Sven Koscielny

Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs approximately US

A Technical Triade for Proteomic Identification and Characterization of Cancer Biomarkers

2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age <or=40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care.

Daily Amifostine Given Concomitantly to Chemoradiation in Head and Neck Cancer

Biomarkers are needed to elucidate the biological background and to improve the detection of cancer. Therefore, we have analyzed laser-microdissected cryostat sections from head and neck tumors and adjacent mucosa on ProteinChip arrays. Two differentially expressed proteins (P = 3.34 × 10−5 and 4.6 × 10−5) were isolated by two-dimensional gel electrophoresis and identified as S100A8 (calgranulin A) and S100A9 (calgranulin B) by in-gel proteolytic digestion, peptide mapping, tandem mass spectrometry analysis, and immunodepletion assay. The relevance of these single marker proteins was evaluated by immunohistochemistry. Positive tissue areas were reanalyzed on ProteinChip arrays to confirm the identity of these proteins. As a control, a peak with low P was identified as calgizzarin (S100A11) and characterized in the same way. This technical triade of tissue microdissection, ProteinChip technology, and immunohistochemistry opens up the possibility to find, identify, and characterize tumor relevant biomarkers, which will allow the movement toward the clonal heterogeneity of malignant tumors. Taking this approach, proteins were identified that might be responsible for invasion and metastasis.

The prognostic relevance of p16 inactivation in head and neck cancer.

Background: In patients with loco-regionally advanced head and neck cancer conventionally fractionated radiotherapy alone results in poor loco-regional control and survival rates. Treatment intensification by simultaneous administration of cytotoxic drugs produces higher acute morbidity. Therefore chemical radioprotection of normal tissues may be of clinical benefit. Patients and Methods: In a pilot study patients with advanced nonresectable head and neck cancer treated with conventionally fractionated radical radiotherapy (60 to 66 Gy total doses) and concomitantly given 5-fluorouracil as protracted venous infusion, 250 mg/sqm/24 h over the entire treatment period were given amifostine 300 mg absolutely before each fraction. Acute treatment related morbidity was scored according to CTC classification and loco-regional control and survival rates were estimated. Comparison was made with a historical control group of identical chemoradiation but without amifostine application. Results: Chemoradiation induced oral mucositis was delayed and showed significant lower degrees at all 10 Gy increments (p < 0.05) except 60 Gy and over (p > 0.05). No significant toxicity was recorded with respect to blood pressure, serum calcium, potassium, hematologic parameters, emesis, nausea or body weight loss. Progression free survival and overall survival probability at 2 years were not statistically different in both cohorts. Conclusions: Amifostine given before each fraction of radiotherapy over 6 weeks has no cumulative toxicity, was well tolerated and may reduce treatment induced oral mucositis. No tumor protective effect was observed.Hintergrund: Bei Patienten mit lokoregionär fortgeschrittenen Karzinomen im Kopf-Hals-Bereich führt die alleinige konventionell fraktionierte Radiotherapie zu ungünstigen lokoregionären Tumorkontrollraten und Überlebensraten. Die Therapieintensivierung durch simultane Radiochemotherapie führt zu gesteigerter Akutmorbidität. Die chemische Radioprotektion von Normalgeweben könnte daher die Akutmorbidität senken und eine weitere Therapieintensivierung zulassen. Patienten und Methode: In einer Pilotstudie wurden Patienten mit lokoregionär fortgeschrittenem Plattenepithelkarzinom im Kopf-Hals-Bereich mit einer primären Radiotherapie (Gesamtdosis 60 bis 66 Gy) und simultaner Chemotherapie (5-Fluorouracil, 250 mg/m2/24 Stunden, protrahierte Infusion über den gesamten Behandlungszeitraum) therapiert. Vor jeder Fraktion wurde Amifostin 300 mg absolut intravenös appliziert. Die therapieassoziierte Akuttoxizität wurde semiquantitativ untersucht (CTC-Klassifikation). Lokoregionäre Tumorkontrolle und Gesamtüberleben wurden berechnet. Die Ergebnisse wurden mit einer historischen Kontrollgruppe verglichen. Ergebnisse: Die radiochemotherapieinduzierte orale Mukositis setzte unter Amifostin später ein und war in allen Dosisschritten zu 10 Gy mit Ausnahme der höchsten Dosisbereiche (60 Gy und höher) signifikant geringer ausgeprägt im Vergleich zur Kontrollgruppe. Hinsichtlich Blutdruck, Kalium- und Calciumkonzentrationen im Serum, Übelkeit, Erbrechen, Körpergewicht und hämatologischer Parameter wurden keine Unterschiede gefunden. Amifostin war gut verträglich und zeigte keine kumulative Toxizität. Das progressionsfreie Überleben sowie das Gesamtüberleben zeigten keine Unterschiede in beiden Gruppen. Schlußfolgerung: Die wiederholte Gabe von Amifostin wird gut vertragen und vermindert möglicherweise die radiochemotherapieinduzierte akute Mukositis. Ein tumorprotektiver Effekt wurde nicht beobachtet.

Speech rehabilitation during the first year after total laryngectomy

The inactivation of the tumor suppressor gene p16 plays an important role in the development of malignant tumors. p16 loss can result from point mutations, loss of heterozygosity (LOH) or methylation of the promoter region. A total of 67 samples of tumor tissue from squamous cell carcinoma of the oral cavity, the pharynx and the larynx were analyzed for an inactivation of p16. The results of the molecular-biological investigations were correlated with the known clinical prognostic parameters after a follow-up period of approximately 3 years. Methylation of the promoter region and LOH were the main mechanisms of p16 inactivation. Point mutations presented as rare events. An inactivation of p16 did not have any statistical influence on tumor prognosis. Patients with a p16 gene inactivated by promoter methylation appeared to have a slightly lower tendency for local and regional recurrences. The inactivation of the tumor suppressor gene p16 plays a role in the carcinogenesis of head and neck cancer.

3D-conformal-intensity modulated radiotherapy with compensators for head and neck cancer: clinical results of normal tissue sparing

Gaining a new voice is one of the major aims after total laryngectomy. The objective of this study was to describe the process and results of speech rehabilitation during the first year after surgery.

Clinical relevance of quality-of-life data in laryngectomized patients.

BackgroundTo investigate the potential of parotic gland sparing of intensity modulated radiotherapy (3D-c-IMRT) performed with metallic compensators for head and neck cancer in a clinical series by analysis of dose distributions and clinical measures.Materials and methods39 patients with squamous cell cancer of the head and neck irradiated using 3D-c-IMRT were evaluable for dose distribution within PTVs and at one parotid gland and 38 patients for toxicity analysis. 10 patients were treated primarily, 29 postoperatively, 19 received concomittant cis-platin based chemotherapy, 20 3D-c-IMRT alone. Initially the dose distribution was calculated with Helax ® and photon fluence was modulated using metallic compensators made of tin-granulate (n = 22). Later the dose distribution was calculated with KonRad ® and fluence was modified by MCP 96 alloy compensators (n = 17). Gross tumor/tumor bed (PTV 1) was irradiated up to 60–70 Gy, [5 fractions/week, single fraction dose: 2.0–2.2 (simultaneously integrated boost)], adjuvantly irradiated bilateral cervical lymph nodes (PTV 2) with 48–54 Gy [single dose: 1.5–1.8]). Toxicity was scored according the RTOG scale and patient-reported xerostomia questionnaire (XQ).ResultsMean of the median doses at the parotid glands to be spared was 25.9 (16.3–46.8) Gy, for tin graulate 26 Gy, for MCP alloy 24.2 Gy. Tin-granulate compensators resulted in a median parotid dose above 26 Gy in 10/22, MCP 96 alloy in 0/17 patients. Following acute toxicities were seen (°0–2/3): xerostomia: 87%/13%, dysphagia: 84%/16%, mucositis: 89%/11%, dermatitis: 100%/0%. No grade 4 reaction was encountered. During therapy the XQ forms showed °0–2/3): 88%/12%. 6 months postRT chronic xerostomia °0–2/3 was observed in 85%/15% of patients, none with °4 xerostomia.Conclusion3D-c-IMRT using metallic compensators along with inverse calculation algorithm achieves sufficient parotid gland sparing in virtually all advanced head and neck cancers. Since the concept of lower single (and total) doses in the adjuvantly treated volumes reduces acute morbidity 3D-c-IMRT nicely meets demands of concurrent chemotherapy protocols.

Feasibility of real-time near-infrared indocyanine green fluorescence endoscopy for the evaluation of mucosal head and neck lesions.

Statistically significant differences in health‐related quality of life (HRQL) are not always clinically relevant. It is also plausible that patients perceive other changes to be relevant than health professionals do. The objective of this study was to find thresholds for HRQL that laryngectomees consider to be clinically relevant 1 year after surgery, (i.e., the level of HRQL that patients rate as satisfactory). A second aim was to investigate how many laryngectomized patients reached those targets.

Berufliche Rehabilitation nach Laryngektomie

The purpose of this study was to explore the feasibility and potential drawbacks of near‐infrared (NIR) endoscopy with indocyanine green (ICG) to examine mucosal head and neck lesions.

Feasibility and safety of dilatational tracheotomy using the rigid endoscope: a multicenter study

BACKGROUND Aim of this study was to find out how many patients after a total laryngectomy (TLE) return to work successfully and what factors support vocational rehabilitation. PATIENTS AND METHODS Laryngectomees (n=231) aged up to 60 years completed questionnaires and structured interviews before TLE (t1), before rehabilitation (t2), at the end of rehabilitation (t3), 1 year after TLE (t4), 2 years after TLE (t5), and 3 years after TLE (t6). RESULTS Prior to TLE, 38% of all respondents were employed, 34% were unemployed, 23% received disability-related and 3% age-related pension retirement. One year after TLE, 13% were employed, 15% 2 years and 14% 3 years after TLE. Unemployed were 10% (t4), 5% (t5), and 7% (t6) of the patients. For 59% of all respondents it was very important to have a job. Predictors of successful vocational rehabilitation were employment prior to TLE, age <50 years, being self-employed or clerical employee, good physical functioning, good speech intelligibility, high motivation to go back to work, and support from colleagues. CONCLUSION Only few laryngectomees return to work. However, even before TLE only a third of the patients was employed, another third was unemployed. Most of the patients receive pension retirement after TLE. As return to work is important for many patients, patient consultations should consider possibilities to support vocational rehabilitation before offering to apply for retirement.