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BackgroundAnti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction.Patients and methodsWe conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation.ResultsWe studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2).Conclusions: ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.

Background: Parapneumonic empyema continues to be a disease of significant morbidity and mortality among children despite recent advances in medical management. To date, only a limited number of studies have assessed the burden of empyema in Asia.Methods: We surveyed medical records of four representative large pediatric hospitals in China, Korea, Taiwan and Vietnam using ICD-10 diagnostic codes to identify children <16 years of age hospitalized with empyema or pleural effusion from 1995 to 2005. We also accessed microbiology records of cultured empyema and pleural effusion specimens to describe the trends in the epidemiology and microbiology of empyema.Results: During the study period, we identified 1,379 children diagnosed with empyema or pleural effusion (China, n = 461; Korea, n = 134; Taiwan, n = 119; Vietnam, n = 665). Diagnoses of pleural effusion (n = 1,074) were 3.5 times more common than of empyema (n = 305), although the relative proportions of empyema and pleural effusion noted in hospital records varied widely between the four sites, most likely because of marked differences in coding practices. Although pleural effusions were reported more often than empyema, children with empyema were more likely to have a cultured pathogen. In addition, we found that median age and gender distribution of children with these conditions were similar across the four countries. Among 1,379 empyema and pleural effusion specimens, 401 (29%) were culture positive. Staphylococcus aureus (n = 126) was the most common organism isolated, followed by Streptococcus pneumoniae (n = 83), Pseudomonas aeruginosa (n = 37) and Klebsiella (n = 35) and Acinetobacter species (n = 34).Conclusion: The age and gender distribution of empyema and pleural effusion in children in these countries are similar to the US and Western Europe. S. pneumoniae was the second leading bacterial cause of empyema and pleural effusion among Asian children. The high proportion of culture-negative specimens among patients with pleural effusion or empyema suggests that culture may not be a sufficiently sensitive diagnostic method to determine etiology in the majority of cases. Future prospective studies in different countries would benefit from standardized case definitions and coding practices for empyema. In addition, more sensitive diagnostic methods would improve detection of pathogens and could result in better prevention, treatment and outcomes of this severe disease. [ABSTRACT FROM AUTHOR]

Background: Effective techniques for eliciting patients' preferences regarding their own care, when treatment options offer marginal gains and different risks, is an important clinical need. We sought to evaluate the association between patients' considerations of the time burdens of care ("time toxicity") with decisions about hypothetical treatment options., Methods: We conducted a secondary analysis of a multicenter, mixed-methods study that evaluated patients' attitudes and preferences toward palliative-intent cancer treatments that delayed imaging progression-free survival (PFS) but did not improve overall survival (OS). We classified participants based on if they spontaneously volunteered one or more consideration of time burdens during qualitative interviews after treatment trade-off exercises. We compared the percentage of participants who opted for treatments with no PFS gain, some PFS gain, or who declined treatment regardless of PFS gain (in the absence of OS benefit). We conducted narrative analysis of themes related to time burdens., Results: The study cohort included 100 participants with advanced cancer (55% women, 63% age > 60 years, 38% with gastrointestinal cancer, and 80% currently receiving cancer-directed treatment. Forty-six percent (46/100) spontaneously described time burdens as a factor they considered in making treatment decisions. Participants who mentioned time (vs not) had higher thresholds for PFS gains required for choosing additional treatments (P value .004). Participants who mentioned time were more likely to decline treatments with no OS benefit irrespective of the magnitude of PFS benefit (65%, vs 31%). On qualitative analysis, we found that time burdens are influenced by several treatment-related factors and have broad-ranging impact, and illustrate how patients' experiences with time burdens and their preferences regarding time influence their decisions., Conclusions: Almost half of participating patients spontaneously raised the issue of time burdens of cancer care when making hypothetical treatment decisions. These patients had notable differences in treatment preferences compared to those who did not mention considerations of time. Decision science researchers and clinicians should consider time burdens as an important attribute in research and in clinic., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: Salivary gland tumors include numerous subtypes that vary from benign to highly aggressive, with many showing overlapping histopathological features that can make diagnosis challenging. Most subtypes express driver fusion genes that are tumor specific, and detection of such fusions is useful for differentiating amongst specific diagnoses, determining appropriate tumor grading, and guiding effective treatment. Currently, fusions can be detected by FISH, RT-PCR or through next-generation sequencing approaches, all of which are highly effective methodologies but can be costly or time consuming., Methods: We developed a rapid NanoString nCounter platform-based assay to detect salivary gland tumor fusions using a combination of fusion junction-specific probes and an approach through differential exon expression analysis. The assay includes 68 junction-specific probes and analysis of exon expression across 9 fusion-associated genes in a single multiplex assay., Results: Out of 55 retrospective and 171 prospective cases assayed, we accurately detected the majority of cases of pleomorphic adenoma, adenoid cystic carcinoma, cribriform adenocarcinoma, clear cell carcinoma, secretory carcinoma and NUT-rearranged carcinoma, including cases of these tumor types arising in non-salivary gland sites, with the major drawback being an inability to detect MAML2-containing mucoepidermoid samples. With mucoepidermoid carcinoma excluded, the assay shows an overall sensitivity of 96.1% and specificity of 100%., Conclusion: We show that the majority of salivary gland tumor fusions can be effectively detected with a single rapid NanoString based assay, which can serve as a useful adjunctive tool for routine diagnostic head and neck pathology. The assay is low cost with a rapid turnaround time (30 h total assay time per sample batch, with minimal technician input required) compared to alternate detection methods., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objective: The composition of gut microbiota plays an important role in predicting and influencing outcomes of cancer treated with immunotherapy. Our objective is to summarize the role of gut microbiota and immunotherapy in breast cancer., Methods: A systematic search from inception until July 2024 of key search terms including immunity, breast neoplasm, gastrointestinal microbiome/microbiota, fecal microbiota transplantation, pro- and prebiotics, antibiotics and immunotherapy using EMBASE, MEDLINE and CENTRAL was conducted. The results were screened by two reviewers independently and synthesized and presented descriptively., Key Content and Findings: Thirteen studies (5 clinical, 8 pre-clinical) met the eligibility criteria and were published from 2020-2024. Clinical studies showed that the composition and diversity of gut microbiota was associated with patient response to immunotherapy. In pre-clinical studies, dysbiotic states induced by obesity, antibiotics, and diet were associated with immunosuppression and influenced response to programmed cell death-ligand 1 (PD-L1) inhibitors. Microbiota-modulating treatments such as probiotics showed the ability to enhance response to immunotherapy, indicating their potential use as adjunct therapies in breast cancer treatment., Conclusions: The composition of gut microbiota could help predict the chance of response to immunotherapy, and modulating gut microbiota has the potential to enhance the efficacy of chemo-immunotherapy in breast cancer. However, the available data relating to breast cancer are limited. Larger prospective studies are required to further elucidate their role as a biomarker and treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-24-14/coif). T.L.N. serves as the editorial board member of Translational Breast Cancer Research from November 2022 to October 2024. T.L.N. is a post-conference abstract review speaker with AstraZeneca Canada and Lilly Canada and a speaker with the Canadian Breast Cancer Network. He has been a COMPASS Ad board member with Novartis Canada, an ad board member with Knight Therapeutics, and a CONNECT MBC panel member with Gilead Sciences. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Most (60%-80%) of the oral cavity invasive squamous cell carcinoma (OSCC) demonstrate molecular alterations in TP53. The presence of TP53 mutations in multiple organ systems has been associated with a more aggressive clinical course. This study aimed to classify OSCC into p53 wild-type OSCC and p53-abnormal OSCC using p53 immunohistochemistry and to determine if abnormal p53 status correlates with a higher risk of lymph node metastasis at the time of surgery. A total of 101 patients with OSCC resection and cervical lymph node dissection were identified. p53 immunohistochemistry was performed for all cases and scored into p53 wild-type (p53-HPV: midepithelial/basal sparing, markedly reduced [null-like]/basal sparing; p53-conventional: scattered basal, patchy basal/parabasal) and p53-abnormal (overexpression basal/parabasal only, overexpression basal/parabasal to diffuse, null, and cytoplasmic) patterns. p16 immunohistochemistry and high-risk HPV RNA in situ hybridization were used to confirm the HPV status in cases showing midepithelial/basal sparing or markedly reduced (null-like)/basal sparing pattern. Logistic regression analysis was performed to investigate the association of p53 status, tumor size, depth of invasion, and pT stage against lymph node status. We identified 22 cases with p53 wild-type patterns (16 p53-conventional, 6 p53-HPV) and 79 cases with p53-abnormal patterns. Two of 22 p53 wild-type cases had positive lymph nodes (1 p53-conventional, 1 p53-HPV), whereas 40 of 79 p53-abnormal cases had positive lymph nodes (P < .001). Multivariate analysis showed that p53-abnormal pattern was an independent risk factor associated with positive node(s) with an odds ratio of 8.12 (95% CI, 2.10-53.78; P = .008). p53-Abnormal OSCCs were significantly more likely to be associated with positive lymph node status than p53 wild-type OSCCs at the time of surgery. Further investigation with long-term follow-up is required to determine its clinical application before surgery planning., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: Pneumocystis jirovecii pneumonia (PJP) prophylaxis is required by provincial and national drug monographs during glioma treatment using temozolomide (TMZ) concurrently with radiation (TMZ-RT). However, real-world data suggest the potential benefits of PJP prophylaxis may not outweigh its potential harms in this population., Methods: We conducted a single-center patient survey and a national physician survey to explore the role of PJP prophylaxis amongst glioma patients undergoing TMZ-RT., Results: 23% (31/133) of physicians and 60% (44/73) of patients completed a survey. The median patient age was 42 (range 20-77); 85% (34/40) had completed adjuvant TMZ. Although only 2.4% (1/41) of patients received PJP prophylaxis, only one person (without PJP prophylaxis) was hospitalized for pneumonia. When presented with hypothetical PJP risks, 13.2% (5/38) of patients were concerned about PJP infection, while 26% (10/38) were concerned about potential side effects from prophylactic antibiotics. Most physicians (77%, 17/22) perceived the evidence for PJP prophylaxis as weak; 58% (11/19) did not routinely prescribe prophylaxis, and 73% (16/22) felt that PJP prophylaxis should be limited to patients with additional risk factors. Over 95% of physicians estimated that the incidence of PJP was < 1% in their last 5 years of practice regardless of PJP prophylaxis. For 73% (16/22) of physicians, to prescribe PJP prophylaxis, the risk of PJP infection needed to be 3-8%., Conclusion: The current recommendation to routinely prescribe PJP prophylaxis in patients receiving TMZ-RT in the absence of other risk factors warrants reconsideration., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Vasomotor symptoms (VMS) are common among individuals with breast cancer (BC) and poorly managed symptoms are associated with reduced quality of life, treatment discontinuation, and poorer breast cancer outcomes. Direct comparisons among therapies are limited, as prior studies evaluating VMS interventions have utilized heterogeneous change measures which may not fully assess the perceived impact of change in VMS severity., Methods: We performed a prospective study where BC patients chose one of four categories of interventions to manage VMS. Change in VMS severity at 6 weeks was assessed using the validated Hot Flush Rating Scale (HFRS). A novel weighted change score integrating baseline symptom severity and directionality of change was computed to maximize the correlation between the change score and a perceived treatment effectiveness score. Variables influencing change in VMS severity were included in a regression tree to model factors influencing the weighted change score., Results: 100 baseline and follow-up questionnaires assessing VMS were completed by 88 patients. Correlations between treatment effectiveness and VMS outcomes strengthened following adjustment for baseline symptoms. Patients with low VMS severity at baseline did not perceive change in treatment effectiveness. Intervention category was predictive of change in HFRS at 6 weeks., Conclusion: Baseline symptom severity and the directionality of change (improvement or deterioration of symptoms) influenced the perception of clinically meaningful change in VMS severity. Future interventional studies utilizing the weighted change score should target moderate-high baseline severity patients., (© 2024. The Author(s).)

Background: Currently, prostate cancer (PCa) prebiopsy medical image diagnosis mainly relies on mpMRI and PI-RADS scores. However, PI-RADS has its limitations, such as inter- and intra-radiologist variability and the potential for imperceptible features. The primary objective of this study is to evaluate the effectiveness of a machine learning model based on radiomics analysis of MRI T2-weighted (T2w) images for predicting PCa in prebiopsy cases., Method: A retrospective analysis was conducted using 820 lesions (363 cases, 457 controls) from The Cancer Imaging Archive (TCIA) Database for model development and validation. An additional 83 lesions (30 cases, 53 controls) from Hong Kong Queen Mary Hospital were used for independent external validation. The MRI T2w images were preprocessed, and radiomic features were extracted. Feature selection was performed using Cross Validation Least Angle Regression (CV-LARS). Using three different machine learning algorithms, a total of 18 prediction models and 3 shape control models were developed. The performance of the models, including the area under the curve (AUC) and diagnostic values such as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were compared to the PI-RADS scoring system for both internal and external validation., Results: All the models showed significant differences compared to the shape control model (all p < 0.001, except SVM model PI-RADS+2 Features p = 0.004, SVM model PI-RADS+3 Features p = 0.002). In internal validation, the best model, based on the LR algorithm, incorporated 3 radiomic features (AUC = 0.838, sensitivity = 76.85%, specificity = 77.36%). In external validation, the LR (3 features) model outperformed PI-RADS in predictive value with AUC 0.870 vs. 0.658, sensitivity 56.67% vs. 46.67%, specificity 92.45% vs. 84.91%, PPV 80.95% vs. 63.64%, and NPV 79.03% vs. 73.77%., Conclusions: The machine learning model based on radiomics analysis of MRI T2w images, along with simulated biopsy, provides additional diagnostic value to the PI-RADS scoring system in predicting PCa.

Concerns exist regarding increased toxicities, including endocrine therapy toxicity, with concurrent radiation and endocrine therapy in early breast cancer (EBC). We present a pragmatic, randomized trial comparing concurrent versus sequential endocrine and radiotherapy in hormone-responsive EBC. In this multicenter trial, patients were randomized to receive adjuvant endocrine therapy concurrent with, or sequential to, radiotherapy. The primary outcome was change in endocrine therapy toxicity from baseline to 3 months post radiotherapy using the Functional Assessment of Cancer Therapy-Endocrine Symptom (FACT-ES) score. From September 2019 to January 2021, 133 patients were randomized to concurrent endocrine and radiotherapy, and 127 to sequential treatment. Most patients were post-menopausal (72.7%, 189/260) with stage 1 disease (65.8%, 171/260). Tamoxifen was the endocrine therapy of choice for 69.6% (181/260) of patients, and an aromatase inhibitor for the remainder. The median total radiation dose and fractions were 40.1 Gray (range 26-50) and 15 fractions (range 5-25), respectively. For the primary outcome of change in endocrine therapy toxicity per FACT-ES scores from baseline to 3 months post radiotherapy, no significant difference was found between the groups (median [range] = -4.9 (-82, 38.8) for concurrent and -5.1 (-42, 40) for sequential, p = 0.87). This is the first trial to investigate the impact of concurrent versus sequential adjuvant endocrine and radiotherapy on endocrine therapy-related toxicities. The findings provide further support to allow the optimal timing of radiation and endocrine therapy to be tailored for the individual patient.

Objective: To conduct a randomized controlled trial examining the effects of a social network intervention on health., Participants and Methods: The Microclinic Social Network Program randomized controlled trial (implemented from June 1, 2011, through December 31, 2014) delivered weekly social-health classroom interventions for 9 to 10 months vs standard of care. Longitudinal multilevel analyses examined end-of-trial and 6-month post-intervention outcomes. Social network effects were estimated via a novel social induction ratio., Results: We randomized 494 participants, comprising 27 classroom clusters from five neighborhood cohorts. Compared with controls, the intervention showed decreased body weight - 6.32 pounds (95% CI, - 8.65 to - 3.98; overall P<.001), waist circumference - 1.21 inches (95% CI, - 1.84 to - 0.58; overall P<.001), hemoglobin A 1c % change - 1.60 (95% CI, - 1.88 to - 1.33; overall P<.001), mean arterial blood pressure - 1.83 mm Hg (95% CI, - 3.79 to 0.32; overall P<.01), borderline-increased high-density lipoprotein cholesterol 1.09 (95% CI, 0.01-2.17; P=.05; overall P=.01). At 6 months post-intervention, net improvements were: weight change 97% sustained (P<.001), waist circumference change 92% sustained (P<.001), hemoglobin A 1c change 82.5% sustained (P<.001), high-density lipoprotein change 79% sustained (overall P=.01), and mean arterial blood pressure change greater than 100% sustained improvement of - 4.21 mm Hg (P<.001). Mediation analysis found that diet and exercise did not substantially explain improvements. In the intent-to-treat analysis of social causal induction, the weight-change social induction ratio (SIR) was 1.80 for social-network weight change-meaning that social networks explained the greater weight loss in the intervention than controls. Furthermore, we observed an even stronger weight-loss SIR of 2.83 at 6 months post-intervention., Conclusion: Results show intervention effectiveness for improving health in resource-limited communities, with SIR demonstrating that social-network effects helped induce such improvements., Trial Registration: Clinicaltrials.gov Identifier NCT01651065., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Chemotherapy-induced nausea and vomiting (CINV) is a common toxicity that may impair the quality of life of patients with various malignancies ranging from early to end stages. In light of frequent changes to the guidelines for optimal management of CINV, we undertook this narrative review to compare the most recent guidelines published by ASCO (2020), NCCN (2023), MASCC/ESMO (2023), and CCO (2019). The processes undertaken by each organization to evaluate existing literature were also described. Although ASCO, NCCN, MASCC/ESMO, and CCO guidelines for the treatment and prevention of CINV share many fundamental similarities, the literature surrounding low and minimal emetic risk regimens is lacking. Current data regarding adherence to these guidelines is poor and warrants further investigation to improve care., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Microbial bioremediation can provide an environmentally friendly and scalable solution to treat contaminated soil and water. However, microbes have yet to optimize pathways for degrading persistent anthropogenic pollutants, in particular organohalides. In this work, we first expand our repertoire of enzymes useful for bioremediation. By screening a panel of cobalamin (B 12 )-dependent reductive dehalogenases, we identified previously unreported enzymes that dechlorinate perchloroethene and regioselectively deiodinate the thyroidal disruptor 2,4,6-triiodophenol. One deiodinase, encoded by the animal-associated anaerobe Clostridioides difficile , was demonstrated to dehalogenate the naturally occurring metabolites L-halotyrosines. In cells, several combinations of ferredoxin oxidoreductase and flavodoxin extract and transfer low-potential electrons from pyruvate to drive reductive dehalogenation without artificial reductants and mediators. This work provides new insights into a relatively understudied family of B 12 -dependent enzymes and sets the stage for engineering synthetic pathways for degrading unnatural small molecule pollutants.

p53 immunohistochemistry (IHC) has recently been shown to be a clinically useful marker for predicting risk of progression to invasive squamous cell carcinoma in oral epithelial dysplasia (OED). The literature supports the use of p53 IHC as a marker to identify TP53 mutation in in situ and invasive vulvar lesions and as a surrogate marker for high-risk human papillomavirus (HPV) infection, but there is little documentation for similar use in OED. The purpose of this study was to determine whether p53 IHC is a reliable surrogate marker for detecting both TP53 mutation and high-risk HPV infection in OED. We studied 57 cases of OED (11 mild, 18 moderate, and 28 severe), and all were stained for p16 and p53 IHC. High-risk HPV RNA in situ hybridization (ISH) was performed in selected cases (all p16-positive cases and all OED showing abundant apoptotic cells and karyorrhectic cells; N = 27). Targeted next-generation sequencing (NGS) was performed in 33 p16-negative cases and all high-risk HPV RNA ISH-negative cases (N = 36). We identified 21 cases with p53 basal sparing patterns (mid-epithelial and markedly reduced [null-like]), 14 cases with p53 wild-type patterns (scattered basal and patchy basal/parabasal), and 22 cases with p53 abnormal patterns (18 overexpression, 3 null, and 1 novel cytoplasmic pattern). Among cases with p53 basal sparing patterns, 20 were positive for p16 (20/21, 95%), and all were positive for high-risk HPV RNA ISH (21/21, 100%). The 36 sequenced cases had IHC patterns concordant with TP53 mutation status in 92% (33/36) of lesions. This study demonstrates that p53 IHC expression patterns are sensitive and specific for detection of both high-risk HPV infection and TP53 mutation. Coupled with selective p16 IHC testing, this IHC panel can accurately subclassify OED into HPV-associated, p53 wild-type (conventional), and p53 abnormal OED., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Neither paclitaxel plus trastuzumab (P-H) nor docetaxel-cyclophosphamide plus trastuzumab (TC-H) have been prospectively compared in HER2-positive early-stage breast cancer (EBC). A randomized trial was performed to assess the feasibility of a larger study., Methods: Lower-risk HER2-positive EBC patients were randomized to either P-H or TC-H treatment arms. The co-primary feasibility outcomes were: ≥75% patient acceptability rate, active trial participation of ≥50% of medical oncologists, ≥75% and ≥90% treatment completion, and receipt rate of planned cycles of chemotherapy, respectively., Secondary Outcomes: Febrile neutropenia (FN) rate, treatment-related hospitalizations, health-related quality of life (HR-QoL) questionnaires. Analyses were performed by per protocol and intention-to-treat., Results: Between May 2019 and March 2021, 49 of 52 patients agreed to study participation (94% acceptability rate). Fifteen (65%) of 23 medical oncologists approached patients. Rates of FN were higher (8.3% vs. 0%) in the TC-H vs. P-H arm. Median (IQR) changes in scores from baseline in FACT-Taxane Trial Outcome Index at 24 weeks were -4 (-10, -1) vs. -6.5 (-15, -2) for TC-H and P-H arms, respectively., Conclusions: A randomized trial comparing P-H and TC-H was feasible. Expansion to a larger trial would be feasible to explore patient-reported outcomes of these adjuvant HER2 chemotherapy regimens.

Azaserine is a bacterial metabolite containing a biologically unusual and synthetically enabling α-diazoester functional group. Herein, we report the discovery of the azaserine (aza) biosynthetic gene cluster from Glycomyces harbinensis. Discovery of related gene clusters reveals previously unappreciated azaserine producers, and heterologous expression of the aza gene cluster confirms its role in azaserine assembly. Notably, this gene cluster encodes homologues of hydrazonoacetic acid (HYAA)-producing enzymes, implicating HYAA in α-diazoester biosynthesis. Isotope feeding and biochemical experiments support this hypothesis. These discoveries indicate that a 2-electron oxidation of a hydrazonoacetyl intermediate is required for α-diazoester formation, constituting a distinct logic for diazo biosynthesis. Uncovering this biological route for α-diazoester synthesis now enables the production of a highly versatile carbene precursor in cells, facilitating approaches for engineering complete carbene-mediated biosynthetic transformations in vivo., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The diagnosis of oral epithelial dysplasia is based on the degree of architectural and cytologic atypia in the squamous epithelium. The conventional grading system of mild, moderate, and severe dysplasia is considered by many the gold standard in predicting the risk of malignant transformation. Unfortunately, some low-grade lesions, with or without dysplasia, progress to squamous cell carcinoma (SCC) in short periods. As a result, we are proposing a new approach to characterize oral dysplastic lesions that will help identify lesions at high risk for malignant transformation. We included a total of 203 cases of oral epithelial dysplasia, proliferative verrucous leukoplakia, lichenoid, and commonly observed mucosal reactive lesions to evaluate their p53 immunohistochemical (IHC) staining patterns. We identified 4 wild-type patterns, including scattered basal, patchy basal/parabasal, null-like/basal sparing, mid-epithelial/basal sparing, and 3 abnormal p53 patterns, including overexpression basal/parabasal only, overexpression basal/parabasal to diffuse, and null. All cases of lichenoid and reactive lesions exhibited scattered basal or patchy basal/parabasal patterns, whereas human papillomavirus-associated oral epithelial dysplasia demonstrated null-like/basal sparing or mid-epithelial/basal sparing patterns. Of the oral epithelial dysplasia cases, 42.5% (51/120) demonstrated an abnormal p53 IHC pattern. p53 abnormal oral epithelial dysplasia was significantly more likely to progress to invasive SCC when compared to p53 wild-type oral epithelial dysplasia (21.6% vs 0%, P < .0001). Furthermore, p53 abnormal oral epithelial dysplasia was more likely to have dyskeratosis and/or acantholysis (98.0% vs 43.5%, P < .0001). We propose the term p53 abnormal oral epithelial dysplasia to highlight the importance of utilizing p53 IHC stain to recognize lesions that are at high risk of progression to invasive disease, irrespective of the histologic grade, and propose that these lesions should not be graded using the conventional grading system to avoid delayed management., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background and Objective: The gut microbiome has emerged as an important gateway to improving therapeutic outcomes in lung cancer, especially for immunotherapy. Our objective is to review the impact of the bidirectional relationship between the gut microbiome, lung cancer, and the immune system, and to identify areas of future research., Methods: We conducted a search on PubMed, EMBASE, and ClinicalTrials.gov using the search terms non-small cell lung cancer (NSCLC), gut microbiome, and microbiota until July 11, 2022. The authors screened resulting studies independently. Results were synthesized and presented descriptively., Key Content and Findings: Sixty original published studies were identified from PubMed (n=24) and EMBASE (n=36), respectively. Twenty-five ongoing clinical studies were identified on ClinicalTrials.gov. Gut microbiota has been shown to influence tumorigenesis and modulate tumor immunity via local and neurohormonal mechanisms depending on the microbiome ecosystem that populates the gastrointestinal tract. Probiotics, antibiotics, and proton pump inhibitors (PPIs), amongst other medications, can impact gut microbiome health, leading either to improved or worsened therapeutic outcomes with immunotherapy. Most clinical studies assess the impact of the gut microbiome, but emerging data suggest microbiome composition in other host sites may be important., Conclusions: A strong relationship exists between gut microbiome, oncogenesis, and anticancer immunity. Although the underlying mechanisms are poorly understood, immunotherapy outcomes seem to depend on host-related factors such as gut microbiome alpha diversity, relative abundance of microbial genera/taxa, and extrinsic factors such as prior or concurrent exposure to probiotics, antibiotics, and other microbiome-modifying drugs., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-595/coif). HS has received travel awards from Canadian Clinical Trials Group and Canadian Lung Cancer Conference. TLN has received academic research funds from sources without industry or commercial ties. In the past 3 years, TLN has participated in several Advisory boards with Novartis and Knight Therapeutics, has received payment for providing an educational talk to Takeda Canada staff about their product brigatinib, and has received a research grant from Takeda Oncology for an IIT in 2017. The authors have no other conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Outcomes for patients with high-grade glioma remain poor. Temozolomide (TMZ) is the only drug approved for first-line treatment of glioblastoma multiforme, the most aggressive form of glioma. Chronotherapy highlights the potential benefit of timed TMZ administration. This is based on pre-clinical studies of enhanced TMZ-induced glioma cytotoxicity dependent on circadian, oscillating expression of key genes involved in apoptosis, DNA damage repair, and cell-cycle mediated cell death. The current systematic review's primary aim was to evaluate the efficacy and toxicity of TMZ chronotherapy. A systemic review of literature following PRISMA guidelines looking at clinical outcomes on TMZ chronotherapy on gliomas was performed. The search in the English language included three databases (PubMed, EMBASE, and Cochrane) and five conferences from 1946 to April 2022. Two independent reviewers undertook screening, data extraction, and risk-of-bias assessment. A descriptive analysis was conducted due to limited data. Of the 269 articles screened, two unique studies were eligible and underwent abstraction for survival and toxicity findings. Both studies-one a retrospective cohort study (n = 166) and the other a prospective randomized feasibility study (n = 35)-were conducted by the same academic group and suggested a trend for improved overall survival, but possibly increased toxicity when TMZ was administered in the morning (vs. evening). There was limited evidence suggesting possible therapeutic value from administering TMZ in the morning, which may be consistent with the pre-clinical observations of the importance of the timing of TMZ administration in vitro. Larger, pragmatic, prospective randomized controlled trials are needed to ascertain the value of TMZ chronotherapy to provide optimized and equitable care for this population.

Sarcomas are a diverse group of tumors, with >70 subtypes in the current World Health Organization classification, each with distinct biological behavior requiring specific clinical management. A significant portion of sarcomas are molecularly defined by expression of a driver fusion gene; identification of such fusions is the basis of molecular diagnostics in sarcomas, which is of increasing complexity due to the ongoing discovery of new gene fusions. Recently, a multiplex NanoString platform-based assay was developed and clinically implemented, with fusion junction-spanning probes that detect the majority of sarcoma fusion types, with high sensitivity and specificity, and with lower cost and shorter turnaround time than those of targeted next-generation sequencing-based alternatives. Despite the effectiveness of this assay, there are several entities for which fusion-junction probes are not suitable due to multiple possible gene partners or excessive variability at the exon junctions. Here, the development and evaluation of a companion assay are described that uses NanoString-based gene expression analysis to detect aberrant 3'/5' exon expression imbalance and/or total gene overexpression as a surrogate marker for fusion gene rearrangement. This assay evaluates exon imbalance in 23 genes involved in over 25 mesenchymal tumor types and five genes specific to sarcomas with CIC rearrangements. Based on evaluation of 115 retrospectively and 91 prospectively collected cases, an assay sensitivity of 92.8% and specificity of 93.5% are demonstrated., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Both oncogenic and tumor suppressor roles have been assigned to Notch signaling in melanoma. In clinical trials, Notch inhibitors proved to be ineffective for melanoma treatment. Notch signaling has also been implicated in melanoma transdifferentiation, a prognostic feature in primary melanoma. In this study, we investigated the role of Notch signaling in melanoma tumor development and growth using the genetic model of mouse melanoma by crossing BRAFCA/+/Pten+/+/Tyr-CreER+ (B) and BRAFCA/+/Pten-/-/Tyr-CreER + (BP) mice with Notch1 or Notch2 floxed allele mice. The topical application of tamoxifen induced tumors in BP mice but not in B mice with or without the deletion of either Notch1 or Notch2. These data show that the loss of either Notch1 nor Notch2 can substitute the tumor suppressor function of Pten in BRAFV600E-induced melanomagenesis. However, in Pten-null background, the loss of either Notch1 or Notch2 appeared to accelerate BRAFV600E-induced tumor development, suggesting a tumor suppressor role for Notch1 and Notch2 in BRAFV600E/Pten-null driven melanomagenesis. Quantitative immunochemical analysis of a human cutaneous melanoma tissue microarray that consists of >100 primary tumors with complete clinical history showed a weak to moderate correlation between NOTCH protein levels and clinical and pathological parameters. Our data show that Notch signaling is involved during melanomagenesis and suggest that the identification of genes and signaling pathways downstream of Notch could help devise strategies for melanoma prevention.

NUT carcinoma (NC) is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT fusion oncoproteins (the most frequent fusion partner being BRD4 ) that carries a very poor prognosis, with most patients dying in under 1 year. Only rare primary thyroid NCs have been reported. Here, we evaluated a series of 14 cases. The median patient age at diagnosis was 38 years (range: 17 to 72 y). Eight of 13 cases with slides available for review (62%) showed a morphology typical of NC, whereas 5 (38%) had a non-NC-like morphology, some of which had areas of cribriform or fused follicular architecture resembling a follicular cell-derived thyroid carcinoma. For cases with immunohistochemistry results, 85% (11/13) were positive for NUT on biopsy or resection, though staining was significantly decreased on resection specimens due to fixation; 55% (6/11) were positive for PAX8, and 54% (7/13) for TTF-1. Tumors with a non-NC-like morphology were all positive for PAX8 and TTF-1. The fusion partner was known in 12 cases: 9 (75%) cases had a NSD3-NUTM1 fusion, and 3 (25%) had a BRD4-NUTM1 fusion. For our cohort, the 2-year overall survival (OS) was 69%, and the 5-year OS was 58%. Patients with NC-like tumors had a significantly worse OS compared with that of patients with tumors with a non-NC-like morphology ( P =0.0462). Our study shows that NC of the thyroid can mimic other thyroid primaries, has a high rate of NSD3 - NUTM1 fusions, and an overall more protracted clinical course compared with nonthyroid primary NC., Competing Interests: Conflicts of Interest and Source of Funding: Supported by a research grant from the National Institutes of Health (NCI, CA124633 to C.A.F.) and Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748 (R.A.G and B.X.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: ROS1- and ALK-rearranged advanced NSCLCs are associated with increased thromboembolic risk. We hypothesized that a prothrombotic phenotype offers an evolutionary advantage to subsets of these cancers. The impact of this phenotype could alter outcomes from targeted therapy., Methods: In a retrospective analysis of ROS1- and ALK-rearranged NSCLCs treated with crizotinib in a phase 1 trial, we compared progression-free survival (PFS) and objective response rate (ORR) based on the history of anticoagulation use (a possible surrogate of thromboembolism) at baseline (within 90 days before study enrollment) or within 90 days of study treatment., Results: Twelve out of 53 (22.6%) ROS1- and 39 out of 153 (25.5%) ALK-rearranged NSCLCs received anticoagulation before or during the trial. Most ROS1 and ALK patients on anticoagulation received low-molecular-weight heparin (75% and 64.1%, respectively). In the ROS1-rearranged group, the median PFS (95% CI) values were 5.1 (4.4-14.4) and 29.0 (16.5-48.8) months, and the ORR values were 41.7% (95% CI: 15.2 to 72.3) and 80.5% (95% CI: 65.1 to 91.2) among those with and without anticoagulation treatment, respectively. In the ALK-rearranged group, the median PFS (95% CI) was 7.1 (5.4-7.7) and 12.0 (9.4-18.3) months, and the ORR was 41% (95% CI: 25.6 to 57.9) and 74.3% (95% CI: 65.3 to 82.1) among those with and without anticoagulation, respectively., Conclusions: Anticoagulation (as a potential surrogate of a prothrombotic subset) in ROS1- and ALK-rearranged NSCLCs may be associated with a lower PFS and ORR to crizotinib., Clinicaltrial: gov: NCT00585195., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Antibody responses to off-target cancer-associated proteins have been detected following immunotherapies for cancer, suggesting these may be the result of antigen spread. We have previously reported that serum antibodies to prostate cancer-associated proteins were detectable using a high-throughput peptide array. We hypothesized that the breadth of antibody responses elicited by a vaccine could serve as a measure of the magnitude of its induced antigen spread. Consequently, sera from patients with prostate cancer, treated prior to or after vaccination in one of four separate clinical trials, were evaluated for antibody responses to an array of 177,604 peptides derived from over 1600 prostate cancer-associated gene products. Antibody responses to the same group of 5680 peptides previously reported were identified following vaccinations in which patients were administered GM-CSF as an adjuvant, but not with vaccine in the absence of GM-CSF. Hence, antibody responses to off-target proteins following vaccination may not necessarily serve as evidence of antigen spread and must be interpreted with particular caution following vaccine strategies that use GM-CSF, as GM-CSF appears to have direct effects on the production of antibodies. The evaluation of T cell responses to non-target antigens is likely a preferred approach for detection of immune-mediated antigen spread., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Prophylaxis against infusion-related reactions (IRR) from paclitaxel with steroids and antihistamines is a standard of care due to high rates of IRR. This systematic review and meta-analysis aimed to comprehensively summarize the evidence behind various prophylaxis strategies., Methods: EMBASE, MEDLINE, PubMed, and the Cochrane Register of Controlled Trials were searched (1946 to May 14, 2021). The primary outcomes were Grade 3/4 IRR and any-grade IRR. Secondary outcomes included treatment delay or discontinuation and adverse events secondary to pre-medications., Results: Of the 1285 unique citations, 26 studies were selected: 11 studies for quantitative analysis and 15 studies for qualitative analysis. Studies included randomized controlled trials and observational studies (n = 25-281). There was a non-significant benefit in favour of oral steroids starting 12 h prior to paclitaxel administration versus intravenous steroids immediately prior to paclitaxel administration for grade 3/4 IRRs, with a risk difference (RD) of 2% [95%CI 0 to 5%], any-grade IRR with a RD of 4% [95%CI: -1% to 9%] and treatment discontinuation with a RD of 1% [95%CI -1% to 2%]. For de-escalation strategies, a point-estimate for any-grade IRR was 0.44% [95% CI, 0 to 0.02, p = 0.98] and for grade 3/4 IRR was 3.1% (95% CI, 0.02 to 0.07, p = 0.11)., Conclusion: Although studies have high risk of bias and risk, differences between steroid routes of administration were small, there was a non-significant trend in favour of oral steroids. De-escalation strategies after two previous successful paclitaxel infusions have an overall low incidence rate of severe IRR and warrant further prospective clinical trials. Insufficient evidence remains to recommend for or against other interventions for the prevention of paclitaxel IRR., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The effect of longer-term use of bone-modifying agent (BMA) on symptomatic skeletal event (SSE) rates in patients with bone metastases remains unclear. This retrospective study of a cohort of patients in a randomized controlled trial evaluated SSEs in patients receiving BMAs at a single cancer center., Methods: Data from patients with metastatic breast and castration-resistant prostate cancer (CRPC) were interrogated to evaluate the effects of longer-term use of BMAs on incidence, type, and risk factors for SSEs., Results: Of 162 patients, 109 (67%) had breast cancer (BC) and 53 (33%) CRPC. Median age at diagnosis of bone metastases was 61.9 years (range 27.5-97.2) for BC patients and 72.1 (range 37.0-92.2) for CRPC patients. Median duration of BMA use was 2.3 years (range 0.1-9.9 years) for BC and 3.8 years (range 1.5-9.4) for CRPC patients. The initial BMAs in BC patients were pamidronate (46.8%), denosumab (31.2%), and zoledronate (22%). All CRPC patients received denosumab. During follow-up, 59% of BC and 75% of CRPC patients had at least one SSE. The number of patients experiencing ≥ 1 SSE per year was higher in the first year after bone metastasis diagnosis (63/162; 38.9%) compared with that in the second (26/149; 17.5%) and third years (30/123; 24.4%). Neither age, visceral disease, multiple bone metastases, nor biological markers for BC had a significant impact on time to first SSE., Conclusions: The risk for SSEs was greatest in the first year after diagnosis of bone metastasis. Studies evaluating de-escalation and even stopping of BMAs with longer-term use may therefore be warranted., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Suppression of the host innate immune response is a critical aspect of viral replication. Upon infection, viruses may introduce one or more proteins that inhibit key immune pathways, such as the type I interferon pathway. However, the ability to predict and evaluate viral protein bioactivity on targeted pathways remains challenging and is typically done on a single-virus or -gene basis. Here, we present a medium-throughput high-content cell-based assay to reveal the immunosuppressive effects of viral proteins. To test the predictive power of our approach, we developed a library of 800 genes encoding known, predicted, and uncharacterized human virus genes. We found that previously known immune suppressors from numerous viral families such as Picornaviridae and Flaviviridae recorded positive responses. These include a number of viral proteases for which we further confirmed that innate immune suppression depends on protease activity. A class of predicted inhibitors encoded by Rhabdoviridae viruses was demonstrated to block nuclear transport, and several previously uncharacterized proteins from uncultivated viruses were shown to inhibit nuclear transport of the transcription factors NF-κB and interferon regulatory factor 3 (IRF3). We propose that this pathway-based assay, together with early sequencing, gene synthesis, and viral infection studies, could partly serve as the basis for rapid in vitro characterization of novel viral proteins. IMPORTANCE Infectious diseases caused by viral pathogens exacerbate health care and economic burdens. Numerous viral biomolecules suppress the human innate immune system, enabling viruses to evade an immune response from the host. Despite our current understanding of viral replications and immune evasion, new viral proteins, including those encoded by uncultivated viruses or emerging viruses, are being unearthed at a rapid pace from large-scale sequencing and surveillance projects. The use of medium- and high-throughput functional assays to characterize immunosuppressive functions of viral proteins can advance our understanding of viral replication and possibly treatment of infections. In this study, we assembled a large viral-gene library from diverse viral families and developed a high-content assay to test for inhibition of innate immunity pathways. Our work expands the tools that can rapidly link sequence and protein function, representing a practical step toward early-stage evaluation of emerging and understudied viruses.

Aim: Conduct a systematic review of the effectiveness of systemic therapies for adult recurrent glioblastoma (rGBM)., Methods: We electronically searched for randomized controlled trials from three major databases and four conferences from 2009-Dec 2020. Two independent reviewers conducted screening, data extraction, and quality assessment., Results: 48 randomized trials were identified. Outcome reporting was inconsistent: overall survival (OS) in 46 studies, progression free survival in 37 studies, 6-month PFS in 30 studies, objective response rate in 28 studies, and 6-month OS in 7 studies. Network meta-analysis was not feasible due to heterogeneity in outcome reporting and single-study linkages. Most studies compared lomustine (8 studies), bevacizumab (18), or temozolomide (8) with other treatments. The median OS across all studies ranged from 3 to 17.6 months., Conclusions: Based on level one evidence, there is no superior systemic regimen for rGBM. rGBM is a heterogeneous population with no single regimen demonstrating OS benefit. Registration number: CRD42020148512., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Older patients with lower-risk hormone receptor-positive (HR+) breast cancer are frequently offered both radiotherapy (RT) and endocrine therapy (ET) after breast-conserving surgery (BCS). A survey was performed to assess older patients' experiences and perceptions regarding RT and ET, and participation interest in de-escalation trials. Of the 130 patients approached, 102 eligible patients completed the survey (response rate 78%). The median age of respondents was 74 (interquartile range 71-76). Most participants (71%, 72/102) received both RT and ET. Patients felt the role of RT and ET, respectively, was to: reduce ipsilateral tumor recurrence (91%, 90/99 and 62%, 61/99) and improve survival (56%, 55/99 and 49%, 49/99). More patients had significant concerns regarding ET (66%, 65/99) than RT (39%, 37/95). When asked which treatment had the most negative effect on their quality of life, the results showed: ET (35%, 25/72), RT (14%, 10/72) or both (8%, 6/72). Participants would rather receive RT (57%, 41/72) than ET (43%, 31/72). Forty-four percent (44/100) of respondents were either, "not comfortable" or "not interested" in participating in potential de-escalation trials. Although most of the adjuvant therapy de-escalation trials evaluate the omission of RT, de-escalation studies of ET are warranted and patient centered.

Purpose: The optimal frequency for cardiac monitoring of left ventricular ejection fraction (LVEF) in patients receiving trastuzumab-based therapy for early breast cancer (EBC) is unknown. We conducted a randomized controlled trial comparing 3- versus 4-monthly cardiac monitoring., Patients and Method: Patients scheduled to receive trastuzumab-containing cancer therapy for EBC with normal (>53%) baseline LVEF were randomized to undergo LVEF assessments every 3 or 4 months. The primary outcome was the change in LVEF from baseline. Secondary outcomes included the rate of cardiac dysfunction (defined as a decrease in the LVEF of ≥10 percentage points, to a value <53%), delays in or discontinuation of trastuzumab therapy, and cardiology referral., Results: Of the 200 eligible and enrolled patients, 100 (50%) were randomized to 3-monthly and 100 (50%) to 4-monthly cardiac monitoring. Of these patients, 98 and 97 respectively underwent at least one cardiac scan. The estimated mean difference in LVEF from baseline was -0.94% (one-sided 95% lower bound: -2.14), which exceeded the pre-defined non-inferiority margin of -4%. There were also no significant differences between the two study arms for any of the secondary endpoints. The rate of detection of cardiac dysfunction was 16.3% (16/98) and 12.4% (12/97) in the 3- and 4-monthly arms, respectively (95% CI: 4.0 [-5.9, 13.8])., Conclusions: Cardiac monitoring every 4 months was deemed non-inferior to that every 3 months in patients with HER2-positive EBC being treated with trastuzumab-based therapy. Given its costs and inconvenience, cardiac monitoring every 4 months should be considered standard practice. Registration: NCT02696707, 18 February 2016.

Hip implants are a successful solution for osteoarthritis; however, some individuals with metal-on-metal (MoM) and metal-on-polyethylene (MoP) prosthetics develop adverse local tissue reactions (ALTRs). While MoM and MoP ALTRs are presumed to be delayed hypersensitivity reactions to corrosion products, MoM- and MoP-associated ALTRs present with different histological characteristics. We compared MoM- and MoP-associated ALTRs histopathology with cobalt and chromium levels in serum and synovial fluid. We analyzed the gene expression levels of leukocyte aggregates and synovial fluid chemokines/cytokines to resolve potential pathophysiologic differences. In addition, we classified ALTRs from 79 patients according to their leukocyte infiltrates as macrophage-dominant, mixed, and lymphocyte-dominant. Immune-related transcript profiles from lymphocyte-dominant MoM- and MoP-associated ALTR patients with perivascular lymphocytic aggregates were similar. Cell signatures indicated predominantly macrophage, Th1 and Th2 lymphocytic infiltrate, with strong exhausted CD8 + signature, and low Th17 and B cell, relative to healthy lymph nodes. Lymphocyte-dominant ALTR-associated synovial fluid contained higher levels of induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RN), IL-8, IL-6, IL-16, macrophage inflammatory protein 1 (MIP-1α), IL-18, MCP-2, and lower cell-attracting chemokine levels, when compared with prosthetic revisions lacking ALTRs. In addition, the higher levels of IP-10, IL-8, IL-6, MIP-1α, and MCP-2 were observed within the synovial fluid of the lymphocyte-dominant ALTRs relative to the macrophage-dominant ALTRs. Not all cytokines/chemokines were detected in the perivascular aggregate transcripts, suggesting the existence of other sources in the affected synovia. Our results support the hypothesis of common hypersensitivity pathogenesis in lymphocyte-dominant MoM and MoP ALTRs. The exhausted lymphocyte signature indicates chronic processes and an impaired immune response, although the cause of the persistent T-cell activation remains unclear. The cytokine/chemokine signature of lymphocyte-dominant-associated ATLRs may be of utility for diagnosing this more aggressive pathogenesis., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Synthetic biology seeks to redesign biological systems to perform novel functions in a predictable manner. Recent advances in bacterial and mammalian cell engineering include the development of cells that function in biological samples or within the body as minimally invasive diagnostics or theranostics for the real-time regulation of complex diseased states. Ex vivo and in vivo cell-based biosensors and therapeutics have been developed to target a wide range of diseases including cancer, microbiome dysbiosis and autoimmune and metabolic diseases. While probiotic therapies have advanced to clinical trials, chimeric antigen receptor (CAR) T cell therapies have received regulatory approval, exemplifying the clinical potential of cellular therapies. This Review discusses preclinical and clinical applications of bacterial and mammalian sensing and drug delivery platforms as well as the underlying biological designs that could enable new classes of cell diagnostics and therapeutics. Additionally, we describe challenges that must be overcome for more rapid and safer clinical use of engineered systems., (© 2021. Springer Nature Limited.)

Adverse local tissue reactions (ALTRs) are a prominent cause of hip implant failure. ALTRs are characterized by aseptic necrosis and leukocyte infiltration of synovial tissue. The prevalence of ALTRs in hips with failing metal implants, with highest rates occurring in patients with metal-on-metal articulations, suggests a role for CoCrMo corrosion in ALTR formation. Although hypersensitivity reactions are the most accepted etiology, the precise cellular mechanism driving ALTR pathogenesis remains enigmatic. Here we show that cobalt ions released by failing hip implants induce mitochondrial stress and cytokine secretion by synovial fibroblasts: the presumptive initiators of ALTR pathogenesis. We found that in-vitro treatment of synovial fibroblasts with cobalt, but not chromium, generated gene expression changes indicative of hypoxia and mitophagy responses also observed in ALTRs biopsies. Inflammatory factors secreted by cobalt-exposed synovial fibroblasts were among those most concentrated in ALTR synovial fluid. Furthermore, both conditioned media from cobalt-exposed synovial fibroblasts, and synovial fluid from ALTRs patients, elicit endothelial activation and monocyte migration. Finally, we identify the IL16/CTACK ratio in synovial fluid as a possible diagnostic marker of ALTRs. Our results provide evidence suggesting that metal ions induce cell stress in synovial fibroblasts that promote an inflammatory response consistent with initiating ALTR formation. STATEMENT OF SIGNIFICANCE: We demonstrate that the cytotoxic effects of cobalt ions on the synovial cells (fibroblast) is sufficient to trigger inflammation on hip joints with metal implants. Cobalt ions affect mitochondrial function, leading to the auto phagocytosis of mitochondria and trigger a hypoxic response. The cell's hypoxic response includes secretion of cytokines that are capable of trigger inflammation by activating blood vessels and enhancing leukocyte migration. Among the secreted cytokines is IL-16, which is highly concentrated in the synovial fluid of the patients with adverse local tissue reactions and could be use as diagnostic marker. In conclusion we define the cells of the hip joint as key players in triggering the adverse reactions to hip implants and providing biomarkers for early diagnosis of adverse reactions to hip implants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

A cost-utility analysis was performed based on the Rethinking Clinical Trials (REaCT) bone-targeted agents (BTA) clinical trial that compared 12-weekly (once every 12 weeks) ( n = 130) versus 4-weekly (once every 4 weeks) ( n = 133) BTA dosing for metastatic breast and castration-resistant prostate (CRPC) cancer. Using a decision tree model, we calculated treatment and symptomatic skeletal event (SSE) costs as well as quality-adjusted life-years (QALYs) for each treatment option. Deterministic and probabilistic sensitivity analyses were performed to assess the robustness of the study findings. The total cost of BTA treatment in Canadian dollars (C$) and estimated QALYs was C$8965.03 and 0.605 QALY in the 4-weekly group versus C$5669.95 and 0.612 QALY in the 12-weekly group, respectively. De-escalation from 4-weekly to 12-weekly BTA reduces cost (C$3293.75) and improves QALYs by 0.008 unit, suggesting that 12-weekly BTA dominates 4-weekly BTA in breast and CRPC patients with bone metastases. Sensitivity analysis suggests high levels of uncertainty in the cost-effectiveness findings. De-escalation of bone-targeted agents is cost-effective from the Canadian public payer's perspective.

Aims: Uterine sarcomas can be grouped into tumours with pathognomonic genetic fusions such as low-grade endometrial stromal sarcoma (LGESS), high-grade endometrial stromal sarcoma (HGESS), and inflammatory myofibroblastic tumour (IMT), and tumours lacking genetic fusions such as leiomyosarcoma (LMS) and undifferentiated uterine sarcoma (UUS). Members of the latter group frequently harbour TP53 mutations. The aim of this study was to evaluate TP53 mutations by the use of immunohistochemistry in fusion-positive uterine sarcomas., Methods and Results: We performed p53 immunohistochemical staining on 124 uterine sarcomas harbouring genetic fusions and 38 fusion-negative LMSs and UUSs. These included 41 HGESSs with YWHAE, BCOR and BCORL1 fusions/rearrangements, 13 IMTs with ALK fusion, 12 sarcomas with NTRK1/3 fusion, three sarcomas with PDGFB fusion, and 55 LGESSs with JAZF1, SUZ12 and PHF1 fusions/rearrangements. All HGESSs, LGESSs, IMTs and sarcomas with PDGFB fusion showed wild-type p53 expression. Among NTRK1/3-positive sarcomas, a TPR-NTRK1-positive sarcoma with nuclear pleomorphism showed mutation-type p53 expression. The remaining 11 NTRK1/3-positive sarcomas showed wild-type p53 expression, except for the subclonal p53 mutation-type staining in a minor pleomorphic focus of an NTRK3-positive sarcoma. Twenty-one of 27 (78%) LMSs and six of nine (67%) UUSs showed mutation-type p53 expression., Conclusion: p53 immunohistochemistry may be considered in the initial work-up of a uterine sarcoma, as mutation-type staining would make a fusion-positive sarcoma very unlikely. Mutation-type p53 expression, however, can be seen in a small subset of NTRK1/3-positive sarcomas showing pleomorphic round/ovoid cell histology, which may represent a mechanism of progression in these tumours., (© 2020 John Wiley & Sons Ltd.)

Backgrounds: Pathologic features of oropharyngeal squamous cell carcinoma (OPSCC) treated with trans-oral robotic surgery predict prognosis and adjuvant therapy. We hypothesized that pathologic muscle invasion (pMI) is associated with poor pathological markers., Methods: Retrospective review of surgically treated OPSCC to identify pMI and its association with poor pathologic markers., Results: pMI was present in 12/37 patients, and compared to non-pMI, was associated with higher rates of lymphovascular invasion (75% vs. 36%, p = 0.03), perineural invasion (16.7% vs. 0%, p = 0.04), extranodal extension (66.7% vs. 20%, p < 0.01), and tumor stage (8.3% vs. 48% pT1, 75% vs. 52% pT2 and 16.7% vs. 0% pT3). pMI was associated with having a positive margin on main specimen (41.7% vs. 12%, p = 0.04) but not after considering additional margins., Conclusions: Muscle invasion was associated with higher pathologic tumor staging, poor pathologic factors, and higher rates of positive margin on main specimen., (© 2020 Wiley Periodicals LLC.)

Introduction: Symptomatic early onset pulmonary events (EOPEs) were observed in 3% to 6% of patients within 1 week of starting brigatinib at 90 mg daily for 7 days followed by 180 mg daily. We conducted a prospective observational cohort study to measure pulmonary function changes on initiating brigatinib., Methods: Patients initiating brigatinib were eligible. Pulmonary function test (PFT) with diffusing capacity for carbon monoxide (DLCO), Borg dyspnea scale, six-minute walk test, and blood draw for cytometry by time-of-flight were performed at baseline, day 2, and day 8 plus or minus day 15 of brigatinib. The primary end point was the incidence of PFT-defined EOPEs, prespecified as greater than or equal to 20% DLCO reduction from baseline. An interim analysis was performed owing to a higher than expected incidence of DLCO reduction., Results: A total of 90% (nine of 10) experienced DLCO reduction with the nadir occurring on day 2 or day 8. Median DLCO nadir was -13.33% from baseline (range: -34.44 to -5.00). Three participants met the PFT-defined EOPE criteria. All patients, including these three, were asymptomatic, none required brigatinib interruption or dose reduction, and all patients escalated to 180 mg without further issues. Despite continued dosing, by day 15, all assessed patients experienced DLCO recovery. Dyspnea and six-minute walk test results did not correlate with DLCO changes. Patients with a PFT-defined EOPE had significantly higher levels of activated neutrophils at baseline and day 8., Conclusions: DLCO reduction occurred in 90% during the first 8 days of brigatinib dosing without any related symptoms. DLCO improved in all six patients assessed at day 15 despite continued dosing and dose escalation. Pretreatment levels of neutrophil activation should be explored as a biomarker for developing EOPEs., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Despite the increasing use of adjuvant bisphosphonates for early stage breast cancer (EBC), little is known about the patient experience with such treatments. A patient survey was performed to identify current prescribing practices, perceptions around the role of treatment, the impact of treatment on patients' quality of life, and future trial designs., Methods: EBC patients who had either completed or were currently receiving adjuvant bisphosphonates were sent an anonymized survey. The survey collected information on patient and disease characteristics, bisphosphonate scheduling, compliance, and tolerance. Questions also assessed patient interest in trials of de-escalated bisphosphonate therapy., Results: A total of 255 patients were contacted, with 164 eligible respondents (eligible response rate 164/255, 64.3%). Median patient age was 52 years (range 28 to 82 years). The majority (111/163, 68.1%) were postmenopausal at the time of diagnosis, 23.3% (38/163) were premenopausal, and 7.4% (12/163) were perimenopausal. Most patients (78%) had received chemotherapy. Zoledronate was the most commonly used bisphosphonate (92%), with the majority receiving treatment every 6 months for 3 years (73%). While 66% (107/161) of respondents had experienced side effects with treatment, most had, or expected to, complete treatment (154/163, 94%). Provided there was no detriment in breast cancer outcomes, there was strong interest in future studies of de-escalating adjuvant bisphosphonate therapy., Conclusion: While most patients tolerate their treatment, there is interest in performing trials of de-escalation of these agents., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SMG reports receipt of honorarium from Novartis for insights on management of breast cancer patients. AAA reports Advisory board: Eli Lily, Exact Sciences, Exactis, Novartis, Pfizer, Honoraria: Apotex, Roche, Travel: Roche. BH and MC reports consulting fees from Cornerstone Research, outside the submitted work. GP reports consulting fees from Merck, Astra-Zeneca, Profound Medical, outside of submitted work; honorarium for DSMB membership from Takeda outside of submitted work; a close family member works for Roche Canada Ltd and owns stock in Roche Ltd. All other authors declare no competing interests., (© 2021 The Authors.)

Purpose: Bone-modifying agents (BMAs) for bone metastases are commonly prescribed for many years even though randomized clinical trials are only 1-2 years in duration. A systematic review on the risk-benefit of BMA use for > 2 years in breast cancer or castrate-resistant prostate cancer was conducted., Methods: MEDLINE, Embase, and Cochrane databases were searched (1970-February 2019) for randomized and observational studies, and case series reporting on BMA efficacy (skeletal-related events and quality of life) and toxicity (osteonecrosis of the jaw, renal impairment, hypocalcemia, and atypical femoral fractures) beyond 2 years., Results: Of 2107 citations, 64 studies were identified. Three prospective and 9 retrospective studies were eligible. Data beyond 2 years was limited to subgroup analyses in all studies. Only one study (n = 181) reported skeletal-related event rates based on bisphosphonate exposure, with decreased rates from 27.6% (0-24 months) to 15.5% (> 24 months). None reported on quality of life. All 12 studies (denosumab (n = 948), zoledronate (n = 1036), pamidronate (n = 163), pamidronate-zoledronate (n = 522), ibandronate (n = 118)) reported ≥ 1 toxicity outcome. Seven bisphosphonate studies (n = 1077) and one denosumab study (n = 948) reported on osteonecrosis of the jaw. Across three studies (n = 1236), osteonecrosis of the jaw incidence ranged from 1 to 4% in the first 2 years to 3.8-18% after 2 years. Clinically significant hypocalcemia ranged from 1 to 2%. Severe renal function decline was ≤ 3%. Atypical femoral fractures were rare., Conclusions: Evidence informing the use of BMA beyond 2 years is heterogeneous and based on retrospective analysis. Prospective randomized studies with greater emphasis on quality of life are needed., Prospero Registration Number: CRD42019126813.

Background: Previous studies of prostate cancer autoantibodies have largely focused on diagnostic applications. So far, there have been no reports attempting to more comprehensively profile the landscape of prostate cancer-associated antibodies. Specifically, it is unknown whether the quantity of antibodies or the types of proteins recognized change with disease progression., Methods: A peptide microarray spanning the amino acid sequences of the gene products of 1611 prostate cancer-associated genes was synthesized. Serum samples from healthy male volunteers (n=15) and patients with prostate cancer (n=85) were used to probe the array. These samples included patients with various clinical stages of disease: newly diagnosed localized prostate cancer (n=15), castration-sensitive non-metastatic prostate cancer (nmCSPC, n=40), castration-resistant non-metastatic prostate cancer (n=15) and castration-resistant metastatic disease (n=15). The patients with nmCSPC received treatment with either standard androgen deprivation therapy (ADT) or an antitumor DNA vaccine encoding prostatic acid phosphatase. Serial sera samples from these individuals were also used to probe the array, to secondarily determine whether this approach could be used to detect treatment-related changes., Results: We demonstrated that this peptide array yielded highly reproducible measurements of serum IgG levels. We found that the overall number of antibody responses did not increase with disease burden. However, the composition of recognized proteins shifted with clinical stage of disease. Our analysis revealed that the largest difference was between patients with castration-sensitive and castration-resistant disease. Patients with castration-resistant disease recognized more proteins associated with nucleic acid binding and gene regulation compared with men in other groups. Our longitudinal data showed that treatments can elicit antibodies detectable by this array, and notably vaccine-treated patients developed increased responses to more proteins over the course of treatment than did ADT-treated patients., Conclusions: This study represents the largest survey of prostate cancer-associated antibodies to date. We have been able to characterize the classes of proteins recognized by patients and determine how they change with disease burden. Our findings further demonstrate the potential of this platform for measuring antigen spread and studying responses to immunomodulatory therapies., Competing Interests: Competing interests: DGM has ownership interest, has received research support and serves as consultant to Madison Vaccines, which has licensed intellectual property related to this content., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)