Citations

Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in KRAS -mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC.

Background A classification system describing clinical presentation before aortic valve replacement (AVR) has recently been proposed (stable valve syndrome [SVS]), mildly symptomatic (progressive valve syndrome), or with acute and severe signs and symptoms (acute valve syndrome [AVS]). We aimed to evaluate the clinical impact, health care costs, and resource use associated with the mode of clinical presentation at the time of AVR among patients presenting with aortic stenosis. Methods Using the Market Clarity database (2017–2023), patients >18 years old with aortic stenosis and undergoing AVR (transcatheter or surgical) were included. Patients were categorized as SVS, progressive valve syndrome, or AVS based on their clinical presentation during the 1 year before AVR. All‐cause death, heart failure hospitalization, total health care costs (index hospitalization plus 1‐year follow‐up), and resource use were compared across clinical presentation groups using adjusted regression models. Results Of the 24 075 patients undergoing AVR for aortic stenosis, 270 (1.1%) had SVS, 10 195 (42.3%) progressive valve syndrome, and 13 610 (56.5%) AVS. Compared with SVS, AVS presentation was associated with increased risk of 1‐year death (adjusted hazard ratio [aHR], 2.93 [95% CI, 1.1–7.8]; P =0.03) and heart failure hospitalization (aHR, 4.15 [95% CI, 1.6–11.1]; P <0.01) after AVR. The total costs of AVR and 1‐year follow‐up were significantly higher in both the progressive valve syndrome (difference $27 410 [$13 507–$41 314]) and AVS groups (difference $36 267 [$22 302–$50 232]) compared with patients with SVS. Conclusions AVS was frequent among patients undergoing AVR and was associated with increase in death, heart failure hospitalization, health care costs, and resource use 1 year after AVR, and SVS presentation was associated with the best clinical and economic outcomes.

ABSTRACT Objectives To characterize practice patterns and outcomes in the management of low‐ and intermediate‐grade salivary gland carcinoma prior to the existence of treatment guidelines. Methods Analysis of a registry of patients who underwent parotid and submandibular gland resections for low‐and intermediate‐grade carcinomas between 2010 and 2019. Results Of all 786 patients included in the study, 726 (92%) had preoperative imaging and 653 (83%) had preoperative biopsy. Of the 729 patients with parotid gland cancer, the majority underwent superficial ( n = 384, 53%) or total ( n = 254, 35%) parotidectomy. In patients with facial nerve preservation, total parotidectomy was associated with a significant increase in transient facial weakness (72/177 (41%) vs. 82/311 (26%), RR 0.65, 95% CI 0.50–0.84, p < 0.05) and permanent facial nerve weakness (23/176 (13%) vs. 16/301 (5%), RR 0.41, 95% CI 0.22–0.75, p < 0.05) compared to superficial parotidectomy. Adjuvant radiation therapy ( RT ) was delivered to 285 (36%) patients. The proportion of patients receiving adjuvant RT declined significantly over the time period from 2015 to 2019 compared to 2010 to 2014 at 162/504 (32%) and 123/282 (44%), respectively ( RR 0.74, 95% CI 0.61–0.89, p < 0.05). When comparing the time periods from 2015 to 2019 and 2010 to 2014, there was no significant difference in local control rates ( RR 0.52, 95% CI 0.26–1.04, p = 0.06) or regional control rates ( RR 0.75, 95% CI 0.26–2.13, p = 0.58). Conclusions Management of low‐ and intermediate‐grade salivary cancer from 2010 to 2019 was variable, which is expected given the rarity and heterogeneity of the disease and the lack of treatment guidelines prior to 2021. Most patients with parotid malignancies underwent superficial or total parotidectomy. The extent of parotidectomy had an impact on facial nerve function outcomes. Delivery of adjuvant radiation trended down with time. The data presented here will support dissemination of the guidelines and provide data that could inform future trials. Level of Evidence 2b.

Abstract Background Despite 40 years of evidence supporting psychosocial interventions as a component of comprehensive cancer care, patients continue to report vast unmet psychosocial needs and distress. Cognitive behavioral therapies for cancer distress (CBT-C) are the most rigorously tested class of psychosocial interventions for cancer care. Purpose To report clinical effectiveness outcomes of cancer-related distress and self-efficacy following implementation of best-evidence CBT-C, adapted for a real-world, billable practice setting. Methods Patients who completed group-delivered, CBT-C (10 intervention hours, 5 sessions) in the practice setting were invited to enroll in a research study to document cancer distress across the year following CBT-C. Participants (n = 65) were primarily middle-aged (mean 50.5 years, 17% were young adults ≤40 years), female, and White. Analyses utilized mixed linear models with intent-to-treat procedures. Given group delivery and social skills training content within CBT-C, social self-efficacy was assessed as a potential treatment mechanism. Results Distress decreased across the year following CBT-C (mean score change of 20 points for YAs, 6 points for non-YAs), with statistically significant age x time effects. Within-person improvements in social self-efficacy scores were related to reductions in cancer distress, including distress subscales of intrusive thoughts, avoidant coping, and hyperarousal. The model explained 76.6% of the total variance in cancer distress. Conclusions This study demonstrates the effective translation of CBT-C from controlled research trials to the practice setting. CBT-C effectiveness within a mixed-cancer population and relatively rural region of the US is also supported. CBT-C can be effectively translated to the practice settings for which it is intended.

Background and Objectives The genetic basis of adult-onset multiple sclerosis (MS) is well-studied, but less is known about pediatric-onset MS (pedMS), comprising approximately 5% of all MS onsets. Mendelian randomization (MR) studies have demonstrated evidence for a causal association between MS and both 25-hydroxyvitamin D [25(OH)D] serum levels and genetic variation related to vitamin D receptor (VDR) binding. The objective was to identify whether VDR binding variants (VDR-BVs) previously implicated in adult-onset MS were associated with pedMS using genetic instrumental variables (GIVs). Methods Using previously identified VDR-BVs to construct individual GIVs with two-sample MR, we investigated associations with pedMS in 725 cases and 592 controls of European ancestry from the US Network of Pediatric MS Centers. Associations between each VDR-BV and pedMS were estimated using logistic regression adjusting for the first three genome-wide principal components. A significant interaction between a VDR-BV and 25(OH)D GIV provided evidence for a causal association unbiased by pleiotropy. Results One VDR-BV, rs2531804, previously associated with adult-onset MS, was also significantly associated with pedMS after multiple testing correction. Discussion This study is the first to use VDR-BVs from previous MR studies to demonstrate causal differences in VDR binding at a locus contributing to pedMS susceptibility.

Objectives: Surgical site infections (SSIs) are the most common hospital-acquired infections in the United States, of which methicillin-resistant Staphylococcus aureus (MRSA) accounts for 43%. Preoperative povidone-iodine nasal swab (PNS) is considered an effective and cost-saving treatment for Staphylococcus aureus decolonization. We aim to assess the impact of preoperative PNS on SSI incidence. Materials and Methods: This retrospective observational study utilized elective surgical cases between January 1, 2018 and May 31, 2023, at a single academic medical center. The cohort was divided into PNS and no PNS groups. The cohort was propensity-matched, and Pearson χ2/Kruskal-Wallis tests were performed to compare group differences. Multivariable logistic regression was utilized to compare events between cohorts before and after matching. An alpha of <0.05 was considered significant. Results: A total of 45,998 (22,999 per group) matched participants were evaluated. On multivariate regression, the non-PNS treatment group was associated with an increase in hospital overall SSI occurrence (OR: 1.48, P = 0.02) but not specifically in-hospital methicillin-sensitive Staphylococcus aureus SSI, MRSA-SSI, or any 30-day SSI (P > 0.05). Compared with PNS treatment and prophylactic antibiotics, in-hospital SSI was higher in the absence of PNS treatment (OR: 1.83, P < 0.001), antibiotic (OR: 2.63, P < 0.001), or both (OR: 2.06, P < 0.01). Compared with PNS treatment plus prophylactic antibiotic, in-hospital MRSA-SSI was only higher in the absence of antibiotic (OR: 2.92, P < 0.01) treatment. Conclusions: Preoperative treatment with PNS may reduce overall in-hospital SSI but has no independent impact on MRSA SSI.

PURPOSE Survival for patients with melanoma has recently improved. The propensity of melanoma to metastasize to the brain remains a common and serious feature of this disease. The purposes of this study were to evaluate prognostic factors for patients with newly diagnosed melanoma brain metastases (MBMs) in a large cohort treated with modern multimodal therapies, compare those results with those in prior eras, and update the Melanoma Graded Prognostic Assessment (GPA). METHODS Univariable and multivariable (MVA) analyses of prognostic factors and treatments associated with survival were performed on 1,796 patients with newly diagnosed MBM treated between January 01, 2015, and December 31, 2021, using a multi-institutional retrospective database. Multiple imputation was used to address missingness of potential predictors. Significant variables in combined MVA were used to update the Melanoma GPA. Comparisons were made with legacy cohorts. RESULTS Median survivals for cohorts A (1985-2007, n = 481), B (2006-2015, n = 823), and C (2015-2021, n = 1,796) were 6.7, 9.8, and 16.6 months and median follow-up times were 40.1, 43.6, and 48.8 months, respectively. In combined MVA, significant prognostic factors for survival were higher Karnofsky Performance Status, fewer MBMs, absence of extracranial metastases, lower serum lactate dehydrogenase, and no immunotherapy before MBM. These factors were incorporated into the updated Melanoma GPA. The combined median and 3-year survivals for patients with GPA 0-1, 1.5-2, and 2.5-4.0 were 5.4, 13.2, and 43.2 months and 12.4%, 28.8%, and 51.6%, respectively. CONCLUSION Prognostic factors have changed and survival has improved for patients with MBM but varies widely by GPA. The updated Melanoma GPA calculator (BrainMetGPA), available free online, can be used to estimate survival, individualize treatment, stratify clinical trials, guide surveillance, and augment clinical trial eligibility. Multidisciplinary treatment is essential. Trials are needed to elucidate the optimal sequencing of various therapeutic modalities.

Abstract Purpose Data regarding the incidence, onset, and management of complex outpatient antimicrobial therapy–induced neutropenia (COIN) are limited, and pharmacist involvement in COIN management has not been reported. This report describes the incidence, onset, and management of COIN at a large academic medical center. Methods This multisite retrospective cohort study examined adult patients undergoing serum laboratory monitoring for antimicrobials over a 4-year period. Patients receiving chemotherapy or immunosuppressants were excluded. Data collected included the antimicrobial regimen, complete blood count, duration of antimicrobial therapy until outcome occurrence, infectious syndrome, type of intervention, outcome, and pharmacist involvement. Logistic regression was used to assess risk factors for COIN incidence. The primary outcome was the incidence of COIN by antimicrobial drug. Results From 4,261 treatment episodes, 161 cases of COIN were identified (3.8% COIN incidence). The most common antimicrobials associated with COIN were intravenous piperacillin/tazobactam, cefepime, and meropenem. The majority of COIN events were attributed to a combination of at least 2 antimicrobials. Piperacillin/tazobactam was significantly associated with higher odds of developing COIN (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.04-3.34; P = 0.038), whereas ertapenem was associated with significantly lower odds of COIN (OR, 0.43; 95% CI, 0.24-0.77; P = 0.005). The median time to neutropenia diagnosis was 22 days (interquartile range, 14-29 days) from the time of inpatient antimicrobial start. Intervention for COIN occurred in 66.5% of cases, with neutrophil count recovering in 96.9% of these patients. Clinical pharmacists initiated 74.8% of interventions. Conclusion COIN can be effectively identified and managed by a multidisciplinary team reviewing routine laboratory monitoring, enabling most patients to safely complete antimicrobial treatment.

ABSTRACTObjectiveTo explore pre–hematopoietic stem cell transplant (HSCT) demographic, disease, and psychological factors predictive of future transplant regret and to determine post‐HSCT variables associated with regret.Patients and MethodsHSCT candidates participated in a prospective cohort study (June 2008–October 2013) examining health behaviors and HSCT outcomes, including completion of standardized surveys at pre‐HSCT (baseline) and 1‐year post‐HSCT. Cases were participants that endorsed regret at 1‐year post‐HSCT follow‐up, and controls were participants without regret at 1 year, matched on age, sex, and transplant type. For cases and controls, pre‐HSCT psychosocial evaluations were abstracted from the electronic health record and coded to determine the Psychosocial Assessment of Candidates for Transplantation score, psychosocial stressors, and mental health diagnoses. The association of selected factors with regret was estimated with odds ratios and 95% confidence intervals from conditional logistic regression models.ResultsAt post‐HSCT, 49 participants of 638 endorsed transplant regret (8%) and formed the case group; 98 controls were matched from remaining participants. Cases and controls were well matched on age (56.6 vs. 57.2 years), sex (both groups 34.7% female), and transplant type (both groups 81.6% autologous). After controlling for the number of hospitalizations and active treatment status, conditional logistic regression revealed that patients who endorsed regret were 3.7 times (95% CI = 1.37–9.69, p = 0.008) more likely to not be in remission compared to controls at 1‐year post‐HSCT.ConclusionMatched case–control analyses revealed that no pre‐HSCT variables collected during the pre‐HSCT evaluation period were predictive of transplant regret, while poorer outcomes at 1‐year after transplant were associated with regret.

Abstract Bisphosphonates (BPs) have been the major class of medicines used to treat disorders of excessive bone loss for over five decades. Recently it has been recognized that BPs may also have additional significant beneficial extra-skeletal effects. These include a reduction of all-cause mortality and of conditions commonly linked to ageing, such as cancer and cardiovascular disease. Here we show that bisphosphonates co-localize with lysosomal and endosomal organelles in non-skeletal cells and stimulate cell growth at low doses. In vivo spatial transcriptomic analysis revealed differentially expressed senescence markers in multiple organs of aged BP-treated mice, and a shift in cellular composition toward those of young counterparts. Similarly, a 5000-plex plasma proteome analysis from osteopenic patients before and after BP-treatment showed significant alterations in ∼400 proteins including GTPase regulators and markers of senescence, autophagy, apoptosis, and inflammatory responses. Furthermore, treatment with BPs protected against the onset of senescence in vitro . Proteome-wide target deconvolution using 2D thermal profiling revealed novel BP-binding targets (PHB2, ASAH1), and combined with RNA- and ATAC-seq of BP-treated cells and patient data, suggests downstream regulation of the MEF2A transcription factor within the heart. Collectively, these results indicate how BPs may beneficially modify the human plasma proteome, and directly impact multiple non-skeletal cell types through previously unidentified proteins, thereby influencing a range of pathways related to senescence and ageing.