Salivary gland cancer organoids are valid for preclinical genotype-oriented medical precision trials.

Salivary gland cancers (SGCs) are heterogeneous tumors, and precision oncology represents a promising therapeutic approach; however, its impact on SGCs remains obscure. This study aimed to establish a translational model for testing molecular-targeted therapies by combining patient-derived organoids and genomic analyses of SGCs. We enrolled 29 patients, including 24 with SGCs and 5 with benign tumors. Resected tumors were subjected to organoid and monolayer cultures, as well as whole-exome sequencing. Organoid and monolayer cultures of SGCs were successfully established in 70.8% and 62.5% of cases, respectively. Organoids retained most histopathological and genetic profiles of their original tumors. In contrast, 40% of the monolayer-cultured cells did not harbor somatic mutations of their original tumors. The efficacy of molecular-targeted drugs tested on organoids depended on their oncogenic features. Organoids recapitulated the primary tumors and were useful for testing genotype-oriented molecular targeted therapy, which is valuable for precision medicine in patients with SGCs.

Nrf2 protects against radiation-induced oral mucositis via antioxidation and keratin layer thickening.

Radiation-induced oral mucositis is one of the most common adverse events in radiation therapy for head and neck cancers, but treatments for oral mucositis are limited to palliative and supportive care. New approaches are required to prevent radiation-induced mucositis and to improve treatments. The Keap1-Nrf2 system regulates cytoprotection against oxidative and electrophilic stresses. Nrf2 also regulates keratin layer thickness in mouse tongues. Therefore, we hypothesized that Nrf2 may protect the tongue epithelium against radiation-induced mucositis via elimination of reactive oxygen species and induction of keratin layer thickening. To test this hypothesis, we prepared a system for γ-ray exposure of restricted areas and irradiated the tongues of model mice with Nrf2 and Keap1 loss-of-function. We discovered that loss of Nrf2 expression indeed sensitized the tongue epithelium to radiation-induced ulcer formation with inflammation. Constitutive Nrf2 activation by genetic Keap1 knockdown alleviated radiation-induced DNA damage by increasing antioxidation. In agreement with the genetic Nrf2 activation model, the Nrf2 inducer CDDO-Im prevented irradiation damage to the tongue epithelium. These results demonstrate that Nrf2 activation has the potential to prevent the development of radiation-induced mucositis and that Nrf2 inducers are an important therapeutic drug for protection of the upper aerodigestive tract from radiation-induced mucositis.

Eustachian Tube Functions in Concurrent Chemoradiotherapy for Head and Neck Cancer Patients.

Ototoxicity is a dose-limiting adverse event for concurrent chemoradiotherapy (CCRT) with high-dose cisplatin for locally advanced head and neck squamous cell carcinoma (HNSCC). Both irradiation to the Eustachian tube (ET) and weight loss are risk factors for patulous ET. The aim of this prospective, observational study was to elucidate the incidences of patulous ET conditions before and after CCRT in HNSCC patients by means of ET function tests. This prospective, observational study was conducted in 27 HNSCC patients who received CCRT with high-dose cisplatin, and ET function tests (sonotubometry and tubo-tympano-aerodynamic graphy) were performed before and 3 months after CCRT. Factors potentially affecting the incidence of patulous ET conditions after CCRT were evaluated. Of the 54 ears from 27 patients investigated, patulous ET conditions were observed in 12 ears (22.2%) from 9 patients (33.3%) before CCRT and 15 ears (27.8%) from 11 patients (40.7%) at 3 months after CCRT. Only patulous ET conditions before CCRT in each ear were significantly associated with patulous ET conditions after CCRT (p = 0.010). This is the first report to describe the incidences of patulous ET conditions before and after CCRT in HNSCC patients. HNSCC patients are potentially at higher risk of patulous ET.

Serum selenium predicts achievement of full-dose cisplatin in concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma: A prospective, observational study.

OBJECTIVE: Concurrent chemoradiotherapy (CCRT) with three-weekly high-dose cisplatin (100 mg/m2) is a standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC), but compliance with cisplatin is often poor due to various adverse events. The aim of this prospective, observational study was to determine the predictors of achievement of full-dose cisplatin. METHODS: A prospective, observational study was conducted involving 60 patients who received CCRT with three-weekly high-dose cisplatin (100 mg/m2) for locally advanced HNSCC. Possible predictors affecting compliance with cisplatin were subjected to univariate and multivariate logistic regression analyses. Age, sex, primary site, clinical stage, treatment intent, history of hypertension, diabetes mellitus, smoking and drinking habits, body mass index, creatinine clearance, serum albumin, controlling nutrition status, trace elements (Fe, Zn, Cu, Se), acute kidney injury, white blood cell count decrease, neutrophilia, and weight loss were the variables evaluated. RESULTS: Twenty-seven patients achieved full-dose cisplatin (300 mg/m2), and the other 33 patients did not. Multivariate logistic regression analysis showed that both mild renal dysfunction and selenium deficiency before treatment independently had negative impacts on achievement of full-dose cisplatin. CONCLUSIONS: As well as renal function, selenium deficiency is a potential therapeutic target for CCRT with high-dose cisplatin in HNSCC patients.

Clinical utility of apparent diffusion coefficient and diffusion-weighted magnetic resonance imaging for resectability assessment of head and neck tumors with skull base invasion.

BACKGROUND: The usefulness of apparent diffusion coefficient (ADC) and diffusion-weighted magnetic resonance imaging (DWI) in the detection of malignant tumors has been reported. The purpose of this study is to clarify the role of ADC and DWI for diagnosis of skull base tumors. METHODS: A total of 27 patients with head and neck tumors with skull base invasions undergoing skull base surgery were enrolled in this study. Pathological findings of dural invasion and bone invasion were compared with the diagnostic imaging. RESULTS: Advanced magnetic resonance imaging techniques revealed that ADC values in regions of pathological bone and dural invasions were significantly lower than in regions of no invasion. The area under the curve of ADC in bone invasions and dural invasions were 0.957 and 0.894, respectively. CONCLUSIONS: Our findings indicate that ADC and DWI are useful tools for the diagnosis of head and neck tumors with skull base invasion.

Management of adenoid cystic carcinoma of the head and neck: a single-institute study with over 25-year follow-up.

BACKGROUND: Adenoid cystic carcinoma is a rare malignant tumor arising from exocrine glands such as the major and minor salivary glands of the paranasal sinuses or the external auditory canal. Although multiple retrospective clinical studies of ACC have been reported to date, clinical questions, such as 1) long-term prognosis beyond 20 years, 2) usefulness and suitability for treatment of therapeutic interventions, 3) therapeutic goal to aim for, and 4) prognosis by recurrence sites, are still unclear. METHODS: To improve understanding and management of adenoid cystic carcinoma of the head and neck (ACC), a retrospective study with 58 new ACC cases between 1991 and 2016 was performed. The median observation period was 66.8 months (range 3-316 months). The overall clinical stages were as follows: I, 6.9%; II, 25.9%; III, 19.0%; and IV, 48.2%. Histology was cribriform/tubular type (C-T type) in 62.0% and solid type in 27.5%. The main treatment strategy was definitive surgery, which was performed in 75.2% of cases. RESULTS: Overall 10-year, 20-year, and 25-year survivals were 63.7, 27.3, and 20.0%, respectively. Similarly, disease-specific survival (DSSs) was 65.7, 51.2, and 38.4%, respectively, and disease-free survival was 25.2, 9.4, and 9.4%, respectively. Conducting surgery (HR: 0.19, 95% CI: 0.06-0.61, p = 0.005) and C-T type (HR: 0.32, 95% CI: 0.11-0.93, p = 0.036) were independent prognostic predictors of DSS. DSS was significantly prolonged after salvage surgery for both locoregional recurrence (p = 0.004) and lung metastatic recurrence (p = 0.012, vs best supportive care). CONCLUSIONS: In ACC cases, both initial surgical treatment and repetitive surgical resection of resectable recurrent lesions, including both locoregional and lung metastases, resulted in longer survival. The major goal of treatment for ACC may be long-term survival including cancer-bearing survival, resulting in either natural death or intercurrent-disease death, since judging cure of ACC is almost impossible. TRIAL REGISTRATION: Retrospectively registered.

Retrospective observational study of occult cervical lymph-node metastasis in T1N0 tongue cancer.

Objective: Delayed neck metastasis is the most significant prognostic factor for early tongue cancer. The main strategies for controlling cervical lymph nodes in Japan are elective neck dissection or watchful waiting. Elective neck dissection offers significantly better survival, but adversely impacts patient quality of life; consequently, here we investigated how to identify high-risk patients warranting elective neck dissection. Methods: We retrospectively evaluated 67 patients with T1N0 oral tongue squamous cell carcinoma who underwent primary treatment in our department from April 2001 to March 2015. All the patients underwent watchful waiting alone for neck management. We investigated the rates of occult neck metastasis, prognosis and circumstances of recurrence, and associations with pathological tumor thickness, depth and muscle invasion by the primary tumor. Correlation between the thickness in pathological specimens and that at magnetic resonance imaging was additionally investigated. Results: Neck recurrence was evident in 20 patients, of which 19 developed within 1 year. Therefore, the rate of occult neck metastasis was 29.9%. Patients with muscle invasion, tumor thickness ≥2 mm or tumor depth ≥2 mm on surgical specimens were significantly more likely to develop delayed neck metastasis. Prognosis was significantly worse for patients with muscle invasion or tumor thickness ≥2 mm. Thickness using magnetic resonance imaging was well correlated with pathological thickness. Conclusions: Patients with tumors ≥2 mm in thickness or muscle invasion developed neck metastasis, suggesting that elective neck dissection may be warranted for patients with these findings. For preoperative assessment of the need for elective neck dissection, magnetic resonance imaging would be a potential modality for T1N0 tongue cancer.