Trial Of Therapy Research Articles

A qualitative analysis of patients’ day-to-day living with functional cognitive disorder (FCD)

Purpose Functional cognitive disorder (FCD) is an increasingly recognised condition which causes significant disability and distress. While it is known to be associated with depression, anxiety and reduced functioning, like other functional neurological disorders it may be marred by stigma. To date, little is known about the lived experience of those with FCD. Materials & methods As part of a randomised controlled feasibility trial of online group Acceptance and Commitment Therapy (ACT) for FCD we conducted in-depth qualitative interviews and utilised a thematic analysis approach to explore the challenges of living with FCD; how individuals cope with the symptoms; and their experiences of healthcare services. Results We recruited six women and three men, with a median age of 54. They described living with FCD which included experiences of loss of identity, altered role, feelings of confusion, frustration and low self-esteem, stigma, social isolation, and dismissal by healthcare services. Nevertheless, suffers strove to find strategies to ameliorate their symptoms. Conclusions FCD is a common and disabling condition which like other functional neurological symptoms leads to altered sense of self and unsatisfactory interactions with others, including healthcare professionals. The diagnosis should be made on positive grounds, clearly explained, and potential therapies investigated.

On the use of sham transcutaneous spinal cord stimulation in spinal cord injury clinical trials.

Kramer et al. examine the reasons put forth by investigators for excluding a sham condition in trials of neuromodulation therapies for individuals with spinal cord injury. They conclude that current dogma does not justify this design, and emphasize the need for future trials to include appropriate controls.

Targeting the "Undruggable": Small-Molecule Inhibitors of Proliferating Cell Nuclear Antigen (PCNA) in the Spotlight in Cancer Therapy.

PCNA plays multiple roles in cancer development, including cell proliferation regulation, DNA repair, replication, and serving as a widely used biomarker and therapeutic target. Despite its significant role in oncology, PCNA has historically been considered "undruggable" due to the absence of known endogenous small molecule modulators and identifiable ligand binding sites. Unlike other protein-protein interfaces, PCNA lacks explicit binding grooves, featuring a relatively small and shallow surface pocket, which hinders the discovery of traditional small molecule targets. Recent breakthroughs have introduced promising PCNA-targeting candidates, with ATX-101 and AOH1996 entering phase I clinical trials for cancer therapy, garnering academic and industry interest. These achievements provide new evidence for PCNA as a drug target. This article provides insight and perspective on the application of small-molecule PCNA inhibitors in cancer treatment, covering PCNA function, its relationship with cancer, structural modification of small molecule inhibitors, and discovery strategies.

Pilot Trial of a Transdiagnostic Cognitive Behavioral Therapy (CBT)-Based Group Intervention to Reduce Psychological Distress, Facilitate Positive Behavior Change, and Mitigate Inflammation in Older People with HIV.

More than half of adults with HIV in the United States are aged 50 or older. Older people with HIV (OPWH) are disproportionately affected by age-related health disparities and non-communicable diseases associated with inflammation. The current pilot randomized controlled trial (RCT) evaluated the feasibility and acceptability, while exploring signals of effects of a transdiagnostic cognitive behavioral therapy (CBT) modular group teaching skills to cope with distress, make positive health behavior changes, and ultimately reduce inflammation. Participants were 31 virally undetectable, and psychiatrically stable OPWH (age [Formula: see text]50 years). Participants were randomized 1:1 to enhanced usual care or CBT for HIV and Symptom Management (CHAMP). CHAMP consists of 12-weekly virtual group sessions led by two interventionists. Self-report questionnaires and intravenous blood draws were collected at baseline and follow-up. Intervention participants completed an exit interview. Of those screened eligible, 96.8% (30/31) were randomized (n = 15 per group), 86.7% (13/15) completed the intervention, and 87% (26/30) completed the follow-up. On acceptability questionnaires scaled 0-3, participants reported high satisfaction and the intervention to be of high quality (M(SD)=3.00(0.0) for both). They also indicated their needs were met (2.67(0.50)) and coping improved (2.60(0.52)). Intervention participants showed a mean decrease in anxiety (-1.07(6.08)) and depressive (-1.71(5.37)) symptoms on clinical screeners, and mean increase in quality of life (2.86(3.59)). CHAMP is both feasible and acceptable for OPWH. Exploratory analyses indicate favorable outcomes for improving psychological distress and health-related quality of life.

Sleeping for Two: a randomized controlled trial of cognitive behavioral therapy for insomnia in pregnancy.

Insomnia and sleep problems are common in pregnancy and have potentially negative impacts on both parental and infant health. This study examined the Sleeping for Two adaptation of cognitive behavioral therapy for insomnia (CBT-I) in pregnancy. A parallel (1:1) randomized controlled trial evaluated CBT-I (n = 32) compared to a treatment as usual waitlist (n = 32) among pregnant individuals from Alberta, Canada experiencing insomnia. Five weekly individual sessions of CBT-I pivoted from in-person delivery to telehealth due to the COVID-19 pandemic physical distancing regulations. Insomnia symptom severity (primary outcome), insomnia diagnosis by structured interview, self-reported sleep problems, as well as sleep parameters measured by diary and actigraphy were assessed pretreatment at 12-28 weeks gestation, 1-week posttreatment, and 6 months postpartum. Birth information (secondary outcomes) were collected via delivery record and parent report of infant sleep (exploratory outcome) was taken at 6 months postpartum. Multilevel modeling using an intention-to-treat approach showed that CBT-I was associated with a decrease in insomnia symptoms and improved sleep quality across time compared to treatment as usual. The CBT-I group had fewer diagnoses of insomnia posttreatment, but the difference did not reach statistical significance until 6 months postpartum. Participants with worse sleep quality at baseline benefitted substantially more from CBT-I vs treatment as usual waitlist. CBT-I delivered in pregnancy can reduce symptoms of insomnia and improve sleep quality, which could in turn minimize risk of negative consequences for birthing parent and infant health. Registry: ClinicalTrials.gov; Name: Sleeping for Two: RCT of CBT-Insomnia in Pregnancy; URL: https://www.clinicaltrials.gov/study/NCT03301727; Identifier: NCT03918057. MacKinnon AL, Silang K, Watts D, etal. Sleeping for Two: a randomized controlled trial of cognitive behavioral therapy for insomnia in pregnancy. J Clin Sleep Med. 2025;21(2):365-376.

Disease-free survival as a surrogate endpoint for overall survival in adults with early-stage pancreatic cancer: A trial-level surrogacy analysis.

708 Background: In early-stage cancer, overall survival (OS) is the gold-standard endpoint for assessing therapeutic efficacy. However, long follow-up periods make OS challenging and costly to measure in clinical trials. Disease-free survival (DFS), which captures the time to recurrence or death, has been proposed as a surrogate endpoint for OS in early-stage pancreatic cancer (PC). This surrogacy relationship could allow for a more rapid assessment of treatment benefits, but its validity requires robust analysis across clinical trials. Understanding the trial-level correlation between DFS and OS is crucial to optimizing trial design and grant accelerated drug approval. Methods: We conducted a systematic search of Embase, PubMed, and Cochrane databases through August 2024, identifying randomized controlled trials (RCTs) that evaluated adjuvant or neoadjuvant systemic therapies in adult patients with PC. Included studies reported both OS and DFS outcomes. Hazard ratios for DFS (HR_DFS) were analyzed as surrogate endpoints for OS (HR_OS). Statistical analyses utilized linear regression models, weighted by trial sample sizes, to determine the strength of the correlation. Surrogacy strength was categorized by the coefficient of determination (R²), with R² ≥ 0.7 indicating a strong correlation, 0.69–0.5 a moderate correlation, and values < 0.5 indicating weak correlation. Results: Out of 3,048 studies screened, 30 RCTs met the inclusion criteria, comprising 5,275 patients in adjuvant therapy trials and 557 patients in neoadjuvant therapy trials. The median follow-up duration ranged from 16 to 53.5 months, with 12 phase II trials included. Overall, DFS showed strong surrogacy for OS in adjuvant trials (R² = 0.70; 95% CI, 0.50–0.91). Subgroup analysis indicated strong correlation in phase III trials (R² = 0.71; 95% CI, 0.46–0.96) and moderate correlation in phase II trials (R² = 0.67; 95% CI, 0.21–1.00). The strongest surrogacy was observed in studies incorporating adjuvant radiation therapy (R² = 0.81; 95% CI, 0.52–1.00). In the analysis of neoadjuvant trials, HR-DFS also presented strong correlation with OS (R² = 0.90; 95% CI, 0.56–1.00). Conclusions: There is a strong trial-level correlation between DFS and OS in both adjuvant and neoadjuvant therapy trials for early-stage pancreatic cancer, particularly in phase III studies and trials incorporating adjuvant radiation therapy. However, the strength of this surrogacy varies depending on the treatment setting and trial design.

Secondary Analysis of Trials of Prolonged Exposure Therapy Among Adults With Co-Occurring Posttraumatic Stress Disorder and Opioid Use Disorder by Gender

Secondary Analysis of Trials of Prolonged Exposure Therapy Among Adults With Co-Occurring Posttraumatic Stress Disorder and Opioid Use Disorder by Gender

A phase IIa clinical trial of first-line cyclical therapy alternating gemcitabine, cisplatin, and durvalumab with pemigatinib for advanced biliary tract cancers with FGFR2 -alterations.

TPS645 Background: Unresectable biliary tract cancer (BTC) has a poor prognosis. Frontline chemo-immunotherapy (C-IO) for advanced BTC leads to ~25% overall survival (OS) at 24-month, but 93-99% of patients reported adverse events (AEs), and 13-19% of patients stopped treatment drugs due to AEs. FGFR kinase inhibitors (FGFRi) are second-line therapy for 10% of BTC with FGFR2 fusions. However, clinical trials of upfront FGFRi have not accrued well. Cumulative toxicities frequently interrupt treatment and limit feasibility of concurrent C-IO + FGFRi. Over time, side effects from each of therapies have a negative impact on patients’ quality of life (QoL). We previously treated two FGFR2 -altered BTC patients with cyclical chemotherapy (CT) and FGFRi and observed prolonged survival with better QoL. By monitoring serial circulating tumor DNA (ctDNA), we observed development of FGFRi-resistant subclones while on FGFRi and their subsequent clearance after resuming CT. Thus, we have developed a clinical trial to validate our hypothesis that upfront cyclical therapy alternating between C-IO and FGFRi can improve therapeutic efficacy and QoL. Alternating therapy is hypothesized to avoid accumulating toxicities and treat emerging resistance subclones. Methods: In this single-center, single-arm, Phase IIa trial, all treatment-naive patients with FGFR2 -altered advanced BTCs, PS ≤ 1, are eligible. Patients will receive cyclical therapy alternating between two therapy-blocks, starting from C-IO block (2 cycles of gemcitabine, cisplatin and durvalumab, 28-day/cycle), then FGFRi block (3 cycles of pemigatinib on day 1-14 of 21-day/cycle). Block-switch continues until progressive disease (PD), and then we will continue alternated block until the next PD. A sample size of 30 is calculated based on an expected 12-month OS rate of ≥ 55%. The trial is anticipated to enroll the first patient in early 2025. Results: The primary objective is 12-month OS rate. Secondary objectives are overall response rate, progression-free survival, AEs. We will stratify patients to PD-L1 CPS <1 or ≥ 1 to assess if cyclical therapy can enhance IO. Exploratory objectives are (1) assessing dynamics of FGFR2 -ctDNA variants throughout therapy correlating with clinical outcomes, using a custom liquid biopsy (FGFR-Dx) developed at the Ohio State University; (2) assessing QoL scores with EORTC-QLQ-C30 and -BIL21 questionnaires, correlating with clinical outcomes. Results will be compared to historical controls from TOPAZ-1 trial. Conclusions: Cyclical therapy will be one of the first to combine alternating C-IO and targeted therapy in cancer. This strategy can be validated in other tumors if it is proven effective in our trial. Cyclical therapy holds great promise to introduce FGFRi earlier into treatment for BTC and improve both efficacy and QoL.

A qualitative study exploring depressed participants’ experiences of receiving Augmented Depression Therapy (ADepT)

ObjectivesThe current study aimed to explore participants’ views on the acceptability, impact and mechanisms of change of Augmented Depression Therapy (ADepT), a novel wellbeing-focused and recovery-oriented psychological therapy for depression.DesignA semi-structured qualitative interview design was used, with data analysed using the framework approach.Participants20 participants with anhedonic depression who had received up to 20 sessions of ADepT, sampled from a pilot randomised controlled trial of ADepT versus Cognitive Behavioural Therapy (CBT).SettingA primary care psychological therapy clinic in Devon, UK, with interviews occurring between May 2018 and February 2020.ResultsParticipants found the wellbeing focus of ADepT acceptable. Helpful aspects of therapy were a positive therapeutic bond, the structure and flow of therapy scaffolding the learning journey, the tools and techniques of therapy helping building wellbeing and booster sessions supporting long-term recovery. Negative aspects for some participants were therapy feeling too intense and triggering feelings of failure. Participants reported significant positive impacts of treatment on wellbeing, functioning and hope. Perceived mechanisms of change were reorienting to the positive, engaging with valued goals, taking a proactive life stance, gaining confidence and motivation for change, breaking down tasks into small steps, cultivating self-care and self-compassion, enhancing help seeking and interpersonal effectiveness, changing the relationship to depression, and rediscovering the self beyond depression.ConclusionsFindings suggest that the wellbeing focus of ADepT is acceptable and leads to positive impacts, supports the logic model underpinning the intervention, and warrants continuation to a definitive trial.Trial registration numberISRCTN85278228.

Results from GALILEO1, a first in human clinical trial of FLT201 AAV-gene therapy in adult patients with Gaucher disease type 1

Results from GALILEO1, a first in human clinical trial of FLT201 AAV-gene therapy in adult patients with Gaucher disease type 1

KIRROS: A phase II trial in progress of first-line atezolizumab (atezo) with or without bevacizumab (bev) in patients with unresectable hepatocellular carcinoma (HCC) and Child-Pugh B (CPB) cirrhosis.

TPS647 Background: HCC treatment is more complex for the sizable proportion of patients with CPB cirrhosis. These patients have poor survival due to both the cancer and underlying liver dysfunction. As such, they are typically excluded from pivotal clinical trials for first-line systemic therapy for unresectable HCC. The IMbrave150 trial established atezo + bev as a global standard of care for unresectable HCC, demonstrating a statistically significant improvement in overall survival (OS), progression-free survival (PFS) and confirmed objective response rate (ORR) of atezo + bev vs sorafenib (Finn N Engl J Med 2020; Cheng J Hepatol 2022). Real-world studies have consistently suggested benefit of atezo + bev in patients with HCC and CPB cirrhosis (e.g., Tanaka Hepatol Res 2022, D’Alessio Hepatol [Baltimore, Md] 2022). However, prospective clinical trial data are needed to comprehensively characterize safety and efficacy in this population. Single-agent immunotherapy is often used in patients with HCC and CPB cirrhosis given potential safety concerns of combination therapy. Safety data from real-world studies are limited by ascertainment and measurement biases. Therefore, a prospective study is warranted to address the unmet need for safety and efficacy data for first-line atezo ± bev in patients with CPB cirrhosis. Methods: KIRROS (NCT06096779) is a prospective, open-label, multicohort, multicenter phase II study in patients aged ≥18 years who have measurable and confirmed unresectable HCC, and CPB-7 or -8 cirrhosis who have not received prior systemic therapy. Eligible patients will be recruited into 2 cohorts for which endpoints will be non-comparatively assessed: Cohort A (n=60) patients will be treated with atezo 1200 mg intravenous (IV) + bev 15 mg/kg every 3 weeks (Q3W), and Cohort B (n=60) patients, those who do not meet Cohort A inclusion criteria (e.g., main portal vein tumor thrombus and proteinuria), will receive atezo 1200 mg IV Q3W only. Patients will receive treatment until unacceptable toxicity or loss of clinical benefit. The primary objective is to evaluate the safety of the treatment regimens as determined by incidence, nature and severity of adverse events and laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Secondary objectives are to estimate efficacy with ORR, duration of response, and PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and HCC modified RECIST, as well as OS. Quality-of-life secondary endpoints include patient-reported tolerability of the treatment regimens assessed by PRO-CTCAE and EORTC IL46, and health-related quality of life per EORTC QLQ-C30 and QLQ-HCC18 scores. As of September 2024, the KIRROS study is recruiting patients at 40 sites in the US and Puerto Rico. Clinical trial information: NCT06096779 .

Investigation of synergistic effects in trials of combination therapies with immune-checkpoint inhibitors in advanced gastric or gastroesophageal junction cancer.

405 Background: Combinations of immune checkpoint inhibitors (ICI) and chemotherapy (CT) have been approved for gastric cancer. However, there is a hypothesis that this combination may blunt antitumor immune responses because most chemotherapeutic agents also target lymphocytes. The primary objective was to investigate that the ICI and CT does not interfere each other’s therapeutic effects in advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) patients. Methods: The reconstructed individual patient data was electronically extracted from the Kaplan-Meier curve of phase III randomized controlled trials (RCTs). The observed PFS curve of each constituent monotherapies was used to estimate simulated PFS curves expected under a model of independent drug action. If the observed curve demonstrated significantly better PFS than simulated curve, the combination of ICI and CT may have a synergistic effect, implying a superior outcome compared to simply adding the component monotherapy. Results: The study included 2,538 unresectable advanced, recurrent, or metastatic GC or GEJC patients from three RCTs comparing pembrolizumab (KEYNOTE-061, KEYNOTE-062 and KEYNOTE-859). In patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater, the 1-year and median PFS of the observed and simulated curves were 28.0% vs. 27.9%, and 6.89 months vs. 6.88 months, respectively. One sample log-rank test showed no significant differences between the observed and simulated curves (p = 0.107). In the subgroups with PD-L1 CPS ≥10 or <1, the 1-year PFS of the observed and simulated curves was 34.7% vs 32.8%, and 28.5% vs 26.8%. Conclusions: The observed PFS of ICT involving pembrolizumab was comparable to the simulated PFS estimated from the data for each monotherapy regardless of the magnitude of PD-L1 CPS. Although it was not clear whether potential synergies existed for ICT, these findings at least suggest that the benefits of ICI and CT are not interfering each other, thereby providing theoretical support for the efficacy of ICT in patients with advanced GC or GEJC.

BMI as a predictor of progression from TB infection to active TB in PLHIV.

<sec><title>BACKGROUND</title>Low body mass index (BMI) is a globally important risk factor for TB progression. Little is known about this association in people living with HIV (PLHIV) and the functional form of the BMI-TB incidence curve.</sec><sec><title>METHODS</title>Secondary analysis of a randomised controlled trial of TB preventive therapy among PLHIV in South Africa, Mozambique, and Ethiopia. Participants received 3 months of weekly high-dose rifapentine-isoniazid given once or twice over a period of 2 years. Multivariable fractional polynomials (MFPs) were used to investigate functional forms of BMI. Time to incident TB was modelled using Cox's proportional hazard regression.</sec><sec><title>RESULTS</title>A total of 76 TB events were documented, giving an overall TB incidence rate of 1.2 per 100 person-years (95%CI 1.0-1.6). Baseline BMI <18.5 kg/m² was associated with a 2.6-fold increased hazard of TB compared with BMI 18.5-24.9 kg/m² (aHR 2.6, 95% CI 1.4-4.8, P < 0.001). BMI ≥30 kg/m² was associated with a lower hazard of TB (aHR 0.5, 95% CI 0.2-1.0). Continuous and categorical BMI showed weak evidence of quadratic dose-response relationships (P = 0.08 and P = 0.09, respectively). MFP analysis was consistent with a decline in TB incidence for increasing BMI to around 25 kg/m², followed by a less steep decline in TB incidence for increasing BMI >25 kg/m².</sec><sec><title>CONCLUSIONS</title>In PLHIV, BMI showed an inverse log-linear association with TB incidence. The MFP approach showed that the relationship is more complex than a simple log-linear association.</sec>.

Prognostic and predictive role of circulating tumor DNA (ctDNA) in stage III colon cancer treated with celecoxib: Findings from CALGB (Alliance)/SWOG 80702.

LBA14 Background: CALGB/SWOG 80702 previously showed that the addition of celecoxib to standard adjuvant chemotherapy with FOLFOX did not significantly improve disease-free survival (DFS) in patients with stage III colon cancer. Here, we evaluated the prognostic and predictive value of ctDNA in identifying a subpopulation of patients who may benefit from celecoxib. Methods: In the subset of patients with adequate biospecimens who participated in CALGB/SWOG 80702, a randomized phase III trial of 3 versus 6 months of adjuvant 5-FU, leucovorin, oxaliplatin (FOLFOX) +/- celecoxib, ctDNA assessment was performed using a clinically validated, tumor-informed 16-plex mPCR-NGS assay (Signatera(TM), Natera, Inc.) after surgery and before the start of adjuvant therapy (baseline). The Kaplan-Meier method was used to describe the distribution of survival time based on ctDNA positivity and log-rank testing was performed. Cox proportional hazards models were used to examine unadjusted associations between ctDNA positivity and disease-free (DFS) and overall survival (OS). Two-sided P values equal to or less than 0.05 were considered statistically significant, except for interaction P values (tested with a likelihood ratio). Results: In total, 1,011 of the 2,526 patients who participated in 80702 had ctDNA testing results from baseline; 189 were ctDNA positive (18.7%). ctDNA positivity associated with male sex, higher T stage, and N2 (versus N1) stage. ctDNA positivity was significantly associated with worse DFS (hazard ratio [HR] 6.52 [95% confident interval (CI) 5.09-8.34; p&lt;0.0001] and OS (HR 6.28 [95% CI 4.63-8.51; p&lt;0.0001]). Three-year DFS was 86.6% in ctDNA-negative cases and 36.8% in ctDNA-positive cases. Among patients who were ctDNA negative, celecoxib use was not significantly associated with worse DFS as compared to placebo (HR 0.75 [95% CI 0.54-1.05; p=0.095]) with a three-year DFS of 87.7% versus 85.5%, respectively. Among ctDNA-positive patients, celecoxib significantly improved DFS compared to placebo (HR 0.59 [95% CI 0.42-0.85; p=0.004]) with a three-year DFS of 44.1% versus 26.6% (P interaction = 0.25). Similar results were seen for overall survival with a hazard ratio of 0.86 (95% CI 0.56-1.33; p=0.49) for ctDNA negative cases and 0.63 (95% CI 0.41-0.96; p=0.028) for ctDNA-positive cases for celecoxib versus placebo (P interaction = 0.28). Conclusion: In a randomized phase III adjuvant therapy trial for stage III colon cancer, ctDNA was highly prognostic of DFS and OS. ctDNA positivity also appeared predictive of the benefit of adjuvant celecoxib for DFS and OS. These results suggest a potential role for ctDNA in determining which patients should consider celecoxib in addition to standard FOLFOX adjuvant therapy. Clinical trial information: NCT01150045 .

Validation of a Novel MRI Biomarker of Infarct Severity to Predict Functional Outcome After Endovascular Thrombectomy.

Background: Endovascular thrombectomy (EVT) dramatically improves clinical outcomes, but the final infarct volume (FIV) on MRI only accounts for a minority of the treatment effect. An imaging biomarker that more strongly correlates with post-EVT functional outcome would be helpful for clinical prognosis and serve as a surrogate outcome measure in trials of EVT-adjuvant therapies. Here, we aimed to validate a novel MRI-based metric, infarct density, which leverages post-EVT apparent diffusion coefficient (ADC) as a marker of infarct severity. Methods:A retrospective cohort was derived from a single-center prospective EVT registry. Consecutive anterior circulation EVT patients were included from 2018-2019 who achieved successful reperfusion (mTICI ≥2b). MRI was performed 12-48 hours post-EVT and processed via RAPID to quantify FIV using the ADC <620 threshold. Lesion volume was also collected using ADC <470 threshold, and infarct density was calculated as: (volume <470/volume <620)x100%. Good outcome was defined as ≤2 on the 90-day modified Rankin Scale. Multivariable logistic regression models quantified the association between clinical/imaging variables and outcome. ROC analysis quantified model classification performance. Results: Of 319 EVT patients, 272 met inclusion criteria. The mean age was 69 ±13 years, 41% were female, and 62% achieved a good outcome. After adjusting for clinical and radiographic factors, FIV (aOR 0.99 per 1mL; 95%CI: 0.98-1.00; p=0.03) and infarct density (aOR 0.95 per 1%; 95%CI: 0.94-0.97; p<0.001) were both independently inversely associated with good outcome. The final model incorporating both FIV and infarct density achieved excellent classification performance (AUC 0.87; 95%CI: 0.83-0.91). Removing infarct density from the model diminished its performance (AUC 0.83; 95%CI: 0.78-0.88; p=0.01). Conclusion: ADC-based infarct density after EVT is independently associated with long-term outcome and provides greater prognostic information than FIV alone. Post-EVT infarct density may be useful in clinical care and as a surrogate outcome measure in trials of EVT-adjuvant therapies.

Recent progress in xenotransplantation and its application to pediatric kidney disease.

Patients with kidney failure require dialysis or kidney transplantation. Kidney transplantation offers great benefits, including reduced mortality; however, many patients who wish to undergo kidney transplantation are unable to do so due to a shortage of donor organs. This shortage is a global issue, and xenotransplantation has emerged as a potential solution. The history of xenotransplantation is characterized by overcoming the immunological challenge of hyperacute rejection. Recently, breakthroughs such as gene-edited pigs and novel immunosuppressants have successfully lowered rejection rates. Recent clinical studies have reported transplants in patients diagnosed with brain death, and in March 2024, a gene-edited pig kidney was transplanted into a patient with kidney failure at Massachusetts General Hospital, marking the first instance of a gene-edited xenotransplantation into a living patient. Our research focuses on applying xenotransplantation in pediatric and obstetric fields, specifically exploring fetal therapy using pig fetal kidneys. We have long been researching the development of a novel kidney replacement therapy involving the transplantation of fetal pig kidneys. Fetal pig kidneys have the advantage of not requiring vascular anastomosis and are less likely to be rejected compared to adult pig kidneys. Currently, we are advancing nonhuman primate studies aimed at clinical trials of pig fetal kidney transplant therapy for fetuses diagnosed with Potter syndrome, characterized by bilateral kidney agenesis. We sincerely hope that xenotransplantation will soon become a viable treatment option for adult, pediatric, and fetal patients with kidney failure.

Using pupillometry to predict outcome in cognitive behavioral therapy for negative symptoms of schizophrenia.

Clinical trials of cognitive-behavioral therapy (CBT) for negative symptoms of schizophrenia have provided mixed results, perhaps because some patients are more likely to benefit than others. Patients likely to benefit may be those with greater pre-treatment motivation. To better examine the effects of motivation on treatment outcome, more objective measures of motivation are needed. Pupillary responses provide an objective biomarker of cognitive effort and motivation, with greater dilation associated with greater effort and motivation. The current study examined whether pre-treatment baseline pupil dilation predicted motivation and pleasure (MAP) negative symptom reduction in an open clinical trial of CBT for individuals with schizophrenia. Pupil dilation was recorded during the digit-span task at low (3 digits), moderate (6 digits) and high (9 digits) loads in participants with schizophrenia or schizoaffective disorder (N=31) with persistent negative symptoms prior to delivery of mobile-assisted CBT for negative symptoms (mCBTn). Greater pre-treatment pupil dilation during low, but not moderate or high, loads of the digit-span task significantly predicted greater reduction in MAP negative symptoms. However, while MAP negative symptoms improved throughout treatment, pupil dilation did not significantly change throughout treatment for any digit-span loads. Pupil dilation may provide a much-needed prognostic biomarker of patients most likely to benefit from CBT for MAP symptoms, but did not change with change in MAP symptoms.

P-106. Preliminary Results of the Comparing Oral versus Parenteral Antimicrobial Therapy (COPAT) Clinical Trial

Abstract Background Early intravenous (IV) to oral (PO) antibiotic transition for serious infections such as bacteremia, endocarditis, and bone/joint infections is noninferior to continued IV antibiotics. Our experience shows that Complex Outpatient Antimicrobial Therapy with PO antimicrobials (COpAT) is not only clinically effective but much safer. However, COpAT programs are not yet widely incorporated into clinical practice. Comparing Oral vs. Parenteral Antimicrobial Therapy (COPAT) Trial was designed to demonstrate improved safety with equivalent effectiveness of early IV to PO antibiotic transition across almost all infectious diseases. We hypothesized that, without compromising clinical outcomes, adverse events (readmissions, antibiotic toxicities, and line issues) will be significantly lower in patients discharged with PO antibiotics. Methods COPAT Trial is an ongoing open-label, pragmatic, randomized controlled trial at five Infectious Disease faculty staffed hospitals in one health system. A total 135 hospitalized patients otherwise being discharged with two or more weeks of IV antibiotics are randomized 2:1 to early PO (Experimental) vs. continued IV (Control) antibiotics. Two primary outcomes, assessed at 12 weeks, are efficacy equivalence and Experimental group safety superiority. From Aug 4, 2023 through Apr 30, 2024, 73 (Experimental 48, Control 25) active patients were enrolled and 64 (Experimental 42, Control 22) completed the trial. Results Demographics and infection type were similarly distributed between both groups with a predominance of bone/joint followed by endovascular infections (Table 1). While total antibiotic durations were comparable, Experimental group received disproportionately more PO antibiotics (87 vs. 37%, p&amp;lt; 0.05) (Figure 1). Both groups had a strong preference for PO antibiotics, and all patients felt their infection had been successfully treated (Table 2). Experimental group had a significantly lower total adverse event rate (2.8 vs. 7.2%, p&amp;lt; 0.05) (Table 3). All patients achieved clinical cure at 12 weeks. Conclusion Early IV to PO transition significantly improves antimicrobial treatment safety without compromising effectiveness across many serious infectious diseases. Patients report a strong preference for PO antibiotics. Disclosures All Authors: No reported disclosures

Efficacy and Safety of Four Weeks of Moderately Hypofractionated Chemoradiation for Unresectable, Stage 3 Non-Small Cell Lung Cancer: A Systematic Review.

Shortening treatment time with moderately hypofractionated radiotherapy benefits patients by reducing inconvenience and costs, but its use in the definitive treatment of unresectable Stage 3 non-small cell lung cancer is controversial due to lack of level one evidence and toxicity concerns. Pivotal systemic therapy trials utilize conventionally fractionated chemoradiation at 2Gy per fraction given over 6weeks. In practice, 4weeks of chemoradiation at 2.75Gy per fraction is sometimes employed to reduce the treatment burden for selected patients, especially those who are older or have comorbidities. It is uncertain if the two fractionation regimens are similar in biologically effectiveness, especially with varying systemic therapy. This systematic review aimed to collate the survival and toxicity outcomes for 4weeks of moderately hypofractionated chemoradiation, using >50-60Gy in 20 fractions. Eight studies met the eligibility criteria; seven studies were from a database search of MEDLINE, EMBASE, Cochrane Library, and Web of Science and one study was added later. Two studies were prospective randomized trials and six were retrospective cohort studies. No study included immunotherapy. The historical evidence has been limited, but emerging data is promising, especially when compared to outcomes of standard chemoradiation. Thus, further investigation of this strategy is justified.

Advances in Huntington’s Disease Biomarkers: A 10-Year Bibliometric Analysis and a Comprehensive Review

Neurodegenerative disorders (NDs) cause progressive neuronal loss and are a significant public health concern, with NDs projected to become the second leading global cause of death within two decades. Huntington’s disease (HD) is a rare, progressive ND caused by an autosomal-dominant mutation in the huntingtin (HTT) gene, leading to severe neuronal loss in the brain and resulting in debilitating motor, cognitive, and psychiatric symptoms. Given the complex pathology of HD, biomarkers are essential for performing early diagnosis, monitoring disease progression, and evaluating treatment efficacy. However, the identification of consistent HD biomarkers is challenging due to the prolonged premanifest HD stage, HD’s heterogeneous presentation, and its multiple underlying biological pathways. This study involves a 10-year bibliometric analysis of HD biomarker research, revealing key research trends and gaps. The study also features a comprehensive literature review of emerging HD biomarkers, concluding the need for better stratification of HD patients and well-designed longitudinal studies to validate HD biomarkers. Promising candidate wet HD biomarkers— including neurofilament light chain protein (NfL), microRNAs, the mutant HTT protein, and specific metabolic and inflammatory markers— are discussed, with emphasis on their potential utility in the premanifest HD stage. Additionally, biomarkers reflecting brain structural deficits and motor or behavioral impairments, such as neurophysiological (e.g., motor tapping, speech, EEG, and event-related potentials) and imaging (e.g., MRI, PET, and diffusion tensor imaging) biomarkers, are evaluated. The findings underscore that the discovery and validation of reliable HD biomarkers urgently require improved patient stratification and well-designed longitudinal studies. Reliable biomarkers, particularly in the premanifest HD stage, are crucial for optimizing HD clinical management strategies, enabling personalized treatment approaches, and advancing clinical trials of HD-modifying therapies.