The impact of distance to facility on treatment modality, short-term outcomes, and survival of patients with HPV-positive oropharyngeal squamous cell carcinoma.

PURPOSE: This study compared treatment and outcomes for patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) based on their travel distance to treatment facility. MATERIALS AND METHODS: Patients with cT1-4, N0-3, M0 HPV-positive OPSCC in the National Cancer Database from 2010 to 2019 were identified and split into four quartiles based on distance to facility, with quartile 4 representing patients with furthest travel distances. Multivariable-adjusted logistic regression and Cox proportional hazards modeling were used to analyze the primary outcome of treatment received, and secondary outcomes of clinical stage, overall survival, surgical approach (i.e., TORS versus other), and 30-day surgical readmissions. RESULTS: 17,207 patients with HPV-positive OPSCC were evenly distributed into four quartiles. Compared to patients in quartile 1, patients in quartile 4 were 40 % less likely to receive radiation versus surgery (OR = 0.60; 95 % CI = 0.54-0.66). Among the patients who received surgery, quartile 4 had a higher odds of receiving TORS treatment compared to quartile 1 (4v1: OR = 2.38; 95 % CI = 2.05-2.77), quartile 2 (4v2: OR = 2.31, 95 % CI = 2.00-2.66), and quartile 3 (4v3: OR = 1.75; 95 % CI = 1.54-1.99). Quartile 4 had a decreased odds of mortality compared to Quartile 1 (4v1: OR = 0.87; 95 % CI = 0.79-0.97). There were no differences among the quartiles in presenting stage and 30-day readmissions. CONCLUSIONS: This study found that patients with furthest travel distance to facility were more often treated surgically over non-surgical management, with TORS over open surgery, and had better overall survival. These findings highlight potential disparities in access to care for patients with HPV-positive OPSCC.

Treatment discordance in the utilization of neck dissection for stage I-II supraglottic tumors.

BACKGROUND: In 2018, the National Comprehensive Cancer Network treatment guidelines began recommending the use of neck dissection during surgical management of stage I-II supraglottic laryngeal squamous cell carcinoma (LSCC). METHODS: Trends and factors associated with the use of neck dissection during larynx-preserving surgery for patients with cT1-2, N0, M0 supraglottic LSCC in the National Cancer Database (2004-2020) were evaluated using multivariable-adjusted logistic regression. RESULTS: Of the 2080 patients who satisfied study eligibility criteria, 633 (30.4%) underwent neck dissection. Between 2018 and 2020, the rate of neck dissection was 39.0% (114/292). After multivariable adjustment, academic facility type, undergoing biopsy prior to surgery, and more radical surgery were significant predictors of receiving neck dissection. CONCLUSIONS: The results of this national analysis suggest that the utilization of guideline-concordant neck dissection for management of stage I-II supraglottic LSCC remains low and highlight the need to promote the practice of neck dissection for this patient population.

Evaluating human papillomavirus testing, prevalence, and association with prognosis in head and neck squamous cell carcinoma by subsite: A national cancer database study.

PURPOSE: To compare human papillomavirus (HPV) testing, prevalence, and association with prognosis between head and neck squamous cell carcinoma (HNSCC) subsites. MATERIALS AND METHODS: This study utilized the National Cancer Database (NCDB) to identify patients diagnosed with HNSCC between 2010 and 2017. Rates of HPV testing, HPV-positivity, and changes in these rates over time were measured by subsite. The impact of HPV-positivity on overall survival across six head and neck subsites was assessed using multivariable-adjusted Cox proportional hazards analysis. RESULTS: A total of 121,550 patients were included. Of this cohort, 87,575 (72.1%) were tested for HPV, with the oropharynx (55,049/64,158; 85.8%) displaying the highest rates of testing and the sinonasal tract (1519/2853; 53.2%) displaying the lowest testing rates. Of the 86,136 with a definitive result, 46,878 (54.4%) were HPV-positive, with the oropharynx (40,313/54,205; 74.4%) displaying the highest rates of HPV-positivity and the oral cavity (1818/11,505; 15.8%) displaying the lowest. HPV-positive malignancy was associated with significantly improved adjusted overall survival in the oropharynx (HR = 0.42 [95% CI: 0.43-0.47]), oral cavity (HR = 0.86 [95% CI: 0.79-0.95]), sinonasal tract (HR = 0.63 [95% CI: 0.48-0.83]), larynx (HR = 0.78 [95% CI: 0.71-0.87]), and hypopharynx (HR = 0.56 [95% CI: 0.48-0.66]), but not the nasopharynx (HR = 0.93 [95% CI: 0.77-1.14]). CONCLUSION: HPV testing rates were significantly lower in non-oropharyngeal subsites. This is relevant as HPV-associated disease displayed significantly improved overall survival in both the oropharynx and four of five non-oropharyngeal subsites. While validation with prospective studies is necessary, these findings may warrant HPV testing in all HNSCC subsites.

Surgery for M1A Non-Small-Cell Lung Cancer With Additional Pulmonary Nodules in a Contralateral Lobe.

INTRODUCTION: Limited consensus exists on the optimal treatment strategy for clinical M1a non-small-cell lung cancer (NSCLC) presenting as a primary tumor with additional intrapulmonary nodules in a contralateral lobe ("M1a-Contra"). This study sought to compare long-term survival of patients with M1a-Contra tumors receiving multimodal therapy with versus without thoracic surgery. METHODS: Overall survival of patients with cT1-4, N0-3, M1a NSCLC with contralateral intrapulmonary nodules who received surgery as part of multimodal therapy ("Thoracic Surgery") versus systemic therapy with or without radiation ("No Thoracic Surgery") in the National Cancer Database from 2010 to 2015 was evaluated using Kaplan-Meier analysis, Cox proportional hazards modeling, and propensity score matching. RESULTS: Of the 5042 patients who satisfied study inclusion criteria, 357 (7.1%) received multimodal therapy including surgery. In multivariable-adjusted analysis, the Thoracic Surgery cohort had better overall survival than the No Thoracic Surgery cohort (HR: 0.66, 95% CI: 0.56-0.79, P < 0.001). In a propensity score-matched analysis of 386 patients, well-balanced on 12 common prognostic covariates, the Thoracic Surgery group had better 5-year overall survival than the No Thoracic Surgery group (P = 0.020). In propensity score-matched analyses stratified by clinical N status, Thoracic Surgery was associated with better overall survival than No Thoracic Surgery for patients with cN0 disease and cN1-2 disease. CONCLUSIONS: In this national analysis, multimodal treatment including surgery was associated with better overall survival than systemic therapy with or without radiation without surgery for patients with M1a-Contra tumors. These preliminary findings highlight the importance of further evaluation of surgery in a multidisciplinary treatment setting for M1a-Contra tumors.

The Impact of Hospital Safety-Net Burden Status on Patients with HPV-Positive Oropharyngeal Cancer.

OBJECTIVES: The objective of this study was to compare treatment characteristics and outcomes between patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) treated at hospitals of varying safety-net burden status. METHODS: Patients with cT1-4, N0-3, M0 HPV-positive OPSCC who underwent definitive surgery or radiation were included. Patients were grouped based on their treating hospital safety-net burden status, defined as the percentage of uninsured and Medicaid-insured patients with OPSCC treated at the facility and stratified as low burden (LBH: 0-25th percentile), medium burden (MBH: 25th-75th percentile), or high burden (HBH: 75th-100th percentile). The primary outcome was primary treatment with surgery versus radiation, evaluated with multivariable-adjusted logistic regression. Secondary outcomes included TORS versus open surgical approach, and overall survival evaluated with Cox proportional hazards analysis. RESULTS: Of the 19,810 patients with cT1-4, N0-3, M0 HPV-positive OPSCC included in this study, 4921 (24.8%) were treated at LBH, 12,201 (61.6%) were treated at MBH, and 2688 (13.6%) were treated at HBH. In multivariable-adjusted analysis, compared with treatment at LBH, treatment at HBH was associated with more frequent radiation over surgical treatment (OR: 1.26, 95% CI: 1.12-1.40, p < 0.001). For patients undergoing surgery, patients at HBH had less frequent transoral robotic surgery (OR: 0.30, 95% CI 0.24-0.38, p < 0.001) compared with patients treated at LBH. Overall survival of patients treated at HBH was worse than that of patients treated at LBH (HR: 1.27, 95% CI 1.13-1.43, p < 0.001). CONCLUSION: These findings highlight underlying disparities at higher safety-net burden facilities that impact patterns of care and outcomes for patients with OPSCC. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1733-1740, 2024.

Evaluating depth of invasion across oral cavity subsites as part of the AJCC 8th edition T staging criteria for oral cavity squamous cell carcinoma.

BACKGROUND: The prognostic impact of depth of invasion (DOI) in American Joint Committee on Cancer 8th edition TNM staging for oral cavity squamous cell carcinoma (OCSCCa) across oral cavity subsites is unknown. METHODS: Overall survival of patients with pT1-4a OCSCCa in the National Cancer Database (2010-2017), stratified by tumor size and DOI across eight oral cavity subsites, was evaluated using multivariable-adjusted Cox proportional hazards modeling. RESULTS: When stratified by tumor size ≤2 cm and >2 cm, DOI >5 mm and DOI >10 mm were only associated with worse overall survival, respectively, for tumors of the oral tongue (Tumor size ≤2 cm, DOI >5 mm v DOI ≤5 mm: HR: 1.31, 95% CI: 1.12-1.53, p < 0.001; Tumor size >2 cm, DOI >10 mm v DOI ≤10 mm: HR: 1.15, 95% CI: 1.01-1.30, p = 0.03). DOI >5 mm and DOI >10 mm was not prognostic for any other tumor location. CONCLUSIONS: These findings suggest that the current staging schema for DOI in OCSCCa may not be prognostic across all oral cavity subsites.

The impact of undergoing surgical margin evaluation during endoscopic surgery for early-stage laryngeal squamous cell carcinoma.

BACKGROUND: The impact of evaluating versus not evaluating surgical margins for early-stage laryngeal squamous cell carcinoma (LSCC) has not been evaluated. METHODS: Overall survival was compared between patients who underwent endoscopic surgery for cT1-2, N0, M0 LSCC and had surgical margins evaluated versus not evaluated versus unevaluable in the National Cancer Database (2010-2019) using multivariable-adjusted Cox proportional hazards analyses. RESULTS: 7597 patients met study eligibility criteria. 4123 (54.3%) patients underwent margin evaluation, 1631 (21.5%) did not undergo margin evaluation, and 1843 (24.3%) had unevaluable margins. Patients undergoing margin evaluation had better overall survival than patients who did not undergo margin evaluation (HR: 0.88, 95% CI: 0.78-1.00, p = 0.044) and patients with unevaluable margins (HR: 0.88, 95% CI: 0.78-0.98, p = 0.021). Patients undergoing margin evaluation received significantly less adjuvant radiation. CONCLUSIONS: Surgical margin evaluation is an important prognostic factor for patients receiving endoscopic surgery for early-stage LSCC and should be conducted whenever possible.

The Knosp Criteria Revisited: 3-Dimensional Volumetric Analysis as a Predictive Tool for Extent of Resection in Complex Endoscopic Pituitary Surgery.

BACKGROUND: The Knosp criteria have been the historical standard for predicting cavernous sinus invasion, and therefore extent of surgical resection, of pituitary macroadenomas. Few studies have sought to reappraise the utility of this tool after recent advances in visualization and modeling of tumors in complex endoscopic surgery. OBJECTIVE: To evaluate our proposed alternative method, using 3-dimensional (3D) volumetric imaging, and whether it can better predict extent of resection in nonfunctional pituitary adenomas. METHODS: Patients who underwent endoscopic transsphenoidal resection of pituitary macroadenomas at our institution were reviewed. Information was collected on neurological, endocrine, and visual function. Volumetric segmentation was performed using 3D Slicer software. Relationship of tumor volume, clinical features, and Knosp grade on extent of resection was examined. RESULTS: One hundred forty patients were identified who had transsphenoidal resection of nonfunctional pituitary adenomas. Macroadenomas had a median volume of 6 cm 3 (IQR 3.4-8.7), and 17% had a unilateral Knosp grade of at least 3B. On multiple logistic regression, only smaller log-transformed preoperative tumor volume was independently associated with increased odds of gross total resection (GTR; odds ratio: 0.27, 95% CI: 0.07-0.89, P < .05) when controlling for tumor proliferative status, age, and sex (area under the curve 0.67). The Knosp criteria did not independently predict GTR in this cohort ( P > .05, area under the curve 0.46). CONCLUSION: Increasing use of volumetric 3D imaging may better anticipate extent of resection compared with the Knosp grade metric and may have a greater positive predictive value for GTR. More research is needed to validate these findings and implement them using automated methods.

Post-operative vision loss: analysis of 587 patients undergoing endoscopic surgery for pituitary macroadenoma.

PURPOSE: Vision loss following surgery for pituitary adenoma is poorly described in the literature and cannot be reliably predicted with current prognostic models. Detailed characterization of this population is warranted to further understand the factors that predispose a minority of patients to post-operative vision loss. MATERIALS AND METHODS: The medical records of 587 patients who underwent endoscopic transsphenoidal surgery at the Mount Sinai Medical Centre between January 2013 and August 2018 were reviewed. Patients who experienced post-operative vision deterioration, defined by reduced visual acuity, worsened VFDs, or new onset of blurry vision, were identified and analysed. RESULTS: Eleven out of 587 patients who received endoscopic surgery for pituitary adenoma exhibited post-operative vision deterioration. All eleven patients presented with preoperative visual impairment (average duration of 13.1 months) and pre-operative optic chiasm compression. Seven patients experienced visual deterioration within 24 h of surgery. The remaining four patients experienced delayed vision loss within one month of surgery. Six patients had complete blindness in at least one eye, one patient had complete bilateral blindness. Four patients had reduced visual acuity compared with preoperative testing, and four patients reported new-onset blurriness that was not present before surgery. High rates of graft placement (10/11 patients) and opening of the diaphragma sellae (9/11 patients) were found in this series. Four patients had hematomas and four patients had another significant post-operative complication. CONCLUSIONS: While most patients with pituitary adenoma experience favourable ophthalmological outcomes following endoscopic transsphenoidal surgery, a subset of patients exhibit post-operative vision deterioration. The present study reports surgical and disease features of this population to further our understanding of factors that may underlie vision loss following pituitary adenoma surgery. Graft placement and opening of the diaphragma sellae may be important risk factors in vision loss following ETS and should be an area of future investigation.

Reconsidering the American Joint Committee on Cancer Eighth Edition TNM Staging Manual Classifications for T2b and T3 NSCLC.

INTRODUCTION: The American Joint Committee on Cancer (AJCC) eighth edition TNM staging manual for NSCLC, derived from the International Association for the Study of Lung Cancer (IASLC) Staging Project, designates tumors with additional nodule(s) in the same lobe as T3. This study sought to externally validate the results of the IASLC, which showed a trend in improved survival for such tumors, but excluded treatment-based adjustment, by assessing whether these tumors have worse survival than T2b NSCLC. METHODS: Overall survival of patients with T2b-T3, N0-3, M0 NSCLC (satisfying a single T descriptor of tumors >4 cm but ≤5 cm in greatest dimension ["T2b"], tumors >5 cm but ≤7 cm in greatest dimension ["T3-Size"], or tumors with additional nodule(s) in the same lobe ["T3-Add"]), according to the AJCC eighth edition, in the National Cancer Database (2010-2015), was evaluated using multivariable Cox proportional hazards modeling and propensity score matching. RESULTS: 31,563 patients with T2b-T3, N0-3, M0 NSCLC met the study inclusion criteria. In multivariable-adjusted analysis, T3-Add tumors had improved overall survival compared with T3-Size tumors (Hazard Ratio = 0.86, 95% Confidence Interval: 0.82-0.89, p < 0.001) and similar survival compared with T2b tumors (Hazard Ratio = 1.04, 95% Confidence Interval: 0.97-1.12, p = 0.28). A propensity score-matched analysis of 2260 T3-Add and 2,260 T2b patients, well-balanced on 16 common prognostic covariates, including treatment type (surgery, chemotherapy, or radiation), revealed similar 5-year survival (53.4% versus 52.3%, p = 0.30). CONCLUSIONS: In this national analysis, T3-Add tumors had better survival than other T3 tumors and similar survival to T2b tumors. These findings may be taken into consideration for the AJCC ninth edition staging classifications.

E-Cadherin Represses Anchorage-Independent Growth in Sarcomas through Both Signaling and Mechanical Mechanisms.

CDH1 (also known as E-cadherin), an epithelial-specific cell-cell adhesion molecule, plays multiple roles in maintaining adherens junctions, regulating migration and invasion, and mediating intracellular signaling. Downregulation of E-cadherin is a hallmark of epithelial-to-mesenchymal transition (EMT) and correlates with poor prognosis in multiple carcinomas. Conversely, upregulation of E-cadherin is prognostic for improved survival in sarcomas. Yet, despite the prognostic benefit of E-cadherin expression in sarcoma, the mechanistic significance of E-cadherin in sarcomas remains poorly understood. Here, by combining mathematical models with wet-bench experiments, we identify the core regulatory networks mediated by E-cadherin in sarcomas, and decipher their functional consequences. Unlike carcinomas, E-cadherin overexpression in sarcomas does not induce a mesenchymal-to-epithelial transition (MET). However, E-cadherin acts to reduce both anchorage-independent growth and spheroid formation of sarcoma cells. Ectopic E-cadherin expression acts to downregulate phosphorylated CREB1 (p-CREB) and the transcription factor, TBX2, to inhibit anchorage-independent growth. RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on CREB levels and restores sensitivity to anchorage-independent growth in sarcoma cells. Beyond its signaling role, E-cadherin expression in sarcoma cells can also strengthen cell-cell adhesion and restricts spheroid growth through mechanical action. Together, our results demonstrate that E-cadherin inhibits sarcoma aggressiveness by preventing anchorage-independent growth. IMPLICATIONS: We highlight how E-cadherin can restrict aggressive behavior in sarcomas through both biochemical signaling and biomechanical effects.

EMT and MET: necessary or permissive for metastasis?

Epithelial-to-mesenchymal transition (EMT) and its reverse mesenchymal-to-epithelial transition (MET) have been suggested to play crucial roles in metastatic dissemination of carcinomas. These phenotypic transitions between states are not binary. Instead, carcinoma cells often exhibit a spectrum of epithelial/mesenchymal phenotype(s). While epithelial/mesenchymal plasticity has been observed preclinically and clinically, whether any of these phenotypic transitions are indispensable for metastatic outgrowth remains an unanswered question. Here, we focus on epithelial/mesenchymal plasticity in metastatic dissemination and propose alternative mechanisms for successful dissemination and metastases beyond the traditional EMT/MET view. We highlight multiple hypotheses that can help reconcile conflicting observations, and outline the next set of key questions that can offer valuable insights into mechanisms of metastasis in multiple tumor models.

Induction of Mesenchymal-Epithelial Transitions in Sarcoma Cells.

Phenotypic plasticity refers to a phenomenon in which cells transiently gain traits of another lineage. During carcinoma progression, phenotypic plasticity drives invasion, dissemination and metastasis. Indeed, while most of the studies of phenotypic plasticity have been in the context of epithelial-derived carcinomas, it turns out sarcomas, which are mesenchymal in origin, also exhibit phenotypic plasticity, with a subset of sarcomas undergoing a phenomenon that resembles a mesenchymal-epithelial transition (MET). Here, we developed a method comprising the miR-200 family and grainyhead-like 2 (GRHL2) to mimic this MET-like phenomenon observed in sarcoma patient samples.We sequentially express GRHL2 and the miR-200 family using cell transduction and transfection, respectively, to better understand the molecular underpinnings of these phenotypic transitions in sarcoma cells. Sarcoma cells expressing miR-200s and GRHL2 demonstrated enhanced epithelial characteristics in cell morphology and alteration of epithelial and mesenchymal biomarkers. Future studies using these methods can be used to better understand the phenotypic consequences of MET-like processes on sarcoma cells, such as migration, invasion, metastatic propensity, and therapy resistance.

Mesenchymal-Epithelial Transition in Sarcomas Is Controlled by the Combinatorial Expression of MicroRNA 200s and GRHL2.

Phenotypic plasticity involves a process in which cells transiently acquire phenotypic traits of another lineage. Two commonly studied types of phenotypic plasticity are epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). In carcinomas, EMT drives invasion and metastatic dissemination, while MET is proposed to play a role in metastatic colonization. Phenotypic plasticity in sarcomas is not well studied; however, there is evidence that a subset of sarcomas undergo an MET-like phenomenon. While the exact mechanisms by which these transitions occur remain largely unknown, it is likely that some of the same master regulators that drive EMT and MET in carcinomas also act in sarcomas. In this study, we combined mathematical models with bench experiments to identify a core regulatory circuit that controls MET in sarcomas. This circuit comprises the microRNA 200 (miR-200) family, ZEB1, and GRHL2. Interestingly, combined expression of miR-200s and GRHL2 further upregulates epithelial genes to induce MET. This effect is phenocopied by downregulation of either ZEB1 or the ZEB1 cofactor, BRG1. In addition, an MET gene expression signature is prognostic for improved overall survival in sarcoma patients. Together, our results suggest that a miR-200, ZEB1, GRHL2 gene regulatory network may drive sarcoma cells to a more epithelial-like state and that this likely has prognostic relevance.