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

Opposing function of MYBBP1A in proliferation and migration of head and neck squamous cell carcinoma cells

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent and lethal cancers worldwide and mortality mostly results from loco-regional recurrence and metastasis. Despite its significance, our knowledge on molecular, cellular and environmental mechanisms that drive disease pathogenesis remains largely elusive, and there are limited therapeutic options, with only negligible clinical benefit. METHODS: We applied global gene expression profiling with samples derived from a recently established mouse model for oral cancer recurrence and identified a list of genes with differential expression between primary and recurrent tumors. RESULTS: One differentially expressed gene codes for Myb-binding protein 1a (MYBBP1A), which is known as a transcriptional co-regulator that physically interacts with nuclear transcription factors, such as NFκB and p53. We confirmed significantly reduced MYBBP1A protein levels on tissue sections of recurrent mouse tumors compared to primary tumors by immunohistochemistry, and found aberrant MYBBP1A protein levels also in tumor samples of HNSCC patients. Interestingly, silencing of MYBBP1A expression in murine SCC7 and in human HNSCC cell lines elicited increased migration but decreased cell growth. CONCLUSION: We provide experimental evidence that MYBBP1A is an important molecular switch in the regulation of tumor cell proliferation versus migration in HNSCC and it will be a major challenge for the future to proof the concept whether regulation MYBBP1A expression and/or function could serve as a novel option for anti-cancer therapy

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

Impaired aldehyde dehydrogenase 1 subfamily member 2A-dependent retinoic acid signaling is related with a mesenchymal-like phenotype and an unfavorable prognosis of head and neck squamous cell carcinoma

Background: An inverse correlation between expression of the aldehyde dehydrogenase 1 subfamily A2 (ALDH1A2) and gene promoter methylation has been identified as a common feature of oropharyngeal squamous cell carcinoma (OPSCC). Moreover, low ALDH1A2 expression was associated with an unfavorable prognosis of OPSCC patients, however the causal link between reduced ALDH1A2 function and treatment failure has not been addressed so far. Methods: Serial sections from tissue microarrays of patients with primary OPSCC (n = 101) were stained by immunohistochemistry for key regulators of retinoic acid (RA) signaling, including ALDH1A2. Survival with respect to these regulators was investigated by univariate Kaplan-Meier analysis and multivariate Cox regression proportional hazard models. The impact of ALDH1A2-RAR signaling on tumor-relevant processes was addressed in established tumor cell lines and in an orthotopic mouse xenograft model. Results: Immunohistochemical analysis showed an improved prognosis of ALDH1A2high OPSCC only in the presence of CRABP2, an intracellular RA transporter. Moreover, an ALDH1A2highCRABP2high staining pattern served as an independent predictor for progression-free (HR: 0.395, p = 0.007) and overall survival (HR: 0.303, p = 0.002), suggesting a critical impact of RA metabolism and signaling on clinical outcome. Functionally, ALDH1A2 expression and activity in tumor cell lines were related to RA levels. While administration of retinoids inhibited clonogenic growth and proliferation, the pharmacological inhibition of ALDH1A2-RAR signaling resulted in loss of cell-cell adhesion and a mesenchymal-like phenotype. Xenograft tumors derived from FaDu cells with stable silencing of ALDH1A2 and primary tumors from OPSCC patients with low ALDH1A2 expression exhibited a mesenchymal-like phenotype characterized by vimentin expression. Conclusions: This study has unraveled a critical role of ALDH1A2-RAR signaling in the pathogenesis of head and neck cancer and our data implicate that patients with ALDH1A2low tumors might benefit from adjuvant treatment with retinoids

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

Salvage radiotherapy for recurrent hypopharyngeal and laryngeal squamous cell carcinoma (SCC) after first-line treatment with surgery alone: a 10-year single-centre experience

Purpose: Salvage surgery of recurrent hypopharyngeal and laryngeal squamous cell carcinoma (SCC) results in limited local control and survival rates. As a result of recent technological progress, radiotherapy (RT) has become a valuable, potentially curative therapeutic option. Thus, we aimed to determine prognostic factors for survival outcome in order to optimize patient selection for salvage radiotherapy after failure of first-line treatment with surgery alone in this special patient cohort. Methods: Seventy-five patients (85% male, median age of 64 years) underwent salvage RT in a secondary setting for recurrent hypopharyngeal or laryngeal SCC after prior surgery alone between 2007 and 2017. On average, patients were treated with one prior surgery (range 1–4 surgeries). Median time between surgery and salvage RT was 7 months (range 1–47 months) for initially advanced tumors (T3/4, N+, extracapsular spread) and 18 months (range 5–333 months) for initially early stage tumors. The majority of patients received concomitant chemotherapy (n = 48; 64%) or other kind of systemic treatment concurrent to radiotherapy (n = 10; 13%). Results: Median follow-up was 41 months (range 3–120 months). Overall, fifteen patients were diagnosed with local failure (all were in-field) at last follow-up (20%). Median time to recurrence was 35 months (range 3–120 months) and 3-year local progression-free survival (LPFS) was 75%, respectively. Dose-escalated RT with 70.4 Gy applied in 2.1 Gy or 2.2 Gy fractions corresponding an EQD2 > 70 Gy (p = 0.032) and the use of concomitant cisplatin weekly chemotherapy (p = 0.006) had a significant positive impact on LPFS. 3-year OS and DPFS were 76 and 85%, respectively. No toxicity-related deaths occurred. Reported grade >  3 side effects were rare (n = 4/70, 6%). Conclusion: Salvage radiotherapy resulted in excellent local control rates while radiation dose and the use of cisplatin weekly chemotherapy were identified as prognostic factors for LPFS. Nevertheless, patient selection for curative salvage treatment remains challenging