Proteomic features of soft tissue tumours in adolescents and young adults.

BACKGROUND: Adolescents and young adult (AYA) patients with soft tissue tumours including sarcomas are an underserved group with disparities in treatment outcomes. METHODS: To define the molecular features between AYA and older adult (OA) patients, we analysed the proteomic profiles of a large cohort of soft tissue tumours across 10 histological subtypes (AYA n = 66, OA n = 243), and also analysed publicly available functional genomic data from soft tissue tumour cell lines (AYA n = 5, OA n = 8). RESULTS: Biological hallmarks analysis demonstrates that OA tumours are significantly enriched in MYC targets compared to AYA tumours. By comparing the patient-level proteomic data with functional genomic profiles from sarcoma cell lines, we show that the mRNA splicing pathway is an intrinsic vulnerability in cell lines from OA patients and that components of the spliceosome complex are independent prognostic factors for metastasis free survival in AYA patients. CONCLUSIONS: Our study highlights the importance of performing age-specific molecular profiling studies to identify risk stratification tools and targeted agents tailored for the clinical management of AYA patients.

Soft tissue tumours are cancers that develop in the connective and supporting tissues of the body, such as muscle or fat. These tumours arise in patients across the entire age range. However, improvements in survival outcomes in adolescent and young adult (AYA) patients have lagged behind outcomes in older adults (OA) and children. To better understand the biology of AYA patients with soft tissue tumours, we analysed protein profiles across 10 different types. We identified biological differences between AYA and OA patients and report an age-specific signature that can potentially be used to help predict which AYA patients are more likely to have aggressive cancers that will spread to other parts of the body. Our study highlights the importance of performing age-specific studies to identify new tools to predict patient outcomes and potentially find more suitable treatments.

Sarcoma incidence worldwide: regional differences in histology and molecular subtypes.

PURPOSE OF REVIEW: There are numerous sarcoma subtypes and vary widely in terms of epidemiology, clinical characteristics, genetic profiles, and pathophysiology. They also differ widely between ethnic groups. This review focuses on the different incidence rates of sarcomas in different regions and the potential explanations for these disparities. RECENT FINDINGS: In an intercontinental study using national cancer registry databases from France and Taiwan, the French population had a higher risk of liposarcomas, leiomyosarcomas, and synovial sarcomas, whereas the Taiwanese population had a higher incidence of angiosarcomas and malignant peripheral nerve sheath tumors. The anatomical distribution of these sarcomas also varied between these two regions. In France, most angiosarcoma cases occurred in the extremities and trunk, whereas in Taiwan, angiosarcoma cases in the abdomen and pelvis were more common. Another international study showed that in addition to the common known TP53 and NF1 germline mutations, genes involved in centromere and telomere maintenance were also involved in sarcomagenesis. We reviewed factors related to genetics, environmental effects, chemical exposure, and radiation exposure that could explain the differences in sarcoma incidence among different geographical or ethnic regions. SUMMARY: Our understanding of the potential cause of sarcomas with different subtypes is limited. Establishing a comprehensive global database for patients with sarcomas from all ethnic groups is essential to deepen our understanding of the potential risk factors and the pathophysiology of all sarcoma subtypes.

A case of primary pleural epithelioid hemangioendothelioma achieving stable disease with paclitaxel treatment: A case report and literature review.

Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm with a clinical behaviour that falls between a benign hemangioma and a high-grade angiosarcoma. Pleural EHE is exceptionally rare, and its prognosis is grim, with most patients experiencing survival of less than 1 year. Here, we present a case of pleural EHE in a 45-year-old woman with a month-long history of right-sided pleuritic chest pain. Chest computed tomography revealed consolidation, atelectasis of the right lung, right pleural thickening, and pleural effusion. She underwent video-assisted thoracoscopic surgery for decortication and was diagnosed with conclusively pleural EHE, showing a CAMTA1 rearrangement. Paclitaxel treatment, administered once weekly on days 1, 8 and 15 of a 28-day cycle, resulted in a stable disease after 12 cycles. Managing patients with pleural EHE is challenging because there are still no established standard treatments. Our case achieved 11-month progression-free survival following paclitaxel treatment.

Predictors of 30-day recurrent emergency department visits for hyperglycemia in patients with types 1 and 2 diabetes: a population-based cohort study.

OBJECTIVES: This study's aims were to describe the outcomes of patients with diabetes presenting with their first ED visit for hyperglycemia, and to identify predictors of recurrent ED visits for hyperglycemia. METHODS: Using linked databases, we conducted a population-based cohort study of adult and pediatric patients with types 1 and 2 diabetes presenting with a first ED visit for hyperglycemia from April 2010 to March 2020 in Ontario, Canada. We determined the proportion of patients with a recurrent ED visit for hyperglycemia within 30 days of the index visit. Using multivariable regression analysis, we examined clinical and socioeconomic predictors for recurrent visits. RESULTS: There were 779,632 patients with a first ED visit for hyperglycemia. Mean (SD) age was 64.3 (15.2) years; 47.7% were female. 11.0% had a recurrent visit for hyperglycemia within 30 days. Statistically significant predictors of a recurrent visit included: male sex, type 1 diabetes, regions with fewer visible minority groups and with less education or employment, higher hemoglobin A1C, more family physician or internist visits within the past year, being rostered to a family physician, previous ED visits in the past year, ED or hospitalization within the previous 14 days, access to homecare services, and previous hyperglycemia encounters in the past 5 years. Alcoholism and depression or anxiety were positive predictors for the 18-65 age group. CONCLUSIONS: This population-level study identifies predictors of recurrent ED visits for hyperglycemia, including male sex, type 1 diabetes, regions with fewer visible minority groups and with less education or employment, higher hemoglobin A1C, higher previous healthcare system utilization (ED visits and hospitalization) for hyperglycemia, being rostered to a family physician, and access to homecare services. Knowledge of these predictors may be used to develop targeted interventions to improve patient outcomes and reduce healthcare system costs.

ABSTRAIT: OBJECTIFS: Les objectifs de cette étude étaient de décrire les résultats des patients diabétiques présentant leur première visite aux urgences pour hyperglycémie, et d'identifier les prédicteurs des visites récurrentes aux urgences pour hyperglycémie. MéTHODES: À l'aide de bases de données couplées, nous avons mené une étude de cohorte basée sur la population de patients adultes et pédiatriques atteints de diabète de type 1 et 2 présentant une première visite aux urgences pour l'hyperglycémie d'avril 2010 à mars 2020 en Ontario, au Canada. Nous avons déterminé la proportion de patients présentant une visite récurrente à l'urgence pour hyperglycémie dans les 30 jours suivant la visite d'index. À l'aide d'une analyse de régression multivariée, nous avons examiné les prédicteurs cliniques et socioéconomiques des visites récurrentes. RéSULTATS: Il y avait 779 632 patients avec une première visite à l'urgence pour hyperglycémie. L'âge moyen (ET) était de 64,3 (15,2) ans; 47,7% étaient des femmes. 11,0 % avaient une visite récurrente pour hyperglycémie dans les 30 jours. Les prédicteurs statistiquement significatifs d'une visite récurrente comprenaient le sexe masculin, le diabète de type 1, les régions comptant moins de groupes de minorités visibles et ayant moins d'études ou d'emploi, une hémoglobine A1C plus élevée, plus de visites chez un médecin de famille ou un interniste au cours de la dernière année, être inscrit auprès d'un médecin de famille, consulter le service d'urgence au cours de la dernière année, être hospitalisé au cours des 14 derniers jours, avoir accès à des services de soins à domicile et avoir été confronté à une hyperglycémie au cours des 5 dernières années. L'alcoolisme et la dépression ou l'anxiété étaient des prédicteurs positifs pour le groupe des 18-65 ans. CONCLUSIONS: Cette étude au niveau de la population identifie des prédicteurs de visites récurrentes aux urgences pour l'hyperglycémie, y compris le sexe masculin, le diabète de type 1, les régions avec moins de groupes de minorités visibles et avec moins d'études ou d'emploi, plus d'hémoglobine A1C, l'utilisation antérieure plus élevée du système de soins de santé (visites aux urgences et hospitalisation) pour l'hyperglycémie, le fait d'être inscrit auprès d'un médecin de famille et l'accès aux services de soins à domicile. La connaissance de ces prédicteurs peut être utilisée pour élaborer des interventions ciblées afin d'améliorer les résultats pour les patients et de réduire les coûts du système de santé.

Sequential multimodal treatments with chemotherapy and surgery for advanced soft tissue sarcoma may be associated with better survival than chemotherapy.

BACKGROUND: In patients with advanced soft tissue sarcoma (STS), surgery had been reported to be associated with superior overall survival (OS). Chemotherapy details for such patients were less reported, and whether multimodal treatment with surgery and chemotherapy provides extra survival benefit remains unclear. METHODS: We retrospectively reviewed patients with newly diagnosed advanced STS treated at National Taiwan University Hospital from January 1, 2011, to December 31, 2017. OS was calculated from the day of diagnosis of advanced STS to the day of death or last follow-up. Baseline patient characteristics and details regarding surgery and chemotherapy were recorded. RESULTS: A total of 545 patients were diagnosed with STS from 2011 to 2017, of which 226 patients had advanced STS. The median age was 54.7 years, and 54% of patients were women. Approximately 38% of patients with advanced STS underwent surgery and exhibited a trend of longer OS compared with who did not (median = 18.6 vs. 11.9 months, p = 0.083). In the chemotherapy subgroup, the benefit of surgery was more prominent (median = 21.9 vs. 16.5 months, p = 0.037). Patients who received chemotherapy prior to surgery exhibited numerically longer OS than those who underwent surgery first (median = 33.9 vs. 18.3 months, p = 0.155). After adjusting other clinical factors, chemotherapy remained an independent factor associated with favourable OS. CONCLUSION: Surgery may be more beneficial for the patients who receive chemotherapy. Our results support evaluation of sequential multimodal treatments strategy including surgery and chemotherapy in patients with advanced STS.

Electronic Health Records Versus Survey Small Area Estimates for Public Health Surveillance.

INTRODUCTION: Electronic health records (EHRs) are increasingly being leveraged for public health surveillance. EHR-based small area estimates (SAEs) are often validated by comparison to survey data such as the Behavioral Risk Factor Surveillance System (BRFSS). However, survey and EHR-based SAEs are expected to differ. In this cross-sectional study, SAEs were generated using MDPHnet, a distributed EHR-based surveillance network, for all Massachusetts municipalities and zip code tabulation areas (ZCTAs), compared to BRFSS PLACES SAEs, and reasons for differences explored. METHODS: This study delineated reasons a priori for how SAEs derived using EHRs may differ from surveys by comparing each strategy's case classification criteria and reviewing the literature. Hypertension, diabetes, obesity, asthma, and smoking EHR-based SAEs for 2021 in all ZCTAs and municipalities in Massachusetts were estimated with Bayesian mixed effects modeling and poststratification in the summer/fall of 2023. These SAEs were compared to BRFSS PLACES SAEs published by the U.S. Centers for Disease Control and Prevention. RESULTS: Mean prevalence was higher in EHR data versus BRFSS in both municipalities and ZCTAs for all outcomes except asthma. ZCTA and municipal symmetric mean absolute percentages ranged from 12.0 to 38.2% and 13.1 to 39.8%, respectively. There was greater variability in EHR-based SAEs versus BRFSS PLACES in both municipalities and ZCTAs. CONCLUSIONS: EHR-based SAEs tended to be higher than BRFSS and more variable. Possible explanations include detection of undiagnosed cases and over-classification using EHR data, and under-reporting within BRFSS. Both EHR and survey-based surveillance have strengths and limitations that should inform their preferred uses in public health surveillance.

COVID-19 Severity in People With HIV Compared With Those Without HIV.

BACKGROUND: People with HIV (PWH) may be at risk for more severe COVID-19 outcomes. We compared risk for severe COVID-19 in PWH with matched individuals without HIV. METHODS: We identified adults in Massachusetts with a positive SARS-CoV-2 test, March 2020-July 2022, using electronic medical record data from 3 large clinical practice groups. We then used regression models to compare outcomes among PWH versus propensity score-matched people without HIV (matched 20:1) for severe COVID-19 (pneumonia or acute respiratory distress syndrome), hospitalization, and hospital length of stay. RESULTS: We identified 171,058 individuals with COVID-19; among them, 768 PWH were matched to 15,360 individuals without HIV. Overall, severe COVID-19 and hospitalization were similar in PWH and those without HIV (severe COVID-19: 3.8% vs 3.0%, adjusted odds ratio [OR] 1.27, 95% confidence interval [CI]: 0.86-1.87; hospitalization: 12.1% vs 11.3%, adjusted OR: 1.08, 95% CI: 0.87 to 1.35). Compared with people without HIV, PWH with low CD4 T-cell counts (<200 cells/mm 3 ) had more severe COVID-19 (adjusted OR: 3.99, 95% CI: 2.06 to 7.74) and hospitalization (adjusted OR: 2.26, 95% CI: 1.35 to 3.80), but PWH with high CD4 counts had lower odds of hospitalization (adjusted OR: 0.73, 95% CI: 0.52 to 1.03). CONCLUSIONS: PWH with low CD4 T-cell counts had worse COVID-19 outcomes compared with people without HIV, but outcomes for those with high CD4 counts were similar to, or better than, those without HIV. It is unclear whether these findings are generalizable to settings where PWH have less access to and engagement with health care.

Whole-Brain Radiotherapy Alone vs Preceded by Bevacizumab, Etoposide, and Cisplatin for Untreated Brain Metastases From Breast Cancer: A Randomized Clinical Trial.

Importance: The incidence of brain metastasis is increasing in patients with metastatic breast cancer. Treatments to extend the control of brain metastasis are urgently required. Objective: To investigate whether the addition of an induction treatment of bevacizumab, etoposide, and cisplatin (BEEP) improves brain-specific progression-free survival (PFS) after whole-brain radiotherapy (WBRT). Design, Setting, and Participants: This open-label, randomized, multicenter clinical trial assessed patients with brain metastases from breast cancer (BMBC) in Taiwan from September 9, 2014, to December 24, 2018, with survival follow-up until December 31, 2021. Key inclusion criteria included metastatic brain tumors not suitable for focal treatment, WBRT naivety, age 20 to 75 years, and at least 1 measurable brain metastatic lesion. The primary end point was brain-specific PFS, with an expected hazard ratio of 0.60, a 2-sided α ≤ .20, and power of 0.8. Interventions: Eligible patients were randomly assigned at a ratio of 2:1 to the experimental arm, which involved 3 cycles of BEEP followed by WBRT, or the control arm, which involved WBRT alone. Main Outcomes and Measures: The primary end point was the determination of brain-specific PFS by local investigators according to the Response Evaluation Criteria in Solid Tumors, version 1.1, the initiation of other brain-directed treatment after WBRT, or death. Other key end points included brain-specific objective response rate after 8 weeks of BEEP treatment or WBRT and 8-month brain-specific PFS rate, PFS, and overall survival. Results: A total of 118 patients with BMBC were randomized, with the intention-to-treat cohort comprising 112 patients. The median age was 56 years (range, 34-71 years), and 61 patients (54.5%) had ERBB2 (formerly HER2 or HER2/neu)-positive disease. The median (range) brain-specific PFS was 8.1 (0.3-29.5) vs 6.5 (0.9-25.5) months in the experimental and control arms, respectively (hazard ratio, 0.71; 95% CI, 0.44-1.13; P = .15; significant at predefined α ≤ .20). The brain-specific objective response rate at 2 months was not significantly different (BEEP treatment vs WBRT, 41.9% vs 52.6%), but the 8-month brain-specific PFS rate was significantly higher in the experimental group (48.7% vs 26.3%; P = .03). Adverse events were generally manageable with prophylactic granulocyte colony-stimulating factor treatment. Conclusions and Relevance: The findings show that induction BEEP before WBRT may improve the control of BMBC compared with using upfront WBRT, which could address an unmet need for an effective systemic treatment for intractable brain and extracranial metastases from metastatic breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02185352.

Disparity in survival benefits of pembrolizumab between Asian and non-Asian patients with advanced cancers: A systematic review and meta-regression analysis.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment of malignancies. However, disproportionate enrollment among races and ethnicities places the generalizability of global trial results in doubt. METHODS: In this systematic review, phase 3 randomized controlled trials investigating pembrolizumab in advanced cancers and providing subgroup analyses of Asian and non-Asian participants were included. The primary and secondary effect measures were the mean differences (MDs) in the natural logarithms of the hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) between these two subgroups, respectively. We used random-effects meta-analysis to calculate the pooled ratios of HRs (i.e., exp(MD)) and implemented a meta-regression analysis to identify significant covariates. RESULTS: A total of 17 and 11 trials were included in the meta-analyses of OS and PFS, respectively. These trials included 2732 (25.49%) Asian and 7000 (65.32%) non-Asian participants in the OS analysis and 1438 (22.5%) Asian and 4129 (64.61%) non-Asian participants in the PFS analysis. The pooled ratio of HRs for OS was 0.87 (95% CI: 0.76-0.99; p = 0.0391), favoring Asian participants, but no significant difference was found in PFS (pooled ratio of HRs: 0.93; 95% CI: 0.82-1.07; p = 0.2391). Both linear meta-regression analyses revealed an open-label design as a crucial covariate, which indicated more benefits for non-Asian participants. CONCLUSIONS: Compared with non-Asian patients, Asian patients with advanced cancers may derive superior OS benefits from pembrolizumab. Although the results warrant further exploration, this meta-analysis provides insight into clinical research design.

Use of Electronic Clinical Data to Track Incidence and Mortality for SARS-CoV-2-Associated Sepsis.

Importance: Efforts to quantify the burden of SARS-CoV-2-associated sepsis have been limited by inconsistent definitions and underrecognition of viral sepsis. Objective: To describe the incidence and outcomes of SARS-CoV-2-associated sepsis vs presumed bacterial sepsis using objective electronic clinical criteria. Design, Setting, and Participants: This retrospective cohort study included adults hospitalized at 5 Massachusetts hospitals between March 2020 and November 2022. Exposures: SARS-CoV-2-associated sepsis was defined as a positive SARS-CoV-2 polymerase chain reaction test and concurrent organ dysfunction (ie, oxygen support above simple nasal cannula, vasopressors, elevated lactate level, rise in creatine or bilirubin level, and/or decline in platelets). Presumed bacterial sepsis was defined by modified US Centers for Disease Control and Prevention adult sepsis event criteria (ie, blood culture order, sustained treatment with antibiotics, and organ dysfunction using identical thresholds as for SARS-CoV-2-associated sepsis). Main Outcomes and Measures: Trends in the quarterly incidence (ie, proportion of hospitalizations) and in-hospital mortality for SARS-CoV-2-associated and presumed bacterial sepsis were assessed using negative binomial and logistic regression models. Results: This study included 431 017 hospital encounters from 261 595 individuals (mean [SD] age 57.9 [19.8] years, 241 131 (55.9%) females, 286 397 [66.5%] from academic hospital site). Of these encounters, 23 276 (5.4%) were from SARS-CoV-2, 6558 (1.5%) had SARS-CoV-2-associated sepsis, and 30 604 patients (7.1%) had presumed bacterial sepsis without SARS-CoV-2 infection. Crude in-hospital mortality for SARS-CoV-2-associated sepsis declined from 490 of 1469 (33.4%) in the first quarter to 67 of 450 (14.9%) in the last (adjusted odds ratio [aOR], 0.88 [95% CI, 0.85-0.90] per quarter). Crude mortality for presumed bacterial sepsis was 4451 of 30 604 patients (14.5%) and stable across quarters (aOR, 1.00 [95% CI, 0.99-1.01]). Medical record reviews of 200 SARS-CoV-2-positive hospitalizations confirmed electronic health record (EHR)-based SARS-CoV-2-associated sepsis criteria performed well relative to sepsis-3 criteria (90.6% [95% CI, 80.7%-96.5%] sensitivity; 91.2% [95% CI, 85.1%-95.4%] specificity). Conclusions and Relevance: In this retrospective cohort study of hospitalized adults, SARS-CoV-2 accounted for approximately 1 in 6 cases of sepsis during the first 33 months of the COVID-19 pandemic. In-hospital mortality rates for SARS-CoV-2-associated sepsis were high but declined over time and ultimately were similar to presumed bacterial sepsis. These findings highlight the high burden of SARS-CoV-2-associated sepsis and demonstrate the utility of EHR-based algorithms to conduct surveillance for viral and bacterial sepsis.

Impact of SARS-CoV-2 Prevention Measures on Non-SARS-CoV-2 Hospital-Onset Respiratory Viral Infections: An Incidence Trend Analysis From 2015-2023.

We reviewed hospital-onset respiratory viral infections, 2015-2023, in one hospital to determine whether Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission prevention measures prevented non-SARS-CoV-2 respiratory viral infections. Masking, employee symptom attestations, and screening patients and visitors for symptoms were associated with a 44%-53% reduction in hospital-onset influenza and respiratory syncytial virus (RSV), accounting for changes in community incidence.

The Application of 18 F-FES PET in Clinical Cancer Care : A Systematic Review.

INTRODUCTION: [ 18 F]fluoroestradiol (FES) can be used for the noninvasive visualization and quantification of tumor estrogen receptor (ER) expression and activity and was FDA-approved as a diagnostic agent in May 2022 for detecting ER-positive lesions in patients with recurrent or metastatic breast cancer. PET imaging was also used to detect ER-positive lesions and malignancy among patients with uterine, ovarian, and other ER-positive solid tumors. We conducted a systemic review of the studies on FES PET imaging used among patients with cancer not limited to breast cancer to better understand the application of FES PET imaging. METHODS: PubMed/MEDLINE and Cochrane Library databases were used to perform a comprehensive and systematic search and were updated until August 15, 2022. Two authors independently reviewed the titles and abstracts of the retrieved articles by using the search algorithm and selected the articles based on the inclusion and exclusion criteria. All statistical analyses were conducted using R statistical software. RESULTS: Forty-three studies with 2352 patients were included in the qualitative synthesis, and 23 studies with 1388 patients were included in the quantitative analysis, which estimated the FES-positive detection rate. Thirty-two studies (77%) included breast cancer patients in 43 included studies. The FES SUV mean was higher in patients with endometrial cancer (3.4-5.3) than in those with breast cancer (2.05) and uterine sarcoma (1.1-2.6). The pooled detection rates of FES PET imaging were 0.80 for breast and 0.84 for ovarian cancer patients, both similar to that of 18 F-FDG. The FES uptake threshold of 1.1 to 1.82 could detect 11.1% to 45% ER heterogeneity, but the threshold of FES uptake did not have consistent predictive ability for prognosis among patients with breast cancer, unlike uterine cancer. However, FES uptake can effectively predict and monitor treatment response, especially endocrine therapy such as estradiol, ER-blocking agents (fulvestrant and tamifoxen), and aromatase inhibitors (such as letrozole and Z-endoxifen). CONCLUSIONS: [ 18 F]fluoroestradiol PET is not only a convenient and accurate diagnostic imaging tool for detecting ER-expressing lesions in patients with breast and ovarian cancer but also among patients with uterine cancer. [ 18 F]fluoroestradiol PET is a noninvasive predictive and monitoring tool for treatment response and prognosis.

The proteomic landscape of soft tissue sarcomas.

Soft tissue sarcomas (STS) are rare and diverse mesenchymal cancers with limited treatment options. Here we undertake comprehensive proteomic profiling of tumour specimens from 321 STS patients representing 11 histological subtypes. Within leiomyosarcomas, we identify three proteomic subtypes with distinct myogenesis and immune features, anatomical site distribution and survival outcomes. Characterisation of undifferentiated pleomorphic sarcomas and dedifferentiated liposarcomas with low infiltrating CD3 + T-lymphocyte levels nominates the complement cascade as a candidate immunotherapeutic target. Comparative analysis of proteomic and transcriptomic profiles highlights the proteomic-specific features for optimal risk stratification in angiosarcomas. Finally, we define functional signatures termed Sarcoma Proteomic Modules which transcend histological subtype classification and show that a vesicle transport protein signature is an independent prognostic factor for distant metastasis. Our study highlights the utility of proteomics for identifying molecular subgroups with implications for risk stratification and therapy selection and provides a rich resource for future sarcoma research.

Plasma cell-free tumor DNA, PIK3CA and TP53 mutations predicted inferior endocrine-based treatment outcome in endocrine receptor-positive metastatic breast cancer.

PURPOSE: How to factor both tumor burden and oncogenic genomic mutations as variables to predict the outcome of endocrine-based therapy (ET) in ER-positive/HER2-negative metastatic breast cancer patients (MBC) remains to be explored. METHOD: Blood samples prospectively collected from 163 ER-positive/HER2-negative female MBC patients, before ET, were used for cell-free tumor DNA (cfDNA) analysis. cfDNA was subjected to next-generation sequencing (NGS) to interrogate oncogenic PIK3CA hotspot and TP53 DNA-binding domain (DBD) mutations, including single nucleotide variants (SNVs) or small insertions and deletions (InDels). The variant calling threshold was set at 0.5%. Progression-free survival (PFS) was measured from the start of the ET treatment to the time of disease progression of the same treatment regimen. RESULTS: Overall, the median PFS was 8.3 months (95% CI 5.7-11.1 months). The median cfDNA was 38.5 ng (range 4.4-1935 ng). The proportion of patients with PIK3CA and TP53 alterations were 25.1 and 15.3%, respectively. Patients with high total cfDNA (HR 1.74, p = 0.003), PIK3CA mutation (HR 1.74, p = 0.007), and TP53 mutation (HR 1.64, p = 0.047) in liquid biopsy conferred worse outcome after ET. Even for patients with low tumor burden, the detrimental effect of PIK3CA or TP53 mutation remained significant (p < 0.001). For patients with either PIK3CA (p < 0.001) or TP53 mutation (p = 0.004), there was significant positive correlation between allele frequency (AF) and total cfDNA. CONCLUSION: After adjustment of cfDNA level, PIK3CA and TP53 mutations observed in liquid biopsy exerted detrimental effects on the outcome of ET-based regimens. The AF of PIK3CA or TP53 may be a surrogate marker for PFS.

New targeted treatments for advanced sarcomas.

PURPOSE OF REVIEW: The purpose of this review is to provide the rationale and results behind recent clinical trials regarding molecular-targeted agents for advanced sarcomas. RECENT FINDINGS: Tazemetostat, a first-in-class EZH2 inhibitor, was approved to treat advanced epithelioid sarcoma. In synovial sarcoma, the interaction between pathognomonic SS18-SSX fusion protein and the BAF complex has brought insight in using BRD9 inhibitors as a treatment based on synthetic lethality. MDM2 overexpression is an important mechanism to suppress p53 function, and MDM2 gene amplification is pathognomonic in well differentiated and dedifferentiated liposarcoma. Two MDM2 inhibitors, milademetan and BI907828, have both reached the optimal dosing and have shown promising efficacy in MDM2-amplified liposarcoma. Late-stage pivotal studies are ongoing for both of these MDM2 inhibitors. The co-amplification of CDK4 and MDM2 in liposarcoma also provided a rationale for CDK4/6 inhibitors as a potential therapy. Selinexor, an exportin-1 inhibitor, has shown single-agent activity in dedifferentiated liposarcoma and action in gastrointestinal stromal tumour in combination with imatinib. Lastly, a new formulation of mTOR inhibitor, nab-sirolimus, was recently approved for perivascular epithelioid cell tumour (PEComa). SUMMARY: Molecular-guided precision medicine holds a bright future in bringing more active treatments for advanced sarcoma patients.

L-carnitine enhances developmental potential of bovine oocytes matured under high lipid concentrations in vitro.

Maternal obesity elevates non-esterified fatty acids (NEFA) follicular concentrations. Bovine cumulus-oocyte complexes (COCs) matured in vitro under high NEFA have altered metabolism and reduced quality. Systemically, obesity promotes altered mitochondrial metabolism linked to L-carnitine insufficiency. We hypothesized that L-carnitine supplementation during IVM of bovine COCs in the presence of high NEFA would lessen the negative effects of exposure to excessive lipids on embryonic development and oxidative stress. COCs were collected from abattoir ovaries and matured in four groups: CON (control), LC (3 mM L-carnitine), HN (high NEFA: 200uM oleic, 150uM palmitic and 75uM stearic acid), and HNLC (HN and LC). Mature oocytes were assayed for aerobic and anaerobic metabolism utilizing oxygen and pH microsensors or fertilized in vitro (D0). Cleavage (D3) and blastocyst (D7, D8) rates were assessed. D3 embryos with ≥ 4 cells were stained for cytosolic and mitochondrial ROS. D8 blastocysts were assayed for gene transcript abundance of metabolic enzymes. Oocyte metabolism was not affected by IVM treatment. D3 formation of embryos with ≥ 4 cells were lower in LC or HN than CON or HNLC; blastocyst rates were greater for CON and lower for HN than LC and HNLC. D3 embryo mitochondrial and cytosolic ROS were reduced in HNLC when compared to other groups. IVM in HN altered blastocyst gene transcript abundance when compared to CON, but not LC or HNLC. In conclusion, supplementation with L-carnitine protects oocytes exposed to high NEFA during IVM and improves their developmental competence, suggesting that high lipid exposure may lead to L-carnitine insufficiency in bovine oocytes.

Impact of changing case definitions for coronavirus disease 2019 (COVID-19) hospitalization on pandemic metrics.

OBJECTIVE: To examine the impact of commonly used case definitions for coronavirus disease 2019 (COVID-19) hospitalizations on case counts and outcomes. DESIGN, PATIENTS, AND SETTING: Retrospective analysis of all adults hospitalized between March 1, 2020, and March 1, 2022, at 5 Massachusetts acute-care hospitals. INTERVENTIONS: We applied 6 commonly used definitions of COVID-19 hospitalization: positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) polymerase chain reaction (PCR) assay within 14 days of admission, PCR plus dexamethasone administration, PCR plus remdesivir, PCR plus hypoxemia, institutional COVID-19 flag, or COVID-19 International Classification of Disease, Tenth Revision (ICD-10) codes. Outcomes included case counts and in-hospital mortality. Overall, 100 PCR-positive cases were reviewed to determine each definition's accuracy for distinguishing primary or contributing versus incidental COVID-19 hospitalizations. RESULTS: Of 306,387 hospital encounters, 15,436 (5.0%) met the PCR-based definition. COVID-19 hospitalization counts varied substantially between definitions: 4,628 (1.5% of all encounters) for PCR plus dexamethasone, 5,757 (1.9%) for PCR plus remdesivir, 11,801 (3.9%) for PCR plus hypoxemia, 15,673 (5.1%) for institutional flags, and 15,868 (5.2%) for ICD-10 codes. Definitions requiring dexamethasone, hypoxemia, or remdesivir selected sicker patients compared to PCR alone (mortality rates 12.2%, 10.7%, and 8.8% vs 8.3%, respectively). Definitions requiring PCR plus remdesivir or dexamethasone did not detect a reduction in in-hospital mortality associated with the SARS-CoV-2 Omicron variant. ICD-10 codes had the highest sensitivity (98.4%) but low specificity (39.5%) for distinguishing primary or contributing versus incidental COVID-19 hospitalizations. PCR plus dexamethasone had the highest specificity (92.1%) but low sensitivity (35.5%). CONCLUSIONS: Commonly used definitions for COVID-19 hospitalizations generate variable case counts and outcomes and differentiate poorly between primary or contributing versus incidental COVID-19 hospitalizations. Surveillance definitions that better capture and delineate COVID-19-associated hospitalizations are needed.

Clinical assessment of a novel machine-learning automated contouring tool for radiotherapy planning.

Contouring has become an increasingly important aspect of radiotherapy due to inverse planning. Several studies have suggested that the clinical implementation of automated contouring tools can reduce inter-observer variation while increasing contouring efficiency, thereby improving the quality of radiotherapy treatment and reducing the time between simulation and treatment. In this study, a novel, commercial automated contouring tool based on machine learning, the AI-Rad Companion Organs RT™ (AI-Rad) software (Version VA31) (Siemens Healthineers, Munich, Germany), was assessed against both manually delineated contours and another commercially available automated contouring software, Varian Smart Segmentation™ (SS) (Version 16.0) (Varian, Palo Alto, CA, United States). The quality of contours generated by AI-Rad in Head and Neck (H&N), Thorax, Breast, Male Pelvis (Pelvis_M), and Female Pelvis (Pevis_F) anatomical areas was evaluated both quantitatively and qualitatively using several metrics. A timing analysis was subsequently performed to explore potential time savings achieved by AI-Rad. Results showed that most automated contours generated by AI-Rad were not only clinically acceptable and required minimal editing, but also superior in quality to contours generated by SS in multiple structures. In addition, timing analysis favored AI-Rad over manual contouring, indicating the largest time saving (753s per patient) in the Thorax area. AI-Rad was concluded to be a promising automated contouring solution that generated clinically acceptable contours and achieved time savings, thereby greatly benefiting the radiotherapy process.

Transcriptomic alterations underlying metaplasia into specific metaplastic components in metaplastic breast carcinoma.

BACKGROUND: Metaplastic breast carcinoma (MpBC) typically consists of carcinoma of no special type (NST) with various metaplastic components. Although previous transcriptomic and proteomic studies have reported subtype-related heterogeneity, the intracase transcriptomic alterations between metaplastic components and paired NST components, which are critical for understanding the pathogenesis underlying the metaplastic processes, remain unclear. METHODS: Fifty-nine NST components and paired metaplastic components (spindle carcinomatous [SPS], matrix-producing, rhabdoid [RHA], and squamous carcinomatous [SQC] components) were microdissected from specimens obtained from 27 patients with MpBC for gene expression profiling using the NanoString Breast Cancer 360 Panel on a NanoString nCounter FLEX platform. BC360-defined signatures were scored using nSolver software. RESULTS: Hierarchical clustering and principal component analysis revealed a heterogeneous gene expression profile (GEP) corresponding to the NST components, but the GEP of metaplastic components exhibited subtype dependence. Compared with the paired NST components, the SPS components demonstrated the upregulation of genes related to stem cells and epithelial-mesenchymal transition and displayed enrichment in claudin-low and macrophage signatures. Despite certain overlaps in the enriched functions and signatures between the RHA and SPS components, the specific differentially expressed genes differed. We observed the RHA-specific upregulation of genes associated with vascular endothelial growth factor signaling. The chondroid matrix-producing components demonstrated the upregulation of hypoxia-related genes and the downregulation of the immune-related MHC2 signature and the TIGIT gene. In the SQC components, TGF-ß and genes associated with cell adhesion were upregulated. The differentially expressed genes among metaplastic components in the 22 MpBC cases with one or predominantly one metaplastic component clustered paired NST samples into clusters with correlation with their associated metaplastic types. These genes could be used to separate the 31 metaplastic components according to respective metaplastic types with an accuracy of 74.2%, suggesting that intrinsic signatures of NST may determine paired metaplastic type. Finally, the EMT activity and stem cell traits in the NST components were correlated with specimens displaying lymph node metastasis. CONCLUSIONS: We presented the distinct transcriptomic alterations underlying metaplasia into specific metaplastic components in MpBCs, which contributes to the understanding of the pathogenesis underlying morphologically distinct metaplasia in MpBCs.