Predicting Clinical Outcomes of SARS-CoV-2 Drug Efficacy with a High-Throughput Human Airway Microphysiological System.

The average cost to bring a new drug from its initial discovery to a patient's bedside is estimated to surpass $2 billion and requires over a decade of research and development. There is a need for new drug screening technologies that can parse drug candidates with increased likelihood of clinical utility early in development in order to increase the cost-effectiveness of this pipeline. For example, during the COVID-19 pandemic, resources were rapidly mobilized to identify effective therapeutic treatments but many lead antiviral compounds failed to demonstrate efficacy when progressed to human trials. To address the lack of predictive preclinical drug screening tools, PREDICT96-ALI, a high-throughput (n = 96) microphysiological system (MPS)  that recapitulates primary human tracheobronchial tissue,is adapted for the evaluation of differential antiviral efficacy of native SARS-CoV-2 variants of concern. Here, PREDICT96-ALI resolves both the differential viral kinetics between variants and the efficacy of antiviral compounds over a range of drug doses. PREDICT96-ALI is able to distinguish clinically efficacious antiviral therapies like remdesivir and nirmatrelvir from promising lead compounds that do not show clinical efficacy. Importantly, results from this proof-of-concept study track with known clinical outcomes, demonstrate the feasibility of this technology as a prognostic drug discovery tool.

Exploration of Patient Retention in Seeking a Second Opinion: A Retrospective Cohort Study.

INTRODUCTION: It is common for cancer patients to seek a second opinion for a variety of reasons. Understanding what drives patients to choose to receive treatment with their second opinion provider may uncover opportunities to improve the second opinion process. Therefore, we sought to identify the patient, disease, and treatment characteristics that were associated with second opinion retention rates in patients seeking a second surgical opinion for breast, colon, and pancreatic cancer. METHODS: We conducted a retrospective cohort study to evaluate patients who sought a second opinion within a large academic health-care system for breast, colon, and pancreatic cancer. Electronic medical records were reviewed for second opinions. Patient demographics and characteristics were collected and compared between the retained group and the nonretained groups. RESULTS: A total of 237 patients obtained second opinions for breast, colorectal, and pancreatic cancer. Patients that were offered a different treatment plan at their second opinion were more likely to be retained for systemic therapy (P = 0.009) for pancreatic cancer and any treatment for colon cancer (P = 0.003). Seeing a radiation oncologist (P = 0.007) or a plastic surgeon (P = 0.02) during the multidisciplinary consultation increased retention rates for breast cancer. CONCLUSIONS: Surgeons can better identify patients that are more likely to be retained after a second opinion by the individual patient characteristics and treatment factors. Understanding the factors that lead to retention for these three cancer types may help physicians provide the best possible resources for most patients presenting for second opinion evaluations.

Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

Online and Offline Prioritization of Chemicals of Interest in Suspect Screening and Non-targeted Screening with High-Resolution Mass Spectrometry.

Recent advances in high-resolution mass spectrometry (HRMS) have enabled the detection of thousands of chemicals from a single sample, while computational methods have improved the identification and quantification of these chemicals in the absence of reference standards typically required in targeted analysis. However, to determine the presence of chemicals of interest that may pose an overall impact on ecological and human health, prioritization strategies must be used to effectively and efficiently highlight chemicals for further investigation. Prioritization can be based on a chemical's physicochemical properties, structure, exposure, and toxicity, in addition to its regulatory status. This Perspective aims to provide a framework for the strategies used for chemical prioritization that can be implemented to facilitate high-quality research and communication of results. These strategies are categorized as either "online" or "offline" prioritization techniques. Online prioritization techniques trigger the isolation and fragmentation of ions from the low-energy mass spectra in real time, with user-defined parameters. Offline prioritization techniques, in contrast, highlight chemicals of interest after the data has been acquired; detected features can be filtered and ranked based on the relative abundance or the predicted structure, toxicity, and concentration imputed from the tandem mass spectrum (MS2). Here we provide an overview of these prioritization techniques and how they have been successfully implemented and reported in the literature to find chemicals of elevated risk to human and ecological environments. A complete list of software and tools is available from https://nontargetedanalysis.org/.

PFAS ghosts: how to identify, evaluate, and exorcise new and existing analytical interference.

With increasing public awareness of PFAS, and their presence in biological and environmental media across the globe, comes a matching increase in the number of PFAS monitoring studies. As more matrices and sample cohorts are examined, there are more opportunities for matrix interferents to appear as PFAS where there are none (i.e., "seeing ghosts"), impacting subsequent reports. Addressing these ghosts is vital for the research community, as proper analytical measurements are necessary for decision-makers to understand the presence, levels, and potential risks associated with PFAS and protect human and environmental health. To date, PFAS interference has been identified in several matrices (e.g., food, shellfish, blood, tissue); however, additional unidentified interferents are likely to be observed as PFAS research continues to expand. Therefore, the aim of this commentary is several fold: (1) to create and support a publicly available dataset of all currently known PFAS analytical interferents, (2) to allow for the expansion of that dataset as more sources of interference are identified, and (3) to advise the wider scientific community on how to both identify and eliminate current or new analytical interference in PFAS analyses.

Analyte and matrix method extension of per- and polyfluoroalkyl substances in food and feed.

The development and expansion of analytical methods for per- and polyfluoroalkyl substances (PFAS) in food are essential for the continued monitoring of the United States (US) food supply and assessments of dietary exposure. In March 2022, the European Union Reference Laboratory for Halogenated Persistent Organic Pollutants in Feed and Food (EURL POPs) released a guidance document covering priority PFAS of interest, including analytical method parameters and limits of quantification (LOQs). As a result, the Food and Drug Administration (FDA) began method extension work to incorporate ten new additional analytes to method C-010.02 including long-chain perfluorosulfonic acids, fluorotelomer sulfonates, and perfluorooctane sulfonamide. Four long-chain carboxylic acids were also validated across all foods, which were previously added to C-010.02 but only validated in seafood. In December 2022, the European Union published Commission Regulation 2022/2388, establishing maximum levels for perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS) in certain foodstuffs, primarily fish, molluscs, crustaceans, and eggs. As a result, the FDA method was evaluated for performance in reaching LOQs defined in Commission Regulation (EU) 2022/1431. The FDA method was found to be able to reach all required LOQs for analytes in matrices with established maximum levels. Currently, method detection limits (MDLs), which are used by the FDA as the lower limit for reporting PFAS in surveillance samples, were in the same range as defined indicative levels. With further method modifications, required LOQs could be met in fruits, vegetables, and milk. Reaching the lower targeted LOQs for these food matrices will require moving the method to an instrument that can provide increased signal:noise gains at the lower limits of quantification.

Characterizing informational needs and information seeking behavior of patients with breast cancer.

BACKGROUND: Appropriate information may facilitate adjustment to cancer diagnoses. Our study aims to characterize informational satisfaction in breast cancer patients and assess resources used by patients to gain information. METHODS: Newly diagnosed Stage 0-III breast cancer patients seen at an academic medical center between May and September 2020 received questionnaires assessing information satisfaction. Patients indicated resources used to obtain information along with satisfaction with information received in various topics. A subset of questionnaire respondents completed semi-structured interviews. RESULTS: Fifty-two (35 â€‹%) patients completed the questionnaire. Patients received information from physicians (96 â€‹%), the internet (81 â€‹%), nurses (79 â€‹%), and fellow breast cancer patients (54 â€‹%). Interview participants preferred receiving information from providers when making medical decisions but found patient forums and social media to be important adjuncts for receiving information. CONCLUSION: Patients are satisfied with information received about diagnosis and treatment, but finances, sexual health, and fertility are less frequently discussed.

NCCN Guidelines® Insights: Cervical Cancer, Version 1.2024.

The NCCN Guidelines for Cervical Cancer provide recommendations for all aspects of management for cervical cancer, including the diagnostic workup, staging, pathology, and treatment. The guidelines also include details on histopathologic classification of cervical cancer regarding diagnostic features, molecular profiles, and clinical outcomes. The treatment landscape of advanced cervical cancer is evolving constantly. These NCCN Guidelines Insights provide a summary of recent updates regarding the systemic therapy recommendations for recurrent or metastatic disease.

A High-Throughput, High-Containment Human Primary Epithelial Airway Organ-on-Chip Platform for SARS-CoV-2 Therapeutic Screening.

COVID-19 emerged as a worldwide pandemic in early 2020, and while the rapid development of safe and efficacious vaccines stands as an extraordinary achievement, the identification of effective therapeutics has been less successful. This process has been limited in part by a lack of human-relevant preclinical models compatible with therapeutic screening on the native virus, which requires a high-containment environment. Here, we report SARS-CoV-2 infection and robust viral replication in PREDICT96-ALI, a high-throughput, human primary cell-based organ-on-chip platform. We evaluate unique infection kinetic profiles across lung tissue from three human donors by immunofluorescence, RT-qPCR, and plaque assays over a 6-day infection period. Enabled by the 96 devices/plate throughput of PREDICT96-ALI, we also investigate the efficacy of Remdesivir and MPro61 in a proof-of-concept antiviral study. Both compounds exhibit an antiviral effect against SARS-CoV-2 in the platform. This demonstration of SARS-CoV-2 infection and antiviral dosing in a high-throughput organ-on-chip platform presents a critical capability for disease modeling and therapeutic screening applications in a human physiology-relevant in vitro system.

Prospective Clinical Prognostication of Endometrial Carcinomas Based on Next-Generation Sequencing and Immunohistochemistry-Real-World Implementation and Results at a Tertiary Care Center.

Based on findings from The Cancer Genome Atlas and the Proactive Molecular Risk Classifier for Endometrial Cancer algorithm, endometrial carcinoma can now be stratified into 4 prognostically distinct subgroups based on molecular alterations and immunohistochemical (IHC) aberrations. In this study, we describe the de novo adoption and clinical reporting of prognostic subgroup classification based on next-generation sequencing (NGS) and IHC analyses of all endometrial carcinoma resections at a single institution, framed by the Exploration, Preparation, Implementation, and Sustainment model. Results from the first 13 months show 188 tumors underwent analysis by a combination of IHC and a medium-sized (56 analyzed genes) NGS-based assay. All cases were assigned as either POLE (POLE-mutated) (5.3%), mismatch repair deficient (27.7%), no specific molecular profile (45.7%), or p53 abnormal (21.3%) inclusive of multiple-classifier cases. NGS-based analysis revealed additional distinctions among the subgroups, including reduced levels of PI3K pathway activation in the p53 abnormal subgroup, an increased rate of CTNNB1 activating mutation in the no specific molecular profile subgroup, and lower TP53 mutation variant allele frequencies in POLE and mismatch repair deficient subgroups compared with the p53 abnormal subgroup. Overall, we describe the testing protocol, reporting, and results of a combination of NGS and IHC to prospectively prognosticate endometrial carcinomas at a single tertiary care center.

A practical guide to hybrid interstitial/intracavitary brachytherapy for locally-advanced cervical cancer.

PURPOSE: In select cases of locally advanced cervical cancer, a hybrid brachytherapy (HBT) approach consisting of a combined intracavitary (IC)/insterstitial (IS) implant can yield improved target coverage and/or decreased organ at risk dose compared to IC techniques while limiting invasiveness compared to IS techniques. METHODS AND MATERIALS: The technique involves placement of transvaginal and/or perineal needles in addition to the tandem and ring/ovoids using either a specialized applicator or free-hand placement. Following applicator and needle placement, brachytherapy may then be planned using principles similar to IC or IS techniques. During treatment planning, it can be helpful to obtain both MRI and CT imaging, as plastic MRI-compatible needles do not show up well on MRI. RESULTS: In patients where acceptable target coverage cannot be achieved using IC alone or doses to nearby OAR are too high, HBT should be evaluated. HBT can improve both dose to target and OAR while sparing patients the morbidity of perineal template-based interstitial brachytherapy. Specific scenarios where HBT may be preferred include bulky residual primary tumor especially with poor response to EBRT, extension into the lateral parametrium, vaginal extension of tumor, and an asymmetric target. Use of HBT can typically permit extension of dose coverage by an additional 1-2 cm beyond what can be achieved with an IC alone technique. CONCLUSION: HBT allows for improved therapeutic ratio by improving target volume coverage and/or lowering doses to OARs. Brachytherapists should be trained on the practical aspects of administering HBT to be able to offer a less invasive and impactful treatment option when appropriate.

Knowledge, attitudes, and behaviors with mask use and vaccines for COVID-19 prevention at 13 colleges and universities, April 2021.

Objectives: To understand college and university student knowledge, attitudes, and behaviors (KAB) regarding COVID-19 prevention strategies. Methods: Thirteen colleges and universities volunteered to conduct an anonymous electronic survey in April 2021 to assess students' KAB about mask use and vaccination to prevent COVID-19. Results: Three-quarters of students indicated they "Always" wore a mask correctly when in public indoor places. Of those not yet vaccinated, 55% expressed concern about unknown side effects. Over half of students were unsure or believe they do not need to continue wearing masks after vaccination and older students more likely to be vaccinated. There was a significant inverse correlation between intention of getting vaccinated and intention to attend a large indoor party without a mask. Conclusions: Colleges and universities are important to community efforts to slow the COVID-19 pandemic. The KAB findings can inform approaches to increase overall mask use and vaccination uptake among young students.

Breast cancer brain metastases localization and risk of hydrocephalus: a single institution experience.

PURPOSE: Brain metastases occur in up to one-third of patients with breast cancer. aromatase, a marker for estrogen activity that has been shown to promote such metastasis, heavily concentrates in certain midline structures of brain. We hypothesize that breast cancer metastasizes more often to brain areas with higher aromatase activity and that these patients have a higher risk of developing obstructive hydrocephalus. METHODS: In our retrospective review of 709 patients who underwent stereotactic radiosurgery (January 2014-May 2020), we identified 358 patients treated for metastatic breast or lung cancer. The MRI scan that first showed evidence of brain metastases was reviewed and number of metastases counted by location. Procedures used to treat obstructive hydrocephalus were recorded. Chi square test was used for statistical analysis. RESULTS: Of 358 patients, 99 patients with breast cancer had 618 brain metastases and 259 patients with lung cancer had 1487 brain metastases. Compared with expected distribution of brain metastases based on regional brain volumes and metastatic lung carcinoma as a control, patients with breast cancer more often had metastases to the cerebellum, diencephalon, medulla, and parietal lobe, and underwent significantly more neurosurgical interventions for treatment of obstructive hydrocephalus. CONCLUSION: Brain metastases in patients with breast cancer occurred more often along midline structures of the brain, which we believe may be associated with the increased estrogen activity in these structures. This finding is important for physicians who treat patients with metastatic breast cancer given the higher possibility of developing obstructive hydrocephalus.

Uterine Neoplasms, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 65,950 new uterine cancer cases will have occurred in 2022, with 12,550 deaths resulting from the disease. Endometrial carcinoma includes pure endometrioid cancer and carcinomas with high-risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Müllerian tumor], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately 3% of all uterine cancers. This selection from the NCCN Guidelines for Uterine Neoplasms focuses on the diagnosis, staging, and management of pure endometrioid carcinoma. The complete version of the NCCN Guidelines for Uterine Neoplasms is available online at NCCN.org.

Consensus Quality Measures and Dose Constraints for Breast Cancer From the Veterans Affairs Radiation Oncology Quality Surveillance Program and American Society for Radiation Oncology Expert Panel.

PURPOSE: Using evidence-based radiation therapy to direct care for patients with breast cancer is critical to standardize practice, improve safety, and optimize outcomes. To address this need, the Veterans Affairs (VA) National Radiation Oncology Program (NROP) established the VA Radiation Oncology Quality Surveillance Program to develop clinical quality measures (QMs). The VA NROP contracted with the American Society for Radiation Oncology to commission 5 Blue Ribbon Panels for breast, lung, prostate, rectal, and head and neck cancers. METHODS AND MATERIALS: The Breast Cancer Blue Ribbon Panel experts worked collaboratively with the NROP to develop consensus QMs for use throughout the VA system, establishing a set of QMs for patients in several areas, including consultation and work-up; simulation, treatment planning, and treatment; and follow-up care. As part of this initiative, consensus dose-volume histogram (DVH) constraints were outlined. RESULTS: In total, 36 QMs were established. Herein, we review the process used to develop QMs and final consensus QMs pertaining to all aspects of radiation patient care, as well as DVH constraints. CONCLUSIONS: The QMs and expert consensus DVH constraints are intended for ongoing quality surveillance within the VA system and centers providing community care for Veterans. They are also available for use by greater non-VA community measures of quality care for patients with breast cancer receiving radiation.

Exploring chemical space in non-targeted analysis: a proposed ChemSpace tool.

Non-targeted analysis (NTA) using high-resolution mass spectrometry allows scientists to detect and identify a broad range of compounds in diverse matrices for monitoring exposure and toxicological evaluation without a priori chemical knowledge. NTA methods present an opportunity to describe the constituents of a sample across a multidimensional swath of chemical properties, referred to as "chemical space." Understanding and communicating which region of chemical space is extractable and detectable by an NTA workflow, however, remains challenging and non-standardized. For example, many sample processing and data analysis steps influence the types of chemicals that can be detected and identified. Accordingly, it is challenging to assess whether analyte non-detection in an NTA study indicates true absence in a sample (above a detection limit) or is a false negative driven by workflow limitations. Here, we describe the need for accessible approaches that enable chemical space mapping in NTA studies, propose a tool to address this need, and highlight the different ways in which it could be implemented in NTA workflows. We identify a suite of existing predictive and analytical tools that can be used in combination to generate scores that describe the likelihood a compound will be detected and identified by a given NTA workflow based on the predicted chemical space of that workflow. Higher scores correspond to a higher likelihood of compound detection and identification in a given workflow (based on sample extraction, data acquisition, and data analysis parameters). Lower scores indicate a lower probability of detection, even if the compound is truly present in the samples of interest. Understanding the constraints of NTA workflows can be useful for stakeholders when results from NTA studies are used in real-world applications and for NTA researchers working to improve their workflow performance. The hypothetical ChemSpaceTool suggested herein could be used in both a prospective and retrospective sense. Prospectively, the tool can be used to further curate screening libraries and set identification thresholds. Retrospectively, false detections can be filtered by the plausibility of the compound identification by the selected NTA method, increasing the confidence of unknown identifications. Lastly, this work highlights the chemometric needs to make such a tool robust and usable across a wide range of NTA disciplines and invites others who are working on various models to participate in the development of the ChemSpaceTool. Ultimately, the development of a chemical space mapping tool strives to enable further standardization of NTA by improving method transparency and communication around false detection rates, thus allowing for more direct method comparisons between studies and improved reproducibility. This, in turn, is expected to promote further widespread applications of NTA beyond research-oriented settings.

Analysis of Per- and Poly(fluoroalkyl) Substances (PFASs) in Highly Consumed Seafood Products from U.S. Markets.

Seafood consumption has been identified as one of the major contributors of per- and poly(fluoroalkyl) substances (PFASs) to the human diet. To assess dietary exposure, highly consumed seafood products in the United States were selected for analysis. The analytical method previously used for processed food was extended to include four additional long-chain perflurocarboxylic acids (PFCAs), which have been reported in seafood samples. This method was single-lab-validated, and method detection limits were reported at 345 ng kg-1 for perfluorobutanoic acid (PFBA) and 207 ng kg-1 for perfluoropentanoic acid (PFPeA) and below 100 ng kg-1 for the rest of the PFAS analytes. The 81 seafood samples (clams, crab, tuna, shrimp, tilapia, cod, salmon, pollock) were analyzed for 20 PFASs using the updated analytical method. Most of the seafood packaging was also analyzed by Fourier transform infrared-attenuated total reflectance (FTIR-ATR) to identify packaging potentially coated with PFASs. None of the packaging samples in this study were identified as having PFASs. A wide range of concentrations was observed among the seafood samples, ranging from below the method detection limit to the highest concentration of 23 µg kg-1 for the sum of PFASs in one of the canned clam samples. Such a wide range is consistent with those reported in previous studies. The highest concentrations were reported in clams and crabs, followed by cod, tuna, pollock, tilapia, salmon, and shrimp. Technical perfluorooctanoic acid (PFOA) dominated the profile of the clam samples, which has been consistently found in other clam samples, especially in Asia. Long-chain PFCAs, specifically perfluoroundecanoic (PFUdA) and perfluorododecanoic (PFDoA), were the most frequently detected analytes across all seafood samples. The trends observed are comparable with those in the literature where benthic organisms tend to have the highest PFAS concentrations, followed by lean fish, fatty fish, and aquaculture. The results from this study will be used to prioritize future studies and to inform steps to reduce consumer exposure to PFASs.

The Kelowna template for combined intracavitary and interstitial brachytherapy for gynecologic malignancies: Design, application, treatment planning, dosimetric and treatment outcomes.

PURPOSE: We report the feasibility, experience, and early outcomes of the combined intracavitary and interstitial dedicated applicator using the Kelowna GYN template (Varian, Palo Alto, CA). METHODS AND MATERIALS: The Kelowna GYN template is CT compatible and used for the treatment of gynecologic cancers. In cases with patients that have an intact uterus, a modified applicator system using the Kelowna GYN template and a 3D printed adapter piece allows for compatibility with an intrautaerine tandem. RESULTS: We reviewed the treatment course of 23 patients comprising of 86 fractions of HDR treatment. Median D90 for cervical tumors (n = 7) was 82.4 Gy (range 77.7-92.6); for postoperative cervical tumors (n = 2) was 73.9 Gy (range 72.0-5.8); for vaginal tumors (n = 4) was 85.8 Gy (range 79.8-88.1); for recurrent endometrial (n = 10) was 86.9 Gy (range 74.8-103.2). Median EQD2 D2cc for bladder was 72.4 Gy (range 47.7-99.4), for rectum was 61.2 Gy (range 52.4-80.6), and for sigmoid colon of 50.5 Gy (44.3-66.9). At a median follow-up of 12 months, 2 patients had a local recurrence. Two patients had distant recurrence: one with carcinomatosis at 6 months, and one with pulmonary metastases at 3 months. No patients had late grade three toxicities. CONCLUSIONS: Our single institutional experience supports the use of the Kelowna template as a robust system as a combined IC-IS applicator resulting in versatile and reproducible implants for a variety of gynecologic malignancies.