Publications by authors named "Brendan Heiden"

8 Publications

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Striking a balance: Surveillance of non-small cell lung cancer after resection.

J Thorac Cardiovasc Surg 2020 Dec 10. Epub 2020 Dec 10.

Division of Cardiothoracic Surgery, Washington University School of Medicine, St Louis, Mo. Electronic address:

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December 2020

Assessment of Preoperative Opioid Use Prevalence and Clinical Outcomes in Pulmonary Resection.

Ann Thorac Surg 2020 Oct 1. Epub 2020 Oct 1.

Washington University School of Medicine, Division of Cardiothoracic Surgery.

Background: Preoperative opioid use is associated with increased healthcare utilization after elective abdominal surgery. However, the scope of preoperative opioid use and its association with outcomes have not been described in elective pulmonary resection. We aimed to characterize prevalent preoperative opioid use in patients undergoing elective pulmonary resection and compare clinical outcomes between patients with and without preoperative opioid exposure.

Methods: We assembled a retrospective cohort of adult patients undergoing elective pulmonary resection using the IBM® Watson Health MarketScan® Database (2007-2015). We compared opioid-naïve patients to those with a history of preoperative opioid exposure (>0 morphine milligram equivalent prescription filled within 90 days prior to surgery). Multivariable logistic and linear regression adjusting for patient sociodemographic, comorbidity, and operative characteristics were used to compare odds of postoperative complication, prolonged length-of-stay (>14 days), 30-day post-discharge emergency room visits, 90-day readmissions, and 90-day costs.

Results: We identified 14,373 patients, of which 4,502 (31.3%) had opioid exposure prior to pulmonary resection. In multivariable regression, patients with preoperative opioid exposure had significantly higher odds of experiencing prolonged length-of-stay (OR: 1.32, 95% CI: 1.11-1.58), 30-day emergency room visits (OR: 1.24, 95% CI: 1.01-1.41), and 90-day readmissions (OR: 1.41, 95% CI: 1.28-1.55). Adjusted 90-day costs were approximately 5% higher for patients with preoperative opioid use (p<0.0001).

Conclusions: One-third of pulmonary resection patients used opioids preoperatively and were at risk of experiencing adverse outcomes and having significantly higher health care utilization. They represent a unique high-risk population that will require novel, targeted interventions.
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October 2020

Positron Emission Tomography 18F-Fluorodeoxyglucose Uptake Correlates with KRAS and EMT Gene Signatures in Operable Esophageal Adenocarcinoma.

J Surg Res 2018 12 10;232:621-628. Epub 2018 Aug 10.

Department of Surgery, Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan. Electronic address:

Background: 18F-fluorodeoxyglucose positron emission tomography is an imaging modality critical to the diagnosis and staging of esophageal cancer. Despite this, the genetic abnormalities associated with increased 18F-fluorodeoxyglucose (FDG)-maximum standardized uptake value (SUVmax) have not been previously explored in esophageal adenocarcinoma.

Materials And Methods: Treatment-naïve patients, for whom frozen tissue and 18F-fluorodeoxyglucose positron emission tomography data were available, undergoing esophagectomy from 2003 to 2012, were identified. Primary tumor FDG-uptake (SUVmax) was quantified as low (<5), moderate, or high (>10). Genome-wide expression analyses (e.g., microarray) were used to examine gene expression differences associated with FDG-uptake.

Results: Eighteen patients with stored positron emission tomography data and tissue were reviewed. Overall survival was similar between patients with high (n = 9) and low (n = 6) FDG-uptake tumors (P = 0.71). Differences in gene expression between tumors with high and low FDG-uptake included enriched expression of various matrix metalloproteinases, extracellular-matrix components, oncogenic signaling members, and PD-L1 (fold-change>2.0, P < 0.05) among the high-FDG tumors. Glycolytic gene expression and pathway involvement were similar between the high- and low-FDG tumor subsets (P = 0.126). Gene ontology analysis of the most differentially expressed genes demonstrated significant upregulation of gene sets associated with extracellular matrix organization and vascular development (P < 0.005). Gene set enrichment analysis further demonstrated associations between FDG-uptake intensity and canonical oncogenic processes, including hypoxia, angiogenesis, KRAS signaling, and epithelial-to-mesenchymal transition (P < 0.001). Interestingly, KRAS expression did not predict worse survival in a larger cohort (n = 104) of esophageal adenocarcinomas (P = 0.64).

Conclusions: These results suggest that elevated FDG-uptake is associated with a variety of oncogenic alterations in operable esophageal adenocarcinoma. These pathways present potential therapeutic targets among tumors exhibiting high FDG-uptake.
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December 2018

18F-FDG PET intensity correlates with a hypoxic gene signature and other oncogenic abnormalities in operable non-small cell lung cancer.

PLoS One 2018 2;13(7):e0199970. Epub 2018 Jul 2.

Department of Surgery, Section of Thoracic Surgery, University of Michigan, Ann Arbor, MI, United States of America.

Background: 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is critical for staging non-small-cell lung cancer (NSCLC). While PET intensity carries prognostic significance, the genetic abnormalities associated with increased intensity remain unspecified.

Methods: NSCLC samples (N = 34) from 1999 to 2011 for which PET data were available were identified from a prospectively collected tumor bank. PET intensity was classified as mild, moderate, or intense based on SUVmax measurement or radiology report. Associations between genome-wide expression (RNAseq) and PET intensity were determined. Associations with overall survival were then validated in two external NSCLC cohorts.

Results: Overall survival was significantly worse in patients with PET-intense (N = 11) versus mild (N = 10) tumors (p = 0.039). Glycolytic gene expression patterns were markedly similar between intense and mild tumors. Gene ontology analysis demonstrated significant enhancement of cell-cycle and proliferative processes in FDG-intense tumors (p<0.001). Gene set enrichment analysis (GSEA) suggested associations between PET-intensity and canonical oncogenic signaling pathways including MYC, NF-κB, and HIF-1. Using an external cohort of 25 tumors with PET and genomic profiling data, common genes and gene sets were validated for additional study (P<0.05). Of these common gene sets, 20% were associated with hypoxia or HIF-1 signaling. While HIF-1 expression did not correlate with poor survival in the NSCLC validation cohort (N = 442), established targets of hypoxia signaling (PLAUR, ADM, CA9) were significantly associated with poor overall survival.

Conclusions: PET-intensity is associated with a variety of oncogenic alterations in operable NSCLC. Adjuvant targeting of these pathways may improve survival among patients with PET-intense tumors.
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January 2019

Increased Variance in Oral and Gastric Microbiome Correlates With Esophagectomy Anastomotic Leak.

Ann Thorac Surg 2018 03 5;105(3):865-870. Epub 2018 Jan 5.

Division of Periodontology, Department of Orofacial Sciences, University of California, San Francisco, San Francisco, California.

Background: Anastomotic leak after esophagectomy remains a significant source of morbidity and mortality. The gastrointestinal (GI) microbiome has been found to play a significant role in tumor oncogenesis and postoperative bowel anastomotic leak. We hypothesized that the GI microbiome could differentiate between esophageal cancer histologies and predict postoperative anastomotic leak.

Methods: A prospective study of esophagectomy patients was performed from May 2013 to August 2014, with the collection of oral saliva, intraoperative esophageal and gastric mucosa, and samples of postoperative infections (neck swab or sputum). The presence and level for each bacterial probe as end points were used to analyze correlations with tumor histology, tumor stage, and presence of postoperative complications by unequal variances t tests for multiple comparisons and principal coordinate analysis.

Results: Esophagectomy was successful in 55 of 66 patients who were enrolled. Among those, the diagnosis was adenocarcinoma in 44 (80%) squamous cell carcinoma in (13%), and benign disease in 4 (7%). The 30-day mortality was 1.8% (1 of 55). Complications included anastomotic leak requiring local drainage in 18% (10 of 55) and postoperative pneumonia in 2% (1 of 55). No correlation was noted between GI microbiome flora and tumor histology or tumor stage. A significant difference (p = 0.015) was found when the variance in bacterial composition between the preoperative oral flora was compared with intraoperative gastric flora in patients who had a leak but not in patients with pneumonia.

Conclusions: Patients with anastomotic leaks had increased variance in their preoperative oral and gastric flora. Microbiome analysis could help identify patients at higher risk for leak after esophagectomy.
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March 2018

Impact of neoadjuvant chemotherapy on surgical outcomes among patients with hormone receptor positive breast cancer.

J Surg Oncol 2017 Nov 3;116(6):665-670. Epub 2017 Jul 3.

Department of Surgery, University of Michigan Health Systems, Ann Arbor, Michigan.

Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) is a surrogate for outcome, but not necessarily conversion to BCT eligibility. We sought to examine the impact of NACT on surgical decision making among HR+ patients.

Methods: Our IRB-approved breast cancer database was queried for patients who underwent NACT, including the clinicopathologic data and surgeon's pre- and post-NACT assessment. Surgical conversion rate (SCR) was defined as patients ineligible for BCT prior to NACT, who were given the choice following NACT.

Results: Among 289 patients, pCR rates were highest among patients with HER2-enriched subtype (60%) and lowest in patients with luminal A disease (4%). Overall, the BCT rate was 41%, while 28% opted for bilateral mastectomy across subtypes. Despite a low pCR, the SCR was still high (54%) among patients with the luminal A subtype.

Conclusion: Despite poor pCR rates, NACT still has potential to improve surgical outcomes among hormone receptor positive patients. The surgical conversion rate is a superior measure of the impact of NACT on surgical decision making than examining BCT rates.
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November 2017

Integration of Th17- and Lymphotoxin-Derived Signals Initiates Meningeal-Resident Stromal Cell Remodeling to Propagate Neuroinflammation.

Immunity 2015 Dec;43(6):1160-73

Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Tertiary lymphoid tissues (TLTs) have been observed in the meninges of multiple sclerosis (MS) patients, but the stromal cells and molecular signals that support TLTs remain unclear. Here, we show that T helper 17 (Th17) cells induced robust TLTs within the brain meninges that were associated with local demyelination during experimental autoimmune encephalitis (EAE). Th17-cell-induced TLTs were underpinned by a network of stromal cells producing extracellular matrix proteins and chemokines, enabling leukocytes to reside within, rather than simply transit through, the meninges. Within the CNS, interactions between lymphotoxin αβ (LTαβ) on Th17 cells and LTβR on meningeal radio-resistant cells were necessary for the propagation of de novo interleukin-17 responses, and activated T cells from MS patients expressed elevated levels of LTβR ligands. Therefore, input from both Th17 cells and the lymphotoxin pathway induce the formation of an immune-competent stromal cell niche in the meninges.
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December 2015

The role of multicellular aggregation in the survival of ErbB2-positive breast cancer cells during extracellular matrix detachment.

J Biol Chem 2015 Apr 13;290(14):8722-33. Epub 2015 Feb 13.

From the Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556

The metastasis of cancer cells from the site of the primary tumor to distant sites in the body represents the most deadly manifestation of cancer. In order for metastasis to occur, cancer cells need to evade anoikis, which is defined as apoptosis caused by loss of attachment to extracellular matrix (ECM). Signaling from ErbB2 has previously been linked to the evasion of anoikis in breast cancer cells but the precise molecular mechanisms by which ErbB2 blocks anoikis have yet to be unveiled. In this study, we have identified a novel mechanism by which anoikis is inhibited in ErbB2-expressing cells: multicellular aggregation during ECM-detachment. Our data demonstrate that disruption of aggregation in ErbB2-positive cells is sufficient to induce anoikis and that this anoikis inhibition is a result of aggregation-induced stabilization of EGFR and consequent ERK/MAPK survival signaling. Furthermore, these data suggest that ECM-detached ErbB2-expressing cells may be uniquely susceptible to targeted therapy against EGFR and that this sensitivity could be exploited for specific elimination of ECM-detached cancer cells.
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April 2015