The heart is the first organ to form during embryonic development. Given the complex nature of cardiac differentiation and morphogenesis, it is not surprising that some form of congenital heart disease is present in approximately one percent of newborns. The molecular determinants of heart development have received much attention over the past several decades. This has been driven in large part by an interest in understanding the etiology of congenital heart disease coupled with the potential of utilizing knowledge from developmental biology to generate functional cells and tissues that could be used for regenerative medicine purposes. In this review, we highlight the critical signaling pathways and transcription factor networks that regulate cardiomyocyte lineage specification in both in vivo and in vitro models. Special focus will be given to epigenetic regulators that drive the commitment of cardiomyogenic cells from nascent mesoderm and their differentiation into chamber-specific myocytes as well as regulation of myocardial trabeculation.

Background Heart development is tightly regulated by signaling events acting upon a defined number of progenitor and differentiated cardiac cells. While loss-of-function of these signaling pathways leads to congenital malformation, the consequences of cardiac progenitor cell (CPC) or embryonic cardiomyocyte loss are less clear. In this study, we tested the hypothesis that embryonic mouse hearts exhibit a robust mechanism for regeneration following extensive cell loss. Methods and Results By combining a conditional cell ablation approach with a novel blastocyst complementation strategy, we generated murine embryos that exhibit a full spectrum of CPC or cardiomyocyte ablation. Remarkably, ablation of up to 60% of CPCs at embryonic day 7.5 was well-tolerated and permitted embryo survival. Ablation of embryonic cardiomyocytes to a similar degree (50-60%) at embryonic day 9.0 could be fully rescued by residual myocytes with no obvious adult cardiac functional deficit. In both ablation models, an increase in cardiomyocyte proliferation rate was detected and accounted for at least some of the rapid recovery of myocardial cellularity and heart size. Conclusions Our study defines the threshold for cell loss in the embryonic mammalian heart and reveals a robust cardiomyocyte compensatory response that sustains normal fetal development.

Objectives/Hypothesis Compare treatment‐related quality of life (QOL) impact for early‐stage human papillomavirus–associated oropharynx squamous cell carcinoma (HPV+ OPSCC) patients. Study Design Retrospective cohort at a tertiary center. Methods Stage I (T0‐2/N0‐1) HPV+ OPSCC patients (n = 76) with pretreatment Karnofsky scores ≥80 reported QOL after surgery alone (n = 17, 22%), surgery with adjuvant radiation ± chemotherapy (S‐a[C]XRT) (n = 23, 30%), or definitive radiation ± chemotherapy (d[C]XRT) (n = 36, 47%) with the University of Washington QOL version 4 (UW‐QOL); European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core Module (EORTC QLQ‐C30) and Head and Neck Module (EORTC QLQ‐HN35); University of Michigan Xerostomia, and Neck Dissection Impairment Index questionnaires (median follow‐up = 2.2 years, interquartile range = 1.0–4.2 years). Treatment adverse events and gastrostomy tube rates were assessed. Results Over 87% of each treatment group reported good or better overall QOL. Each group had low gastrostomy tube and treatment‐specific complication rates. S‐a(C)XRT and d(C)XRT patients had similar mean scores with wide ranges for most individual and all composite categories. S‐a(C)XRT compared to d(C)XRT patients reported significantly fewer dental problems (EORTC QLQ‐C30/HN35 means = 10.1 vs. 34.3, P = .007), worse appearance (UW‐QOL means = 72.8 vs. 82.6, P = .02), and worse coughing (EORTC QLQ‐C30/HN35 means = 31.9 vs. 15.7, P = .007). Surgery alone compared to d(C)XRT and S‐a(C)XRT patients reported significantly better salivary/taste/oral functions and less pain, financial, oral/dental, and sexual problems. Conclusions For early‐stage HPV+ OPSCC, patients usually achieve acceptable QOL regardless of treatment. S‐a(C)XRT and d(C)XRT patients report generally similar QOL including neck/shoulder pain/function, but with a wide range in a limited patient sample. Surgery alone should be considered, when oncologically and functionally safe, given the better associated QOL. Level of Evidence 4 Laryngoscope, 130:E48–E56, 2020

Objective To characterize patterns of neck lymph node (LN) metastases in human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma, represented by p16 positivity (p16+OPSCC). Study Design Case series with chart review. Setting Tertiary care center. Subjects and Methods Neck dissection (ND) specimens of nonirradiated p16+OPSCC patients were analyzed for frequencies of clinically evident and occult LNs by neck level. Local, regional, and distant recurrences were reviewed. Results Seventy p16+OPSCC patients underwent primary site transoral robotic surgery and 82 NDs of varying levels. Metastatic pathologic LNs were found at the following frequencies: 0% (0/28) in level I, 75.6% (62/82) in level II with 57.4% (35/61) in level IIA and 13.1% (8/61) in level IIB, 22.0% (18/82) in level III, 7.0% (5/71) in level IV, and 6.3% (1/16) in level V. The level V LN was clinically evident preoperatively. Five of 21 (23.8%) elective NDs contained occult LNs, all of which were in level II and without extranodal extension. Twenty-seven (38.6%) patients underwent adjuvant radiation; 19 (27.1%) patients underwent adjuvant chemoradiation. With a mean follow-up of 29 months, 3 patients had developed recurrences, with all but 1 patient still alive. All patients who recurred had refused at least a component of indicated adjuvant treatment. Conclusions For p16+OPSCC, therapeutic NDs should encompass any levels bearing suspicious LNs and levels IIA-B, III, and IV, while elective NDs should be performed and encompass at least levels IIA-B and III. These selective ND plans, followed by indicated adjuvant treatment, are associated with a low nodal recurrence rate.

Objectives/Hypothesis: Machine learning (ML) is a type of artificial intelligence wherein a computer learns patterns and associations between variables to correctly predict outcomes. The objectives of this study were to 1) use a ML platform to identify factors important in predicting surgical complications in patients undergoing head and neck free tissue transfer, and 2) compare ML outputs to traditionally employed logistic regression models. Study Design: Retrospective cohort study. Methods: Using a dataset of 364 consecutive patients who underwent head and neck microvascular free tissue transfer at a single institution, 14 clinicopathologic characteristics were analyzed using a supervised ML algorithm of ensemble decision trees to predict surgical complications. The relative importance values of each variable in the ML analysis were then compared to logistic regression models. Results: There were 166 surgical complications, which included bleeding or hematoma in 30 patients (8.2%), fistulae in 25 patients (6.9%), and infection or dehiscence in 52 patients (14.4%). There were 59 take-backs (16.2%), and six total (1.6%) and five partial (1.4%) flap failures. ML models were able to correctly classify outcomes with an accuracy of 65% to 75%. Factors that were identified in ML analyses as most important for predicting complications included institutional experience, flap ischemia time, age, and smoking pack-years. In contrast, the significant factors most frequently identified in traditional logistic regression analyses were patient age (P = .03), flap type (P = .03), and primary site of reconstruction (P = .06). Conclusions: In this single-institution dataset, ML algorithms identified factors for predicting complications after free tissue transfer that were distinct from traditional regression models.