Prognostic Role of Circulating Tumor Cells during Induction Chemotherapy Followed by Curative Surgery Combined with Postoperative Radiotherapy in Patients with Locally Advanced Oral and Oropharyngeal Squamous Cell Cancer.

BACKGROUND: The prognostic role of circulating tumor cells (CTCs) after induction chemotherapy using docetaxel, cisplatin and fluorouracil (TPF) prior to surgery and adjuvant (chemo)radiation in locally advanced oral squamous cell cancer (OSCC) was evaluated. METHODS: In this prospective study, peripheral blood samples from 40 patients of the phase II study TISOC-1 (NCT01108042) with OSCC before, during, and after treatment were taken. CTCs were quantified using laser scanning cytometry of anti- epithelial cell adhesion molecule-stained epithelial cells. Their detection was correlated with clinical risk factors, recurrence-free (RFS) and overall survival (OS). RESULTS: Before starting the treatment CTCs were detected in 32 of 40 patients (80%). The median number at baseline was 3295 CTCs/ml. The median maximal number of CTCs during treatment was 5005 CTCs/ml. There was a significant increase of CTCs before postoperative radiotherapy compared to baseline before 1st cycle of IC (p = 0.011), 2nd cycle of IC (p = 0.001), 3rd cycle of IC (p = 0.004), and before surgery (p = 0.002), but not compared to end of therapy (p = 0.118). CTCs at baseline >median was also associated to risk of recurrence (p = 0.014). Maximal CTCs during therapy >median was more frequently observed in tumors of the oral cavity (p=0.022) and related to higher risk of death during follow-up (p = 0.028). Patients with CTCs at baseline >median value had significant lower RFS than patients with CTCs at baseline median during the complete course of therapy had a significantly lower OS than patients with values

Altered autonomic regulation as a cardiovascular risk marker for patients with sudden sensorineural hearing loss.

OBJECTIVES: To measure autonomic nervous system function after idiopathic sudden sensorineural hearing loss (ISSHL). STUDY DESIGN: Diagnostic prospective cohort single-center study. SETTING: Tertiary referral university hospital. PATIENTS: Twenty-three adult patients with ISSHL and 10 normal-hearing control patients without ISSHL (CON) matched with respect to age, sex, hypertension, and medication. MAIN OUTCOME MEASURES: Bivariate analysis of autonomic regulation (ISSHL versus CON) using 30-minute heart rate (HR) and systolic and diastolic blood pressure (BP) time series at baseline, based on cardiovascular coupling, HR and BP regulatory patterns, high-resolution coupling analysis based on joint symbolic dynamics (High-Resolution Joint Symbolic Dynamics). INTERVENTION: No intervention. RESULTS: Multivariate discrimination between ISSHL and CON achieved values of area under the receiver operator characteristic curve = 95.5, sensitivity = 90.9%, and specificity = 88.9%. Independent from medication and hypertension increased the complexity of nonlinear HR regulation and reduced cardiovascular coupling of ISSHL patients and independent from hypertension altered nonlinear systolic and diastolic BP regulation. Coupling patterns are characterized by a less pronounced strong and fast decrease of systolic BP when HR increases and rapidly changes in ISSHL patients. Disturbed BP modulation and complexity by impaired baroreflex activities resulting in short-term BP fluctuations, altered peripheral resistance, and reduced cochlear blood flow. Increased values for the pulse wave velocity in the aorta and carotid-femoral were early indicators that the elasticity of the arteries might be restricted in ISSHL patients. CONCLUSION: ISSHL patients show an altered autonomic regulation. At least a subgroup of ISSHL patients seems to exist where a vascular impairment might play an important role in the pathogenesis of this disease.

Quantification of autonomic regulation in patients with sudden sensorineural hearing loss.

Previous studies have proposed varying causes for idiopathic sudden sensorineural hearing loss (SSNHL), including vascular occlusion, ruptured inner ear membrane, acoustic tumours and circulatory disturbances in the inner ear. The objective of this study was to characterise the autonomic regulation in 19 SSNHL patients in comparison to 19 healthy age-gender matched normal-hearing control subjects (CON) in order to improve the diagnostics of vascular caused hearing loss in SSNHL patients. A high-resolution short-term electrocardiogram (ECG) and the continuous noninvasive blood pressure signal were simultaneously recorded under resting conditions (30min). Linear and nonlinear indices of heart rate- and blood pressure variability (HRV, BPV) were calculated to characterise autonomic regulation. The results showed that HRV analysis did not produce significantly different results between SSNHL and CON, whereas linear and nonlinear BPV indices showed significant differences between both groups (p<0.01). This study was the first to show an altered cardiovascular regulation in SSNHL patients when compared to CON subjects, based on continuous blood pressure analysis. This was characterised by reduced variability, complexity and dynamics of blood pressure time series in SSNHL. These findings may contribute to an improved classification of the controversially discussed causes of SSNHL and, in addition, may lead to improved diagnostic strategies for a subgroup of SSNHL patients whose hearing loss is caused by cardiovascular factors.

Phase I trial of split-dose induction docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1).

BACKGROUND: Induction chemotherapy (ICT) with docetaxel, cisplatin and fluorouracil (TPF) followed by radiotherapy is an effective treatment option for unresectable locally advanced head and neck cancer. This phase I study was designed to investigate the safety and tolerability of a split-dose TPF ICT regimen prior to surgery for locally advanced resectable oral and oropharyngeal cancer. METHODS: Patients received TPF split on two dosages on day 1 and 8 per cycle for one or three 3-week cycles prior to surgery and postoperative radiotherapy or radiochemotherapy. Docetaxel was escalated in two dose levels, 40 mg/m2 (DL 0) and 30 mg/m2 (DL -1), plus 40 mg/m2 cisplatin and 2000 mg/m2 fluorouracil per week using a 3 +3 dose escalation algorithm. RESULTS: Eighteen patients were enrolled and were eligible for toxicity and response. A maximum tolerated dose of 30 mg/m2 docetaxel per week was reached. The most common grade 3+ adverse event was neutropenia during ICT in 10 patients. Surgery reached R0 resection in all cases. Nine patients (50%) showed complete pathologic regression. CONCLUSIONS: A split-dose regime of TPF prior to surgery is feasible, tolerated and merits additional investigation in a phase II study with a dose of 30 mg/m docetaxel per week. TRIAL REGISTRATION NUMBER: NCT01108042 (ClinicalTrials.gov Identifier).