G272V and P301L Mutations Induce Isoform Specific Tau Mislocalization to Dendritic Spines and Synaptic Dysfunctions in Cellular Models of 3R and 4R Tau Frontotemporal Dementia.

Tau pathologies are detected in the brains of some of the most common neurodegenerative diseases including Alzheimer's disease (AD), Lewy body dementia (LBD), chronic traumatic encephalopathy (CTE), and frontotemporal dementia (FTD). Tau proteins are expressed in six isoforms with either three or four microtubule-binding repeats (3R tau or 4R tau) due to alternative RNA splicing. AD, LBD, and CTE brains contain pathological deposits of both 3R and 4R tau. FTD patients can exhibit either 4R tau pathologies in most cases or 3R tau pathologies less commonly in Pick's disease, which is a subfamily of FTD. Here, we report the isoform-specific roles of tau in FTD. The P301L mutation, linked to familial 4R tau FTD, induces mislocalization of 4R tau to dendritic spines in primary hippocampal cultures that were prepared from neonatal rat pups of both sexes. Contrastingly, the G272V mutation, linked to familial Pick's disease, induces phosphorylation-dependent mislocalization of 3R tau but not 4R tau proteins to dendritic spines. The overexpression of G272V 3R tau but not 4R tau proteins leads to the reduction of dendritic spine density and suppression of mEPSCs in 5-week-old primary rat hippocampal cultures. The decrease in mEPSC amplitude caused by G272V 3R tau is dynamin-dependent whereas that caused by P301L 4R tau is dynamin-independent, indicating that the two tau isoforms activate different signaling pathways responsible for excitatory synaptic dysfunction. Our 3R and 4R tau studies here will shed new light on diverse mechanisms underlying FTD, AD, LBD, and CTE.

Mechanical injuries of neurons induce tau mislocalization to dendritic spines and tau-dependent synaptic dysfunction.

Chronic traumatic encephalopathy (CTE) is associated with repeated traumatic brain injuries (TBI) and is characterized by cognitive decline and the presence of neurofibrillary tangles (NFTs) of the protein tau in patients' brains. Here we provide direct evidence that cell-scale mechanical deformation can elicit tau abnormalities and synaptic deficits in neurons. Using computational modeling, we find that the early pathological loci of NFTs in CTE brains are regions of high deformation during injury. The mechanical energy associated with high-strain rate deformation alone can induce tau mislocalization to dendritic spines and synaptic deficits in cultured rat hippocampal neurons. These cellular changes are mediated by tau hyperphosphorylation and can be reversed through inhibition of GSK3ß and CDK5 or genetic deletion of tau. Together, these findings identify a mechanistic pathway that directly relates mechanical deformation of neurons to tau-mediated synaptic impairments and provide a possibly exploitable therapeutic pathway to combat CTE.

The Prognostic Value of the AJCC 8th Edition Staging System for Patients Undergoing Neoadjuvant Chemotherapy for Breast Cancer.

BACKGROUND: The American Joint Committee on Cancer (AJCC) 8th edition staging system for breast cancer has been validated in the upfront surgery setting, but has not been examined for its prognostic impact on patients undergoing neoadjuvant chemotherapy. METHODS: The National Cancer Data Base was used to identify patients with invasive unilateral breast cancer from 2010 to 2015 who underwent neoadjuvant chemotherapy. AJCC clinical stage classification was compared between the 7th and 8th editions. Receiver operating characteristic analysis of Kaplan-Meier overall survival (OS) was used to determine the predictive fit of the 7th and 8th edition staging in estimating OS. RESULTS: AJCC 7th and 8th clinical staging assignments were applied to 57,466 patients who underwent neoadjuvant chemotherapy for stage I-III breast cancer from 2010 to 2015. Overall, 37.5% of patients were downstaged and 27.8% were upstaged from the 7th to the 8th edition classification. Kaplan-Meier curves comparing 7th and 8th edition staging differed in OS rates, with a mean follow-up time of 41.5 months. AJCC 8th edition prognostic staging was a better predictor of OS than 7th edition anatomic staging for both clinical stage [area under the curve (AUC) 0.67 vs. 0.62, p < 0.01] and pathological stage (AUC 0.70 vs. 0.66, p < 0.01). CONCLUSIONS: Sixty-five percent of patients have a shift in clinical stage in the AJCC 8th edition. AJCC 8th edition staging has better predictive value for OS than 7th edition staging. While validation of these findings with an independent dataset is needed, 8th edition staging will help improve prognostic modeling in patients undergoing neoadjuvant chemotherapy.

Challenges in Clinical Trial Implementation: Results from a Survey of the National Accreditation Program of Breast Centers (NAPBC).

BACKGROUND: Although the results of clinical trials often guide best practices, changing clinical practice based on clinical trial results can be challenging. The objective of this study was to examine provider-reported barriers to adopting best clinical practices according to clinical trial data. METHODS: A cross-sectional survey was conducted of providers from the National Accreditation Program for Breast Centers about barriers that prevent the incorporation of trial findings. Descriptive analyses and multivariable analyses were performed to determine provider characteristics that were significantly associated with reported barriers. RESULTS: Overall, 383 institutions participated (63.5% response rate), with a total of 1226 physicians responding to the survey (80% response rate). Providers identified national guidelines and meetings as the most compelling way to receive practice-changing information. They reported the following internal barriers to trial implementation: patient preference (45%), strongly held beliefs by partners/colleagues (37%), and insufficient time to discuss new practices (30%). External barriers preventing trial implementation included a lack of agreement from multidisciplinary tumor boards (32%), fear of reimbursement loss (23%), and resistance from clinical staff (20%). Reported barriers differed by provider specialty, with plastic surgeons and radiation oncologists reporting that strongly held beliefs by partners/colleagues and disagreement from multidisciplinary tumor boards were the most significant factors preventing clinical trial implementation. CONCLUSIONS: Physician beliefs and patient preferences are the most frequently reported barriers to clinical trial implementation. Tactics to better educate providers about how to explain new clinical trial data to their patients and colleagues are needed.

Utilization of radiotherapy for malignant phyllodes tumors: analysis of the National Cancer Data Base, 1998-2009.

BACKGROUND: Malignant phyllodes tumors of the breast have traditionally been treated with surgical excision. Recently, the use of adjuvant radiotherapy has been advocated to reduce the risk of local recurrence; however, this recommendation is controversial in the absence of consistent outcome data. We hypothesize that there has been a trend toward increased utilization of adjuvant radiotherapy for malignant phyllodes tumors despite its uncertain effect on outcomes. METHODS: Using the National Cancer Data Base, predictors of radiotherapy utilization were examined for women with malignant phyllodes from 1998 to 2009. Kaplan-Meier and Cox regression models were generated to determine the effect of radiotherapy on local recurrence (LR), disease-free survival (DFS), and overall survival (OS). RESULTS: Of the 3,120 patients with malignant phyllodes, 57 % underwent breast conservation surgery and 42 % underwent mastectomy. Overall, 14.3 % of women received adjuvant radiotherapy. Utilization of radiotherapy doubled over the study period (9.5 % in 1998-1999 vs. 19.5 % in 2008-2009, p < 0.001). Women were significantly more likely to receive radiotherapy if they were diagnosed later in the study, were age 50-59 years old, had tumors >10 cm, or had lymph nodes removed. For the 1,774 patients with available recurrence data, overall recurrence was 14.1 %, and LR was 5.9 %. In adjusted models, adjuvant radiotherapy reduced LR (aHR 0.43, 95 % CI 0.19-0.95) but did not impact DFS or OS after 53 months' median follow-up. CONCLUSIONS: Utilization of adjuvant radiotherapy for malignant phyllodes doubled from 1998 to 2009. Radiotherapy significantly reduced LR but had no effect on DFS or OS.

Germline Testing in Patients With Breast Cancer: ASCO-Society of Surgical Oncology Guideline.

PURPOSE: To develop recommendations for germline mutation testing for patients with breast cancer. METHODS: An ASCO-Society of Surgical Oncology (SSO) panel convened to develop recommendations based on a systematic review and formal consensus process. RESULTS: Forty-seven articles met eligibility criteria for the germline mutation testing recommendations; 18 for the genetic counseling recommendations. RECOMMENDATIONS: BRCA1/2 mutation testing should be offered to all newly diagnosed patients with breast cancer ≤65 years and select patients >65 years based on personal history, family history, ancestry, or eligibility for poly(ADP-ribose) polymerase (PARP) inhibitor therapy. All patients with recurrent breast cancer who are candidates for PARP inhibitor therapy should be offered BRCA1/2 testing, regardless of family history. BRCA1/2 testing should be offered to women who develop a second primary cancer in the ipsilateral or contralateral breast. For patients with prior history of breast cancer and without active disease, testing should be offered to patients diagnosed ≤65 years and selectively in patients diagnosed after 65 years, if it will inform personal and family risk. Testing for high-penetrance cancer susceptibility genes beyond BRCA1/2 should be offered to those with supportive family histories; testing for moderate-penetrance genes may be offered if necessary to inform personal and family cancer risk. Patients should be provided enough pretest information for informed consent; those with pathogenic variants should receive individualized post-test counseling. Variants of uncertain significance should not impact management, and patients with such variants should be followed for reclassification. Referral to providers experienced in clinical cancer genetics may help facilitate patient selection and interpretation of expanded testing, and provide counseling of individuals without pathogenic germline variants but with significant family history.Additional information is available at www.asco.org/breast-cancer-guidelines.

Uses of mHealth in Injury Prevention and Control: a Critical Review.

Purpose of Reviews: The purpose of this review was to summarize the current state of the literature on the use of "mHealth" (the use of mobile devices for health promotion) for injury prevention and control. Recent Findings: mHealth is being used to measure, predict, and prevent the full spectrum of injuries. However, most literature remains preliminary or in a pilot stage. Use of best-of-class design principles (e.g., user-centered design, theory-based development) is uncommon, and wide-scale dissemination of effective monitoring or intervention tools is rare. Summary: mHealth for injury prevention holds promise, but further work is needed across the full spectrum of development and translation.

Reliability of point-of-care shoulder ultrasound measurements for subacromial impingement in asymptomatic participants.

Background: Rehabilitation is the key to management of patients with subacromial impingement syndrome to prevent disability and loss of function. While point-of-care musculoskeletal ultrasound aids clinical diagnosis of subacromial impingement syndrome, many patients do not demonstrate the classic findings of dynamic supraspinatus tendon impingement beneath the acromion on ultrasound. The objective of this study was to establish the most reliable shoulder ultrasound measurements for subacromial impingement, by evaluating the intra-rater and inter-rater reliability of measurements in asymptomatic participants. Methods: Eighteen participants (9 women, 9 men, mean ± standard deviation: 34.6 ± 7.9 years of age) underwent bilateral shoulder ultrasound evaluations with measurements for subacromial impingement (acromiohumeral distance, acromion-greater tuberosity distance, supraspinatus tendon, subacromial-subdeltoid bursa, and subacromial-subdeltoid bursal fluid thickness) performed by two sports medicine physicians. Intra-class coefficients were calculated to determine the intra- and inter-rater reliability of shoulder ultrasound images and measurements. Results: Intra-rater reliability for acromiohumeral distance (0.76-0.79), supraspinatus tendon (0.91-0.95), subacromial-subdeltoid bursa (0.76-0.84), and subacromial-subdeltoid bursal fluid thickness (0.75-0.81) was found to be good to excellent, whereas inter-rater reliability ranged from poor to moderate. Conclusions: Acromiohumeral distance in neutral position and short axis ultrasound measurements of supraspinatus tendon, subacromial-subdeltoid bursa, and subacromial-subdeltoid bursal fluid thickness in the modified Crass position were the most reliable for subacromial impingement in asymptomatic participants. We recommend validation of these measurements in a symptomatic population to aid diagnosis and direct rehabilitation of patients with suspected subacromial impingement, and to increase point-of-care ultrasound uptake, availability, and training among rehabilitation professionals across health systems.

Caspase-2 Inhibitor Blocks Tau Truncation and Restores Excitatory Neurotransmission in Neurons Modeling FTDP-17 Tauopathy.

Synaptic and cognitive deficits mediated by a severe reduction in excitatory neurotransmission caused by a disproportionate accumulation of the neuronal protein tau in dendritic spines is a fundamental mechanism that has been found repeatedly in models of tauopathies, including Alzheimer's disease, Lewy body dementia, frontotemporal dementia, and traumatic brain injury. Synapses thus damaged may contribute to dementia, among the most feared cause of debilitation in the elderly, and currently there are no treatments to repair them. Caspase-2 (Casp2) is an essential component of this pathological cascade. Although it is believed that Casp2 exerts its effects by hydrolyzing tau at aspartate-314, forming Δtau314, it is also possible that a noncatalytic mechanism is involved because catalytically dead Casp2 is biologically active in at least one relevant cellular pathway, that is, autophagy. To decipher whether the pathological effects of Casp2 on synaptic function are due to its catalytic or noncatalytic properties, we discovered and characterized a new Casp2 inhibitor, compound 1 [pKi (Casp2) = 8.12], which is 123-fold selective versus Casp3 and >2000-fold selective versus Casp1, Casp6, Casp7, and Casp9. In an in vitro assay based on Casp2-mediated cleavage of tau, compound 1 blocked the production of Δtau314. Importantly, compound 1 prevented tau from accumulating excessively in dendritic spines and rescued excitatory neurotransmission in cultured primary rat hippocampal neurons expressing the P301S tau variant linked to FTDP-17, a familial tauopathy. These results support the further development of small-molecule Casp2 inhibitors to treat synaptic deficits in tauopathies.

Endometrial stem cell transplantation restores dopamine production in a Parkinson's disease model.

Parkinson's disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons. Adult human endometrial derived stem cells (HEDSC), a readily obtainable type of mesenchymal stem-like cell, were used to generate dopaminergic cells and for transplantation. Cells expressing CD90, platelet derived growth factor (PDGF)-Rß and CD146 but not CD45 or CD31 were differentiated in vitro into dopaminergic neurons that exhibited axon projections, pyramidal cell bodies and dendritic projections that recapitulate synapse formation; these cells also expressed the neural marker nestin and tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Whole cell patch clamp recording identified G-protein coupled inwardly rectifying potassium current 2 channels characteristic of central neurons. A 1-methyl 4-phenyl 1,2,3,6-tetrahydro pyridine induced animal model of PD was used to demonstrate the ability of labelled HEDSC to engraft, migrate to the site of lesion, differentiate in vivo and significantly increase striatal dopamine and dopamine metabolite concentrations. HEDSC are a highly inducible source of allogenic stem cells that rescue dopamine concentrations in an immunocompetent PD mouse model.

Viral Diseases and Youth Sports: How to Handle Common Infections that Sideline Athletes.

The coronavirus disease 2019 (COVID-19) pandemic has brought to forefront the large morbidity, mortality, and complications that viral illnesses can cause. For athletes, viral illnesses can be disruptive toward their participation in youth sports. This article outlines the details of how the most common viral illnesses affect the youth athlete and youth sports, including COVID-19, non-COVID-19 upper respiratory infections, influenza, Epstein-Barr virus, varicella, herpes, and other dermatologic infections. In this article, we review current available guidelines and recommendations on how to handle these infections in athletes during sports as well as return-to-play recommendations. [Pediatr Ann. 2021;50(11):e454-e460.].

ACR Appropriateness Criteria® Supplemental Breast Cancer Screening Based on Breast Density.

Mammography remains the only validated screening tool for breast cancer, however, there are limitations to mammography. One of the limitations of mammography is the variable sensitivity based on breast density. Supplemental screening may be considered based on the patient's risk level and breast density. For average-risk women with nondense breasts, the sensitivity of digital breast tomosynthesis (DBT) screening is high; additional supplemental screening is not warranted in this population. For average-risk women with dense breasts, given the decreased sensitivity of mammography/DBT, this population may benefit from additional supplemental screening with contrast-enhanced mammography, screening ultrasound (US), breast MRI, or abbreviated breast MRI. In intermediate-risk women, there is emerging evidence suggesting that women in this population may benefit from breast MRI or abbreviated breast MRI. In intermediate-risk women with dense breasts, given the decreased sensitivity of mammography/DBT, this population may benefit from additional supplemental screening with contrast-enhancedmammography or screening US. There is strong evidence supporting screening high-risk women with breast MRI regardless of breast density. Contrast-enhanced mammography, whole breast screening US, or abbreviated breast MRI may be also considered. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Sentinel lymph node biopsy for papillary thyroid cancer: 12 years of experience at a single institution.

BACKGROUND: The purpose of this study was to report our experience with sentinel lymph node dissection (SLND) for papillary thyroid carcinoma, to evaluate the feasibility and safety of the procedure, and to examine its potential utility as a guide for central neck dissection. MATERIALS AND METHODS: A retrospective chart review of patients undergoing total thyroidectomy from January 1998 thru January 2010 was conducted. Intratumoral injection of blue dye was used to identify the SLN. Central neck dissection (CND) was performed if the SLN was positive on frozen section. Locally advanced disease, previous thyroid surgery, or lymphadenopathy on preoperative imaging or intraoperative palpation were exclusion criteria. RESULTS: A total of 211 patients underwent SLN mapping. Of these, 165 patients (78%) were female and 46 (22%) were male. Also, 75 (36%) were ≤45 years of age, and 136 (64%) were older than 45. Tumors were ≤2.0 cm (T1) in 142 patients (67%), 2-4 cm (T2) in 35 patients (17%), >4 cm with minimal invasion (T3) in 32 patients (15%), and locally invasive (T4) in 2 patients (1%). At least 1 blue node was found in 192 patients (91%). Also, 47 patients had a positive SLN on frozen section, with an additional 24 node-positive patients on permanent section, for a total of 71 (37%). There were 43 patients (91%) who underwent central neck dissection; 26 (60%) had additional metastases. CONCLUSIONS: Sentinel lymphadenectomy for papillary thyroid carcinoma is feasible, safe, and can identify patients who may benefit from central neck dissection.

Shoulder Double Crush Syndrome: A Retrospective Study of Patients With Concomitant Suprascapular Neuropathy and Cervical Radiculopathy.

PURPOSE: While the double crush phenomena (compression along two points on a nerve) has been established between median neuropathy and cervical radiculopathy, combined suprascapular neuropathy (SSN) and cervical C5/C6 radiculopathy-so-called shoulder double crush syndrome-has not been well examined. We aim to identify the incidence of shoulder double crush syndrome in patients undergoing arthroscopic suprascapular nerve release for SSN. METHODS: One hundred consecutive patients >18 years of age who were positive for SSN on electromyography and motor nerve conduction studies (EMG/NCS) and underwent a suprascapular nerve release were included. Patients with evidence of shoulder double crush syndrome were identified based on x ray, cervical spine magnetic resonance imaging (MRI) and examination findings. Demographics, electrodiagnostics results, treatment courses, and clinical outcomes (visual analog scores and rotator cuff strength) following arthroscopic suprascapular nerve release were compared between patients with double crush syndrome versus isolated SSN. RESULTS: Thirty one percent of patients had evidence of shoulder crush syndrome. Two significant electrophysiologic differences were noted in shoulder double crush patients compared to isolated SSN patients. Patients with double crush had an increased incidence of median neuropathy (51% vs 30%, P = .04). Double crush patients had less supraspinatus motor amplitude difference between the affected side and non-affected side compared to isolated SSN patients (2.62 mV vs 3.44 mV, P = .03). In general, most double crush patients were treated conservatively with regard to their cervical spine pathology. CONCLUSION: A significant percentage of patients with SSN have evidence of shoulder double crush syndrome. Patients with SSN and concomitant median neuropathy should have a detailed neck examination performed.

Heparin-coated stents do not protect cancer patients from cardiac complications after noncardiac surgery.

Previous studies regarding preoperative coronary stents and antithrombotic agents have excluded patients with cancer as a result of hypercoagulability. The objective of this study is to determine whether preoperative heparin-coated coronary stents are as safe in patients with cancer undergoing surgery as patients without cancer. Between February 2003 and February 2005, 29 patients had heparin-coated coronary stents placed before noncardiac surgery. The incidence of postoperative myocardial infarction (MI) and/or death was compared in patients with and without cancer, and outcomes were further evaluated based on preoperative antithrombotic status. Postoperative MI occurred in three of 13 (23%) patients with cancer compared with zero of 16 noncancer patients. Patients with cancer were 9.6 times more likely to have a postoperative MI resulting in death compared with noncancer patients. There was a positive correlation between patients having cancer and having a postoperative MI (r = 0.38, P = 0.044) and between patients with cancer being on antithrombotic medications during surgery and having a postoperative MI (r = 0.567, P = 0.044). After stent placement, patients with cancer undergoing surgery experienced a higher incidence of postoperative MI resulting in death compared with noncancer patients despite continued antithrombotic use. In these patients, alternatives to stenting should be considered to avoid perioperative cardiac complications.

Cough-induced costal cartilage fracture.

We present two cases of atraumatic costal cartilage fracture secondary to violent coughing. Although costal cartilage fractures due to trauma and bony rib fractures due to violent coughing have been described, to our knowledge there have been no prior reported cases of cough-induced costal cartilage fracture. It is important for radiologists to consider costal cartilage fractures, which are often more subtle than osseous injuries, in patients with chest pain, and understand that they may not always be preceded by direct trauma. Identifying this injury is clinically important and will prevent patients from undergoing unnecessary examinations to rule out a cardiac cause of chest pain or a pulmonary embolism.

Predictors of pathologic upstaging in early esophageal adenocarcinoma: Results from the national cancer database.

BACKGROUND: Upstaging in early esophageal adenocarcinoma (EAC) patients happens at a high rate and has implications for treatment. We sought to identify risk factors predicting upstaging. STUDY DESIGN: The National Cancer Database (2010-2013) was queried for all patients with clinical T1/T2 and N0 EAC who underwent esophagectomy without neoadjuvant therapy. Logistic regression models were developed to investigate risk factors for upstaging. RESULTS: A total of 1120 patients were included. Pathologic upstaging occurred in 21.3% (n = 239). After adjustment, risk of upstaging increased with tumor size (tumor size 1-3 cm, OR 4.57,95% CI 2.58-8.10, tumor size >3 cm, OR 10.57, 95% CI 5.77-19.35, as compared to tumors <1 cm) as well as with positive margins (OR 4.13, 95% CI 2.17-7.87) and > than 10 lymph nodes examined (OR 1.85, 95% CI 1.29-2.63), while facility volume was not significant. Odds of upstaging increased linearly with number of lymph nodes examined (OR 1.02 per node). CONCLUSION: Our data underscore the importance of tumor size as a predictor for upstaging and of completing a thorough lymph node dissection for staging purposes.

De novo metastasis in breast cancer: occurrence and overall survival stratified by molecular subtype.

Breast cancer molecular subtypes, categorized jointly by hormone receptors (HR) and human epidermal growth factor-2 (HER2), are utilized to guide systemic therapy. We hypothesized distinct patterns of de novo metastasis and overall survival by molecular subtype using a retrospective cohort of 399,772 women in the National Cancer Database diagnosed with first primary invasive breast cancer between 2010 and 2014, of whom 13,924 were diagnosed with de novo metastasis from 2010 to 2013 and had follow up data. The relationship of molecular subtype with patient and tumor characteristics, including site of de novo metastasis, were examined using Chi-squared tests. Kaplan-Meier and Cox proportional hazards analyses were used to examine overall survival by molecular subtype. Bone was the most frequent de novo metastatic site for all molecular subtypes. Compared to HR+/HER2-, patients with HR-/HER2+ experienced 4.5, 3.0, and 6.0 times the de novo brain, lung, and liver metastasis respectively. In survival analyses of women diagnosed with de novo metastasis, the mortality risk relative to HR+/HER2- was twice as high for triple-negative (hazard ratio = 2.02, 95% CI 1.89-2.16) and modestly lower for HR+/HER2+ (hazard ratio = 0.83, 95% CI 0.78-0.88). The median survival difference between metastatic patients with and without chemotherapy was 28.6 months in HR+/HER2+ and 28.2 months in HR-/HER2+, but only 10.9 months in triple-negative and 5.2 months in HR+/HER2-. In conclusion, despite unfavorable patterns of de novo metastasis, HER2+ breast cancers had relatively better survival in recent years, probably due to treatment differences. Utilizing molecular subtype and site of de novo metastasis may predict prognosis and guide treatment.