Revisiting Expectations in an Era of Precision Oncology.

As we enter an era of precision medicine and targeted therapies in the treatment of metastatic cancer, we face new challenges for patients and providers alike as we establish clear guidelines, regulations, and strategies for implementation. At the crux of this challenge is the fact that patients with advanced cancer may have disproportionate expectations of personal benefit when participating in clinical trials designed to generate generalizable knowledge. Patient and physician goals of treatment may not align, and reconciliation of their disparate perceptions must be addressed. However, it is particularly challenging to manage a patient's expectations when the goal of precision medicine-personalized response-exacerbates our inability to predict outcomes for any individual patient. The precision medicine informed consent process must therefore directly address this issue. We are challenged to honestly, clearly, and compassionately engage a patient population in an informed consent process that is responsive to their vulnerability, as well as ever-evolving indications and evidence. This era requires a continual reassessment of expectations and goals from both sides of the bed.

Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis.

We report a new class of thiophene (TP) compounds that kill Mycobacterium tuberculosis by the previously uncharacterized mechanism of Pks13 inhibition. An F79S mutation near the catalytic Ser55 site in Pks13 conferred TP resistance in M. tuberculosis. Overexpression of wild-type Pks13 resulted in TP resistance, and overexpression of the Pks13(F79S) mutant conferred high resistance. In vitro, TP inhibited fatty acyl-AMP loading onto Pks13. TP inhibited mycolic acid biosynthesis in wild-type M. tuberculosis, but it did so to a much lesser extent in TP-resistant M. tuberculosis. TP treatment was bactericidal and equivalent to treatment with the first-line drug isoniazid, but it was less likely to permit emergent resistance. Combined isoniazid and TP treatment resulted in sterilizing activity. Computational docking identified a possible TP-binding groove within the Pks13 acyl carrier protein domain. This study confirms that M. tuberculosis Pks13 is required for mycolic acid biosynthesis, validates it as a druggable target and demonstrates the therapeutic potential of simultaneously inhibiting multiple targets in the same biosynthetic pathway.

Lymph node level ratio as a predictor of survival in oral cavity squamous cell carcinoma.

OBJECTIVE: To evaluate whether nodal yields and ratios based on level serves as prognostic indicators in patients with oral cavity squamous cell carcinoma undergoing neck dissection. MATERIALS AND METHODS: A retrospective analysis of 342 patients with oral cavity squamous cell carcinoma treated surgically between 1998 and 2017 were included.Demographics and clinicopathologic data were collated. Disease specific survival and overall survival were analyzed via Kaplan-Meier method and log-rank test as well as univariable and multivariable Cox models. RESULTS: Total nodal yield is associated with improved overall and disease specific survival (p < 0.01). Total positive nodal yield (p < 0.01), positive nodal ratio per level (p < 0.001), and identification of <4 lymph nodes/level (p < 0.001) are associated with worse disease specific survival and overall survival. A ratio of at least 4 lymph nodes/level dissected yields the maximal hazard ratio on for both disease specific and overall survival optimizes the Kaplan-Meier split between survival groups. After controlling for sex, age, margin status, disease stage, extranodal extension, perineural invasion, and lymphovascular invasion as fixed covariates in the Cox models, a nodal level ratio of 4 lymph nodes/level provides hazard ratio (95% CI) of 3.59 (1.69, 7.60); p < 0.0006) for disease free survival and 2.90 (1.54, 5.46; p < 0.001) for overall survival. CONCLUSION: Nodal level ratio of < 4 lymph nodes/level is associated with worse disease specific and overall survival in oral cavity squamous cell carcinoma. This level-specific metric may prove useful qualitatively and in predicting survival in oral cavity cancer with broader utility to address variations in levels of neck dissection performed.

Peripheral lymphocytes and lactate dehydrogenase correlate with response and survival in head and neck cancers treated with immune checkpoint inhibitors.

BACKGROUND: Little is known regarding associations between peripheral blood biomarkers (PBBMs) and survival, response, and toxicity in recurrent/metastatic head and neck squamous cell carcinomas (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs). METHODS: In this single-institution retrospective cohort study, a dataset of patients with R/M HNSCC treated with ICIs between 08/2012-03/2021 was established, including demographic and clinicopathologic characteristics. Pretreatment PBBMs were collected and evaluated for associations with grade ≥3 adverse events (G ≥ 3AE) by CTCAEv5, objective response (ORR) by RECIST 1.1, overall survival (OS), and progression-free survival (PFS). Multivariable models for each outcome were created using elastic net variable selection. RESULTS: Our study included 186 patients, with 51 (27%) demonstrating complete or partial response to immunotherapy. Multivariable models adjusted for ECOG performance status (PS), p16, and smoking demonstrated that pretreatment higher LDH and absolute neutrophils, as well as lower percent lymphocytes correlated with worse OS and PFS. Higher LDH and lower % lymphocytes also correlated with worse ORR. CONCLUSIONS: In the largest study to date examining PBBMs in ICI-treated R/M HNSCCs, our variable selection method revealed PBBMs prognostic for survival and response to immunotherapy. These biomarkers warrant further investigation in a prospective study along with validation with CPS biomarker.

Neurotization of the radial forearm free flap improves swallowing outcomes in hemiglossectomy defects.

BACKGROUND: We examined the effect of free tissue neurotization on speech and swallowing outcomes for patients undergoing reconstruction of hemiglossectomy defects with a radial forearm free flap (RFFF). METHODS: A retrospective study was performed in patients with oral cavity squamous cell carcinoma undergoing a hemiglossectomy and reconstruction with a RFFF. Functional outcomes including nutritional mode, range of liquids and solids, and speech understandability were analyzed 1-year post-treatment. RESULTS: Eighty-four patients were included in this analysis, 41 of whom had neurotized flaps (49%). No significant differences in demographic or clinical variables were seen between the neurotized and non-neurotized groups. On multivariate analysis controlling for BMI, flap area, and N-classification, patients with neurotized flaps were significantly more likely to have normal range of liquids and solids and less likely to have a G-tube. CONCLUSIONS: Neurotization of RFFF reconstructing hemiglossectomy defects results in decreased G-tube dependence and improved range of liquids and solids.

Factors affecting operative autonomy and performance during otolaryngology training: A multicenter trial.

Objective: Surgical education is changing in an era of new regulations and evolving training cultures. We sought to understand the factors that affect operative experiences during otolaryngology residency. Methods: From December 2019 to December 2020, five otolaryngology training programs used the SIMPL OR smartphone application to evaluate residents after each operation. Residents and attendings rated the trainee's autonomy on a 4-level Zwisch scale, performance on a 5-level scale, and case complexity on a 3-level scale. We examined associations between ratings of autonomy and performance with variables including postgraduate year (PGY), case complexity, gender, week of the academic year (AY), and whether multiple procedures were logged. Results: 78 attendings and 92 residents logged 2984 evaluations. PGY level and week of the AY were positively associated with attending ratings of autonomy and performance (PGY3 vs. PGY2: B = 0.63, p < .001 for autonomy and B = 1.05, p < .001 for performance; week of the AY: B = 0.013, p = .002 for autonomy; B = 0.025, p < .001 for performance). Multiple procedures logged and increasing case complexity were negatively associated with attending ratings (multiple procedures: B = -0.19, p = .04 for autonomy and B = -0.48, p < .001 for performance; hardest vs. easiest 1/3 of cases: B = -1.01, p < .001 for autonomy and B = -0.59, p < .001 for performance). Attending and trainee genders were not associated with attending ratings of autonomy or performance. Conclusion: Resident autonomy and performance were positively associated with PGY level and week of the academic year, and negatively associated with case complexity and multiple procedures. These findings highlight the need to align training level with case complexity to promote quality operative experiences. Level of Evidence: 2.

Multi-institutional Study of Otolaryngology Resident Intraoperative Experiences for Key Indicator Procedures.

OBJECTIVE: There is concern that current otolaryngology residents may not receive adequate surgical training. We aimed to characterize residents' surgical experiences at 5 academic centers performing the 14 key indicator procedures (KIPs) outlined by the Accreditation Council for Graduate Medical Education. STUDY DESIGN: Prospective study. SETTING: Five otolaryngology training programs. METHODS: Data were gathered from December 2019 to December 2020 with a smartphone application from the Society for Improving Medical Professional Learning. After each operation, residents and faculty rated trainee autonomy on a 4-level Zwisch scale and performance on a 5-level modified Dreyfus scale. RESULTS: Residents and attendings (n = 92 and 78, respectively) logged 2984 evaluations. Attending ratings of resident autonomy and performance increased with training level (P < .001). Resident self-assessments of autonomy and performance were lower than paired attending assessments (P < .001). Among attending evaluations of KIPs performed by senior residents (postgraduate year 4 or 5), 55% of cases were performed with meaningful autonomy (passive help or supervision only). Similarly, attendings rated 55% of these cases as a practice-ready or exceptional performance. Senior residents had meaningful autonomy for ≥50% of cases for most KIPs, with the exception of flaps and grafts (40%), pediatric/adult airway (39%), and stapedectomy/ossiculoplasty (33%). Similarly, senior residents received practice-ready or exceptional performance ratings for ≥50% of cases across all KIPs other than pediatric/adult airway (42%) and stapedectomy/ossiculoplasty (33%). CONCLUSION: In this multicenter study, resident surgical autonomy and performance varied across otolaryngology KIPs. The development of nationwide benchmarks will help programs and residents set educational goals. LEVEL OF EVIDENCE: 2.

Mutational and phylogenetic analyses of the mycobacterial mbt gene cluster.

The mycobactin siderophore system is present in many Mycobacterium species, including M. tuberculosis and other clinically relevant mycobacteria. This siderophore system is believed to be utilized by both pathogenic and nonpathogenic mycobacteria for iron acquisition in both in vivo and ex vivo iron-limiting environments, respectively. Several M. tuberculosis genes located in a so-called mbt gene cluster have been predicted to be required for the biosynthesis of the core scaffold of mycobactin based on sequence analysis. A systematic and controlled mutational analysis probing the hypothesized essential nature of each of these genes for mycobactin production has been lacking. The degree of conservation of mbt gene cluster orthologs remains to be investigated as well. In this study, we sought to conclusively establish whether each of nine mbt genes was required for mycobactin production and to examine the conservation of gene clusters orthologous to the M. tuberculosis mbt gene cluster in other bacteria. We report a systematic mutational analysis of the mbt gene cluster ortholog found in Mycobacterium smegmatis. This mutational analysis demonstrates that eight of the nine mbt genes investigated are essential for mycobactin production. Our genome mining and phylogenetic analyses reveal the presence of orthologous mbt gene clusters in several bacterial species. These gene clusters display significant organizational differences originating from an intricate evolutionary path that might have included horizontal gene transfers. Altogether, the findings reported herein advance our understanding of the genetic requirements for the biosynthesis of an important mycobacterial secondary metabolite with relevance to virulence.

Osteotomized folded scapular tip free flap for complex midfacial reconstruction.

Aim: To describe a novel technique for the reconstruction of geometrically complex defects of the midface using an osteotomized folded scapular tip-free flap. Methods: Five patients underwent maxillectomy with defects disrupting two or more of the following facial axes: orbital, nasofacial, and palatal axes. Patients underwent primary reconstruction using an angular artery-based scapular tip-free flap with an osteotomy to fold the flap. Harvest techniques, including placement of osteotomies, folding and plating, surgical esthetic, and functional outcomes, are presented. Results: Osteotomies placed in the scapular tip-free flap allowed folding of the osseous flap and improved restoration of all three facial axes with a single flap. In one patient, the tip of the scapula was used to reconstruct the nasofacial axis, while the body and lateral border were used to reconstruct the palate. In four patients, the tip of the scapula was used to reconstruct the orbital axis, while the body and lateral border were used to reconstruct the nasofacial axis. Patients had successful oronasal separation, healed wounds withstanding adjuvant therapy, satisfactory orbital positioning and facial projection, preserved masticatory surfaces and opportunity for dental implants. Conclusion: The midface is geometrically complex and is one of the most challenging head and neck sites to reconstruct. Ablative defects in this area can disrupt facial axes resulting in poor esthetic and functional outcomes. This study demonstrates the reconstructive advantages of a novel osteotomized folded scapular tip-free flap.

Virtual Resident Mentorship Groups for Fourth Year Medical Students Applying into Otolaryngology-Head and Neck Surgery.

OBJECTIVE: To create a longitudinal near-peer mentorship program for medical students applying to otolaryngology. METHODS: A program for longitudinal near-peer mentorship was designed based on a needs analysis of senior medical students. Program objectives were to (1) provide didactic education on common otolaryngology consults, (2) facilitate resident-student networking, and (3) enable applicants to meet other students. Senior otolaryngology residents were matched with medical students from across the United States applying to otolaryngology for a series of online small group meetings. Sessions included resident-designed didactics covering high-yield clinical scenarios and a mentorship component focused on transition to residency topics. Program evaluation included anonymized pre- and post-tests for each didactic session and an anonymous post-program participant survey. RESULTS: There were 40 student participants from across the United States, with an average attendance of 73% of sessions per participant. Performance on didactic testing improved for 2 of the 3 sessions. Participants stated they would be very likely to recommend each session to another student in the future (4.96/5.00, obs = 155). Participants stated the most valuable part of the program was interacting with residents (82% of responses), transition to residency advice (28%), and learning about otolaryngology consults (28%). Suggestions for improvement included expanding content, increasing the number of sessions, and involving additional faculty and residents. CONCLUSION: A longitudinal virtual experience can be valuable for near-peer mentorship for medical students applying to otolaryngology.

Addressing the Impact of COVID-19 on the Residency Application Process Through a Virtual Subinternship.

Senior medical students are facing an unparalleled experiential gap left by COVID-19 restrictions. Due to a shared commitment to safety, equity, and well-being, away rotations are actively being discouraged or even prohibited. As a result, students transitioning to residency encounter reduced clinical training experiences and decreased access to advising, mentorship, and research opportunities. In addition, limited exposure to residency life across subspecialties and institutions poses unique challenges during the current residency application cycle. The otolaryngology-head and neck surgery community has met these unprecedented challenges by producing diverse electronic resources for specialty-specific clinical education, as well as discussing ways to increase access to advising. In this commentary, we review these initiatives and propose an institutional virtual event as a platform for meeting goals previously achieved by visiting subinternships.

Three-dimensional modeling of the scapular tip for anterolateral and lateral mandibular defects.

OBJECTIVE: Three-dimensional (3D) computational modeling represents an invaluable surgical tool for complex reconstructive cases. There exists limited data on 3D imaging to evaluate the use of the scapular tip free flap in complex, anterolateral mandibular reconstructions. The purpose of this study is to radiographically assess the scapular tip free flap in anterolateral defects of the mandible. METHODS: A retrospective case series of 50 patients was performed on head and neck cancer patients treated at Michigan Medicine from 2013 to 2018. Patients who had pre-operative computed tomography neck and thorax for review were included. RESULTS: The scapular tip was able to cover defects from the ipsilateral mandibular angle to the symphysis in all cases. On average, the bone extended to cover defects from the mandibular angle to 17 mm (SD ± 3.6 mm) beyond the mandibular symphysis, which equates to 70% (95% CI 0.66-0.74) of the distance from the symphysis to the contralateral mental foramen. CONCLUSION: Use of the scapular tip as a donor site for reconstruction of the mandibular body can be evaluated pre-operatively utilizing 3D imaging. All patients were able to achieve posterior coverage to the vertical plane of the mandibular condyle and contralateral extension across the symphysis on average extends almost three-fourths of the distance to the mandibular foramen. The extent of contralateral coverage can be more accurately delineated utilizing the patient's pre-operative imaging.

An Algorithm to Evaluate Suspected Lung Metastases in Patients with HPV-Associated Oropharyngeal Cancer.

Distinguishing between distantly metastatic and metachronous lung primary carcinoma is challenging for patients with a history of head and neck cancer. There are implications for registry data, prognosis and related counseling, and management options, including eligibility for precision oncology trials. Patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma who were treated under a uniform clinical protocol and achieved a complete response were identified in a single-institution prospective head and neck cancer epidemiology database (n = 205). Fifteen patients presented with pulmonary nodule(s) after completion of therapy. We describe our algorithm for the evaluation of these patients, including histopathology, p16 immunohistochemistry, and HPV in situ hybridization.

The Spider Limb Positioner in subscapular system free flaps.

BACKGROUND: The subscapular system is a versatile vascular network that can provide multiple flaps for reconstruction of the head and neck. A significant drawback of using the subscapular system is that patient positioning can preclude the use of simultaneous two-team ablative and reconstructive surgery. Herein, we describe a novel use of an upper extremity limb positioner (Spider Limb Positioner) used primarily in orthopedic surgery to facilitate concurrent two-team technique in head and neck surgery. METHODS: Using a bean bag and the Spider Limb Positioner for the upper extremity, a semidecubitus position was used for subscapular donor site dissection. Ablative and reconstructive teams worked concurrently in all cases. RESULTS: This technique was utilized 78 times on 73 patients, with chimeric flaps used in 38% of cases. The average operative time was 466 min. Only one patient required repositioning intraoperatively due to a change in the subscapular donor site side. There were no nerve compression injuries or positioning related complications. CONCLUSION: Scapular and parascapular free flaps are useful tools for reconstruction of the head and neck. In a two-team approach, the use of a semidecubitus position in conjunction with the Spider Limb Positioner facilitates exposure for the reconstructive team without compromising access for the ablative team.

Extended Endoscopic and Open Sinus Surgery for Refractory Chronic Rhinosinusitis.

This review discusses extended endoscopic and open sinus surgery for refractory chronic rhinosinusitis. Extended maxillary sinus surgery including endoscopic maxillary mega-antrostomy, endoscopic modified medial maxillectomy, and inferior meatal antrostomy are described. Total/complete ethmoidectomy with mucosal stripping (nasalization) is discussed. Extended endoscopic sphenoid sinus procedures as well as their indications and potential risks are reviewed. Extended endoscopic frontal sinus procedures, such the modified Lothrop procedure, are described. Extended open sinus surgical procedures, such as the Caldwell-Luc approach, frontal sinus trephine procedure, external frontoethmoidectomy, frontal sinus osteoplastic flap with or without obliteration, and cranialization, are discussed.

Pediatric head and neck bone sarcomas: An analysis of 204 cases.

OBJECTIVES: To analyze the demographics, survival, and treatment efficacy of pediatric sarcomas of the facial skeleton and skull. METHODS: Retrospective study of cases from the US National Cancer Institute's Surveillance, Epidemiology, and End Results database. Pediatric patients between the ages of 0 and 18 diagnosed with a malignant sarcoma of either the mandible or the bones of skull, face, and associated joints from 1973 to 2013 were studied. RESULTS: In total, 204 patients were included in the analysis. The average age at diagnosis was 11.39 (±5.15) years with a male-to-female ratio of 1.4:1. Whites were the most commonly affected race (76.0%). Malignant mandible sarcomas accounted for 29.9% of the cohort (n = 61). The most common pathology was osteosarcoma, which accounted for 43.6% of the cohort (n = 89). Among patients with known histologic grade (n = 95), 26.0% were AJCC stage III or IV. Overall, 5-year disease-specific survival (DSS) was 80.6%. When stratified by treatment modality, 5-year DSS was 86.0% for surgery alone, 67.9% for radiation alone, and 75.3% for surgery with adjuvant radiotherapy (p = 0.041). CONCLUSIONS: Osteosarcoma, Ewing's sarcoma, and chondrosarcoma are the most common subtypes of pediatric head and neck bone sarcoma. Such sarcomas more commonly affect whites and males during pubertal ages. Disease-specific survival is not affected by primary site. Surgery alone is the mainstay of treatment, and demonstrates higher 5-year disease-specific survival compared to radiotherapy alone. Adjuvant radiotherapy does not seem to increase survival, but further investigation is warranted.

An Analysis of Patients Treated for Cerebrospinal Fluid Rhinorrhea in the United States from 2002 to 2010.

Background The Nationwide Inpatient Sample (NIS) database was used to analyze the demographic features and concomitant diagnoses in patients admitted with cerebrospinal fluid (CSF) rhinorrhea. Methods We analyzed the NIS database for all hospital admissions of CSF rhinorrhea between 2002 and 2010. Patient demographics, length of stay, hospital charges, concomitant diagnoses, hospital level characteristics, and complications were analyzed for patients undergoing surgical repair (group I) and for those treated without surgical repair (group II). Results Patients in group I were significantly older, the majority were female (67.5%), and were more likely to be obese (12.9%), have diabetes mellitus (15.7%), and hypertension (41.6%). Lengths of stay were similar between the two groups, but group I patients incurred higher hospital charges (p < 0.001). Group I patients were more likely classified as an elective admission (59.8 vs. 38.6%), and were more frequently admitted to a teaching hospital (83.6%) with a large bed size (79.0%). Acute medical complications and concomitant diagnosis of meningitis were similar in both groups. Conclusion Rates of meningitis did not differ between the two groups. Patients who underwent surgical repair were more likely to be an elective admission and admitted to a teaching hospital. Hospital charges were higher in patients undergoing repair.

Management of Skull Base Defects After Surgical Resection of Sinonasal and Ventral Skull Base Malignancies.

Over the past 2 decades, there has been a significant increase in the resection of larger and more complex ventral skull base malignancies. The resection of these lesions has resulted in the creation of larger and more difficult to repair skull base defects. There are many available options for ventral skull base reconstruction. Despite the variety of reconstructive options, the key objective is to eliminate any communication between the intracranial space and the sinonasal cavity. This article discusses some of the more common techniques currently used for repair of these skull base defects.

Impact of chronic obstructive pulmonary disease on patients undergoing laryngectomy for laryngeal cancer.

OBJECTIVES/HYPOTHESIS: Although chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients undergoing laryngeal cancer surgery, the impact of this comorbidity in this setting is not well established. In this analysis, we used the Nationwide Inpatient Sample (NIS) to elucidate the impact of COPD on outcomes after laryngectomy for laryngeal cancer. METHODS: The NIS was queried for patients admitted from 1998 to 2010 with laryngeal cancer who underwent total or partial laryngectomy. Patient demographics, type of admission, length of stay, hospital charges, and concomitant diagnoses were analyzed. RESULTS: Our inclusion criteria yielded a cohort of 40,441 patients: 3,051 with COPD and 37,390 without. On average, COPD was associated with an additional $12,500 (P < 0.001) in hospital charges and an additional 1.4 days (P < 0.001) of hospital stay. There was no significant difference in incidence of in-hospital mortality between the COPD and non-COPD groups after total laryngectomy (1.1% in COPD vs. 1.0% in non-COPD; P = 0.776); however, there was an increased incidence of in-hospital mortality in the COPD group compared to the non-COPD group after partial laryngectomy (3.4% in COPD vs. 0.4% in non-COPD; P < 0.001). Multivariate adjusted logistic regression revealed that COPD was associated with greater odds of pulmonary complications after both partial laryngectomy (odds ratio [OR] = 3.198; P < 0.001) and total laryngectomy (OR = 1.575; P < 0.001). CONCLUSION: Chronic obstructive pulmonary disease appears to be associated with greater hospital charges, length of stay, and postoperative pulmonary complications in patients undergoing laryngectomy for laryngeal cancer. Chronic obstructive pulmonary disease after partial, but not total, laryngectomy appears to be associated with increased risk of in-hospital mortality. LEVEL OF EVIDENCE: 2C. Laryngoscope, 2016 127:417-423, 2017.