Dose-Adjusted EPOCH Plus Inotuzumab Ozogamicin in Adults With Relapsed or Refractory B-Cell ALL: A Phase 1 Dose-Escalation Trial.

Importance: Options for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma (B-ALL) are limited, and new approaches are needed. Inotuzumab ozogamicin (InO) has been combined with low-intensity chemotherapy, with modest improvements over historical controls, and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) treatment is safe and active for newly diagnosed ALL. Objective: To assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL. Design, Setting, and Participants: This single-center, single-arm, nonrandomized, phase 1 dose-escalation trial included adults with relapsed or refractory CD22+ B-ALL and was conducted between September 2019 and November 2022. At least 5% blood or marrow blasts or measurable extramedullary disease (EMD) was required for enrollment. Interventions: DA-EPOCH was given on days 1 to 5, while InO was given on day 8 and day 15 of a 28-day cycle. Three dose levels were studied using a bayesian optimal interval design. Main Outcomes and Measures: The primary outcome was the maximum tolerated dose of InO when combined with DA-EPOCH, defined as the highest dose level that produced a rate of dose-limiting toxicity below 33%. Secondary objectives included response rates, survival estimates, and descriptions of toxic effects. Results: A total of 24 participants were screened and enrolled (median age, 46 [range, 28-76] years; 15 [62%] male). The median number of lines of prior therapy was 3 (range, 1-12). Three of 11 participants (27%) treated at the highest dose level (InO, 0.6 mg/m2, on day 8 and day 15) experienced dose-limiting toxicity, making this the maximum tolerated dose. No deaths occurred during the study, and only 1 patient (4%; 95% CI, 0.1%-21%) developed sinusoidal obstructive syndrome after poststudy allograft. The morphologic complete response rate was 84% (95% CI, 60%-97%), 88% (95% CI, 62%-98%) of which was measurable residual disease negative by flow cytometry. Five of 6 participants with EMD experienced treatment response. The overall response rate was 83% (95% CI, 63%-95%). Median overall survival, duration of response, and event-free survival were 17.0 (95% CI, 8.4-not reached), 15.0 (95% CI, 6.7-not reached), and 9.6 (95% CI, 4.5-not reached) months, respectively. Conclusions: In this study, adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and sinusoidal obstructive syndrome occurring rarely in a heavily pretreated population. Many patients were able to proceed to poststudy consolidative allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy. Further investigation of this combination is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT03991884.

Intensive Re-Induction Chemotherapy Followed by Early Allogeneic Hematopoietic Cell Transplant for Relapsed/Refractory High-Grade Myeloid Neoplasms.

Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplant (HCT) the only therapy likely to result in cure. Therefore, we conducted a study to determine the feasibility of early HCT - within 60 days of beginning reinduction chemotherapy - to see if getting patients to HCT in an expeditious manner would facilitate a larger number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults 18-75 with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis, who were eligible for a reduced-intensity HCT. Subjects received reinducton chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/melphalan). We enrolled 30 patients: all received CLAG-M reinduction, although only 9 received HCT within 60 days (< 15, the predetermined threshold for feasibility "success"), with a median time to HCT of 48 days (range 42-60). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplant of 83 days (range 53-367). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit real-world uptake of such early-to-transplant protocols.

Comparison of rectal swabs and fecal samples for the detection of Clostridioides difficile infections with a new in-house PCR assay.

The detection of Clostridioides difficile infections (CDI) relies on testing the stool of patients by toxin antigen detection or PCR methods. Although PCR and antigenic methods have significantly reduced the time to results, delays in stool collection can significantly add to the turnaround time. The use of rectal swabs to detect C. difficile could considerably reduce the time to diagnosis of CDI. We developed a new rapid PCR assay for the detection of C. difficile and evaluated this PCR assay on both stool and rectal swab specimens. We recruited a total of 623 patients suspected of C. difficile infection. Stool samples and rectal swabs were collected from each patient and tested by our PCR assay. Stool samples were also tested by the cell cytotoxicity neutralization assay (CCNA) as a reference. The PCR assay detected C. difficile in 60 stool specimens and 61 rectal swabs for the 64 patients whose stool samples were positive for C. difficile by CCNA. The PCR assay detected an additional 35 and 36 stool and rectal swab specimens positive for C. difficile, respectively, for sensitivity with stools and rectal swabs of 93.8% and 95.3%, specificity of 93.7% and 93.6%, positive predictive values of 63.2% and 62.9%, and negative predictive values of 99.2% and 99.4%. Detection of C. difficile using PCR on stools or rectal swabs yielded reliable and similar results. The use of PCR tests on rectal swabs could reduce turnaround time for CDI detection, thus improving CDI management and control of C. difficile transmission. IMPORTANCE: Clostridioides difficile infection (CDI) is the leading cause of healthcare-associated diarrhea, resulting in high morbidity, mortality, and economic burden. In clinical laboratories, CDI testing is currently performed on stool samples collected from patients with diarrhea. However, the diagnosis of CDI can be delayed by the time required to collect stool samples. Barriers to sample collection could be overcome by using a rectal swab instead of a stool sample. Our study showed that CDI can be identified rapidly and reliably by a new PCR assay developed in our laboratory on both stool and rectal swab specimens. The use of PCR tests on rectal swabs could reduce the time for the detection of CDI and improve the management of this infection. It should also provide a useful alternative for infection-control practitioners to better control the spread of C. difficile.

Equine bone marrow MSC-derived extracellular vesicles mitigate the inflammatory effects of interleukin-1ß on navicular tissues in vitro.

BACKGROUND: Safe, efficacious therapy for treating degenerate deep digital flexor tendon (DDFT) and navicular bone fibrocartilage (NBF) in navicular horses is critically necessary. While archetypal orthobiologic therapies for navicular disease are used empirically, their safety and efficacy are unknown. Mesenchymal stem cell-derived extracellular vesicles (EV) may overcome several limitations of current orthobiologic therapies. OBJECTIVES: To (1) characterise cytokine and growth factor profiles of equine bone marrow mesenchymal stem cell (BM-MSC)-derived extracellular vesicles (BM-EV) and (2) evaluate the in vitro anti-inflammatory and extracellular matrix (ECM) protective potentials of BM-EV on DDFT and NBF explant co-cultures in an IL-1ß inflammatory environment. STUDY DESIGN: In vitro experimental study. METHODS: Cytokines (IL-1ß, IL-6, IL-10, IL-1ra and TNF-α) and growth factors (TGFß1, VEGF, IGF1 and PDGF) in equine BM-EV isolated via ultracentrifugation and precipitation methods were profiled. Forelimb DDFT and NBF explant co-cultures from seven horses were exposed to media alone, or media containing 2 × 109 ± 0.1 × 109 particles/mL or 10 µg/mL BM-EV (BM-EV), 10 ng/mL interleukin-1ß (IL-1ß), or IL-1ß + BM-EV for 48 h. Co-culture media IL-6, TNF-α, MMP-3, MMP-13 concentrations and explant sulphated glycosaminoglycan (sGAG) content were quantified. RESULTS: IL-6, IGF1 and VEGF concentrations were 102.1 (37.61-256.2) and 182.3 (163.1-226.3), 72.3 (8-175.6) and 2.4 (0.1-2.6), 108.3 (38.3-709.1) and 211.4 (189.1-318.2) pg/mL per 2 × 109 ± 0.1 × 109 particles/mL or 10 µg/mL 10 µg of BM-EV isolated via ultracentrifugation and precipitation methods, respectively. Co-culture media MMP-3 in BM-EV- (p = 0.03) and BM-EV + IL-1ß-treated (p = 0.01) groups were significantly lower than the respective media and IL-1ß groups. DDFT explant sGAG content of BM-EV (p = 0.003) and BM-EV + IL-1ß groups were significantly higher compared with IL-1ß group. MAIN LIMITATIONS: Specimen numbers are limited, in vitro model may not replicate clinical case conditions, lack of non-MSC-derived EV control group. CONCLUSIONS: Equine BM-EV contains IL-6 and growth factors, IGF1 and VEGF. The anti-inflammatory and ECM protective potentials of BM-EV were evident as increased IL-6 and decreased MMP-3 concentrations in the DDFT-NBF explant co-culture media. These results support further evaluation of BM-EV as an acellular and 'off-the-shelf' intra-bursal/intrasynovial therapy for navicular pathologies.

Isoform Switching Regulates the Response to Ionizing Radiation Through SRSF1.

PURPOSE: This study investigated how isoform switching affects the cellular response to ionizing radiation (IR), an understudied area despite its relevance to radiation therapy in cancer treatment. We aimed to identify changes in transcript isoform expression post-IR exposure and the proteins mediating these changes, with a focus on their potential to modulate radiosensitivity. METHODS AND MATERIALS: Using RNA sequencing, we analyzed the B-cell lines derived from 10 healthy individuals at 3 timepoints, applying the mixture of isoforms algorithm to quantify alternative splicing. We examined RNA binding protein motifs within the sequences of IR-responsive isoforms and validated the serine/arginine-rich splicing factor 1 (SRSF1) as a predominant mediator through RNA immunoprecipitation. We further investigated the effects of SRSF1 on radiosensitivity by RNA interference and by analyzing publicly available data on patients with cancer. RESULTS: We identified ∼1900 radiation-responsive alternatively spliced isoforms. Many isoforms were differentially expressed without changes in their overall gene expression. Over a third of these transcripts underwent exon skipping, while others used proximal last exons. These IR-responsive isoforms tended to be shorter transcripts missing vital domains for preventing apoptosis and promoting cell division but retaining those necessary for DNA repair. Our combined computational, genetic, and molecular analyses identified the proto-oncogene SRSF1 as a mediator of these radiation-induced isoform-switching events that promote apoptosis. After exposure to DNA double-strand break-inducing agents, SRSF1 expression decreased. A reduction in SRSF1 increased radiosensitivity in vitro and among patients with cancer. CONCLUSIONS: We establish a pivotal role for isoform switching in the cellular response to IR and propose SRSF1 as a promising biomarker for assessing radiation therapy effectiveness.

Presence and Relevance of Myocardial Bridge in LAD-PCI of CTO and Non-CTO Lesions.

BACKGROUND: Intravascular ultrasound (IVUS) studies show that one-quarter of left anterior descending (LAD) arteries have a myocardial bridge. An MB may be associated with stent failure when the stent extends into the MB. OBJECTIVES: The aim of this study was to investigate: 1) the association between an MB and chronic total occlusion (CTO) in any LAD lesions; and 2) the association between an MB and subsequent clinical outcomes after percutaneous coronary intervention in LAD CTOs. METHODS: A total of 3,342 LAD lesions with IVUS-guided percutaneous coronary intervention (280 CTO and 3,062 non-CTO lesions) were included. The primary outcome was target lesion failure (cardiac death, target vessel myocardial infarction, definite stent thrombosis, and ischemic-driven target lesion revascularization). RESULTS: An MB by IVUS was significantly more prevalent in LAD CTOs than LAD non-CTOs (40.4% [113/280] vs 25.8% [789/3,062]; P < 0.0001). The discrepancy in CTO length between angiography and IVUS was greater in 113 LAD CTOs with an MB than 167 LAD CTOs without an MB (6.0 [Q1, Q3: 0.1, 12.2] mm vs 0.2 [Q1, Q3: -1.4, 8.4] mm; P < 0.0001). Overall, 48.7% (55/113) of LAD CTOs had a stent that extended into an MB after which target lesion failure was significantly higher compared to a stent that did not extend into an MB (26.3% vs 0%; P = 0.0004) or compared to an LAD CTO without an MB (26.3% vs 9.6%; P = 0.02). CONCLUSIONS: An MB was more common in LAD CTO than non-CTO LAD lesions. If present, approximately one-half of LAD CTOs had a stent extending into an MB that, in turn, was associated with worse outcomes.

Ostial right coronary artery lesion morphology and outcomes after treatment with drug-eluting stents.

BACKGROUND: Outcomes after percutaneous coronary intervention (PCI) for de novo ostial right coronary artery (RCA) lesions are poor. AIMS: We used intravascular ultrasound (IVUS) to clarify the morphological patterns of de novo ostial RCA lesions and their associated clinical outcome. METHODS: Among 5,102 RCA IVUS studies, 170 de novo ostial RCA stenoses (within 3 mm from the aorto-ostium) were identified. These were classified as 1) isolated ostial lesions (no disease extending beyond 10 mm from the ostium and without a calcified nodule [CN]); 2) ostial CN, typically with diffuse disease (disease extending beyond 10 mm); and 3) ostial lesions with diffuse disease but without a CN. The primary outcome was target lesion failure (TLF: cardiac death, target vessel myocardial infarction, definite stent thrombosis, and ischaemia-driven target lesion revascularisation). RESULTS: The prevalence of an isolated ostial lesion was 11.8% (n=20), 47.6% (n=81) were ostial CN, and 40.6% (n=69) were ostial lesions with diffuse disease. Compared to ostial lesions with diffuse disease, isolated lesions were more common in women (75.0% vs 42.0%; p=0.01), and CN were associated with older age (median [first, third quartile] 76 [70, 83] vs 69 [63, 81] years old; p=0.002). The Kaplan-Meier rate of TLF at 2 years was significantly higher in patients with CN (21.6%) compared to diffuse lesions (8.2%) (p=0.04), and patients with isolated lesions had no events. A multivariable Cox proportional hazard model revealed that CN were significantly associated with TLF (hazard ratio 6.63, 95% confidence interval: 1.28-34.3; p=0.02). CONCLUSIONS: Ostial RCA lesions have specific morphologies - detectable by IVUS - that may be associated with long-term clinical outcomes.

The 'Pants-Sign': A Predictor for Falling in People with Parkinson's Disease?

BACKGROUND: A history of falls is the most established predictor of future falls in people with Parkinson's disease (PD). However, predicting a first fall remains challenging. OBJECTIVE: To assess whether experiencing difficulties putting on pants while standing is a viable predictor of future falling, and specifically a first fall, in persons with PD. We define this 'Pants-sign' as people who resort to putting on their pants only while seated. METHODS: 264 persons with PD were included. Information on the Pants-sign, history of falls, disease severity (MDS-UPDRS part III), freezing of gait (N-FOGQ > 0), cognitive function (MoCA), self-reported disability (Schwab & England scale), health-related quality of life (SF-12), Timed-Up-and-Go, and one-legged stance were determined at baseline and after one-year follow-up. The association between the Pants-sign and future falling was examined by univariate logistic regression analysis. A multivariate step-wise logistic regression with forward selection was employed to identify the strongest associations in the entire cohort and a sub-cohort of people without falls in the year prior to baseline. RESULTS: The Pants-sign was univariably associated with a future fall (OR = 2.406, 95% CI [1.313-4.409], p = 0.004]), but was not an independent predictor in the multivariate logistic regression; predictors were higher MDS-UPDRS part III scores (OR = 1.088, 95% CI [1.056-1.121], p < 0.001] and history of falls (OR = 5.696, 95% CI [2.650-12.243], p≤0.001]. For the sub-cohort of people without falls in the previous year (n = 189), the Pants-sign was not associated with future falls. CONCLUSIONS: The Pants-sign is simple to assess and is associated with future falling in PD but is not an independent predictor.

Estimated Savings After Stopping Tyrosine Kinase Inhibitor Treatment Among Patients With Chronic Myeloid Leukemia.

Importance: Patients with chronic myeloid leukemia (CML) who have a sustained deep molecular response using tyrosine kinase inhibitors (TKIs) can safely attempt to stop their use. As these medications are very costly, this change in treatment protocols may result in large savings. Objective: To estimate future savings from attempting to stop TKI use among patients with CML who have deep molecular response. Design, Setting, and Participants: A microsimulation model was developed for this decision analytical modeling study to estimate costs for US adults moving from using a TKI, to attempting discontinuation and then reinitiating TKI therapy, if clinically appropriate. Estimates were calculated for US patients who currently have CML and simulated newly diagnosed cohorts of patients over the next 30 years. Exposure: Attempting to stop using a TKI. Main Outcomes and Measures: Estimated savings after attempted discontinuation of TKI use. Results: A simulated population of individuals with CML in 2018 and future populations were created using estimates from the SEER*Explorer website. The median age at diagnosis was 66 years for men and 65 years for women. Between 2022 and 2052, the savings associated with eligible patients attempting discontinuation of TKI therapy was estimated at more than $30 billion among those currently diagnosed and over $15 billion among those who will develop CML in the future, for a total savings of over $54 billion by 2052 for drug treatment and polymerase chain reaction testing. The estimate is conservative as it does not account for complications and other health care-associated costs for patients continuing TKI therapy. Conclusions and Relevance: The findings of this decision analytical modeling study of patients with CML suggest that attempting discontinuation of TKI therapy could save over $54 billion during the next 30 years. Further education for patients and physicians is needed to safely increase the number of patients who can successfully attain treatment-free remission.

Guanine quadruplexes mediate mitochondrial RNA polymerase pausing.

The information content within nucleic acids extends beyond the primary sequence to include secondary structures with functional roles in cells. Guanine-rich sequences form structures called guanine quadruplexes (G4) that result from non-canonical base pairing between guanine residues. These stable structures are enriched in gene promoters and have been correlated with the locations of RNA polymerase II pausing (Pol II). While promoter-proximal RNA polymerase pausing regulates gene expression, the effects of guanine quadruplexes on gene transcription have been less clear. We determined the pattern of mitochondrial RNA polymerase (mtRNAP) pausing in human fibroblasts and found that it pauses over 400 times on the mitochondrial genome. We identified quadruplexes as a mediator of mtRNAP pausing and show that stabilization of quadruplexes impeded transcription by mtRNAP. Gene products encoded by the mitochondrial genome are required for oxidative phosphorylation and the decreased transcription by mtRNAP resulted in lower expression of mitochondrial genes and significantly reduced ATP generation. Energy from mitochondria is essential for transport function in renal epithelia, and impeded mitochondrial transcription inhibits transport function in renal proximal tubule cells. These results link formation of guanine quadruplex structures to regulation of mtRNAP elongation and mitochondrial function.

Clinical Validation of FusionPlex RNA Sequencing and Its Utility in the Diagnosis and Classification of Hematologic Neoplasms.

Recurrent gene rearrangements result in gene fusions that encode chimeric proteins, driving the pathogenesis of many hematologic neoplasms. The fifth edition World Health Organization classification and International Consensus Classification 2022 include an expanding list of entities defined by such gene rearrangements. Therefore, sensitive and rapid methods are needed to identify a broad range of gene fusions for precise diagnosis and prognostication. In this study, we validated the FusionPlex Pan-Heme panel analysis using anchored multiplex PCR/targeted RNA next-generation sequencing for routine clinical testing. Furthermore, we assessed its utility in detecting gene fusions in myeloid and lymphoid neoplasms. The validation cohort of 61 cases demonstrated good concordance between the FusionPlex Pan-Heme panel and other methods, including chromosome analysis, fluorescence in situ hybridization, RT-PCR, and Sanger sequencing, with an analytic sensitivity and specificity of 95% and 100%, respectively. In an independent cohort of 28 patients indicated for FusionPlex testing, gene fusions were detected in 21 patients. The FusionPlex Pan-Heme panel analysis reliably detected fusion partners and patient-specific fusion sequences, allowing accurate classification of hematologic neoplasms and the discovery of new fusion partners, contributing to a better understanding of the pathogenesis of the diseases.

Hyper-CVAD versus dose-adjusted EPOCH as initial treatment for adults with acute lymphoblastic leukemia.

OBJECTIVES: We recently performed a single-arm phase II trial of DA-EPOCH in adults with acute lymphoblastic leukemia (ALL). We sought to compare these results to those with standard Hyper-CVAD. METHODS: We created a retrospective matched cohort of patients who received Hyper-CVAD (n = 69) at our center and otherwise met eligibility criteria for the DA-EPOCH trial (n = 53). RESULTS: Our outcomes support the use of Hyper-CVAD over DA-EPOCH in Ph- disease for both overall survival (OS; HR 0.18, p = .004) and event-free survival (EFS; HR 0.51, p = .06). In contrast, outcomes were similar in Ph+ disease (OS HR 0.97, p = .96; EFS HR 0.65, p = .21). Rates of morphologic remission and measurable residual-disease negativity were similar between the regimens. Hyper-CVAD was associated with significantly more febrile neutropenia (OR 1.9, p = .03) and a greater incidence of Grade 4 or 5 adverse events (20% vs. 6%). Average transfusions per cycle of both red blood cells (p < .001) and platelets (p < .001) were five-fold higher with Hyper-CVAD. CONCLUSIONS: Our findings support continued use of Hyper-CVAD for Ph- ALL but suggest that DA-EPOCH may be a reasonable alternative for Ph+ ALL. These data also highlight a potential role for DA-EPOCH in resource-limited settings or when more intense therapy is not feasible.

Nanopore-based direct sequencing of RNA transcripts with 10 different modified nucleotides reveals gaps in existing technology.

RNA undergoes complex posttranscriptional processing including chemical modifications of the nucleotides. The resultant-modified nucleotides are an integral part of RNA sequences that must be considered in studying the biology of RNA and in the design of RNA therapeutics. However, the current "RNA-sequencing" methods primarily sequence complementary DNA rather than RNA itself, which means that the modifications present in RNA are not captured in the sequencing results. Emerging direct RNA-sequencing technologies, such as those offered by Oxford Nanopore, aim to address this limitation. In this study, we synthesized and used Nanopore technology to sequence RNA transcripts consisting of canonical nucleotides and 10 different modifications in various concentrations. The results show that direct RNA sequencing still has a baseline error rate of >10%, and although some modifications can be detected, many remain unidentified. Thus, there is a need to develop sequencing technologies and analysis methods that can comprehensively capture the total complexity of RNA. The RNA sequences obtained through this project are made available for benchmarking analysis methods.

Transcatheter aortic valve-in-valve implantation within stentless landing zones: Procedural insights from a single-center experience.

BACKGROUND: Valve-in-valve (VIV) transcatheter aortic valve implantation (TAVI) is a less invasive therapeutic option compared with redo surgical valve replacement for high-risk patients. Relative to procedures within stented surgical valves, VIV-TAVI within stentless valves is associated with a higher complication rate due to challenging underlying anatomy and absence of fluoroscopic landmarks. AIMS: We share a single-center experience with VIV-TAVI in stentless valves, discussing our procedural insights and associated outcomes. METHODS: Our institutional database was queried, and 25 patients who had undergone VIV-TAVI within a stentless bioprosthesis, homograft, or valve-sparing aortic root replacement between 2013 and 2022 were found. Outcome endpoints were based on the Valve Academic Research Consortium-3 criteria. RESULTS: The mean age of the cohort was 69.5 ± 13.6 years. VIV implantation was performed within a homograft in 11 patients, a stentless bioprothesis in 10 patients, and a valve-sparing aortic root replacement in 4 patients. Nineteen (76%) balloon-expandable valves, 5 (20%) self-expanding valves, and one mechanically-expandable (4%) valve were implanted with 100% procedural success, with no instances of significant paravalvular leak, coronary occlusion, or device embolization. There was one (4%) in-hospitality mortality after an emergency procedure; one (4%) patient experienced a transient ischemic attack; and two (8%) patients required permanent pacemaker implantation. The median length of hospital stay was 2 days. After a median follow-up time of 16.5 months, valve function was acceptable in all patients with available data. CONCLUSION: VIV-TAVI within stentless valves can be safely performed with methodical procedural technique and can provide clinical benefit in patients at high reoperation risk.

Mechanisms and treatment outcomes of ostial right coronary artery in-stent restenosis.

BACKGROUND: Despite a high rate of in-stent restenosis (ISR) after stenting the right coronary artery (RCA) ostium, the mechanism of ostial RCA ISR is not well understood. AIMS: We aimed to clarify the cause of ostial RCA ISR using intravascular ultrasound (IVUS). METHODS: Overall, 139 ostial RCA ISR lesions were identified with IVUS, pre-revascularisation. Primary ISR mechanisms were classified as follows: 1) neointimal hyperplasia (NIH); 2) neoatherosclerosis; 3) ostium not covered by the stent; 4) stent fracture or deformation; 5) stent underexpansion (old minimum stent area <4.0 mm2 or stent expansion <50%); or 6) a protruding calcified nodule. RESULTS: The median duration from prior stenting was 1.2 (first quartile 0.6, third quartile 3.1) years. The primary mechanisms of ISR were NIH in 25% (n=35) of lesions, neoatherosclerosis in 22% (n=30), uncovered ostium in 6% (n=9) (biological cause 53%, n=74), stent fracture or deformation in 25% (n=35), underexpansion in 11% (n=15), and protruding calcified nodules in 11% (n=15) (mechanical cause 47%, n=65). Including secondary mechanisms, 51% (n=71) of ostial RCA ISRs had stent fractures that were associated with greater hinge motion of the ostial-aorta angle during the cardiac cycle. The Kaplan-Meier rate of target lesion failure at 1 year was 11.5%. When the mechanically caused ISRs were treated without new stents, they suffered a higher subsequent event rate (41.4%) compared with non-mechanical causes or mechanical causes treated without restenting (7.8%, unadjusted hazard ratio 6.44, 95% confidence interval: 2.33-17.78; p<0.0001). CONCLUSIONS: Half of the ostial RCA ISRs were due to mechanical causes. Subsequent event rates were high, especially in mechanically caused ISRs treated without the implantation of a new stent.

Minimum Core Data Elements for Transcatheter Mitral Therapies: Scientific Statement by PASSION CV, HVC, and TVTR.

Mitral regurgitation is the most common valvular disease and is estimated to affect over 5 million Americans. Real-world data collection contributes to safety and effectiveness evidence for the U.S. Food and Drug Administration, quality evaluation for the Centers for Medicare and Medicaid Services and hospitals, and clinical best practice research. We aimed to establish a minimum core data set in mitral interventions to promote efficient, reusable real-world data collection for all of these purposes. Two expert task forces separately evaluated and reconciled a list of candidate elements derived from: 1) 2 ongoing transcatheter mitral trials; and 2) a systemic literature review of high-impact mitral trials and U.S multicenter, multidevice registries. From 703 unique data elements considered, unanimous consensus agreement was achieved on 127 "core" data elements, with the most common reasons for exclusion from the minimum core data set being burden or difficulty in accurate assessment (41.2%), duplicative information (25.0%), and low likelihood of affecting outcomes (19.6%). After a systematic review and extensive discussions, a multilateral group of academicians, industry representatives, and regulators established and implemented into the national Society of Thoracic Surgery/American College of Cardiology Transcatheter Valve Therapies Registry 127 interoperable, reusable core data elements to support more efficient, consistent, and informative transcatheter mitral device evidence for regulatory submissions, safety surveillance, best practice development, and hospital quality assessments.

Phase 1/2 study of sorafenib added to cladribine, high-dose cytarabine, G-CSF, and mitoxantrone in untreated AML.

The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7 + 3 in adults with newly-diagnosed acute myeloid leukemia (AML), irrespective of the FLT3-mutation status. Here, we evaluated adding sorafenib to cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone (CLAG-M) in a phase 1/2 trial of 81 adults aged ≤60 years with newly diagnosed AML. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone 18 mg/m2 per day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at RP2D, a measurable residual disease-negative complete remission (MRD- CR) rate of 83% was obtained. Four-week mortality was 2%. One-year overall survival (OS) and EFS were 80% and 76%, without differences in MRD- CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes using CLAG-M/sorafenib with those of a matched cohort of 76 patients treated with CLAG-M alone, multivariable-adjusted survival estimates were improved for 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio,0.24 [95% confidence interval, 0.07-0.82]; P = .023; EFS: hazard ratio, 0.16 [95% confidence interval, 0.05-0.53]; P = .003). Benefit was limited to patients with intermediate-risk disease (univariate analysis: P = .01 for OS; P = .02 for EFS). These data suggest that CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefits primarily in patients with intermediate-risk disease. The trial was registered at www.clinicaltrials.gov as #NCT02728050.