Use of 3-Dimensional Stereophotogrammetry to Detect Disease Progression in Craniofacial Morphea.

Importance: Objectively determining disease progression in craniofacial morphea (CM) is challenging, as clinical findings of disease activity are often lacking. Objective: To evaluate the utility of 3-dimensional (3D) stereophotogrammetry in detecting disease progression in CM over time. Design, Setting, and Participants: This prospective cohort study included 27 pediatric and adult patients with CM from 2 hospitals in Boston (Boston Children's Hospital and Brigham & Women's Hospital) consecutively enrolled from April 1, 2019, to March 1, 2023. Review of 3D stereophotogrammetry images and data analysis occurred from March 1 to April 1, 2023. Main Outcomes and Measures: Clinical and 3D stereophotogrammetry assessments were performed at 2- to 12-month intervals, depending on the clinical context. The 3D stereophotogrammetry images were then qualitatively rated as demonstrating no progression or definitive progression by an expert (board-certified plastic craniofacial surgeon) and nonexpert (board-certified dermatologist) in 3D stereophotogrammetry. In addition, κ coefficients were calculated for interrater reliability. Results: Of 27 patients with CM (19 female; median age, 14 [range, 5-40] years) and 3D stereophotogrammetry images obtained from a minimum of 2 time points (median, 4 [range, 2-10] images) spaced a median of 3 (range, 2-12) months apart, 10 experienced progression of their disease based on clinical assessments performed during the study period. In all cases in which clinical progression was favored, blinded qualitative assessment of 3D stereophotogrammetry images also favored progression with substantial interrater reliability (κ = 0.80 [95% CI, 0.61-0.99]). Furthermore, review of 3D stereophotogrammetry detected occult progression of asymmetry not noted on clinical examination in 3 additional patients. Conclusions and Relevance: In this prospective cohort study, blinded assessment of sequential 3D stereophotogrammetry images in patients with CM not only corroborated clinical assessment of disease progression but also detected occult progression of facial asymmetry not appreciable on clinical examination alone. Therefore, 3D stereophotogrammetry may serve as a useful adjunct to clinical examination of patients with CM over time. Future investigations are warranted to validate 3D stereophotogrammetry as an outcome measure in CM.

Etiology, Diagnosis, and Modern Management of Chronic Pancreatitis: A Systematic Review.

Importance: The incidence of chronic pancreatitis is 5 to 12 per 100 000 adults in industrialized countries, and the incidence is increasing. Treatment is multimodal, and involves nutrition optimization, pain management, and when indicated, endoscopic and surgical intervention. Objectives: To summarize the most current published evidence on etiology, diagnosis, and management of chronic pancreatitis and its associated complications. Evidence Review: A literature search of Web of Science, Embase, Cochrane Library, and PubMed was conducted for publications between January 1, 1997, and July 30, 2022. Excluded from review were the following: case reports, editorials, study protocols, nonsystematic reviews, nonsurgical technical publications, studies pertaining to pharmacokinetics, drug efficacy, pilot studies, historical papers, correspondence, errata, animal and in vitro studies, and publications focused on pancreatic diseases other than chronic pancreatitis. Ultimately, the highest-level evidence publications were chosen for inclusion after analysis by 2 independent reviewers. Findings: A total of 75 publications were chosen for review. First-line imaging modalities for diagnosis of chronic pancreatitis included computed tomography and magnetic resonance imaging. More invasive techniques such as endoscopic ultrasonography allowed for tissue analysis, and endoscopic retrograde cholangiopancreatography provided access for dilation, sphincterotomy, and stenting. Nonsurgical options for pain control included behavior modification (smoking cessation, alcohol abstinence), celiac plexus block, splanchnicectomy, nonopioid pain medication, and opioids. Supplemental enzymes should be given to patients with exocrine insufficiency to avoid malnutrition. Surgery was superior to endoscopic interventions for long-term pain control, and early surgery (<3 years from symptom onset) had more superior outcomes than late surgery. Duodenal preserving strategies were preferred unless there was suspicion of cancer. Conclusions and Relevance: Results of this systematic review suggest that patients with chronic pancreatitis had high rates of disability. Strategies to improve pain control through behavioral modification, endoscopic measures, and surgery must also accompany management of the sequalae of complications that arise from endocrine and exocrine insufficiency.

Art in Surgery: A Review of Art-based Medical Humanities Curricula in Surgical Residency.

OBJECTIVE: Numerous programs integrate arts and humanities methods to advance medical education competencies. Despite the highly visual and technical nature of the field of surgery, the current state of art utilization in surgical training is unclear. The purpose of this review is to gain a comprehensive understanding of how art has been utilized in surgical training, to investigate the purpose of such interventions, and to assess how art interventions may benefit surgeons. DESIGN: A systematic literature review using PRISMA methodology was conducted to identify articles published prior to February 2022 that investigated or described using art in surgical resident training. Qualitative themes were developed upon full review of the literature and categorized based on fundamental aspects of surgical education. The data was summarized by a narrative approach. RESULTS: Six hundred seventy-four unique articles were initially identified, thirteen of which met inclusion criteria. Twelve studies employed drawing or sculpture in surgical residency training; one discussed art observation to foster mindfulness, teambuilding, and empathy. Eight articles utilized art as an evaluation tool, 2 for didactic and archival purposes, one employed exercises in art analysis to improve empathy and physician wellbeing, and 2 described courses in which art making was treated as a foundational skill. No articles discussed use of art for honing diagnostic skills, observation, or patient communication - competencies that have been addressed in other fields. CONCLUSIONS: This review highlights the small number of examples in the medical literature about visual arts in surgical training. The existing art-based surgical humanities studies identify opportunities for curricular innovation within surgical training.

Immune Responses Vary in Preinvasive Colorectal Lesions by Tumor Location and Histology.

Immune responses vary in colorectal cancers, which strongly influence prognosis. However, little is known about the variance in immune response within preinvasive lesions. The study aims to investigate how the immune contexture differs by clinicopathologic features (location, histology, dysplasia) associated with progression and recurrence in early carcinogenesis. We performed a cross-sectional study using preinvasive lesions from the surgical pathology laboratory at the Medical University of South Carolina. We stained the tissues with immunofluorescence antibodies, then scanned and analyzed expression using automated image analysis software. We stained CD117 as a marker of mast cells, CD4/RORC to indicate Th17 cells, MICA/B as a marker of NK-cell ligands, and also used antibodies directed against cytokines IL6, IL17A, and IFNγ. We used negative binomial regression analysis to compare analyte density counts by location, histology, degree of dysplasia adjusted for age, sex, race, and batch. All immune markers studied (except IL17a) had significantly higher density counts in the proximal colon than distal colon and rectum. Increases in villous histology were associated with significant decreases in immune responses for IL6, IL17a, NK ligand, and mast cells. No differences were observed in lesions with low- and high-grade dysplasia, except in mast cells. The lesions of the proximal colon were rich in immune infiltrate, paralleling the responses observed in normal mucosa and invasive disease. The diminishing immune response with increasing villous histology suggests an immunologically suppressive tumor environment. Our findings highlight the heterogeneity of the immune responses in preinvasive lesions, which may have implications for prevention strategies. PREVENTION RELEVANCE: Our study is focused on immune infiltrate expression in preinvasive colorectal lesions; our results suggest important differences by clinicopathologic features that have implications for immune prevention research.

Preinvasive Colorectal Lesions of African Americans Display an Immunosuppressive Signature Compared to Caucasian Americans.

BACKGROUND: African Americans (AAs) have higher colorectal cancer (CRC) incidence and mortality rate than Caucasian Americans (CAs). Recent studies suggest that immune responses within CRCs contribute to the disparities. If racially distinct immune signatures are present in the early phases of carcinogenesis, they could be used to develop interventions to prevent or slow disease. METHODS: We selected a convenience sample of 95 patients (48 CAs, 47 AAs) with preinvasive colorectal adenomas from the surgical pathology laboratory at the Medical University of South Carolina. Using immunofluorescent-conjugated antibodies on tissue slides from the lesions, we quantified specific immune cell populations: mast cells (CD117+), Th17 cells (CD4+RORC+), and NK cell ligand (MICA/B) and inflammatory cytokines, including IL-6, IL-17A, and IFN-γ. We compared the mean density counts (MDCs) and density rate ratios (RR) and 95% CI of immune markers between AAs to CAs using negative binomial regression analysis. We adjusted our models for age, sex, clinicopathologic characteristics (histology, location, dysplasia), and batch. RESULTS: We observed no racial differences in age or sex at the baseline endoscopic exam. AAs compared to CAs had a higher prevalence of proximal adenomas (66% vs. 40%) and a lower prevalence of rectal adenomas (11% vs. 23%) (p =0.04) but no other differences in pathologic characteristics. In age, sex, and batch adjusted models, AAs vs. CAs had lower RRs for cells labeled with IFNγ (RR 0.50 (95% CI 0.32-0.81); p=0.004) and NK cell ligand (RR 0.67 (0.43-1.04); p=0.07). In models adjusted for age, sex, and clinicopathologic variables, AAs had reduced RRs relative to CAs for CD4 (p=0.02), NK cell ligands (p=0.01), Th17 (p=0.005), mast cells (p=0.04) and IFN-γ (p< 0.0001). CONCLUSIONS: Overall, the lower RRs in AAs vs. CAs suggests reduced effector response capacity and an immunosuppressive ('cold') tumor environment. Our results also highlight the importance of colonic location of adenoma in influencing these differences; the reduced immune responses in AAs relative to CAs may indicate impaired immune surveillance in early carcinogenesis. Future studies are needed to understand the role of risk factors (such as obesity) in influencing differences in immune responses by race.

Assessment of 18F-PBR-111 in the Cuprizone Mouse Model of Multiple Sclerosis.

The study aims to assess site assessment of the performance of 18F-PBR-111 as a neuroinflammation marker in the cuprizone mouse model of multiple sclerosis (MS). 18F-PBR-111 PET imaging has not been well evaluated in multiple sclerosis applications both in preclinical and clinical research. This study will help establish the potential utility of 18F-PBR-111 PET in preclinical MS research and future animal and future human applications. 18F-PBR-111 PET/CT was conducted at 3.5 weeks (n = 7) and 5.0 weeks (n = 7) after cuprizone treatment or sham control (n = 3) in the mouse model. A subgroup of mice underwent autoradiography with cryosectioned brain tissue. T2 weighted MRI was performed to obtain the brain structural data of each mouse. 18F-PBR-111 uptake was assessed in multiple brain regions with PET and autoradiography images. The correlation between autoradiography and immunofluorescence staining of neuroinflammation (F4/80 and CD11b) was measured. Compared to control mice, significant 18F-PBR-111 uptake in the corpus callosum (p < 0.001), striatum (caudate and internal capsule, p < 0.001), and hippocampus (p < 0.05) was identified with PET images at both 3.5 weeks and 5.0 weeks, and validated with autoradiography. No significant uptake differences were detected between 3.5 weeks and 5.0 weeks assessing these regions as a whole, although there was a trend of increased uptake at 5.0 weeks compared to 3.5 weeks in the CC. High 18F-PBR-111 uptake regions correlated with microglial/macrophage locations by immunofluorescence staining with F4/80 and CD11b antibodies. 18F-PBR-111 uptake in anatomic locations correlated with activated microglia at histology in the cuprizone mouse model of MS suggests that 18F-PBR-111 has potential for in vivo evaluation of therapy response and potential for use in MS patients and animal studies.

Protein-based immune profiles of basal-like vs. luminal breast cancers.

Tumor-infiltrating lymphocytes play an important, but incompletely understood role in chemotherapy response and prognosis. In breast cancer, there appear to be distinct immune responses by subtype, but most studies have used limited numbers of protein markers or bulk sequencing of RNA to characterize immune response, in which spatial organization cannot be assessed. To identify immune phenotypes of Basal-like vs. Luminal breast cancer we used the GeoMx® (NanoString) platform to perform digital spatial profiling of immune-related proteins in tumor whole sections and tissue microarrays (TMA). Visualization of CD45, CD68, or pan-Cytokeratin by immunofluorescence was used to select regions of interest in formalin-fixed paraffin embedded tissue sections. Forty-four antibodies representing stromal markers and multiple immune cell types were applied to quantify the tumor microenvironment. In whole tumor slides, immune hot spots (CD45+) had increased expression of many immune markers, suggesting a diverse and robust immune response. In epithelium-enriched areas, immune signals were also detectable and varied by subtype, with regulatory T-cell (Treg) markers (CD4, CD25, and FOXP3) being higher in Basal-like vs. Luminal breast cancer. Extending these findings to TMAs with more patients (n = 75), we confirmed subtype-specific immune profiles, including enrichment of Treg markers in Basal-likes. This work demonstrated that immune responses can be detected in epithelium-rich tissue, and that TMAs are a viable approach for obtaining important immunoprofiling data. In addition, we found that immune marker expression is associated with breast cancer subtype, suggesting possible prognostic, or targetable differences.

A Circle RNA Regulatory Axis Promotes Lung Squamous Metastasis via CDR1-Mediated Regulation of Golgi Trafficking.

Lung squamous carcinoma (LUSC) is a highly metastatic disease with a poor prognosis. Using an integrated screening approach, we found that miR-671-5p reduces LUSC metastasis by inhibiting a circular RNA (circRNA), CDR1as. Although the putative function of circRNA is through miRNA sponging, we found that miR-671-5p more potently silenced an axis of CDR1as and its antisense transcript, cerebellar degeneration related protein 1 (CDR1). Silencing of CDR1as or CDR1 significantly inhibited LUSC metastases and CDR1 was sufficient to promote migration and metastases. CDR1, which directly interacted with adaptor protein 1 (AP1) complex subunits and coatomer protein I (COPI) proteins, no longer promoted migration upon blockade of Golgi trafficking. Therapeutic inhibition of the CDR1as/CDR1 axis with miR-671-5p mimics reduced metastasis in vivo. This report demonstrates a novel role for CDR1 in promoting metastasis and Golgi trafficking. These findings reveal an miRNA/circRNA axis that regulates LUSC metastases through a previously unstudied protein, CDR1. SIGNIFICANCE: This study shows that circRNA, CDR1as, promotes lung squamous migration, metastasis, and Golgi trafficking through its complimentary transcript, CDR1.

IL-11 antagonist suppresses Th17 cell-mediated neuroinflammation and demyelination in a mouse model of relapsing-remitting multiple sclerosis.

IL-11 induced differentiation and expansion of Th17 cells in patients with early relapsing-remitting multiple sclerosis (RRMS). In mice with relapsing-remitting experimental autoimmune encephalomyelitis (RREAE), IL-11 exacerbated disease, induced demyelination in the central nervous system (CNS), increased the percentage of IL-17A+CD4+ Th17 cells in the CNS in the early acute phase, and up-regulated serum IL-17A levels and the percentage of IL-17A+CD4+ Th17 cells in lymph nodes, and IFN-γ+CD4+ T cells in spinal cord in the RR phase. IL-11 antagonist suppressed RREAE disease activities, inhibited IL-17A+CD4+ cell infiltration and demyelination in the CNS, and decreased the percentage of IL-17A+CD4+ T cells in peripheral blood mononuclear cells and ICAM1+CD4+ T cells in brain and SC. Diffusion Tensor Imaging indicated that IL-11 antagonist inhibited demyelination in several brain regions. We conclude that by suppressing Th17 cell-mediated neuroinflammation and demyelination, IL-11 antagonist can be further studied as a potential selective and early therapy for RRMS.

TP53 protein levels, RNA-based pathway assessment, and race among invasive breast cancer cases.

Mutations in tumor suppressor TP53 have been inconsistently linked to breast cancer risk factors and survival. Immunohistochemistry (IHC) staining, a primary clinical means of TP53 mutation determination, only detects mutations that facilitate protein accumulation (e.g., missense mutations). RNA-based pathway methods capture functional status and may aid in understanding the role of TP53 function in racial disparities of breast cancer. TP53 status was assessed among invasive breast cancer cases from the Carolina Breast Cancer Study (CBCS) (2008-2013) using IHC and an established RNA-based TP53 signature (CBCS and The Cancer Genome Atlas (TCGA)). Frequency of TP53 status (IHC, RNA-based) was estimated in association with tumor characteristics, PAM50 intrinsic subtype, age, and race using relative frequency differences (RFDs) and 95% confidence intervals (95% CI) as the measure of association. Approximately 60% of basal-like tumors were TP53 protein positive (IHC), while nearly 100% were TP53 mutant-like (RNA). Luminal A tumors had low frequency of TP53 positivity (IHC: 7.9%) and mutant-like status (RNA: 1.7%). Mutant-like TP53 (RNA) was strongly associated with age ≤50 years, high tumor grade, advanced stage of disease, large tumor size, and basal-like and HER2 intrinsic subtypes. Black race was strongly associated with TP53 mutant-like status (RNA) (RFD: 24.8%, 95% CI: 20.5, 29.0) even after adjusting for age, grade, stage (RFD: 11.3%; 95% CI: 7.6, 15.0). Associations were attenuated and non-significant when measured by IHC. IHC-based TP53 status is an insensitive measurement of TP53 functional status. RNA-based methods suggest a role for TP53 in tumor prognostic features and racial disparities.

Frequency of breast cancer subtypes among African American women in the AMBER consortium.

BACKGROUND: Breast cancer subtype can be classified using standard clinical markers (estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)), supplemented with additional markers. However, automated biomarker scoring and classification schemes have not been standardized. The aim of this study was to optimize tumor classification using automated methods in order to describe subtype frequency in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. METHODS: Using immunohistochemistry (IHC), we quantified the expression of ER, PR, HER2, the proliferation marker Ki67, and two basal-like biomarkers, epidermal growth factor receptor (EGFR) and cytokeratin (CK)5/6, in 1381 invasive breast tumors from African American women. RNA-based (prediction analysis of microarray 50 (PAM50)) subtype, available for 574 (42%) cases, was used to optimize classification. Subtype frequency was calculated, and associations between subtype and tumor characteristics were estimated using logistic regression. RESULTS: Relative to ER, PR and HER2 from medical records, central IHC staining and the addition of Ki67 or combined tumor grade improved accuracy for classifying PAM50-based luminal subtypes. Few triple negative cases (< 2%) lacked EGFR and CK5/6 expression, thereby providing little improvement in accuracy for identifying basal-like tumors. Relative to luminal A subtype, all other subtypes had higher combined grade and were larger, and ER-/HER2+ tumors were more often lymph node positive and late stage tumors. The frequency of basal-like tumors was 31%, exceeded only slightly by luminal A tumors (37%). CONCLUSIONS: Our findings indicate that automated IHC-based classification produces tumor subtype frequencies approximating those from PAM50-based classification and highlight high frequency of basal-like and low frequency of luminal A breast cancer in a large study of African American women.

MerTK as a therapeutic target in glioblastoma.

Background: Glioma-associated macrophages and microglia (GAMs) are components of the glioblastoma (GBM) microenvironment that express MerTK, a receptor tyrosine kinase that triggers efferocytosis and can suppress innate immune responses. The aim of the study was to define MerTK as a therapeutic target using an orally bioavailable inhibitor, UNC2025. Methods: We examined MerTK expression in tumor cells and macrophages in matched patient GBM samples by double-label immunohistochemistry. UNC2025-induced MerTK inhibition was studied in vitro and in vivo. Results: MerTK/CD68+ macrophages increased in recurrent tumors while MerTK/glial fibrillary acidic protein-positive tumor cells did not. Pharmacokinetic studies showed high tumor exposures of UNC2025 in a syngeneic orthotopic allograft mouse GBM model. The same model mice were randomized to receive vehicle, daily UNC2025, fractionated external beam radiotherapy (XRT), or UNC2025/XRT. Although median survival (21, 22, 35, and 35 days, respectively) was equivalent with or without UNC2025, bioluminescence imaging (BLI) showed significant growth delay with XRT/UNC2025 treatment and complete responses in 19%. The responders remained alive for 60 days and showed regression to 1%-10% of pretreatment BLI tumor burden; 5 of 6 were tumor free by histology. In contrast, only 2% of 98 GBM mice of the same model treated with XRT survived 50 days and none survived 60 days. UNC2025 also reduced CD206+ macrophages in mouse tumor samples. Conclusions: These results suggest that MerTK inhibition combined with XRT has a therapeutic effect in a subset of GBM. Further mechanistic studies are warranted.

Racial Differences in PAM50 Subtypes in the Carolina Breast Cancer Study.

Background: African American breast cancer patients have lower frequency of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative disease and higher subtype-specific mortality. Racial differences in molecular subtype within clinically defined subgroups are not well understood. Methods: Using data and biospecimens from the population-based Carolina Breast Cancer Study (CBCS) Phase 3 (2008-2013), we classified 980 invasive breast cancers using RNA expression-based PAM50 subtype and recurrence (ROR) score that reflects proliferation and tumor size. Molecular subtypes (Luminal A, Luminal B, HER2-enriched, and Basal-like) and ROR scores (high vs low/medium) were compared by race (blacks vs whites) and age (≤50 years vs > 50 years) using chi-square tests and analysis of variance tests. Results: Black women of all ages had a statistically significantly lower frequency of Luminal A breast cancer (25.4% and 33.6% in blacks vs 42.8% and 52.1% in whites; younger and older, respectively). All other subtype frequencies were higher in black women (case-only odds ratio [OR] = 3.11, 95% confidence interval [CI] = 2.22 to 4.37, for Basal-like; OR = 1.45, 95% CI = 1.02 to 2.06, for Luminal B; OR = 2.04, 95% CI = 1.33 to 3.13, for HER2-enriched). Among clinically HR+/HER2- cases, Luminal A subtype was less common and ROR scores were statistically significantly higher among black women. Conclusions: Multigene assays highlight racial disparities in tumor subtype distribution that persist even in clinically defined subgroups. Differences in tumor biology (eg, HER2-enriched status) may be targetable to reduce disparities among clinically ER+/HER2- cases.

Biology and Etiology of Young-Onset Breast Cancers among Premenopausal African American Women: Results from the AMBER Consortium.

Background: African American (AA) women have higher incidence of aggressive, young-onset (<40 years) breast cancers. Young- and older-onset disease may have distinct tumor biologies and etiologies; however, studies investigating age differences among AA women have been rare and generally underpowered.Methods: We examined tumor characteristics and breast cancer risk factors associated with premenopausal young (<40) vs. older (≥40) AA women's breast cancer in the African American Breast Cancer Epidemiology and Risk Consortium (2,008 cases and 5,144 controls). Unconditional logistic regression models assessed heterogeneity of tumor biology and risk factor associations by age, overall, and by estrogen receptor status.Results: Premenopausal AA women <40 years had higher frequency of poorer-prognosis tumor characteristics compared with older women, including negative estrogen and progesterone receptor status, triple-negative subtype, higher grade, higher stage, and larger tumors. Adiposity (i.e., waist-to-hip ratio) and family history of breast cancer were more strongly associated with young-onset disease [case-control OR = 1.46, 95% confidence interval (CI) = 1.04-2.05; OR = 3.10, 95% CI = 2.08-4.63, respectively] compared with older-onset disease (OR = 1.11, 95% CI = 0.91-1.35; OR = 1.57, 95% CI = 1.26-1.94). Breastfeeding showed a slight inverse risk association among young women (OR = 0.70, 95% CI = 0.43-1.16). Oral contraceptive use was associated with increased risk regardless of age. Considering various cutoff points for young age (<40, <45, <50), age-related heterogeneity was greatest when <40 was used.Conclusions: Among premenopausal AA women, diagnosis before age 40 is associated with more aggressive breast tumor biology and some etiologic differences.Impact: Modifiable risk factors including breastfeeding, adiposity, and oral contraceptive use may be important targets for mitigating harms of young-onset breast cancer. Cancer Epidemiol Biomarkers Prev; 26(12); 1722-9. ©2017 AACR.

Ki-67 Expression in Breast Cancer Tissue Microarrays: Assessing Tumor Heterogeneity, Concordance With Full Section, and Scoring Methods.

OBJECTIVES: Ki-67 has been proposed to be used as a surrogate marker to differentiate luminal breast carcinomas (BCs). The purpose of this study was to determine the utility of and best approaches for using tissue microarrays (TMAs) and Ki-67 staining to distinguish luminal subtypes in large epidemiology studies of luminal/human epidermal growth factor receptor 2 (HER2)-negative BC. METHODS: Full-section and TMA (three 0.6-mm cores and two 1.0-mm cores) slides of 109 cases were stained with Ki-67 antibody. We assessed two ways of collapsing TMA cores: a weighted approach and mitotically active approach. RESULTS: For cases with at least a single 0.6-mm TMA core (n = 107), 16% were misclassified using a mitotically active approach and 11% using a weighted approach. For cases with at least a single 1.0-mm TMA core (n = 101), 5% were misclassified using either approach. For the 0.6-mm core group, there were 33.3% discordant cases. The number of discordant cases increased from 18% in the group of two cores to 40% in the group of three cores (P = .039). CONCLUSIONS: Ki-67 tumor heterogeneity was common in luminal/HER2- BC. Using a weighted approach was better than using a mitotically active approach for core to case collapsing. At least a single 1.0-mm core or three 0.6-mm cores are required when designing a study using TMA.

An Analysis of Independent Variables Affecting Surgical Outcomes in Patients Undergoing Repair of Maxillofacial Trauma: An American College of Surgeons National Surgical Quality Improvement Program Study.

INTRODUCTION: Facial fractures, from straightforward closed nasal reductions to complex pan facial fractures, are commonly encountered in the Plastic Surgical community. However, very little has been discussed in the literature regarding the outcomes of facial fractures relating to contributing factors. Our aim was to evaluate a battery of independent variables in order to identify, which, if any, factors correlate with suboptimal outcomes in patients who have undergone facial fracture surgery. METHODS: Under the data use agreement of the American College of Surgeons public use files of the NSQIP, patients involving repair of facial fractures, Current Procedural Terminology codes 21310 to 21470 inclusive, were queried. The outcomes examined included: wound dehiscence, superficial surgical site infection, deep surgical site infection, readmission, open wound/wound infection and return to the operating room. RESULTS: There were 2069 facial fracture patients in the National Surgical Quality Improvement Program datasets (2005-2013). Thirteen perioperative risk factors and patient comorbidities were evaluated for correlation with the 6 outcomes. Of the 6 outcomes evaluated, open wound/wound infection was the most prevalent outcome (6%). Factors statistically significant for presence of open wound/wound infection were American Society of Anesthesiology classification (P = 0.002), presence of bleeding disorder (P = 0.008), emergency patient (P = 0.001), chronic alcohol use (P = 0.002), and chronic steroid use (P = 0.034). DISCUSSION: Several factors correlated with presence of an open wound/wound infection; however, variables such as diabetes and active tobacco use, which are often thought to contribute to wound infections, were shown to be statistically nonsignificant. Although this study was limited by its observational nature, these data may indicate a change in perception of the factors correlated with wound infections.

Robin sequence: what the multidisciplinary approach can do.

Robin sequence (RS) is a commonly encountered triad of micrognathia, glossoptosis, and airway obstruction, with or without a cleft palate. The management of airway obstruction is of paramount importance, and multiple reviews and retrospective series outline the diagnosis and treatment of RS. This article focuses on the multidisciplinary nature of RS and the specialists' contributions and thought processes regarding the management of the RS child from birth to skeletal maturity. This review demonstrates that the care of these children extends far beyond the acute airway obstruction and that thorough monitoring and appropriate intervention are required to help them achieve optimal outcomes.

Intratumoral heterogeneity as a source of discordance in breast cancer biomarker classification.

BACKGROUND: Spatial heterogeneity in biomarker expression may impact breast cancer classification. The aims of this study were to estimate the frequency of spatial heterogeneity in biomarker expression within tumors, to identify technical and biological factors contributing to spatial heterogeneity, and to examine the impact of discordant biomarker status within tumors on clinical record agreement. METHODS: Tissue microarrays (TMAs) were constructed using two to four cores (1.0 mm) for each of 1085 invasive breast cancers from the Carolina Breast Cancer Study, which is part of the AMBER Consortium. Immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) was quantified using automated digital imaging analysis. The biomarker status for each core and for each case was assigned using clinical thresholds. Cases with core-to-core biomarker discordance were manually reviewed to distinguish intratumoral biomarker heterogeneity from misclassification of biomarker status by the automated algorithm. The impact of core-to-core biomarker discordance on case-level agreement between TMAs and the clinical record was evaluated. RESULTS: On the basis of automated analysis, discordant biomarker status between TMA cores occurred in 9 %, 16 %, and 18 % of cases for ER, PR, and HER2, respectively. Misclassification of benign epithelium and/or ductal carcinoma in situ as invasive carcinoma by the automated algorithm was implicated in discordance among cores. However, manual review of discordant cases confirmed spatial heterogeneity as a source of discordant biomarker status between cores in 2 %, 7 %, and 8 % of cases for ER, PR, and HER2, respectively. Overall, agreement between TMA and clinical record was high for ER (94 %), PR (89 %), and HER2 (88 %), but it was reduced in cases with core-to-core discordance (agreement 70 % for ER, 61 % for PR, and 57 % for HER2). CONCLUSIONS: Intratumoral biomarker heterogeneity may impact breast cancer classification accuracy, with implications for clinical management. Both manually confirmed biomarker heterogeneity and misclassification of biomarker status by automated image analysis contribute to discordant biomarker status between TMA cores. Given that manually confirmed heterogeneity is uncommon (<10 % of cases), large studies are needed to study the impact of heterogeneous biomarker expression on breast cancer classification and outcomes.

Evaluating markers of epithelial-mesenchymal transition to identify cancer patients at risk for metastatic disease.

Most cancer deaths are due to metastases. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells could be helpful to assess patient risk of metastatic disease, even among those otherwise diagnosed with local disease. Previous studies of EMT markers and patient outcomes used inconsistent methods and did not compare the clinical impact of different expression cut points for the same marker. Using digital image analysis, we measured the EMT markers Snail and E-cadherin in primary tumor specimens from 190 subjects in tissue microarrays from a population-based prospective cohort of colorectal cancer patients and estimated their associations with time-to-death. After measuring continuous marker expression data, we performed a systematic search for the cut point for each marker with the best model fit between dichotomous marker expression and time-to-death. We also assessed the potential clinical impact of different cut points for the same marker. After dichotomizing expression status at the statistically-optimal cut point, we found that Snail expression was not associated with time-to-death. When measured as a weighted average of tumor cores, low E-cadherin expression was associated with a greater risk of dying within 5 years of surgery than high expression (risk difference = 33 %, 95 % confidence interval 3-62 %). Identifying a clinically-optimal cut point for an EMT marker requires trade-offs between strength and precision of the association with patient outcomes, as well as consideration of the number of patients whose treatments might change based on using the marker at a given cut point.

Performance of Three-Biomarker Immunohistochemistry for Intrinsic Breast Cancer Subtyping in the AMBER Consortium.

BACKGROUND: Classification of breast cancer into intrinsic subtypes has clinical and epidemiologic importance. To examine accuracy of IHC-based methods for identifying intrinsic subtypes, a three-biomarker IHC panel was compared with the clinical record and RNA-based intrinsic (PAM50) subtypes. METHODS: Automated scoring of estrogen receptor (ER), progesterone receptor (PR), and HER2 was performed on IHC-stained tissue microarrays comprising 1,920 cases from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. Multiple cores (1-6/case) were collapsed to classify cases, and automated scoring was compared with the clinical record and to RNA-based subtyping. RESULTS: Automated analysis of the three-biomarker IHC panel produced high agreement with the clinical record (93% for ER and HER2, and 88% for PR). Cases with low tumor cellularity and smaller core size had reduced agreement with the clinical record. IHC-based definitions had high agreement with the clinical record regardless of hormone receptor positivity threshold (1% vs. 10%), but a 10% threshold produced highest agreement with RNA-based intrinsic subtypes. Using a 10% threshold, IHC-based definitions identified the basal-like intrinsic subtype with high sensitivity (86%), although sensitivity was lower for luminal A, luminal B, and HER2-enriched subtypes (76%, 40%, and 37%, respectively). CONCLUSION: Three-biomarker IHC-based subtyping has reasonable accuracy for distinguishing basal-like from nonbasal-like, although additional biomarkers are required for accurate classification of luminal A, luminal B, and HER2-enriched cancers. IMPACT: Epidemiologic studies relying on three-biomarker IHC status for subtype classification should use caution when distinguishing luminal A from luminal B and when interpreting findings for HER2-enriched cancers.