Citations

Abstract The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO exposed). InO-exposed patients were more heavily pretreated (P = .02) and frequently had active marrow disease before apheresis (P = .03). Response rate and toxicity profile after brexu-cel were comparable for InO-exposed and InO-naïve patients; however, consolidation therapy after brexu-cel response was used at a higher rate in InO-naïve patients (P = .005). With a median follow-up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS; P = .013) and overall survival (OS; P = .006) in univariate analyses; however, prior InO exposure did not influence PFS (hazard ratio, 1.20; 95% confidence interval, 0.71-2.03) in multivariate models. Within InO-exposed patients, InO responders had superior PFS (P = .002) and OS (P < .0001) relative to InO-refractory patients. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (P = .51) and OS (P = .86) for patients receiving InO as bridging therapy or before apheresis. In conclusion, although InO exposure was associated with inferior survival outcomes after brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively affects brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.

With an annual cumulative occurrence of approximately 15,000 in North America, all childhood cancers are rare. Very rare cancers as defined by both the European Cooperative Study Group for Rare Pediatric Cancers (EXPeRT) and the Children’s Oncology Group (COG) fall into two principal categories: those so uncommon (fewer than 2 cases/million) that their study is challenging even through cooperative group efforts (e.g. pleuropulmonary blastoma, desmoplastic small round cell tumor) and those that are far more common in adults and therefore rarely studied in children (e.g. thyroid, melanoma, gastrointestinal stromal tumor). [1](#ref-0001) Treatment strategies for these latter tumors are typically based on adult guidelines, although the pediatric variants of these tumors may harbor different genetic signatures and demonstrate different behavior. If melanoma and differentiated thyroid cancer are excluded, other rare cancer types account for only 2% of the cancers in children aged 0 to 14.[1](#ref-0001) This article highlights several of the most common rare tumor types.

As modern medicine offers novel surgical therapies for conditions simple and complex, the proper resource allocation of operating rooms, surgical staff and supporting services is becoming increasingly important for healthcare organisations. Surgical services are one of the most essential parts of any healthcare system, substantially influencing patient choice of healthcare services. These services are typically the centre for revenue but also impart considerable costs. Given the complexity of surgical schedule planning, expectations of high reliability and demand on resources, many healthcare organisations have resorted to using a static block schedule based on historic utilisation patterns. This is based on the dogma that surgical schedules are not predictable, surgical blocks are stable, and surgical yield has no direct correlation with outpatient schedules. Here we share our two-year experience with a Surgical Predictor Tool using our surgical practice management principles and the cost-effective use of these means to meet the needs of patients and our surgical staff in an integrated community health system.

OBJECTIVE Cerebral revascularization surgery (CRS) has been used to prevent stroke in children with sickle cell disease (SCD) and cerebral vasculopathy (e.g., moyamoya syndrome). While results suggest that it may be an effective treatment, surgical indications have not been well defined. This study sought to determine indications for offering revascularization surgery in centers with established sickle cell programs in the US. METHODS Three sequential surveys utilizing the Delphi methodology were administered to neurosurgeons participating in the Stroke in Sickle Cell Revascularization Surgery study. Respondents were presented with clinical scenarios of patients with SCD and varying degrees of ischemic presentation and vasculopathy, and the group’s agreement to offer surgical revascularization was measured. Consensus was defined as ≥ 75% similar responses. RESULTS The response rate to all 3 surveys was 100%. Seventeen neurosurgeons from 16 different centers participated. The presence of moyamoya collaterals (MMCs) and arterial stenosis matching an ischemic distribution yielded the strongest recommendations to offer surgery. There was consensus to offer revascularization in the presence of MMCs and at least 50% arterial stenosis matching an ischemic distribution. In contrast, there was no consensus to offer revascularization with 50%–70% stenosis not matching an ischemic presentation in the absence of MMCs. The presence of the ivy sign in the distribution of the stenotic artery also contributed to the consensus to offer surgery in certain scenarios. CONCLUSIONS There were several clinical scenarios that attained consensus to offer surgery; the strongest was moderate to severe arterial stenosis that matched the distribution of ischemic presentation in the presence of MMCs. Radiological findings of decreased cerebral flow or perfusion also facilitated attaining consensus to offer surgery. The findings of this study reflect expert opinion about questions that deserve prospective clinical research. Determination of indications for CRS can guide clinical practice and aid the design of prospective studies.

OBJECTIVE To compare postprandial glucose excursions following a bolus with inhaled technosphere insulin (TI) or subcutaneous rapid-acting analog (RAA) insulin. RESEARCH DESIGN AND METHODS A meal challenge was completed by 122 adults with type 1 diabetes who were using multiple daily injections (MDI), a nonautomated pump, or automated insulin delivery (AID) and who were randomized to bolus with their usual RAA insulin (n = 61) or TI (n = 61). RESULTS The primary outcome, the treatment group difference in area under the curve for glucose >180 mg/dL over 2 h, was less with TI versus RAA (adjusted difference −12 mg/dL, 95% CI −22 to −2, P = 0.02). With TI, the glucose excursion was smaller (P = 0.01), peak glucose lower (P = 0.01), and time to peak glucose shorter (P = 0.006). Blood glucose <70 mg/dL occurred in one participant in each group. CONCLUSIONS Postmeal glucose excursion was smaller with TI than with RAA insulin in a cohort that included both AID and MDI users.

We developed a generally applicable method, CRISPR/Cas9-targeted long-read sequencing (CTLR-Seq), to resolve, haplotype-specifically, the large and complex regions in the human genome that had been previously impenetrable to sequencing analysis, such as large segmental duplications (SegDups) and their associated genome rearrangements. CTLR-Seq combines in vitro Cas9-mediated cutting of the genome and pulse-field gel electrophoresis to isolate intact large (i.e., up to 2,000 kb) genomic regions that encompass previously unresolvable genomic sequences. These targets are then sequenced (amplification-free) at high on-target coverage using long-read sequencing, allowing for their complete sequence assembly. We applied CTLR-Seq to the SegDup-mediated rearrangements that constitute the boundaries of, and give rise to, the 22q11.2 Deletion Syndrome (22q11DS), the most common human microdeletion disorder. We then performed de novo assembly to resolve, at base-pair resolution, the full sequence rearrangements and exact chromosomal breakpoints of 22q11.2DS (including all common subtypes). Across multiple patients, we found a high degree of variability for both the rearranged SegDup sequences and the exact chromosomal breakpoint locations, which coincide with various transposons within the 22q11.2 SegDups, suggesting that 22q11DS can be driven by transposon-mediated genome recombination. Guided by CTLR-Seq results from two 22q11DS patients, we performed three-dimensional chromosomal folding analysis for the 22q11.2 SegDups from patient-derived neurons and astrocytes and found chromosome interactions anchored within the SegDups to be both cell type-specific and patient-specific. Lastly, we demonstrated that CTLR-Seq enables cell-type specific analysis of DNA methylation patterns within the deletion haplotype of 22q11DS.

Objectives: The purpose of this study is to assess the efficacy, short- and long-term cardiovascular and non-cardiovascular mortalities and postoperative morbidities of surgical pulmonary embolectomy (SPE) for patients with massive or submassive pulmonary embolism. Methods: A comprehensive literature review was performed to identify articles reporting SPE for pulmonary embolism. The outcomes included in-hospital and long-term mortality in addition to postoperative morbidities. The random effect inverse variance method was used. Cumulative meta-analysis, leave-one-out sensitivity analysis, subgroup analysis and meta-regression were performed. Results: Among the 1949 searched studies in our systematic literature search, 78 studies met our inclusion criteria, including 6859 cases. The mean age ranged from 42 to 65 years. The percentage of males ranged from 25.6% to 86.7%. The median rate of preoperative cardiac arrest was 27.6%. The percentage of contraindications to preoperative systemic thrombolysis was 30.4%. The preoperative systemic thrombolysis use was 11.5%. The in-hospital mortality was estimated to be 21.96% (95% CI: 19.21–24.98); in-hospital mortality from direct cardiovascular causes was estimated to be 16.05% (95% CI: 12.95–19.73). With a weighted median follow-up of 3.05 years, the late cardiovascular and non-cardiovascular mortality incidence rates were 0.39 and 0.90 per person-year, respectively. The incidence of pulmonary bleeding, gastrointestinal bleeding, surgical site bleeding, non-surgical site bleeding and wound complications was 0.62%, 4.70%, 4.84%, 5.80% and 7.2%, respectively. Cumulative meta-analysis showed a decline in hospital mortality for SPE from 42.86% in 1965 to 20.56% in 2024. Meta-regression revealed that the publication year and male sex were associated with lower in-hospital mortality, while preoperative cardiac arrest, the need for inotropes or vasopressors and preoperative mechanical ventilation were associated with higher in-hospital mortality. Conclusions: This study demonstrates acceptable perioperative mortality rates and late cardiovascular and non-cardiovascular mortality in patients who undergo SPE for massive or submassive pulmonary embolism.

AbstractObjectiveCritical components of the nasal endoscopic examination have not been definitively established for either the normal examination or for clinical disorders. This study aimed to identify concordance among rhinologists regarding the importance of examination findings for various nasal pathologies.Study DesignA consortium of 19 expert rhinologists across the United States was asked to rank the importance of findings on nasal endoscopy for 5 different sinonasal symptom presentations.SettingAn online questionnaire was distributed in July 2023.MethodsThe questionnaire utilized JotForm® software and featured 5 cases with a set of 4 identical questions per case, each covering a common indication for nasal endoscopy. Rankings were synthesized into Normalized Attention Scores (NASs) and Weighted Normalized Attention Scores (W‐NASs) to represent the perceived importance of each feature, scaled from 0 to 1.ResultsGeneral concordance was found for examination findings on nasal endoscopy within each case. The perceived features of importance differed between cases based on clinical presentation. For instance, in evaluating postnasal drip, the middle meatus was selected as the most important structure to examine (NAS, 0.73), with mucus selected as the most important abnormal finding (W‐NAS, 0.66). The primary feature of interest for mucus was whether it was purulent or not (W‐NAS, 0.67). Similar analyses were performed for features in each case.ConclusionThe implicit framework existing among rhinologists may help standardize examinations and improve diagnostic accuracy, augment the instruction of trainees, and inform the development of artificially intelligent algorithms to enhance clinical decision‐making during nasal endoscopy.