Mismatch Repair and Microsatellite Testing for Individuals With Colorectal Cancer.

This cohort study examines the institution-level and patient-level factors associated with mismatch repair and microsatellite testing for individuals with colorectal cancer.

The Rise of Patients Declining Rectal Cancer Surgery in the Era of Total Neoadjuvant Therapy.

BACKGROUND: The treatment landscape for rectal cancer is rapidly evolving, particularly with the increasing use of neoadjuvant therapies. Still, up to 50% of patients with stage II-III disease require surgical resection post-neoadjuvant therapy to achieve the best oncologic outcomes. Many patients, however, hope to avoid surgery. This study aimed to assess trends and factors associated with declining recommended oncologic resection after systemic therapy nationally and in our institution. PATIENTS AND METHODS: This is a retrospective analysis using the National Cancer Database from 2009 to 2021 and an institutional cohort at an academic center between 2009 and 2022 including adults with stage I-III rectal adenocarcinoma who underwent neoadjuvant therapy and were suitable for surgery. RESULTS: Of 96,997 patients nationally, the rate of declining surgery increased from 2.3% in 2009 to 6.3% in 2021, a trend mirrored in our institutional cohort of 365 patients (0% in 2009/2010 to approximately 6-12% in 2021/2022). Locally, patients who declined surgery had higher rates of tobacco use, temporary loss to follow-up during therapy, and a more robust, albeit incomplete, tumor response to neoadjuvant therapy compared with controls who underwent surgery. Despite a stoma being the most cited reason for declining surgery, 30.4% of patients who declined oncologic resection died with a stoma. CONCLUSIONS: Our findings underscore a notable trend of patients declining oncologic resections following neoadjuvant therapy for rectal cancer. By shedding light on the outcomes of patients who opt against surgery, we address a critical gap in the literature essential for informing patients about potential risks.

Pan-lysyl oxidase inhibition disrupts fibroinflammatory tumor stroma, rendering cholangiocarcinoma susceptible to chemotherapy.

BACKGROUND: Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1-4) catalyze collagen cross-linking, thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA. METHODS: Resected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays. RESULTS: All 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy. CONCLUSIONS: CCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA.

The Open Pediatric Cancer Project.

Background: In 2019, the Open Pediatric Brain Tumor Atlas (OpenPBTA) was created as a global, collaborative open-science initiative to genomically characterize 1,074 pediatric brain tumors and 22 patient-derived cell lines. Here, we extend the OpenPBTA to create the Open Pediatric Cancer (OpenPedCan) Project, a harmonized open-source multi-omic dataset from 6,112 pediatric cancer patients with 7,096 tumor events across more than 100 histologies. Combined with RNA-Seq from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA), OpenPedCan contains nearly 48,000 total biospecimens (24,002 tumor and 23,893 normal specimens). Findings: We utilized Gabriella Miller Kids First (GMKF) workflows to harmonize WGS, WXS, RNA-seq, and Targeted Sequencing datasets to include somatic SNVs, InDels, CNVs, SVs, RNA expression, fusions, and splice variants. We integrated summarized CPTAC whole cell proteomics and phospho-proteomics data, miRNA-Seq data, and have developed a methylation array harmonization workflow to include m-values, beta-vales, and copy number calls. OpenPedCan contains reproducible, dockerized workflows in GitHub, CAVATICA, and Amazon Web Services (AWS) to deliver harmonized and processed data from over 60 scalable modules which can be leveraged both locally and on AWS. The processed data are released in a versioned manner and accessible through CAVATICA or AWS S3 download (from GitHub), and queryable through PedcBioPortal and the NCI's pediatric Molecular Targets Platform. Notably, we have expanded PBTA molecular subtyping to include methylation information to align with the WHO 2021 Central Nervous System Tumor classifications, allowing us to create research- grade integrated diagnoses for these tumors. Conclusions: OpenPedCan data and its reproducible analysis module framework are openly available and can be utilized and/or adapted by researchers to accelerate discovery, validation, and clinical translation.

Propagation of distinct CWD prion strains during peripheral and intracerebral challenges of gene-targeted mice.

Since prion diseases result from infection and neurodegeneration of the central nervous system (CNS), experimental characterizations of prion strain properties customarily rely on the outcomes of intracerebral challenges. However, natural transmission of certain prions, including those causing chronic wasting disease (CWD) in elk and deer, depends on propagation in peripheral host compartments prior to CNS infection. Using gene-targeted GtE and GtQ mice, which accurately control cellular elk or deer PrP expression, we assessed the impact that peripheral or intracerebral exposures play on CWD prion strain propagation and resulting CNS abnormalities. Whereas oral and intraperitoneal transmissions produced identical neuropathological outcomes in GtE and GtQ mice and preserved the naturally convergent conformations of elk and deer CWD prions, intracerebral transmissions generated CNS prion strains with divergent biochemical properties in GtE and GtQ mice that were changed compared to their native counterparts. While CWD replication kinetics remained constant during iterative peripheral transmissions and brain titers reflected those found in native hosts, serial intracerebral transmissions produced 10-fold higher prion titers and accelerated incubation times. Our demonstration that peripherally and intracerebrally challenged Gt mice develop dissimilar CNS diseases which result from the propagation of distinct CWD prion strains points to the involvement of tissue-specific cofactors during strain selection in different host compartments. Since peripheral transmissions preserved the natural features of elk and deer prions, whereas intracerebral propagation produced divergent strains, our findings illustrate the importance of experimental characterizations using hosts that not only abrogate species barriers but also accurately recapitulate natural transmission routes of native strains.

IRF5 suppresses metastasis through the regulation of tumor-derived extracellular vesicles and pre-metastatic niche formation.

Metastasis is driven by extensive cooperation between a tumor and its microenvironment, resulting in the adaptation of molecular mechanisms that evade the immune system and enable pre-metastatic niche (PMN) formation. Little is known of the tumor-intrinsic factors that regulate these mechanisms. Here we show that expression of the transcription factor interferon regulatory factor 5 (IRF5) in osteosarcoma (OS) and breast carcinoma (BC) clinically correlates with prolonged survival and decreased secretion of tumor-derived extracellular vesicles (t-dEVs). Conversely, loss of intra-tumoral IRF5 establishes a PMN that supports metastasis. Mechanistically, IRF5-positive tumor cells retain IRF5 transcripts within t-dEVs that contribute to altered composition, secretion, and trafficking of t-dEVs to sites of metastasis. Upon whole-body pre-conditioning with t-dEVs from IRF5-high or -low OS and BC cells, we found increased lung metastatic colonization that replicated findings from orthotopically implanted cancer cells. Collectively, our findings uncover a new role for IRF5 in cancer metastasis through its regulation of t-dEV programming of the PMN.

Demonstration of event position reconstruction based on diffusion in the NEXT-white detector.

Noble element time projection chambers are a leading technology for rare event detection in physics, such as for dark matter and neutrinoless double beta decay searches. Time projection chambers typically assign event position in the drift direction using the relative timing of prompt scintillation and delayed charge collection signals, allowing for reconstruction of an absolute position in the drift direction. In this paper, alternate methods for assigning event drift distance via quantification of electron diffusion in a pure high pressure xenon gas time projection chamber are explored. Data from the NEXT-White detector demonstrate the ability to achieve good position assignment accuracy for both high- and low-energy events. Using point-like energy deposits from 83mKr calibration electron captures (E∼45 keV), the position of origin of low-energy events is determined to 2 cm precision with bias <1mm. A convolutional neural network approach is then used to quantify diffusion for longer tracks (E≥1.5 MeV), from radiogenic electrons, yielding a precision of 3 cm on the event barycenter. The precision achieved with these methods indicates the feasibility energy calibrations of better than 1% FWHM at Qßß in pure xenon, as well as the potential for event fiducialization in large future detectors using an alternate method that does not rely on primary scintillation.

Patient and Care Partner Perspective on Potential Undertreatment of Patients With Mild Cognitive Impairment for Cardiovascular Disease.

BACKGROUND AND OBJECTIVES: Mild cognitive impairment (MCI) affects up to 22% of US older adults aged 65 and older. Research suggests that physicians may recommend less cardiovascular disease (CVD) treatment for older adults with MCI due to assumptions about their preferences. To delve into the disparity between patient preferences and physician assumptions in CVD treatment recommendations, we conducted a multi-site qualitative study to explore the underlying reasons for this discrepancy, providing insights into potential communication barriers and strategies to enhance patient-physician relationships. RESEARCH DESIGN AND METHODS: Employing a descriptive qualitative approach, we conducted interviews with 20 dyads, comprising older adults with MCI (n = 11) and normal cognition NC (n = 9), and their respective care partners. During these interviews, participants were prompted to reflect on physicians recommending fewer guideline-concordant CVD treatments to older adults with MCI than those with NC and physicians presuming that older adults with MCI desired less care or treatment in general than those with NC. RESULTS: We identified three primary themes: (1) Most participants had negative reactions to the data that physicians might undertreat patients with MCI for CVD; (2) Participants suggested that physicians may undertreat patients with MCI due to physician assumptions about treatment effectiveness, patient prognosis, value, and treatment adherence, and (3) Participants proposed that physicians may elicit less input from patients with MCI about treatments because of negative physician assumptions about patient decision-making capacity and physician time limitations. DISCUSSION AND IMPLICATIONS: This study underscores the pressing need for person-centered communication and involvement of older adults with MCI and their care partners in the decision-making process to ensure that decisions are well-informed, reflecting patients' genuine preferences and values. Addressing these concerns has the potential to substantially enhance the quality of care and treatment outcomes for this vulnerable population, ultimately promoting their overall well-being.

Management of Persistent Low-Suspicion Cervical Lymphadenopathy in Pediatric Patients.

INTRODUCTION: Cervical lymphadenopathy in children is typically self-limited; however, the management of persistent lymphadenopathy remains unclear. This study aimed to evaluate the management and outcomes of patients with persistent cervical lymphadenopathy. METHODS: Single-institution, retrospective review of children <18 years undergoing ultrasound (US) for cervical lymphadenopathy from 2013 to 2021 was performed. Patients were stratified into initial biopsy, delayed biopsy, or no biopsy groups. Clinical characteristics and workup were compared, and multivariate analyses were performed to assess predictors of delayed biopsy. RESULTS: 568 patients were identified, with 493 patients having no biopsy, 41 patients undergoing initial biopsy, and 34 patients undergoing delayed biopsy. Presenting symptoms differed: no biopsy patients were younger, were more likely to present to the emergency department, and had clinical findings often associated with acute illness. Patients with USs revealing abnormal vascularity or atypical architecture were more likely to be biopsied. History of malignancy, symptoms >1 week but <3 months, and atypical or change in architecture on US was associated with delayed biopsy. Patients with long-term follow-up (LTF) were followed for a median of 99.0 days. Malignancies were identified in 12 patients (2.1%). All malignancies were diagnosed within 14 days of presentation, and no malignancies were identified in LTF. CONCLUSIONS: Patients with persistent low suspicion lymphadenopathy are often followed for long durations; however, in this cohort, no malignancies were diagnosed during LTF. We propose an algorithm of forgoing a biopsy and employing primary care surveillance and education, which may be appropriate for these patients in the proper setting.

A clinician's guide to pulmonary hypertension.

ABSTRACT: Despite advances in diagnosis and treatment, pulmonary hypertension has high morbidity and mortality. The presenting symptoms often are vague and may mimic other more common diseases, so patients can be misdiagnosed or missed early in the disease process. Early detection of pulmonary hypertension by primary care providers can play an important role in patient outcomes and survival. Identifying signs and symptoms, understanding the causes and classifications, and knowing the systematic approach to evaluating and diagnosing patients with suspected pulmonary hypertension are key to preventing premature patient decline.

Association of freeze-dried plasma with 24-h mortality among trauma patients at risk for hemorrhage.

BACKGROUND: Blood products form the cornerstone of contemporary hemorrhage control but are limited resources. Freeze-dried plasma (FDP), which contains coagulation factors, is a promising adjunct in hemostatic resuscitation. We explore the association between FDP alone or in combination with other blood products on 24-h mortality. STUDY DESIGN AND METHODS: This is a secondary data analysis from a cross-sectional prospective observational multicenter study of adult trauma patients in the Western Cape of South Africa. We compare mortality among trauma patients at risk of hemorrhage in three treatment groups: Blood Products only, FDP + Blood Products, and FDP only. We apply inverse probability of treatment weighting and fit a multivariable Cox proportional hazards model to assess the hazard of 24-h mortality. RESULTS: Four hundred and forty-eight patients were included, and 55 (12.2%) died within 24 h of hospital arrival. Compared to the Blood Products only group, we found no difference in 24-h mortality for the FDP + Blood Product group (p = .40) and a lower hazard of death for the FDP only group (hazard = 0.38; 95% CI, 0.15-1.00; p = .05). However, sensitivity analyses showed no difference in 24-h mortality across treatments in subgroups with moderate and severe shock, early blood product administration, and accounting for immortal time bias. CONCLUSION: We found insufficient evidence to conclude there is a difference in relative 24-h mortality among trauma patients at risk for hemorrhage who received FDP alone, blood products alone, or blood products with FDP. There may be an adjunctive role for FDP in hemorrhagic shock resuscitation in settings with significantly restricted access to blood products.

Pediatric, Adolescent and Young Adult (AYA) Peritoneal and Pleural Mesothelioma: A National Cancer Database Review.

PURPOSE: Malignant peritoneal and pleural mesothelioma are rare in young patients, with a paucity of data regarding clinical characteristics and outcomes. We aimed to describe the clinical characteristics, treatment strategies, and outcomes for pediatric and adolescent/young adult (AYA) patients. METHODS: The National Cancer Database (NCDB) was queried for malignant peritoneal and pleural mesothelioma in pediatric and AYA patients (ages 0-39) from 2004 to 2019. Stratification was performed for pediatric (age 0-21) and young adult (age 22-39) patients. Chi-squared, multivariable cox regression, and Kaplan-Meier analyses were performed. RESULTS: We identified 570 total patients, 46 pediatric and 524 young adult, with mesothelioma (363 peritoneal and 207 pleural). There were significant differences in sex distribution as patients with peritoneal mesothelioma were more frequently female (63.1%). Patients with peritoneal mesothelioma were more likely to have radical surgery compared to pleural mesothelioma (56.7% v. 24.6%, respectively). A majority of patients with peritoneal and pleural mesothelioma received chemotherapy (66.4% and 61.4%, respectively). For peritoneal mesothelioma, surgical resection was associated with improved overall survival, whereas male sex, neoadjuvant chemotherapy, and radiation were associated with worse overall survival. For pleural mesothelioma, intraoperative chemotherapy was associated with improved overall survival, whereas Black race was associated with worse overall survival. Mean overall survival was greater for patients with peritoneal mesothelioma (125 months) compared to those with pleural mesothelioma (69 months), which remained significant after stratification of pediatric and young adult patients. CONCLUSION: By analyzing a large cohort of pediatric and AYA mesothelioma, this study highlights clinical, prognostic, and survival differences between peritoneal and pleural disease. LEVEL OF EVIDENCE: Level III. TYPE OF STUDY: Retrospective.

Estimating cutoff values for diagnostic tests to achieve target specificity using extreme value theory.

BACKGROUND: Rapidly developing tests for emerging diseases is critical for early disease monitoring. In the early stages of an epidemic, when low prevalences are expected, high specificity tests are desired to avoid numerous false positives. Selecting a cutoff to classify positive and negative test results that has the desired operating characteristics, such as specificity, is challenging for new tests because of limited validation data with known disease status. While there is ample statistical literature on estimating quantiles of a distribution, there is limited evidence on estimating extreme quantiles from limited validation data and the resulting test characteristics in the disease testing context. METHODS: We propose using extreme value theory to select a cutoff with predetermined specificity by fitting a Pareto distribution to the upper tail of the negative controls. We compared this method to five previously proposed cutoff selection methods in a data analysis and simulation study. We analyzed COVID-19 enzyme linked immunosorbent assay antibody test results from long-term care facilities and skilled nursing staff in Colorado between May and December of 2020. RESULTS: We found the extreme value approach had minimal bias when targeting a specificity of 0.995. Using the empirical quantile of the negative controls performed well when targeting a specificity of 0.95. The higher target specificity is preferred for overall test accuracy when prevalence is low, whereas the lower target specificity is preferred when prevalence is higher and resulted in less variable prevalence estimation. DISCUSSION: While commonly used, the normal based methods showed considerable bias compared to the empirical and extreme value theory-based methods. CONCLUSIONS: When determining disease testing cutoffs from small training data samples, we recommend using the extreme value based-methods when targeting a high specificity and the empirical quantile when targeting a lower specificity.

Exploring the Lived Experiences of Individuals With Spinal Cord Injury During the COVID-19 Pandemic.

The global spread of severe acute respiratory syndrome coronavirus 2019 (COVID-19) has affected over 100 countries and has led to the tragic loss of life, overwhelmed health care systems and severely impacted the global economy. Specifically, individuals living with spinal cord injury (SCI) are particularly vulnerable during the COVID-19 pandemic as they often face adverse impacts on their health, emotional well-being, community participation, and life expectancy. The objective of this study was to investigate the lived experience of individuals with SCI during the COVID-19 pandemic in Ontario, Canada. An exploratory design with a qualitative descriptive approach was used to address the study objective. Nine semi-structured interviews were conducted with individuals with traumatic and non-traumatic SCI (37-69 years, C3-L5, AIS A-D, and 5-42 years post-injury). Using reflexive thematic analysis, the following themes were created: (1) Caregiver exposure to COVID-19; (2) Staying physically active in quarantine; (3) Living in social isolation; (4) Difficulty obtaining necessary medical supplies; (5) Access to health services and virtual care during COVID-19; and (6) Fighting COVID-19 misinformation. This is one of the first studies to explore the impact of COVID-19 on individuals living with SCI in Ontario. This study contributes to a greater understanding of the challenges faced by individuals living with SCI and provides insight into how to better support and respond to the specific and unique needs of individuals with SCI and their families during a national emergency or pandemic.

Role of interferon regulatory factor 5 (IRF5) in tumor progression: Prognostic and therapeutic potential.

Canonically, the transcription factor interferon regulatory factor 5 (IRF5) is a key mediator of innate and adaptive immunity downstream of pathogen recognition receptors such as Toll-like receptors (TLRs). Hence, dysregulation of IRF5 function has been widely implicated in inflammatory and autoimmune diseases. Over the last few decades, dysregulation of IRF5 expression has been also reported in hematologic malignancies and solid cancers that support a role for IRF5 in malignant transformation, tumor immune regulation, clinical prognosis, and treatment response. This review will provide an in-depth overview of the current literature regarding the mechanisms by which IRF5 functions as either a tumor suppressor or oncogene, its role in metastasis, regulation of the tumor-immune microenvironment, utility as a prognostic indicator of disease, and new developments in IRF5 therapeutics that may be used to remodel tumor immunity.

Implementing an electronic sideband offset lock for isotope shift spectroscopy in radium.

We demonstrate laser frequency stabilization with at least 6 GHz of offset tunability using an in-phase/quadrature (IQ) modulator to generate electronic sidebands (ESB) on a titanium sapphire laser at 714 nm and we apply this technique to perform isotope shift spectroscopy of 226Ra and 225Ra. By locking the laser to a single resonance of a high finesse optical cavity and adjusting the lock offset, we determine the frequency difference between the magneto-optical trap (MOT) transitions in the two isotopes to be 2630.0 ± 0.3 MHz, a factor of 29 more precise than the previously available data. Using the known value of the hyperfine splitting of the 3P1 level, we calculate the isotope shift for the 1S0 to 3P1 transition to be 2267.0 ± 2.2 MHz, a factor of 8 more precise than the best available value. Our technique could be applied to countless other atomic systems to provide unprecedented precision in isotope shift spectroscopy and other relative frequency comparisons.