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Abstract In preclinical studies, p53 loss of function impacts chemotherapy response, but this has not been consistently validated clinically. We trained a TP53-loss phenocopy gene expression signature from pan-cancer clinical samples in the TCGA. In vitro, the TP53-loss phenocopy signature predicted chemotherapy response across cancer types. In a clinical dataset of 3003 breast cancer samples treated with neoadjuvant chemotherapy, the TP53-loss phenocopy samples were 56% more likely to have a pathologic complete response (pCR), with a significant association between TP53-loss phenocopy and pCR in both ER positive and ER negative tumors. In an independent clinical validation in the I-SPY2 trial (N = 987), we confirmed the association with neoadjuvant chemotherapy pCR and found higher rates of chemoimmunotherapy response in TP53-loss phenocopy tumors compared to non-TP53-loss phenocopy tumors (64% vs. 28%). The TP53-loss phenocopy signature predicts chemotherapy response across cancer types in vitro, and in a proof-of-concept clinical validation is associated with neoadjuvant chemotherapy response across multiple clinical breast cancer cohorts.

Objective: The pathway to cardiothoracic surgery is often obscure for premedical students and aspiring applicants and requires navigating various known and unknown obstacles. Recognizing the challenges encountered on the path to a career in cardiothoracic surgery in the United States, we present this guide for students interested in the field to maximize success in their premedical, preclinical, and preresidency years. Methods: This is a joint collaboration between the Thoracic Surgery Residents Association and the Thoracic Surgery Medical Student Association. Drawing from firsthand experiences and insights gathered from numerous student applicants and current surgical residents, a comprehensive guide was constructed for students from the point of undergraduate school to advanced training options, including super-fellowship training. Results: Several intricacies to cardiothoracic surgery career planning were discussed, including differences between traditional and integrated/fast-track pathways, college and medical school selection, networking, performing during clinical rotations, extracurricular and research activities, building mentorship relationships, and pursuing alternate career and advanced training opportunities. Conclusions: For premedical students and aspiring applicants, the road to cardiothoracic surgery requires meticulous planning, grit, and thoughtful dedication. This document consolidates firsthand insights and advice from numerous aspiring and matched applicants to serve as a comprehensive guide for students seeking a career in cardiovascular and thoracic surgery.

Among repairs for ventriculoarterial discordance, ventricular septal defect, and pulmonary stenosis, aortic root translocation (Nikaidoh operation) offers the most anatomic result. With a diminutive pulmonary annulus or hypoplastic left ventricular outflow tract, the distance gained posteriorly with aortic translocation is negligible. We developed the “hemi-Nikaidoh” procedure as an alternative. Geometric shift is achieved by mobilizing the anterior two-thirds of the aortic root, and posterior aortic translocation is performed by plicating the left ventricular outflow tract without dividing the conus. The right ventricular outflow tract is reconstructed with an orthotopic conduit. Herein, we describe the hemi-Nikaidoh operation.

BackgroundThe coronavirus pandemic has caused a worldwide health crisis. Bariatric patients require extensive pre- and post-operative follow-up, which may be less feasible during public health social distancing mandates. We assessed the impact of the pandemic on the behaviors and weight loss outcomes of our pre- and post-operative bariatric patients.MethodsA retrospective review of a prospectively maintained database identified patients who underwent either sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) at a single institution between March 2018 and May 2020. A cohort undergoing surgery within 12 months before the pandemic as well as a cohort undergoing a medically supervised diet prior to surgery was surveyed regarding pre- and post-COVID-19 lifestyle habits. Excess weight loss (EWL) outcomes from a group of pre-COVID surgical patients were compared to that of a group of post-COVID surgical patients. Primary outcome was whether the lockdown changed 1-year weight loss outcomes. Secondary outcome was whether patient lifestyle behaviors were changed during the pandemic.ResultsThere was no difference in 1-year EWL between pre- and post-COVID SG patients (51.7% versus 55.9%, p = 0.35), or between pre- and post-COVID RYGB patients (88.9% versus 80.4%, p = 0.42). Pre-stay-at-home order, 91.8% endorsed physical activity compared to 80.3% post-stay-at-home order (p = 0.0025). Mean physical activity decreased from 4.2 h/week to 2.7 h/week after the stay-at-home order (p

Introduction Xerostomia, the subjective feeling of dry mouth typically accompanied by hyposalivation (1-3), is a common but often overlooked condition that can profoundly impair an individual's quality of life. Xerostomia [...], Salivary gland dysfunction is a common side effect of cancer treatments. Salivary function plays key roles in critical daily activities. Consequently, changes in salivary function can profoundly impair quality of life for cancer patients. We discuss salivary gland anatomy and physiology to understand how anticancer therapies such as chemotherapy, bone marrow transplantation, immunotherapy, and radiation therapy impair salivary function. We discuss approaches to quantify xerostomia in the clinic, including the advantages and limitations of validated quality-of-life instruments and approaches to directly measuring salivary function. Current and emerging approaches to treat cancer therapy-induced dry mouth are presented using radiation-induced salivary dysfunction as a model. Limitations of current sialagogues and salivary analogues are presented. Emerging approaches, including cellular and gene therapy and novel pharmacologic approaches, are described.

Abstract Histopathologic diagnosis and classification of cancer plays a critical role in guiding treatment. Advances in next-generation sequencing have ushered in new complementary molecular frameworks. However, existing approaches do not independently assess both site-of-origin (e.g. prostate) and lineage (e.g. adenocarcinoma) and have minimal validation in metastatic disease, where classification is more difficult. Utilizing gradient-boosted machine learning, we developed ATLAS, a pair of separate AI Tumor Lineage and Site-of-origin models from RNA expression data on 8249 tumor samples. We assessed performance independently in 10,376 total tumor samples, including 1490 metastatic samples, achieving an accuracy of 91.4% for cancer site-of-origin and 97.1% for cancer lineage. High confidence predictions (encompassing the majority of cases) were accurate 98–99% of the time in both localized and remarkably even in metastatic samples. We also identified emergent properties of our lineage scores for tumor types on which the model was never trained (zero-shot learning). Adenocarcinoma/sarcoma lineage scores differentiated epithelioid from biphasic/sarcomatoid mesothelioma. Also, predicted lineage de-differentiation identified neuroendocrine/small cell tumors and was associated with poor outcomes across tumor types. Our platform-independent single-sample approach can be easily translated to existing RNA-seq platforms. ATLAS can complement and guide traditional histopathologic assessment in challenging situations and tumors of unknown primary.

Background The diffusion of innovation in healthcare is sluggish. Evidence-based care models and interventions take years to reach patients. We believe the healthcare community could deliver innovation to the bedside faster if it followed other sectors by employing an organisational framework for efficiently accomplishing work. Home hospital is an example of sluggish diffusion. This model provides hospital-level care in a patient’s home instead of in a traditional hospital with equal or better outcomes. Home hospital uptake has steadily grown during the COVID-19 pandemic, yet barriers to launch remain for healthcare organisations, including access to expertise and implementation tools. The Home Hospital Early Adopters Accelerator was created to bring together a network of healthcare organisations to develop tools necessary for programme implementation.Methods The accelerator used the Agile framework known as Scrum to rapidly coordinate work across many different specialised skill sets and blend individuals who had no experience with one another into efficient teams. Its goal was to take 40 weeks to develop 20 ‘knowledge products’,or tools critical to the development of a home hospital programme such as workflows, inclusion criteria and protocols. We conducted a mixed-methods evaluation of the accelerator’s implementation, measuring teams’ productivity and experience.Results 18 healthcare organisations participated in the accelerator to produce the expected 20 knowledge products in only 32 working weeks, a 20% reduction in time. Nearly all (97.4%) participants agreed or strongly agreed the Scrum teams worked well together, and 96.8% felt the teams produced a high-quality product. Participants consistently remarked that the Scrum team developed products much faster than their respective organisational teams. The accelerator was not a panacea: it was challenging for some participants to become familiar with the Scrum framework and some participants struggled with balancing participation in the Accelerator with their job duties.Conclusions Implementation of an Agile-based accelerator that joined disparate healthcare organisations into teams equipped to create knowledge products for home hospitals proved both efficient and effective. We demonstrate that implementing an organisational framework to accomplish work is a valuable approach that may be transformative for the sector.

Aortic insufficiency (AI) is a valvular disease with increasing prevalence in older patients. The modern era provides numerous options for the management of AI which is explored here. Traditional interventions included aortic valve replacement with either mechanical or bioprosthetic aortic valves. While the former is known for its durability, it has grown out of favor due to the potential complications of anticoagulation. The preference for bioprosthetic valves is thus on the rise, especially with the advancements of transcatheter technology and the use of valve-in-valve therapy. Surgical options are also no longer limited to replacement but include complex techniques such as those required for aortic valve repair, Ozaki neocuspidization, Ross procedure and valve-sparring aortic root repair. Transcatheter options for the management of AI are not commercially available currently; however, preliminary data from ad-hoc trials, showed promising results and potential use of transcatheter technology in a variety of patients with pure AI.

BackgroundEarly experience with indocyanine green-based fluorescent cholangiography during laparoscopic cholecystectomy suggests the potential to improve outcomes. However, the cost-effectiveness of routine use has not been studied. Our objective was to evaluate the cost-effectiveness of fluorescent cholangiography versus standard bright light laparoscopic cholecystectomy for noncancerous gallbladder disease.MethodsA Markov model decision analysis was performed comparing fluorescent cholangiography versus standard bright light laparoscopic cholecystectomy alone. Probabilities of outcomes, survival, toxicities, quality-adjusted life-years, and associated costs were determined from literature review and pooled analysis of currently available studies on fluorescent cholangiography (n = 37). Uncertainty in the model parameters was evaluated with 1-way and probabilistic sensitivity analyses, varying parameters up to 40% of their means. Cost-effectiveness was measured with an incremental cost-effectiveness ratio expressed as the dollar amount per quality-adjusted life-year.ResultsThe model predicted that fluorescent cholangiography reduces lifetime costs by $1,235 per patient and improves effectiveness by 0.09 quality-adjusted life-years compared to standard bright light laparoscopic cholecystectomy. Reduced costs were due to a decreased operative duration (21.20 minutes, P < .0001) and rate of conversion to open (1.62% vs 6.70%, P < .0001) associated with fluorescent cholangiography. The model was not influenced by the rate of bile duct injury. Probabilistic sensitivity analysis found that fluorescent cholangiography was both more effective and less costly in 98.83% of model iterations at a willingness-to-pay threshold of $100,000/quality-adjusted life year.ConclusionThe current evidence favors routine use of fluorescent cholangiography during laparoscopic cholecystectomy as a cost-effective surgical strategy. Our model predicts that fluorescent cholangiography reduces costs while improving health outcomes, suggesting fluorescence imaging may be considered standard surgical management for noncancerous gallbladder disease. Further study with prospective trials should be considered to verify findings of this predictive model.

Some anterior chambers do not readily shallow because of insufficient posterior pressure and/or very deep anterior chamber anatomy, which can make unscrolling descemet membrane endothelial keratoplasty (DMEK) tissue more challenging with an unmodified tap technique. We present a hands-free method for augmenting posterior pressure by temporarily tucking cellulose sponges under the blades of the eyelid speculum. The sponges transfer some of the eyelid speculum’s weight onto the bulbar surface posterior to the iris, thereby indenting the sclera and causing the iris diaphragm to bulge further forward. This hands-free technique can transform a potentially challenging DMEK case into a more straightforward one by facilitating both a shallow anterior chamber and a bimanual unscrolling technique. However, it only works in bicameral eyes with a vitreous body (e.g., an eye with penetrating keratoplasty, vitreous syneresis, and axial myopia) and will not work in unicameral eyes after vitrectomy (e.g., an eye with an Anterior Chamber Intraocular Lens (ACIOL)).

OBJECTIVE: To delineate research priorities for improving clinical management of laryngeal dystonia, the NIH convened a multidisciplinary panel of experts for a 1-day workshop to examine the current progress in understanding its etiopathophysiology and clinical care. METHODS: The participants reviewed the current terminology of disorder and discussed advances in understanding its pathophysiology since a similar workshop was held in 2005. Clinical and research gaps were identified, and recommendations for future directions were delineated. RESULTS: The panel unanimously agreed to adopt the term laryngeal dystonia instead of spasmodic dysphonia to reflect the current progress in characterizations of this disorder. Laryngeal dystonia was recognized as a multifactorial, phenotypically heterogeneous form of isolated dystonia. Its etiology remains unknown, whereas the pathophysiology likely involves large-scale functional and structural brain network disorganization. Current challenges include the lack of clinically validated diagnostic markers and outcome measures and the paucity of therapies that address the disorder pathophysiology. CONCLUSION: Research priorities should be guided by challenges in clinical management of laryngeal dystonia. Identification of disorder-specific biomarkers would allow the development of novel diagnostic tools and unified measures of treatment outcome. Elucidation of the critical nodes within neural networks that cause or modulate symptoms would allow the development of targeted therapies that address the underlying pathophysiology. Given the rarity of laryngeal dystonia, future rapid research progress may be facilitated by multicenter, national and international collaborations.