Single Clinical Trial Research Articles

Estimated Lifetime Gained With Cancer Screening Tests

Cancer screening tests are promoted to save life by increasing longevity, but it is unknown whether people will live longer with commonly used cancer screening tests. To estimate lifetime gained with cancer screening. A systematic review and meta-analysis was conducted of randomized clinical trials with more than 9 years of follow-up reporting all-cause mortality and estimated lifetime gained for 6 commonly used cancer screening tests, comparing screening with no screening. The analysis included the general population. MEDLINE and the Cochrane library databases were searched, and the last search was performed October 12, 2022. Mammography screening for breast cancer; colonoscopy, sigmoidoscopy, or fecal occult blood testing (FOBT) for colorectal cancer; computed tomography screening for lung cancer in smokers and former smokers; or prostate-specific antigen testing for prostate cancer. Searches and selection criteria followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Data were independently extracted by a single observer, and pooled analysis of clinical trials was used for analyses. Life-years gained by screening was calculated as the difference in observed lifetime in the screening vs the no screening groups and computed absolute lifetime gained in days with 95% CIs for each screening test from meta-analyses or single randomized clinical trials. In total, 2 111 958 individuals enrolled in randomized clinical trials comparing screening with no screening using 6 different tests were eligible. Median follow-up was 10 years for computed tomography, prostate-specific antigen testing, and colonoscopy; 13 years for mammography; and 15 years for sigmoidoscopy and FOBT. The only screening test with a significant lifetime gain was sigmoidoscopy (110 days; 95% CI, 0-274 days). There was no significant difference following mammography (0 days: 95% CI, -190 to 237 days), prostate cancer screening (37 days; 95% CI, -37 to 73 days), colonoscopy (37 days; 95% CI, -146 to 146 days), FOBT screening every year or every other year (0 days; 95% CI, -70.7 to 70.7 days), and lung cancer screening (107 days; 95% CI, -286 days to 430 days). The findings of this meta-analysis suggest that current evidence does not substantiate the claim that common cancer screening tests save lives by extending lifetime, except possibly for colorectal cancer screening with sigmoidoscopy.

AN OPEN LABEL CLINICAL TRIAL OF KANCHNAR SYRUP IN TUNDIKERI (TONSILLITIS)

AIM: To determine the efficacy of Kanchnar syrup in Tundikeri roga (tonsillitis) in children. OBJECTIVE To determine the efficacy of Kanchnar syrup on graded subjective and objective parameters of Tundikeri roga (tonsillitis) in children. Study Design: Open label, Single arm clinical trial. Material and Methods: The study was conducted on 40 children of Tundikeri for a period of 45 days. Subjective parameters Toda (Pricking pain), Daah (Burning sensation), Galoprodha (Dysphagia), Mukha daurgandhya (Halitosis), Sore throat, Jwara (Fever), Swara bheda (Hoarseness of voice), Kasa (Cough), Kathin shopha (Inflammation), Lasika granthi vriddhi (Enlarged jugulodigastric lymph nodes) and lab parameters Hb%, TLC, DLC, ESR were documented before and after the completion of treatment. Statistical Analysis used: Observations of the study were analysed, and findings were evaluated using Statistical technique. The tests adopted were-Wilcoxon Signed Rank test, Paired t-test using SPSS software. Results: Overall assessment of drug was done for subjective and objective parameters based on the significance of statistical test. Marked improvement was observed in 40% patients, moderate improvement in 22.5% patients, mild improvement in 30% patients and no change was seen in 7.5% patients. Maximum effect was seen in Toda and least effect was seen in Kasa and Lasika granthi vriddhi. Conclusion: It can be concluded that there is significant effect of Kanchnar syrup on sign and symptoms of Tundikeri with no side effects observed.

Efficacy and Safety of Diphenylcyclopropenone (DPCP) as a Depigmenting Therapy in Extensive Vitiligo

Abstract Background Patients with extensive vitiligo who have residual pigmentation affecting exposed areas especially acral sites or patients with vitiligo universalis often seek depigmentation. At present, there is no ideal depigmenting therapy available. Possible options include; monobenzyl ether of hydroquinone (MBEH) cream, phenol, cryotherapy and Q-switched lasers. Diphenylcyclopropenone (DPCP) has been reported to rarely cause vitiligo as a side effect during the treatment of alopecia areata. Aim The aim of the present work is to evaluate the efficacy and safety of DPCP as a depigmenting therapy in extensive Vitiligo. Patients and Methods This is a pilot single arm clinical trial study. Twenty patients with extensive vitiligo were recruited from the vitiligo outpatient clinic of Dermatology, Venereology and Andrology Department, Ain Shams University Hospitals. We used DPCP applied topically to residual pigmented patches (sensitization session then therapeutic sessions). Results Depigmentation occurred among 5 patients (25% of cases). Depigmentation occurred in different tested sites including the scalp, forearm and back. Itching and blister formation were the main side effects leading to intolerability to the DPCP treatment. Conclusion Cosmetic result of DPCP depigmentation was acceptable with no skin atrophy. Further studies could be done following other protocols using sensitization dose with less concentrations of DPCP to avoid patients' intolerance to the therapy.

How Reliable Is Fluorescence-Guided Surgery in Low-Grade Gliomas? A Systematic Review Concerning Different Fluorophores.

Fluorescence-guided surgery has been increasingly used to support glioma surgery with the purpose of obtaining a maximal safe resection, in particular in high-grade gliomas, while its role is less definitely assessed in low-grade gliomas. A systematic review was conducted. 5-aminolevulinic acid, sodium fluorescein, indocyanine green and tozuleristide were taken into account. The main considered outcome was the fluorescence rate, defined as the number of patients in whom positive fluorescence was detected out of the total number of patients. Only low-grade gliomas were considered, and data were grouped according to single fluorophores. 16 papers about 5-aminolevulinic acid, 4 about sodium fluorescein, 2 about indocyanine green and 1 about tozuleristide were included in the systematic review. Regarding 5-aminolevulinic acid, a total of 467 low-grade glioma patients were included, and fluorescence positivity was detected in 34 out of 451 Grade II tumors (7.3%); while in Grade I tumors, fluorescence positivity was detected in 9 out of 16 cases. In 16 sodium fluorescein patients, seven positive fluorescent cases were detected. As far as indocyanine is concerned, two studies accounting for six patients (three positive) were included, while for tozuleristide, a single clinical trial with eight patients (two positive) was retrieved. The current evidence does not support the routine use of 5-aminolevulinic acid or sodium fluorescein with a standard operating microscope because of the low fluorescence rates. New molecules, including tozuleristide, and new techniques for fluorescence detection have shown promising results; however, their use still needs to be clinically validated on a large scale.

Phase I / II trial of metformin as a chemo-radiosensitizer in a head and neck cancer patient population

ObjectivesRetrospective studies have shown that head and neck squamous cell carcinoma (HNSCC) patients taking metformin demonstrate superior survival compared to their counterparts. We sought to determine whether metformin combined with chemoradiation would improve HNSCC patient survival compared to historical controls. Materials and methodsWe conducted a Phase I/II prospective, single arm clinical trial in patients with newly diagnosed HNSCC (NCT02949700). Patients received platinum-based chemoradiation in combination with orally dosed metformin at one of 2 doses- 850 mg BID or 1500 mg BID administered during radiation, with a 2-week lead-in phase. Toxicity, disease response and survival metrics were ascertained throughout the study period. ResultsA total of 25 patients were evaluable for toxicity and survival; 9 failed to reach the predetermined 70% compliance with the study drug. No dose limiting toxicities were identified in the Phase I component and there were no grade 4 adverse events likely related to metformin throughout the study. The primary outcome for the Phase II component was met with a response rate of 96%. Three-year overall survival was ∼70% in the per protocol p16 + cohort and 0% in the per protocol p16- cohort. Survival among participants with a ≥70% metformin compliance to <70% metformin compliance demonstrated a trend towards improvement in the ≥70% compliance cohort, though this did not reach significance. ConclusionMetformin is well tolerated during concurrent chemoradiation for HNSCC. Its effectiveness as a chemo-radiosensitizer remains unclear and will require further study with randomized controlled clinical trials in this patient population.

3D bioprinting for auricular reconstruction: A review and future perspectives

Congenital abnormalities or acquired trauma to the auricle can result in a need for ear reconstruction and negatively impact a person&amp;rsquo;s quality of life. Autografting, alloplastic implants, and prostheses are available to treat these issues, but each requires multiple surgical stages and has limitations and complications. Three-dimensional (3D) bioprinting promises to allow the creation of living, patient-specific ear substitutes that could reduce operative morbidity. In this review, we evaluate the current state of 3D bioprinting methods through a systematic search and review of 27 studies, aiming to examine this emerging technology within the context of existing reconstructive options. The included studies were all non-randomized experimental studies, except for a single pilot clinical trial. Most of these studies involved both in vitro and in vivo experiments demonstrating the potential of 3D bioprinting to create functional and anatomically accurate engineered cartilaginous frameworks for surgical implantation. Various ways of optimizing printing were identified, from choosing the most suitable material and cell type for the construct to addressing scaffold deformation and shrinkage issues. 3D printing has the potential to revolutionize reconstructive ear surgery by creating functional and aesthetically pleasing auricles. While more research into printing parameters, bioinks, cell types, and materials could optimize results, the next step is to conduct long-term in vivo clinical trials in humans.

TIPS-13 A PHASE II STUDY OF NEOADJUVANT CAMRELIZUMAB AND APATINIB IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMAS

Abstract BACKGROUND A single arm clinical trial (NCT04588987) about combination therapy of programmed cell death protein 1 blockades camrelizumab with antiangiogenic agent apatinib has been initiated to investigate their effectiveness for patients with recurrent high-grade Gliomas (HGG). METHODS Patients with recurrent HGG will receive single-dose intravenous injection of camrelizumab (200 mg) and daily oral administration of apatinib (250 mg/day for 7 days) 14 days before surgery for recurrent tumor. Sequential therapy will begin 2 weeks after surgery with the biweekly injection of camrelizumab and 4 weeks after surgery with the daily administration of apatinib. RESULTS Up to date (March 9, 2023), 18 patients are enrolled (13 for recurrent glioblastomas and 5 for anaplastic astrocytoma), with a medial follow-up time is 19 months. The median cycles of postoperative combination therapies were 4.5 cycles (95%CI: 3.87-5.12 ), with median progression-free survival of 4.0 months (95%CI: 2.78-5.28 ). One patient (1/18, 5.5%) discontinue the combination treatment because the patient often underwent the extended periods of hospitalization because of unacceptable liver dysfunction, and the other patient (1/18, 5.5%) withdraw the from the trail after receiving the surgery. All enrolled patients appeared one or more treatment-related adverse effects. The most common adverse effects were constipation(58%), hypertension (52%), leukocytopenia (52%), and nausea (47%). CONCLUSION the short-term results indicated that the combination therapy might be beneficial for patients with recurrent HGG and improve the patients’ overall survivals. We will present our detailed progress and results on the conference.

EP1 receptor: Devil in emperors coat.

EP1 receptor belongs to prostanoid receptors and is activated by prostaglandin E2. The receptor performs contrasting functions in central nervous system (CNS) and other tissues. Although the receptor is neurotoxic and proapoptotic in CNS, it has also been reported to act in an antiapoptotic manner by modulating cell survival, proliferation, invasion, and migration in different types of cancers. The receptor mediates its neurotoxic effects by increasing cytosolic Ca2+ levels, leading to the activation of its downstream target, protein kinase C, in different neurological disorders including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and epilepsy. Antagonists ONO-8713, SC51089, and SC51322 against EP1 receptor ameliorate the neurotoxic effect by attenuating the neuroinflammation. The receptor also shows increased expression in different types of cancers and has been found to activate different signaling pathways, which lead to the development, progression, and metastasis of different cancers. The receptor stimulates the cell survival pathway by phosphorylating the AKT and PTEN (phosphatase and tensin homolog deleted on chromosome 10) signaling pathways. Although there are limited studies about this receptor and not a single clinical trial has been targeting the EP1 receptor for different neurological disorders or cancer, the receptor is appearing as a potential candidate for therapeutic targets. The aim of this article is to review the recent progress in understanding the pathogenic roles of EP1 receptors in different pathological conditions.

Defining estimands for efficacy assessment in single arm phase 1b or phase 2 clinical trials in oncology early development.

The addendum of the ICH E9 guideline on the statistical principles for clinical trials introduced the estimand framework. The framework is designed to strengthen the dialog between different stakeholders, to introduce greater clarity in the clinical trial objectives and to provide alignment between the estimand and statistical analysis. Estimand framework related publications thus far have mainly focused on randomized clinical trials. The intention of the Early Development Estimand Nexus (EDEN), a task force of the cross-industry Oncology Estimand Working Group (www.oncoestimand.org), is to apply it to single arms Phase 1b or Phase 2 trials designed to detect a treatment-related efficacy signal, typically measured by objective response rate. Key recommendations regarding the estimand attributes include that in a single arm early clinical trial, the treatment attribute should start when the first dose is received by the participant. Focusing on the estimation of an absolute effect, the population-level summary measure should reflect only the property used for the estimation. Another major component introduced in the ICH E9 addendum is the definition of intercurrent events and the associated possible ways to handle them. Different strategies reflect different clinical questions of interest that can be answered based on the journeys an individual subject can take during a trial. We provide detailed strategy recommendations for intercurrent events typically seen in early-stage oncology. We highlight where implicit assumptions should be made transparent as whenever follow-up is suspended, a while-on-treatment strategy is implied.

Indolent cancer and pattern of progression: Two missing parameters in trial design for hepatology.

The indolent and aggressive behaviors of HCC might have a role in clinical trial (CT) results; however, the indolent HCC is less analyzed compared to others cancer. Indolent profile could be characterized as follows: (1) patients with low risk of progression itself due to the HCC molecular profile and/or due to the interaction between cancer cell their microenvironment; (2) patients who achieve objective response or present spontaneous regression; and (3) patients who develop radiological progression with no consequence on either the liver function or general status, and without trigger a change in the tumor stage. Patients with "indolent HCC" generally never develop cancer-related symptoms neither die for HCC-related causes. Thus, we hypothesize that the imbalance in the proportion of "indolent" versus "aggressive HCC" between arms or the underestimation/overestimation of HCC behavior at baseline in single-arm CT could be associated with CT failure or under-overestimation of trial results. The "indolent progression" may also explain the discrepancy between radiological progression-based end points and survival. Moreover, we discuss the related causes that explain the indolent profile of HCC and propose (1) refining the progression-related end point by the pattern of progression to minimize the limitations of the current end points; (2) considering alternative statistical tools for survival analysis such as milestone survival, or restricted mean survival time to capture the value of indolent HCC. According to these considerations, we propose incorporating novel end points into the single arm of phase I/II CT as exploratory analysis or as a secondary end point in phase III CT.

Participant Perceptions in a Long-term Clinical Trial of Autosomal Dominant Polycystic Kidney Disease

The development of new therapies for autosomal dominant polycystic kidney disease requires clinical trials to be conducted efficiently. In this study, the factors affecting the recruitment and retention of participants enrolled in a 3-year randomized controlled trial in autosomal dominant polycystic kidney disease were investigated. Qualitative study. All participants (N=187) were invited to complete a 16-item questionnaire at the final study visit of the primary trial. Participants were recruited to complete a semistructured interview using purposeful sampling according to age, self-reported gender, and randomization group. Descriptive statistics were used for demographic data and questionnaires. The interview transcripts underwent inductive thematic coding. One hundred and forty-six of the 187 randomized participants (79%) completed the post-trial questionnaire, and 31 of the 187 participants (21%) completed the interview. Most participants (94%) rated their global satisfaction with the trial as high (a score of 8 or more out of 10). Altruism, knowledge gain, and access to new treatments were the main motivators for recruitment. The main reasons for considering leaving the study were concerns about the risk of intervention and family or work issues. Strategies that favored retention included flexibility in attending different study sites, schedule flexibility, staff interactions, and practical support with parking and reminders. The main burden was time away from work with lost wages, and burden associated with magnetic resonance imaging scans and 24-hour urine output collections. The study population was restricted to participants in a single nondrug clinical trial, and the results could be influenced by selection and possible social desirability bias. Participants reported high levels of satisfaction that occurred as a function of the trial meeting participants' expectations. Furthermore, retention was a balance between the perceived benefits and burden of participation. Consideration of these perspectives in the design of future clinical trials will improve their efficiency and conduct. Advances in the clinical practice of autosomal dominant polycystic kidney disease (ADPKD) require affected individuals to voluntarily participate in long-term multicenter randomized controlled trials (RCTs). In this qualitative post hoc study of a 3-year RCT of increased water intake in ADPKD, altruism, knowledge gain, and access to a nondrug treatment positively influenced the decision to volunteer. Ongoing participation was enabled by building flexibility into the study protocol and staff prioritizing a participant's needs during study visits. Although participants completed the required tests, most were considered burdensome. This study highlights the importance of incorporating protocol flexibility into trial design; the preference for interventions with a low risk of adverse effects; and the urgent requirement for robust surrogate noninvasive biomarkers to enable shorter RCTs in ADPKD.

Multi-center real-world data curation and assessment of tumor growth rate and overall survival in advanced NSCLC treated with PD-(L)1 immune checkpoint inhibitor therapy.

9124 Background: While Immune Checkpoint Inhibitors (ICI) have become the standard-of-care for advanced non-small cell lung cancer (NSCLC) for certain patient populations, durable responses only occur in a small subset of patients. Therefore, there is an unmet need to identify patients that will respond before and during treatment to optimize treatment strategies. Multiple studies have shown promise that quantitative imaging biomarkers can predict response to ICI therapy. Studies have also shown that tumor growth parameters derived from time series data can provide early indications of long-term response. However, most studies to date have investigated single institution or clinical trial datasets, which are inadequate to capture the broad spectrum of real-world diversity of ICI treatments. In this study, we aimed to build a generalizable, well-validated imaging biomarker for treatment response. Methods: We have curated a retrospective dataset including serial imaging data of 1,215 advanced NSCLC patients who received ICIs from nine institutions across the US and Europe, capturing the diversity of the imaging data, such as CT scanner models, image acquisition parameters, reconstruction algorithms, as well as diversity in patient population, performance status, and treatment settings. Expert lesion annotations and manual volumetric segmentations were performed on all visible lesions (ranging from 1-18 lesions per subject, totaling 6,441 lesions) across the serial imaging data (ranging from 1-18 follow-up scans per subject), which enables lesion and organ-specific tumor burden assessment. We stratified overall survival based on volumetric response and tumor growth rate using a model defined by the sum of exponential growth ( g) and decay ( d), vol(t) = vol(0)*(egt + e-dt -1). Results: Survival analysis showed that the 3-month volumetric response (N = 875) was significantly associated with overall survival (OS) for the lowest quartile (Q1; log-rank p-value, P = 2.1e-4) and highest quartile (Q4; P = 9.8e-8) compared to the middle quartiles (Q2+Q3). The median overall survival (OS) stratified by the volumetric response was 547.7, 450.9, and 332.0 days in the Q1, Q2+Q3, Q4 quadrants, respectively. Among patients having a minimum of 2 follow-up scans in the first 18 weeks (N = 264), we found that patients with the tumor growth parameter ( g) in the highest quartile had significantly lower OS compared to the patients in the Q2+Q3 quadrants (P = 7.2e-5). Conclusions: Our results demonstrate the potential of large multi-center real-world imaging datasets in investigating novel early response assessment methodologies, such as volumetric tumor burden quantification and tumor growth modeling. In our further work, we will investigate response patterns at individual lesion levels and correlations with overall patient-level response.

Association of quantitative MRI features of DCIS with surgical upstaging and recurrence after treatment.

e12540 Background: Ductal carcinoma in situ (DCIS) is a common preinvasive breast cancer typically identified on screening mammography. Pure DCIS is nonlethal, but 20-25% of DCIS cases identified on core biopsy upstage to invasive cancer at surgery and about half progress to invasive disease if not treated. As a result, most DCIS patients undergo excision and radiation therapy. DCIS score is a multigene assay that can aid in radiation treatment decision-making and serve as a surrogate marker of ipsilateral breast recurrence (IBR) risk. Breast MRI can accurately depict DCIS span and has potential to assess biology and IBR risk. We sought to assess the associations of advanced quantitative MRI features with upstaging and DCIS score. Methods: In this IRB-approved single institution prospective clinical trial, patients recommended for biopsy of calcifications or those who had residual calcifications after a biopsy yielding pure DCIS consented to receive a multiparametric breast MRI (dynamic contrast-enhanced and diffusion-weighted) prior to surgery. The following quantitative MRI features were obtained: functional tumor volume (FTV), volume transfer constant (Ktrans), extracellular extravascular volume fraction (ve), background parenchymal enhancement (BPE), and apparent diffusion coefficient (ADC). Patients with biopsy-proven DCIS were followed through completion of surgery to determine upstaging. DCIS score was performed in those with sufficient excision-proven pure DCIS. Associations of MRI features with invasive upstaging and DCIS score and were evaluated by Spearman’s correlation and the Wilcoxon rank-sum test. Results: Of the 120 patients enrolled in the study, 57 (48%) were diagnosed with pure DCIS on core biopsy. Fifty-five patients underwent surgery, 13 of whom (24%) upstaged to invasive disease. Thirty-eight pure DCIS lesions had sufficient tissue to generate a DCIS Score. Several MRI features were associated with upstaging and DCIS Score: Ktrans (p &lt; 0.01) was significantly higher in lesions that upstaged to invasive disease. Higher DCIS scores were associated with lower Ktrans (p = 0.04) and ve (p = 0.05) values. No statistically significant associations were observed between FTV, BPE, or ADC and invasive upstaging or DCIS Score. Conclusions: This trial suggests advanced quantitative MRI features may help identify DCIS lesions at risk for upstaging to invasive disease and IBR. Specifically, an imaging feature of vascular permeability (Ktrans) showed an expected positive association with upstaging. Imaging features of vascular permeability (Ktrans and ve) showed counterintuitive inverse associations with DCIS Scores. Future research in larger cohorts is needed to validate these findings, better determine the biological reasons for these associations, and determine whether MRI features can be used clinically to optimize DCIS treatment. Clinical trial information: NCT03495011 .

Comparison of conventional clinical models and a multigene assay to assess DCIS risk in a prospective single center study.

e12578 Background: Ductal carcinoma in situ (DCIS) is a preinvasive breast cancer typically excised and treated with adjuvant therapy. While there is consensus that this results in overtreatment, there is little agreement on who may avoid radiation or endocrine therapy. Two freely available prediction models, Van Nuys Prognostic Index (VNPI) and Memorial Sloan Kettering Nomogram (MSK-N), are commonly used to identify low-risk DCIS based on standard clinicopathological features. Oncotype DCIS is a newer commercially available tissue-based multigene assay also used to assess risk, but its use is limited due to cost and unclear value over VNPI and MSK-N. We sought to compare these tests’ agreement in determining DCIS ipsilateral breast recurrence (IBR) risk and potential to de-escalate therapy. Methods: In this subanalysis from a prospective single center clinical trial, we analyzed 38 patients with newly diagnosed pure DCIS confirmed at excision. Each risk assessment tool presents risk in a different manner. Oncotype DCIS provides multiple assessments: a raw score (0-100), a DCIS Score Category (low, intermediate, high), and a Refined Score incorporating clinical features (10-year IBR risk). The VNPI calculates a raw score (4-12) and assigns a risk category (low, intermediate, high). MSK-N calculates a 10-year IBR risk. The tests were dichotomized as low vs. not-low risk categories using these thresholds: DCIS Score Category = low, DCIS Refined Score ≤ 10% IBR risk, VNPI risk category = low, MSK-N ≤ 10% IBR risk. Agreement of the 4 models (DCIS Score Category, DCIS Refined Score, VNPI, MSK-N) were compared using Spearman’s rank correlation for continuous data; percent agreement and Cohen’s kappa (k) were used to compare categorized data. Results: There was poor agreement of continuous risk assessments across the 4 models, with only VNPI and DCIS Refined Score showing significant but moderate correlation (r = 0.53, p = 0.001; others ranged r = 0-0.27, p &gt; 0.1). The number of cases identified as low-risk for each assay was DCIS Score Category = 14 (37%), DCIS Refined Score = 3 (8%), VNPI = 1 (3%), and MSK-N = 0. Percent agreement of low vs. not-low risk categorizations between DCIS Refined Score, VNPI, and MSK-N was 92-97%, but each assay classified 3 or fewer cases as low-risk and kappa was not significant (k = 0-0.48, p &gt; .1). DCIS Score Category demonstrated 63-71% agreement with the other 3 assays (k = 0-0.26). Only 1 case was classified as low-risk DCIS on multiple tests. Conclusions: DCIS risk models have poor agreement for determining IBR risk. DCIS Score Category initially identified many low-risk lesions; however, inclusion of clinical features to create a Refined Score decreased this substantially, providing very few additional low-risk cases for de-escalation over VNPI or MSK-N. Additional studies are needed to determine precise IBR rates when these models are used for adjuvant therapy decision-making. Clinical trial information: NCT03495011 .

(547) Erectile Dysfunction Following Radical Prostatectomy: An Overview, Critique, and Guidance on Future Directions

Abstract Introduction Despite modern surgical advancements and nerve-sparing techniques, men continue to endure delayed and incomplete erection recovery after radical prostatectomy (RP). Erectile rehabilitation has been described as an approach to promote erection recovery, but thus far studies on the most beneficial approach have been indeterminate. Objective This study serves to test the hypothesis that clinical trials that are meeting appropriate rigor in advancing the management of erectile dysfunction following radical prostatectomy. Methods We searched the clinicaltrials.gov website using the keywords “Erectile Dysfunction Radical Prostatectomy”. We included all resulting clinical trials with a time span ranging from 2005-2022. The specific parameters were interrogated to include disease state definitions, demographics, study design, assessment methodology, outcome measures, and data analysis. Results 46 trials were identified. 34 were Randomized Control Clinical Trials, 7 were Single Group Clinical Trials, and 5 were Observational Trials. 18 of the trials are complete, 7 ended before completion, and 21 are in progress. The trials included interventions ranging from mechanical devices (n=11), medical therapies (n=9), regenerative therapies (n=3), biological therapies (n=4), surgical interventions (n=12), and psychosocial interventions (n=2); validation of diagnostic questionnaires (n=3); and safety studies (n=2). Amongst the 18 completed studies, rigorous methods and randomization was applied. Observations included: short-term (6-12 month) erectile function measured by IIEF scores, lack of long-term follow up after treatment, and relative lack of trials focusing on erection recovery (n=2). Confounding variables were either exclusion criteria or matched appropriately. Study groups were primarily men aged 40-70 with localized prostate cancer who had normal sexual potency measured by IIEF scores prior to RP. Definitions such as erection recovery and erectile rehabilitation used in study introductions and titles are not always consistent with the primary outcomes measured. The vast majority of patients had well-defined pre-operative functional statuses. The surgical approaches are stated and well-defined. Compared to placebo at postoperative follow-up: Biologic therapies have been shown to improve IIEF scores up to 18 months but not to statistical significance; Shockwave therapy has not been shown to improve IIEF scores at 6 months; medical therapy with PDE-5i has shown to improve IIEF scores at 3, 6, and 12 months; regenerative therapy has shown improvements in IIEF scores at 6 months but not to statistical significance; medical devices have been shown to improve IIEF scores up to 12 months; psychosocial treatments have not demonstrated improvements in IIEF scores up to 12 months; intraoperative techniques have not been demonstrated to show a difference in IIEF scores up to 12 months. Conclusions This study shows that clinical trials have a potential to advance erectile function outcomes in men after RP. Trials that are randomized, controlled, representative of diverse populations, and characterized by well-defined terms, outcomes, and baseline functional status will be most useful in assessing the benefit of a treatment. Surgical interventions, medical therapies, and mechanical devices have been the primary interventions of focus, but other treatment options continue to show promising results. Nonetheless, more studies are needed with a long-term follow up to inform erection recovery and erectile rehabilitation protocols. Disclosure No

A phase 2 study of stereotactic body radiation therapy for squamous cell carcinoma of the head and neck (SHINE): a single arm clinical trial protocol

BackgroundCancers of the head and neck region are often characterized by locally advanced, non-metastatic disease. Standard treatments for advanced cervico-facial cancers of the skin or primary head and neck squamous cell carcinoma (HNSCC) include combinations of surgery, radiation and chemotherapy, which are associated with high rates of acute toxicity and complications. Stereotactic body radiotherapy (SBRT) has been shown to be a promising modality of treatment for this patient population in retrospective studies; to our knowledge, there are no prospective clinical studies evaluating the safety and efficacy of SBRT in these patients.MethodsThis phase 2, single institution, single arm study aims to evaluate response rates to SBRT in older age patients with locally advanced HNSCC for whom primary surgery is not recommended or performed. The intervention is SBRT 45 Gy in 5 fractions given every 3–4 days. Toxicity, quality of life and patient outcomes will be recorded regularly up to 24 months after completion of SBRT.DiscussionFor this patient population, SBRT may offer a shorter and more effective treatment than the current standard of care palliative regimens. If the study demonstrates that SBRT is safe and effective, then this may lead to randomized studies comparing conventional radiotherapy to SBRT for selected head and neck cancer patients.Trial registrationClinicalTrials.gov Identifier: NCT04435938. Date registered: June 17, 2020.

Evaluating the Effectiveness of Intravenous Ozonated Normal Saline in the Treatment of Severe COVID-19 Disease: A randomized control trial

Background: There is still no specific treatment strategy for COVID-19 other than supportive management. The potential biological benefits of ozone therapy include reduced tissue hypoxia, decreased hypercoagulability, modulated immune function by inhibiting inflammatory mediators, improved phagocytic function, and impaired viral replication. This study aimed to evaluate the effect of intravenous ozonated normal saline on patients with severe COVID-19 disease. Methods: In this study, a single centralized randomized clinical trial was conducted on 80 hospitalized patients with severe COVID-19. The patients were selected by random allocation method and divided into two groups A and B. In group A (control group), patients were given standard drug treatment, and in group B (intervention group), patients received ozonated normal saline in addition to the standard drug treatment. In the intervention group, 400 mL of normal saline was weighed by 40 μg/ kg of body weight and was injected into patients within 15 to 30 minutes (80 to 120 drops per minute). This process was done daily every morning for a week. Primary and secondary outcomes of the disease included changes in the following items: length of hospital stay, inflammatory markers including C-reactive protein (CRP), clinical recovery, arterial blood oxygen status, improvement of blood disorders such as leukopenia and leukocytosis, duration of ventilator attachment, and rapid clearance of lung lesions on CT scans. The need for intensive care unit (ICU) hospitalization, the length of ICU stay, and the mortality rate in patients of the two groups was compared. Results: According to the results of the initial outcome variable analysis, the probability of discharge of patients who received the normal ozonated saline intervention was 33% higher than patients who did not receive this intervention; however, this relationship was not statistically significant (HR=0.67, 95%, CI=0.42-1.06, P value=0.089). The chance of ICU hospitalization in patients of the intervention group was three times more than that of the comparison group, but this relationship was not significant (odds ratio=4.4 95% CI=1.32-14.50, P value=0.016). The use of ozonated normal saline was found to increase the risk of death by 1.5 times but this relationship was not statistically significant (odds ratio=1.5, 95% CI=.24-9.75, P value=0.646). Ozonated normal saline had a significant effect on changes in respiration rate (in the intervention group the number of breaths was decreased) and the erythrocyte sedimentation rate (in the intervention group the erythrocyte sedimentation rate was increased); however, it had no significant effect on other indicators. Conclusion: The present study showed that ozone therapy in hospitalized patients with severe COVID-19 could help improve some primary and secondary outcomes of the disease. Governments and health policymakers should make ozone therapy an available care service so that the need for advanced treatment facilities decreases; consequently, this measure may improve patient safety, prevent lung tissue destruction, and control cytokine storms in patients. Additionally, health decision-makers need to aim for the effective clinical improvement of patients, especially severe ones, and the reduction of their mortality. However, further large-scale multicenter studies with larger sample sizes considering drug side effects and other variables influencing the clinical course of COVID-19 can provide more information on the effectiveness and importance of ozone therapy.

Abstract 5259: Bazedoxifene plus conjugated estrogen improves metabolic health and reduces mammary gland epithelial proliferation in an ovary intact rat model of obesity and breast cancer risk

Abstract Background: The majority of women risk eligible for primary breast cancer prevention with tamoxifen or aromatase inhibitors refuse uptake due to concerns about side effects, especially vasomotor symptoms. Tamoxifen may also have detrimental metabolic effects in overweight/obese women. Duavee™, a complex of bazedoxifene (BZA) and conjugated estrogen (CE), is FDA approved for relief of hot-flashes and prevention of osteoporosis. Preclinical studies suggest favorable metabolic effects in ovariectomized animals and potential for breast cancer risk reduction. A single arm clinical trial found reduction in Ki-67 and mammographic density such that BZA+CE is being further evaluated in a Phase IIB trial of peri and early postmenopausal women with vasomotor symptoms who are at high risk for breast cancer. Here, in a companion study, we assessed the effect of BZA+ CE on metabolic health and cancer risk in a rat model of carcinogen induced ER+ tumors and high fat diet induced obesity. Methods: Rats received 50 mg/kg N-methylnitrosourea at 7 weeks to increase mammary tumor risk and were fed a high fat diet (46% kcal fat) to promote obesity. At 16 weeks lean and obese rat were selected based on % body fat and were then randomized to 8 weeks of daily oral vehicle control or 3mg BZA + 0.07mg CE/kg body weight. Systemic metabolic variables were measured at 16 and 24 weeks, and RNA from mammary glands analyzed by gene expression microarray (Affymetrix). Results: BZA+CE resulted in systemic as well as mammary changes indicative of improved metabolic health, including: reduction in total and visceral fat (p&amp;lt;0.01), glucose (p&amp;lt;0.05), cholesterol (p&amp;lt;0.001), and triglycerides(p=0.08), as well as an increase in the adiponectin:leptin ratio (p&amp;lt;0.01). BZA+CE vs control increased the ratio of small (insulin sensitive) to large adipocytes in the mammary gland. Gene set enrichment analysis (GSEA) showed BZA+CE downregulated proliferation-associated pathways which had been upregulated in obese rats, consistent with anti-cancer effects. Obese rats treated with BZA+CE also had upregulation of metabolic pathways, including adipocyte differentiation, fatty acid metabolism, and inflammatory response pathways. Conclusions: Unlike tamoxifen, BZA+CE improved whole body and mammary gland metabolic health, particularly in obese rats. Transcriptional profiling and GSEA demonstrated a blunting of cell cycle and proliferation and enrichment of metabolic and immune-related pathways. Together this supports BZA+CE (Duavee) as an agent to be explored for breast cancer risk reduction in obese individuals. Funding: This work was supported in part by P30 CA168524, R00 CA169430, and R25 CA203650. Citation Format: Ramsey M. Jenschke, Karen A. Corleto, Carol J. Fabian, Stephen D. Hursting, Bruce F. Kimler, Danilo Landrock, Tara N. Mahmood, Katherine L. Cook, Erin D. Giles. Bazedoxifene plus conjugated estrogen improves metabolic health and reduces mammary gland epithelial proliferation in an ovary intact rat model of obesity and breast cancer risk. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5259.

The Role of Tocotrienol in Arthritis Management—A Scoping Review of Literature

Arthritis is a cluster of diseases impacting joint health and causing immobility and morbidity in the elderly. Among the various forms of arthritis, osteoarthritis (OA) and rheumatoid arthritis (RA) are the most common. Currently, satisfying disease-modifying agents for arthritis are not available. Given the pro-inflammatory and oxidative stress components in the pathogenesis of arthritis, tocotrienol, a family of vitamin E with both anti-inflammatory and antioxidant properties, could be joint-protective agents. This scoping review aims to provide an overview of the effects of tocotrienol on arthritis derived from the existing scientific literature. A literature search using PubMed, Scopus and Web of Science databases was conducted to identify relevant studies. Only cell culture, animal and clinical studies with primary data that align with the objective of this review were considered. The literature search uncovered eight studies investigating the effects of tocotrienol on OA (n = 4) and RA (n = 4). Most of the studies were preclinical and revealed the positive effects of tocotrienol in preserving joint structure (cartilage and bone) in models of arthritis. In particular, tocotrienol activates the self-repair mechanism of chondrocytes exposed to assaults and attenuates osteoclastogenesis associated with RA. Tocotrienol also demonstrated strong anti-inflammatory effects in RA models. The single clinical trial available in the literature showcases that palm tocotrienol could improve joint function among patients with OA. In conclusion, tocotrienol could be a potential anti-arthritic agent pending more results from clinical studies.

Abstract P4-07-53: Adverse events (AEs) in phase III clinical trials of patients with human epidermal growth factor receptor-2 positive (HER2+) breast cancer (BC): a meta-analysis

Abstract Background. In the last five years, several new drugs have been approved for BC in the United States, many of which target HER2, including neratinib, margetuximab, tucatinib, and trastuzumab deruxtecan. These approvals depend on a drug’s benefits outweighing its risks in clinical trials (CTs). However, limited information on safety is available from single CTs. The objective of this study is to identify recently published phase III CTs that report AEs in patients (pts) with HER2+ BC and perform a meta-analysis to estimate the frequency of the most common AEs reported in ≥2 CTs. Methods. A literature search was conducted (Ovid, ClinicalTrials.Gov) to identify phase III CTs published from 2017-2021. Search terms included BC, HER2+, phase III, CT, and others. Articles were independently screened by two researchers in two levels (title/abstract; full text) and were included if they reported AEs in pts with HER2+ BC. Meta-analysis was performed in Comprehensive Meta Analysis v3 to estimate frequency of AEs using random effects models. Results. Of 519 articles identified, 33 were included for analysis (455 excluded in level 1 screening; 31 excluded in level 2 screening). Most excluded articles were not phase III or did not include only pts with HER2+ BC. BC treatments most commonly included chemotherapy and HER2-targeted agents (e.g., trastuzumab), including antibody-drug conjugates (ADCs; e.g., trastuzumab emtansine). Most trials (N=27) included ≥1 treatment arm with pts who received chemotherapy in combination with a HER2-targeted agent. Fewer trials (N=10) included ≥1 treatment arm with pts who received only a HER2-targeted agent. Across all 33 trials, 181 unique AEs were reported. Specific chemotherapy agents used were not always reported, but included taxanes, anthracyclines, cyclophosphamide, 5-fluorouracil, capecitabine, and carboplatin. In chemotherapy treated pts (with or without reported concomitant HER2-targeted agent), the most frequent any grade AEs were hand-foot syndrome (63.8%, N=1814), alopecia (56.6%, N=9677), and diarrhea (39.9%, N=12628); the most frequent grade ≥3 AEs were neutropenia (21.7%, N=14349), hand-foot syndrome (12.2%, N=2252), and leukopenia (8.4%, N=3852). HER2-targeted agents included trastuzumab emtansine, trastuzumab, pertuzumab, lapatinib, and neratinib. In pts treated with any HER2-targeted agent (without reported concomitant chemotherapy), the most frequent any grade AEs were diarrhea (31.7%, N=5518), nausea (30.8%, N=5518), and epistaxis (24.9%, N=3622); the most frequent grade ≥3 AEs were thrombocytopenia (4.8%, N=3980), anemia (4.2%, N=3845), and aspartate aminotransferase increase (3.3%, N=3975). In the subgroup of pts treated with an ADC (trastuzumab emtansine), the most frequent any grade AEs were nausea (41.4%, N=3622), fatigue (31.6%, N=2895), and headache (28.0%, N=3622); the most frequent grade ≥3 AEs were similar to those in pts treated with any HER2-targeted agent. Significant heterogeneity was detected among trials for the outcomes reported here (Q statistic ranged from 12-2176, p&amp;lt; 0.05). No analysis was conducted in pts who received hormone therapy due to limited available information about this group in the included trials. Conclusion. When evaluating pooled data, the most commonly reported AEs in CTs of patients with HER2+ BC varied by drug classes included in treatment regimens. This meta-analysis provides a more comprehensive understanding of the most frequent AEs in this population by pooling patient data from several CTs and will contribute to better contextualize the safety of products used in this population. Future research including real-world studies can be used to better understand the safety profile of these medications. Citation Format: Mackenzie Henderson, Priyanka Yalamanchili, Eric Wang, Maribel Salas. Adverse events (AEs) in phase III clinical trials of patients with human epidermal growth factor receptor-2 positive (HER2+) breast cancer (BC): a meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-53.