Targeting MDSC-HTR2B to Improve Immune Checkpoint Inhibitors in Breast to Brain Metastasis.

Myeloid Derived Suppressor Cells (MDSCs) support breast cancer growth via immune suppression and non-immunological mechanisms. Although 15% of patients with breast cancer will develop brain metastasis, there is scant understanding of MDSCs' contribution within the breast-to-brain metastatic microenvironment. Utilizing co-culture models mimicking a tumor-neuron-immune microenvironment and patient tissue arrays, we identified serotonergic receptor, HTR2B, on MDSCs to upregulate pNF-κB and suppress T cell proliferation, resulting in enhanced tumor growth. In vivo murine models of metastatic and intracranial breast tumors treated with FDA-approved, anti-psychotic HTR2B antagonist, clozapine, combined with immunotherapy anti-PD-1 demonstrated a significant increase in survival and increased T cell infiltration. Collectively, these findings reveal a previously unknown role of MDSC-HTR2B in breast-to-brain metastasis, suggesting a novel and immediate therapeutic approach using neurological drugs to treat patients with metastatic breast cancer.

The Impact of Changing Race-Specific Equations for Lung Function Tests among Veterans with COPD.

RATIONALE: The American Thoracic Society recommended a single reference equation for spirometry but the impact to patients is not known. OBJECTIVE: To estimate the effect of changing to a single reference equation among Veterans with chronic obstructive pulmonary disease (COPD). METHODS: Cross-sectional study including Veterans aged ≥40 to ≤89 years with COPD and spirometry results from 21 facilities between 2010 - 2019. We collected race/ethnicity data from the electronic health record. We estimated the percentage change in the number of Veterans with lung function meeting clinical thresholds used to determine eligibility for lung resection for cancer, lung volume reduction surgery (LVRS), and lung transplant referral. We estimated the change for each level of VA service connection and financial impact. RESULTS: We identified 44,892 Veterans; Asian (0.5%), Black (11.8%), White (80.8%), and Hispanic (1.8%). When changing to a single reference equation, Asian and Black Veterans had reduced predicted lung function that could result in less surgical lung resection (4.4% and 11.1% respectively), while increasing LVRS (1.7% and 3.8%), and lung transplant evaluation for Black Veterans (1.2%). White Veterans had increased predicted lung function and could experience increased lung resection (8.1%), with less LVRS (3.3%), and lung transplant evaluation (0.9%). Some Asian and Black Veterans could experience an increase in monthly disability payments (+$540.38 and $398.38), while Hispanic White and White Veterans could see a decrease (-$588.79). When aggregated, Hispanic Veterans experienced changes attributable to their racial identity, and because this sample was predominantly Hispanic White, had similar results to White Veterans. CONCLUSIONS: Changing the reference equation could affect access to treatment and disability benefits, depending on race. If adopted, the use of discrete clinical thresholds needs to be reassessed, considering patient-centered outcomes.

A new Neu-a syngeneic model of spontaneously metastatic HER2-positive breast cancer.

Metastatic disease results from the dissemination of tumor cells beyond their organ of origin to grow in distant organs and is the primary cause of death in patients with advanced breast cancer. Preclinical murine models in which primary tumors spontaneously metastasize are valuable tools for studying metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. The NT2.5-lung metastasis (-LM) cell line was derived from serial passaging of tumor cells that were macro-dissected from spontaneous lung metastases after orthotopic mammary implantation of parental NT2.5 cells. Within one week of NT2.5-LM implantation, metastases are observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. We demonstrate that NT2.5-LM metastases are positive for NeuN-the murine equivalent of human epidermal growth factor 2 (HER2). We further demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT), suggestive of their enhanced metastatic potential. Genomic analyses support these findings and reveal enrichment in EMT-regulating pathways. In addition, the metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. The new NT2.5-LM model provides certain advantages over the parental NT2/NT2.5 model, given its more rapid and spontaneous development of metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses.

Evaluation of markers of immunity in different metastatic immune microenvironments suggests more suppression within breast to liver metastases in breast cancer.

PURPOSE: Programmed death receptor ligand-1 (PD-L1) expression and tumor mutational burden (TMB) are approved screening biomarkers for immune checkpoint inhibition (ICI) in advanced triple negative breast cancer. We examined these biomarkers along with characterization of the tumor microenvironment (TME) between breast tumors (BrTs), axillary metastases (AxMs), liver metastases (LvMs), non-axillary lymph node metastases, and non-liver metastases to determine differences related to site of metastatic disease. METHODS: 3076 unpaired biopsies from breast cancer patients were analyzed using whole transcriptome sequencing and NextGen DNA depicting TMB within tumor sites. The PD-L1 positivity was determined with VENTANA PD-L1 (SP142) assay. The immune cell fraction within the TME was calculated by QuantiSeq and MCP-counter. RESULTS: Compared to BrT, more LvM samples had a high TMB (≥ 10 mutations/Mb) and fewer LvM samples had PD-L1+ expression. Evaluation of the TME revealed that LvM sites harbored lower infiltration of adaptive immune cells, such as CD4+, CD8+, and regulatory T-cells compared with the BrT foci. We saw differences in innate immune cell infiltration in LvM compared to BrT, including neutrophils and NK cells. CONCLUSIONS: LvMs are less likely to express PD-L1+ tumor cells but more likely to harbor high TMB as compared to BrTs. Unlike AxMs, LvMs represent a more immunosuppressed TME and demonstrate lower gene expression associated with adaptive immunity compared to BrTs. These findings suggest biopsy site be considered when interpreting results that influence ICI use for treatment and further investigation of immune composition and biomarkers expression by metastatic site.

Mimicking the breast metastatic microenvironment: characterization of a novel syngeneic model of HER2+ breast cancer.

Preclinical murine models in which primary tumors spontaneously metastasize to distant organs are valuable tools to study metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line, NT2.5-lung metastasis (-LM), that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. Within one week of orthotopic implantation of NT2.5-LM in NeuN mice, distant metastases can be observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. Metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. We demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT) and enrichment in EMT-regulating pathways, suggestive of their enhanced metastatic potential. The new NT2.5-LM model provides more rapid and spontaneous development of widespread metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses targeting distant visceral metastases.

Association of Preoperative Lung Function with Complications after Lobectomy Using Race-Neutral and Race-Specific Normative Equations.

Rationale: Pulmonary function testing (PFT) is performed to aid patient selection before surgical resection for non-small cell lung cancer (NSCLC). The interpretation of PFT data relies on normative equations, which vary by race, but the relative strength of association of lung function using race-specific or race-neutral normative equations with postoperative pulmonary complications is unknown. Objectives: To compare the strength of association of lung function, using race-neutral or race-specific equations, with surgical complications after lobectomy for NSCLC. Methods: We studied 3,311 patients who underwent lobectomy for NSCLC and underwent preoperative PFT from 2001 to 2021. We used Global Lung Function Initiative equations to generate race-specific and race-neutral normative equations to calculate percentage predicted forced expiratory volume in 1 second (FEV1%). The primary outcome of interest was the occurrence of postoperative pulmonary complications within 30 days of surgery. We used unadjusted and race-adjusted logistic regression models and least absolute shrinkage and selection operator analyses adjusted for relevant comorbidities to measure the association of race-specific and race-neutral FEV1% with pulmonary complications. Results: Thirty-one percent of patients who underwent surgery experienced pulmonary complications. Higher FEV1, whether measured with race-neutral (odds ratio [OR], 0.98 per 1% change in FEV1% [95% confidence interval (CI), 0.98-0.99]; P < 0.001) or race-specific (OR, 0.98 per 1% change in FEV1% [95% CI, 0.98-0.98]; P < 0.001) normative equations, was associated with fewer postoperative pulmonary complications. The area under the receiver operator curve for pulmonary complications was similar for race-adjusted race-neutral (0.60) and race-specific (0.60) models. Using least absolute shrinkage and selection operator regression, higher FEV1% was similarly associated with a lower rate of pulmonary complications in race-neutral (OR, 0.99 per 1% [95% CI, 0.98-0.99]) and race-specific (OR, 0.99 per 1%; 95% CI, 0.98-0.99) models. The marginal effect of race on pulmonary complications was attenuated in all race-specific models compared with all race-neutral models. Conclusions: The choice of race-specific or race-neutral normative PFT equations does not meaningfully affect the association of lung function with pulmonary complications after lobectomy for NSCLC, but the use of race-neutral equations unmasks additional effects of self-identified race on pulmonary complications.

African American race is associated with worse sleep quality in heavy smokers.

STUDY OBJECTIVES: To examine the association of self-identified race with sleep quality in heavy smokers. METHODS: We studied baseline data from 1965 non-Hispanic White and 462 African American participants from SPIROMICS with ≥ 20 pack-years smoking history. We first examined the Pittsburgh Sleep Quality Index's (PSQI) internal consistency and item-total correlation in a population with chronic obstructive pulmonary disease. We then used staged multivariable regression to investigate the association of race and sleep quality as measured by the PSQI) The first model included demographics, the second added measures of health status, and the third, indicators of socioeconomic status. We next explored the correlation between sleep quality with 6-minute walk distance and St. George's Respiratory Questionnaire score as chronic obstructive pulmonary disease-relevant outcomes. We tested for interactions between self-identified race and the most important determinants of sleep quality in our conceptual model. RESULTS: We found that the PSQI had good internal consistency and item-total correlation in our study population of heavy smokers with and without chronic obstructive pulmonary disease. African American race was associated with increased PSQI in univariable analysis and after adjustment for demographics, health status, and socioenvironmental exposures (P = .02; 0.44 95%CI: .06 to .83). Increased PSQI was associated with higher postbronchodilator forced expiratory volume in 1 second and lower household income, higher depressive symptoms, and female sex. We identified an interaction wherein depressive symptoms had a greater impact on PSQI score for non-Hispanic White than African American participants (P for interaction = .01). CONCLUSIONS: In heavy smokers, self-reported African American race is independently associated with worse sleep quality. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Study of COPD Subgroups and Biomarkers (SPIROMICS); URL: https://clinicaltrials.gov/ct2/show/NCT01969344; Identifier: NCT01969344. CITATION: Baugh AD, Acho M, Arhin A, et al. African American race is associated with worse sleep quality in heavy smokers. J Clin Sleep Med. 2023;19(8):1523-1532.

Epidemiology of Sarcoidosis in U.S. Veterans from 2003 to 2019.

Rationale: United States veterans represent an important population to study sarcoidosis. Their unique history of environmental exposures, wide geographic distribution, and long-term enrollment in a single integrated healthcare system provides an unparalleled opportunity to understand the incidence, prevalence, and risk factors for sarcoidosis. Objectives: To determine the epidemiology, patient characteristics, geographic distribution, and associated risk factors of sarcoidosis among U.S. veterans. Methods: We used data from the Veterans Health Administration (VHA) electronic health record system between 2003 and 2019 to evaluate the annual incidence, prevalence, and geographic distribution of sarcoidosis (defined using the International Classification of Diseases codes). We used multivariate logistic regression to examine patient characteristics associated with sarcoidosis incidence. Results: Among more than 13 million veterans who received care through or paid for by the VHA, 23,747 (0.20%) incident diagnoses of sarcoidosis were identified. Compared with selected VHA control subjects using propensity score matching, veterans with sarcoidosis were more likely to be female (13.5% vs. 9.0%), of Black race (52.2% vs. 17.0%), and ever-tobacco users (74.2% vs. 64.5%). There was an increase in the annual incidence of sarcoidosis between 2004 and 2019 (from 38 to 52 cases/100,000 person-years) and the annual prevalence between 2003 and 2019 (from 79 to 141 cases/100,000 persons). In a multivariate logistic regression model, Black race (odds ratio [OR], 4.49; 95% confidence interval [CI], 4.33-4.65), female sex (OR, 1.64; 95% CI, 1.56-1.73), living in the Northeast compared with the western region (OR, 1.57; 95% CI, 1.48-1.67), history of tobacco use (OR, 1.36; 95% CI, 1.31-1.41), and serving in the Army, Air Force, or multiple branches compared with the Navy (OR, 1.08; 95% CI, 1.03-1.13; OR, 1.10; 95% CI, 1.04-1.17; OR, 1.27; 95% CI, 1.16-1.39, respectively) were significantly associated with incident sarcoidosis (P < 0.0001). Conclusions: The incidence and prevalence of sarcoidosis are higher among veterans than in the general population. Alongside traditionally recognized risk factors such as Black race and female sex, we found that a history of tobacco use within the Veterans Affairs population and serving in the Army, Air Force, or multiple service branches were associated with increased sarcoidosis risk.

Entinostat Decreases Immune Suppression to Promote Antitumor Responses in a HER2+ Breast Tumor Microenvironment.

Therapeutic combinations to alter immunosuppressive, solid tumor microenvironments (TME), such as in breast cancer, are essential to improve responses to immune checkpoint inhibitors (ICI). Entinostat, an oral histone deacetylase inhibitor, has been shown to improve responses to ICIs in various tumor models with immunosuppressive TMEs. The precise and comprehensive alterations to the TME induced by entinostat remain unknown. Here, we employed single-cell RNA sequencing on HER2-overexpressing breast tumors from mice treated with entinostat and ICIs to fully characterize changes across multiple cell types within the TME. This analysis demonstrates that treatment with entinostat induced a shift from a protumor to an antitumor TME signature, characterized predominantly by changes in myeloid cells. We confirmed myeloid-derived suppressor cells (MDSC) within entinostat-treated tumors associated with a less suppressive granulocytic (G)-MDSC phenotype and exhibited altered suppressive signaling that involved the NFκB and STAT3 pathways. In addition to MDSCs, tumor-associated macrophages were epigenetically reprogrammed from a protumor M2-like phenotype toward an antitumor M1-like phenotype, which may be contributing to a more sensitized TME. Overall, our in-depth analysis suggests that entinostat-induced changes on multiple myeloid cell types reduce immunosuppression and increase antitumor responses, which, in turn, improve sensitivity to ICIs. Sensitization of the TME by entinostat could ultimately broaden the population of patients with breast cancer who could benefit from ICIs.

Contribution of Individual and Neighborhood Factors to Racial Disparities in Respiratory Outcomes.

Rationale: Black adults have worse health outcomes compared with white adults in certain chronic diseases, including chronic obstructive pulmonary disease (COPD).Objectives: To determine to what degree disadvantage by individual and neighborhood socioeconomic status (SES) may contribute to racial disparities in COPD outcomes.Methods: Individual and neighborhood-scale sociodemographic characteristics were determined in 2,649 current or former adult smokers with and without COPD at recruitment into SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). We assessed whether racial differences in symptom, functional, and imaging outcomes (St. George's Respiratory Questionnaire, COPD Assessment Test score, modified Medical Research Council dyspnea scale, 6-minute-walk test distance, and computed tomography [CT] scan metrics) and severe exacerbation risk were explained by individual or neighborhood SES. Using generalized linear mixed model regression, we compared respiratory outcomes by race, adjusting for confounders and individual-level and neighborhood-level descriptors of SES both separately and sequentially.Measurements and Main Results: After adjusting for COPD risk factors, Black participants had significantly worse respiratory symptoms and quality of life (modified Medical Research Council scale, COPD Assessment Test, and St. George's Respiratory Questionnaire), higher risk of severe exacerbations and higher percentage of emphysema, thicker airways (internal perimeter of 10 mm), and more air trapping on CT metrics compared with white participants. In addition, the association between Black race and respiratory outcomes was attenuated but remained statistically significant after adjusting for individual-level SES, which explained up to 12-35% of racial disparities. Further adjustment showed that neighborhood-level SES explained another 26-54% of the racial disparities in respiratory outcomes. Even after accounting for both individual and neighborhood SES factors, Black individuals continued to have increased severe exacerbation risk and persistently worse CT outcomes (emphysema, air trapping, and airway wall thickness).Conclusions: Disadvantages by individual- and neighborhood-level SES each partly explain disparities in respiratory outcomes between Black individuals and white individuals. Strategies to narrow the gap in SES disadvantages may help to reduce race-related health disparities in COPD; however, further work is needed to identify additional risk factors contributing to persistent disparities.

Higher serum vitamin D levels are associated with decreased odds of obstructive lung disease in the general population: an NHANES analysis (2007-2008 to 2009-2010).

BACKGROUND: Obstructive lung disease is a significant cause of morbidity and healthcare burden within the USA. A growing body of evidence has suggested that vitamin D levels can influence the course or incidence of obstructive lung disease. However, there is an insufficient previous investigation of this association. STUDY DESIGN AND METHODS: We used the National Health and Nutrition Examination Survey (NHANES) cycles 2007-2008 and 2009-2010 spirometry results of individuals aged 40 years and older to assess the association between serum 25-hydroxyvitamin D levels and obstructive lung disease, as defined by the American Thoracic Society using the lower limit of normal. We used stage multivariate survey-logistic regression. RESULTS: The final model included age, gender, body mass index, pack-years smoking history, season, income-to-poverty ratio and race/ethnicity. In the primary analysis using vitamin D as a continuous variable, there was no association between vitamin D levels and obstructive lung disease. We noted a trend between 'other Hispanic' self-identified race and serum vitamin D levels wherein higher levels were associated with higher odds of obstructive lung disease in this ethnicity, but not among other racial or ethnic groups (OR (95% CI)=1.40 (0.98 to 1.99), p=0.06). In a secondary analysis, when vitamin D was measured as a categorical variable, there was a significant association between the highest levels of serum vitamin D levels and lesser odds of obstructive lung disease (OR (95% CI)=0.77 [0.61 to 0.98], p=0.04). CONCLUSIONS: Higher serum vitamin D levels among adults are associated with decreased odds of obstructive lung disease in the general population. Results among non-Mexican Hispanic participants highlight the need for further research in minority populations. More work is needed to address the course and incidence of lung disease in the USA.

Synchronous presentation of invasive ductal carcinoma and mantle cell lymphoma: a diagnostic challenge in menopausal patients.

Synchronous presentation of breast carcinoma and non-Hodgkin lymphoma (NHL) is a rare occurrence (Bradford PT, Freedman DM, Goldstein AM, Tucker MA. Increased risk of second primary cancers after a diagnosis of melanoma. Arch Dermatol 2010; 146: :265-72; Dutta Roy S, Stafford JA, Scally J, Selvachandran SN. A rare case of breast carcinoma co-existing with axillary mantle cell lymphoma. World J Surg Oncol 2003; 1: :27; Suresh Attili VS, Dadhich HK, Rao CR, Bapsy PP, Batra U, Anupama G et al. A case of breast cancer coexisting with B-cell follicular lymphoma. Austral Asian J Cancer 2007; 6: :155-6). In particular, only two reported cases on synchronous presentation of invasive ductal carcinoma (IDC) and mantle cell lymphoma (MCL) exist in the English literature. Owing to the rarity, there is a lack of consensus about underlying mechanism as well as optimal treatment strategy, and diagnosing both malignancies together without a delay remains a complex clinical challenge. We report a case of synchronous presentation of IDC and MCL in a 67-year-old female patient whose MCL diagnosis was delayed due to a misinterpretation of her B symptoms as postmenopausal, with a review of the literature on concurrently occurring breast carcinoma and NHL.

Relative value units and payer mix analysis of facial trauma coverage at a level 1 trauma center: is the current model sustainable?

PURPOSE: We aimed to approximate the annual clinical work that is performed during facial trauma coverage and analyze the economic incentives for subspecialty surgeons providing the coverage. METHODS: A retrospective, clinical productivity data analysis of 6 consecutive years of facial trauma coverage at an American College of Surgeons-verified Level I trauma center was performed by the use of a trauma database and relative value unit (RVU) data. A payer mix analysis also was completed. SPSS V19 was used for analysis. RESULTS: Between 2006 and 2011, 526 patients were treated for facial injuries. The annual nonoperative RVUs ranged from 371 to 539, whereas the annual operative RVUs range was 235-426. Trend analysis displayed that most of the annual RVUs were nonoperative until the year 2011, when the operative RVUs surpassed the nonoperative. Payer mix analysis revealed that commercial insurance coverage was the most common (range 21-54%, median 41%) followed by self-pay coverage (18-32%, median 29%). This finding was a consistent phenomenon except in the year 2009, when self-pay covered the majority of the RVUs (32%). Nasal bone fractures (24%) and mandibular fractures (16%) were the two most common diagnoses. Open reduction and internal fixation of mandibular fractures (17%), open reduction and internal fixation orbital bone fractures (15%), and complex facial repair (12%) constituted the most common operative procedures. Facial trauma consultations were obtained 22% (16-24%) of covered days. The percent of days requiring emergency procedures was (0.5-1%). CONCLUSION: The infrequency of subspecialty consultations and operative interventions, and significant payer mix differences between facial trauma patients relative to the current ambulatory surgery population of the covering subspecialties poses economical challenges for both the hospitals and providers that use the traditional coverage models.

Craniofacial trauma and double epidural hematomas from horse training.

INTRODUCTION: A case of complex poly-trauma requiring multi-service management of rare, diagnoses is reviewed. PRESENTATION OF CASE: A healthy 20 year old female suffered double epidural hematoma, base of, skull fracture, traumatic cranial nerve X palsy, benign positional paroxysmal vertigo and supraorbital, neuralgia following equestrian injury. DISCUSSION: Epidemiology, differential diagnosis, and principles of management for each condition, are reviewed. CONCLUSION: Coordinated trauma care is well suited to address the complex poly trauma following, equestrian injury.