Fibroblast activation protein inhibitor (FAPI) PET for diagnostics and advanced targeted radiotherapy in head and neck cancers.

PURPOSE: Cancer-associated fibroblasts (CAFs) expressing fibroblast activation protein (FAP) have been associated with the aggressive nature of head and neck cancers (HNCs). These tumours grow diffusely, leading to extremely challenging differentiation between tumour and healthy tissue. This analysis aims to introduce a novel approach of tumour detection, contouring and targeted radiotherapy of HNCs using visualisation of CAFs: PET-CT with 68Ga-radiolabeled inhibitors of FAP (FAPI). METHODS: FAPI PET-CT was performed without complications prior to radiotherapy in addition to contrast enhanced CT (CE-CT) and MRI on 14 patients with HNC. First, for tissue biodistribution analysis, volumes of interest were defined to quantify SUVmean and SUVmax in tumour and healthy parenchyma. Secondly, using four thresholds of three-, five-, seven- and tenfold increase of FAPI enhancement in the tumour as compared with normal tissue, four different gross tumour volumes (FAPI-GTV) were created automatically. These were compared with GTVs created conventionally with CE-CT and MRI (CT-GTV). RESULTS: The biodistribution analysis revealed high FAPI avidity within tumorous lesions (e.g. primary tumours, SUVmax 14.62 ± 4.44; SUVmean 7.41 ± 2.39). In contrast, low background uptake was measured in healthy tissues of the head and neck region (e.g. salivary glands: SUVmax 1.76 ± 0.31; SUVmean 1.23 ± 0.28). Considering radiation planning, CT-GTV was of 27.3 ml, whereas contouring with FAPI resulted in significantly different GTVs of 67.7 ml (FAPI × 3, p = 0.0134), 22.1 ml (FAPI × 5, p = 0.0419), 7.6 ml (FAPI × 7, p = 0.0001) and 2.3 ml (FAPI × 10, p = 0.0001). Taking these significant disparities between the GTVs into consideration, we merged FAPI-GTVs with CT-GTVs. This resulted in median volumes, that were, as compared to CT-GTVs, significantly larger with FAPI × 3 (54.7 ml, + 200.5% relative increase, p = 0.0005) and FAPI × 5 (15.0 ml, + 54.9%, p = 0.0122). Furthermore, FAPI-GTVs were not covered by CE-CT-based planning target volumes (CT-PTVs) in several cases. CONCLUSION: We present first evidence of diagnostic and therapeutic potential of FAPI ligands in head and neck cancer. Larger studies with histopathological correlation are required to validate our findings.

Early nasal reconstruction after skin-preserving excision of squamous cell carcinoma of the nasal vestibule.

Surgery for early-stage squamous cell carcinoma of the nasal vestibule (SCCNV) may lead to facial disfigurement. We wanted to investigate if skin-preserving excision of SCCNV with reconstruction is oncologically, aesthetically, and functionally justifiable in cases with proximity to the skin. From 2010 to 2016, 16 patients underwent skin-preserving excision of T1-2 N0 SCCNV by a lateral rhinotomy approach at a tertiary referral center. The inner nose was reconstructed using a mucoperichondrial septal flap for the inner lining and a septal pivot flap and/or auricular cartilage grafting for the framework. Nasal appearance was measured on pre- and postoperative photographs. Median follow-up was 5.4 years. Three (19%) patients received adjuvant radiotherapy. Two (12.5%) recurrences occurred locally, but not at the site of preserved skin. The Kaplan-Meier estimate of local control rate after 5 years was 83%. All patients could be salvaged, giving an ultimate control rate of 100%. Nasal tip projection decreased by 6.7% (p < 0.001), and it was retained normal or near normal in 87.5% of patients. Nasal axis changed by 1.7° (p = 0.5). Nasal deviation occurred in 6.25% (1/16) of patients, and minor alar retraction in 6.25% of patients (1/16). Nasal breathing was normal or close to normal in 75% (12/16) of patients. Skin-preserving excision of SCCNV is oncologically justifiable in selected cases even in proximity to nasal skin. Early inner nasal reconstruction preserves nasal form and function to a high degree. This technique is a suitable alternative to rhinectomy and to avoid the sequelae of radiotherapy in selected cases.

Measurement of bone thickness at the site of titanium miniplates used to retain nasal prostheses in fused computed tomographic data.

Our aim was to investigate the bone thickness at the site of titanium miniplates inserted to retain nasal prostheses. We studied 13 patients who had had titanium miniplates inserted for retention of nasal prostheses with a total of 60 titanium bone screws. A trajectory along each bone screw was segmented in fused computed tomographic (CT) data. Bone thickness was measured along this trajectory on the preoperative CT. The median bone thickness at the positions of the screws implanted on the frontal process of the maxillary bone was 1.4 (range 0.2-6.9) mm (mean 1.8). The median (range) values for men and women were 1.4 (0.2-6.9) mm and 1.3 (0.2-3.3) mm, respectively. The thickest bone was at the cranial part of the frontal process of the maxilla with a median of 2.0 (range 0.3-4.1) mm. However, differences in sex and position were not significant. None of the implant miniplates lost osseointegration. Despite the low bone stock at the lateral aspect of the pyriform aperture, survival of implanted titanium miniplates was 100% in this study group.

Primary surgical treatment of nasal vestibule cancer - therapeutic outcome and reconstructive strategies.

OBJECTIVE: The treatment strategy of squamous cell carcinoma of the nasal vestibule (SCCNV) is controversial. The objective of this study is to investigate the role of surgery, which is the preferred treatment option at our institution. DESIGN: This was a monocentric prospective study of patients that were diagnosed with SCCNV between 2005 and 2013. MATERIAL AND METHODS: Twenty-six patients were included. Tumors were staged using the UICC (7th edition) TNM classification of nasal cavity cancer and the classification proposed by Wang. The primary treatment was surgery in all patients. Survival data were statistically analyzed using the Kaplan-Meier method. The median follow-up time was 6 years. RESULTS: Using the UICC classification, 9/26 tumors were staged as pT1 (35%), 7/26 as pT2 (27%), and 10/26 as pT4a (39%). Using the classification by Wang, 9/26 tumors were staged as pT1 (35%), 15/26 as pT2 (58%), and 2/26 as pT3 (8%). Reconstruction was performed using an implant-retained prosthesis in 50% of patients and by plastic surgery in the remaining 50%. Only 2/26 patients (8%) needed adjuvant radiation therapy. The five-year recurrence-free survival (RFS) was 86.7%, disease-specific survival was 96.2% and overall survival was 91.8% after five years. CONCLUSION: Surgery in SCCNV gives an excellent prognosis and minimized the need for radiotherapy.

Quality of life after nasal cancer resection - surgical versus prosthetic rehabilitation.

BACKGROUND: Nose reconstruction following resection of nasal carcinomas is controversial. The objective of this study is to investigate the effect of surgical reconstruction versus prosthetic rehabilitation on patient quality of life (QOL). DESIGN: This was a monocentric prospective study of patients diagnosed with nasal carcinoma from 2003 to 2013. QOL was evaluated using two organ-specific questionnaires (Rhinoplasty Outcome Evaluation [ROE] and the Functional Rhinoplasty Outcome Inventory-17 [FROI-17]) and a generic questionnaire, the Short-Form 36 Health Survey (SF-36). MATERIAL AND METHODS: Sixty-four patients were included. Patients completed the ROE, FROI-17, and SF-36 questionnaires after nasal reconstruction. Questionnaires were completed by 62.8% of the 51 alive patients. RESULTS: Recurrence-free survival (RFS) was 89.9%, disease-specific survival was 94.5%, and overall survival was 75.5% after five years according to the Kaplan-Meier method. Considering initial tumor stage, early stage patients had a significantly higher self-confidence score in FROI-17 subgroup analysis. In contrast, advanced stage patients showed a significantly higher score for social functioning in SF-36. Prosthetically fitted patients scored highly on the ROE questionnaire showing a high degree of aesthetic satisfaction. Surgically reconstructed patients showed a high degree of self-confidence on the FROI-17 questionnaire. However, the organ-specific ROE and FROI-17 scores were not significantly different between patients who received surgical reconstruction and prosthetic rehabilitation after oncological resection. When comparing the rehabilitation method as a function of tumor stage, there was significantly better score for physical functioning in early stage surgically reconstructed patients in the SF-36, but no significant differences in organ-specific QOL. CONCLUSION: Surgical reconstruction and prosthetic rehabilitation after nasal cancer resection have the same effect on organ- and non-organ-specific QOL.

[Diagnostics and management of choanal atresia]. / Diagnostik und Management der Choanalatresie.

Choanal atresia is a rare malformation that represents a special challenge. While bilateral choanal atresia usually needs to be surgically treated within a few days of birth, the intervention for one-sided choanal atresia can be postponed for years. Treatment planning requires adequate imaging (CT or MRI), which also serves to exclude other skull base malformities. Surgical treatment currently focuses on transnasal endoscopic techniques. Simultaneous resection of the parts of the vomer involved in the atresia seems to be important surgical success. Postoperative stenting is still controversially discussed. Postoperative application of corticosteroid nasal sprays and saline nasal rinsing for several weeks is of great importance. Due to the rarity of the diagnosis, the absence of prospective randomized controlled trials does not allow definitive statements regarding the optimal surgical technique or stenting.

[Quality of life in patients with vestibular schwannoma]. / Lebensqualität von Patienten mit Vestibularisschwannom.

BACKGROUND: Vestibular schwannoma (VS) is a disease which might affect health-related quality of life (HR-QOL) in a negative manner. For many years, only generic quality of life instruments such as SF-36 were available to measure HR-QOL. However, some years ago, the Penn Acoustic Neuroma Quality Of Life (PANQOL) tool, a disease-specific instrument, was developed and validated. It is expected that the application of this instrument will be able to better assess relevant aspects of the HR-QOL of VS patients in the future. A validated German version of the instrument does not exist yet. The disease-specific symptoms most frequently named by patients are headache and dizziness. RESULTS AND DISCUSSION: The available literature shows that the therapeutic approaches affect HR-QOL differently. In particular, radiation therapy of small and medium-sized tumors has no pronounced negative effects on HR-QOL. However, restrictions after surgery become similar to those after radiotherapy over the course of several years. For large VS with a diameter >3 cm, no guiding data on this aspect are currently available. To clarify the outstanding issues, future prospective studies with long-term follow-up of 10 years and more are desirable.

Acupuncture in posttonsillectomy pain : A prospective, double-blinded, randomized, controlled trial.

BACKGROUND: Postoperative swallowing pain is one of the most unpleasant after-effects of tonsillectomy. During recent years, the demand for alternatives to drug-based pain therapy has continued to grow, although the topic has received little research attention until now. MATERIALS AND METHODS: A total of 46 patients were randomized into verum acupuncture, control acupuncture, and drug-based treatment groups. All patients received nonsteroidal antirheumatic drugs (NSAIDs). One hour after drug intake, the verum group also received acupuncture according to classical acupuncture rules (S34, S44 and PC5). The control group had acupuncture needles placed at nonspecific acupuncture points in the midaxillary line. Acupuncture was performed by a blinded acupuncturist, who had learnt exclusively these techniques in the run up to the study. Patients were asked to evaluate their pain before, and at intervals of 20 min, 1 h, 2 h, and 3 h after drug intake/acupuncture treatment using a visual analog scale (VAS). RESULTS: The analgesic effect of acupuncture was significant up to 3 hours in the verum group (p < 0.05). The analgesic effect in the control acupuncture group was significant for up to 1 h after acupuncture (p < 0.05). With reference to the time point before acupuncture, the differences between both acupuncture groups and the drug group were significant (p < 0.01) over the whole time. CONCLUSION: Acupuncture is an effective complement to NSAIDs in the treatment of posttonsillectomy pain. Particularly patients with allergies, drug intolerance, or reduced response to the commonly administered drugs may benefit from acupuncture.

[Acupuncture in posttonsillectomy pain : A prospective double-blind randomized controlled trial. German version]. / Einsatz von Akupunktur bei Posttonsillektomieschmerz : Eine prospektive, randomisierte und kontrollierte Doppelblindstudie.

BACKGROUND: Postoperative swallowing pain is one of the most unpleasant after-effects of tonsillectomy. During recent years, the demand for alternatives to drug-based pain therapy has continued to grow, although the topic has received little research attention until now. MATERIALS AND METHODS: A total of 46 patients were randomized into verum acupuncture, control acupuncture, and drug-based treatment groups. All patients received nonsteroidal antirheumatic drugs (NSAIDs). One hour after drug intake, the verum group also received acupuncture according to classical acupuncture rules (S34, S44 and PC5). The control group had acupuncture needles placed at nonspecific acupuncture points in the midaxillary line. Acupuncture was performed by a blinded acupuncturist, who had learnt exclusively these techniques in the run up to the study. Patients were asked to evaluate their pain before, and at intervals of 20 min, 1 h, 2 h, and 3 h after drug intake/acupuncture treatment using a visual analog scale (VAS). RESULTS: The analgesic effect of acupuncture was significant up to 3 hours in the verum group (p < 0.05). The analgesic effect in the control acupuncture group was significant for up to 1 h after acupuncture (p < 0.05). With reference to the time point before acupuncture, the differences between both acupuncture groups and the drug group were significant (p < 0.01) over the whole time. CONCLUSION: Acupuncture is an effective complement to NSAIDs in the treatment of posttonsillectomy pain. Particularly patients with allergies, drug intolerance, or reduced response to the commonly administered drugs may benefit from acupuncture.

Quality of life after primary septorhinoplasty in deviated- and non-deviated nose measured with ROE, FROI-17 and SF-36.

BACKGROUND: Quality of life measurements are gaining in importance. The present study was conducted with the aim to compare patient satisfaction after septorhinoplasty according to their preoperative nasal deformity. METHODS: The patients completed two disease-specific questionnaires before their surgery: the Functional Rhinoplasty Outcome Inventory (FROI-17), the Rhinoplasty Outcome Evaluation (ROE) and as a general instrument, the Short Form 36 Health Survey (SF-36). The second measurement was taken during an outpatient examination 12 months after their primary septorhinoplasty. Patients were grouped in nasal axis deviation (NAD), nasal hump deformity (NHD) and NAD plus NHD. Additionally the patients with preoperative NAD and NAD+NHD were combined as deviated nose and compared to the non-deviation group. RESULTS: One hundred and two patients (51 male and 51 female) underwent primary septorhinoplasty. The ROE- and the FROI-17 overall score including all three subgroups showed significant postoperative improvements. Regarding the SF-36, the postoperative score improved significantly only in two scales (role-functioning physical and mental health). Looking at the the different QoL questionnaires, there were significant postoperative differences in regards to deviated versus non-deviated nose in the FROI-17 overall- and FROI-17 subscores (nasal and general symptoms) and in three scales of the SF-36 (vitality, social functioning, role-functioning emotional), showing a greater postoperative satisfaction in the deviated-nose patient. CONCLUSION: Patients with and without nasal deviation showed improved QoL after their surgery, as measured with the ROE, the FROI-17 and the SF-36. The patients with a nasal deviation showed a significantly better outcome, as measured with the FROI-17, in comparison with the non-deviated group.

[Diabetes mellitus as a prognostic marker in oropharyngeal and laryngeal squamous cell carcinoma]. / Diabetes mellitus als prognostischer Marker beim Oropharynx- und Larynxkarzinom.

Recent experimental and clinical studies have provided compelling evidence that diabetes mellitus (DM) is an important risk factor in various cancers, and may affect both pathogenesis and prognosis. Additionally, antidiabetic agents such as metformin exhibit an antitumorigenic effect. However, to date there is insufficient knowledge about the role of DM in the pathogenesis and prognosis of head and neck squamous cell carcinoma (HNSCC).In a retrospective monocentric study including 424 patients with SCC of the oropharynx (OPSCC) or larynx (LaSCC), the impact of DM on clinical and histopathologic parameters was investigated. The authors found a rising incidence of DM among LaSCC patients (<10 % until 2005 and 20 % since 2006) and a significant association between DM and clinical and histopathologic features (age, gender, tumor size, and pathologic grading), which depended on the anatomic site. Moreover, a clear trend toward unfavorable progression-free and overall survival of HNSCC patients with DM upon current treatment modalities was evident.The presented data support a relative increase in patients with DM, particularly for LaSCC. This might have a sustained influence on treatment decisions and management, and should be considered in future clinical trials. A better understanding of the cellular and molecular traits of HNSCC in DM could pave the way for innovative therapeutic strategies in terms of personalized medicine.

Music therapy as specific and complementary training for adults after cochlear implantation: A pilot study.

OBJECTIVES: Although cochlear implant (CI) users achieve good speech comprehension, they experience difficulty perceiving music and prosody in speech. As the provision of music training in rehabilitation is limited, a novel concept of music therapy for rehabilitation of adult CI users was developed and evaluated in this pilot study. METHODS: Twelve unilaterally implanted, postlingually deafened CI users attended ten sessions of individualized and standardized training. The training started about 6 weeks after the initial activation of the speech processor. Before and after therapy, psychological and musical tests were applied in order to evaluate the effects of music therapy. CI users completed the musical tests in two conditions: bilateral (CI + contralateral, unimplanted ear) and unilateral (CI only). RESULTS: After therapy, improvements were observed in the subjective sound quality (Hearing Implant Sound Quality Index) and the global score on the self-concept questionnaire (Multidimensional Self-Concept Scales) as well as in the musical subtests for melody recognition and for timbre identification in the unilateral condition. Discussion Preliminary results suggest improvements in subjective hearing and music perception, with an additional increase in global self-concept and enhanced daily listening capacities. CONCLUSIONS: The novel concept of individualized music therapy seems to provide an effective treatment option in the rehabilitation of adult CI users. Further investigations are necessary to evaluate effects in the area of prosody perception and to separate therapy effects from general learning effects in CI rehabilitation.

[The impact of cochlear implants on the quality of life of patients with single-sided deafness]. / Der Einfluss der CI-Versorgung von einseitig tauben Patienten auf die Lebensqualität.

BACKGROUND: Unilaterally deaf patients are increasingly supplied with a cochlear implant (CI). In the present study the change in quality of life following implantation was investigated. PATIENTS AND METHODS: The study comprised 20 postlingual CI recipients with single-sided deafness, who were divided into two groups: "normal hearing" (group 1) and "moderate impairment" (group 2) contralaterally. Their quality of life was determined using four standardized questionnaires (NCIQ, HPS, APHAB, HHIE) and a visual analogue scale. RESULTS: With the exception of the sensation of loud everyday sounds (APHAB AV scale) reported by patients from group 2, all study participants benefited significantly from the implantation. DISCUSSION: The problems caused by the aversiveness of loud everyday sounds can be explained by the enhanced transmission of high frequencies and the associated unfamiliar sensations by the CI system. The effects of deafness duration and response shift remain to be investigated. CONCLUSION: Cochlear implantation for unilaterally deaf patients was found to be a legitimate and meaningful rehabilitation measure.

[Grafts with microvascular anastomosis. Their use in the head and neck region following radiotherapy and vessel depletion]. / Mikrovaskulär anastomosierte Transplantate. Verwendung in der Kopf-Hals-Region nach Bestrahlung und Gefäßdepletion.

Surgical tumor removal is often the treatment of choice in patients with head and neck squamous cell carcinoma. Depending on the extent of tumor resection, large defects are often produced in the individual head and neck regions, necessitating reconstructive surgery to avoid further functional impairment. In principle, this decision depends on the size and location of the defect, the aesthetic importance of the region and the functional significance of the area to be replaced. Reconstructive free flap procedures in patients who have undergone radiotherapy or exhibit vessel depletion in the neck due to multiple previous surgical interventions are particularly challenging. In order to ensure the best possible outcomes of surgical oncology therapies under difficult circumstances, this paper discusses the important factors and variables that can increase the success rate of microvascular grafts in irradiated or multiply resected patients.

[Reconstruction of maxillary defects using a free scapular angle flap]. / Rekonstruktion von Oberkieferdefekten mit einem freien Skapula-angle-Lappen.

BACKGROUND: In addition to prosthetic rehabilitation, maxillary defects can also be surgically reconstructed. Soft-tissue reconstruction employs a radial forearm or latissimus dorsi muscle flap, while bony reconstruction can be achieved using a fibula, iliac crest, or scapular flap. Reconstruction using a scapular flap is further divided into two subgroups: the traditional scapular flap with the circumflex scapular artery as the donor vessel and the scapular angle flap with the angular artery originating from the thoracodorsal artery as the donor vessel. MATERIALS AND METHODS: We report on four patients who underwent successful reconstruction with a free scapular angle flap between 2009 and 2011, following maxillary resection due to malignancy. RESULTS: Vertical positioning of the scapular angle flap enables reconstruction of the facial contour, whereas its horizontal alignment and microvascular anastomosis makes a bony reconstruction of the hard palate possible. CONCLUSIONS: The versatility, low rate of donor site morbidity and shape of the scapular angle flap--which resembles that of the hard palate--render it ideal for plastic reconstruction. The suitability of bone quality for dental rehabilitation with implants is a topic of controversial discussion. The scapular angle flap represents an alternative to obturator prosthesis for the reconstruction of maxillary defects ≥ grade I according to Okay et al.

[Development and validation of the Tonsillectomy Outcome Inventory 14]. / Entwicklung und Validierung des Tonsillectomy Outcome Inventory 14.

BACKGROUND: Until now, no validated instrument to measure disease-specific, health-related quality of life (HR-QOL) in adults with chronic tonsillitis (CTO) exists. MATERIAL AND METHODS: After an item reduction of the alpha-version of the Tonsillectomy Outcome Inventory (TOI), the TOI-14 resulted. In addition to the total score, it includes the subscales throat problems, overall health, resources, and social-psychological restrictions. In phase 2, the TOI-14 was prospectively validated on 108 adults with CTO, who had undergone a tonsillectomy. RESULTS: The TOI-14 had, on average, good reliability. It included all important aspects of the HR-QOL. Patients with CTO can be distinguished with high sensitivity from healthy subjects. All scores showed moderate to good correlation with the subjective limitation in quality of life. The sensitivity of the questionnaire demonstrated major effects postoperatively. CONCLUSION: The TOI-14 constitutes the first worldwide-validated, disease-specific instrument to measure HR-QOL in adults with CTO. Due to its ease of use, it can be utilized both in the outcome research and in clinical routine.

Chemovirotherapy for head and neck squamous cell carcinoma with EGFR-targeted and CD/UPRT-armed oncolytic measles virus.

First-line treatment of recurrent and/or refractory head and neck squamous cell carcinoma (HNSCC) is based on platinum, 5-fluorouracil (5-FU) and the monoclonal antiEGFR antibody cetuximab. However, in most cases this chemoimmunotherapy does not cure the disease, and more than 50% of HNSCC patients are dying because of local recurrence of the tumors. In the majority of cases, HNSCC overexpress the epidermal growth factor receptor (EGFR), and its presence is associated with a poor outcome. In this study, we engineered an EGFR-targeted oncolytic measles virus (MV), armed with the bifunctional enzyme cytosine deaminase/uracil phosphoribosyltransferase (CD/UPRT). CD/UPRT converts 5-fluorocytosine (5-FC) into the chemotherapeutic 5-FU, a mainstay of HNSCC chemotherapy. This virus efficiently replicates in and lyses primary HNSCC cells in vitro. Arming with CD/UPRT mediates efficient prodrug activation with high bystander killing of non-infected tumor cells. In mice bearing primary HNSCC xenografts, intratumoral administration of MV-antiEGFR resulted in statistically significant tumor growth delay and prolongation of survival. Importantly, combination with 5-FC is superior to virus-only treatment leading to significant tumor growth inhibition. Thus, chemovirotherapy with EGFR-targeted and CD/UPRT-armed MV is highly efficacious in preclinical settings with direct translational implications for a planned Phase I clinical trial of MV for locoregional treatment of HNSCC.