Toward a more patient-specific model of post-radiotherapy saliva secretion for head and neck cancer patients.

BACKGROUND: Reduction of saliva secretion is a common side effect following radiotherapy (RT) for cancer of the head and neck region. The aim of this study is to predict the post-RT salivary function for individual patients prior to treatment and to recognise possible differences in individual radiosensitivity. MATERIAL AND METHODS: A predictive model for post-RT salivary function was validated for 64 head and neck cancer patients. The input parameters for the model were salivary excretion fraction (sEF) measured by 99mTc-pertechnetate scintigraphy, total stimulated salivary flow and mean absorbed dose for the major salivary glands. SEF values after RT relative to the baseline before RT (rEF) were compared among the patients using the distance ΔrEF between single gland rEF and the corresponding expected value at the dose response curve. RESULTS: A significant correlation (R = 0.86, p = 0.018) was found between the modelled and the measured values of stimulated salivary flow six months after RT. The average prediction error for the saliva flow rate was 6 ml/15 min. A linear relationship between ΔrEF for the left and the right parotid glands was observed both six (R = 0.53) and 12 (R = 0.79) months after RT. The average of absolute values of ΔrEF was 0.20 for parotid glands and 0.22 for submandibular glands. CONCLUSIONS: The salivary flow model was validated for 64 patients. The results imply, that one explanation for the discrepancies between the predicted and the measured salivary flow rate values and the common variations found in ΔrEF for the parotid glands may be differences in patients' individual response to radiation. However, quantitative extraction of individual radiosensitivity would require further studies in order to take it into account in predictive models.

Adenovirus Encoding Tumor Necrosis Factor Alpha and Interleukin 2 Induces a Tertiary Lymphoid Structure Signature in Immune Checkpoint Inhibitor Refractory Head and Neck Cancer.

Immune checkpoint inhibitors (ICI) have provided significant improvement in clinical outcomes for some patients with solid tumors. However, for patients with head and neck cancer, the response rate to ICI monotherapy remains low, leading to the exploration of combinatorial treatment strategies. In this preclinical study, we use an oncolytic adenovirus (Ad5/3) encoding hTNFα and hIL-2 and non-replicate adenoviruses (Ad5) encoding mTNFα and mIL-2 with ICI to achieve superior tumor growth control and improved survival outcomes. The in vitro effect of Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 was characterized through analyses of virus replication, transgene expression and lytic activity using head and neck cancer patient derived cell lines. Mouse models of ICI naïve and refractory oral cavity squamous cell carcinoma were established to evaluate the local and systemic anti-tumor immune response upon ICI treatment with or without the non-replicative adenovirus encoding mTNFα and mIL-2. We delineated the mechanism of action by measuring the metabolic activity and effector function of CD3+ tumor infiltrating lymphocytes (TIL) and transcriptomic profile of the CD45+ tumor immune compartment. Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 demonstrated robust replicative capability in vitro across all head and neck cell lines screened through potent lytic activity, E1a and transgene expression. In vivo, in both ICI naïve and refractory models, we observed improvement to tumor growth control and long-term survival when combining anti-PD-1 or anti-PD-L1 with the non-replicative adenovirus encoding mTNFα and mIL-2 compared to monotherapies. This observation was verified by striking CD3+ TIL derived mGranzyme b and interferon gamma production complemented by increased T cell bioenergetics. Notably, interrogation of the tumor immune transcriptome revealed the upregulation of a gene signature distinctive of tertiary lymphoid structure formation upon treatment of murine anti-PD-L1 refractory tumors with non-replicative adenovirus encoding mTNFα and mIL-2. In addition, we detected an increase in anti-tumor antibody production and expansion of the memory T cell compartment in the secondary lymphoid organs. In summary, a non-replicative adenovirus encoding mTNFα and mIL-2 potentiates ICI therapy, demonstrated by improved tumor growth control and survival in head and neck tumor-bearing mice. Moreover, the data reveals a potential approach for inducing tertiary lymphoid structure formation. Altogether our results support the clinical potential of combining this adenovirotherapy with anti-PD-1 or anti-PD-L1.

Prognostic Value of Apparent Diffusion Coefficient in Oropharyngeal Carcinoma.

PURPOSE: To investigate clinical and radiological factors predicting worse outcome after (chemo)radiotherapy ([C]RT) in oropharyngeal squamous cell carcinoma (OPSCC) with a focus on apparent diffusion coefficient (ADC). METHODS: This retrospective study included 67 OPSCC patients, treated with (C)RT with curative intent and diagnosed during 2013-2017. Human papilloma virus (HPV) association was detected with p16 immunohistochemistry. Of all 67 tumors, 55 were p16 positive, 9 were p16 negative, and in 3 the p16 status was unknown. Median follow-up time was 38 months. We analyzed pretreatment magnetic resonance imaging (MRI) for factors predicting disease-free survival (DFS) and locoregional recurrence (LRR), including primary tumor volume and the largest metastasis. Crude and p16-adjusted hazard ratios were analyzed using Cox proportional hazards model. Interobserver agreement was evaluated. RESULTS: Disease recurred in 13 (19.4%) patients. High ADC predicted poor DFS, but not when the analysis was adjusted for p16. A break in RT (hazard ratio, HR = 3.972, 95% confidence interval, CI 1.445-10.917, p = 0.007) and larger metastasis volume (HR = 1.041, 95% CI 1.007-1.077, p = 0.019) were associated with worse DFS. A primary tumor larger than 7 cm3 was associated with increased LRR rate (HR = 4.861, 1.042-22.667, p = 0.044). Among p16-positive tumors, mean ADC was lower in grade 3 tumors compared to lower grade tumors (0.736 vs. 0.883; p = 0.003). CONCLUSION: Low tumor ADC seems to be related to p16 positivity and therefore should not be used independently to evaluate disease prognosis or to choose patients for treatment deintensification.

Diffusion-weighted magnetic resonance imaging for evaluation of salivary gland function in head and neck cancer patients treated with intensity-modulated radiotherapy.

BACKGROUND AND PURPOSES: Permanent xerostomia as a result of radiation-induced salivary gland damage remains a common side effect of radiotherapy (RT) of the head and neck. The purpose of this study was to evaluate the usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI) in assessing the post-RT salivary gland function in patients with head and neck cancer (HNC). MATERIALS AND METHODS: In this prospective study, 20 HNC patients scheduled for bilateral neck chemoradiotherapy (CRT) with weekly cisplatin went through diffusion-weighted magnetic resonance imaging (DW-MRI) and salivary gland scintigraphy (SGS) prior to and at a mean of six months after completing the treatment. The changes in apparent diffusion coefficient (ADC) before and after treatment were compared with ejection fraction (EF) measured with SGS and the radiation dose absorbed by the salivary glands. RESULTS: As a result of gustatory stimulation with ascorbic acid, the ADC showed a biphasic response with an initial increase and subsequent decrease. This pattern was seen both before and after RT. Post-RT ADC increased as a function of RT dose absorbed by the salivary glands. A moderate statistical correlation between pre- and post-RT ADCs at rest and EF measured with SGS was found. CONCLUSIONS: DW-MRI seems a promising tool for detection of physiological and functional changes in major salivary glands after RT.

Rapidly growing and ulcerating metastatic renal cell carcinoma of the lower lip: A case report and review of the literature.

Renal cell carcinomas (RCCs) have a tendency to metastasize at an early stage, therefore, the patients frequently exhibit metastatic disease at the time of diagnosis. Common locations for the metastases are adjacent organs and abdominal lymph nodes; however, occasionally metastasis to the peripheral organs may be the initial clinical symptom. The 71-year-old male patient in the current case suffered from radioresistant and aggressively behaving RCC metastasis in the mandible and lower lip, which was successfully managed by surgical resection. RCC metastasis to the facial area is considered to be uncommon based on a review of the existing literature. RCC are somewhat radioresistant and therefore, palliative surgery must be considered when treating patients with this metastatic disease.

Patterns of relapse following definitive treatment of head and neck squamous cell cancer by intensity modulated radiotherapy and weekly cisplatin.

Eighty-three patients with oropharyngeal, hypopharyngeal or laryngeal cancer were treated with concomitant cisplatin 40 mg/m(2) once a week during the radiotherapy and IMRT up to a total dose of 70 Gy. The 2-year rate of local control, overall survival and disease specific survival were 84%, 82% and 89%, respectively. The corresponding 5-year Kaplan-Meier estimates were 79%, 69% and 76%.