Purpose Human papilloma virus (HPV), HPV-16, is one of the most important prognostic factors for patients with head and neck squamous cell carcinomas (HNSCCs). HPV-positive HNSCCs have a favorable response to radiation therapy (RT) and superior overall survival (OS) compared to HPV-negative HNSCCs. However, an explanation for the mechanisms responsible for the inherent radiosensitivity of HPV-positive HNSCC remains elusive. Methods and Materials Records of a cohort of 162 HNSCC patients were reviewed and their outcomes were correlated with their HPV status. Using a panel of HPV-positive and HPV-negative HNSCC cell lines expressing a reporter for cancer stem cells (CSCs) we characterized HPV-positive and HPV-negative lines via flow cytometry, sphereforming capacity assays in vitro, and limiting dilution assays in vivo. Non-CSCs were treated with different doses of radiation and the dedifferentiation of non-CSCs into CSCs was investigated via flow cytometry and qRT-PCR for re-expression of reprogramming factors. Results Patients with HPV-positive tumors have superior OS and local-regional control. HPV-positive HNSCC cell lines have lower numbers of CSCs, which inversely correlates with radiosensitivity. HPV-negative HNSCC cell lines lack hierarchy due to enhanced spontaneous dedifferentiation. Non-CSCs from HPV-negative lines show enhanced radiation-induced dedifferentiation compared to HPV-positive lines, and RT induced re-expression of Yamanaka reprogramming factors. Conclusions Supporting the favorable prognosis of HPV-positive HNSCCs, we show that HPV-positive HNSCCs have (1) a lower frequency of CSCs, (2) RT can dedifferentiate HNSCC cells into CSCs, and (3) radiation-induced dedifferentiation depends on the HPV status of the tumor.

Background Individuals of advanced age with comorbidities face a higher risk of death from coronavirus disease 2019 (COVID‐19), especially once they are ventilator‐dependent. Respiratory decline in patients with COVID‐19 is precipitated by a lung‐mediated aberrant immune cytokine storm. Low‐dose lung radiation was used to treat pneumonia in the pre‐antibiotic era. Radiation immunomodulatory effects may improve outcomes for select patients with COVID‐19. Methods A single‐institution trial evaluating the safety and efficacy of single‐fraction, low‐dose whole‐lung radiation for patients with COVID‐19 pneumonia is being performed for the first time. This report describes outcomes of a planned day 7 interim analysis. Eligible patients were hospitalized, had radiographic consolidation, required supplemental oxygen, and were clinically deteriorating. Results Of 9 patients screened, 5 were treated with whole‐lung radiation on April 24 until April 28 2020, and they were followed for a minimum of 7 days. The median age was 90 years (range, 64‐94 years), and 4 were nursing home residents with multiple comorbidities. Within 24 hours of radiation, 3 patients (60%) were weaned from supplemental oxygen to ambient air, 4 (80%) exhibited radiographic improvement, and the median Glasgow Coma Scale score improved from 10 to 14. A fourth patient (80% overall recovery) was weaned from oxygen at hour 96. The mean time to clinical recovery was 35 hours. There were no acute toxicities. Conclusions In a pilot trial of 5 oxygen‐dependent elderly patients with COVID‐19 pneumonia, low‐dose whole‐lung radiation led to rapid improvements in clinical status, encephalopathy, and radiographic consolidation without acute toxicity. Low‐dose whole‐lung radiation appears to be safe, shows early promise of efficacy, and warrants further study. Lay Summary Researchers at Emory University report preliminary safety outcomes for patients treated with low‐dose lung irradiation for coronavirus disease 2019 (COVID‐19) pneumonia. Five residents of nursing or group homes were hospitalized after testing positive for COVID‐19. Each had pneumonia visible on a chest x‐ray, required supplemental oxygen, and experienced a clinical decline in mental status or in work of breathing or a prolonged or escalating supplemental oxygen requirement. A single treatment of low‐dose (1.5‐Gy) radiation to both lungs was delivered over the course of 10 to 15 minutes. There was no acute toxicity attributable to radiation therapy. Within 24 hours, 4 patients had rapidly improved breathing, and they recovered to room air at an average of 1.5 days (range, 3‐96 hours). Three were discharged at a mean time of 12 days, and 1 was preparing for discharge. Blood tests and repeat imaging confirm that low‐dose whole‐lung radiation treatment appears safe for COVID‐19 pneumonia. Further trials are warranted.

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IMPORTANCE Survival of patients with head and neck cancer can be affected by competing causes of mortality, as well as comorbidities that result in radiation treatment interruptions. OBJECTIVE To discern how differences in preexisting medical and psychosocial comorbidities potentially influence adherence to radiation therapy according to human papillomavirus (HPV) status. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis at a comprehensive cancer center of 162 consecutive patients with locally advanced squamous cell carcinoma of the oropharynx treated with primary chemoradiation (n = 95) or primary surgery followed by adjuvant radiation (n = 67). Immunostaining for p16 was used to determine HPV status. MAIN OUTCOMES AND MEASURES Difference in alcohol, tobacco, and marijuana use was compared between patients with HPV-positive and HPV-negative tumors, as well as the prevalence of the following comorbidities: diabetes mellitus, chronic obstructive pulmonary disease (COPD), anxiety disorder, and major depression. The number of total missed treatment days was analyzed as both a continuous and categorical variable. RESULTS Rates of self-reported heavy alcohol use (47% vs 16%; P = .02) and any marijuana use (47% vs 23%; P = .003) were significantly higher among HPV-negative patients. Fifty-four percent of HPV-positive patients self-identified as never smokers, compared with only 12% of HPV-negative patients (P < .001). HPV-negative patients had more missed treatment days (mean, 2.8 vs 1.7 days; P = .02), as well as an increased rate of at least 5 missed days (24% vs 10%; P = .04), and higher prevalences of COPD (12% vs 7%; P = .37) and anxiety disorder (12% vs 6%; P = .35). CONCLUSIONS AND RELEVANCE Pronounced differences exist in lifestyle habits between patients with HPV-negative and HPV-positive oropharyngeal cancer at diagnosis. These differences, as well as those of medical and psychosocial burden, may contribute to observed discrepancies in treatment adherence and need to be considered in outcomes reporting and clinical trial design.

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