Citations

ABSTRACT How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a guanine nucleotide-binding protein, which promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes nonhomologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard-of-care genotoxic treatments. The GTP–Rac1–PP5–Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in nonmalignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment. SIGNIFICANCE: A newly described GTP-dependent signaling axis is an unexpected link between nucleotide metabolism and DNA repair. Disrupting this pathway can overcome cancer resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues. This article is featured in Selected Articles from This Issue, p. 5

The Health Level 7 (HL7) organization introduced the Information Sensitivity Policy Value Set with 45 sensitive data categories to facilitate the implementation of granular electronic consent technology. The goal is to allow patients to have control over the sharing of their sensitive medical records. This study represents the first attempt to explore physicians’ viewpoints on these categories. Twelve physicians participated in a survey, leading to revisions in 21 HL7 categories. They later classified 600 clinical data items through a second survey using the updated categories. Participants’ perspectives were documented, and data analysis included descriptive measures and heat maps. In the first survey, six participants suggested adding 19 new categories (e.g., personality disorder), and modifying 25 category definitions. Two new categories and sixteen revised category definitions were incorporated to support more patient-friendly content and inclusive language. Fifteen new category recommendations were addressed through a revision of category definitions (e.g., personality disorder described as a behavioral health condition). In the second survey, data categorizations led to recommendations for more categories from ten participants. Future revisions of the HL7 categories should incorporate physicians’ viewpoints, validate the categories using patient data or/and include patients’ perspectives, and develop patient-centric category specifications.

339 Background: Limited health insurance literacy (HIL) has been linked to problems paying medical bills or delaying care among patients with cancer. In this study, we describe the prevalence and correlates of HIL in a cohort of cancer patients measured using a ten-question HIL quiz developed by the Kaiser Family Foundation. Methods: We examined HIL in 393 adult patients (aged >18 years) receiving cancer treatment in two ambulatory infusion centers, Mayo Clinic in Phoenix, Arizona (12/2019 to 2/2020 and 8/2020 to 10/2020) and University of Mississippi Medical Center in Jackson, Mississippi (9/2020 to 1/2021). HIL was categorized as low, moderate, or high based on the total number of correct answers: 0-4 (low), 5-6 (moderate), and 7-10 (high). Descriptive statistics characterized the sample and chi-square statistics compared HIL by sociodemographic factors. Results: Most patients understood basic insurance terms, such as premiums and deductibles (Table). However, fewer patients answered questions correctly about provider networks (46.1%), formularies (48.6%), and calculating out-of-pocket (OOP) spending (16.8%). 53 (13.5%), 69 (17.6%), and 271 (69.0%) patients had low, moderate, and high HIL scores, respectively. Lower HIL was more common among patients of younger age (<65 years: 17.8%, 65+ years: 8.7%), lower educational attainment (less than college: 23.2%; college or higher: 4.4%), and lower household income (<$4999: 21.1%, $5000+: 6.1%) (all p-values<0.05). Conclusions: Although HIL in our cohort of cancer patients was relatively high - 69% answered at least 7 questions correctly - there were gaps in understanding of provider networks, formularies, and calculation of OOP spending. Efforts to improve HIL and help with navigation of health insurance plans may be required, especially for socioeconomically vulnerable patients.[Table: see text]

269 Background: There are strong data showing that patients (pts) with metastatic non-small cell lung cancer (NSCLC) receiving chemotherapy experience better quality of life (QOL) and longer overall survival (OS) when palliative care (PC) services are integrated early in their treatment course. Therefore, at our cancer center, pts with stage IV NSCLC have been referred to PC by oncology providers. In this study, we evaluated the uptake of PC services, specifically in pts with NSCLC who received immune checkpoint inhibitors (ICIs). ICIs have been considered to have less severe or less frequent adverse effects as compared to chemotherapy, possibly leading to fewer referrals to PC. Methods: We conducted a retrospective review of all pts at the Mayo Clinic Cancer Center in Florida who received single-agent ICI therapy for the treatment of stage IV NSCLC at any point between July 1, 2015, and July 1, 2022. The primary aim was to evaluate the uptake of PC services before or during treatment with ICIs. Descriptive statistics were used to characterize pt demographics and outcomes. Results: 129 pts were identified. 53.4% were male, and 46.6% were female. The majority of pts (84.4%) were white. 62 pts (48.0%) were seen by a PC provider before or during ICI treatment; 41 of these (31.7%) were seen by PC after starting ICI therapy. When grouped by year of ICI initiation, 30/73 pts (41.0%) treated between 2015 and June 2018 were seen by a PC provider, as compared to 15/31 pts (48.3%) treated between July 2018 and June 2020 and 17/25 pts (68.0%) treated between July 2020 and July 2022. Interestingly, the majority of pts who received PC services in the 2020-2022 group (12/17, or 70.5%) were seen by a PC provider for the first time prior to ICI initiation, whereas the majority of pts who received PC services prior to July 2020 (37/45, or 82.2%) were seen by a PC provider for the first time after ICI initiation. The mean number of PC visits increased from 1.59 in the 2015-2018 group to 1.84 in the 2018-2020 group and 4.96 in the 2020-2022 group. Conclusions: Uptake of PC services in pts with stage IV NSCLC receiving single-agent ICIs at our cancer center has increased over time, which is encouraging. Nevertheless, the numbers remain suboptimal, with less than 70% of pts receiving PC services. We plan to develop a multidisciplinary quality improvement project involving implementation of a mechanism to ensure that most patients with stage IV NSCLC, regardless of the type of systemic treatment they receive, are receiving PC services.

Context.— Next-generation sequencing (NGS)–based assays are used for diagnosis of diverse inherited disorders. Limited data are available pertaining to interlaboratory analytical performance of these assays. Objective.— To report on the College of American Pathologists (CAP) NGS Germline Program, which is methods based, and explore the evolution in laboratory testing practices. Design.— Results from the NGS Germline Program from 2016–2020 were analyzed for interlaboratory analytical performance. Self-reported laboratory testing practices were also evaluated. Results.— From 2016–2020, a total of 297 laboratories participated in at least 1 program mailing. Of the 289 laboratories that provided information on tests offered, 138 (47.8%) offered only panel testing throughout their enrollment, while 35 (12.1%) offered panels and exome testing, 30 (10.4%) offered only exomes, 9 (3.1%) offered only genomes, and 15 (5.2%) offered panels, exomes, and genomes. The remainder (62 laboratories, 21.4%) changed their test offerings during the 2016–2020 timeframe. Considering each genomic position/interval, the median detection percentage at variant positions across the 2016–2020 mailings ranged from 94.3% to 100%, while at reference positions (no variant detected), the median correct response percentage was 100% across all mailings. When considering performance of individual laboratories, 89.5% (136 of 152) to 98.0% (149 of 152) of laboratories successfully met the detection threshold (≥90% of the variants present), while 94.6% (87 of 92) to 100% (163 of 163) of laboratories met the 95% specificity threshold across mailings. Conclusions.— Since the inception of this program, laboratories have consistently performed well. The median sensitivity and specificity of detection of sequence variants included in this program (eg, single nucleotide variants, insertions, and deletions) were 100.0%.

Background: Time-lapse incubators allow for ongoing evaluation of embryos without culture condition disruption. The use of time-lapse incubation has been shown to improve outcomes either by improving overall conditions or providing additional information to aid in embryo selection for transfer. Time-lapse incubators can also utilise morphokinetic models to rank embryos based on morphokinetic parameters. We sought to compare a morphokinetic model for embryo comparison to traditional morphologic evaluation. Aims: The aim of the study is to compare a morphokinetic model for embryo comparison to traditional morphologic evaluation. Settings and Design: This is a retrospective cohort design. Materials and Methods: Embryos cultured in a time-lapse culture system that had traditional morphologic evaluation, morphokinetic modelling and known live birth outcomes were included in this study. Embryos with unknown competence were excluded, including when two embryos were transferred with a single live birth resulted. Statistical Analysis Used: Receiver operating characteristic (ROC) curves were determined for both the morphologic analysis and the morphokinetic model on culture day 3 and day 5. Using the ROC-determined cutoff that optimised both sensitivity and specificity, a binary outcome for each test was analysed using agreement statistics to determine if one method of embryo evaluation was superior to the other. Results: Morphological and morphokinetic grading were both predictive of embryo competence on days 3 and 5. However, on day 3, morphologic grading was superior to morphokinetic grading with area under the curve (AUC) of 0.66 ( P < 0.001) and 0.58 ( P = 0.009), respectively. Contrarily, on day 5, the morphokinetic model had a higher AUC of 0.65 ( P = 0.03) compared to the morphologic grading, AUC 0.56 ( P = 0.02). Conclusion: Traditional morphology was noted to be a better diagnostic tool (higher AUC) on culture day 3 while a morphokinetic model was superior on day 5.

Abstract Intraductal carcinoma of the prostate (IDC-P) is a lethal prostate cancer subtype that generally coexists with invasive high-grade prostate acinar adenocarcinoma (PAC) but exhibits distinct biological features compared with concomitant adenocarcinoma. In this study, we performed whole-exome, RNA, and DNA-methylation sequencing of IDC-P, concurrent invasive high-grade PAC lesions, and adjacent normal prostate tissues isolated from 22 radical prostatectomy specimens. Three evolutionary patterns of concurrent IDC-P and PAC were identified: early divergent, late divergent, and clonally distant. In contrast to those with a late divergent evolutionary pattern, tumors with clonally distant and early divergent evolutionary patterns showed higher genomic, epigenomic, transcriptional, and pathologic heterogeneity between IDC-P and PAC. Compared with coexisting PAC, IDC-P displayed increased expression of adverse prognosis–associated genes. Survival analysis based on an independent cohort of 505 patients with metastatic prostate cancer revealed that IDC-P carriers with lower risk International Society of Urological Pathology (ISUP) grade 1–4 adenocarcinoma displayed a castration-resistant free survival as poor as those with the highest risk ISUP grade 5 tumors that lacked concurrent IDC-P. Furthermore, IDC-P exhibited robust cell-cycle progression and androgen receptor activities, characterized by an enrichment of cellular proliferation–associated master regulators and genes involved in intratumoral androgen biosynthesis. Overall, this study provides a molecular groundwork for the aggressive behavior of IDC-P and could help identify potential strategies to improve treatment of IDC-P. Significance: The genomic, transcriptomic, and epigenomic characterization of concurrent intraductal carcinoma and adenocarcinoma of the prostate deepens the biological understanding of this lethal disease and provides a genetic basis for developing targeted therapies.

Abstract The dismal outcome of acute leukemia undergoing immunophenotype-switch, compounded by the increased incidence in the era of immunotherapy, highlights the need for in-depth systemic studies. We investigated the clinicopathological, cytogenetic, and molecular features of 33 patients experiencing switch between acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The median duration from the primary diagnosis to lineage switch was 7.8 months, with the subsequent median survival being < 3 months. The majority experienced a transition from B-ALL to AML. The AML cases demonstrated a spectrum of differentiation, ranging from minimal to erythroid, with monocytic being the most common. Cytogenetic analysis revealed 11q23/KMT2A fusions as the most recurrent abnormalities (n = 18); also observed were complex karyotype, 7/7q-, 9p-/CDKN2A deletion, t(5;14)/TCLX3::BCL11b, t(8;9)/PCM1::JAK2, t(9;22)/BCR::ABL1, and t(12;19)/TCF3::ZNF384. Remarkably, in 60% of patients lacking KMT2A fusions, a chronic myeloid neoplasm was observed preceding the first leukemia. In contrast, no prior hematological malignancies were observed in KMT2A cases. Deep mutational profiling reinforced the inherent clonal relationship between the initial and subsequent leukemias, evident from the overlapping mutational signatures. The presence of distinct additional mutations across the two phases supports the long-standing theory of lineage switch emerging via divergent evolution of a multipotential progenitor.

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross‐sectional and prospective association analyses of blood‐derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole‐genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1‐SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04–1.12; P <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P =0.11) or in the reverse direction (β=−0.012; P =0.076). Additional bidirectional Mendelian randomization analyses revealed that low‐density lipoprotein cholesterol had a causal effect on mtDNA CN (β=−0.084; P <0.001), but the reverse direction was not significant ( P =0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low‐density lipoprotein cholesterol level ( P =0.52), whereas there was a strong direct causal effect of higher low‐density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=−0.092; P <0.001). Conclusions Our findings indicate that high low‐density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.