCT05426369 .

Medicare medication therapy Management: Beneficiary characteristics and utilization patterns in a national CMS Medicare fee-for-service sample (2013 to 2016)

BackgroundThe Medicare Medication Therapy Management (MTM) program has been available to eligible Medicare Part D beneficiaries since 2006, but research regarding program utilization and characterization is limited. ObjectiveTo describe enrollee and MTM program characteristics in a national sample of Medicare fee-for-service (FFS) beneficiaries (2013 to 2016). MethodsUsing a 5% random sample of Medicare FFS beneficiaries, we conducted a descriptive time series analysis to examine annual MTM enrollment and describe the type of MTM criteria at enrollment (Center for Medicare and Medicaid Services [CMS] vs. expanded). We investigated the offer of Comprehensive Medication Review (CMR) along with CMR receipt status, and delivery characteristics, as well as frequencies of Target Medication Reviews (TMRs). ResultBeneficiaries who met CMS enrollment criteria, compared to those eligible under expanded criteria, were significantly older, more likely to be of white race, more likely to be female, and had a significantly higher number of comorbidities. Of those meeting CMS criteria, the proportion receiving TMR increased from 95% in 2013% to 98.1% in 2016, and over 97% were offered a CMR. Although the proportion of beneficiaries offered a CMR was stable over the study period, the proportion who received a CMR increased from 17% in 2013% to 35.4% in 2016. Telephone CMR delivery was the most common method used (87.8% to 89.1% of CMRs over the study period). Over 95% of the CMRs were delivered by a pharmacist. ConclusionDuring the years 2013 to 2016, enrollment in the MTM program increased, as did the proportion of enrollees receiving TMRs and CMRs. However, uptake remained low and the main factors driving participation remain unclear. Significant differences in demographic characteristics between beneficiaries enrolled under the CMS MTM enrollment criteria and the expanded criteria suggest the need to further investigate the optimal provision of such programs.

Stable Ozonides plus Vitamin E Acetate (Ozoile) for Treatment of Genitourinary Syndrome.

Background and Objectives: Genitourinary syndrome, previously defined as vulvovaginal atrophy, manifests with signs and symptoms deriving from estrogen diminution in the female genitourinary tract. Stable ozonides are derivatives of artemisinin found to be stable against strong basic and acidic conditions. Vitamin E is an important antioxidant diminishing the output of reactive oxygen species in the oxidation of fats and the emanation of free radicals, reducing cellular injury and aging. The primary aim of the present study was to assess the positive effects of an ozonide plus a vitamin E acetate-based compound (Ozoile) on genitourinary syndrome symptom relief after a maximum of 20 days of treatment. Materials and Methods: The inclusion criteria for patients' enrollment were women of child-bearing age or in menopause reporting genitourinary syndrome's related symptoms, such as pain, burning, a bad smell, dyspareunia, dryness, itching, bleeding, and nervousness. The exclusion criteria were Sjogren's syndrome and patients administered retinoic acid, an agent that causes mucosal dryness. Participants completed a questionnaire before and after 20 days of treatment. Results: The incidence of pain decreased from 16.7% to 11.8% (p-value < 0.0001). In addition, the mean symptom intensity decreased from 2.10 to 0.87 (p-value < 0.0001). Dryness was the most frequent pre-treatment symptom and decreased from 85.5% to 53.8% (p-value < 0.0001) (mean: 2.21 vs. 0.90; p-value < 0.0001). Conclusions: Ozoile was effective in reducing most gynecologic symptoms related to genitourinary syndrome. However, further studies are needed to compare its effect with other standards of care.

Metronomic Chemotherapy After Palliative Radiotherapy in Rare Soft Tissue Sarcomas: An Insight into Radiation Therapy and the Immune Response.

Soft tissue sarcomas (STSs) account for less than 1% of the overall human burden of malignant tumors. The intent of treatment in metastatic STSs is palliative and prognosis is dismal. This study aims to evaluate the role of low-dose radiotherapy and low-dose oral metronomic therapy in heavily pretreated metastatic infrequent STSs. This study was conducted in a prospective observational manner in a tertiary care center. A total of 16 cases met the inclusion criteria for enrollment in the study group. The diagnosis of all subtypes of STS was confirmed by histopathology and immunohistochemistry or cytogenetic studies. All the enrolled patients with metastatic STSs who were treated with surgery and two lines of chemotherapy were initially treated with low-dose radiotherapy of 20Gy in 5 fractions or 30Gy in 10 fractions according to the ECOG performance status of the patient. Out of 16 patients, seven patients (43.75%) were treated with 20Gy, 5#, and 9 patients (56.25%) were treated with 30Gy, 10# radiotherapy (RT). Out of 16 patients, four were of malignant fibrohistiocytic sarcoma, three were angiosarcoma, three were malignant phylloides tumor of the breast, two were fibrosarcoma, and one patient from each of the following subtypes inflammatory myofiroblastic tumor, leiomyosarcoma, synovial sarcoma, and dermato fibrosarcoma protuberance. Out of 16 patients, seven (43.75%) had a partial response (PR), nine (56.25%) had stable disease (SD) at 3months, and all the patients had SD at 6months of evaluation. All the patients had enjoyed a better quality of life as compared to their life during injectable chemotherapy. Targeted low-dose radiation and metronomic chemotherapy leads to quantifiable antiangiogeneic effects and immune effects in the local tumor microenvironment, and influences circulating immune mediators and anti-angiogenesis that could potentially help eradicate disease both within and outside the radiation treatment field.

Exploring the impact of digital health literacy on quality of life in patients undergoing retrograde intrarenal surgery for kidney stone treatment: a prospective, single-center study

Retrograde intrarenal surgery (RIRS) is the recommended treatment for renal stones up to two cm in size. As digital health literacy (e-HL) has become increasingly important in promoting informed health decisions and healthy behaviors, it is necessary to investigate its impact on RIRS treatment outcomes. We aimed to explore the influence of patients’ e-HL level on their postoperative quality of life (QoL). We conducted an observational prospective study of 111 patients who underwent RIRS for renal pelvis stones. Before RIRS, we evaluated patients’ e-HL using the electronic health literacy scale (eHEALS). QoL was evaluated using the five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) one month after RIRS. SFR was determined by a negative CT scan or asymptomatic patients with stone fragments < 3 mm. Adult individuals aged 18 years or older with typical calyceal anatomy met the eligibility criteria for enrollment. Exclusion criteria for the study included patients with ureteric stones, anomalous kidneys, or bilateral renal stones. The relationship between patients’ QoL and stone-free rate was explored using Spearman’s rank correlation coefficient. The mean stone burden was 14 ± 3 mm (6–19 mm). The overall SFR was 83.3% after one month. The median EQ-5D-5L utility index and VAS score were 0.826 (0.41–1) and 70 (20–100) respectively, for the overall population. We found that poorer e-HL was associated with being older (p = 0.035), having less education (p = 0.005), and not having access to the internet (p < 0.001). A significant difference was observed between patients with sufficient e-HL and patients with limited e-HL in the self-care (p = 0.02) and anxiety/depression (p = 0.021) dimensions. To date, no study has examined the impact of patients’ e-HL levels on postoperative QoL in patients undergoing RIRS. This study also revealed that e-HL levels in patients undergoing RIRS were related to postoperative QoL, especially self-care and anxiety/depression dimensions, whereas there was no relationship between them and SFR.

Predicting which intervention works better for whom: Moderators of treatment effect of Mindfulness-Based Cognitive Therapy and Positive Psychology Intervention in patients with bipolar disorder

BackgroundThis study aimed to identify moderators of treatment effect (i.e. depressive symptoms and well-being) of Mindfulness-Based Cognitive Therapy (MBCT) and Positive Psychology Intervention (PPI) in patients with bipolar disorder. MethodsData were drawn from two multicenter randomized controlled trials investigating effectiveness of MBCT vs treatment as usual (TAU; n = 144) and PPI vs TAU (n = 97) in bipolar disorder. Outcomes were assessed at baseline, posttreatment, and 12 months after baseline. Data were analyzed using separate linear regression models, comparing the pooled MBCT or PPI outcomes to TAU, and comparing MBCT to PPI. ResultsThe exploratory analyses not corrected for multiple comparisons showed a number of variables that were associated with stronger response to the interventions, including higher baseline anxiety, lower well-being, and lower levels of self-focused positive rumination, well-being, and self-compassion, and variables associated with a stronger response to either MBCT (higher levels of depression and anxiety and being married) or PPI (being male). After correcting for multiple testing, depressive symptoms appeared to be the most robust variable associated with better response to MBCT than PPI. LimitationsThe RCTs handled slightly different enrollment criteria and outcome measures. ConclusionsThe most robust finding is that patients with more severe symptomatology seem to benefit more from MBCT than PPI. Clinical implicationsThis is a first step to improve personalized assignment of third-wave CBT interventions for patients with bipolar disorder. However, before definite treatment assignment criteria can be formulated and implemented in clinical practice, these findings should be replicated.

Time is of the essence: Age at autism diagnosis, sex assigned at birth, and psychopathology.

Previous research has shown that girls/women are diagnosed later than boys/men with autism. Individuals who are diagnosed later in life, especially girls/women, have greater anxious and depressive symptoms. Previous research has been limited due to narrow inclusionary criteria for enrollment in studies. The present study uses two samples-one clinic-based, large "real-world" sample and another research-based sample with strict criteria for autism diagnosis-to understand the relationships between diagnostic age, sex assigned at birth, and symptoms of anxiety/depression. In both samples, those who were diagnosed later had greater anxious/depressive symptoms, and anxiety was not predicted by sex. In the clinic-based but not research-based sample, those assigned female at birth were diagnosed later than those assigned male at birth. In the clinic-based sample only, individuals assigned female at birth and who were later diagnosed experienced greater symptoms of anxiety/depression compared to those assigned male who benefited from earlier diagnostic timing. Within the research-based sample, those assigned female at birth had greater depressive symptoms than those assigned male. These findings highlight the importance of timely identification of autism, especially for girls/women who are often diagnosed later. Community-based samples are needed to better understand real-world sex-based and diagnostic age-based disparities in mental health.