High-grade salivary gland cancer: is surgery followed by radiotherapy an adequate treatment to reach tumor control? Results from a tertiary referral centre focussing on incidence and management of distant metastases.

PURPOSE: Salivary Gland cancer (SGC) is a rare and heterogenous group of tumors. Standard therapeutic options achieve high local but poor distant control rates, especially in high-grade SGC. The aim of this monocentric study was to evaluate patterns of recurrence and its treatment options (local ablative vs. systemic) in a homogenously treated patient population with high-grade SGC after surgery and radio(chemo)therapy. METHODS: Monocentric, retrospective study of patients with newly diagnosed high-grade salivary gland cancer. We retrospectively reviewed clinical reports from 69 patients with high-grade salivary gland cancer in a single-center audit. Survival rates were calculated using the Kaplan-Meier method and prognostic variables were analyzed (univariate analysis: log-rank test; multivariate analysis: Cox regression analysis). RESULTS: The median time of follow-up was 31 months. After 5 years, the cumulative overall survival was 65.2%, cumulative incidence of local recurrence was 7.2%, whereas the cumulative incidence of distant metastases was 43.5% after 5 years. 30 of 69 patients developed distant metastases during the time of follow-up, especially patients with adenoid cystic carcinoma, salivary duct carcinoma, adenocarcinoma NOS and acinic cell carcinoma with high-grade transformation. The most common type of therapy therefore was chemotherapy (50%). 85.7% of patients with local ablative therapy of distant metastases show disease progression during follow-up afterwards. CONCLUSION: With surgery and radio-chemotherapy, a high rate of loco-regional control is reached, but over 40% of patients develop distant metastases in the further follow-up which usually present a diffuse pattern involving in a diffuse metastases. Therefore, in the future, intensified interdisciplinary combination therapies even in the first-line treatment in certain subtypes of high-grade SGC should be investigated.

Questionnaire-based detection of immune-related adverse events in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) have become standard treatment in different tumor entities. However, safe treatment with ICI targeting the PD-1/PD-L1 axis requires early detection of immune-related adverse events (irAE). There exist different questionnaires of drug manufacturers for the detection of irAE that have not been validated so far. METHODS: The prospective non-interventional ST-ICI trial studied treatment with PD-1/PD-L1 ICI alone or combined with radiotherapy. In the current analysis, the detection rate of self-reported irAE with a patient questionnaire containing 41 different questions was compared to clinician-reported irAE. RESULTS: Between April 2017 and August 2019, a total of 104 patients were prospectively enrolled. NSCLC (44%) and HNSCC (42%) were the most frequent tumor entities. A total of 784 questionnaires were collected. A total of 29 irAE were reported by clinicians. The most frequent irAE was hypothyroidism (9%), followed by skin reactions (5%), hepatitis (4%), diarrhea (3%), and pneumonitis (3%). Questions that became significantly more often positive at time points of clinician-reported irAE were "weight change", "difficulty to grip things", "bloody or mucous stool" and "insomnia". Self-reported organ-specific questions detected at least 50% of clinician-reported irAE of gastrointestinal, lung, endocrine, and skin irAE. It was not possible to detect hepatic irAE with the questionnaire. CONCLUSION: Questionnaires can help to detect gastrointestinal, lung, endocrine, or skin irAE, but not hepatic irAE. Questions on "weight change" and "insomnia" may help to increase the detection rate of irAE, besides organ-specific questions. These results are a valuable contribution to the future development of a specific and practicable questionnaire for early self-reported detection of irAE during ICI therapy in cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03453892 . Registered on 05 March 2018.

Treatment with (chemo)-radiation in old patients (≥76 years of age) with newly diagnosed non-metastatic squamous cell cancer of the head and neck region: real-world data from a tertiary referral center.

Purpose: Treatment of patients with cancer of the head and neck region is in focus in a multitude of studies. Of these patients, one patient group, those aged 76 and more, is mostly underrepresented despite requiring thorough and well-reasoned treatment decisions to offer curative treatment. This study investigates real-world data on curative treatment of old (≥76 years) patients with newly diagnosed squamous cell carcinoma of the head and neck region (HNSCC). Patients and methods: Between January 2010 and December 2021, we identified 71 patients older than 76 years with newly diagnosed HNSCC and cM0 at the Department of Radiation Oncology of the University Hospital of Erlangen-Nuremberg. Using electronic medical records, we analyzed treatment patterns and outcomes in terms of overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) rate. Additionally, we performed univariate risk analysis and Cox regression in order to identify predictive factors associated with the abovementioned treatment outcomes. Results: The median follow-up was 18 months. OS was 83%, 79%, and 72% after 1 year, 2 years, and 3 years, respectively. PFS was 69%, 54%, and 46% after 1 year, 2 years, and 3 years, respectively. A total of 34 (48%) patients were treated with standard therapy according to current guidelines. The reasons for deviation from standard therapy before or during treatment were as follows: unfitness for cisplatin-based chemotherapy (n = 37), reduction of chemotherapy (n = 3), and dose reduction/interruption of radiotherapy (n = 8). Carboplatin-based systemic therapy showed improved PFS compared to cisplatin or cetuximab (60 vs. 28 vs. 15 months, p = 0.037) but without impact on OS (83 vs. 52 vs. 38 months, p = 0.807). Oropharyngeal tumor localization (p = 0.026) and combined treatment (surgery and postoperative treatment) (p = 0.008) were significant predictors for a better OS. In multivariate analysis, oropharyngeal tumor localization (p = 0.011) and combined treatment (p = 0.041) showed significantly increased PFS. After 1 year, 2 years, and 3 years, the cumulative incidence of locoregional recurrences (LRRs) was 13%, 24%, and 27%, respectively, and was significantly decreased in patients with oropharyngeal tumor localization (p = 0.037). Conclusions: Adherence to treatment protocols for radiotherapy alone in old patients with HNSCC is good, whereas the application of concurrent chemotherapy often deviates from guidelines in terms of de-escalation. An important risk factor for decreased OS, PFS, and a higher rate of LRR appears to be non-oropharyngeal tumor location in old patients.

Sinonasal mixed transitional epithelial-seromucinous papillary glandular neoplasms with BRAF p.V600E mutations - sinonasal analogues to the sialadenoma papilliferum family tumors.

Sinonasal non-intestinal type adenocarcinoma (non-ITAC) is a heterogeneous category that may benefit from improved taxonomy. With the recognition that most non-ITAC are phenotypically seromucinous, stratification may be improved by applying salivary type morphologic criteria and molecular findings. We report two cases of papillary seromucinous adenocarcinoma with sinonasal papilloma-like surface components that show histologic and molecular features analogous to the salivary sialadenoma papilliferum family of tumors. Case 1 concerns a 50-year-old female who presented with a left anterior nasoethmoid polyp, while case 2 is that of a 74 year old female with nasal polyposis. Histologically, both cases demonstrated a surface transitional sinonasal papilloma-like component (more prominent in case 2) with a deeper bilayered glandular component showing papillary and tufted micropapillary growth of monomorphic columnar to cuboidal cells with eosinophilic cytoplasm. Case 1 also showed a deep cribriform/microcystic component. Immunostains showed a delimiting p63/p40 positive basal layer around the SOX-10 positive glandular elements, while the transitional sinonasal papilloma-like components were diffusely p63/p40 positive. Like sialadenoma papilliferum and related tumors, both cases demonstrated BRAF p.V600E mutations in both components and no other alterations. The patients remain disease free at 9 and 19 months respectively. Our cases illustrate a novel sinonasal lesion and suggest that improved morphologic and molecular categorization may refine and reduce the category of non-ITAC.

Results of contralateral anastomosis of microvascular free flaps in head and neck reconstruction.

OBJECTIVES: Despite various solutions to the issue of ipsilateral vessel-depleted neck in microvascular head and neck reconstruction, concrete data on its safety and implementation are scarce. This paper focuses on the feasibility and success rates of contralateral anastomosis in free flap reconstruction in the head and neck region. METHODS: This single-center retrospective study at a tertiary referral center includes all patients who underwent free flap reconstruction of the head and neck with contralateral anastomosis between January 1st, 2007 and February 28th, 2021. Primary objectives were frequency, success, and flap-associated complication rates. Secondary objectives were recipient vessels and flap type. RESULTS: Of 318 patients who underwent microvascular reconstruction, anastomosis was performed on the contralateral side of the neck in 32 patients (10.0%). Recipient vessels involved mainly the superior thyroid artery (74.2%; n = 23) and the facial vein (51.1%; n = 23). Thirty patients (93.8%) received a radial forearm free flap. Flap-associated complications occurred in 12.5% of included cases (n = 4): one partial flap necrosis (3.1%), one anastomotic insufficiency (3.1%), one venous thrombosis of the microvascular pedicle (3.1%), and one wound dehiscence (3.1%). All of these complications were resolved without complete flap loss. CONCLUSION: This study demonstrates that contralateral anastomosis is a successful and safe option in microvascular head and neck reconstruction, especially using a radial forearm free flap. Thus, anastomosing to the contralateral side of the neck can be advocated as a valuable option in the ipsilateral vessel-depleted neck.

Histopathology of Parotid Pleomorphic Adenomas: A "Pleomorphic Approach" to a Demanding Lesion.

OBJECTIVES/HYPOTHESIS: The aim of this study was to identify potential associations between epidemiologic, morphologic, and histopathologic features in pleomorphic adenomas (PAs) of the parotid gland in order to extract information about the natural course and biologic behavior of these lesions on the basis of a single-center series of 845 cases within a period of 15 years. STUDY DESIGN: Retrospective study in a tertiary academic center. METHODS: For this study, an experienced head and neck pathologist critically re-evaluated the histological slides of the pathological specimens of all patients who underwent a parotidectomy for PA of the parotid gland between 2006 and 2020. RESULTS: A total of 845 cases made up our study sample. Our analysis showed a statistically significant association of the histologic subtype with younger age (P = .001) and maximal diameter (P = .044), with the hypocellular type being encountered more often in younger patients and in smaller lesions. The same subtype was significantly associated with an incomplete capsule (P = .001), pseudopodia (P = .006), and satellite nodules (P = .001). An incomplete capsule was associated with the presence of pseudopodia (P = .001) and satellite nodules (P = .001). CONCLUSION: It seems that various histologic subtypes have different capsule-producing properties. Apparently, over the course of time, tumor material builds a finger-like projection still inside the capsule, separates itself from the parenchyma with fibrous tissue still remaining enclosed within the capsule (pseudopodium), slowly penetrates the capsule (incomplete capsule), and leaves the main lesion taking a part of the capsule with it (satellite nodules). Laryngoscope, 132:73-77, 2022.

A complex fracture of the hyoid bone and the larynx after a bicycle accident - Case report and review of literature.

INTRODUCTION AND IMPORTANCE: Reports about laryngeal trauma and fractures of the hyoid bone are rare in the literature. Most cases are forensic cases and the results of postmortem analysis. Traumatic larynx and hyoid bone fractures represent a rare but important differential diagnosis of the common symptom hoarseness. CASE PRESENTATION: A 60-year-old female patient presented with unclear dysphonia and globus sensation following intubation for a surgical treatment for a lower leg fracture after a bicycle accident two months ago. Endoscopy and the computed tomography (CT) of the neck revealed a fixed and immobile fractured piece of the larynx, a hyoid bone fracture and a pseudarthrosis between the greater horn of the hyoid bone and the upper edge of the thyroid cartilage. The hyoid bone fracture led to a distortion of the supraglottis. After surgical removal of the fractured part of the hyoid bone and the pseudarthrosis separation, the supraglottis appeared symmetrical again. Four weeks after surgery the patient was symptom-free. CLINICAL DISCUSSION: Though combined hyoid bone and larynx fractures after traumatic injuries are rare, they represent an important differential diagnosis in trauma patients with dysphagia or dysphonia. The clinical symptoms can vary and occur immediately or within a latent period taking weeks or months until the proper diagnosis. Depending on the symptoms, surgical management can be effective. CONCLUSION: An isolated partial resection of the hyoid bone with separation of the pseudarthrosis is a reasonable therapeutic option and can lead to completely resolving symptom. Preoperatively, a CT provides further valuable information.

Human Laryngeal Mucus from the Vocal Folds: Rheological Characterization by Particle Tracking Microrheology and Oscillatory Shear Rheology.

Mucus consistency affects voice physiology and is connected to voice disorders. Nevertheless, the rheological characteristics of human laryngeal mucus from the vocal folds remain unknown. Knowledge about mucus viscoelasticity enables fabrication of artificial mucus with natural properties, more realistic ex-vivo experiments and promotes a better understanding and improved treatment of dysphonia with regard to mucus consistency. We studied human laryngeal mucus samples from the vocal folds with two complementary approaches: 19 samples were successfully applied to particle tracking microrheology (PTM) and five additional samples to oscillatory shear rheology (OSR). Mucus was collected by experienced laryngologists from patients together with demographic data. The analysis of the viscoelasticity revealed diversity among the investigated mucus samples according to their rigidity (absolute G' and G″). Moreover some samples revealed throughout solid-like character (G' > G″), whereas some underwent a change from solid-like to liquid-like (G' < G″). This led to a subdivision into three groups. We assume that the reason for the differences is a variation in the hydration level of the mucus, which affects the mucin concentration and network formation factors of the mucin mesh. The demographic data could not be correlated to the differences, except for the smoking behavior. Mucus of predominant liquid-like character was associated with current smokers.

Lewy body pathology is associated with mitochondrial DNA damage in Parkinson's disease.

Mitochondrial dysfunction has been strongly implicated in the pathogenesis of Parkinson's disease (PD) and Alzheimer's disease (AD), but its relation to protein aggregation is unclear. PD is characterized by synuclein aggregation (i.e., Lewy body [LB] formation). In AD, the abnormal accumulation of tau protein forms neurofibrillary tangles. In this study, we laser-dissected LB-positive and -negative neurons from the substantia nigra of postmortem PD brains, and tau-positive and -negative hippocampal neurons from AD brains. We quantified mitochondrial DNA deletions in relation to the cellular phenotype and in comparison with age-matched controls. Deletion levels were highest in LB-positive neurons of PD brains (40.5 ± 16.8%), followed by LB-negative neurons of PD cases (31.8 ± 14.4%) and control subjects (25.6 ± 17.5%; analysis of variance p < 0.005). In hippocampal neurons, deletion levels were 25%-30%, independent of disease status and neurofibrillary tangles. The presented findings imply increased mitochondrial DNA damage in LB-positive midbrain neurons, but do not support a direct causative link of respiratory chain dysfunction and protein aggregation.

Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions.

BACKGROUND: Deletions of the mitochondrial DNA (mtDNA) accumulate to high levels in dopaminergic neurons of the substantia nigra pars compacta (SNc) in normal aging and in patients with Parkinson's disease (PD). Human nigral neurons characteristically contain the pigment neuromelanin (NM), which is believed to alter the cellular redox-status. The impact of neuronal pigmentation, neurotransmitter status and brainstem location on the susceptibility to mtDNA damage remains unclear. We quantified mtDNA deletions (ΔmtDNA) in single pigmented and non-pigmented catecholaminergic, as well as non-catecholaminergic neurons of the human SNc, the ventral tegmental area (VTA) and the locus coeruleus (LC), using laser capture microdissection and single-cell real-time PCR. RESULTS: In healthy aged individuals, ΔmtDNA levels were highest in pigmented catecholaminergic neurons (25.2 ± 14.9%), followed by non-pigmented catecholamergic (18.0 ± 11.2%) and non-catecholaminergic neurons (12.3 ± 12.3%; p < 0.001). Within the catecholaminergic population, ΔmtDNA levels were highest in dopaminergic neurons of the SNc (33.9 ± 21.6%) followed by dopaminergic neurons of the VTA (21.9 ± 12.3%) and noradrenergic neurons of the LC (11.1 ± 11.4%; p < 0.001). In PD patients, there was a trend to an elevated mutation load in surviving non-pigmented nigral neurons (27.13 ± 16.73) compared to age-matched controls (19.15 ± 11.06; p = 0.052), but levels where similar in pigmented nigral neurons of PD patients (41.62 ± 19.61) and controls (41.80 ± 22.62). CONCLUSIONS: Catecholaminergic brainstem neurons are differentially susceptible to mtDNA damage. Pigmented dopaminergic neurons of the SNc show the highest ΔmtDNA levels, possibly explaining the exceptional vulnerability of the nigro-striatal system in PD and aging. Although loss of pigmented noradrenergic LC neurons also is an early feature of PD pathology, mtDNA levels are not elevated in this nucleus in healthy controls. Thus, ΔmtDNA are neither an inevitable consequence of catecholamine metabolism nor a universal explanation for the regional vulnerability seen in PD.