Testing In Clinical Trials Research Articles

Poxvirus Vaccines: Past, Present, and Future.

Smallpox was a significant cause of mortality for over three thousand years, amounting to 10% of deaths yearly. Edward Jenner discovered smallpox vaccination in 1796, which rapidly became a smallpox infection preventive practice throughout the world and eradicated smallpox infection by 1980. After smallpox eradication, monkeypox vaccines have been used primarily in research and in outbreaks in Africa, where the disease is endemic. In the present, the vaccines are being used for people who work with animals or in high-risk areas, as well as for healthcare workers treating patients with monkeypox. Among all orthopoxviruses (OPXV), monkeypox viral (MPXV) infection occurs mainly in cynomolgus monkeys, natural reservoirs, and occasionally causes severe multi-organ infection in humans, who were the incidental hosts. The first case of the present epidemic of MXPV was identified on May 7, 2022, and rapidly increased the number of cases. In this regard, the WHO declared the outbreak, an international public health emergency on July 23, 2022. The first monkeypox vaccine was developed in the 1960s by the US Army and was based on the vaccinia virus, which is also used in smallpox vaccines. In recent years, newer monkeypox vaccines have been developed based on other viruses such as Modified Vaccinia Ankara (MVA). These newer vaccines are safer and can provide longer-lasting immunity with fewer side effects. For the future, there is ongoing research to improve the current vaccines and to develop new ones. One notable advance has been the development of a recombinant vaccine that uses a genetically modified vaccinia virus to express monkeypox antigens. This vaccine has shown promising results in pre-clinical trials and is currently undergoing further testing in clinical trials. Another recent development has been the use of a DNA vaccine, which delivers genetic material encoding monkeypox antigens directly into cells. This type of vaccine has shown effectiveness in animal studies and is also undergoing clinical testing in humans. Overall, these recent advances in monkeypox vaccine development hold promise for protecting individuals against this potentially serious disease.

Preoperative Prediction of Microvascular Invasion in Hepatocellular Carcinoma from Multi-sequence Magnetic Resonance Imaging based on Deep Fusion Representation Learning.

Recent studies have identified microvascular invasion (MVI) as the most vital independent biomarker associated with early tumor recurrence. With advancements in medical technology, several computational methods have been developed to predict preoperative MVI using diverse medical images. These existing methods rely on human experience, attribute selection or clinical trial testing, which is often time-consuming and labor-intensive. Leveraging the advantages of deep learning, this study presents a novel end-to-end algorithm for predicting MVI prior to surgery. We devised a series of data preprocessing strategies to fully extract multi-view features from the data while preserving peritumoral information. Notably, a new multi-branch deep fused feature algorithm based on ResNet (DFFResNet) is introduced, which combines Magnetic Resonance Images (MRI) from different sequences to enhance information complementarity and integration. We conducted prediction experiments on a dataset from the Radiology Department of the First Hospital of Lanzhou University, comprising 117 individuals and seven MRI sequences. The model was trained on 80% of the data using 10-fold cross-validation, and the remaining 20% were used for testing. This evaluation was processed in two cases: CROI, containing samples with a complete region of interest (ROI), and PROI, containing samples with a partial ROI region. The robustness results from repeated experiments at both image and patient levels demonstrate the superior performance and improved generalization of the proposed method compared to alternative models. Our approach yields highly competitive prediction results even when the ROI region outline is incomplete, offering a novel and effective multi-sequence fused strategy for predicting preoperative MVI.

Immunotherapy combination approaches: mechanisms, biomarkers and clinical observations.

The approval of the first immune checkpoint inhibitors provided a paradigm shift for the treatment of malignancies across a broad range of indications. Whereas initially, single-agent immune checkpoint inhibition was used, increasing numbers of patients are now treated with combination immune checkpoint blockade, where non-redundant mechanisms of action of the individual agents generally lead to higher response rates. Furthermore, immune checkpoint therapy has been combined with various other therapeutic modalities, including chemotherapy, radiotherapy and other immunotherapeutics such as vaccines, adoptive cellular therapies, cytokines and others, in an effort to maximize clinical efficacy. Currently, a large number of clinical trials test combination therapies with an immune checkpoint inhibitor as a backbone. However, proceeding without inclusion of broad, if initially exploratory, biomarker investigations may ultimately slow progress, as so far, few combinations have yielded clinical successes based on clinical data alone. Here, we present the rationale for combination therapies and discuss clinical data from clinical trials across the immuno-oncology spectrum. Moreover, we discuss the evolution of biomarker approaches and highlight the potential new directions that comprehensive biomarker studies can yield.

Massed cognitive processing therapy for combat-related posttraumatic stress disorder: Study design and methodology of a non-inferiority randomized controlled trial

BackgroundPosttraumatic stress disorder (PTSD) is prevalent among military personnel. Cognitive processing therapy (CPT) is identified as one of the most effective treatments for PTSD, although smaller effects have been found in military populations. High rates of dropout from treatment may contribute to reduced efficacy, and military personnel may face unique barriers to treatment completion. One method of improving efficacy may be to reduce dropout by decreasing the time required to receive a full dose of treatment. This paper describes the design and methodology of the first randomized clinical trial testing whether CPT delivered in an intensive format is non-inferior to standard delivery of CPT. MethodParticipants are 140 active duty service members randomized to receive CPT in a 5-day combined group and individual intensive outpatient format (MCPT) or standard CPT (delivered individually twice weekly over 6 weeks). Participants are assessed at baseline, and 1 month, 4 months, and 1 year following the conclusion of the therapy. Reduction in PTSD symptomatology is the primary outcome of interest. Secondary outcomes include comorbid psychological symptoms, health, and functioning. A secondary objective is to examine predictors of treatment outcome to determine which service members benefit most from which treatment modality. ConclusionIf determined to be non-inferior, MCPT would provide an efficient and accessible modality of evidence-based PTSD treatment. This therapy format would improve access to care by reducing the amount of time required for treatment and improving symptoms and functioning more rapidly, thereby minimizing interference with work-related activities and disruption to the mission.

Intramuscular ketamine vs. midazolam for rapid risk-reduction in suicidal, depressed emergency patients: Clinical trial design and rationale

Emergency department (ED) visits for suicidal ideation or behavior have been increasing in all age groups, particularly younger adults. A rapid-acting treatment to reduce suicidal thinking, adapted for ED use, is needed. Previous studies have shown a single dose of ketamine can improve depression and suicidal ideation within hours. However, most studies used 40 min intravenous infusions which can be impractical in a psychiatric ED. The ER-Ketamine study we describe here is a randomized midazolam-controlled clinical trial (RCT; NCT04640636) testing intramuscular (IM) ketamine's feasibility, safety, and effectiveness to rapidly reduce suicidal ideation and depression in a psychiatric ED. A pre-injection phase involves screening, informed consent, eligibility confirmation, and baseline assessment of suicidal ideation, depression, and comorbidities. The randomized double-blind IM injection is administered in the ED under research staff supervision, vital sign monitoring, pharmacokinetic blood sampling, and clinical assessments. The post-injection phase occurs on a psychiatric inpatient unit with follow-up research assessments through four weeks post-discharge. Outcome measures are feasibility, safety, and effects on suicidal ideation and depression at 24 h post-injection, and through follow-up. The target sample is N = 90 adults in a major depressive episode, assessed by ED clinicians as warranting hospitalization for suicide risk. Here we report design, rationale, and preliminary feasibility and safety for this ongoing study. Demographics of the 53 participants (ages 18 to 65 years) randomized to date suggest a diverse sample tending towards younger adults.

Sex modulates the role of astrocyte reactivity in preclinical Alzheimer’s disease

AbstractBackgroundAstrocyte reactivity is a common finding in individuals across the Alzheimer’s disease (AD) continuum. Recently, we demonstrated that individuals with higher levels of plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, present a stronger association between amyloid‐ß (Aß) and tau pathologies in preclinical AD. Because cohort studies and clinical trials show sex differences in AD biomarkers, we investigated whether the effects of astrocyte reactivity on the association between Aß and tau differs in men and womenMethodWe assessed 1,016 CU individuals from three cohorts with available Aß (plasma/PET), plasma p‐tau181 and GFAP measures. A subset of individuals also has plasma p‐tau217 available (n = 136).Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP of younger Aß‐ individuals.Linear regressions accounting for age and sex were used to evaluate the association between plasma p‐tau epitopes and Aß burden.An interaction between term between Aß*sex was also added to the models.Voxel‐wise associations between biomarkers were tested using linear regressions accounting for age, sex, and adjusting for multiple comparisons.ResultWe found that Aß burden was associated with plasma p‐tau in Ast+ but not in Ast‐ . Men in the Ast+ group presented a much increased association between Aß with plasma p‐tau181 (ß = 0.71,p<0.0001,Fig.1a) or p‐tau217 (ß = 1.23,p = 0.00086,Fig.1b) compared to women. Similarly, a significant interaction between Aß and sex on plasma p‐tau181 (ß = 0.47,p = 0.005,Fig1a) and p‐tau217 (ß = 1.01,p = 0.002,Fig.1b) was observed only in the Ast+ individuals. Voxel‐wise analysis showed the differences in the topographical association between Aß and plasma p‐tau epitopes between men and women. In men but not women, Aß‐PET associates with plasma p‐tau181 (Fig.2) and plasma p‐tau217 (Fig.3) in important AD regions such as precuneus, posterior cingulate and orbitofrontal cortex.ConclusionA sex effect was observed in the association between Aß burden and plasma p‐tau epitopes in individuals with increased astrocyte reactivity, with the association being stronger in men than women. The greater effect of Aß on tau phosphorylation in the presence of Ast+ in men than in women may have implications for interpretation of biomarkers in clinical trials testing as anti‐Aß therapies already showed different effects between men and women.

Normative data on the CERAD Word List in a robustly intact sample of older adults

AbstractBackgroundList learning and memory tests are frequently used to evaluate older adults for late life cognitive disorders, such as Alzheimer’s disease. The Word List subtest of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery has been widely‐used in clinical research, including clinical trials, to identify and track such disorders. It is also freely‐available, as it is in the public domain. However, normative data, especially in robustly intact older adults, is lacking.MethodCERAD Word List data from 897 older adults (age in years: M = 81.1, SD = 8.1, range 55‐100; 67% women; education in years: M = 14.8, SD = 2.8, range = 7‐24) deemed to be cognitively intact at two annual visits in a longitudinal observational study from the Uniform Data Set of the National Alzheimer’s Coordinating Center were used to generate predicted Word List scores based on age, sex, and education. Predicted scores were compared to observed scores to preliminarily validate these normative values.ResultFor six primary scores from the Word List subtest (Trial 1, Trial 2, Trial 3, Total Acquisition, Delay Recall, Recognition Total Correct), the three demographic variables significantly predicted test scores, with R2s ranging from 0.03 – 0.18 (p‐values<0.001). When these predicted scores were compared to observed scores, there were no significant differences (p‐values>0.40), indicating preliminary support for these prediction scores.ConclusionAlthough further validation is needed in independent intact and impaired samples, the current demographically‐based prediction scores provide normative data for the CERAD Word List subtest for older adults being evaluated for cognitive complaints. The inclusion of additional variables needs to be examined to improve the accuracy of these prediction scores. Nonetheless, normative data allows providers and researchers to be confident in using this learning and memory test in clinics and clinical trials.

Abstract A011: Evaluation of a theory-informed video intervention to educate underrepresented groups on clinical and genomic research using the Theoretical Framework of Acceptability

Abstract Introduction: Emerging evidence supports the potential effectiveness of technologically based interventions to disseminate health information to underserved populations. Considering the multifactorial barriers to clinical trial and genomic testing participation especially for African Americans (AA), who have been shown to make up less than 10% of all cancer clinical trial participants, a video was developed to inform minority populations on the importance of diversity in clinical trials and genomic research. To confirm that the video was deemed acceptable by the target audience, a quantitative assessment was conducted. Methods: We utilized the Theoretical Framework of Acceptability to create a survey aimed at assessing the animated video. Participants viewed the video and were asked to fill out the survey. Thirty-seven surveys were completed which included members of a patient advisory council at a local hospital (n=6) and graduate students from a medical school (n=29). Results: Responses were recorded on a five-point Likert scale ranging from 1 (Strongly Disagree) to 5 (Strongly Agree). Participants agreed that they enjoyed viewing the illustrations in the video (𝑋̅=4.32, s=0.97) and listening to the audio (𝑋̅=4.22, s=1.03). After watching the video, participants reported that it educated them on what a “genome” is (𝑋̅=4.16, s=0.83), as well as the benefits of participating in a clinical trial (𝑋̅=4.62, s=0.49) and donating biospecimens (𝑋̅=4.14, s=0.95). Participants moderately agreed that the video informed them on the disadvantages of participation in a clinical trial (𝑋̅=3.38 s=1.36) and biospecimen donation (𝑋̅=3.70, s=1.10). Participants reported feeling confident in making well-informed decisions about participating in clinical trials (𝑋̅=4.27, s=0.69) or donating biospecimens after watching the video (𝑋̅=4.24, s=0.80). However, after watching the video participants reported being somewhat unclear on how to sign up for a clinical trial (𝑋̅=3.57, s=1.21) and how to donate biospecimens (𝑋̅=3.43, s=1.21). Overall, the video was inclusive of the participants’ beliefs and values (𝑋̅=4.24, s=0.76) and attitudes towards the video were favorable with a mean score of 4.4 (s=0.62) on a scale from 1 (Completely Unacceptable) to 5 (Completely Acceptable). Discussion: The feedback received through the TFA adapted questionnaire will be utilized to improve the content of the video. Health communication methods should consider creating technologically based interventions that are deemed acceptable by target populations, in order to engage with and educate underrepresented populations. Citation Format: Victoria Churchill, Jamirah Y. Chevrin, Roland Matthews, Brian Rivers. Evaluation of a theory-informed video intervention to educate underrepresented groups on clinical and genomic research using the Theoretical Framework of Acceptability [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A011.

Incidence and symptomatology of ARIA

AbstractBackgroundTo summarize available evidence on ARIAs from randomized clinical trials (RCTs) testing anti–β‐amyloid mAbs in patients with AD and to provide a comprehensive update about risk factors, clinical correlates, and implications for withholding and reinitiating treatment.MethodA literature search of MEDLINE/PubMed, Embase, and Cochrane Library and a search of ClinicalTrials.gov were conducted through September 15, 2021. Publications describing RCTs, secondary analyses of RCT data, and case reports of ARIAs were included. Strengths of clinical data were graded according to the Oxford Centre for Evidence‐Based Medicine.ResultTwenty‐two RCTs, 11 secondary analyses of RCTs, and 1 case report, including in total 15 508 adult patients (8483 women [54.7%]; mean [SD] age, 69.6 [8.3] years) were selected for inclusion. Signal alterations that included parenchymal edema and sulcal effusion leading to transient hyperintensities on fluid‐attenuated inversion recovery and T2‐weighted sequences were termed ARIA‐E, whereas those consisting of hemosiderin deposits, including parenchymal microhemorrhages and leptomeningeal superficial siderosis, were termed ARIA‐H. Apolipoprotein E (ApoE) ε4 genotype was the main risk factor for both ARIA types; ARIA‐E incidence was further associated with treatment dose, affecting the 55%of ApoE ε4 carriers in the high‐dose aducanumab treatment group. Both ARIA types manifested early during study course, and symptomatic cases accounted for the 6.1% to 39.3%of ARIA‐E cases at higher treatment doses across RCTs, whereas ARIA‐H cases were generally asymptomatic. Most ARIA‐E cases resolved with treatment withholding, although corticosteroid administration was required anecdotally. ARIA‐E recurrence after dose reinitiation or adjustment varied from 13.8% to 25.6%across RCTs.ConclusionEvidence suggests that ARIAs are frequent, mostly asymptomatic collateral events of amyloid‐modifying therapies, highlighting the need for standardized clinical and neuroradiological management protocols in real‐world clinical settings.

Comparison of the CXCR5-Antibody Drug Conjugate (ADC; VIP924) to a CD19-ADC and a CD79b-ADC in a Humanized Rec-1 Mantle Cell Lymphoma (MCL) Mouse Model

Introduction The chemokine receptor CXCR5 is highly expressed in MCL, which is a rare subtype of non-Hodgkin lymphoma. VIP924 is a first-in-class CXCR5-targeting ADC composed of a legumain-cleavable linker and a kinesin spindle protein inhibitor (KSPi) payload. We compared VIP924 with a CD19- and a CD79b- targeting ADC in a humanized mouse model of MCL. Methods Expression of CXCR5 and the B-cell targets CD19 and CD79b were analyzed on tumor samples from patients with MCL using immunohistochemistry. Slides were examined by a pathologist and scored for expression. NSG-SGM3 mice were transplanted with human hematopoietic stem cells from 4 different donors and after engraftment transplanted subcutaneously with REC-1 MCL cells into their flanks. When subcutaneous tumors reached a size of 100 mm 3, mice were randomized into 5 groups and treated with 10 mg/kg of an isotype control ADC, 3 mg/kg polatuzumab vedotin, 0.66 mg/kg loncastuximab teserine, 3 mg/kg VIP924, or 10 mg/kg VIP924 every 5 days for 4 doses. Immunophenotyping of peripheral blood was performed by flow cytometry before starting treatment (Day 0) and on Day 5 and Day 18 during the treatment. At the end of the experiment, immunophenotyping was also done on tumors, spleen, and bone marrow. Complete blood count was analyzed based on single cell evaluation (Drew Scientific HemaVet 950FS Auto Blood Analyzer). Results By immunohistochemistry CXCR5 and CD19 showed comparable high expression on patient samples, whereas CD79b expression was moderate. Treatment of humanized mice bearing REC-1 tumors with VIP924 at 10 mg/kg reduced tumor growth effectively (p<0.0001 vs. isotype control on Day 10), while treatment with polatuzumab vedotin and loncastuximab teserine showed no effects on tumor growth. This outcome was also reflected in the median survival rates for the different groups with 17 days for isotype control and polatuzumab vedotin, 14 days for loncastuximab teserine and not reached for the 10-mg/kg VIP924 group. However, polatuzumab vedotin treatment significantly reduced hCD45+ cells in peripheral blood and spleen, while loncastuximab teserine treatment showed a clear trend for reduction. VIP924 treatment in both arms had no effect on peripheral or splenic hCD45+ cells. All tested ADCs reduced the CD19+ and more mature CD19+/CXCR5+ B-cells in peripheral blood and spleen, with polatuzumab vedotin and loncastuximab teserine showing significant (p<0.0001 vs. isotype control on Day 18) effects on CD19+ cell reductions, while VIP924 treatment showed a milder reduction in CD19+ cells (p= 0.0051 for 3 mg/kg and p= 0.0407 for 10 mg/kg VIP924). Loncastuximab teserine treatment increased the amount of myeloid derived suppressor cells in the peripheral blood significantly (p= 0.0467). In contrast, VIP924 led to a significant (p< 0.0001) increase in peripheral regulatory T-cells compared with isotype control. Complete blood counts from treated mice showed a reduction of white blood cells (WBC), absolute lymphocyte count, and absolute monocyte count in loncastuximab teserine-treated animals. Loncastuximab teserine treatment also reduced red blood cell count and hemoglobin values. In VIP924-treated animals, no effects on WBC, red blood cell count, or hemoglobin values were observed. All treatments showed no detrimental effects on body weights of the mice. Conclusion CXCR5 is a highly attractive target in B-cell malignancies such as diffuse large B-cell lymphoma and MCL due to high CXCR5 surface expression. VIP924, a CXCR5-targeting ADC, showed high potency and superiority to other B-cell-targeted ADCs in a humanized mouse model of MCL. In this MCL model in humanized mice, VIP924 at 10 mg/kg treatment showed a significant reduction in tumor growth and improvement in survival, while polatuzumab vedotin and loncastuximab teserine had no effect on tumor growth or survival. Interestingly, VIP924 was the only ADC to cause a significant increase in peripheral T regulatory cells, which may enhance tumor growth inhibition. Loncastuximab teserine had a deleterious effect on several hematologic parameters, which was not observed with VIP924 or polatuzumab vedotin. The efficacy and tolerability observed in this study with VIP924 suggests further testing in human clinical trials is warranted.

Protocol for a pragmatic stepped wedge cluster randomized clinical trial testing behavioral economic implementation strategies to increase supplemental breast MRI screening among patients with extremely dense breasts

BackgroundIncreased breast density augments breast cancer risk and reduces mammography sensitivity. Supplemental breast MRI screening can significantly increase cancer detection among women with dense breasts. However, few women undergo this exam, and screening is consistently lower among racially minoritized populations. Implementation strategies informed by behavioral economics (“nudges”) can promote evidence-based practices by improving clinician decision-making under conditions of uncertainty. Nudges directed toward clinicians and patients may facilitate the implementation of supplemental breast MRI.MethodsApproximately 1600 patients identified as having extremely dense breasts after non-actionable mammograms, along with about 1100 clinicians involved with their care at 32 primary care or OB/GYN clinics across a racially diverse academically based health system, will be enrolled. A 2 × 2 randomized pragmatic trial will test nudges to patients, clinicians, both, or neither to promote supplemental breast MRI screening. Before implementation, rapid cycle approaches informed by clinician and patient experiences and behavioral economics and health equity frameworks guided nudge design. Clinicians will be clustered into clinic groups based on existing administrative departments and care patterns, and these clinic groups will be randomized to have the nudge activated at different times per a stepped wedge design. Clinicians will receive nudges integrated into the routine mammographic report or sent through electronic health record (EHR) in-basket messaging once their clinic group (i.e., wedge) is randomized to receive the intervention. Independently, patients will be randomized to receive text message nudges or not. The primary outcome will be defined as ordering or scheduling supplemental breast MRI. Secondary outcomes include MRI completion, cancer detection rates, and false-positive rates. Patient sociodemographic information and clinic-level variables will be examined as moderators of nudge effectiveness. Qualitative interviews conducted at the trial’s conclusion will examine barriers and facilitators to implementation.DiscussionThis study will add to the growing literature on the effectiveness of behavioral economics-informed implementation strategies to promote evidence-based interventions. The design will facilitate testing the relative effects of nudges to patients and clinicians and the effects of moderators of nudge effectiveness, including key indicators of health disparities. The results may inform the introduction of low-cost, scalable implementation strategies to promote early breast cancer detection.Trial registrationClinicalTrials.gov NCT05787249. Registered on March 28, 2023.

Lessons learned from phase 3 trials of immunotherapy for glioblastoma: Time for longitudinal sampling?

Glioblastoma (GBM)'s median overall survival is almost 21 months. Six phase 3 immunotherapy clinical trials have recently been published, yet 5/6 did not meet approval by regulatory bodies. For the sixth, approval is uncertain. Trial failures result from multiple factors, ranging from intrinsic tumor biology to clinical trial design. Understanding the clinical and basic science of these 6 trials is compelled by other immunotherapies reaching the point of advanced phase 3 clinical trial testing. We need to understand more of the science in human GBMs in early trials: the "window of opportunity" design may not be best to understand complex changes brought about by immunotherapeutic perturbations of the GBM microenvironment. The convergence of increased safety of image-guided biopsies with "multi-omics" of small cell numbers now permits longitudinal sampling of tumor and biofluids to dissect the complex temporal changes in the GBM microenvironment as a function of the immunotherapy.

Ultrasound-guided pericapsular nerve group (PENG) block for early analgesia in elderly patients with hip fractures: a single-center prospective randomized controlled study

BackgroundThe aim of this study was to compare the efficacy of ultrasound-guided PENG (pericapsular nerve group) block and drug therapy with intravenous flurbiprofen for early analgesia in elderly patients with hip fractures after hospitalization.MethodsThis is a single-center, observer-blinded, prospective, randomized, controlled trial. A total of 41 elderly patients (aged 60 or older) with hip fractures were enrolled in the current study. Patients were randomly assigned to two groups: Group P (ultrasound-guided PENG block, 20 mL of 0.375% ropivacaine) and Group F (intravenous flurbiprofen 50 mg). The primary outcome measure was the dynamic (passive straight leg raising 15°) NRS (numerical rating scale 0 to 10) pain scores at different time points. The secondary outcomes were the static NRS scores at different time points, the number of rescue analgesia sessions, patient satisfaction, and the incidence of complications.ResultsPatients in the two groups had comparable baseline characteristics. The group P had lower dynamic and static NRS scores at 15 min, 30 min, 6 h, and 12 h after intervention (P<0.05) than the group F. The highest NRS pain scores in the group P were still lower than the NRS scores in the group F at 30 min-12 h (Group F: 5.57±1.54 vs. Group P: 3.00±1.12, P<0.001), and there was no significant difference between the two groups at 12-24 h (Group F: 6.35±1.79 vs. Group P: 5.90±1.83, P>0.05). The group P had higher satisfaction scores (Group P: 9 (9,9) vs. Group F: 8 (7,8), P<0.001). There was no statistically significant difference in the number of rescue analgesics at 0-12 h or 12-24 h or the incidence of complications between the groups.ConclusionsCompared with intravenous flurbiprofen, ultrasound-guided PENG block provides better early analgesic effects in elderly patients with hip fractures, and a PENG block is safe for elderly patients with hip fractures after hospitalization.Trial registrationThis study was registered in the Chinese Clinical Trial Testing Center (ID: ChiCTR2200062400).

Virtual Molecular and Precision Medicine Clinic to Improve Access to Clinical Trials for Patients With Metastatic Breast Cancer: An Academic/Community Collaboration.

There is a demand for improved care delivery surrounding genomic testing and clinical trial enrollment among patients with metastatic breast cancer (MBC). We sought to improve the current process via real-time informal consultation and prescreening assessment for patients with MBC treated by community and academic medical oncologists by implementing a virtual molecular and precision medicine (vMAP) clinic. The vMAP program used a virtual referral system directed to a multidisciplinary team with precision medicine expertise. Providers contacted vMAP regarding patients with MBC, and on receipt of referral, the vMAP team engaged in discussion to identify if further diagnostics were needed (including genomic testing) and to identify potential clinical trials or standard treatment options. Recommendations were then sent to the referring provider within 72 hours. Pre-/postsurveys were issued to network physicians to assess for barriers, clinical trial access, and vMAP referral experience. Program implementation was evaluated with the Squire 2.0 reporting guidelines for quality improvement in health care as a framework. Eighty-one cases from 22 providers were referred to vMAP over a 26-month period. The average response time to the referring provider with a finalized recommendation was 1.90 ± 1.82 days. A total of 86.4% of cases had clinical trial options on vMAP prescreen, with 40.7% initiating formal screening assessments and 27 patients (33.3%) ultimately enrolling on trials. On resurvey, 92% of survey responses across community oncology referring providers said that they were very likely to use vMAP again. In the initial 2-year period, vMAP demonstrated an efficient means to offer real-time interpretation of genomic testing and identification of clinical trials for patients with MBC, with effective clinical trial enrollment and high rates of referring provider satisfaction.

High Success Rates Utilizing Local Standard of Care Cytogenetic Testing for Risk Stratified Frontline Therapy for Newly Diagnosed Multiple Myeloma: Experience from the Ukmra RADAR Study

Background. Recent studies in genetically high risk (HR) multiple myeloma (MM) such as the UKMRA OPTIMUM study have reported high response rates with intensive induction and post-ASCT consolidation and maintenance strategies, providing the rationale for stratified therapy based on genetic risk. Whilst centralised testing in clinical trials offers ready uniformity and quality control, the use of local laboratories for testing within a clinical trial paves the way for genetic testing to be available for all patients, facilitating risk stratified therapy in routine care. We designed the UKMRA RADAR study to use local laboratories for cytogenetic (CGN) testing to assign treatment according to genetic risk. Methods. RADAR is an ongoing national, multi-center, risk-adapted, response-guided multi-arm, multi-stage (MAMS) phase II/III trial for patients with newly diagnosed MM eligible for ASCT. Patients receive induction with RCyBorD (lenalidomide, cyclophosphamide, bortezomib, dexamethasone), followed by high-dose melphalan and stem cell rescue. Post ASCT, HR patients are randomised to receive isatuximab or not, alongside RBorD consolidation and R maintenance whilst standard risk (SR) patients receive MRD response guided regimens. A protocol amendment (2022) included isatuximab throughout the HR pathway, removing the post-ASCT randomisation. Risk assessment, failure rates and turnaround time are overseen by a genomics working group (GWG) including clinical and specialist cytogenetic representation. Genetic risk testing is undertaken in local genetic labs on CD138 selected bone marrow (BM) plasma cells. HR is assigned based on the presence of at least two of: t(4;14), t(14;16), t(14:20), del(17p), del(1p) and gain(1q). Clone size cut-offs are 10% for IgH translocations and 20% for copy number changes. CGN results from local laboratories are centrally reviewed to assign risk in real-time. Indeterminate cases are discussed by the GWG. Repeat testing is mandated if the initial sample fails to yield a definitive risk result for risk. Subjects with no definitive result despite 2 samples are treated as SR. Results. As of 19 th June 2023, the trial has recruited 472 patients from 72 sites across the UK. Median age is 61 years, 59.3% male, 79.9% white, 11.7% other ethnicity and 8.5% missing ethnicity data. 25 local laboratories were used for CGN testing. Of those with CGN results 354/453 patients (78.1%) were assigned standard risk, 84 (18.5%) high risk and 15 (3.3%) risk category undefined. Risk stratification is ongoing for 19 patients. Of the high risk lesions gain(1q) was most prevalent (35%), followed by t(4;14)(10.6%), del(17p)(8.7%), del(1p32)(8.7%), t(14;16)(3.8%) and t(14;20)(0.8%). In 376/453 patients (83.0%), risk was assigned from a first BM sample. 77 (17.0%) patients required a second sample; the success rate of repeat samples is 71.4%, 22 (4.9%) patients were unable to be risk-stratified despite 2 samples. Figure 1 shows the success rate of first and repeat tests. The overall median turnaround time (from D1 cycle 1 until site notified of result) was 11 days (IQR 0 to 21). Sites were sent risk status prior to cycle 1 in 99 (21.9%) patients , 285 (62.9%) prior to cycle 2 and 341 (75.3%) cycle 3. Note this is calculated where treatment data is available. Conclusion. The RADAR study demonstrates that risk-stratified treatment approaches are feasible in the context of a national phase II/III clinical trial with the use of local laboratories for risk assignment. The vast majority of patients have been successfully allocated to a risk-adapted treatment pathway following a first FISH test (83.0%). Protocol v4 requires time-critical risk-stratification for addition of isatuximab to induction treatment from cycle 2 in high-risk patients, and this has proven to be achievable in almost 2/3 of patients with over ¾ by the end of cycle 2. The RADAR study also enables hospitals across the UK to access CGN testing via a network model of laboratories with standardization of testing and clinically relevant turnaround times. This model is applicable internationally in both public and privately funded healthcare systems and supports the infrastructure for accessible genetic risk stratification for all newly diagnosed MM patients. Ongoing studies within the RADAR trial are evaluating novel and clinically deliverable risk stratification protocols to inform risk stratified approaches in newly diagnosed MM.

Minimally Invasive Assessment of Measurable Residual Disease (MRD) in Multiple Myeloma (MM)

BACKGROUND MRD is an established test in MM clinical trials but not in routine practice. A hindrance to its wider adoption is invasive bone marrow (BM) aspirates. Thus, the possibility of assessing MRD using minimally invasive methods could be paramount to facilitate its transition from clinical trials to routine practice, but also to improve patients' (pts) quality of life and to generate more meaningful MRD results based on periodic assessments instead of limited time points. However, the methods developed for MRD evaluation in BM are less sensitive when used in peripheral blood (PB). AIM Investigate the complementarity and prognostic value of new multimodal minimally invasive MRD assessment in MM. METHODS This study included 243 transplant eligible and ineligible pts who were on maintenance or observation at the time of MRD assessment in PETHEMA/GEM clinical trials. In all cases, MRD was evaluated in PB using BloodFlow, which is a highly sensitive method (10 -7) that combines immunomagnetic enrichment with next-generation flow (NGF) cytometry. Periodic assessment of MRD in peripheral blood (PB) using BloodFlow was performed every six months. In 27 patients, MRD was further investigated in cfDNA using CloneSight, a highly sensitive (10 -4) next-generation sequencing method based on pt-specific mini-panels of multiplexed amplicons covering somatic mutations identified at diagnosis. In 169 of the 243 patients, MRD was analyzed in the serum using Quantitative Immunoprecipitation Mass Spectrometry (QIP-MS) with anti-IgG/A/M, total κ and λ beads. RESULTS BloodFlow was performed in a total of 867 PB samples, out of which 77 (9%) were MRD positive. The median number of CTCs/µL was 0.016 (range, 0.0003 - 0.29). In 506 of the 867 assessments, MRD was simultaneously analyzed in the BM using NGF. The concordance between BloodFlow in PB and NGF in BM was 78.9% (70.4% double negative and 8.5% double positive MRD results). The frequency of BloodFlow-/NGF+ and BloodFlow+/NGF- discordant assessments was 20.3% and 0.8%, respectively. Serial assessment of MRD in PB using BloodFlow showed that 221 of the 243 (91%) pts had sustained MRD negativity and 13 (5%) were persistently positive. MRD conversions from negative to positive were noted in 9 (4%) pts. The landmark median PFS from the latest MRD assessment was not reached (NR) vs 3 months in negative vs positive patients (HR: 0.09, P &amp;lt; .001). Of note, only 11 of the 221 (5%) MRD negative pts relapsed thus far. Of the 27 pts in whom MRD was simultaneously analyzed in cfDNA using CloneSight, five were MRD positive. The landmark median PFS from the latest MRD assessment was NR vs 5 months in negative vs positive pts (HR: 0.23, P = .057). The number of patients with BloodFlow-/CloneSight-, BloodFlow+/CloneSight-, BloodFlow-/CloneSight+ and BloodFlow+/CloneSight+ results were 17, 5, 2 and 3. The landmark median PFS from the latest MRD assessment in patients with double negative MRD vs positive by either method was NR vs 8 months (HR: 0.20, P = .056). Of note, only 2 of the 17 double negative MRD patients relapsed thus far. Of the 169 pts in whom MRD was simultaneously analyzed in serum using QIP-MS, 37 (22%) were MRD positive. The landmark median PFS from the latest MRD assessment was NR in negative and positive patients (HR: 0.13, P &amp;lt; .001). The number of patients with BloodFlow-/QIPMS-, BloodFlow+/QIPMS-, BloodFlow-/QIPMS+ and BloodFlow+/QIPMS+ results were 130, 2, 26 and 11. The landmark median PFS from the latest MRD assessment in patients with double negative MRD vs positive by either method was NR and 8 months, respectively (HR: 0.07, P &amp;lt; .001). Of note, only 3 of the 130 (2%) double negative MRD patients relapsed thus far. The negative predictive value (NPV) of a double negative MRD detection in PB/serum using BloodFlow/QIP-MS and MRD negativity in BM using NGF was 86%. CONCLUSIONS This is the first study of multimodal minimally invasive MRD assessment in MM. Our results show that BloodFlow, CloneSight and QIP-MS are empowered to detect MRD with high sensitivity in PB, cfDNA and serum. The presence of CTCs, mutations and M-component was systematically associated with dismal PFS. The complementarity between these methods achieved a high NPV of MRD negativity in BM, and enabled the identification of multimodal MRD negative pts with very low risk of relapse. Thus, this study paves the way towards minimally invasive MRD assessment in MM pts on maintenance or observation.

Production of leishmanin skin test antigen from Leishmania donovani for future reintroduction in the field

The leishmanin skin test was used for almost a century to detect exposure and immunity to Leishmania, the causative agent of leishmaniasis, a major neglected tropical disease. Due to a lack of antigen used for the intradermal injection, the leishmanin skin test is no longer available. As leishmaniasis control programs are advancing and new vaccines are entering clinical trials, it is essential to re-introduce the leishmanin skin test. Here we establish a Leishmania donovani strain and describe the production, under Good Laboratory Practice conditions, of leishmanin soluble antigen used to induce the leishmanin skin test in animal models of infection and vaccination. Using a mouse model of cutaneous leishmaniasis and a hamster model of visceral leishmaniasis, soluble antigen induces a leishmanin skin test response following infection and vaccination with live attenuated Leishmania major (LmCen-/-). Both the CD4+ and CD8+ T-cells are necessary for the leishmanin skin test response. This study demonstrates the feasibility of large-scale production of leishmanin antigen addressing a major bottleneck for performing the leishmanin skin test in future surveillance and vaccine clinical trials.

Using Machine Learning to Predict Near-Term Thrombosis Risk in Patients with Polycythemia Vera

Introduction: Thrombosis (arterial and venous) remains the leading cause of morbidity/mortality for patients (pts) with polycythemia vera (PV) [1-2]. With appropriate therapy, thrombosis risk can be reduced to 1-5% per year (yr) [3]. Yet some seemingly well-controlled pts still suffer thrombotic events. This rate means that a well-powered clinical trial testing anti-thrombotic strategies in PV to improve thrombosis-free survival is prohibited by the large number of pts and study duration required. For example, the high-end annual incidence of thrombosis in ELN high-risk pts is &amp;lt;5%/yr, so a 2yr study hoping to demonstrate a 50% thrombosis reduction (α=5%, 1-ß=80%) requires 1104 pts. This study would be vastly more efficient if we could enroll only pts with high near-term thrombotic risk but we cannot accurately identify these pts. To address this, we developed a machine learning (ML) approach to dynamically predict this risk. Methods: After obtaining institutional approval, 526 pts with manually verified PV diagnoses were identified by querying electronic health records and our research database repository. The dataset (4M data elements,14K hematology clinic visits) includes lab measures, molecular/pathology studies, medications, and pt history. Data completeness varied with &amp;gt;90% availability in 200+ features. To assess the error introduced by imputation, we computed the Euclidean distance/Jaccard index between masked pre-imputed data and imputed data over 8K iterations. We found that features with &amp;lt;50% missingness could be imputed without dataset corruption. ML classification models (random forest (RF), boosted models, and support vector machines) were evaluated using AutoGluon. RF emerged as the top performer. Feature engineering, guided by Gini feature importance and clinical feedback, identified 21 training features. A parallelized pipeline optimized 1.6M model combinations (# of trees, node splitting features, max depth, thresholding) via grid search. Several optimization strategies were assessed. Of 470 pts with clinic visits through Mar 31, 2020, 75% were used for model training (Training Cohort) and 25% for model evaluation (Testing Cohort). Cohort details were previously reported [4]. A prospective Validation Cohort included clinic visits after Apr 1, 2020 and was unseen by trained models. A risk calculator designed in RShiny applied models corresponding to user-entered clinical data and computed 1yr thrombosis risk. User-entered data are not stored to protect data privacy. Results: Training/Testing pts had median age of 54, and 64 (14%) had a prior thrombosis at dx (8% venous, 7% arterial). Over a median followup of 10 yrs, 159 thromboses occurred in 115 pts (88 venous, 71 arterial). Annual incidence rates (IR) of thrombosis were higher shortly after dx (IR: 4% vs 1%, 2yr cutoff) and following a thrombotic event (IR: 10% vs 2%, 2yr cutoff). The full model performed very well (F1=0.91, AUC=0.84) when compared with ELN (F1=0.1, AUC=0.39) (Figure 1). High-performing simplified models (&amp;gt;90% testing/validation sensitivity) were applied to the Validation Cohort. The full 21-feature model and high-performing models (Figure 2) showed clear separation for 1yr thrombosis risk prediction. Features of importance included blood counts, body mass index (BMI), and time since dx were frequently represented in these models. Discussion: Over 1M models were trained on high-volume clinical data to predict near-term thrombosis risk in PV pts, considering intrinsic factors (age, blood type), disease events (time since dx/thrombosis), and short-term changes (BMI) to tailor risk mitigation strategies. Prospective validation demonstrates model generalizability. External validation using REVEAL study [1] and the Danish Registry data is ongoing. Our tool's ability to identify high-risk pt populations can be applied as an inclusion criterion for prospective clinical trials, reducing the time and pt numbers needed for a well-powered study. Whereas using ELN-defined high risk would require 1K pts to demonstrate a 50% reduction in thrombosis rates, our prospective ML model-defined high near-term risk would only require ~80 pts, making such a study very feasible.

The drug efficacy testing in 3D cultures platform identifies effective drugs for ovarian cancer patients

Most patients with advanced ovarian cancer (OC) relapse and progress despite systemic therapy, pointing to the need for improved and tailored therapy options. Functional precision medicine can help to identify effective therapies for individual patients in a clinically relevant timeframe. Here, we present a scalable functional precision medicine platform: DET3Ct (Drug Efficacy Testing in 3D Cultures), where the response of patient cells to drugs and drug combinations are quantified with live-cell imaging. We demonstrate the delivery of individual drug sensitivity profiles in 20 samples from 16 patients with ovarian cancer in both 2D and 3D culture formats, achieving over 90% success rate in providing results six days after operation. In this cohort all patients received carboplatin. The carboplatin sensitivity scores were significantly different for patients with a progression free interval (PFI) less than or equal to 12 months and those with more than 12 months (p < 0.05). We find that the 3D culture format better retains proliferation and characteristics of the in vivo setting. Using the DET3Ct platform we evaluate 27 tailored combinations with results available 10 days after operation. Notably, carboplatin and A-1331852 (Bcl-xL inhibitor) showed an additive effect in four of eight OC samples tested, while afatinib and A-1331852 led to synergy in five of seven OC models. In conclusion, our 3D DET3Ct platform can rapidly define potential, clinically relevant data on efficacy of existing drugs in OC for precision medicine purposes, as well as provide insights on emerging drugs and drug combinations that warrant testing in clinical trials.

Understanding the promising role of antibody drug conjugates in breast and ovarian cancer

A nascent category of anticancer therapeutic drugs called antibody-drug conjugates (ADCs) relate selectivity of aimed therapy using chemotherapeutic medicines with high cytotoxic power. Progressive linker technology led to the advancement of more efficacious and safer treatments. It offers neoteric as well as encouraging therapeutic strategies for treating cancer. ADCs selectively administer a medication by targeting antigens which are abundantly articulated on the membrane surface of tumor cells. Tumor-specific antigens are differently expressed in breast and ovarian cancers and can be utilized to direct ADCs. Compared to conventional chemotherapeutic drugs, this approach enables optimal tumor targeting while minimizing systemic damage. A cleavable linker improves the ADCs because it allows the toxic payload to be distributed to nearby cells that do not express the target protein, operating on assorted tumors with dissimilar cell aggregation. Presently fifteen ADCs are being studied in breast and ovarian carcinoma preclinically, and assortment of few have already undergone promising early-phase clinical trial testing. Furthermore, Phase I and II studies are investigating a wide variety of ADCs, and preliminary findings are encouraging. An expanding sum of ADCs will probably become feasible therapeutic choices as solo agents or in conjunction with chemotherapeutic agents. This review accentuates the most recent preclinical findings, pharmacodynamics, and upcoming applications of ADCs in breast and ovarian carcinoma.