Citations

AbstractBackgroundGastrointestinal bleeding (GIB) in patients with continuous flow left ventricular assist devices (CF‐LVADs) is often related to GI angiodysplasia (GIAD). We previously reported data on VEGF inhibition with IV bevacizumab in the treatment of LVAD‐associated GIAD bleeding, and now present follow‐up data on patients treated with IV bevacizumab and/or low‐dose oral pazopanib.MethodsAll consecutive adult patients with LVAD‐associated GIB from GIAD treated with bevacizumab or pazopanib, from July 20, 2017 to June 22, 2022, were included in the analysis. Data on hospitalizations, GI endoscopic procedures, and blood transfusions were obtained from first admission for GIB up to a median of 35.7 months following treatment initiation (range 1.3–59.8 months).ResultsEleven patients (91% male, mean 69.5 ± 8.9 years) were included. Eight patients (73%) received IV bevacizumab, two patients (18%) received oral pazopanib, and one patient (9%) received bevacizumab followed by pazopanib therapy. We observed a significantly decreased number of annualized hospitalizations for GIB (median difference − 2.87, p = 0.002), blood transfusions (median difference − 20.9, p = 0.01), and endoscopies (median difference − 6.95, p = 0.007) in patients pre‐ and post‐anti‐angiogenic therapy (bevacizumab and/or pazopanib). Similarly, a significant improvement in these clinical outcomes was noted in the bevacizumab group with decreased annualized hospitalizations (median difference − 2.75, p = 0.014), blood transfusions (median difference − 24.5, p = 0.047), and number of endoscopies (median differences −6.88, p = 0.006).ConclusionAnti‐angiogenic therapy with IV bevacizumab and/or low‐dose oral pazopanib appears to provide benefits in patients with LVAD‐associated GIB with reduced hospitalizations, blood transfusions, and need for GI endoscopic procedures.

Background: Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are two common atypical Alzheimer’s disease (AD) variants. Little is known about behavioral and neuropsychiatric symptoms or activities of daily living (ADLs) in PCA and LPA, and whether they differ across syndromes. Objective: To characterize the behavioral and neuropsychiatric profiles and ADLs of PCA and LPA and compare presence/absence and severity of symptoms between syndromes. Methods: Seventy-eight atypical AD patients, 46 with PCA and 32 with LPA, completed the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Cambridge Behavioral Inventory-Revised (CBI-R) at baseline and longitudinally over-time. Mann-Whitney U and Fisher’s Exact Tests assessed for differences in symptoms between the two syndromes with significance set at p ≤0.01. To eliminate demographic differences as confounders the groups were matched, and differences reanalyzed. Results: PCA were younger at onset ( p = 0.006), at time of baseline assessment ( p = 0.02) and had longer disease duration ( p = 0.01). Neuropsychiatric symptoms were common in PCA and LPA, although more common and severe in PCA. At baseline, PCA had a higher NPI-Q total score ( p = 0.01) and depression subscore ( p = 0.01) than LPA. Baseline total CBI-R scores were also higher in PCA than LPA ( p = 0.001) with PCA having worse scores in all 10 CBI-R categories. Longitudinally, there was no difference between groups on the NPI-Q. However, on the CBI-R, PCA had faster rates of worsening on self-grooming ( p = 0.01) and self-dressing ( p = 0.01) compared to LPA. Conclusions: Behavioral and neuropsychiatric symptoms are common in PCA and LPA although these symptoms are more common and severe in PCA.

Abstract Background Pediatric residents frequently manage critically ill neonates but have limited systematic training in mechanical ventilation (MV). Competing demands, varying learner levels, and topic complexity contribute to inconsistent education. A blended learning approach may be ideally suited to achieve meaningful learning but has not been described for this topic and learner. Objective To design, implement, and evaluate a flipped classroom for pediatric residents in neonatal MV. Methods We used Kern’s six-step framework for curricular development to create a flipped classroom curriculum in neonatal MV. Individual prework included interaction with six prerecorded animated whiteboard videos, while in-person learning occurred in small groups at the bedside of a ventilated infant. A mixed-methods evaluation included surveys, quantitative knowledge test scores (before, immediately after, and six months after course completion), and qualitative analysis of participant focus groups. Results Twenty-six learners participated in the curriculum. Mean knowledge test scores rose and were sustained after course completion (51% baseline, 82% immediate posttest, 90% retention; P < 0.001). Learners identified various design elements, technology affordances, and instructor factors as meaningful, and they identified unexpected impacts of the curriculum beyond knowledge acquisition, including effects on professional identities, interdisciplinary communication skills, and contribution to the culture of safety. Conclusion This curriculum aligned with resident roles, was meaningful to learners, and led to long-term increases in knowledge scores and access to quality education; flipped classroom design using meaningful learning theory and leveraging animated whiteboard technology may be a useful strategy for other highly complex topics in graduate medical education.

Abstract Objectives . (1) To examine to what extent the cell- and exposure- specific information neglected in the phenomenological proton relative biological effectiveness (RBE) models could influence the computed RBE in proton therapy. (2) To explore similarities and differences in the formalism and the results between the linear energy transfer (LET)-based phenomenological proton RBE models and the microdosimetry-based Mayo Clinic Florida microdosimetric kinetic model (MCF MKM). (3) To investigate how the relationship between the RBE and the dose-mean proton LET is affected by the proton energy spectrum and the secondary fragments. Approach . We systematically compared six selected phenomenological proton RBE models with the MCF MKM in track-segment simulations, monoenergetic proton beams in a water phantom, and two spread-out Bragg peaks. A representative comparison with in vitro data for human glioblastoma cells (U87 cell line) is also included. Main results . Marked differences were observed between the results of the phenomenological proton RBE models, as reported in previous studies. The dispersion of these models’ results was found to be comparable to the spread in the MCF MKM results obtained by varying the cell-specific parameters neglected in the phenomenological models. Furthermore, while single cell-specific correlation between RBE and the dose-mean proton LET seems reasonable above 2 keV μ m −1 , caution is necessary at lower LET values due to the relevant contribution of secondary fragments. The comparison with in vitro data demonstrates comparable agreement between the MCF MKM predictions and the results of the phenomenological models. Significance . The study highlights the importance of considering cell-specific characteristics and detailed radiation quality information for accurate RBE calculations in proton therapy. Furthermore, these results provide confidence in the use of the MCF MKM for clonogenic survival RBE calculations in proton therapy, offering a more mechanistic approach compared to phenomenological models.

BACKGROUND AND OBJECTIVES: Lesions located in the retrosellar region, interpeduncular cistern, and petroclival region are among the most difficult to access in neurosurgery. Transcranial approaches are useful; however, the large distance between the surgeon and the lesion as well as the presence of major neurovascular structures surrounding the lesion may limit surgical exposure. A midline transsphenoidal route avoids transgression of the neurovascular plane and provides direct access to the interpeduncular cistern. To safely access the interpeduncular fossa, it requires mobilization of the pituitary gland. The pituitary hemitransposition technique permits mobilization of the gland, while preserving its venous drainage and arterial supply to the gland on one of its sides, preserving gland function. The authors aim to describe the intradural pituitary hemitransposition technique and to demonstrate its safe application for resection of skull base tumors in the retrosellar space. METHODS: The authors describe the surgical technique and illustrate its application in 5 cases of different types of skull base tumors, including a video demonstrating all the steps to perform this approach. In addition, the authors discuss the advantages and limitations of this technique compared with other approaches to the retrosellar space. RESULTS: The intradural pituitary hemitransposition technique was used to safely resect a chondrosarcoma, chordoma, craniopharyngioma, teratoma, and meningioma involving the parasellar and retrosellar spaces, while minimizing endocrine morbidity. We had one patient with mild, albeit permanent hyperprolactinemia and hypothyroidism after surgery. No other patients had permanent dysfunction related to surgery. CONCLUSION: The endonasal endoscopic intradural pituitary hemitransposition approach is an effective technique for resection of lesions located within the retrosellar and petroclival regions, allowing adequate exposure while potentially optimizing the preservation of the pituitary function.

Abstract Background Diagnosis of breast cancer in young women has been shown to affect their decision‐making with regard to fertility and family planning. Limited data are available from populations across the U.S. regarding this issue; thus, we sought to describe fertility concerns and efforts to preserve fertility in a national clinical trial population of young breast cancer patients. Methods The young and strong study was a cluster‐randomized controlled trial testing an intervention program for young women with breast cancer. Patients were surveyed within 3 months after diagnosis and at 3, 6, and 12 months after. Surveys asked about sociodemographics, psychosocial domains, fertility concerns, and fertility preservation strategies. Univariable and multivariable models were used to investigate sociodemographic, clinical, and psychosocial predictors of fertility concerns. Results Of 467 women from 54 clinical sites across the U.S. (14 academic, 40 community), 419 were evaluable regarding fertility concerns. Median age was 40 years (range 22–45), 11% were Black, 6% Hispanic, and 75% had children. Tumor stage was I (35%), II (51%), or III (14%); 82% received chemotherapy. At time of the treatment decision, 133 (32%) participants had fertility concerns, among whom 47% indicated this affected their treatment decisions. Sixty percent of participants reported having discussed fertility with their physician. Twenty percent of those with fertility concerns used fertility preservation strategies. History of difficulty becoming pregnant and younger age were associated with higher odds of fertility concerns in multivariable modeling. Conclusion Many young women with newly diagnosed breast cancer are concerned about fertility in a way that impacts their treatment decisions. Concerns were discussed, but few used fertility preservation strategies. These findings have implications for counseling young patients.

For patients with locoregionally confined pancreatic ductal adenocarcinoma (PDAC), margin-negative surgical resection is the only known curative treatment; however, the majority of patients are not operable candidates at initial diagnosis. Among patients with resectable disease who undergo surgery alone, the 5-year survival remains poor. Adjuvant therapies, including systemic therapy or chemoradiation, are utilized as they improve locoregional control and overall survival. There has been increasing interest in the use of neoadjuvant therapy to obtain early control of occult metastatic disease, allow local tumor response to facilitate margin-negative resection, and provide a test of time and biology to assist with the selection of candidates most likely to benefit from radical surgical resection. However, limited guidance exists regarding the relative effectiveness of treatment options. In this systematic review, the American Radium Society multidisciplinary gastrointestinal expert panel convened to develop Appropriate Use Criteria evaluating the evidence regarding neoadjuvant treatment for patients with PDAC, including surgery, systemic therapy, and radiotherapy, in terms of oncologic outcomes and quality of life. The evidence was assessed using the Population, Intervention, Comparator, Outcome, and Study (PICOS) design framework and “Preferred Reporting Items for Systematic Reviews and Meta-analyses” 2020 methodology. Eligible studies included phases 2 to 3 trials, meta-analyses, and retrospective analyses published between January 1, 2012 and December 30, 2022 in the Ovid Medline database. A summary of recommendations based on the available literature is outlined to guide practitioners in the management of patients with PDAC.

Abstract INTRODUCTION Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS We included 436 patients from the European‐DLB consortium and the Mayo Clinic. Sex differences and sex‐by‐age interactions were assessed through visual atrophy rating scales ( n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness ( n = 165; 69 ± 9 years, 72% males). RESULTS We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex‐by‐age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. Highlights Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.

AbstractUnesbulin is being investigated in combination with dacarbazine (DTIC) as a potential therapeutic agent in patients with advanced leiomyosarcoma (LMS). This paper reports the pharmacokinetics (PK) of unesbulin, DTIC, and its unreactive surrogate metabolite 5‐aminoimidazole‐4‐carboxamide (AIC) in 29 patients with advanced LMS. Drug interactions between DTIC (and AIC) and unesbulin were evaluated. DTIC (1000 mg/m2) was administered to patients with LMS via 1‐h intravenous (i.v.) infusion on day 1 of every 21‐day (q21d) cycle. Unesbulin dispersible tablets were administered orally twice weekly (b.i.w.), starting on day 2 of every cycle, except for cycle 2 (C2), where unesbulin was dosed either on day 1 together with DTIC or on day 2, 1 day after DTIC administration. The PK of DTIC, AIC, and unesbulin in cycle 1 (C1) and C2 were estimated using noncompartmental analysis. DTIC and AIC were measurable immediately after the start of infusion and reached maximum plasma concentration (Cmax) immediately or shortly after end of infusion at 1.0 and 1.4 h (time to Cmax), respectively. Co‐administration of unesbulin orally at 200 mg or above with DTIC inhibited cytochrome P450 (CYP)1A2‐mediated DTIC metabolism, resulting in 66.7% reduction of AIC exposures. Such inhibition could be mitigated when unesbulin was dosed the day following DTIC infusion. Repeated unesbulin dosing demonstrated evidence of clinical CYP1A2 induction and increased AIC Cmax by 69.4% and area under concentration‐time curve to infinity by 57.9%. No meaningful difference in unesbulin PK was observed between C2 and C1. The combination therapy of 1000 mg/m2 i.v. DTIC q21d and 300 mg unesbulin b.i.w. in a staggered regimen is well‐tolerated in patients with LMS.

AbstractThe DPYD gene encodes dihydropyrimidine dehydrogenase, the rate‐limiting enzyme for the metabolism of fluoropyrimidines 5‐fluorouracil and capecitabine. Genetic variants in DPYD have been associated with altered enzyme activity, therefore accurate detection and interpretation is critical to predict metabolizer status for individualized fluoropyrimidine therapy. The most commonly observed deleterious variation is the causal variant linked to the previously described HapB3 haplotype, c.1129‐5923C>G (rs75017182) in intron 10, which introduces a cryptic splice site. A benign synonymous variant in exon 11, c.1236G>A (rs56038477) is also linked to HapB3 and is commonly used for testing. Previously, these single‐nucleotide polymorphisms (SNPs) have been reported to be in perfect linkage disequilibrium (LD); therefore, c.1236G>A is often utilized as a proxy for the function‐altering intronic variant. Clinical genotyping of DPYD identified a patient who had c.1236G>A, but not c.1129‐5923C>G, suggesting that these two SNPs may not be in perfect LD, as previously assumed. Additional individuals with c.1236G>A, but not c.1129‐5923C>G, were identified in the Children's Mercy Data Warehouse and the All of Us Research Program version 7 cohort substantiating incomplete SNP linkage. Consequently, testing only c.1236G>A can generate false‐positive results in some cases and lead to suboptimal dosing that may negatively impact patient therapy and prospect of survival. Our data show that DPYD genotyping should include the functional variant c.1129‐5923C>G, and not the c.1236G>A proxy, to accurately predict DPD activity.