Radiation Oncology Virtual Education Rotation (ROVER) 2.0 for Residents: Implementation and Outcomes.

The COVID-19 pandemic catalyzed the integration of a virtual education curriculum to support radiation oncologists in training. We report outcomes from Radiation Oncology Virtual Education Rotation (ROVER) 2.0, a supplementary virtual educational curriculum created for radiation oncology residents globally. A prospective cohort of residents completed surveys before and after the live virtual webinar sessions (pre- and post-surveys, respectively). Live sessions were structured as complex gray-zone cases across various core disease sites. Resident demographics and responses were summarized using means, standard deviations, and proportions. Nine ROVER sessions were held from October 2020 to June 2021. A total of 1487 registered residents completed the pre-survey, of which 786 attended the live case discussion and 223 completed post-surveys. A total of 479 unique radiation oncology residents (of which 95, n = 19.8%, were international attendees) from 147 institutions (national, n = 81, 55.1%; international, n = 66, 44.9%) participated in the sessions. There was similar participation across post-graduate year (PGY) 2 through 5 (range n = 86 to n = 105). Of the 122 unique resident post-surveys, nearly all reported learning through the virtual structure as "very easy" or "easy" (97.5%, n = 119). A majority rated the ROVER 2.0 educational sessions to be "valuable or "very valuable" (99.2%, n = 121), and the panelists-attendee interaction as "appropriate" (97.5%, n = 119). Virtual live didactics aimed at radiation oncology residents are feasible. These results suggest that the adoption of the ROVER 2.0 curricula may help improve radiation oncology resident education.

Validation of automated body composition analysis using diagnostic computed tomography imaging in patients with pancreatic cancer.

BACKGROUND: Sarcopenia is associated with complications and inferior oncologic outcomes in solid tumors. Axial computed tomography (CT) scans can be used to evaluate sarcopenia, however manual quantification is laborious. We sought to validate an automated method of quantifying muscle cross-sectional area (CSA) in patients with pancreatic adenocarcinoma (PDAC). METHODS: Mid-L3 CT images from patients with PDAC were analyzed: CSAs of skeletal muscle (SM) were measured using manual segmentation and the software AutoMATiCA, and then compared with linear regression. RESULTS: Five-hundred-twenty-five unique scans were analyzed. There was robust correlation between manual and automated segmentation for L3 CSA (R2 0.94, P < 0.001). Bland-Altman analysis demonstrated a consistent overestimation of muscle CSA by AutoMATiCA with a mean difference of 5.7%. A correction factor of 1.06 was validated using a unique test dataset of 36 patients with non-PDAC peripancreatic malignancies. CONCLUSIONS: Automated muscle CSA measurement with AutoMATiCA is highly efficient and yields results highly correlated with manual measurement. These findings support the potential use of high-throughput sarcopenia analysis with abdominal CT scans for both clinical and research purposes.

Neoadjuvant Therapy Is Associated with Improved Chemotherapy Delivery and Overall Survival Compared to Upfront Resection in Pancreatic Cancer without Increasing Perioperative Complications.

The role of neoadjuvant chemoradiotherapy and/or chemotherapy (neoCHT) in patients with pancreatic ductal adenocarcinoma (PDAC) is poorly defined. We hypothesized that patients who underwent neoadjuvant therapy (NAT) would have improved systemic therapy delivery, as well as comparable perioperative complications, compared to patients undergoing upfront resection. This is an IRB-approved retrospective study of potentially resectable PDAC patients treated within an academic quaternary referral center between 2011 and 2018. Data were abstracted from the electronic medical record using an institutional cancer registry and the National Surgical Quality Improvement Program. Three hundred and fourteen patients were eligible for analysis and eighty-one patients received NAT. The median overall survival (OS) was significantly improved in patients who received NAT (28.6 vs. 20.1 months, p = 0.014). Patients receiving neoCHT had an overall increased mean duration of systemic therapy (p < 0.001), and the median OS improved with each month of chemotherapy delivered (HR = 0.81 per month CHT, 95% CI (0.76-0.86), p < 0.001). NAT was not associated with increases in early severe post-operative complications (p = 0.47), late leaks (p = 0.23), or 30-90 day readmissions (p = 0.084). Our results show improved OS in patients who received NAT, driven largely by improved chemotherapy delivery, without an apparent increase in early or late perioperative complications compared to patients undergoing upfront resection.

Radiation Oncology Virtual Education Rotation (ROVER) for Medical Students.

PURPOSE: We describe the implementation of a novel virtual educational program for medical students, Radiation Oncology Virtual Education Rotation (ROVER), and its effect on student interest and knowledge in radiation oncology. METHODS AND MATERIALS: ROVER comprised a series of virtual educational panels with case-based discussions across disease sites tailored to medical students. The panels were moderated by radiation oncology residents and included faculty panelists from academic radiation oncology programs across the country. Student pre- and postsession surveys were collected. Paired t tests were used to compare the pre- and postsession assessment results. RESULTS: Six ROVER sessions were held from June 4, 2020, to August 20, 2020, with a total of 427 medical students registering for at least 1 session. Of these, 231 students attended at least 1 session, with 140 completing at least 1 postsession survey (60.6% response rate). Fourth-year medical students were the largest group represented among attendees (32.0%). Most attendees had exposure to radiation oncology (78.8%) before the sessions. The majority of students signed up for these sessions for education (90.6%). Some students signed up for the sessions to help with specialty selection (30.9%) and to network (30.4%). Medical students' understanding of the role of radiation oncology in each disease site (breast, sarcoma, central nervous system, pediatrics, gastrointestinal, genitourinary, gynecologic, lymphoma, lung, and head and neck) was improved by attending each session (pre- vs postsession; P < .0001 for all disease sites). Over three-quarters of respondents stated they were considering applying or were likely to apply to radiation oncology both before and after the sessions. CONCLUSIONS: ROVER improved medical student perceived knowledge of radiation oncology across all disease sites covered. ROVER fulfills a need for a national medical student education platform for radiation oncology. Future work is warranted to augment virtual and open educational platforms to improve access to radiation oncology education.

Networking and Applying to Radiation Oncology During A Pandemic: Cross-Sectional Survey of Medical Student Concerns.

PURPOSE: We assessed the effectiveness of a virtual networking session tailored for third- and fourth-year medical students interested in radiation oncology, and report students' concerns about applying to radiation oncology during the pandemic. METHODS AND MATERIALS: A multi-institutional networking session was hosted on Zoom and included medical students, faculty, and residents from across the country. The breakout room feature was used to divide participants into smaller groups. Participants were randomly shuffled into new groups every 10 to 15 minutes. Students completed pre- and post-session surveys. RESULTS: Among the 134 students who registered, 69 students participated in the session, and 53 students completed a post-session survey. Most students reported the session was valuable or very valuable (79%), and it was easy or very easy to network through the virtual format (66%). After the session, 18 (33.9%) students reported their interest in radiation oncology increased, and 34 (64.2%) reported their interest remained the same. Most students believed COVID-19 (55%) and virtual interviews and platforms (55%) negatively or somewhat negatively affected their ability to select a residency program. Most students (62%) were concerned they will be inaccurately evaluated as an interviewee on a virtual platform. Although 30% agreed or strongly agreed the cost-savings and convenience of virtual interviews outweigh potential downsides, 66% of students were planning to visit cities of interest in person before rank list submission. CONCLUSIONS: Medical students reported significant concerns with their ability to be accurately evaluated and to choose among residency programs on a virtual platform. Students found the networking session to be a valuable resource for most students, and programs could continue similar efforts during the residency application cycle to better represent their program while maintaining certain financial and geographic advantages of a virtual environment.

Application of ASCO Value Framework to Treatment Advances in Hepatocellular Carcinoma.

BACKGROUND: Determination of the comparative efficacy of one therapy over another for hepatocellular carcinoma (HCC) can be challenging. Application of a recognized value framework to published studies could objectively compare the potential benefit across available therapies. MATERIALS AND METHODS: An umbrella review of phase III trials for HCC therapies was performed. ASCO Value Framework Net Health Benefit Score version 2 (ASCO-NHB v2) scores, the primary analysis, and European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 scores, the secondary analysis, were computed using selected drug registration trials. Both scores were compared between drugs that were Food and Drug Administration (FDA)-approved by 2020 and those that were not. RESULTS: Of the 22 studies identified, nine were FDA-approved and 13 were not. Across 22 trials, the median overall survival (OS) was 9.2 months (range, 1.9-16.4 months), with a median gain of 0.35 month (range, 2.3-3.3 months). HCC therapies that were FDA-approved showed longer OS (median 10.7 v 7.9 months, P < .01) and higher ASCO NHB scores (+18.4 v -5.7 scores, P < .01). The median gain in OS was 2.2 months in the approved treatments compared with -0.3 months in the unapproved group, with no difference in progression-free survival between the two groups. CONCLUSION: The nine FDA-approved therapies for HCC have higher mean NHB score than those that were not FDA-approved. The application of ASCO-NHB v2 and other proposed value frameworks could examine data of future therapies for HCC through a patient-oriented approach.

The Feasibility of Patient-Specific Circulating Tumor DNA Monitoring throughout Multi-Modality Therapy for Locally Advanced Esophageal and Rectal Cancer: A Potential Biomarker for Early Detection of Subclinical Disease.

As non-operative management (NOM) of esophageal and rectal cancer is becoming more prevalent, blood-biomarkers such as circulating tumor DNA (ctDNA) may provide clinical information in addition to endoscopy and imaging to aid in treatment decisions following chemotherapy and radiation therapy. In this feasibility study, we prospectively collected plasma samples from locally advanced esophageal (n = 3) and rectal cancer (n = 2) patients undergoing multimodal neoadjuvant therapy to assess the feasibility of serial ctDNA monitoring throughout neoadjuvant therapy. Using the Dual-Index Degenerate Adaptor-Sequencing (DIDA-Seq) error-correction method, we serially interrogated plasma cell-free DNA at 28-41 tumor-specific genomic loci throughout therapy and in surveillance with an average limit of detection of 0.016% mutant allele frequency. In both rectal cancer patients, ctDNA levels were persistently elevated following total neoadjuvant therapy with eventual detection of clinical recurrence prior to salvage surgery. Among the esophageal cancer patients, ctDNA levels closely correlated with tumor burden throughout and following neoadjuvant therapy, which was associated with a pathologic complete response in one patient. In this feasibility study, patient- and tumor-specific ctDNA levels correlated with clinical outcomes throughout multi-modality therapy suggesting that serial monitoring of patient ctDNA has the potential to serve as a highly sensitive and specific biomarker to risk-stratify esophageal and rectal cancer patients eligible for NOM. Further prospective investigation is warranted.

Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma.

Despite tremendous gains in the molecular understanding of exocrine pancreatic cancer, the prognosis for this disease remains very poor, largely because of delayed disease detection and limited effectiveness of systemic therapies. Both incidence rates and mortality rates for pancreatic cancer have increased during the past decade, in contrast to most other solid tumor types. Recent improvements in multimodality care have substantially improved overall survival, local control, and metastasis-free survival for patients who have localized tumors that are amenable to surgical resection. The widening gap in prognosis between patients with resectable and unresectable or metastatic disease reinforces the importance of detecting pancreatic cancer sooner to improve outcomes. Furthermore, the developing use of therapies that target tumor-specific molecular vulnerabilities may offer improved disease control for patients with advanced disease. Finally, the substantial morbidity associated with pancreatic cancer, including wasting, fatigue, and pain, remains an under-addressed component of this disease, which powerfully affects quality of life and limits tolerance to aggressive therapies. In this article, the authors review the current multidisciplinary standards of care in pancreatic cancer with a focus on emerging concepts in pancreatic cancer detection, precision therapy, and survivorship.

Artificial Intelligence in Radiation Oncology.

The integration of artificial intelligence in the radiation oncologist's workflow has multiple applications and significant potential. From the initial patient encounter, artificial intelligence may aid in pretreatment disease outcome and toxicity prediction. It may subsequently aid in treatment planning, and enhanced dose optimization. Artificial intelligence may also optimize the quality assurance process and support a higher level of safety, quality, and efficiency of care. This article describes components of the radiation consultation, planning, and treatment process and how the thoughtful integration of artificial intelligence may improve shared decision making, planning efficiency, planning quality, patient safety, and patient outcomes.

Predictors of Nodal and Metastatic Failure in Early Stage Non-small-cell Lung Cancer After Stereotactic Body Radiation Therapy.

INTRODUCTION/BACKGROUND: Many patients with early stage non-small-cell lung cancer (ES-NSCLC) undergoing stereotactic body radiation therapy (SBRT) develop metastases, which is associated with poor outcomes. We sought to identify factors predictive of metastases after lung SBRT and created a risk stratification tool. MATERIALS AND METHODS: We included 363 patients with ES-NSCLC who received SBRT; the median follow-up was 5.8 years. The following patient and tumor factors were retrospectively analyzed for their association with metastases (defined as nodal and/or distant failure): gender; age; lobe involved; centrality; previous NSCLC; smoking status; gross tumor volume (GTV); T-stage; histology; dose; minimum, maximum, and mean GTV dose; and parenchymal lung failure. A metastasis risk-score linear-model using beta coefficients from a multivariate Cox model was built. RESULTS: A total of 111 (27.3%) of 406 lesions metastasized. GTV and dose were significantly associated with metastases on univariate and multivariate Cox proportional hazards modeling (P < .001 and hazard ratio [HR], 1.02 per mL; P < .05 and HR, 0.99 per Gy, respectively). Histology, T-stage, centrality, lung parenchymal failures, and previous NSCLC were not associated with development of metastasis. A metastasis risk-score model using GTV and prescription dose was built: risk score = (0.01611 × GTV) - (0.00525 × dose [BED10]). Two risk-score cutoffs separating the cohort into low-, medium-, and high-risk subgroups were examined. The risk score identified significant differences in time to metastases between low-, medium-, and high-risk patients (P < .001), with 3-year estimates of 81.1%, 63.8%, and 38%, respectively. CONCLUSION: GTV and radiation dose are associated with time to metastasis and may be used to identify patients at higher risk of metastasis after lung SBRT.

Histology, Tumor Volume, and Radiation Dose Predict Outcomes in NSCLC Patients After Stereotactic Ablative Radiotherapy.

INTRODUCTION: It remains unclear if histology should be independently considered when choosing stereotactic ablative body radiotherapy dose prescriptions for NSCLC. METHODS: The study population included 508 patients with 561 lesions between 2000 and 2016, of which 442 patients with 482 lesions had complete dosimetric information. Eligible patients had histologically or clinically diagnosed early-stage NSCLC and were treated with 3 to 5 fractions. The primary endpoint was in-field tumor control censored by either death or progression. Involved lobe control was also assessed. RESULTS: At 6.7 years median follow-up, 3-year in-field control, involved lobe control, overall survival, and progression-free survival rates were 88.1%, 80.0%, 49.4%, and 37.2%, respectively. Gross tumor volume (GTV) (hazard ratio [HR] = 1.01 per mL, p = 0.0044) and histology (p = 0.0225) were independently associated with involved lobe failure. GTV (HR = 1.013, p = 0.001) and GTV dose (cutoff of 110 Gy, biologically effective dose with α/ß = 10 [BED10], HR = 2.380, p = 0.0084) were independently associated with in-field failure. For squamous cell carcinomas, lower prescription doses were associated with worse in-field control (12 Gy × 4 or 10 Gy × 5 versus 18 Gy or 20 Gy × 3: HR = 3.530, p = 0.0447, confirmed by propensity score matching) and was independent of GTV (HR = 1.014 per mL, 95% confidence interval: 1.005-1.022, p = 0.0012). For adenocarcinomas, there were no differences in in-field control observed using the above dose groupings (p = 0.12 and p = 0.31, respectively). CONCLUSIONS: In the absence of level I data, GTV and histology should be considered to personalize radiation dose for stereotactic ablative body radiotherapy. We suggest lower prescription doses (i.e., 12 Gy × 4 or 10 G × 5) should be avoided for squamous cell carcinomas if normal tissue tolerances are met.

In Vitro Cell-free DNA Quantification: A Novel Method to Accurately Quantify Cell Survival after Irradiation.

Circulating tumor DNA (ctDNA) analysis has been shown to aid in both the detection of cancer and evaluation of somatic mutations in tumors. CtDNA concentration in plasma increases in proportion to tumor volume and/or metabolic activity and growth; however, this principle has yet to be applied to cell culture. We hypothesized that cell line-specific cell-free DNA (cfDNA) can be used to measure cell viability and cell survival in cell culture. Clonogenic assays on non-small cell lung cancer (NSCLC) cell lines H322, A549 and H322 were exposed to radiation doses of 0, 4 and 8 Gy. Prior to colony fixation and counting, cfDNA was extracted and quantified from cell culture media. The correlation between cell line-specific cfDNA and number of colonies grown on culture plates was examined. An H1299:A549 coculture model was used to evaluate the differential release of cell line-specific cfDNA. The results of this work indicate a strong correlation between CfDNA quantification from cell culture media and clonogenic survival at all radiation doses and in all cell lines tested (R2 range = 0.77-0.99). Cell survival curves derived from cfDNA were virtually indistinguishable from matched traditional clonogenic survival data ( P > 0.05; no significant difference exists between clonogenic curves). CfDNA quantification also accurately estimates colony count in a two-cell-line coculture model. In conclusion, cell-free DNA quantification from cell culture media can be used to measure cell survival, and appears suitable for development in a high-throughput clonogenic assay and radiosensitizer screening platform.

Blood-Based Nucleic Acid Biomarkers as a Potential Tool to Determine Radiation Therapy Response in Non-Small Cell Lung Cancer.

Lung cancer is the leading cause of cancer deaths worldwide, with smoking as the main risk factor. The use of low-dose computed tomography (LDCT) as a screening method has shown a 20% lung cancer specific mortality benefit; however, widespread implementation is estimated to add $1.3-$2.0 billion in annual national health care expenditures. Blood-based microRNAs (miRNAs) have been investigated in detail and found to be potentially useful biomarkers indicating the presence of lung cancer, especially when used as a companion test to LDCT. Testing for miRNAs and circulating tumor DNA (ct-DNA) in the blood are anticipated to become more affordable in the near future, and therefore these potentially sensitive methods could serve as first-line screening modalities prior to obtaining LDCT and definitive diagnostic tests for lung cancer. Furthermore, miRNAs may shed light not only on the tumor burden, but also perhaps on tumor aggressiveness, histology, treatment response and the patient's overall survival. In the near future, analysis of ct-DNA may reveal somatic mutations beyond EGFR, tumor burden and the presence of occult progression of disease. In theory, these biomarkers may also help oncologists to elucidate the tumor response to radiotherapy, and in the future, may assist the radiation oncologist in making data-driven treatment decisions and providing patients with quantitative information regarding their treatment response.

Obstructing in utero oropharyngeal mass: Case report of a lymphatic malformation arising within an oropharyngeal teratoma.

An ex utero intrapartum treatment procedure was performed to deliver a fetus with a multiseptated, entirely cystic, 4.5 × 5.0 × 4.0-cm mass occupying the oropharynx and oral cavity with protrusion from the mouth. Surgical excision was performed, and final pathologic diagnosis revealed a lymphatic malformation arising within a cystic oropharyngeal teratoma. Lymphatic malformations are virtually indistinguishable radiologically from rare, purely cystic teratomata, and efforts have been made to distinguish between the two in utero because of differing available treatment modalities. This represents the first documented case in the literature of a lymphatic malformation arising from within an oropharyngeal teratoma.

Modulation of Wnt Signaling Enhances Inner Ear Organoid Development in 3D Culture.

Stem cell-derived inner ear sensory epithelia are a promising source of tissues for treating patients with hearing loss and dizziness. We recently demonstrated how to generate inner ear sensory epithelia, designated as inner ear organoids, from mouse embryonic stem cells (ESCs) in a self-organizing 3D culture. Here we improve the efficiency of this culture system by elucidating how Wnt signaling activity can drive the induction of otic tissue. We found that a carefully timed treatment with the potent Wnt agonist CHIR99021 promotes induction of otic vesicles-a process that was previously self-organized by unknown mechanisms. The resulting otic-like vesicles have a larger lumen size and contain a greater number of Pax8/Pax2-positive otic progenitor cells than organoids derived without the Wnt agonist. Additionally, these otic-like vesicles give rise to large inner ear organoids with hair cells whose morphological, biochemical and functional properties are indistinguishable from those of vestibular hair cells in the postnatal mouse inner ear. We conclude that Wnt signaling plays a similar role during inner ear organoid formation as it does during inner ear development in the embryo.

Ability of the National Surgical Quality Improvement Program Risk Calculator to Predict Complications Following Total Laryngectomy.

Importance: The accuracy of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) risk calculator has been assessed in multiple surgical subspecialties; however, there have been no publications doing the same in the head and neck surgery literature. Objective: To evaluate the accuracy of the calculator's predictions in a single institution's total laryngectomy (TL) population. Design, Setting, and Participants: Total laryngectomies performed between 2013 and 2014 at a tertiary referral academic center were evaluated using the risk calculator. Predicted 30-day outcomes were compared with observed outcomes for return to operating room, surgical site infection, postoperative pneumonia, length of stay, and venous thromboembolism. Main Outcomes and Measures: Comparison of the NSQIP risk calculator's predicted postoperative complication rates and length of stay to what occurred in this patient cohort using percent error, Brier scores, area under the receiver operating characteristic curve, and Pearson correlation analysis. Results: Of 49 patients undergoing TL, the mean (SD) age at operation was 59 (9.3) years, with 67% male. The risk calculator had limited efficacy predicting perioperative complications in this group of patients undergoing TL with or without free tissue reconstruction or preoperative chemoradiation or radiation therapy with a few exceptions. The calculator overestimated the occurrence of pneumonia by 165%, but underestimated surgical site infection by 7%, return to operating room by 24%, and length of stay by 13%. The calculator had good sensitivity and specificity of predicting surgical site infection for patients undergoing TL with free flap reconstruction (area under the curve, 0.83). For all other subgroups, however, the calculator had poor sensitivity and specificity for predicting complications. Conclusions and Relevance: The risk calculator has limited utility for predicting perioperative complications in patients undergoing TL. This is likely due to the complexity of the treatment of patients with head and neck cancer and factors not taken into account when calculating a patient's risk.

ACS NSQIP Risk Calculator: An Accurate Predictor of Complications in Major Head and Neck Surgery?

The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) calculator is meant to provide an estimation of perioperative risk. Our goal was to determine the clinical applicability of the calculator in major head and neck surgery. A retrospective chart review was completed for major head and neck operations performed at 1 institution from 2013 to 2014. The calculated perioperative complication risks from the ACS NSQIP calculator were compared with observed complication rates. Overall, the ACS NSQIP calculator had little predictive value for pneumonia, surgical site infection, 30-day return to operating room, or length of stay within this cohort (P > .05). The calculator appears to have some value predicting total numbers of complications but has poor performance predicting an individual's risk of suffering a perioperative complication. In conclusion, in our small cohort of patients, the ACS NSQIP calculator was a poor predictor of perioperative complications following major head and neck operations.

Vibratory stimulus reduces in vitro biofilm formation on tracheoesophageal voice prostheses.

OBJECTIVES/HYPOTHESIS: Demonstrate that biofilm formation will be reduced on tracheoesophageal prostheses when vibratory stimulus is applied, compared to controls receiving no vibratory stimulus, in a dynamic in vitro model of biofilm accumulation simulating the interface across the tracheoesophageal puncture site. STUDY DESIGN: Prospective, randomized, controlled, crossover in university laboratory. METHODS: Ex vivo tracheoesophageal prostheses were obtained from university-affiliated speech language pathologists at Indiana University School of Medicine, Indianapolis. Prostheses demonstrating physical integrity and an absence of gross biofilm accumulation were utilized. Sixteen prostheses were cleansed and sterilized prior to random placement by length in two modified Robbins devices arranged in parallel. Each device was seeded with a polymicrobial oral flora on day 1 and received basal artificial salivary flow continuously with three growth medium meals daily. One device was randomly selected for vibratory stimulus, and 2 minutes of vibration was applied to each prosthesis before and after meals for 5 days. The prostheses were explanted and sonicated, and the biofilm cultured for enumeration. This process was repeated after study arm crossover. RESULTS: Tracheoesophageal prostheses in the dynamic model receiving vibratory stimulus demonstrated reduced gross biofilm accumulation and a significant biofilm colony forming unit per milliliter reduction of 5.56-fold compared to nonvibratory controls (P < 0.001). Significant reductions were observed within length subgroups. CONCLUSION: Application of vibratory stimulus around meal times significantly reduces biofilm accumulation on tracheoesophageal prostheses in a dynamic in vitro model. Further research using this vibratory stimulus method in vivo will be required to determine if reduced biofilm accumulation correlates with longer device lifespan. LEVEL OF EVIDENCE: NA Laryngoscope, 126:2752-2757, 2016.

Impact of Lean on surgical instrument reduction: Less is more.

OBJECTIVES/HYPOTHESIS: To determine whether instrument sets that are frequently used by multiple surgeons can be substantially reduced in size with consensus. STUDY DESIGN: Prospective quality improvement study using Lean Six Sigma for purposeful and consensual reduction of non-value-added instruments in adenotonsillectomy instrument sets. METHODS: Value stream mapping was utilized to determine instrumentation usage and reprocessing workflow. Preintervention instrument utilization surveys allowed consensual and intelligent set reduction. Non-value-added instruments were targeted for waste elimination by placement in a supplemental set. Times for pre- and postintervention instrument assembly, Mayo setup, and surgery were collected for adenotonsillectomies. Postintervention satisfaction surveys of surgeons and staff were conducted. RESULTS: Adenotonsillectomy sets were reduced from 52 to 24 instruments. Median assembly times were significantly reduced from 8.4 to 4.7 minutes (P < .0001) with a set assembly cost reduction of 44%. Following natural log transformations, mean Mayo setup times were significantly reduced from 97.6 to 76.1 seconds (P < .0001), and mean operative times were not significantly affected (1,773 vs. 1,631 seconds, P > .05). The supplemental set was opened in only 3.6% of cases. Satisfaction was >90% regarding the intervention. Set build cost was reduced by $1,468.99 per set. CONCLUSIONS: Lean Six Sigma improves efficiency and reduces waste by empowering team members to improve their environment. Instrument set reduction is ideal for waste elimination because of tool accumulation over time and instrument obsolescence as newer technologies are adopted. Similar interventions could easily be applied to larger sinus, mastoidectomy, and spine sets. LEVEL OF EVIDENCE: NA.

BMP-2 and TGFß2 shared pathways regulate endocardial cell transformation.

Valvular heart disease is a major cause of mortality and morbidity. Revealing the cellular processes and molecules that regulate valve formation and remodeling is required to develop effective therapies. A key step in valve formation during heart development is the epithelial-mesenchymal transformation (EMT) of a subpopulation of endocardial cells in the atrioventricular cushion (AVC). The type III transforming growth factor-ß receptor (TGFßR3) regulates AVC endocardial cell EMT in vitro and mesenchymal cell differentiation in vivo. Little is known concerning the signaling mechanisms downstream of TGFßR3. Here we use endocardial cell EMT in vitro to determine the role of 2 well-characterized downstream TGFß signaling pathways in TGFßR3-dependent endocardial cell EMT. Targeting of Smad4, the common mediator Smad, demonstrated that Smad signaling is required for EMT in the AVC and TGFßR3-dependent EMT stimulated by TGFß2 or BMP-2. Although we show that Smads 1, 2, 3, and 5 are required for AVC EMT, overexpression of Smad1 or Smad3 is not sufficient to induce EMT. Consistent with the activation of the Par6/Smurf1 pathway downstream of TGFßR3, targeting ALK5, Par6, or Smurf1 significantly inhibited EMT in response to either TGFß2 or BMP-2. The requirement for ALK5 activity, Par6, and Smurf1 for TGFßR3-dependent endocardial cell EMT is consistent with the documented role of this pathway in the dissolution of tight junctions. Taken together, our data demonstrate that TGFßR3-dependent endocardial cell EMT stimulated by either TGFß2 or BMP-2 requires Smad4 and the activation of the Par6/Smurf1 pathway.