Sponge-supported cultures of primary head and neck tumors for an optimized preclinical model.

Treatment of advanced head and neck cancer is associated with low survival, high toxicity and a widely divergent individual response. The sponge-gel-supported histoculture model was previously developed to serve as a preclinical model for predicting individual treatment responses. We aimed to optimize the sponge-gel-supported histoculture model and provide more insight in cell specific behaviour by evaluating the tumor and its microenvironment using immunohistochemistry. We collected fresh tumor biopsies from 72 untreated patients and cultured them for 7 days. Biopsies from 57 patients (79%) were successfully cultured and 1451 tumor fragments (95.4%) were evaluated. Fragments were scored for percentage of tumor, tumor viability and proliferation, EGF-receptor expression and presence of T-cells and macrophages. Median tumor percentage increased from 53% at day 0 to 80% at day 7. Viability and proliferation decreased after 7 days, from 90% to 30% and from 30% to 10%, respectively. Addition of EGF, folic acid and hydrocortisone can lead to improved viability and proliferation, however this was not systematically observed. No patient subgroup could be identified with higher culture success rates. Immune cells were still present at day 7, illustrating that the tumor microenvironment is sustained. EGF supplementation did not increase viability and proliferation in patients overexpressing EGF-Receptor.

Identification of a novel ATM inhibitor with cancer cell specific radiosensitization activity.

Treatment of advanced head and neck squamous cell carcinoma (HNSCC) is plagued by low survival and high recurrence rates, despite multimodal therapies. Presently, cisplatin or cetuximab is used in combination with radiotherapy which has resulted in minor survival benefits but increased severe toxicities relative to RT alone. This underscores the urgent need for improved tumor-specific radiosensitizers for better control with lower toxicities. In a small molecule screen targeting kinases, performed on three HNSCC cell lines, we identified GSK635416A as a novel radiosensitizer. The extent of radiosensitization by GSK635416A outperformed the radiosensitization observed with cisplatin and cetuximab in our models, while exhibiting virtually no cytotoxicity in the absence of radiation and in normal fibroblast cells. Radiation induced phosphorylation of ATM was inhibited by GSK635416A. GSK63541A increased DNA double strand breaks after radiation and GSK63541A mediated radiosensitization was lacking in ATM-mutated cells thereby further supporting the ATM inhibiting properties of GSK63541A. As a novel ATM inhibitor with highly selective radiosensitizing activity, GSK635416A holds promise as a lead in the development of drugs active in potentiating radiotherapy for HNSCC and other cancer types.

Feasibility of Primary Tumor Culture Models and Preclinical Prediction Assays for Head and Neck Cancer: A Narrative Review.

Primary human tumor culture models allow for individualized drug sensitivity testing and are therefore a promising technique to achieve personalized treatment for cancer patients. This would especially be of interest for patients with advanced stage head and neck cancer. They are extensively treated with surgery, usually in combination with high-dose cisplatin chemoradiation. However, adding cisplatin to radiotherapy is associated with an increase in severe acute toxicity, while conferring only a minor overall survival benefit. Hence, there is a strong need for a preclinical model to identify patients that will respond to the intended treatment regimen and to test novel drugs. One of such models is the technique of culturing primary human tumor tissue. This review discusses the feasibility and success rate of existing primary head and neck tumor culturing techniques and their corresponding chemo- and radiosensitivity assays. A comprehensive literature search was performed and success factors for culturing in vitro are debated, together with the actual value of these models as preclinical prediction assay for individual patients. With this review, we aim to fill a gap in the understanding of primary culture models from head and neck tumors, with potential importance for other tumor types as well.

Volume changes after stereotactic LINAC radiotherapy in vestibular schwannoma: control rate and growth patterns.

PURPOSE: The purpose of this study was to evaluate the control rate of vestibular schwannomas (VS) after treatment with linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) or radiotherapy (SRT) by using a validated volumetric measuring tool. Volume-based studies on prognosis after LINAC-based SRS or SRT for VS are reported scarcely. In addition, growth patterns and risk factors predicting treatment failure were analyzed. MATERIALS AND METHODS: Retrospectively, 37 VS patients treated with LINAC based SRS or SRT were analyzed. Baseline and follow-up magnetic resonance imaging scans were analyzed with volume measurements on contrast enhanced T1-weighted magnetic resonance imaging. Absence of intervention after radiotherapy was defined as "no additional intervention group, " absence of radiological growth was defined as "radiological control group. " Significant growth was defined as a volume change of 19.7% or more, as calculated in a previous study. RESULTS: The cumulative 4-year probability of no additional intervention was 96.4% ± 0.03; the 4-year radiological control probability was 85.4% ± 0.1). The median follow-up was 40 months. Overall, shrinkage was seen in 65%, stable VS in 22%, and growth in 13%. In 54% of all patients, transient swelling was observed. No prognostic factors were found regarding VS growth. Previous treatment and SRS were associated with transient swelling significantly. CONCLUSIONS: Good control rates are reported for LINAC based SRS or SRT in VS, in which the lower rate of radiological growth control is attributed to the use of the more sensitive volume measurements. Transient swelling after radiosurgery is a common phenomenon and should not be mistaken for treatment failure. Previous treatment and SRS were significantly associated with transient swelling.

Predictors of volumetric growth and auditory deterioration in vestibular schwannomas followed in a wait and scan policy.

OBJECTIVE: The purpose of this study was to identify factors predicting growth and audiologic deterioration during follow-up (FU) in a wait and scan (W&S) policy of vestibular schwannomas (VSs) using a novel volumetric measuring tool. So far, only consecutive magnetic resonance imaging (MRI) is able to show growth objectively, and growth, combined with hearing function, generally dictates further intervention. Other factors predicting growth or hearing deterioration would be invaluable and might ease clinical decision making. STUDY DESIGN: Retrospective case study. SETTING: Tertiary referral center. PATIENTS: Sixty-three patients diagnosed with VS at Maastricht University Medical Center between 2003 and 2008, with FU data available from 36 patients. INTERVENTION(S): A W&S policy for unilateral VS with sequential contrast-enhanced T1- and T2-weighted MRI and audiograms during FU. MAIN OUTCOME MEASURE(S): 1. Patient and radiologic VS features potentially related to growth and auditory function during a W&S policy. 2. The correlation between increase in VS volume and audiologic deterioration during FU. RESULTS: Labyrinthine hypointensity on T2-weighted magnetic resonance images and complaints of hearing loss at presentation are predictive of a faster deterioration of hearing (p < 0.05). Growth during the first FU year predicts further growth. Vestibular schwannoma volume does not correlate with audiologic deterioration significantly. CONCLUSION: Hypointensity on T2-weighted image of the affected labyrinth will result in a significant faster deterioration of hearing. Hearing loss was more profound, and hearing will deteriorate significantly faster in patients presenting with complaints of hearing loss. Significant growth during the first year of FU predicts further growth during FU. Sequential MRI cannot be substituted by audiologic examinations solely because increase in VS volume does not correlate with audiologic deterioration significantly.

Management of large vestibular schwannoma. Part II. Primary Gamma Knife surgery: radiological and clinical aspects.

OBJECT: In large vestibular schwannomas (VSs), microsurgery is the main treatment option. A wait-and-scan policy or radiosurgery are generally not recommended given concerns of further lesion growth or increased mass effect due to transient swelling. Note, however, that some patients do not present with symptomatic mass effect or may still have serviceable hearing. Moreover, others may be old, suffer from severe comorbidity, or refuse any surgery. In this study the authors report the results in patients with large, growing VSs primarily treated with Gamma Knife surgery (GKS), with special attention to volumetric growth, control rate, and symptoms. METHODS: The authors retrospectively analyzed 33 consecutive patients who underwent GKS for large, growing VSs, which were defined as > 6 cm(3) and at least indenting the brainstem. Patients with neurofibromatosis Type 2 were excluded from analysis, as were patients who had undergone previous treatment. Volume measurements were performed on contrast-enhanced T1-weighted MR images at the time of GKS and during follow-up. Medical charts were analyzed for clinical symptoms. RESULTS: Radiological growth control was achieved in 88% of cases, clinical control (that is, no need for further treatment) in 79% of cases. The median follow-up was 30 months, and the mean VS volume was 8.8 cm(3) (range 6.1-17.7 cm(3)). No major complications occurred, although ventriculoperitoneal shunts were placed in 2 patients. The preservation of serviceable hearing and facial and trigeminal nerve function was achieved in 58%, 91%, and 86% of patients, respectively, with any facial and trigeminal neuropathy being transient. In 92% of the patients presenting with trigeminal hypesthesia before GKS, the condition resolved during follow-up. No patient- or VS-related feature was correlated with growth. CONCLUSIONS: Primary GKS for large VSs leads to acceptable radiological growth rates and clinical control rates, with the chance of hearing preservation. Although a higher incidence of clinical control failure and postradiosurgical morbidity is noted, as compared with that for smaller VSs, primary radiosurgery is suitable for a selected group of patients. The absence of symptomatology due to mass effect on the brainstem or cerebellum is essential, as are close clinical and radiological follow-ups, because there is little reserve for growth or swelling.