Pilot Study Research Articles

Long-term Remissions Following CD20-directed Chimeric Antigen Receptor Adoptive T cell Therapy.

Chimeric antigen receptor (CAR) T cell therapy produces high response rates in refractory B-cell non-Hodgkin lymphoma (NHL), but long-term data are minimal to date. Here, we present long-term follow-up of a pilot trial testing a CD20-targeting 3rd generation CAR in patients with relapsed B-cell lymphomas following cyclophosphamide-only lymphodepletion. Two of the 3 patients in the trial, with mantle cell lymphoma and follicular lymphoma, had remissions lasting more than 7 years, though they ultimately relapsed. The absence of B cell aplasia in both patients suggested a lack of functional CAR T cell persistence, leading to the hypothesis that endogenous immune responses were responsible for these long remissions. Correlative immunologic analyses supported this hypothesis, with evidence of new humoral and cellular anti-tumor immune responses proximal to clinical response time points. Collectively, our results suggest that CAR T cell therapy may facilitate epitope spreading and endogenous immune response formation in lymphomas.

Development and content validity of the DizzyQuest

IntroductionVestibular disorders have a high prevalence and impact on general health. Currently questionnaires to measure vestibular symptoms and the impact on daily life, do not capture disease-specific symptoms or induce recall bias. The DizzyQuest was introduced, to measure vestibular symptoms in the flow of daily life, using the ecological momentary assessment (EMA) strategy. The development and content validity of the DizzyQuest are described in this article.MethodsThe development process consisted of two stages: First, the development of a concept version of the DizzyQuest based on the conceptual model of positive health, semi-structured interviews with patients diagnosed with bilateral vestibulopathy (BV) and expert input. Second, the assessment of content validity through a 4-week pilot trial, followed by focus group meetings with patients and professionals separately.ResultsPatient interviews, an expert meeting and a conceptual model resulted in the first pilot version of the DizzyQuest, which included a morning-, within-day-, evening- and attack-questionnaire. To report patient characteristics, complimentary patient- and doctor-questionnaires were added. The pilot trial (N = 5) and two patient focus group meetings resulted in multiple suggestions for response options. Two professional focus group meetings provided recommendations for sampling time and sampling schedule. As a result, two versions of the DizzyQuest were developed, consisting of a regular DizzyQuest (DQ) and an extended DizzyQuest-XL (DQ-XL).ConclusionThe DizzyQuest enables the administration of multiple questionnaires during the flow of daily life, therefore increasing reliability and ecological validity. The DQ and DQ-XL, using a big data approach, has the potential to improve precision medicine.

A multiple technology-based and individually-tailored Sit Less program for people with cardiovascular disease: A randomized controlled trial study protocol.

Sedentary behavior, a key modifiable risk factor for cardiovascular disease, is prevalent among cardiovascular disease patients. However, few interventions target sedentary behavior in this group. This paper describes the protocol of a parallel two-group randomized controlled trial for a novel multi-technology sedentary behavior reduction intervention for cardiovascular disease patients (registered at Clinicaltrial.gov, NCT05534256). The pilot trial (n = 70) will test a 12-week "Sit Less" program, based on Habit Formation theory. The 35 participants in the intervention group will receive an instructional goal-setting session, a Fitbit for movement prompts, a smart water bottle (HidrateSpark) to promote hydration and encourage restroom breaks, and weekly personalized text messages. A control group of 35 will receive the American Heart Association's "Answers by Heart" fact sheets. This trial will assess the feasibility and acceptability of implementing the "Sit Less" program with cardiovascular disease patients and the program's primary efficacy in changing sedentary behavior, measured by the activPAL activity tracker. Secondary outcomes include physical activity levels, cardiometabolic biomarkers, and patient-centered outcomes (i.e. sedentary behavior self-efficacy, habit strength, and fear of movement). This study leverages commonly used mobile and wearable technologies to address sedentary behavior in cardiovascular disease patients, a high-risk group. Its findings on the feasibility, acceptability and primary efficacy of the intervention hold promise for broad dissemination.

Provocative findings from a transdiagnostic counseling intervention to improve psychiatric comorbidity and HIV care engagement among people with HIV: A Pilot Randomized Clinical Trial

Background: Depression, anxiety, post-traumatic stress (PTS), and alcohol/substance use disorders are prevalent among people with HIV (PWH), commonly co-occur, and predict worse HIV care outcomes. Transdiagnostic counseling approaches simultaneously address multiple co-occurring mental health disorders. Methods: We conducted a pilot individually randomized trial of the Common Elements Treatment Approach adapted for people with HIV (CETA-PWH), a transdiagnostic counseling intervention, compared to usual care at a large academic medical center in the southern US. Participants were adults with HIV, at risk for HIV care disengagement, with elevated symptoms of depression, anxiety, PTS, and/or alcohol/substance use. Mental health and HIV care engagement were assessed at four and nine months. Results: Among participants (n=60), follow-up was high at four (92%) and nine (85%) months. Intervention engagement was challenging: 93% attended ≥1 session, 43% attended ≥6 sessions in three months (“moderate dose”), and 30% completed treatment. While not powered for effectiveness, mental health outcomes and HIV appointment attendance improved in CETA-PWH relative to usual care in intent-to-treat analyses; those receiving a moderate dose and completers showed progressively greater improvement. Viral load showed small differences between arms. The dose-response pattern was not explained by differences between those who did and did not complete treatment. Conclusions: This pilot trial provides preliminary evidence for the potential of CETA-PWH to simultaneously address co-occurring mental health co-morbidities and support HIV appointment attendance among PWH. Additional strategies may be an important part of ensuring that clients can engage in the full course of treatment and realize its full benefits.

Oral preparation of hyaluronic acid, chondroitin sulfate, N-acetylglucosamine, and vitamin C improves sexual and urinary symptoms in participants with recurrent urinary tract infections: a randomized crossover trial.

Intravesical instillation of hyaluronic acid (HA) has been associated with reduced sexual dysfunction in participants with recurrent urinary tract infections (rUTIs), but the efficacy of an oral treatment has never been investigated. To investigate the efficacy of an oral preparation of HA, chondroitin sulfate, N-acetylglucosamine, and vitamin C in improving sexual and urinary symptoms in a cohort of reproductive-age participants with rUTI. In a monocentric randomized crossover pilot trial, participants with rUTI who were referred to our institute between March 2022 and April 2023 were randomized 1:1 in 2 groups: intervention vs control. All participants had an oral preparation of cranberry, D-mannose, propolis extract, turmeric, and Boswellia twice a day for 3 months. The intervention group also included an oral preparation of HA, chondroitin sulfate, N-acetylglucosamine, and vitamin C once a day for 3 months. Crossover of treatment occurred at 3 months for an additional 3 months. At baseline and 3 and 6 months, participants were evaluated clinically and with the International Prostate Symptom Score (IPSS) and Female Sexual Function Index (FSFI). Descriptive statistics and logistic regression models tested the impact of the intervention on urinary and sexual symptoms at each follow-up assessment. Improvement in sexual and urinary symptoms as measured by the FSFI and IPSS. Overall, 27 (54%) participants had an FSFI score <26.5 at enrollment. At 3 months, FSFI scores were higher in the intervention group vs control (P < .001), but IPSS scores were lower (P = .03). After crossover of treatment, FSFI and IPSS scores remained stable in the intervention group. However, after crossover, the control group showed a significant improvement in IPSS and FSFI scores (all P < .01) vs the 3-month assessment. At last follow-up, urinary and sexual symptoms were comparable between groups. In logistic regression analyses, the intervention group was associated with early improvement in sexual symptoms (odds ratio, 3.9; P = .04) and urinary symptoms (odds ratio, 5.1; P = .01) after accounting for clinical confounders. Combination treatment with HA, chondroitin sulfate, N-acetylglucosamine, and vitamin C is effective if started immediately or even after a few months from symptoms in participants with rUTI. The main limitation is the lack of long-term follow-up. The oral formulation of HA, chondroitin sulfate, N-acetylglucosamine, and vitamin C could be an effective therapy against urinary and sexual distress in participants with rUTI (NCT06268483; ClinicalTrials.gov).

Does the Workload Change When Using an Impact Wrench in Different Postures?—A Counter-Balanced Trial

Awkward hand-arm posture and overhead work increase the risk of musculoskeletal symptoms. These adverse health effects can also be caused by additional workloads such as hand-arm vibration exposure while carrying or holding a power tool. This pilot trial investigated posture and muscle activity of 11 subjects while using an impact wrench for three working directions: upwards, forwards and downwards. Although the vibration exposure did not show notable differences in the magnitude (4.8 m/s2 upwards, 4.4 m/s2 forwards and 4.7 m/s2 downwards), postural behavior and the muscle activity showed significantly higher workloads for working upwards compared to forwards direction. The muscle activity results for working downwards also showed elevated levels of muscle activity due to the awkward wrist posture. The results demonstrate that not only the working direction but also more importantly the arm, wrist and head posture need to be considered while investigating hand-arm vibration exposure.

Acute Effects of Dairy or Soy Milk on Sex Hormones Following Resistance Exercise in Males: A Randomized, Crossover Pilot Trial

Acute Effects of Dairy or Soy Milk on Sex Hormones Following Resistance Exercise in Males: A Randomized, Crossover Pilot Trial

A Mind–Body Intervention to Improve Physical Activity for Patients with Chronic Hip-Related Pain: Protocol for a Mixed Methods Study

Background: Pain and dysfunction persist for most patients following hip-related pain treatment. Additionally, individuals with hip-related pain are typically less physically active than individuals without hip pain, despite evidence that regular physical activity reduces chronic musculoskeletal pain. Poor psychological health is common in patients with hip-related pain and further reinforces low physical activity. Mind–body interventions can improve psychological health and activity levels but have yet to be integrated to provide comprehensive, psychologically informed care for patients with hip-related pain. Thus, we are using the NCCIH intervention development framework to develop Helping Improve PSychological Health (HIPS), a novel, multimodal mind–body intervention to improve physical activity for individuals with hip-related pain and poor psychological health. Methods: We will recruit physical therapists (N = 20) and patients with hip-related pain (N = 20) to participate in 60 min qualitative interviews (focus groups with therapists; one-on-one interviews with patients). Using these data, we will develop the initial HIPS intervention and provider training materials. One physical therapist will be trained to deliver the HIPS intervention to five participants in an open pilot trial. Participants will attend six 30 min HIPS intervention sessions. We will collect quantitative data on satisfaction, improvement, and physical activity, alongside qualitative exit interviews with participants and the physical therapist in order to refine the HIPS intervention and provider training materials. Results: This study has been approved by the MGB IRB. We aim to develop and test the initial feasibility of the HIPS intervention in an open pilot trial. The findings from this project will inform a subsequent feasibility RCT.

Multispectral optoacoustic tomography of benign parotid tumors in vivo: a prospective observational pilot study

Parotid lumps are a heterogeneous group of mainly benign but also malignant tumors. Preoperative imaging does not allow a differentiation between tumor types. Multispectral optoacoustic tomography (MSOT) may improve the preoperative diagnostics. In this first prospective pilot trial the ability of MSOT to discriminate between the two most frequent benign parotid tumors, pleomorphic adenoma (PA) and Warthin tumor (WT) as well as to normal parotid tissue was explored. Six wavelengths (700, 730, 760, 800, 850, 900 nm) and the parameters deoxygenated (HbR), oxygenated (HbO2), total hemoglobin (HbT), and saturation of hemoglobin (sO2) were analyzed. Ten patients with PA and fourteen with WT were included (12/12 female/male; median age: 51 years). For PA, the mean values for all measured wave lengths as well as for the hemoglobin parameters were different for the tumors compared to the healthy parotid (all p < 0.05). The mean MSOT parameters were all significantly higher (all p < 0.05) in the WT compared to healthy parotid gland except for HbT and sO2. Comparing both tumors directly, the mean values of MSOT parameters were not different between PA and WT (all p > 0.05). Differences were seen for the maximal MSOT parameters. The maximal tumor values for 900 nm, HbR, HbT, and sO2 were lower in PA than in WT (all p < 0.05). This preliminary MSOT parotid tumor imaging study showed clear differences for PA or WT compared to healthy parotid tissue. Some MSOT characteristics of PA and WT were different but needed to be explored in larger studies.

Effect of Fluid Intake on Acute Changes in Plasma Volume: A Randomized Controlled Crossover Pilot Trial

Plasma volume (PV) undergoes constant and dynamic changes, leading to a large intra-day variability in healthy individuals. Hydration is known to induce PV changes; however, the response to the intake of osmotically different fluids is still not fully understood. In a randomized controlled crossover trial, 18 healthy individuals (10 females) orally received an individual amount of an isotonic sodium-chloride (ISO), Ringer (RIN), or glucose (GLU) solution. Hemoglobin mass (Hbmass) was determined with the optimized carbon monoxide re-breathing method. Fluid-induced changes in PV were subsequently calculated based on capillary hemoglobin concentration ([Hb]) and hematocrit (Hct) before and then every 10 minutes until 120 min (t0–120) after the fluid intake and compared to a control trial arm (CON), where no fluid was administered. Within GLU and CON trial arms, no statistically significant differences from baseline until t120 were found (p &gt; 0.05). In the ISO trial arm, PV was significantly increased at t70 (+138 mL, p = 0.01), t80 (+191 mL, p &lt; 0.01), and t110 (+182 mL, p = 0.01) when compared to t0. Moreover, PV in the ISO trial arm was significantly higher at t70 (p = 0.02), t110 (p = 0.04), and t120 (p = 0.01) when compared to the same time points in the CON trial arm. Within the RIN trial arm, PV was significantly higher between t70 and t90 (+183 mL, p = 0.01) and between t110 (+194 mL, p = 0.03) and t120 (+186 mL, p &lt; 0.01) when compared to t0. These results demonstrated that fluids with a higher content of osmotically active particles lead to acute hemodilution, which is associated with a decrease in [Hb] and Hct. These findings underpin the importance of the hydration state on PV and especially on PV constituent levels in healthy individuals.

An open pilot trial of a behavioural intervention to reduce violence by young adults with early psychosis receiving treatment in an early intervention services setting: A protocol.

Despite the public health impact of violence among young adults with psychosis, behavioural interventions to reduce the risk of engaging in violence remain rare. For young adults with early psychosis, cognitive behavioural therapy (CBT)-based psychotherapy has efficacy in reducing impairment and improving functioning. However, no CBT-based intervention to reduce violence has been formally adapted for young adults with early psychosis. This protocol outlines the first clinical trial of a behavioural intervention to reduce violence for young adults with early psychosis. This study is set in an early intervention services (EIS) setting and seeks to adapt and pilot Psychological Intervention for Complex PTSD and Schizophrenia-Spectrum Disorder (PICASSO), a CBT-based intervention, through an iterative process utilizing mixed-methods assessments. All research will occur at OnTrackNY, the largest EIS program in the United States. This study will consist of an open pilot trial, with four EIS clinicians delivering the intervention to one to two EIS participants per round. In this mixed-methods study, both quantitative measures (acceptability, feasibility and hypothesized mediators of target outcome collected on a weekly basis) and qualitative interviews (with EIS clinicians at weeks 4, 8 and 12) will be conducted. Transcripts will be analyzed using thematic content analysis. Two to three rounds of iterative modifications are anticipated (n = 10-16 EIS participants total). Recruitment began in February 2024 and is expected to continue over a 9-12-month period. Because violent behaviour causes interpersonal disruptions such as incarceration and increased caregiver burden, an innovative intervention to reduce violence risk could have broader health impact for this vulnerable population. Adapting the PICASSO intervention to the EIS setting will optimize its acceptability and feasibility by the intended target population.

Speech services by speech volunteers for children with cleft lip and palate in professional lacking area: Pilot study

Background: Cleft lip and cleft palate are the most common birth defects. Children with cleft lip with or without cleft palate (CP±L) face a vary of challenges, depending on the type and severity of the cleft including speech difficulty, dental problems, feeding difficulty, ear infections and hearing loss. Articulation error is the most common residual defect in children with cleft palate with or without cleft lip. Objective: To compare the numbers of pre- and post- articulation errors after using the Model of Speech Therapy by Volunteers (STV) for children with CP±L. Materials and methods: 9 children, aged range 6; 4-14; 2 years old, were included in this study and completely participated in the study. Pre- and post-articulation tests by Myanmar Articulation, Resonation, Nasal Emission and Nasal Turbulence Test were assessed at Mahamuni Monastery, and Thiriyadana Guha Pone Htoon Shan Monastery, Tachileik, Myanmar. STV is composed of a 3-day speech camp (1st month), 3 times 1-day site visits for complicated cases (2nd, 6th, and 10th months) and 3 times of 1-day follow-up speech camps (4th, 8th, and 12th months), Phonological approaches, traditional strategies, and specific techniques for speech correction in children with CP±L were taught to speech volunteers (SVs) and caregivers. Homework was assigned to SVs and caregivers. SVs provided a session of 45-minute speech correction every week. Caregivers practiced 5 sessions of 30 minutes in speech exercises /weeks at home. Results: STV revealed significant reductions in the numbers of articulation errors including articulation screening test [median difference: MD=6 (95% confident interval: CI=5.2-9.2)], and Myanmar articulation standard test at both word and sentence levels; [MD=8 (95% CI=6.5-10.8) and MD=5 (95% CI=4.2-8.3), respectively]. Conclusion: STV significantly decreased a number of articulation errors in children with CP±L of Myanmar, a professional lacking area, and could be applied in any area that has a similar situation. The result was a primary study, the further research should enroll more participants for generalization.

Effects of short-term moderate intensity exercise on the serum metabolome in older adults: a pilot randomized controlled trial

BackgroundWe previously reported changes in the serum metabolome associated with impaired myocardial relaxation in an asymptomatic older community cohort. In this prospective parallel-group randomized control pilot trial, we subjected community adults without cardiovascular disease to exercise intervention and evaluated the effects on serum metabolomics.MethodsBetween February 2019 to November 2019, thirty (83% females) middle-aged adults (53 ± 4 years) were randomized with sex stratification to either twelve weeks of moderate-intensity exercise training (Intervention) (n = 15) or Control (n = 15). The Intervention group underwent once-weekly aerobic and strength training sessions for 60 min each in a dedicated cardiac exercise laboratory for twelve weeks (ClinicalTrials.gov: NCT03617653). Serial measurements were taken pre- and post-intervention, including serum sampling for metabolomic analyses.ResultsTwenty-nine adults completed the study (Intervention n = 14; Control n = 15). Long-chain acylcarnitine C20:2-OH/C18:2-DC was reduced in the Intervention group by a magnitude of 0.714 but increased in the Control group by a magnitude of 1.742 (mean difference −1.028 age-adjusted p = 0.004). Among Controls, alanine correlated with left ventricular mass index (r = 0.529, age-adjusted p = 0.018) while aspartate correlated with Lateral e’ (r = −764, age-adjusted p = 0.016). C20:3 correlated with E/e’ ratio fold-change in the Intervention group (r = −0.653, age-adjusted p = 0.004). Among Controls, C20:2/C18:2 (r = 0.795, age-adjusted p = 0.005) and C20:2-OH/C18:2-DC fold-change (r = 0.742, age-adjusted p = 0.030) correlated with change in E/A ratio.ConclusionsCorresponding relationships between serum metabolites and cardiac function in response to exercise intervention provided pilot observations. Future investigations into cellular fuel oxidation or central carbon metabolism pathways that jointly impact the heart and related metabolic systems may be critical in preventive trials.

Abstract PO4-22-12: Robot-assisted nipple-sparing mastectomy using da Vinci SP single-port system: primary results from the pilot trial RASPIM-01

Abstract Background Robot-assisted breast surgery was developed in 2014 for nipple-sparing mastectomy through a concealable lateral chest wall incision smaller. Although successful experiences have been reported using a multi-arm surgical robotic system, collisions between robotic arms and instruments often result in the discontinuation of console workflow and limit the performance of the surgical robot. Compared to multi-armed robot systems, the SP system is single-armed, equipped with flexible instruments containing multiple joints that may avoid instrument collision, a controllable camera reducing visual dead spots, and a designated non-third-party port that allows single-port entry and full deployment of the instrument. The RASPIM-01 trial (NCT05448963) is a single-armed pilot study assessing the feasibility of robot-assisted nipple-sparing mastectomy (NSM) using a new SP system. Method This study is a pilot trial conducted in a single-arm, non-randomized design with a recruitment of 30 participants. The SP surgical robot is used in NSM through the lateral chest wall incisions. The major inclusion criteria are 1) Breast cancer with preoperative clinical tumor sizes less than 5 cm, with an adequate tumor-skin distance of at least 3mm, and without nipple-areolar involvement in at least 1cm around the nipple by image, 2) Breast cancer up to clinical stage IIIA (T3, N1-2) showing adequate response to neoadjuvant therapy and meeting criteria 1), 3) Germline pathogenic/likely pathogenic BRCA1 or 2 variant carriers with or without a breast cancer diagnosis, requiring unilateral or bilateral therapeutic mastectomy or prophylactic mastectomy. Exclusion criteria include extensive breast skin or nipple involvement such as inflammatory breast cancer, Paget’s disease, nipple discharge associated with malignancy, image suggestive of cancer involvement of the nipple and subareolar tissue, and stage III breast cancer without response to neoadjuvant therapy, and previous radiotherapy of the surgical side breast. The endpoint measurements include Primary endpoint: The ability to complete nipple-sparing mastectomy with an SP system in the per-protocol population without additional assistant port or conversion to open surgery. Statistical analysis includes point estimation with a 95% confidence interval to analyze the mean or proportion of key performance parameters. No interim analysis will be performed due to the limited number intended to recruit. Results The study recruited 30 breast cancer patients and conducted 30 NSMs, while no prophylactic mastectomy case was recruited. The median age was 44 years old, BMI was 22.4 (18.9-30.0) kg/m2. Median tumor size was 3.0 (1.0-14.6) cm, and axillary lymph node metastases were present in 7 cases (23.3%). T2 (13 cases, 43.3%) tumors were the majority, followed by Tis (10 cases, 33.3%), T1 (5 cases, 16.7%), and T3 (2 cases, 6.7%). The anatomical stages of invasive cancer were Ia (16.7%), IIa (26.7%), IIb (16.7%), and IIIa (6.7%), among them 9 (30.3%) received neoadjuvant chemotherapy before surgery. All NSMs met the primary endpoint of successful completion using the SP robot system without conversion to open mastectomy or the addition of an assistant port. Median console time was 108.5 (73-285) min and docking time was 2.5 (1-9) min. Specimen weight was 311.6 (107-838) gm, while 2 (6.7%) cases had their nipple excised due to cancer-involved margin reported from the frozen section. Twenty-six (86.6%) cases received autologous free flap reconstruction, among which 25 (83.3%) cases received DIEP, and 1 (3.3%) received PAP reconstruction. Four cases received implant (2 cases, 6.7%) or tissue expander (3 cases, 6.7%). Conclusion This is the first NSM clinical trial operated with SP surgical robot system and met its primary endpoint showing the feasibility to conduct NSM. Secondary and exploratory endpoints data will be reported after the completion of clinical follow-ups. Citation Format: Wen-Ling Kuo, Chia-Huei Chu, Jung-ju Huang. Robot-assisted nipple-sparing mastectomy using da Vinci SP single-port system: primary results from the pilot trial RASPIM-01 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-22-12.

Abstract RF02-07: Precocious modulation of metabolic and immunological parameters predicts tumor response to fasting-mimicking diet plus chemotherapy in patients with early stage TNBC

Abstract Background: Preclinical studies showed that severely calorie restricted fasting-mimicking diets (FMDs) enhance the antitumor efficacy of chemotherapy (CT) or immunotherapy (IO) in murine triple negative breast cancer (TNBC) models. These effects are mediated by a combination of blood glucose reduction and positive immunomodulatory effects. Moreover, combining fasting and metformin produced synergistic anticancer effects in a broad range of tumor models. The BREAKFAST trial was designed to investigate if FMD, plus/minus metformin, could increase the antitumor activity of neoadjuvant CT in patients with stage I-III TNBC. Methods: BREAKFAST (NCT04248998) is a randomized, non-comparative, phase II, pilot trial that enrolled stage I-III (cT&amp;gt;1 cm) TNBC patients (pts) candidate to receive 4 cycles of neoadjuvant CT with doxorubicin-cyclophosphamide every 3 weeks, followed by 12 cycles of weekly paclitaxel. Pts were randomized 1:1 to receive: CT plus 5-day FMD every 3 weeks, up to 8 cycles (arm A); CT plus FMD plus daily metformin (1700 mg) (arm B). The primary study endpoint was the rate of pCR in either experimental arm. Secondary/exploratory endpoints included safety, compliance, and biomarker analyses based on blood metabolomics and tumor transcriptomics analyses at different timepoints. Results: Between June 2020 and February 2022 we enrolled 30 pts. Then, the study was interrupted after the introduction of chemo-immunotherapy (CT-IO) as a standard neoadjuvant therapy for early stage TNBC pts. Among 30 pts, 13 were treated with CT plus FMD, while 17 pts received CT plus FMD plus metformin. Overall, pCR rate was 56.6%, i.e., significantly higher than pCR rates reported with anthracycline-taxane CT alone in previous phase II/III trials (26-39%), with no significant differences among treatment arms (p=0.49). The FMD acutely reduced blood glucose, insulin and LDH levels, which reflects a reduction in systemic and/or tumor glucose metabolism. Of note, precocious LDH reduction was more pronounced in patients undergoing pCR. RNA-seq analysis of tumor samples revealed a significant downmodulation of glycolysis and TCA cycle pathways after one treatment cycle, paralleled by an increase of intratumor activated T cells, memory T cells and NK cells, as estimated by deconvolution analyses of tumor transcriptomic data. Of note, these changes were observed only in patients achieving pCR. While intratumor metabolic changes were similar in the two treatment arms, the modulation of intratumor immunity was more pronounced in patients not receiving metformin. Conclusion: Preoperative CT plus cyclic FMD (plus/minus metformin) results in excellent pCR rates in localized TNBC patients. Early on-treatment downregulation of systemic and intratumor metabolic parameters related to glucose metabolism predicts pCR, and this is independent of metformin use. Based on results of this study, we recently initiated a large, multicentric trial, namely the BREAKFAST-2 (NCT05763992) study, which will investigate if adding cyclic FMD to neoadjuvant CT-IO increases pCR rates in ~ 145 pts with stage II-III TNBC. Citation Format: Francesca Ligorio, Giovanni Fucà, Andrea Vingiani, Fabio Iannelli, Riccardo Lobefaro, Leonardo Provenzano, Lucrezia Zanenga, Cristina Ferraris, Antonino Belfiore, Silvia Brich, Alessia Bertolotti, Gianfranco Scaperrotta, Catherine Depretto, Antonia Martinetti, Elisa Sottotetti, Paola Antonia Corsetto, Giulia Valeria Bianchi, Giuseppe Capri, Secondo Folli, Saverio Minucci, Marco Foiani, Massimiliano Pagani, Giancarlo Pruneri, Filippo De Braud, Claudio Vernieri. Precocious modulation of metabolic and immunological parameters predicts tumor response to fasting-mimicking diet plus chemotherapy in patients with early stage TNBC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF02-07.

Optimal treatment conditions for low-intensity pulsed ultrasound therapy for Alzheimer's disease: applications from mice to humans.

We previously developed a novel therapy with low-intensity pulsed ultrasound (LIPUS) that ameliorates cognitive decline through upregulation of endothelial nitric oxide synthase (eNOS) in mouse models of Alzheimer's disease (AD). In a randomized, double-blind, placebo-controlled pilot trial, we demonstrated that whole-brain LIPUS therapy is safe and tends to suppress the cognitive decline in early AD patients. We herein report the findings of our basic experiments that we performed for the pilot trial in order to apply whole-brain LIPUS therapy to humans, as well. First, we examined the relationship between bone density/thickness and ultrasound transmittance using human temporal bone. Next, based on the results of ultrasound transmittance, we further examined mRNA expression of VEGF, FGF2, and eNOS in response to variable ultrasound frequencies, duty cycles, and sound pressures. There was a significant correlation between bone thickness and transmittance (1.0MHz, P < 0.001), while there was no significant correlation between bone density and transmittance (1.0MHz, P = 0.421). At a frequency of 0.5MHz, the optimum duty cycle was considered to be up to 20%. When the tissue amplitude was in the range of 0.05-0.5MPa, VEGF, FGF2, and eNOS were significantly upregulated by LIPUS. Thus, the conditions necessary for LIPUS therapy for the human brain were identified as sound pressure just below the probe 1.3MPa (tissue amplitude 0.15MPa), duty cycle 5%, and frequency 0.5MHz. We successfully identified the optimal treatment conditions for LIPUS therapy for patients with AD.

Effect on emergence from anesthesia following induction with diazepam and its association with CYP2C9, CYP2C19 and CYP3A4 gene polymorphisms

Introduction &amp; Objectives: Benzodiazepines are commonly used as adjuvants to IV anesthetic agents. Diazepam dosage varies widely depending on the desired endpoints. The rationale behind such inter-individual variability in drug responses has been attributed to genetically determined alterations in the enzyme activities. We assessed the emergence time in patients after induction of anesthesia with two different doses of diazepam and evaluated if any correlation exists between the emergence time and genetic polymorphism in drug metabolizers CYP2C19, CYP2C9, and CYP3A4 genes.&#x0D; Methodology: The study was conducted on randomly selected adult patients scheduled for elective surgery between 40-60 y of age with predefined inclusion and exclusion criteria. The patients were distributed into 2 groups, with group 1 receiving 0.2 mg/kg and group 2 given 0.3 mg/kg diazepam. Wake-up time after surgery was determined after a standardized verbal command played by a tape-recorder. Three ml blood in Ethylenediaminetetraacetic acid (EDTA) was collected before administering anesthesia.&#x0D; Results: Wake-up time between 8-18 min did not vary between the two groups. Comparatively persons having 2C19 2 took longer time to wake-up but this association was not statistically significant. However, CYP2C9 2 and 2 C9 3 and CYP3A4 genotypes had no influence on wake-up time.&#x0D; Conclusion: The pilot study suggests the emergence time from diazepam is longer in patients having 2C19 2 which confers slow-metabolizer phenotype. However, this study needs to be replicated in larger sample size to arrive at definitive conclusions before clinical applications.&#x0D; Abbreviations: BDZ- benzodiazepine; EDTA- Ethylenediaminetetraacetic acid; GA-General Anesthesia&#x0D; Key words: Diazepam; Emergence; Gene Polymorphism; Pharmacogenetics&#x0D; Citation: Mittal T, Badhe VK, Badhe DSD, Ahluwalia P, Mitta Bl, Mittal R. Effect on emergence from anesthesia following induction with diazepam and its association with CYP2C9, CYP2C19 and CYP3A4 gene polymorphisms.  Anaesth. pain intensive care 2024;28(1):126-138. DOI: 10.35975/apic.v28i1.2380&#x0D; Received: July 20, 2023; Reviewed: December 07, 2023; Accepted: December 07, 2023

Abstract PO1-20-03: Acupuncture for Preventing Progression of Taxane-Induced PeripheralNeuropathy (ATP): A Phase II Randomized, Placebo Controlled Trial

Abstract Background: Chemotherapy-induced peripheral neuropathy (CIPN) from chemotherapy drugs such as taxanes can be detrimental to cancer survival, increasing the risk of falls and worsening physical functions. However, there is no effective treatment or preventative measure for CIPN. The current management of worsening and persistent CIPN during chemotherapy is dose reduction or discontinuation of chemotherapy. Our group previously completed a single-arm phase IIA pilot trial of women who developed National Cancer Institution Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 2 CIPN during weekly paclitaxel for stage I-III breast cancer. The result suggested an acupuncture intervention for grade 2 CIPN might slow CIPN progression during chemotherapy. However, the role of acupuncture still needs to be better defined. Trial design: The ATP trial is a two-arm, parallel, randomized controlled trial comparing weekly real acupuncture (RA) versus sham acupuncture (SA) during preplanned curative intent taxane containing regimens in patients with breast cancer. The study will include two phases: screening and intervention. In the screening phase, eligible patients will consent and receive CIPN screening each week. Patients who develop grade 1 CIPN or higher based on NCI-CTCAE version 5.0 will be consented to the intervention phase and randomized to receive either weekly RA or SA using a standardized, semi-fixed protocol developed in our preliminary studies to improve CIPN pain. Eligibility criteria for the screening phase: English or Spanish-proficient; aged ≥18 years; histological diagnoses of invasive carcinoma of the breast; and plan to receive curative intent chemotherapy regimen containing paclitaxel or nab-paclitaxel weekly or biweekly as standard of care. Eligibility criteria for the intervention phase: in additional to the screening phase eligibility criteria, developed CIPN grade ≥1 based on the NCI-CTCAE version 5.0, while receiving taxane; ≥ four weeks of paclitaxel or nab-paclitaxel weekly or biweekly planned, as standard of care and at treating physician’s discretion; willing to adhere to requirement that no new pain medication or dose changes be taken throughout the first 12 weeks of the study period; and willing to adhere to all study-related procedures, including randomization to one of the two possible acupuncture treatments. Specific aims: The primary aim is to evaluate the effectiveness of RA versus SA in preventing taxane-induced peripheral neuropathy progression as measured by Neuropathic Pain Scale (NPS) in patients with early-stage breast cancer who are receiving curative intent neurotoxic chemotherapy. The secondary aim is to evaluate the effectiveness of RA versus SA on chemotherapy relative dose intensity (RDI) and CIPN-related chemotherapy discontinuation. Statistical methods: We will randomize 80 patients, 40 to each arm. All randomized patients will be evaluable in the Intent to Treat (ITT) analyses because all will have completed the baseline assessment before randomization. We will use a linear mixed model (LMM) to compare the change in NPS between the arms from baseline to week 4. Based on our pilot data, a difference in CIPN grade from 1 to 2 corresponded to a difference in NPS from 12 to 22, a difference of ten points in 27 patients. The NPS standard deviation (SD) in patients with grade 1 CIPN was 17. With 80 patients we will have 80% power to detect a difference between arms as small as 10 points on the NPS, assuming a one-sided test, type I error of 5%, correlation between baseline and follow-up measurements of 0.5, SD of 17, and 15% attrition at week 4. Present accrual and target accrual: We accrued 20 participants in the intervention phase by the end of June 2023; the target accrual is 80 participants. Contact information for people with a specific interest in the trial: W. Iris Zhi, MD, PhD, zhiw@mskcc.org. ClinicalTrails.gov Identifier: NCT05458284. Citation Format: W. Iris Zhi, Lauren Taylor, Raymond Baser, Matthew Weitzman, Qing Li, Christina Seluzicki, Ting Bao, Jun Mao. Acupuncture for Preventing Progression of Taxane-Induced PeripheralNeuropathy (ATP): A Phase II Randomized, Placebo Controlled Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-03.

Abstract PO2-19-04: Trial in Progress: The REJOIN Trial to Use Exercise and Education to Relieve Joint Pain in Older Breast Cancer Survivors Taking Aromatase Inhibitors

Abstract Background: Physical activity (PA) is a recommended part of breast cancer survivorship. PA promotes survival and mitigates symptoms in older breast cancer survivors (BCS), especially in reducing joint pain associated with Aromatase Inhibitors (AIs). The purpose of the study is to test if a self-management intervention (including education and exercise instruction) improve joint pain management better than standard care. Trial Design: This two-armed randomized controlled pilot trial (NCT03955627) includes insufficiently active BCS, 60 years and older, diagnosed with stage I-III hormone-sensitive breast cancer, who have completed primary cancer treatment and are within 6 months of initiating AIs. We adapted an evidence-based PA program for older adults (Fit and Strong!) that includes bi-weekly, supervised exercise sessions plus education (90 minutes total). The 16-week, evidence-based intervention program includes: 8-weeks of supervised sessions delivered remotely plus 8-weeks of self-guided home sessions with periodic phone coaching. We are conducting select geriatric assessments (e.g., cognitive assessment, polypharmacy) plus measurements of exercise (both self-reported and objectively measured by accelerometer), joint pain (brief pain inventory), and AI adherence (confirmed by self-report and prescription records) assessed four times (baseline, 4, 6 and 12 months). Eligibility Inclusion criteria: • Female, aged ≥ 60 years at enrollment  • Planning to initiate (or are &amp;lt; 24 weeks from initiating) AIs  • Diagnosed stages I-III breast cancer  • ER+ tumor (at least 5% of cells)  • Completed surgery, radiation and/or chemotherapy  • Independent ambulator (verified by treating clinician/staff)  • Physician approval to start an exercise program • Insufficiently active (less than 150 minutes per week of moderate intensity activity or less than two sessions per week of strength training)  • Able to complete surveys and forms/understand English  • Agree to random assignment to treatment or control group  • Can commit to 8 weeks, bi-weekly classes offered by Zoom video and 8 Weeks of at-home exercise.  • Must have internet access or data plan to support video conferencing software  • Minimum cognitive impairment (verified by cognitive screening questions administered by phone) Specific Aims: The primary aim is to test the efficacy of a self-management intervention (exercise plus education) on AI-associated arthralgia. Hypothesis: Participants in the treatment group will report less pain than the control group. –A secondary aim is to test the effect of the pilot intervention on adherence to AIs. Hypothesis: Participants in the treatment group will report better AI Adherence than controls. Statistical Methods: We will use the Wilcoxon-Mann-Whitney t-test to assess the effect size from the start to the end of the trial, assuming a power calculation of 80%, a two-sided alpha of 10%, and a pooled standard deviation of one between the outcomes of the two groups (usual care and treatment) being compared. Present Accrual and Target Accrual REJOIN enrolled 12 participants in 2022, but two withdrew after randomization. We now have data on 10 participants with a target accrual of 24 overall. The original 12 were accrued at Penn State College of Medicine. We subsequently opened a second site at Wake Forest University and are recruiting the remaining participants. Contact information: For more information about REJOIN, please contact the study director, Dr. Shirley Bluethmann at sblueth@wakehealth.edu or the REJOIN project manager, Angela Grubb, at agrubb@wakehealth.edu Citation Format: Shirley Bluethmann, Peri Newman, Cristina Truica, Nancy Olsen, Heidi Klepin. Trial in Progress: The REJOIN Trial to Use Exercise and Education to Relieve Joint Pain in Older Breast Cancer Survivors Taking Aromatase Inhibitors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-04.

An integrated mental health video consultations model for patients with somatic symptom disorder in primary care: The randomized VISION pilot trial

ObjectiveSymptoms of somatic symptom disorder (SSD) are one of the most common reasons for consultations in primary care. However, specialized psychological services are mostly unavailable. This pilot trial aimed to determine the feasibility, acceptability, and safety of the integrated mental health video consultations VISION model for patients with SSD in primary care. MethodsWe conducted a parallel group, randomized controlled pilot trial involving fifty-one patients with SSD from ten primary care practices in Germany, who we randomized to the VISION model or enhanced treatment-as-usual (eTAU). The VISION model comprised five video consultations which featured diagnostic clarification, psychoeducation (acknowledging and legitimizing of symptoms), and brief psychological therapy. eTAU included training primary care practice teams on the DSM-5 concept of SSD guideline recommendations for its treatment in primary care. We assessed feasibility as the primary outcome at 6-months, measuring efficiency of recruitment, intervention acceptability, safety. ResultsRecruitment was efficient reflected in an overall recruitment yield (number randomized per number screened) of 55% (51/92) and a consent rate (number randomized per number eligible) of 94% (51/54). Acceptability of the intervention was high with 98% (123/125) of the video consultations conducted as planned. No serious adverse events were reported in either group. ConclusionAn integrated mental health video consultations VISION model for patients with SSD presenting to primary care is feasible, acceptable, and safe. Potential clinical effectiveness of the model should be evaluated in confirmatory trial putting the multifaceted approach tailored to the individual patient with SSD directly into primary care practice. Trial registrationThe trial protocol was registered at German Clinical Trials Register (number: DRKS00026075, https://www.drks.de).