Large Real World Research Articles

Transcatheter Valve Repair for TricuspidRegurgitation: 1-Year Results from a Large European Real-World Registry.

Tricuspid valve transcatheter edge-to-edge repair has emerged as a valuable treatment option for patients with severe tricuspid regurgitation (TR). This study aims to investigate the safety and effectiveness of the PASCAL transcatheter valve repair system in treating severe TR in a real-world patient population. The PASTE (PASCAL for Tricuspid Regurgitation-a European registry) study is an investigator-initiated, multicenter, retrospective, and prospective observational cohort analysis conducted across 16 European heart valve centers including consecutive patients treated with the PASCAL transcatheter valve repair system from February 2019 to November 2023. Echocardiographic assessments were performed at baseline, discharge, and follow-up, and were subjected to centralized analysis. The study included 1,059 high-risk patients (mean age 79 ± 9 years; 53% female; TRI-SCORE risk 23% ± 18%; 87% NYHA functional class III/IV) with multiple comorbidities. Severe or higher graded TR was observed in 96% of patients. Intraprocedural success according to Tricuspid Valve Academic Research Consortium criteria was achieved in 85%, and TR reduced to ≤moderate in 87%. Independent predictors for a postprocedure residual TR of >moderate were coaptation gaps≥8mm (OR: 1.67; 95%CI: 1.03-2.72; P=0.038), tenting height≥10mm (OR: 2.18; CI: 1.30-3.65; P=0.003), the presence of a transvalvular lead (OR: 1.91; 95% CI: 1.19-3.05; P=0.007), right ventricular dilatation >42mm (OR: 3.35; 95% CI: 1.37-9.1; P=0.009) and massive/torrential TR at baseline (OR: 4.59; 95% CI:2.35-8.96; P< 0.001). At 1 year, 83% of patients showed ≤moderate TR. Significant clinical improvements included enhanced NYHA functional class (66% class I/II vs 17% at baseline; P< 0.001). Patients treated with the first-generation PASCAL system (n = 570) and with the new PASCAL Precision system (n = 489) had similar clinical profiles and TR severity at baseline. However, the Precision cohort showed greater TR reduction to trace/mild (63% vs 49%; P< 0.001), shorter procedure times (median 93minutes [Q1-Q3: 69-130 minutes] vs 120minutes [Q1-Q3: 82-165 minutes]; P< 0.001), and higher clinical success rates according to the Tricuspid Valve Academic Research Consortium at 30days and 1 year (87% vs 81% [P=0.021] and 56% vs 50% [P=0.044], respectively). Higher center experience (≥21 patients/year) resulted in higher intraprocedural and clinical success. The PASCAL system effectively treats severe TR in high-risk patients, offering sustained TR reduction and significant clinical improvements at 1-year follow-up. (PASCAL for Tricuspid Regurgitation-a European registry [PASTE]; NCT05328284).

Identification of prognostic genomic biomarkers in metastatic clear cell renal cell carcinoma (mccRCC): An analysis of the large retrospective real world clinico-genomic data from Flatiron Health (FH)-Foundation Medicine, Inc. (FMI) clinico-genomic database (CGDB).

Identification of prognostic genomic biomarkers in metastatic clear cell renal cell carcinoma (mccRCC): An analysis of the large retrospective real world clinico-genomic data from Flatiron Health (FH)-Foundation Medicine, Inc. (FMI) clinico-genomic database (CGDB).

Frequency of comedication of proton pump inhibitors with crystalline dasatinib in chronic myeloid leukemia and effects on TKI-bioavailability.

6561 Background: Tyrosine kinase inhibitors (TKI), including dasatinib, have profoundly improved clinical outcome in chronic myeloid leukemia (CML). However, solubility, bioavailability and systematic exposure of the crystalline formulation of dasatinib (Sprycel) is reduced at higher gastric pH levels. This is problematic for comedication with acid reducing agents as lower bioavailability may reduce clinical response. Methods: We investigated proton pump inhibitor (PPI) and TKI comedication, including dasatinib, in a large real world CML cohort. Furthermore, we assessed the influence of timing of PPI comedication on the absorption and bioavailability of dasatinib. Results: Using the Swedish CML- and Prescribed Drug-Registries, we identified 1,328 chronic phase CML patients, diagnosed 2002-2018. 1,261 (95%) had received specified/known TKI treatment and 685 of those (54%) were prescribed a PPI (ATC-code: “A02BC”) at some point after CML diagnosis. TKIs and PPIs prescribed within 12 months of CML diagnosis were prescribed by different HCPs in 66% of cases (284/432). Of the 388 patients treated with dasatinib, 91 (23.5%) received a concomitant PPI. The PPI prescription rate increased to 53% (204/388) in the dasatinib cohort after dasatinib treatment had ended. Further, we assessed the drug-drug interaction (DDI) in 18 healthy volunteers given crystalline dasatinib (100mg) alone or together with omeprazole (40mg, at steady state) administered 9 hours apart; a time point when a high effect on bioavailability is expected. Compared to dosing with crystalline dasatinib alone, Cmax and AUC0-24 were reduced by 96% and 88% by omeprazole comedication (Table). Conclusions: Despite warnings, comedication with PPI is common among dasatinib treated CML patients. Further, an even larger proportion of patients need PPI co-treatment, which however, cannot fully be administered due to its negative impact on dasatinib pharmacokinetics. Moreover, with an optimized study design, we observed a higher than previously reported negative interaction of PPI comedication on crystalline dasatinib bioavailability. This may compromise clinical efficacy and risk CML disease progression. For patients in need of PPI, selection of a non-crystalline, less pH-sensitive formulation of dasatinib therefore appears more appropriate. Clinical trial information: NCT06145217 . [Table: see text]

Retinal morphological differences in atypical Parkinsonism: A cross-sectional analysis of the AlzEye cohort

ObjectiveAtypical Parkinsonian syndrome (APS) describes a heterogeneous group of disorders mimicking the clinical presentation of Parkinson disease (PD) but with disparate natural history and pathophysiology. While retinal markers of PD are increasingly described, APS has been afforded less attention possibly owing to its lower prevalence. Here, we investigate retinal morphological differences in individuals with APS in a large real world cohort. MethodsWe conducted a cross-sectional analysis of the AlzEye study, a retrospective cohort where ophthalmic data of individuals attending Moorfields Eye Hospital between January 2008 and March 31st 2018 (inclusive) has been linked with systemic disease data through national hospital admissions. Retinal features were extracted from macula-centered color fundus photography (CFP) and optical coherence tomography (OCT) and compared between individuals with APS and those unaffected. Individuals with idiopathic PD were excluded. Retinal neural and vascular features were measured using automated segmentation and analyzed with multivariable-adjusted regression models. ResultsAmong a cohort of 91,170 patients, there were 51 patients with APS and 91,119 controls. Individuals with APS were older and more likely to have hypertension and diabetes mellitus. After adjusting for age, sex, hypertension and diabetes melitus, individuals with APS had a thinner ganglion cell-inner plexiform layer (-3.95 microns, 95% CI: −7.53, −0.37, p = 0.031) but no difference in other retinoneural or retinovascular indices. Optic nerve cup-to-disc ratio was similar between groups. ConclusionOur cross-sectional analysis of the AlzEye cohort reveals distinct retinal morphological characteristics in APS compared to healthy controls. The study notably identifies a thinner ganglion cell-inner plexiform layer in APS patients, without accompanying changes in the inner nuclear layer or significant alterations in retinovascular indices and optic nerve cup-disc ratio. These changes are distinct from those observed in PD, where thinning of the inner nuclear layer (INL) is a characteristic feature. SignificanceThese findings demonstrate a retinal phenotype in APS, markedly different from both healthy controls and idiopathic Parkinson's disease, highlighting the potential of retinal imaging in differentiating neurodegenerative disorders. By establishing a distinct retinal phenotype for APS, our findings underscore the potential of retinal imaging as a valuable, non-invasive diagnostic tool. This advancement is particularly significant for enhancing diagnostic accuracy, facilitating early detection, and offering a window into the underlying disease mechanisms in APS, thereby aiding in the development of targeted therapeutic interventions and personalized patient care strategies.

Effect of combination pioglitazone with sodium-glucose cotransporter-2 inhibitors or glucagon-like peptide-1 receptor agonists on outcomes in type 2 diabetes: A systematic review, meta-analysis, and real-world study from an international federated database.

To evaluate the efficacy and cardiovascular outcomes of combination pioglitazone with either a glucagon-like peptide-1 receptor agonist (GLP-1RA) or a sodium-glucose cotransporter-2 (SGLT2) inhibitor in individuals with type 2 diabetes (T2D) by conducting a systematic review, meta-analysis, and analysis of a large international real-world database. We searched MEDLINE, SCOPUS and Web of Science to identify relevant articles for inclusion (PROSPERO [CRD: 42023483126]). Nineteen studies assessing pioglitazone + SGLT2 inhibitors or GLP-1RAs versus controls were identified, 16 of which were randomized controlled trials. Risk of bias was assessed using Cochrane-endorsed tools and quality of evidence was assessed using GRADE. We additionally performed a retrospective cohort study of all individuals aged 18 years or over with T2D, using the TriNetX platform. We included propensity-score-matched individuals who were treated for at least 1 year with pioglitazone and a GLP-1RA or pioglitazone and an SGLT2 inhibitor, compared against GLP-1RA and SGLT2 inhibitor monotherapy. Outcomes were all-cause mortality, heart failure, chronic kidney disease and composite stroke and transient ischaemic attack. The average follow-up in the included studies ranged from 24 to 52 weeks. Combination of pioglitazone with a GLP-1RA reduced glycated haemoglobin (HbA1c) and weight greater than in controls: mean differences -1% (95% confidence interval [CI] -1.27, -0.74) and -1.19 kg (95% CI -1.80, -0.58), respectively. There was no statistically significant difference in systolic blood pressure (SBP) or mortality between groups: mean difference - 1.56 mmHg (95% CI -4.48, 1.35; p = 0.30) and relative risk (RR) 0.29 (95% CI 0.07-1.15; p = 0.08), respectively. Combination of pioglitazone with SGLT2 inhibitors reduced HbA1c, weight and SBP to a greater extent than control treatment: mean differences -0.48% (95% CI -0.67, -0.28), -2.3 kg (95% CI -2.72, -1.88) and -2.4 mmHg (95% CI -4.1, -0.7; p = 0.01), respectively. There was no statistically significant difference in mortality between groups (RR 1.81, 95% CI 0.30-10.97; p = 0.52). The included trials demonstrated a reduction in risk of heart failure with combination treatment. Similarly, from the real-world database (n = 25 230 identified), pioglitazone and SGLT2 inhibitor combination therapy was associated with reduced risk of heart failure compared to monotherapy alone (hazard ratio 0.50, 95% CI 0.38-0.65; p < 0.001). Both our systematic review/meta-analysis and the real-world dataset show that combination of pioglitazone with either GLP-1RAs or SGLT2 inhibitors is associated with increased weight loss and reduced risk of heart failure compared with monotherapy.

Abstract B003: Real-world (RW) characterization and frequency of TSC1 and/or TSC2 alterations collected from tumor tissue and liquid biopsies from the Tempus genomic database in patients with advanced cancer

Abstract Background Tumor suppressor genes tuberous sclerosis complex subunit 1 and 2 (TSC1, TSC2) are critical negative regulators of mTORC1 activity. Patients (pts) harboring inactivating alterations in TSC1 and/or TSC2 (TSC1/2) in the AMPECT PEComa trial (NCT02494570) and in a pan-tumor Expanded Access Program (NCT03817515) demonstrated response to the mTORC1 inhibitor, nab-sirolimus. PRECISION I (NCT05103358), a currently enrolling tumor-agnostic study, will assess the clinical benefit of nab-sirolimus in pts with cancer with inactivating TSC1/2 alterations. To appreciate the potential for TSC1/2 targeted therapy, here we characterize TSC1/2 alterations across a large RW pt population with advanced cancer using data from tissue and liquid biopsies (LBs). Methods De-identified RW data for 154965 cancer pts profiled with the Tempus xT tumor DNA sequencing assay were obtained from the Tempus database (accessed 28 Apr 2023). Records included next-generation sequencing (NGS) data from the Tempus xT tumor DNA and/or xF LB sequencing assays. Somatic TSC1/2 variants were categorized as pathogenic/likely pathogenic mutations, deletions (copy number loss), or variants of uncertain significance (VUS). Inactivating TSC1/2 mutations and copy number variants were further characterized including frequency across primary vs metastatic tumor samples. Results Of the xT patients, pathogenic/likely pathogenic inactivating TSC1/2 alterations were identified in 2621 (1.7%) pts; TSC1/2 VUS (primarily missense) were identified in 9918 (6.4%) pts. Inactivating TSC1/2 variants consisted of frameshifts (35.9%), stop gains (35.8%), multihits (18.4%), deletions (7.0%), and missense mutations (3.0%), and were most frequently identified in urothelial carcinoma (UC) and pancreatic neuroendocrine tumor (each 8.4%), renal clear cell carcinoma (6.3%), hepatocellular carcinoma (HCC; 5.9%), and endometrial carcinoma (3.9%). Pathogenic TSC1 variants were more common (TSC1 56.6%; TSC2 43.4%), as was their detection among primary (~20380) vs metastatic (~70790) tumors (TSC1 1.1% vs 0.91%; TSC2 0.82% vs 0.60%). Of the 53502 xF pts with LB sequencing, inactivating TSC1/2 mutations were identified in 489 (0.9%) pts; TSC2 variants were slightly more common than TSC1 (TSC2 58.5%; TSC1 41.5%). The most common tumor types harboring inactivating TSC1/2 variants in LBs were HCC (5.2%), UC (3.6%), and gastrointestinal stromal tumor (2.1%). Conclusion In a large (N=154965) NGS database of pts with cancer, inactivating TSC1/2 variants occurred in about 1.7% of pts overall and were frequently identified in commonly occurring cancers. The frequency of TSC1/2 alterations and tumor types were generally consistent between tumor tissue samples and LBs. Consistency between primary vs metastatic samples suggests TSC1/2 alterations may not be acquired, although samples were not longitudinal. Additional research is needed to understand the clinical implications of these observations, but these RW observations suggest TSC1/2 alterations in cancer may be a reasonable therapeutic target. Citation Format: David J. Kwiatkowski, Norma A. Palma, Willis H. Navarro, Gopa Iyer. Real-world (RW) characterization and frequency of TSC1 and/or TSC2 alterations collected from tumor tissue and liquid biopsies from the Tempus genomic database in patients with advanced cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B003.

Abstract C019: Inactivating TSC1 and TSC2 alterations, co-mutations, and genomic instability in advanced cancers: Analysis of a real-world (RW) patient (pt) population using the Foundation Medicine genomic database

Abstract Background Tumor suppressor genes tuberous sclerosis complex subunit 1 and 2 (TSC1, TSC2) are critical negative regulators of mTOR activity. In the exploratory biomarker analysis (AMPECT, NCT02494570) and an Expanded Access Program (NCT03817515), pts with inactivating alterations in TSC1 or TSC2 demonstrated responses with the mTOR inhibitor, nab-sirolimus. While these alterations are observed in most cancer histologies, characterization and distribution of TSC1 and TSC2 alterations across tumor types are not well understood. PRECISION I (NCT05103358), a currently enrolling tumor-agnostic study, will assess the clinical benefit of nab-sirolimus in pts with cancer who harbor inactivating TSC1 and TSC2 alterations. To appreciate the potential for TSC1 and TSC2 as therapeutic biomarkers, we analyzed TSC1 and TSC2 mutational data from a RW genomic database. Methods Next-generation sequencing (NGS) data from Foundation Medicine’s genomic database of pts primarily with advanced cancer were analyzed using the FoundationInsights™ web-based platform. Frequency and actionability of TSC1 and TSC2 alterations were assessed. Known or likely pathogenic inactivating TSC1 and TSC2 alterations (ie, indel, rearrangement, frameshift, biallelic loss, nonsense, and some missense mutations) were further characterized for co-mutations, tumor mutational burden (TMB), and microsatellite instability status. Results As of 29 Mar 2022, 438,974 pts with advanced cancer in the Foundation Medicine genomic database had tumor tissue NGS data available. Known/likely inactivating alterations in TSC1 and TSC2 were identified in 8464 (1.9%) pts; 4.3% had variants of unknown significance, primarily missense (~89%), that were not known to be inactivating. Of the inactivating alterations, 52.1% were TSC1 and 48.6% TSC2, including short variants, defined as base substitutions and short indels (85.0%), rearrangements (10.8%), and copy number deletions (17.9%). Alterations were most frequently identified in urinary bladder (8.6%), kidney and renal pelvis (5.8%), corpus and uterus (3.4%), soft tissue (including heart; 2.4%), and liver and intrahepatic bile duct (2.3%) cancers. The most frequently co-occurring mutations included TP53 (62.2%), CDKN2A (26.2%), and TERT (22.2%). TMB was low (&amp;lt;6 mutations per megabase) in 51.6% of pts with inactivating alterations in TSC1 and TSC2. Samples were mostly microsatellite stable (MSS; 82.2%) across tumor types. Conclusion In a large RW database of pts with advanced cancer, inactivating TSC1 and TSC2 variants occurred in 1.9% of pts. These occurred across common tumor types at rates as high as 8.6% (urinary bladder tumors). A majority of pts had low TMB and/or MSS status, suggesting that these are actionable alterations and not passenger events (Bennett et al, Mod Pathol 2022). Common co-mutations also have limited clinical actionability. These observations suggest cancers with TSC1 and TSC2 alterations may be candidates for targeted therapy; this hypothesis is being tested in the currently enrolling PRECISION I (NCT05103358) study. Citation Format: David J. Kwiatkowski, Norma A. Palma, Willis H. Navarro, Gopa Iyer. Inactivating TSC1 and TSC2 alterations, co-mutations, and genomic instability in advanced cancers: Analysis of a real-world (RW) patient (pt) population using the Foundation Medicine genomic database [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C019.

Is CAR T a Drug or a Therapeutic Pathway? Systematic Review, (Re-)Estimation of Efficacy Endpoints and Metanalyses in Large B-Cell Lymphoma Real World Reports

In everyday clinical practice, the therapeutic pathway of autologous CAR T-cell starts from leukapheresis, but the drug is infused on average 4-7 weeks later. Between leukapheresis and CAR T infusion patients may die following disease progression or exit the therapeutic pathway due to comorbidities or other reasons, thereby introducing a potential bias in the estimation of survival benefit gained with the drug. Moreover, substantial differences may occur (e.g., timing of leukapheresis and enrollment, use of bridging chemotherapy, lymphodepleting regimens) between trials' designs and every-day clinical practice. All of this precludes a robust comparison among the different available CAR T products and the therapies which share the same indication. Considering analyses limited to treated patients with endpoints estimated from date of infusion should be avoided to prevent misleading treatment choices. We conceived a project involving researchers and cooperative groups worldwide which already published real world effectiveness data on per-protocol (PP, i.e. from infusion) or on intention-to-treat (ITT, i.e. from leukapheresis taking into account also subjects who were scheduled for but finally did not receive CAR T) populations with the aim to re-estimate efficacy endpoints in both modalities. This would offer the clinicians the possibility to draw more meaningful interpretations of the data according to these two different approaches (ALMA IDEA 2022 CUP:J33C22001420001). First a systematic review was conducted searching for real world studies on the effectiveness of anti-CD19 CAR T-cell products administered to large B-cell lymphoma patients in third line and beyond between 2017 (after FDA approval) and October 2022. For each study, we asked researchers about both infused and not infused patients, for overall response rate (ORR), complete response rate (CRR), median follow up, median survivals (event-free [EFS], progression-free [PFS] and overall [OS]) duration of response (DoR). ITT EFS, the new endpoint added for our project, was defined as the time the patients remained in the CAR T pathway from leukapheresis to exit due to any cause. When applicable, meta-regressions, metanalyses and pooled analyses were also performed. The results overview with the 10 selected studies is reported in Table 1 (Bachy et al. Nat Med. 2022; Bastos-Oreiro et al. Front Immunol. 2022; Ghafouri et al. Clin Lymphoma Myeloma Leuk. 2021; Iacoboni et al. Cancer Med. 2021; Kittai et al. Transplant Cell Ther. 2021; Kwon et al. Haematologica. 2023; Mian et al. Leuk Lymphoma. 2021; Nastoupil et al. J Clin Oncol. 2020; Pinnix et al. Blood Adv. 2020; Casadei et al. Cancers (Basel). 2021). Rates of not infused patients ranged from 3% to 29%. Meta-regressions did not indicate a statistically significant influence of the different ratio of infused/not infused patients among studies, nor the different lengths of the median follow up seem to bias project results. Metanalyses for ITT ORR and CRR resulted in 57% and 38% respectively while the PP ORR and CRR were 68% and 45% respectively. Although centers kept track of all patients scheduled for CAR T, around 50% did not record the exit date (decision of not infuse, due to any cause) for not-infused subjects, reflecting the inability to calculate the ITT EFS. Three studies reported a median PP PFS shorter than the ITT PFS, which may indicate a high mean time from leukapheresis to infusion, worthy of further investigation. For all studies but one median PP OS was higher than ITT OS: OS may be over-estimated when using a PP analysis. We should be using an ITT analysis, as reporting data in which we do not include the patients who underwent leukapheresis and were never treated could introduce a significant bias in results interpretation. Hematologists should understand which is the most clinical meaningful endpoint for this new therapeutic approach to reach effective results: have we to consider CAR T-cell therapy as a drug or a therapeutic pathway? The importance of considering this new treatment option as a pathway should translate into implementation of CAR T patient registries that include ITT as an endpoint to establish population-level effectiveness of these drugs. In addition, considering both PP and ITT analyses as well as infused and not infused patients provides a complete overview and leads to more information.

TCT-447 Contemporary Practice Patterns and Outcomes for Patients With Mitral Regurgitation: Results From a Large Multicenter Real-World Database

TCT-447 Contemporary Practice Patterns and Outcomes for Patients With Mitral Regurgitation: Results From a Large Multicenter Real-World Database

P-679 Controlled ovarian stimulation using follitropin delta results in higher cumulative live birth rate compared to follitropin alfa/beta in a large prospective real world dataset

Abstract Study question Does IVF/ICSI-treatment using follitropin delta (hrFSH) result in higher pregnancy rates (PR) or live birth rates (LBR) compared to follitropin alfa/beta (recFSH)? Summary answer Real world data (RWD) from a large prospective German registry study shows that using hrFSH results in higher pregnancy rates compared to recFSH. What is known already Follitropin delta represents a new recombinant FSH derived from a human cell line. Contrary to follitropin alfa or beta, follitropin delta has a glycolysation pattern consisting of α2,3- and α2,6-linked sialic acids which is more similar to native human FSH. Follitropin delta is approved for use with an individualized dosing algorithm based on serum AMH and body weight, targeting an optimal ovarian response (8-14 oocytes). Efficacy and safety have been demonstrated in numerous clinical trials. Moreover, Follitropin delta seems to reduce the risk of OHSS although its safety with respect to ovarian hyperstimulation using RWD remains to be investigated. Study design, size, duration The German IVF Registry collects prospectively data about IVF/ICSI-treatments from 140 German IVF centers. The underlying analysis of RWD includes controlled ovarian hyperstimulation cycles that have been performed in Germany between 2017-2021. Study groups were built subject to the gonadotropin used for stimulation, irrespective of previous treatments: (1) hrFSH, n = 3002, (2) recFSH, n = 135293. “Pregnancy” was defined as clinically assessed, intrauterine pregnancy, including miscarriages. Biochemical pregnancies were not defined as “pregnant”. Ectopic pregnancies (n = 558) were excluded. Participants/materials, setting, methods PR and LBR were calculated subject to the number of embryo transfers (ET) (n = 2062 (rFSH) vs. n = 103357 (recFSH)) after excluding freeze-all cycles, (n = 529 (hrFSH) vs. n = 13682 (recFSH)) and cycles that ended without ET (n = 411 (hrFSH) vs. n = 18254 (recFSH)). The collected data were saved in compliance with the applicable data processing regulations. Statistical analysis was performed using Fishers-exact- and students-t-test and Microsoft Excel, whereas p &amp;lt; 0.05 was defined as significant. Main results and the role of chance There was no difference between the study groups regarding age (33.9 ± 4.00y (hrFSH) vs. 33.8y±4.34y (recFSH), p = 0.12) or infertility diagnosis. Stimulation with hrFSH resulted in a higher number of oocytes (11.15±7.2 vs. 10.39±7.01, p &amp;lt; 0.01). Antagonist protocol was used less often in the hrFSH-group (78% (2344/3002 vs. 80% (109217/135293), p &amp;lt; 0.01). PR in 2021 were higher (39.2% (222 pregnancies / 567 embryo transfers) vs. 35.2% (6837/19420), OR = 1.18 [0.99-1.41] p = 0.05) while using hrFSH compared to recFSH. The effect was even stronger when comparing patients aged 30-34y (46.2% (98/212) vs. 38.6% (2967/7865), OR = 1.41 [1.07-1.88], p = 0.01). Another quantitative difference could be observed for patients aged 30-34y in their first IVF/ICSI-cycle (PR 48.5% (63/130) vs. 39.5% (1926/4873), OR = 1.44 [1.00-2.07], p = 0.05). Including all cycles between 2017-2021 resulted in higher PR for couples treated with hrFSH (38.3% (790/2062) vs. 36.2% (37439/103357), OR = 1.09 [1.00-1.20], p = 0.049). Cumulative PR including consecutive frozen embryo transfers after the first stimulation showed significantly higher PR while using hrFSH (81.6% (422/517) vs. 71.3% (17373/24367), OR = 1.79 [1.42-2.23], p &amp;lt; 0.01). Finally, cumulative LBR per ET was significantly increased if hrFSH was used for ovarian stimulation (60.0% (310/517) vs. 51.9% (12648/24367), OR = 1.39 [1.16-1.66], p &amp;lt; 0.01) compared to recFSH. Limitations, reasons for caution Since we analyzed RWD, comparison with large clinical trials should be considered carefully. PR and LBR was calculated only using stimulations which successfully generated ET. Moreover, individual AMH values are not transmitted to the German IVF Registry. Therefore, difference in ovarian reserve between study groups can’t be excluded. Wider implications of the findings In this large, prospective RWD, higher cumulative LBR and PR using hrFSH compared to recFSH, irrespective of age or infertility diagnosis, supports the use of individualized fertility treatment approach based on hrFSH. These results are consistent with previous retrospective findings. Trial registration number Not applicable

Repeat operations in patients with anal fistula, a retrospective study across England and Wales.

This article reports the frequency of repeat operations including waiting times within the National Health Service (NHS) of England and Wales. Retrospective study on repeat operations for anal fistula (AF) performed between 1st January 2010 and 31st December 2016. Data were extracted from the national registry of data entered into Hospital Episode Statistics (HES). Patient factors (age, sex, self-declared ethnicity) and geographical location were tested for association with repeat operations and time to the second operation. We analysed 36,223 patients that had an operation for AF within 148 NHS trusts. The median follow-up time was 28months. The majority of patients (67.4%) had only one operation. Eighty-five per cent of them remained under the care of a single consultant. Six per cent of the repeat surgeries occurred in at least three different treatment sites. Young age and female sex were associated with higher rates of repeat operations. Non-declared and Black or Black British ethnicity were associated with fewer operations. The median waiting time between the first and second operations was 27.4weeks (IQR: 14.7-55.3); between the second and third 28.0weeks (IQR: 14.7-57.0); between the third and fourth 29.0weeks. This large real world population-based study shows that the majority of patients with AF undergo only one operation. Patients requiring multiple procedures tend to stay under the care of a small number of consultants but waiting times between operations are long. There is a geographical variation in the number of operations and the time between them.

Effect of SNPs in TMPRSS2 to severe COVID-19 in patients with prostate cancer.

e17043 Background: The cellular transmembrane protease serine 2 (TMPRSS2) cleaves the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to let viral cell entry. Patients (pts) with prostate carcinoma (PCa) are expected to be at higher risk for coronavirus disease 2019 (COVID-19). However, TMPRSS2 transcription is significantly down-regulated by luteinizing hormone releasing hormone agonists (LHRH-a) and enzalutamide used to treat different PCa stages and this could alter the ability of SARS-CoV-2 to enter target cells. This study aims to evaluate if Single Nucleotide Polymorphisms (SNPs) in the TMPRSS2 gene are associated to a different risk for developing severe COVID-19. Methods: This is the translational part of a large retrospective-prospective real world study designed to estimate whether anti-androgen therapy for PCa is associated to a lower severity of COVID-19. Blood samples were collected from volunteer pts affected with PCa treated at our Institution who developed COVID-19. To be included, pts should receive at least LHRH-a for locally advanced o metastatic hormone sensitive or resistant disease. Genomic DNA of PCa pts was genotyped with the Axiom Human Genotyping SARS-CoV-2 array. Raw genotyping data were analyzed using the Axiom Analysis Suite and genotypes of 219 TMPRSS2 variants were extracted. Identified SNPs were used to compare reference and alternative allele counts between PCa pts and a control cohort of healthy European subjects (n = 2848; DOI:10.1056/NEJMoa2020283) collected in the Milan area (Italy) with chi squared test. Uni- and multivariate logistic regressions were performed to investigate associations between such identified SNPs and severe COVID-19, defined as any between the need for hospitalization or access to an intensive care unit or oxygen therapy. Results: 45 pts were enrolled from November 2020 to May 2022. Median age at COVID-19 detection was 77 years (range 51-94). 10/45 (22%) pts had severe COVID-19, but none died. At COVID-19 diagnosis, 4/45 pts (9%) were receiving chemotherapy for PCa, 13/45 (29%) new generation hormonal agents, 24/45 (53%) LHRH-a, the remaining 4/45 (9%) other therapies. Compared to the control cohort, we identified 52 TMPRSS2 variants associated with the susceptibility to SARS-CoV-2 infection in the cohort of PCa pts (P-value &lt; 0.05). Among them, 3 SNPs were associated with severity in univariable logistic regression models: 2 resulted to be protective (rs9974589, p 0.01, OR 0.26; rs28442123, p 0.04, OR 0.30), and one was associated with increased risk of severe COVID-19 (rs2070788, p 0.01, OR 3.8). A multivariate logistic model (p = 0.0004, AUC = 0.88) was performed considering rs11908828 (p = 0,0109, OR = 32.25), rs28442123 (p = 0.03, OR = 0.11) and rs2070788 (p = 0.02, OR = 6.33). Conclusions: These preliminary findings point to a possible role of TMPRSS2 SNPs in modulating the severity of COVID-19 in PCa pts. Validation in wider series is needed.

Real-world evidence to inform clinical insights on tissue-agnostic approvals of therapies.

6589 Background: Many tissue-agnostic (TA) approvals were based on clinical trials with limited patient numbers without covering all tissue types (TT), raising the question of whether these indications were truly tissue agnostic. Real world evidence (RWE) offers an opportunity to investigate TTs not included in clinical trials/studies to answer this question. Herein we investigate the seven TA approvals to date in a large real world database and report clinical outcomes. Methods: A total of 186,581 tumors from over 35 TTs tested with comprehensive molecular profiling including NextGen sequencing of DNA and RNA were investigated for TA alterations (TMB-High (≥10 mutations/MB), MSI-H/MMRd, BRAF V600E mutations and NTRK1/2/3/RET fusions) at Caris Life Sciences (Phoenix, AZ). Time-on-treatment (TOT) from RWE was obtained from insurance claims and calculated from treatment start to finish. Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Significance was determined as p values of &lt;0.05. Results: Among all tumors, 21.2% carried at least one TA alteration, 17.2%, 3.4% and 0.6% had 1, 2 or 3 alterations, respectively. TMB-H in 18.7%, MSI-H/dMMR was seen in 3.9%, BRAF V600E in 2.8% of tumors, NTRK1/2/3 and RET fusion seen in 0.16% and 0.23%. TA alterations were most prevalent in BCC (86%) &amp; SCC (82%) of skin, MEL (71%), THCA (51%) and NSCLC (44%) and least in liposarcoma (0), meningioma (0.7%) and GIST (1.4%). Among tumors treated based on TA indications, substantial variability of TOT among TTs was observed (see table). Looking at TTs included (INC) and not included (nINC) in KEYNOTE-158 and other studies for TMB-H and pembro, median TOT for nINC was similar to INC (N=242 vs 2322, 6.1 m vs 6.3 m, p = 0.55). Nevertheless, statistically significant differences in median TOTs were seen across nINC when comparing TMB-H vs. TMB-L (6.1m vs. 2.9m, HR: 0.58 [95% CI: 0.50-0.67], p&lt;0.001) and in a subset of 838 MSS tumors (4.9m vs. 2.8m, p&lt;0.001). Conclusions: RWE data adds substantially to our understanding of the demographics of TA indications and suggests that some TA treatment benefits may be tissue-specific. Recent TA indications will require further accumulation of cases to draw meaningful conclusions regarding whether TA indications are, in fact, tissue agnostic. [Table: see text]

Abstract P5-02-02: Genomic Landscape of ER+/HER2- metastatic breast cancer as a function of prior treatment with a CDK4/6 inhibitor

Abstract Background CDK4/6 inhibitors (CDK4/6i), like palbociclib, ribociclib, and abemaciclib, along with antiestrogens, have revolutionized treatment for ER+/HER2- metastatic breast cancer (MBC). Although most patients initially respond, almost all eventually progress, and ER+ HER2- MBC remains incurable. There is an urgent need to understand the molecular processes that drive resistance in order to improve survival. The landscape of acquired somatic alterations causal to CDK4/6i resistance remains unknown. Here we report differences in mutational landscapes between ER+ HER2- MBC patients treated with and without CDK4/6i. Methods Deidentified data from 780 and 1073 ER+ HER2- MBC patients (solid tumor or ctDNA liquid biopsy sequencing respectively) with at least 6 months between diagnosis of Stage 4 disease and biopsy were analyzed. Patients were divided into either treated or untreated with CDK4/6i prior to biopsy. Sequencing was performed using the Tempus xT tumor assay (DNA sequencing of 595-648 genes at 500x coverage) and Tempus xF liquid biopsy (ctDNA sequencing of 105-523 genes). Gene alterations (consisting of pathogenic/likely pathogenic short variants and copy number alterations) were compared between groups by Chi-squared/Fisher’s Exact tests and p-values adjusted for false-discovery. Results We first analyzed sequencing data of both solid tumor and liquid ctDNA from ER+/HER2- MBC patients. ESR1 mutations were significantly more frequent in those that received CDK4/6i than those that did not (Solid tumor 33% vs 16%, p &amp;lt; 0.001, q = 0.001; Liquid biopsy 32% vs 16%, p &amp;lt; 0.001 and q &amp;lt; 0.001). We also saw more frequent mutations/amplifications in the following genes in the CDK4/6i treated cohort vs. those that were not. These results trended towards significance in our solid tumor, but not in our liquid biopsy cohort: CCND1 (18% vs 11% p = 0.028 q =0 .3); FGF3 (17% vs 9.5% p = 0.010 q = 0.2); FGF4 (17% vs 11% p = 0.035 q = 0.3), GATA3 (17% vs 8.9% p = 0.008 q = 0.2), PTEN (12% vs 6.1% p = 0.030 q = 0.3) and FGF19 (8.2% vs 1.7% p = 0.002 q = 0.12). Interestingly, 96-98% of CCND1, FGF3, FGF4 and FGF19 alterations were copy number amplifications. Conversely, we saw a trend towards significance for more mutations in TP53 (37% vs 27% p=0.008 and q=0.2) in those that had not received a CDK4/6i than those that did. Conclusions Here we present the landscape of somatic alterations in ER+/HER2- MBC patients with and without prior CDK4/6i therapy from our large real world de-identified data set. Patients with prior CDK4/6i therapy harbored significantly more ESR1 somatic alterations, demonstrated in both solid tissue and liquid biopsies. In solid tissue biopsies, patients with prior CDK4/6i therapy harbored more CCND1, FGF3, FGF4, and GATA3 alterations and less TP53 alterations. These trends were not significant after adjustment for multiple testing. CCND1, FGF3, FGF4 and FGF19 alterations were copy number amplifications, which may be consistent with 11q13 amplification. Further studies will provide insights into how these trends translate towards our understanding of CDK4/6i related resistance mechanisms. Citation Format: M Rosario Chica-Parrado, Chang-Ching Lin, Timothy Mahoney, Elizabeth Mauer, Ariella Hanker, Carlos Arteaga. Genomic Landscape of ER+/HER2- metastatic breast cancer as a function of prior treatment with a CDK4/6 inhibitor. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-02.

Homologous recombination repair (HRR) mutation concordance between liquid biopsy (LB) and tumor tissue by NGS in a real-world prostate cancer (PC) database.

260 Background: NGS to identify HRR mutations (mut) is indicated in advanced prostate cancer (aPC); samples for testing may be tissue or plasma. In a large real-world (RW) database, we determined concordance between plasma ctDNA and primary tumor tissue (PT) and/or metastatic tissue (MT) for BRCA1, BRCA2, and ATM mut in PC patients (pts) who received both LB and tissue NGS any time during standard of care (SOC) management. The study objective was to assess the utility of LB to detect actionable mut in these HRR genes and demonstrate the utility of combined LB and tissue testing. Methods: We examined de-identified data from pts who had NGS using both Tempus xF (105 genes-LB) and Tempus xT (648 genes-tissue) during SOC for aPC. Analyses included 1) PT and LB and 2) MT and LB. The results from the pts’ earliest PT or MT and earliest LB were used for paired analyses. The prevalence of a pathogenic/likely pathogenic germline and/or somatic mut in BRCA1, BRCA2, or ATM was reported as N (%), 95% CI. The sensitivity of the LB to identify observed HRR mut in tissue was also reported as N (%), 95% CI. Concordance between pairs was evaluated by Cohen’s kappa statistic with 95% CI. Results: HRR results are show for 1074 PC pts who had NGS performed on PT and LB and 451 PC pts with NGS on both MT and LB. In the PT and LB analysis, HRR mut were found in 6.2% (95% CI: 4.9%-7.9%) of LB and 8.8% (95% CI: 7.2%-11%) of PT. The sensitivity of LB to detect HRR mut in the PT was 53% (95% CI: 43%-64%). Cohen’s kappa statistic was 0.59, 95% CI=0.50-0.68, between PT and LB. In the MT and LB analysis, HRR mut were found in 10% (95% CI 7.8%-14%) of LB and 10% (7.6%-13%) of MT. The sensitivity of LB to detect HRR mut in the MT was 70% (95% CI: 54%-82%). Cohen’s kappa statistic was 0.65, 95% CI=0.54-0.77, between MT and LB. Conclusions: In this large RW dataset, plasma ctDNA-based analysis of BRCA1, BRCA2, and ATM mut showed greater concordance between LB and MT than LB and PT, and may be used as an initial tool for HRR mut detection. When LB results are negative, further exploration with tissue-based testing may identify HRR mut to guide clinical decisions. [Table: see text]

Real-world (RW) prevalence of adverse events (AEs) among patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC).

109 Background: Treatment options for mCSPC patients include adding novel hormonal therapy (NHT) with/without docetaxel (DOC) to androgen deprivation therapy (ADT). Uptake of these agents has been slow, and safety concerns may contribute to therapeutic inertia. This study aims to understand the RW occurrence of prespecified AEs among pts with mCSPC in the US. Methods: Claims from the PharMetrics Plus database (IQVIA, Durham, NC) were used to retrospectively estimate the proportion of pts with AEs among those with mCSPC from Jan 2014 through Jun 2021. Common AEs (≥10%) specified in FDA labels of treatments of interest or clinical trials ≥2% more prevalent than ADT alone were included in the study. Results of four clinically important AEs (fatigue, hot flash, sexual function and gastrointestinal [GI] AEs) are reported here. The proportions of pts with each of these AEs at specific timepoints plus 95% confidence intervals (CI) were estimated from cumulative hazard plots. Results were adjusted using inverse probability of treatment weighting across ADT alone, ADT+ nonsteroidal antiandrogen (NSAA), ADT+DOC and ADT+NHT. Results: The mean age of the overall study population (N=4145) was 66 years. At baseline, common sites of metastasis were bone only (n=1886, 45.5%) and node only (n=1237, 29.8%); the most common medications used were for pain (n=2182, 52.6%) and corticosteroids (n=1213, 29.3%). The reference group for all comparisons of AEs was ADT alone. For the entire study period, GI AEs and fatigue were significantly higher only in the ADT+DOC group ( P&lt;0.001). Hot flash was higher in ADT+NHT ( P=0.05) and the ADT+DOC groups ( P&lt;0.001). No statistically significant differences in sexual function AEs in the groups was noted. The table shows the proportions of pts with specified AEs. Conclusions: In this large RW study, all groups, including ADT alone, showed an increase in AE reporting over time. Most AE rates with ADT+NHT were comparable to ADT alone and ADT+NSAA, while ADT+DOC showed an increase in GI AEs, fatigue and hot flash. [Table: see text]

Anticoagulation after pulmonary vein isolation for atrial fibrillation: Associations with CHA₂DS₂-VASc score, sex, and rhythm.

Guidelines recommend using the CHA₂DS₂-VASc score to determine anticoagulation decisions in atrial fibrillation (AF) patients, including those who undergo pulmonary vein isolation (PVI), however this may not consistently occur in the real-world setting because of other clinical factors. We sought to evaluate the anticoagulation prescription rates patterns in AF patients 1 year PVI at our institution.Consecutive AF patients undergoing PVI in our prospective registry during 2014-2018 who were alive at 1-year post-PVI were studied. Anticoagulation prescription rates at this time-point were adjudicated, and correlated to CHA₂DS₂-VASc score, sex, and heart rhythm status at 1 year.Amongst 4596 patients undergoing PVI, mean age was 64.2 ± 10.0 years, 1328 (28.9%) were female, and based on CHA₂DS₂-VASc score anticoagulation was not indicated, can be considered and indicated in 872 (19.0%), 1183 (25.7%), and 2541 (55.3%) patients, respectively. At 1-year after PVI, 3504 (76.2%) patients were on anticoagulation, and 792 (17.2%) had recurrence of AF. Anticoagulation was continued in over half of AF patients without classic CHA₂DS₂-VASc indication particularly in those with AF recurrence and women, while they were mildly under-prescribed in those with indication, especially for those without AF recurrence and men.In a large real world cohort of patients after PVI, anticoagulation prescription is not solely depending on the CHA₂DS₂-VASc score and sex, but also heart rhythm status and other clinical or imaging factors.

The Association Between Body Mass Index and Death Following Elective Endovascular and Open Repair of Abdominal Aortic Aneurysms in the Vascular Quality Initiative

The effect of body mass index (BMI) on post-operative outcomes after abdominal aortic aneurysm (AAA) repair remains poorly defined. The association between BMI and death following elective endovascular aneurysm repair (EVAR) and open aneurysm repair (OAR) of AAA in a large national quality registry is investigated. All elective AAA repairs within the Society for Vascular Surgery Vascular Quality Initiative (VQI; 2010 to September 2021) were reviewed (EVAR, n= 53 426; OAR, n= 9 479). All analyses were conducted separately for EVAR and OAR patients. The primary end points were 30 day mortality and five year survival rates. Study cohorts were divided into World Health Organisation BMI categories (C1 < 18.5, C2 18.5 ≤ BMI < 25, C3 25 ≤ BMI < 30, C4, 30 ≤ BMI < 35, C5 35 ≤ BMI < 40, C6 ≥ 40). BMI was examined as both a categorical and continuous variable. Logistic and Cox proportional hazards regression were used for risk adjustment. Among EVAR patients, BMI distribution was C1, 1 216 (2%); C2, 14 687 (28%); C3, 20 516 (38%); C4, 11 352 (21%); C5, 3 947 (7%); C6, 1 708 (3%). Class 1, 2, and 6 BMI patients experienced an increased 30 day mortality rate (C1 2.6%; C2 1.3%; C6 1.4% vs. C3 - 5 0.7%; p < .001) and C1 and C2 had correspondingly inferior long term survival (five years: C1 69 ± 3%; C2 79 ± 1% vs. C3 - 6 86 - 88 ± 2%; log rank p < .001). These survival disparities persisted after risk adjustment for multiple confounders. In the OAR cohort, BMI distribution was C1, 280 (3%); C2, 2 862 (30%); C3, 3 587 (38%); C4, 1 940 (21%); C5, 581 (6%); C6, 229 (2%). Crude 30 day mortality rates were increased for both the lowest and highest BMI patients (C1 12%, C6 7% vs. C2 - 5 3 - 4%; p < .001); these differences also persisted in long term survival (five years: C1 71 ± 6%, C6 82 ± 6% vs. C2 - 6 85 - 88 ± 3%; log rank p < .001). In risk adjusted analysis, both low and high BMI OAR patients had an increased 30 day and long term mortality rate. Within the VQI, both the extreme low (< 18.5) and high (≥ 40) BMI groups experienced an increased 30 day mortality rate after both elective EVAR and OAR. By comparison, while the lowest BMI cohort was significantly associated with decreased long term survival after both procedures, the highest BMI group only experienced reduced long term survival after OAR. Based upon this large real world registry analysis of elective AAA repairs, differential metabolic signatures exist within extreme BMI categories, which may inform peri-operative risk stratification and clinical decision making.

CABOSEQ: The Effectiveness of Cabozantinib in Patients With Treatment Refractory Advanced Renal Cell Carcinoma: Results From the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

There are limited data evaluating the activity of cabozantinib (CABO) as second line (2L) therapy post standard of care ipilimumab-nivolumab (IPI-NIVO) or immuno-oncology(IO)/vascular endothelial growth factor inhibitor (VEGFi) combinations (IOVE). Using the IMDC database, we sought to identify the objective response rate, time to treatment failure (TTF) and overall survival (OS) of 2L CABO after IPI-NIVO, IOVE combinations, pazopanib or sunitinib (PAZ/SUN) or other first line (1L) therapies. Multivariable Cox regression, adjusted for underlying differences in IMDC groups, was used to compare differences in OS for 2L CABO based on preceding therapy. Three hundred and forty-six patients received 2L CABO (78 post IPI NIVO, 46 post IOVE, 161 post PAZ/SUN, 61 post Other). Of the entire cohort, 12.6%, 62.6%, and 24.8% were IMDC favourable, intermediate, and poor risk, respectively. Patients that received 1L IPI-NIVO had a median OS of 21.4 (95% CI, 12.1 - NE [Not evaluable]) months compared to 15.7 (95% CI, 9.3 - NE) months in 1L IOVE and 20.7 (95% CI, 15.6 - 35.6) months in 1L PAZ/SUN, P=.28. Median TTF from the initiation of 2L CABO in the overall population was 7.6 (95% CI, 6.6 - 9.0) months. We were unable to detect a significant difference in 2L CABO OS based on type of 1L therapy received: 1L IPI-NIVO (reference group) vs. 1L IOVE HR 1.73 (95% CI, 0.83 - 3.62 P=.14), 1L PAZ/SUN 1.16 (95% CI, 0.67 - 2.00 P=.60), however given the retrospective observational nature of this work a lack of sufficient power may contribute to this. In a large real world dataset, we identified clinically meaningful activity of 2L CABO after all evaluated contemporary 1L therapies, irrespective of whether the 1L regimen included a VEGFi. These are real world benchmarks with which to counsel our patients.

Graph Optimized Data Offloading for Crowd-AI Hybrid Urban Tracking in Intelligent Transportation Systems

Urban tracking plays a vital role for people’s urban life in intelligent transportation systems, e.g., public safety, case investigation, finding missing items, etc. However, the current tracking methods consume a large amount of communication and computing resources since they mainly offload all related sensing data, i.e., videos, generated by widely deployed cameras to the cloud where data are stored, processed, and analyzed. In this paper, we propose a graph optimized data offloading algorithm leveraging a crowd-AI hybrid method to minimize the data offloading cost and ensure the reliable urban tracking result. To be specific, we first formulate a crowd-AI hybrid urban tracking scenario, and prove the proposed data offloading problem in this scenario is NP-hard. Then, we solve it by decomposing the problem into two parts, i.e., trajectory prediction and task allocation. The trajectory prediction algorithm, leveraging the state graph, computes possible tracking areas of the target object, and the task allocation algorithm, using the dependency graph, chooses the optimal set of crowds and cameras to cover the tracking area while minimizing the data offloading cost separately. Finally, the extensive simulations with large real world data set are conducted showing that the proposed algorithm outperforms benchmarks in reducing data offloading cost while ensuring the tracking success rate in intelligent transportation systems.