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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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).</p> <p>Conclusions</p> <p>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.</p

Treatment of Sialolithiasis: What Has Changed? An Update of the Treatment Algorithms and a Review of the Literature

Treatment for sialolithiasis has undergone significant changes since the 1990s. Following the development of new minimally invasive and gland-preserving treatment modalities, a 40&ndash;50% rate of gland resection was reduced to less than 5%. Extracorporeal shock-wave lithotripsy (ESWL), refinement and extension of methods of transoral duct surgery (TDS), and in particular diagnostic and interventional sialendoscopy (intSE) are substantial parts of the new treatment regimen. It has also become evident that combining the different treatment modalities further increases the effectiveness of therapy, as has been especially evident with the combined endoscopic&ndash;transcutaneous approach. In the wake of these remarkable developments, a treatment algorithm was published in 2009 including all the known relevant therapeutic tools. However, new developments have also taken place during the last 10 years. Intraductal shock-wave lithotripsy (ISWL) has led to remarkable improvements thanks to the introduction of new devices, instruments, materials, and techniques, after earlier applications had not been sufficiently effective. Techniques involving combined approaches have been refined and modified. TDS methods have been modified through the introduction of sialendoscopy-assisted TDS in submandibular stones and a retropapillary approach for distal parotid sialolithiasis. Recent trends have revealed a potential for significant changes in therapeutic strategies for both major salivary glands. For the submandibular gland, ISWL has replaced ESWL and TDS to some extent. For parotid stones, ISWL and modifications of TDS have led to reduced use of ESWL and the combined transcutaneous&ndash;sialendoscopic approach. To illustrate these changes, we are here providing an updated treatment algorithm, including tried and tested techniques as well as promising new treatment modalities. Prognostic factors (e.g., the size or location of the stones), which are well recognized as having a strong impact on the prognosis, are taken into account and supplemented by additional factors associated with the new applications (e.g., the visibility or accessibility of the stones relative to the anatomy of the duct system)

Frozen Section of Parotid Gland Tumours: The Head and Neck Pathologist as a Key Member of the Surgical Team

Introduction: The aim of this study was to evaluate the impact of subspecialised head and neck versus general surgical pathologists on the reliability of the histopathologic evaluation during intraoperative consultation. Materials and Methods: The medical records of all patients who underwent a parotidectomy with frozen section between 2006 and 2021 were retrospectively evaluated. The frozen section was evaluated for sensitivity, specificity, accuracy, and predictive value. Assessment by two groups of pathologists (subspecialised head and neck versus general surgical pathologists) was compared, and the nature or types of misdiagnoses compared with final diagnoses on paraffin sections were analysed for the two groups. Results: Our study sample was made up of 669 cases. The mean age of patients was 57.7 years (range: 10–94 years). Of these, 490 patients had a benign lesion (73.2%), whereas 179 patients had a malignant lesion (26.8%). Frozen section had an overall accuracy of 97.6%, sensitivity for malignancy was 91.1%, specificity was 100%, PPV was 100%, and the NPV was 96.8%. The exact histologic subtype in the group of malignant tumours was correctly identified in FS in 89.4% of cases. A comparison of head and neck pathologists versus general surgical pathologists revealed a highly statistically significant difference concerning both overall detection of malignancy (p p < 0.001). Conclusion: Involvement of subspecialised head and neck pathologists in the intraoperative consultation for salivary gland tumours results in a gain of 19.8% more sensitivity, underlining the importance of specialisation in salivary gland pathology for the optimisation of frozen section quality

The Offprint of an Abnormal Pre-Parotidectomy Electrodiagnostic Finding in a Normally Functioning Facial Nerve: Correlation with Intraoperative Findings, Histology and Postoperative Facial Nerve Function

The aim of this study was to search for associations between an electrodiagnostically abnormal but clinically normal facial nerve before parotidectomy and the intraoperative findings, as well as the postoperative facial nerve function. The records of all patients treated for parotid tumors between 2002 and 2021 with a preoperative House&ndash;Brackmann score of grade I but an abnormal electrophysiologic finding were studied retrospectively. A total of 285 patients were included in this study, and 222 patients had a benign lesion (77.9%), whereas 63 cases had a malignant tumor (22.1%). Electroneurographic facial nerve involvement was associated with nerve displacement in 185 cases (64.9%) and infiltration in 17 cases (6%). In 83 cases (29.1%), no tumor&ndash;nerve interface could be detected intraoperatively. An electroneurographic signal was absent despite supramaximal stimulation in 6/17 cases with nerve infiltration and in 17/268 cases without nerve infiltration (p &lt; 0.001). The electrophysiologic involvement of a normal facial nerve is not pathognomonic for a malignancy (22%), but it presents a rather rare (~6%) sign of a &ldquo;true&rdquo; nerve infiltration and could also appear in tumors without any contact with the facial nerve (~29%). Of our cases, two thirds of those with an anatomic nerve preservation and facial palsy had already directly and postoperatively recovered to a major extent in the midterm

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

Secondary Tracheoesophageal Puncture After Laryngectomy Increases Complications With Shunt and Voice Prosthesis

Objectives/Hypothesis To evaluate the demographics, clinical features, management, and prognostic indicators of tracheoesophageal puncture complications in patients undergoing placement of voice prosthesis following cancer treatment. Study Design Retrospective analysis. Methods A retrospective analysis was conducted of cases from a tertiary referral center diagnosed between 1996 and 2015. Multivariate logistic regression was used to determine factors associated with tracheoesophageal puncture (TEP) and voice prostheses–complication‐free survival (TEP/VP‐CFS). Results One hundred fourteen cases were identified. Most patients were males (92.9%) with pT3 (26.8%) or pT4 (58.1%) N+ (53.6%) tumors. All patients received laryngectomy as the primary treatment, with 75% of patients receiving adjuvant radiation therapy or chemoradiotherapy. Complications with TEP were common (65.2%). The most frequent problem was salivary leakage (50.0%), which at the same time was the most common reason for changing the prosthesis. On univariate regression analysis, prosthesis placement time after adjuvant radiotherapy (hazard ratio [HR]: 4.17, 95% confidence interval [CI]: 2‐8.69), secondary prosthesis placement after primary surgery (HR: 3.97, 95% CI: 1.99‐7.9), and laryngectomy with flap reconstruction (HR: 1.96, 95% CI: 0.99‐3.89) were significant prognosticators for complications. Multivariate regression analysis revealed secondary prosthesis placement after adjuvant radiotherapy (HR: 3.66, 95% CI: 1.39‐9.68) or after primary surgery (HR: 2.57, 95% CI: 0.92‐7.2) to be the strongest predictors of reduced TEP/VP‐CFS. Conclusions Secondary prosthesis placement after primary surgery, placement after previous irradiation, and laryngectomy with flap reconstruction are predictors of poor TEP/VP‐CFS. Planned adjuvant radiotherapy is not a contraindication for TEP with prosthetic placement, but it is very important to place the prosthesis during the primary surgery or at least before scheduled radiotherapy. Level of Evidence 4 Laryngoscope, 202

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' &gt; G″), whereas some underwent a change from solid-like to liquid-like (G' &lt; 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

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′ &gt; G″), whereas some underwent a change from solid-like to liquid-like (G′ &lt; 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

Table_1_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.docx

PurposeTreatment 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 methodsBetween 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.ResultsThe 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).ConclusionsAdherence 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.</p