Citations

Tryptophan hydroxylase (TPH) is a rate-limiting enzyme for serotonin or 5-hydroxytryptamine (5-HT) synthesis. Previously, adipocyte TPH1 has been linked to increased adipose 5-HT, reduced brown adipose tissue (BAT) thermogenesis, and obesity. However, the role of TPH2, a neural isoform highly expressed in obese adipose tissue, is unknown. Here, we report that adipose tissue expression of TPH2 is dramatically elevated in mice with diet-induced obesity (DIO) and ob/ob mice, as well as in obese humans. In mice fed a high-fat diet, adipocyte TPH2 deficiency improved DIO-induced metabolic complications, enhanced BAT thermogenesis, and increased intestinal energy-harvesting efficiency without affecting adiposity. Conversely, TPH2 overexpression in epididymal adipocytes of chow-fed mice raised adipose and plasma 5-HT levels, suppressed BAT thermogenesis, and exacerbated obesity and metabolic dysfunction. We found that obesity-induced hyperinsulinemia upregulated adipocyte TPH2 expression via activation of mechanistic target of rapamycin complex 1 and SREBP1. In humans, TPH2 mRNA levels in subcutaneous adipose tissue, but not those of TPH1 , are positively correlated with fasting plasma insulin concentrations. In summary, our study demonstrates that obesity-associated increases in adipocyte TPH2 can regulate distal tissue physiology and energy metabolism, suggesting that TPH2 could be a potential therapeutic target for obesity and its associated complications.

e23011 Background: Eligibility criteria for clinical trials are crucial for maintaining safety and study integrity. However, they often exclude patients due to medical conditions that are not relevant, leading to gaps in understanding the real-world effectiveness of treatments. Addressing potentially modifiable exclusions (PMEs) could enhance accessibility and participation in trials without compromising safety, particularly given the low rates of enrollment. Methods: We retrospectively analyzed ‘screen-failed’ patients (those who were excluded after providing consent because they did not meet the eligibility criteria or other protocol requirements) with biliary tract (BTC) or pancreatic cancer (PDAC) between August 2019 and November 2024. Screening logs and electronic health records provided clinical data. PMEs were identified and validated by two independent medical oncologists. Results: Of 585 screen-failed patients from 18 trials, 76 were excluded due to incomplete data. Among the 509 patients analyzed (367-PDAC, 142-BTC), the leading causes of screen failure were declined participation (99, 19%), comorbidities (59, 12%), suboptimal organ function (56, 11%), absence of biomarker (49, 10%), and insufficient biospecimens (36, 7%). Among patients declining participation, reasons included preference for standard care (23%), travel (22%), competing trials (5%), adverse event concerns (4%), financial issues (3%), and unknown reasons (43%). Of the 509 patients deemed ineligible for study entry at screening, we identified 69 patients (13.6%) with PMEs, primarily related to borderline laboratory abnormalities: liver function (16, 23%), kidney function (14, 20%), platelet count (8, 12%), hemoglobin (5, 7%), and white blood cell count (4, 6%). Other PMEs included previous or concurrent malignancies (6, 9%) and viral hepatitis (3, 4%). PMEs were evenly distributed across trials. Notably, all screen-failed patients proceeded to receive standard therapy. Conclusions: This analysis underscores the potential for rigid eligibility criteria to exclude stable patients who might benefit from investigational treatments. Easing specific criteria, particularly those related to laboratory abnormalities, could broaden trial accessibility. Furthermore, examining the reasons for declined participation and addressing PMEs could help develop strategies to enhance trial enrollment.

11506 Background: Catequentinib Hydrochloride (AL3818, Anlotinib, Catequentinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. There remains an unmet need for effective, well tolerated therapies for patients (pts) with advanced/ metastatic leiomyosarcoma (LMS). We performed a randomized, double blind trial of Catequentinib monotherapy versus placebo in advanced/metastatic LMS. Methods: Patients with a diagnosis of LMS requiring third or further line treatment were eligible. Catequentinib was administered in a 21-day cycle with 14 days on and 7 days off regimen. In this double blind phase 3 trial, patients were randomized 2:1 to Catequentinib or placebo, with the option of crossover to Catequentinib after confirmed Progression Disease (PD) on placebo. Progression-free survival (PFS) with Log Rank test was the primary endpoint and the trial was conducted at multiple sites in the US, UK and EU. Results: Total N = 111 patients were enrolled, and N = 110 were treated and evaluated, 74 randomized to Catequentinib (C), and 36 to placebo (P). In arms (C)/(P) median ages were 59.0/60.5 (range: 33-91) years respectively and 59/29 (79.7%/80.6%) were female. Median PFS by Blinded Independent Central Review (BICR) met the primary endpoint at 3.42 months (95% CI: 2.60, 6.83) for (C) and 1.41 months (95% CI: 1.35, 4.86) for (P) with a p-value of 0.0265 and a HR of 0.536 (95% CI: 0.307, 0.936). Median PFS for patients stratified at ≤ 3 prior lines was 4.86 months (95% CI: 2.04, 8.94) for (C) and 1.41 months (95% CI: 1.31, 4.86) for (P) with a p-value of 0.0046 and a HR of 0.386 (95% CI: 0.196, 0.760). The 6-month progression-free rate was 42.37% for (C) and 20.71% for (P). OS was 17.45 months (95% CI: 13.57, 19.32) for (C) and 16.33 months (95% CI: 11.27, NE) for crossover patients in the (P) arm. 30 (40.5%) of patients have experienced grade 3 treatment-related adverse events in the (C) arm compared to 3 (8.3%) of patients in the (P) arm. The most common TEAE for (C) vs (P) were diarrhea (50.0% vs 22.2%), stomatitis (31.1% vs 8.3%), fatigue (64.9% vs 41.7%), and hypertension (47.3% vs 19.4%). Conclusions: This phase 3 trial met the primary PFS endpoint and demonstrates superior PFS for Catequentinib vs placebo in metastatic/advanced LMS. This study confirms the acceptable benefit-risk profile of Catequentinib in LMS. Catequentinib is an effective and well tolerated treatment option for patients with LMS. Clinical trial information: NCT03016819 .

7075 Background: Hepatosplenic T-cell lymphoma (HSTCL) is a rare, aggressive peripheral T-cell lymphoma arising primarily from γδ T-cells. It carries a poor prognosis and resists conventional chemotherapy. Most reports on HSTCL are case-based. This study comprehensively analyzes a large cohort, evaluating treatment strategies and survival outcomes. Methods: This retrospective study included patients (pts) with pathologically confirmed HSTCL diagnosed between 2000-2024, consecutively seen at Mayo Clinic MN. Clinical, pathological, genomic, and treatment-related data were extracted when available. Descriptive statistics were used to summarize baseline characteristics. Time-to-event analyses, including Kaplan-Meier estimates, median overall survival (OS), and survival time estimates were conducted from the date of diagnosis. Results: A total of 20 patients with newly diagnosed HSTCL were included, with a median age of 57 years (range: 35-71). The cohort was predominantly male (70%) and non-Hispanic (93%). Molecular data was available for five patients, revealing abnormalities in STAT5B, MLL3 deletion, TP53, EZH2, TERT, and NF1 E291D . The median follow-up was 27.6 months (m) with a median OS of 17.6 m (95% CI: 11.2 - NA). First-line treatment was anthracycline-based in 68% of pts and non-anthracycline-based in 32%, with higher response rates in the latter group (50% vs.83%). Although non-anthracycline regimens showed a trend toward improved 3-year OS (100% vs. 29%) the difference was not statistically significant (p = 0.16). Achieving a complete response to first-line therapy was also associated with a trend towards a better 3-year OS compared to refractory disease (80% vs. 50%, p = 0.17). Most pts (79%) underwent hematopoietic stem cell transplant (HSCT), primarily allogeneic, with only one receiving autologous HSCT. First-line therapy before HSCT was evenly distributed between anthracycline (55%) and non-anthracycline (45%) regimens. HSCT recipients had significantly higher 3-year OS than non-recipients (83% vs. 33%, p = 0.017). Notably, the patient with a TP53 mutation has remained in remission for over a year post-allogeneic HSCT. Conclusions: HSTCL predominantly affects younger pts, with nearly half dying within a year. Allogeneic HSCT, rarely used in other NHL subtypes, improved survival. Non-anthracycline regimens and achieving CR trended toward better outcomes. Our study, leveraging a sizable cohort, highlights the need for targeted research and novel therapies to improve HSTCL management. Summary of survival outcomes in HSTCL. Characteristics Median OS (y) 3-Year OS (95% CI) 1.48 [0.93- NA] 46% [0.26 - 0.81] Transplant Transplant NA [NA - NA] 83% [0.58 - 1.00] No Transplant 1.02 [0.93 - NA] 33% [0.07 - 1.00] Treatment Anthracycline Based 1.02 [0.36 - NA] 29% [0.11 - 0.73] Non-Anthracycline Based 4.61 [NA- NA] 100% [1.00 - 1.00]

In the INTRIGUE phase III trial (ClinicalTrials.gov identifier: NCT03673501 ), adult patients with advanced gastrointestinal stromal tumor previously treated with imatinib were randomly assigned 1:1 to ripretinib 150 mg once daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off). In the primary analysis, overall survival (OS) was immature. In this study, we report the final planned analysis of OS (key secondary end point), progression-free survival (PFS) on third-line therapy (second PFS; prespecified exploratory end point), and long-term safety. Final OS analysis was prespecified to occur with approximately 200 and ≥145 events in the overall and KIT exon 11 intention-to-treat (ITT) populations, respectively. As of March 15, 2023, there were 211 and 151 OS events in the overall ITT and KIT exon 11 ITT populations, respectively. Median OS was similar between second-line ripretinib and sunitinib in both populations (overall, 35.5 v 31.5 months; KIT exon 11, 35.5 v 32.8 months). Median second PFS (on third-line therapy) for the overall ITT population was similar between the ripretinib and sunitinib arms (7.7 v 7.4 months). Safety was consistent with the primary analysis. OS from this analysis was similar between arms, and second PFS suggests that receiving ripretinib did not adversely affect the PFS of third-line therapy.

ABSTRACT Pneumonia may be caused by a diverse group of microorganisms; however, a microbiologic diagnosis is not universally made. Molecular tests such as the BIOFIRE FILMARRAY Pneumonia Panel (BF-PP) offer the possibility of rapid identification of potential pneumonia pathogens. This retrospective analysis was conducted as a sub-study of a recently published randomized controlled trial. Specimens from patients with suspected pneumonia were tested by the BF-PP, with results compared to cultures. The overall BF-PP positivity rate was 44.8% (252/563), and was higher [64.6% (164/254)] in specimens from patients ultimately diagnosed with pneumonia. Discrepancies between the BF-PP and cultures were most common for Streptococcus pneumoniae , Haemophilus influenzae , Moraxella catarrhalis, and Streptococcus agalactiae . Positive percent agreement (PPA) and negative percent agreement (NPA) between the BF-PP and culture were 91.4% (CI 86.3%–94.9%) and 83.6% (CI 79.5%–87.2%), respectively. For most bacteria, a correlation between high genomic abundance (genomic copies/mL) reported from the BF-PP and culture growth abundance was found. In specimens from patients ultimately diagnosed with pneumonia, clinical consistency—assessed based on whether BF-PP results aligned with associated culture results—was 79.9% and was highest for bronchoalveolar lavage fluid specimens. The BF-PP has reliable analytical performance and offers the potential advantage over conventional cultures of providing higher detection rates and more rapid results. Interestingly, despite the use of this advanced molecular diagnostic tool, one-third of pneumonia cases remained without a microbiologic etiology. IMPORTANCE This study evaluates the BIOFIRE FILMARRAY Pneumonia Panel by comparing its performance to conventional cultures in a real-world patient population (including patients ultimately diagnosed as not having pneumonia) using different types of specimens. Findings show a higher detection rate of microorganisms with the panel compared to cultures, suggesting that this test could aid in tailoring treatments for pneumonia. However, challenges remain and require further study, including distinguishing true pathogens from colonizing microorganisms and determinig why one-third of patients diagnosed with pneumonia still lacked a microbiologic etiology.

ABSTRACTBackgroundRenal medullary carcinoma (RMC) is an aggressive tumor associated with sickle cell trait. Despite treatment advances for other rare renal tumors, RMC survival remains poor. We aimed to describe the contemporary management and survival of children and adults with RMC.ProcedureIn this multicenter retrospective cohort study, Pediatric Surgical Oncology Research Collaborative sites searched their databases for patients diagnosed with RMC (2000–2022). Descriptive statistics were calculated and survival analyses performed using Kaplan–Meier and Cox regression.ResultsThirty‐four patients with RMC were identified. Median age was 19 years (IQR: 15–28; range: 7–52). Most were male (24/34; 71%), Black (27/32; 84%), had sickle cell trait or disease (30/33; 91%), presented with metastatic disease (27/34; 79%), and were symptomatic at presentation (32/34; 94%). Median overall survival (OS) was 24 months from diagnosis (16 months for children, 28 months for adults, p = 0.6). Receipt of platinum‐based chemotherapy (23/34; 68%) was associated with significantly higher OS than other regimens (35 vs. 5 months, p < 0.001). Nephrectomy (24/34; 71%) was associated with significantly improved OS compared with non‐operative management (34 vs. 7 months, p = 0.001). Immunotherapy, targeted therapy, or radiation therapy were not associated with significant differences in OS, nor were age, sex, race, sickle cell status, SMARCB1/INI‐1, stage, nephrectomy approach, retroperitoneal lymph node dissection, gross residual disease, margins, or tumor size.ConclusionsRMC survival remains poor despite newer therapies. Nephrectomy and platinum‐based chemotherapy should be considered in locally advanced and metastatic disease. Coordinated international cooperative group studies are needed to meaningfully improve RMC survival.

Abstract Introduction The SleepImage is an HSAT device (sHSAT) that uses photoplethysmography and oxygen saturation data to generate an apnea hypopnea index (AHI). This sHSAT has been FDA cleared as a software-as-a-medical-device for use in children 2 years and older for diagnosing obstructive sleep apnea (OSA). To our knowledge this sHSAT has not been tested on children concurrent with the gold standard polysomnography (PSG). Methods This study evaluated 50 children 2-6 years of age with tonsillar hypertrophy and OSA symptoms with sHSAT during simultaneous in-lab PSG. Aims were to determine the technical feasibility of using sHSAT in this population and to compare sHSAT results to PSG. The primary endpoint was AHI by sHSAT compared to AHI by PSG and presence of OSA. Sensitivity analysis was performed for presence or absence of OSA diagnosis based on sHSAT versus PSG. Bland-Altman and concordance correlation calculations were used for comparisons. Results 50 patients, median age 4 (IQR 3-5), met criteria; 39 completed PSG and HSAT. The sensitivity with sHSAT for OSA prevalence based on proprietary categorization was 94.1%, specificity 22.7%, LR+ 1.22, and LR- 0.26, with PSG OSA prevalence of 43.6%. There was a 9% sHSAT total failure rate, and the device frequently fell off, resulting in TST difference of -226.9 ±182.8 min between sHSAT and PSG. PSG was trimmed to include only segments where HSAT was confirmed to be on before comparisons. Concordance correlation coefficient between sAHI and AHI-PSG was 0.52. The Bland-Altman analysis comparing sAHI and PSG AHI revealed a mean difference of 0.73 (95% confidence limits: -3.47 to 4.93). Considering only obstructive events, the Bland-Altman the sAHI vs the AHI-PSG shows a mean difference of 1.52 (95%CI -5.40 to 8.44). Conclusion This pilot study demonstrated challenges with feasibility in using the sHSAT in this age group given likelihood of technical difficulties leading to absent or truncated data. When compared with PSG, sHSAT demonstrated a high false-positive rate for diagnosis of OSA, particularly concerning if guiding surgical management. This topic is of considerable importance to the practice of pediatric sleep medicine; further investigation of technological advances in this area is imperative. Support (if any)

Abstract Introduction Despite AASM scoring guidelines encouraging classifying hypopneas as central or obstructive, classification is underutilized in practice. However, without that effort patients may receive an incorrect primary diagnosis and suboptimal treatment. The remedē® System Pivotal Trial studied transvenous phrenic nerve stimulation (TPNS) to treat adult patients with moderate to severe central sleep apnea (CSA). Entry criteria required apnea hypopnea index (AHI)≥20 with the central apnea index (CAI) greater than the obstructive apnea index and obstructive apneas&lt; 20% of AHI but did not consider hypopnea differentiation. This analysis re-examined sleep studies from the trial to assess how hypopnea classification might lead to better patient selection for this therapy. Methods Hypopneas were classified as central versus obstructive by a sleep core laboratory following a modified version of AASM recommended criteria. The AHI composition was assessed at baseline and after 6 months of therapy. Results At baseline, 91% (138/151) of patients had ≥50% of events classified as central when accounting for hypopnea classification. If all hypopneas were assumed to be obstructive, only 63% (95/151) would have had ≥50% central events. Additionally, 95% (144/151) of patients had central AHI ≥15/hour, compared to 73% (110/151) with a central apnea index (CAI) ≥15/hour. The likelihood of achieving a ≥50% AHI reduction increased with the percentage of baseline events that were central: responder rates were 37.5% for patients with &lt; 50% central events at baseline, incrementally increasing to 76.5% for those with ≥90% central events. At 6 months, the residual AHI predominantly consisted of obstructive events. Central events decreased by 89% with treatment, from a baseline median of 32/hour [1st and 3rd quartiles: 22, 50]. Obstructive apneas rose by 2/hour and obstructive hypopneas increased by 2/hour from a baseline median of 5 obstructive events/hour [2, 12]. Conclusion Distinguishing central from obstructive hypopneas is required to accurately determine if a patient has central sleep apnea/Cheyne Stokes respiration, and is crucial for epidemiologic studies, appropriate therapy selection, and managing patient expectations about treatment outcomes. This analysis suggests that accurate hypopnea classification may prevent disqualification of patients who could benefit from TPNS therapy, which effectively treats central sleep apnea syndrome. Support (if any) ZOLL Respicardia, Inc.

Abstract Introduction Adherence with mask-based therapies remains a significant challenge for optimal treatment of patients with sleep disordered breathing. Transvenous phrenic nerve stimulation (TPNS) to treat central sleep apnea offers a novel, automated approach to enhance nightly adherence by initiating therapy based on patient-specific programmed conditions such as sleep schedule, activity, and body position. Therapy automatically pauses when the patient sits up or changes position, facilitating re-initiation of sleep. This research aimed to determine the degree of adherence achieved with TPNS’s automated activation approach. Methods Device data from 128 remedē® System Pivotal Trial participants were analyzed to calculate hours of therapy activation. Daily use from device data within the 14 days prior to scheduled visits were used to calculate median daily hours of therapy per patient, and subsequently the overall median daily use for all patients. Therapy duration was defined as the sum of time of delivered therapy when all conditions to activate therapy were met between the first time therapy came on to the last time off during the night, excluding time when activity or body position did not meet the programmed criteria for therapy activation. Results The median [Q1-Q3] nightly therapy duration at 6, 12, 18, and 24 months was 5.9 [4.9-6.6], 5.7 [5.0-6.8], 6.0 [5.3-6.8], and 5.9 [4.9-6.5] hours, respectively. Using a definition for adequate therapy as the percentage of patients with usage ≥4 hours/night for at least 70% of nights, 86%, 82%, 83%, and 90% of patients met the criteria at these visits. Only two patients (&lt; 2%) who had therapy activated discontinued treatment prior to 6 months due to stimulation intolerance. Patients with median delivered therapy ≥4 hours/night reported more quality of life improvement than patients with &lt; 4 hours of therapy. Conclusion The automatic activation of TPNS therapy resulted in a higher duration of nightly usage and higher rate of adequate delivered therapy than generally are reported for mask-based therapies. This high usage may yield a greater overall reduction in central sleep apnea burden over the whole night compared to therapies that require the patient to initiate the therapy. Support (if any) ZOLL Respicardia, Inc.