The gain-of-function MUC5B promoter variant rs35705950 is the dominant risk factor for developing idiopathic pulmonary fibrosis (IPF). Here we show in humans that MUC5B, a mucin thought to be ...restricted to conducting airways, is co-expressed with surfactant protein C (SFTPC) in type 2 alveolar epithelia and in epithelial cells lining honeycomb cysts, indicating that cell types involved in lung fibrosis in distal airspace express MUC5B. In mice, we demonstrate that Muc5b concentration in bronchoalveolar epithelia is related to impaired mucociliary clearance (MCC) and to the extent and persistence of bleomycin-induced lung fibrosis. We also establish the ability of the mucolytic agent P-2119 to restore MCC and to suppress bleomycin-induced lung fibrosis in the setting of Muc5b overexpression. Our findings suggest that mucociliary dysfunction might play a causative role in bleomycin-induced pulmonary fibrosis in mice overexpressing Muc5b, and that MUC5B in distal airspaces is a potential therapeutic target in humans with IPF.
Positive margins dominate clinical outcomes after surgical resections in most solid cancer types, including head and neck squamous cell carcinoma. Unfortunately, surgeons remove cancer in the same ...manner they have for a century with complete dependence on subjective tissue changes to identify cancer in the operating room. To effect change, we hypothesize that EGFR can be targeted for safe and specific real-time localization of cancer.
A dose escalation study of cetuximab conjugated to IRDye800 was performed in patients (n = 12) undergoing surgical resection of squamous cell carcinoma arising in the head and neck. Safety and pharmacokinetic data were obtained out to 30 days after infusion. Multi-instrument fluorescence imaging was performed in the operating room and in surgical pathology.
There were no grade 2 or higher adverse events attributable to cetuximab-IRDye800. Fluorescence imaging with an intraoperative, wide-field device successfully differentiated tumor from normal tissue during resection with an average tumor-to-background ratio of 5.2 in the highest dose range. Optical imaging identified opportunity for more precise identification of tumor during the surgical procedure and during the pathologic analysis of tissues ex vivo. Fluorescence levels positively correlated with EGFR levels.
We demonstrate for the first time that commercially available antibodies can be fluorescently labeled and safely administered to humans to identify cancer with sub-millimeter resolution, which has the potential to improve outcomes in clinical oncology.
•Blunted stress reactions relate to adverse behavioural and health outcomes.•The same health outcomes correlate with diminished reactions to reward.•Blunted stress reactivity reflects central ...motivational dysregulation.•Blunted reactivity may be characterised by hypoactivation of the fronto-limbic system.
Recent research shows that blunted cardiovascular and cortisol reactions to acute psychological stress are associated with adverse behavioural and health outcomes: depression, obesity, bulimia, and addictions. These outcomes may reflect suboptimal functioning of the brain’s fronto-limbic systems that are needed to regulate motivated behaviour in the face of challenge. In support of this, brain imaging data demonstrate fronto-limbic hypoactivation during acute stress exposure. Those demonstrating blunted reactions also show impairments of motivation, including lower cognitive ability, more rapid cognitive decline, and poorer performance on motivation-dependent tests of lung function. Persons exhibiting blunted stress reactivity display well established temperament characteristics, including neuroticism and impulsivity, characteristic of various behavioural disorders. Notably, the outcomes related to blunted stress reactivity are similar to those that define Reward Deficiency Syndrome. Accordingly, some individuals may be characterised by a broad failure in cardiovascular and cortisol responding to both stress and reward, reflecting fronto-limbic dysregulation. Finally, we proffer a model of blunted stress reactivity, its antecedents and sequelae, and identify future research priorities.
Objective
Evaluate the effect of initial incision margins (IIM) on clinical outcomes after transoral robotic surgery (TORS) for human papillomavirus positive (HPV+) squamous cell cancers of the ...oropharynx (OPSCC).
Methods
Retrospective chart review of patients undergoing TORS for HPV+ OPSCC from 2007 to 2015 was performed. Overall survival (OS), disease‐specific survival (DSS), recurrence, and metastases were evaluated in the context of pathology, IIM, final margins, adjuvant therapy, and patient characteristics.
Results
Ninety‐five patients with HPV+ OPSCC undergoing primary surgery were identified. 88% of these patients had no evidence of disease at the conclusion of the study (average follow‐up 45 months). Twenty were identified that had true positive IIM and 16 had very close IIM, with the remainder demonstrating widely negative margins. Tumor very close to or involving the deep margin but not a mucosal margin was associated with a higher risk of recurrence. Perineural invasion and lymphovascular invasion were associated with positive IIM. Positive or very close IIM on the deep margin was found to impact DSS and recurrence.
Conclusion
Obtaining negative IIM while performing TORS for HPV+ OPSCC is a modifiable factor that affects recurrence and DSS. Larger surgical margins should be considered in patients with perineural invasion or whose tumor abuts the initial deep margin.
Level of Evidence
4 Laryngoscope, 133:1132–1137, 2023
Positive or very close deep initial incision margins impact recurrence and disease specific survival in primary resection of HPV+ oropharyngeal cancer. Intentionally larger initial incision margins should be planned for patients with perineural invasion or lymphovascular invasion on biopsy to decrease the potential for positive initial incision margin as these features make that prospect more likely.
The goal of this study was to experimentally test the additivity of the electrostatic substituent effects (SEs) for the aromatic stacking interaction. The additivity of the SEs was assessed using a ...small molecule model system that could adopt an offset face-to-face aromatic stacking geometry. The intramolecular interactions of these molecular torsional balances were quantitatively measured via the changes in a folded/unfolded conformational equilibrium. Five different types of substituents were examined (CH3, OCH3, Cl, CN, and NO2) that ranged from electron-donating to electron-withdrawing. The strength of the intramolecular stacking interactions was measured for 21 substituted aromatic stacking balances and 21 control balances in chloroform solution. The observed stability trends were consistent with additive SEs. Specifically, additive SE models could predict SEs with an accuracy from ±0.01 to ±0.02 kcal/mol. The additive SEs were consistent with Wheeler and Houk’s direct SE model. However, the indirect or polarization SE model cannot be ruled out as it shows similar levels of additivity for two to three substituent systems, which were the number of substituents in our model system. SE additivity also has practical utility as the SEs can be accurately predicted. This should aid in the rational design and optimization of systems that utilize aromatic stacking interactions.
Men with prostate cancer are often advised to make changes in diet and lifestyle, although the impact of these changes has not been well documented. Therefore, we evaluated the effects of ...comprehensive lifestyle changes on prostate specific antigen (PSA), treatment trends and serum stimulated LNCaP cell growth in men with early, biopsy proven prostate cancer after 1 year.
Patient recruitment was limited to men who had chosen not to undergo any conventional treatment, which provided an unusual opportunity to have a nonintervention randomized control group to avoid the confounding effects of interventions such as radiation, surgery or androgen deprivation therapy. A total of 93 volunteers with serum PSA 4 to 10 ng/ml and cancer Gleason scores less than 7 were randomly assigned to an experimental group that was asked to make comprehensive lifestyle changes or to a usual care control group.
None of the experimental group patients but 6 control patients underwent conventional treatment due to an increase in PSA and/or progression of disease on magnetic resonance imaging. PSA decreased 4% in the experimental group but increased 6% in the control group (p = 0.016). The growth of LNCaP prostate cancer cells (American Type Culture Collection, Manassas, Virginia) was inhibited almost 8 times more by serum from the experimental than from the control group (70% vs 9%, p <0.001). Changes in serum PSA and also in LNCaP cell growth were significantly associated with the degree of change in diet and lifestyle.
Intensive lifestyle changes may affect the progression of early, low grade prostate cancer in men. Further studies and longer term followup are warranted.
Comprehensive cervical lymphadenectomy can be associated with significant morbidity and poor quality of life. This study evaluated the sensitivity and specificity of cetuximab-IRDye800CW to identify ...metastatic disease in patients with head and neck cancer.
Consenting patients scheduled for curative resection were enrolled in a clinical trial to evaluate the safety and specificity of cetuximab-IRDye800CW. Patients (
= 12) received escalating doses of the study drug. Where indicated, cervical lymphadenectomy accompanied primary tumor resection, which occurred 3 to 7 days following intravenous infusion of cetuximab-IRDye800CW. All 471 dissected lymph nodes were imaged with a closed-field, near-infrared imaging device during gross processing of the fresh specimens. Intraoperative imaging of exposed neck levels was performed with an open-field fluorescence imaging device. Blinded assessments of the fluorescence data were compared to histopathology to calculate sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV).
Of the 35 nodes diagnosed pathologically positive, 34 were correctly identified with fluorescence imaging, yielding a sensitivity of 97.2%. Of the 435 pathologically negative nodes, 401 were correctly assessed using fluorescence imaging, yielding a specificity of 92.7%. The NPV was determined to be 99.7%, and the PPV was 50.7%. When 37 fluorescently false-positive nodes were sectioned deeper (1 mm) into their respective blocks, metastatic cancer was found in 8.1% of the recut nodal specimens, which altered staging in two of those cases.
Fluorescence imaging of lymph nodes after systemic cetuximab-IRDye800CW administration demonstrated high sensitivity and was capable of identifying additional positive nodes on deep sectioning.
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Mammary analog secretory carcinoma (MASC) is a recently recognized low-grade salivary carcinoma characterized by a specific ETV6 rearrangement. We describe 14 new MASCs and examine their ...immunophenotypic and genetic profiles in the context of look-alikes, namely, low-and high-grade salivary duct carcinoma and acinic cell carcinoma. ETV6 rearrangement, and robust expression of mammaglobin and S100, were demonstrated in 11/11, 14/14, and 12/14 MASCs, respectively. All low-grade salivary duct carcinomas coexpressed S100/mammaglobin (6/6); none harbored ETV6 rearrangements (0/5). Given that S100/mammaglobin coexpression and absence of zymogen granules are features of both MASC and low-grade salivary duct carcinoma, these two are best distinguished histologically. The former is predominantly an extraductal neoplasm with bubbly pink cytoplasm, whereas the latter is a distinct intraductal micropapillary and cribriform process. Querying ETV6 gene status may be necessary for difficult cases. No acinic cell carcinoma expressed mammaglobin (0/13) or harbored an ETV6 rearrangement (0/7); only 1/13 acinic cell carcinomas weakly expressed S100. DOG1 expression was limited or absent among all tumor types, except acinic cell carcinoma which expressed DOG1 diffusely in a canalicular pattern. Therefore, histology and immunohistochemistry (mammaglobin, S100, DOG1) suffices in distinguishing acinic cell carcinoma from both MASC and low-grade salivary duct carcinoma. HER2 (ERBB2) amplification was detected in only 1/10 acinic cell carcinomas, but none of the MASCs or low-grade salivary duct carcinomas tested. High-grade salivary duct carcinomas frequently expressed mammaglobin (11/18) and harbored HER2 amplifications (13/15); none harbored ETV6 rearrangements (0/12). High-grade salivary duct carcinomas can easily be distinguished from these other entities by histology and HER2 amplification.
Summary and Next Steps2628 Presidents and Staff2629 References2629 Appendix 1 Abbreviations2631 Appendix 2 Author Relationships With Industry and Other Entities (Relevant)2632 Appendix 3 Peer ...Reviewer Relevant RWI2634 Preamble This statement was commissioned as a Multisociety Expert Consensus Systems of Care Document by the American Association for Thoracic Surgery (AATS), American College of Cardiology (ACC), American Society of Echocardiography (ASE), Society for Cardiovascular Angiography and Interventions (SCAI), and Society of Thoracic Surgeons (STS). With the rapid evolution and dissemination of transcatheter technologies, as well as advances in surgical repair and valve replacement techniques, there is an imperative for the cardiovascular community to establish the provider, institutional, and systems-based standards for delivery of high-quality valvular heart disease (VHD) care. ...implementation of optimal treatment strategies for patients with VHD will affect a sizable portion of the population (7). Access to appropriate care is critical, but as the complexity and cost of diagnosis and treatment continues to increase, it will not be feasible for all institutions to provide the full complement of resources and clinical experts necessary to care for the full spectrum of patients with VHD, while also ensuring the highest-quality outcomes.1.2 Statement of the Problem Providing optimal care to patients with VHD is an increasingly complex process, starting with early recognition and diagnosis at the primary care/general cardiology level and including appropriate timing of referral for further evaluation and management, MDT assessment, shared decision-making, and long-term follow-up.
Objectives/Hypothesis
To compare the clinical and cost outcomes of transoral robotic surgery (TORS) versus open procedures following the U.S. Food and Drug Administration approval in December 2009.
...Study Design
Retrospective analysis of the Nationwide Inpatient Sample from 2008 to 2011.
Methods
Elective partial pharyngectomies and partial glossectomies for neoplasm were identified by International Classification of Diseases, 9th Revision, Clinical Modification code.
Results
TORS represented 2.1% in 2010 and 2.2% in 2011 of all transoral ablative procedures. Patients undergoing open partial pharyngectomy for oropharyngeal neoplasms (n = 1426) had more severe illness compared to TORS (n = 641). However, after controlling for minor‐to‐moderate severity of illness, open partial pharyngectomy was associated with longer hospital stay (5.2 vs. 3.7 days, P < 0.001), higher charge ($98,228 vs. $67,317, P < 0.001), higher cost ($29,365 vs. $20,706, P < 0.001), higher rates of tracheostomy and gastrostomy tube placement, and more wound and bleeding complications. TORS was associated with a higher rate of dysphagia (19.5% vs. 8.0%, P < 0.001). The lower cost of TORS remained significant in the major‐to‐extreme severity of illness group but was associated with higher complication rates when compared to open cases of the same severity of illness. A similar analysis of TORS partial glossectomy for base of tongue tumors had similar cost and length of stay benefits, whereas TORS partial glossectomy for anterior tongue tumors revealed longer hospital stays and no benefit in charge or cost compared to open.
Conclusions
Early data demonstrate a clinical and cost benefit in TORS partial pharyngectomy and partial glossectomy for the base of tongue but no benefit in partial glossectomy of the anterior tongue. It is likely that anatomic accessibility and extent of surgery factor into the effectiveness of TORS.
Level of Evidence
2c. Laryngoscope, 125:140–145, 2015
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