A change in the study evaluation paradigm reveals that larynx preservation compromises survival in T4 laryngeal cancer patients

Background: Larynx preservation (LP) is recommended for up to low-volume T4 laryngeal cancer as an evidence-based treatment option that does not compromise survival. However, a reevaluation of the current literature raises questions regarding whether there is indeed reliable evidence to support larynx preservation for T4 tumor patients. Methods: In an observational cohort study of 810 laryngeal cancer patients, we evaluated the outcomes of all T4 tumor patients treated with primary chemo-radiotherapy (CRT) or primary radiotherapy alone (RT) compared with upfront total laryngectomy followed by adjuvant (chemo)radiotherapy (TL + a[C]RT). Additionally, we reevaluated the studies that form the evidence base for the recommendation of LP for patients with up to T4 tumors (Pfister et al., J Clin Oncol 24:3693–704, 2006). Results: The evaluation of all 288 stage III and IV patients together did not show a significant difference in overall survival (OS) between CRT-LP and TL + a(C)RT (hazard ratio (HR) 1.23; 95% confidence interval (CI): 0.82–1.86; p = 0.31) using a multivariate proportional hazard model. However, a subgroup analysis of T4 tumor patients alone (N = 107; 13.9%) revealed significantly worse OS after CRT compared with TL + a(C)RT (HR 2.0; 95% CI: 1.04–3.7; p = 0.0369). A reevaluation of the subgroup of T4 patients in the 5 LP studies that led to the ASCO clinical practice guidelines revealed that only 21–45 T4 patients had differential data on survival outcome. These data, however, showed a markedly worse outcome for T4 patients after LP. Conclusions: T4 laryngeal cancer patients who reject TL as a treatment option should be informed that their chance of organ preservation with primary conservative treatment is likely to result in a significantly worse outcome in terms of OS. Significant loss of survival in T4 patients after LP is also confirmed in recent literature

General and disease-specific quality of life in patients with chronic suppurative otitis media - a prospective study

Background: Chronic suppurative otitis media (CSOM) is frequently associated with symptoms of inflammation like discharge from the ear or pain. In many cases, patients suffer from hearing loss causing communication problems and social withdrawal. The objective of this work was to collect prospective audiological data and data on general and disease-specific quality of life with validated quality of life measurement instruments to assess the impact of the disease on health-related quality of life (HR-QOL). Methods: 121 patients were included in the study. Patients were clinically examined in the hospital before and 6 months after surgery including audiological testing. They filled in the quality of life questionnaires SF-36 and Chronic Otitis Media Outcome Test 15 (COMOT-15) pre-operatively and 6 and 12 months post-operatively, respectively. Results: Complete data records from 90 patients were available for statistical analysis. Disease-specific HR-QOL in patients with CSOM improved after tympanoplasty in all the scales of the COMOT-15. There was no difference in HR-QOL assessment between patients with mesotympanic respectively epitympanic CSOM. However, we did find the outcome to be worse in patients who received revision surgery compared with those receiving primary surgery. Audiometric findings correlated very well with the subscale hearing function from the COMOT-15 questionnaire. General HR-QOL measured with the SF-36 was not significantly changed by tympanoplasty. Conclusions: Tympanoplasty did lead to a significant improvement of disease-specific HR-QOL in patients with CSOM while general HR-QOL did not change. Very well correlations were found between the subscale hearing function from the COMOT-15 questionnaire and audiological findings. Revision surgery seems to be a predictor for a worse outcome

Long-term outcomes and quality of life following parotidectomy for benign disease

Objective: Parotidectomy worsens quality of life (QoL) in the short-term, but the long-term impact is unknown. In this study, we analysed the long-term effects of parotidectomy on QoL. Methods: In this prospective long-term follow-up study, participants were divided into three groups: short-term (ST) follow-up of six weeks, long-term (LT) follow-up of 13 years and short- and long-term (SLT) follow-up. QoL was assessed using the Parotidectomy Outcome Inventory (POI-8). Parotidectomies were classified based on whether the great auricular nerve (GAN) had been preserved or sacrificed. Results: In total, 164 observations were analysed, 74 in the LT group, 57 in the ST group and 33 in the SLT group. Hypoaesthesia was a major problem and facial palsy was a minor problem. Pain (p < 0.01) and hypoaesthesia (p < 0.001) were significantly lower after 13 years compared with after six weeks, and QoL was higher after 13 years compared with after six weeks (p = 0.04). The disease-specific impairment rate decreased from 70% at short-term follow-up to 30% at long-term follow-up. Removal of the GAN was associated with hypoaesthesia in the ST group (p = 0.028). Conclusions: Hypoaesthesia has a long-term impact on the QoL, and this should be emphasised during preoperative discussions

Expression of submaxillary gland androgen-regulated protein 3A (SMR3A) in adenoid cystic carcinoma of the head and neck

Background: Adenoid cystic carcinoma of the head and neck (ACC) is a rare tumor entity which originates from the salivary glands. The prognosis remains poor, as the tumor tends to exhibit perineural invasion and frequently develops distant metastases. The submaxillary gland androgen-regulated protein 3A (SMR3A) belongs to a gene family producing opiorphin homologs and is physiologically secreted by salivary glands. Expression of SMR3A has been identified as an unfavorable risk factor in survival of patients with squamous cell carcinoma in the head and neck, but its value as a prognostic biomarker for ACC has not been addressed. Materials and Methods: Tissue sections from primary ACC (n=86) and healthy glandular tissue as reference, were stained by immunohistochemistry. SMR3A expression levels were correlated with clinical and pathological features, including overall survival. Results: All patients had undergone surgery and 67 received adjuvant radiotherapy. The median disease-free survival (DFS) was 37 months and the median overall survival (OS) was 75 months. Prominent SMR3A expression in tumor cells was found in 24 of 86 patients (27,9%), and was inversely correlated with a male gender (p=0.009). There was no significant correlation between SMR3A expression and DFS, metastasis-free survival or OS. Conclusion: Our data demonstrate for the first time decreased levels of SMR3A in ACC compared to normal glandular tissue. These data suggest a context-dependent regulation of SMR3A expression in the pathogenesis of distinct subtypes of head and neck tumors, and support the assumption that detection of SMR3A expression serves as a surrogate for aberrant differentiation into mucosal- or glandular-like cells in ACC and head and neck squamous cell carcinoma

Expression of Kallikrein-related peptidase 6 in primary mucosal malignant melanoma of the head and neck

Mucosal melanomas of the head and neck (MMHN) are aggressive tumors with poor prognosis, different opposed to cutaneous melanoma. In this study, we characterized primary mucosal malignant melanoma for the expression of Kallikrein-related peptidase 6 (KLK6), a member of the KLK family with relevance to the malignant phenotype in various cancer types including cutaneous melanoma. Paraffin-embedded MMHN of 22 patients were stained immunohistochemically for KLK6 and results were correlated with clinical and pathological data. In 77.3% (17/22) of MMHN cases, positive KLK6 staining was found. Staining pattern for tumor cells showed a predominant cytoplasmic staining. However, in six cases we also observed a prominent nuclear staining. MMHN with a high KLK6 expression showed significantly better outcome concerning local recurrence-free survival (p = 0.013) and nuclear KLK6 staining was significantly associated with the survival status (p = 0.027). Overexpression of KLK6 was detected in more than 70% of MMHN and approximately 40% of tumors showed a strong expression pattern. Correlation between clinical outcome of MMHN patients and overexpression of KLK6 has not been addressed so far. Our data demonstrate for the first time increased levels of KLK6 in MMHN and strengthen the hypothesis that there might be a context-specific regulation and function of KLK6 in mucosal melanoma

Validierung und Reliabilitätsprüfung des Nijmegen Cochlear Implant Questionnaire in deutscher Sprache

Hintergrund: Der Nijmegen Cochlear Implant Questionnaire (NCIQ) ist ein krankheitsspezifischer Fragebogen zur Erhebung der gesundheitsbezogenen Lebensqualität von Patienten vor und nach Cochleaimplantation. Ziel der Arbeit: Validierung und Reliabilitätsprüfung der deutschen Übersetzung des NCIQ. Material und Methoden: Es wurde eine prospektive Studie an 100 postlingual ertaubten oder hochgradig schwerhörigen Patienten durchgeführt, welche präoperativ sowie 3 und 6 Monate nach einer Cochleaimplantation mittels NCIQ, Abbreviated Profile of Hearing Aid Benefit (APHAB) und Hearing Participation Scale (HPS) untersucht wurden. Als Kontrolle fungierte ein postlingual ertaubtes oder hochgradig schwerhöriges, unbehandeltes Patientenkollektiv (n = 54). Cronbach‑α und Test-Retest-Reliabilität dienten der Reliabilitätsüberprüfung. Es wurde auf Inhalts‑, Übereinstimmungs- und auf diskriminative Validität getestet. Die Konstruktvaliditätsprüfung basiert auf kürzlich veröffentlichen Daten. Als Gütekriterien wurden die Sensitivität und eine ROC("Receiver Operating Characteristic")-Analyse, inklusive AUC("Area Under the ROC Curve")-Betrachtung, eingesetzt. Ergebnisse: Das Test-Retesting ergab nach 3 und 6 Monaten postoperativ stabile NCIQ-Werte. Die Cronbach-α-Werte wiesen auf eine gute interne Konsistenz hin. Der NCIQ diskriminierte valide zwischen behandelten und unbehandelten Patientengruppen. Es ergaben sich statistisch signifikante, wenn auch schwache, Korrelationen zwischen dem NCIQ und dem APHAB (r = -0,22; p = 0,04) und dem HPS (r = 0,30; p = 0,01). Sensitivitäts- und ROC-Analysen zeigten eine gute Messqualität des deutschsprachigen NCIQ. Schlussfolgerung: Die deutsche Übersetzung des NCIQ misst zuverlässig und valide die Lebensqualität vor und nach Cochleaimplantation und kann zur klinischen Erfolgskontrolle nach Cochleaimplantationen verwendet werden.Background: The Nijmegen Cochlear Implant Questionnaire (NCIQ) is a disease-specific questionnaire to determine the health-related quality of life (HRQoL) of patients before and after cochlear implantation. Objective: This study aimed to assess the validity and reliability of the German translation of the NCIQ. Materials and methods: A prospective study was performed in 100 postlingually deaf or severely hearing-impaired patients. HRQoL was assessed using the NCIQ, the Abbreviated Profile of Hearing Aid Benefit (APHAB), and the Hearing Participation Scale (HPS) before as well as 3 and 6 months after cochlear implantation. An untreated group of postlingually deaf or severely hearing-impaired patients (n = 54) served as a control. Cronbach's α and test–retest reliability were measured. The content, discrimination, and agreement validity were tested. The evaluation of construct validity was based on recently published data. Sensitivity and receiver operating curve (ROC) analysis, including consideration of the area under the curve (AUC), were used as quality criteria. Results: The test-retest analysis showed stable NCIQ values 3 and 6 months postoperatively. The Cronbach’s α values indicated good internal consistency. The NCIQ validly discriminated between treated and untreated patient groups. There were statistically significant albeit weak correlations between the NCIQ and the APHAB (r = -0.22; p = 0.04) and the HPS (r = 0.30; p = 0.01). Sensitivity and ROC analyses showed good measurement quality of the German-speaking NCIQ. Conclusion: The German translation of the NCIQ reliably and validly measures HRQoL before and after cochlear implantation and can be used for clinical monitoring after treatment with cochlear implants

Organotypic Co-Cultures as a Novel 3D Model for Head and Neck Squamous Cell Carcinoma

Background: Head and neck squamous cell carcinomas (HNSCC) are phenotypically and molecularly heterogeneous and frequently develop therapy resistance. Reliable patient-derived 3D tumor models are urgently needed to further study the complex pathogenesis of these tumors and to overcome treatment failure. Methods: We developed a three-dimensional organotypic co-culture (3D-OTC) model for HNSCC that maintains the architecture and cell composition of the individual tumor. A dermal equivalent (DE), composed of healthy human-derived fibroblasts and viscose fibers, served as a scaffold for the patient sample. DEs were co-cultivated with 13 vital HNSCC explants (non-human papillomavirus (HPV) driven, n = 7; HPV-driven, n = 6). Fractionated irradiation was applied to 5 samples (non-HPV-driven, n = 2; HPV-driven n = 3). To evaluate expression of ki-67, cleaved caspase-3, pan-cytokeratin, p16INK4a, CD45, ∝smooth muscle actin and vimentin over time, immunohistochemistry and immunofluorescence staining were performed Patient checkup data were collected for up to 32 months after first diagnosis. Results: All non-HPV-driven 3D-OTCs encompassed proliferative cancer cells during cultivation for up to 21 days. Proliferation indices of primaries and 3D-OTCs were comparable and consistent over time. Overall, tumor explants displayed heterogeneous growth patterns (i.e., invasive, expansive, silent). Cancer-associated fibroblasts and leukocytes could be detected for up to 21 days. HPV DNA was detectable in both primary and 3D-OTCs (day 14) of HPV-driven tumors. However, p16INK4a expression levels were varying. Morphological alterations and radioresistant tumor cells were detected in 3D-OTC after fractionated irradiation in HPV-driven and non-driven samples. Conclusions: Our 3D-OTC model for HNSCC supports cancer cell survival and proliferation in their original microenvironment. The model enables investigation of invasive cancer growth and might, in the future, serve as a platform to perform sensitivity testing upon treatment to predict therapy response

Kallikrein-related peptidase 6 regulates epithelial-to-mesenchymal transition and serves as prognostic biomarker for head and neck squamous cell carcinoma patients

Background: Dysregulated expression of Kallikrein-related peptidase 6 (KLK6) is a common feature for many human malignancies and numerous studies evaluated KLK6 as a promising biomarker for early diagnosis or unfavorable prognosis. However, the expression of KLK6 in carcinomas derived from mucosal epithelia, including head and neck squamous cell carcinoma (HNSCC), and its mode of action has not been addressed so far. Methods: Stable clones of human mucosal tumor cell lines were generated with shRNA-mediated silencing or ectopic overexpression to characterize the impact of KLK6 on tumor relevant processes in vitro. Tissue microarrays with primary HNSCC samples from a retrospective patient cohort (n = 162) were stained by immunohistochemistry and the correlation between KLK6 staining and survival was addressed by univariate Kaplan-Meier and multivariate Cox proportional hazard model analysis. Results: KLK6 expression was detected in head and neck tumor cell lines (FaDu, Cal27 and SCC25), but not in HeLa cervix carcinoma cells. Silencing in FaDu cells and ectopic expression in HeLa cells unraveled an inhibitory function of KLK6 on tumor cell proliferation and mobility. FaDu clones with silenced KLK6 expression displayed molecular features resembling epithelial-to-mesenchymal transition, nuclear β-catenin accumulation and higher resistance against irradiation. Low KLK6 protein expression in primary tumors from oropharyngeal and laryngeal SCC patients was significantly correlated with poor progression-free (p = 0.001) and overall survival (p < 0.0005), and served as an independent risk factor for unfavorable clinical outcome. Conclusions: In summary, detection of low KLK6 expression in primary tumors represents a promising tool to stratify HNSCC patients with high risk for treatment failure. These patients might benefit from restoration of KLK6 expression or pharmacological targeting of signaling pathways implicated in EMT

Development of the First Force-Controlled Robot for Otoneurosurgery

Objective: In some surgical specialties, e.g. orthopedics, robots are already used in the operating room for bony milling work. Oto- and otoneurosurgery may also greatly benefit by robotic enhanced precision. Study Design: Experimental study on robotic milling on oak wood and human temporal bone specimen. Methods: A standard industrial robot with a 6 degrees-of-freedom serial kinematics was used with force feedback to proportionally control the robot speed. Different milling modes and characteristic path parameters were evaluated to generate milling paths based on CAD geometry data of a cochlear implant and an implantable hearing system. Results: The best suited strategy proofed to be the spiral horizontal milling mode with the burr held perpendicularly to the temporal bone surface. In order to avoid high grooves, the distance in between paths should equal half the radius of the cutting burr head. Due to the vibration of the robot’s own motors, a rather high oscillation of the standard deviation of forces was encountered. This oscillation dropped drastically to nearly 0 N, when the burr head reached contact with the dura mater due to its damping characteristics. The cutting burr could be moved a long time on the dura without damaging it, because of its rather blunt head. The robot moved the burr very smoothly according to the encountered resistances. Conclusion: This is the first development of an functioning robotic milling procedure for otoneurosurgery with force-based speed control. It is planned to implement ultrasound-based local navigation and to perform robotic mastoidectomy

General and disease-specific quality of life in patients with chronic suppurative otitis media - a prospective study

Abstract Background Chronic suppurative otitis media (CSOM) is frequently associated with symptoms of inflammation like discharge from the ear or pain. In many cases, patients suffer from hearing loss causing communication problems and social withdrawal. The objective of this work was to collect prospective audiological data and data on general and disease-specific quality of life with validated quality of life measurement instruments to assess the impact of the disease on health-related quality of life (HR-QOL). Methods 121 patients were included in the study. Patients were clinically examined in the hospital before and 6 months after surgery including audiological testing. They filled in the quality of life questionnaires SF-36 and Chronic Otitis Media Outcome Test 15 (COMOT-15) pre-operatively and 6 and 12 months post-operatively, respectively. Results Complete data records from 90 patients were available for statistical analysis. Disease-specific HR-QOL in patients with CSOM improved after tympanoplasty in all the scales of the COMOT-15. There was no difference in HR-QOL assessment between patients with mesotympanic respectively epitympanic CSOM. However, we did find the outcome to be worse in patients who received revision surgery compared with those receiving primary surgery. Audiometric findings correlated very well with the subscale hearing function from the COMOT-15 questionnaire. General HR-QOL measured with the SF-36 was not significantly changed by tympanoplasty. Conclusions Tympanoplasty did lead to a significant improvement of disease-specific HR-QOL in patients with CSOM while general HR-QOL did not change. Very well correlations were found between the subscale hearing function from the COMOT-15 questionnaire and audiological findings. Revision surgery seems to be a predictor for a worse outcome.</p