A DNA methylation atlas of normal human cell types.

DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2-5. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

Changes in Smoking Behavior, Stress, and Sleep Duration Among Israeli Hospital Workers During the COVID-19 Pandemic: A Cross-sectional Study.

INTRODUCTION: Being on the COVID-19 frontline could negatively impact healthcare workers mental health. AIMS AND METHODS: We examined smoking behavior changes and the association with changes in stress levels and sleeping patterns among hospital workers during the pandemic. An online survey was conducted among employees of a large tertiary medical center in Israel. Data collected included sociodemographic characteristics, smoking status, changes in smoking behavior (for smokers only), stress levels, and sleeping duration during the pandemic, perceptions of risk for COVID-19 infection and disease severity, presence of a chronic illness, COVID-19 exposure and infection status, and involvement in treating COVID-19 patients. Multinominal logistic regression modeling assessed the effects of covariates on smoking behavior change. RESULTS: Overall, 920 healthcare workers participated. More than half (59%) reported an increase in stress and 28% reported changes in sleep duration. Thirty-five percent of current smokers (n = 132), reported smoking more. Increased stress was associated with an increase in smoking (odds ratio [OR] = 3.45, 95% confidence interval [CI] 1.2-9.4, p = .016), and an increase in sleeping hours was significantly associated with a decrease in smoking (OR = 6.42, 95% CI 1.2-32, p = .02). Among smokers who reported perceived levels of stress to be the same or slightly higher than prepandemic, a strong inverse association was observed between sleep and smoking. CONCLUSIONS: The mental health consequences of the pandemic, specifically for health workers, could lead to negative changes in smoking behaviors. Together with offering stress-management skills and coping strategies, mental health support should target smoking behaviors and sleep disturbances. IMPLICATIONS: A high proportion of healthcare employees working in a large tertiary medical center in Israel reported increased stress levels during the COVID-19 pandemic. Among smokers, increased stress levels were associated with increased smoking, suggesting that smoking may be a coping mechanism for COVID-19-related stress. Offering stress-management skills and coping strategies can mitigate the negative impact on health workers' smoking behavior, and reduce stress-related increases in smoking behavior.

Training and competence perception differences in otolaryngology and head and neck surgery training program - an anonymous electronic national survey.

BACKGROUND: Otorhinolaryngology / Head and Neck Surgery consists of different sub-specialties, each comprising unique characteristics and challenges. Herein, we investigate the use of a uniform national electronic questionnaire for curriculum planning. MAIN OUTCOME MEASURES: (1) Analyze the residents' perception of the different sub-specialties training programs and their competence capabilities. (2) Identify sub-specialties requiring attention. (3) Investigate the characteristics associated with competence perception. METHODS: This is a national cross sectional study. An anonymous electronic questionnaire was emailed to all registered Otorhinolaryngology / Head and Neck Surgery residents. RESULTS: 63.5% registered residents responded to the questionnaire. Two sub-specialties, Rhinology and Laryngology, are located in the extremities of the residents' perceptions of competence and training (p < 0.0001), despite similar complexity perception (means 6.10 and 6.01, respectively). Rhinology is perceived as the most well-trained sub-specialty, both surgically and clinically (means 7.08 and 7.66, respectively), whereas Laryngology is bottom scaled (means 5.16 and 6.14, respectively). The same is true for perceived competence, surgical and clinical, in Rhinology (means 6.80 and 8.02, respectively) compared to Laryngology (means 5.04 and 6.75, respectively). Significant positive correlations were found between training, competence perception and workload ("golden training triangle"). CONCLUSIONS: Each ORL-HNS sub-specialty comprises different characteristics and a different learning curve, necessitating a tailored training program. Recognizing its sub-specialties distinctive features may assist in establishment of better-adapted learning curves in residency programs. Herein, we examine the use of anonymous electronic national survey. Laryngology, bottom ranked, is a prototype of a relatively new surgical discipline. Rhinology, ranked top by the residents, is an exemplar of a sub-specialty with an optimal 'educational environment'. Moreover, we have established golden training triangle, implicating, highlights the essential role of institutional and senior staff for proper residency teaching. We demonstrate and advocate the benefit of using an anonymous electronic questionnaire.

The association between COVID-19 vaccination and idiopathic sudden sensorineural hearing loss, clinical manifestation and outcomes.

PURPOSE: Previous data demonstrated an increased incidence of Idiopathic Sensorineural Hearing Loss (ISSNHL) in 2021 compared to 2019-2020, suggesting an association with the anti-COVID-19 vaccine. We aimed to assess our center's incidence and compare the clinical manifestations and outcomes of vaccinated vs. unvaccinated patients. METHODS: A retrospective chart review of all patients diagnosed with ISSNHL during 2021 was conducted and compared to patients who presented in 2018-2020. Patient demographics, audiometry features, vaccination status, and prognosis were evaluated. RESULTS: Throughout 2021, 51 patients were diagnosed with ISSNHL, compared with 31 during 2020, 38 in 2019, and 41 in 2018, demonstrating a 64%, 34%, and 24% increase, respectively. Among patients who presented in 2021, 13 (25.4%) received the anti-COVID-19 vaccine within 30 days before their presentation, and 4 received it within 96 h. Most presented after receiving the second or third dose. Patient characteristics, audiometry features, and prognosis did not significantly differ between vaccinated and unvaccinated patients. CONCLUSIONS: A marked incline was seen in the 2021 ISSNHL incidence at our medical center, of which 25% of cases were within a month post-anti-COVID-19 vaccination. No significant difference was found in clinical manifestations and outcomes between vaccinated and nonvaccinated patients. While other justifications could be sought, an association cannot be ruled out, and further research is needed.

Bilateral Intratonsillar Abscesses: A Deceiving Symmetrical Oral Bulging.

BACKGROUND: Unilateral intratonsillar abscess (ITA) is an underreported, well-known complication of acute tonsillitis. The prevalence of unilateral ITA compared to peritonsillar abscess (PTA) is 1:14. However, bilateral ITA is an extremely rare entity, with only four cases reported thus far. OBJECTIVES: To describe past cases and our experience, elaborating the diagnostic challenge and the surgical treatment for bilateral ITA. METHODS: We conducted a literature search in the PubMed database using the key words intra-tonsillar abscess, tonsillar abscess, bilateral tonsillar abscess, bilateral intra-tonsillar abscess and bilateral peritonsillar abscess. Our search was limited to the years 1980 to 2020. RESULTS: We found that only four cases of bilateral ITA were previously published. All were characterized by a delay in diagnosis with a median of 10 days (4-14 days), symmetrical oral cavity appearance, enlarged bilateral kissing tonsils, and subsequent treatment by surgical drainage/paracentesis. Respiratory compromise was a concern in most cases. Our patient was treated with bilateral quinsy tonsillectomy and had a prompt recovery. CONCLUSIONS: Bilateral ITA is a rare, deceiving entity, with a diagnosis delay attributed to the symmetrical oral bulging. We present the fifth case reported and the first ever reported in a pediatric patient. We describe the assumed pathogenesis and the main characteristics among all five patients, emphasizing the important role of a high index of suspicion and appropriate imaging, guiding to proper diagnosis and treatment.

A Cohort Study of the Surgical Risks and Prediction of Complications in Surgical Tracheostomies.

BACKGROUND: Current protocols favor percutaneous tracheostomies over open procedures. We analyzed the effects of this conversion from the open approach to the percutaneous procedure in terms of relevant clinical status, complications, and mortality in surgical open tracheostomies. Relevant laboratory and clinical parameters, potentially associated with complications, were also examined. MAIN OUTCOME MEASURES: Comparison of clinical, laboratory data and outcome of surgical tracheostomy during the two eras. Investigate potential pertinent predictive parameters associated with complications. METHODS: A single center retrospective case series of consecutive patients who underwent surgical tracheostomy between the years 2006-2009 ("early era") and 2016-2020 ("late era"). RESULTS: The study included 304 patients, 160 in the "early" and 144 in the "late" era. Despite a 78% increase in patient volume in the intensive care units, there was a 55% decrease in surgical tracheostomy during the "late era". Significantly more patients with structural deformities (p < 0.001), insulin dependent diabetes mellitus (p = 0.004), extreme (high and low) body weight (p = 0.006), anemia (p < 0.001) and coagulation disorders (p < 0.001), were referred for an open tracheostomy during the "late era". The complication rate was significantly higher during the "late era" (11.7 vs. 2.5%, OR 6.09 CI 95% [1.91-19.39], p = 0.001). Diabetes mellitus (p = 0.005), anemia (p = 0.033), malnutrition (p = 0.017), thrombocytopenia (p = 0.002) and poor renal function, (p = 0.008), were all significantly associated with higher complication rates. CONCLUSIONS: Risk assessment and training programs must reflect the decrease in surgical volume of open tracheostomies and consequently reduced experience. The increase of a patient subset characterized by pertinent comorbidities should reflect this change.

Minimally Invasive Parathyroidectomy: Can Intraoperative Parathyroid Hormone Monitoring be Omitted?

BACKGROUND: Intraoperative PTH (ioPTH) monitoring has become widely accepted in the era of minimally invasive parathyroidectomy (MIP). The purpose of this study was to evaluate the need for ioPTH during parathyroidectomy in patients with positive preoperative imaging. METHODS: The charts of patients who underwent parathyroidectomy at three tertiary centers between the years 2012 and 2021 were retrospectively reviewed. Patients were defined as MIP candidates with either concordant preoperative imaging or a single positive imaging. Patients with negative or discordant imaging, concomitant thyroidectomy, or previous neck surgery were excluded. RESULTS: Of a total of 1013 patients who underwent parathyroidectomy, 535 (52.8%) were defined as MIP candidates and were included in the statistical analysis. Surgical success was achieved in all patients. A single adenoma that corresponded to the preoperative imaging was identified and resected in 517 (93.8%) patients. In only 18 (3.3%) patients, the ioPTH correctly changed the operative management where additional pathologic glands were identified and excised. Patients with additional lesions were significantly more likely to have decreased index adenoma size as indicated either by preoperative imaging or by intraoperative findings (15.5 ± 6.6 vs. 8.3 ± 2.5 mm, p < 0.001). None of the patients with an adenoma size greater than 13 mm had an additional pathologic gland. CONCLUSIONS: Our findings suggest that the routine use of ioPTH in MIP candidates may be omitted in patients with an index adenoma greater than 13 mm, even with only a single positive preoperative imaging study, without compromising surgical success.

Tranexamic acid administration practice in otolaryngology head & neck surgery; international survey.

PURPOSE: Tranexamic acid (TXA) is a potent pro-coagulation drug. Pre-operative, preventive TXA administration and TXA use for active bleeding are established treatments in many medical situations; yet, less is known about its use in otolaryngology head and neck surgery practice. The primary study goals were: MATERIALS AND METHODS: This is an international survey exploring TXA administration strategy. The electronic, anonymous, questionnaire was emailed to all registered Israeli and American Otolaryngology Head and Neck Surgery (OHNS) physicians, investigating TXA administration: RESULTS: Overall, 317 otolaryngologists participated in the study. TXA was administered to 40.5 % of the pediatric population and 50 % of the adult patients when needed. Epistaxis was the most common indication for TXA administration (48-55 %). A small number of otolaryngologists, 4-13 %, recommended preventive TXA for various operations. More surgeons include TXA in their practice and adjusted the dose according to renal function in academic compared to non-academic medical centers and among otolaryngologists practicing in Israel compared to the United States. CONCLUSIONS: TXA is provided by many otolaryngologists to treat active epistaxis but to a substantially lesser extent as a preventive measure. TXA is given to children and adults, some with substantial comorbidities. Treatment is more common among surgeons working in academic institutes and medical centers in Israel.

Spatial Intratumoral Heterogeneity Expression of PD-L1 Antigen in Head and Neck Squamous Cell Carcinoma.

INTRODUCTION: Immune-checkpoint inhibitors have demonstrated a significant survival benefit in metastatic and non-resectable head and neck squamous cell carcinoma (HNSCC). Patients with a combined positivity score (CPS) of 20 and higher benefit the most from therapy. Inaccurate definition of the CPS category might lead to the incorrect stratification of patients to immunotherapy. This study's main aim was to investigate programmed death-ligand 1 (PD-L1) antigen expression in HNSCC in diverse clinical situations and histological settings. MATERIALS AND METHODS: This is a prospective cohort study conducted in a tertiary referral medical center. Tissues were investigated for PD-L1 expression using the FDA-approved 22C3 immunohistochemistry assay (Dako). We analyzed potential associations between the CPS category and meaningful demographic, clinical, and outcome metrics. Furthermore, we investigated morphologically separate sites for CPS scores in whole surgical tissue specimens and matched preoperative biopsies. RESULTS: We analyzed 36 patients, of whom 26 had oral cavity SCC and 10 had laryngeal SCC. The overall, disease-specific, and progression-free survival of the HNSCC group of patients were not associated with the CPS category (p = 0.45, p = 0.31, and p = 0.88, respectively). There was a significant (18%, 95% CI 0.65-0.9) inconsistency between the CPS category determined in biopsies versus whole carcinoma analyses. We also found an uneven distribution of whole-tumor CPS attributed to spatial carcinoma invasiveness, tumor differentiation, and inflammatory cell infiltration heterogeneity. DISCUSSION AND CONCLUSIONS: Our data suggest that careful selection of tumor area for CPS analysis is important. PD-L1 antigen expression, clinically represented by CPS, may be up- or down-categorized in different clinical and pathological circumstances. The high whole-tissue CPS category scatter may clinically result in potential treatment modifications. We argue that CPS analysis requires not only adequacy (at least 100 viable tumor cells), but also correct representation of the tumor microenvironment.

[HEAD AND NECK MALIGNANCIES CLASSIFICATION, THE 8TH EDITION OF THE AMERICAN JOINT COMMITTEE ON CANCER - WHAT IS NEW?]

INTRODUCTION: The American Joint Committee on Cancer (AJCC) staging manual has become the point of reference for classifying patients with cancer, defining prognosis, and determining the best treatment approaches. The eighth edition of the Head and Neck AJCC Cancer Staging Manual incorporates significant changes based on advances in our understanding of the etiology and certain histologic attributes of tumors. Changes were made only when there was strong evidence for inclusion, while balancing between "population-based" and a more "personalized" approach. We describe the main changes implanted into the AJCC 8th edition while analyzing the effects on treatment plans and survival metrics. 1. The most significant update, to better reflect the variety of diseases arising in the pharynx, creates a separate staging algorithm for high-risk human papillomavirus-associated cancer of the oropharynx. Therefore, pharynx carcinoma has been divided into 3 separate chapters - nasopharynx, high-risk HPV-associated (p16-positive) oropharynx, and hypopharynx and non-high risk HPV-associated (p16-negative) oropharynx. 2. Another important update incorporates extra nodal extension as a prognostic variable for regional lymph node metastases in non-viral associated head and neck tumors. 3. Significant changes to the tumor (T) categories for oral cavity are discussed, where, for every 5-mm increase in depth of invasion (DOI), categories will increase one level, demonstrating better consistent and predictive survival curves. 4. A major tumor (T) category change for nasopharyngeal squamous cell carcinoma (SCC), regarding the prevertebral and pterygoid muscles, is discussed. We go through the rationale behind the major changes while practicing the new staging system among different cases.

[LARYNGEAL MALIGNANCIES IN ISRAEL - THE DIAGNOSIS, CLASSIFICATION AND TREATMENT OF NEUROENDOCRINE TUMORS].

INTRODUCTION: The larynx is the most common site of neuroendocrine tumors in the head and neck region. Tumors are divided morphologically into epithelial-derived tumors (carcinomas) and neural-derived tumors (paragangliomas). The classification of neuroendocrine tumors has evolved over the past two decades. OBJECTIVES: To investigate the incidence and histological types of laryngeal tumors in Israel. To evaluate laryngeal neuroendocrine tumors treated at a single tertiary referral center, while describing current classification and controversies. METHODS: Retrospective investigation was conducted of laryngeal tumors treated at Hadassah University Hospital between the years 2007 and 2016. Analysis was performed of all cases diagnosed in Israel between 2005 and 2014. Previous and current classifications of laryngeal neuroendocrine tumors were reviewed. RESULTS: Two hundred and twenty new laryngeal cancers were diagnosed on average annually in Israel during the study period. Squamous cell carcinoma consisted in most cases (95%); yet, no documentation of neuroendocrine tumors was noted. Three patients, in their fifties, were treated for laryngeal neuroendocrine tumors at Hadassah. Tumors consisted of paraganglioma, typical carcinoid and small cell neuroendocrine carcinoma. Investigation, treatment, outcome, and classification are described. CONCLUSIONS: This is the first description of laryngeal neuroendocrine tumors in Israel. The lack of clarity for diagnosis, documentation and classification of this rare, heterogenic group of tumors, described worldwide, was noted in Israel as well. A multidisciplinary team, including experienced pathologists, radiologists, head and neck surgeons and oncologists, is mandatory for providing the best patient care.

Induction of heparanase by HPV E6 oncogene in head and neck squamous cell carcinoma.

High-risk human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCCs) are highly invasive; however the identity of downstream effectors responsible for their aggressive phenotype remains underinvestigated. Here, we report that HPV-mediated up-regulation of heparanase enzyme can provide mechanistic explanation for augmented invasiveness of HPV-positive HNSCCs. Heparanase is the sole mammalian enzyme (endo-ß-d-glucuronidase) degrading heparan sulphate glycosaminoglycan, key polysaccharide of the extracellular matrix. Cleavage of heparan sulphate by heparanase leads to disassembly of extracellular barriers, enabling local invasion and metastatic spread of the tumour, and releases heparan sulphate-bound growth factors from the extracellular depots. Heparanase is tightly implicated in head and neck cancer progression; yet, molecular mechanisms underlying transcriptional activation of the heparanase gene in HNSCC are largely unknown. We found that HPV16 oncogene E6 is capable of inducing overexpression of heparanase in HNSCC. Notably, radiation treatment dose-dependently suppresses E6-induced heparanase expression in vitro. Our results provide the first evidence for a functional involvement of HPV in heparanase induction in head and neck tumourigenesis and, given ongoing clinical testing of several heparanase-inhibiting compounds, offer important avenue for future therapeutic exploration in HNSCC, as well as other HPV-associated malignancies (i.e. cervical carcinoma).

Extended Follow-Up Outcomes from Pooled Prospective Studies Evaluating Efficacy of Interstitial Alpha Radionuclide Treatment for Skin and Head and Neck Cancers.

The initial favorable efficacy and safety profile for Alpha DaRT have been demonstrated (NCT04377360); however, the longer-term safety and durability of the treatment are unknown. This pooled analysis of four prospective trials evaluated the long-term safety and efficacy of Alpha DaRT for the treatment of head and neck or skin tumors. A total of 81 lesions in 71 patients were treated across six international institutions, with a median follow-up of 14.1 months (range: 2-51 months). Alpha DaRT sources were delivered via a percutaneous interstitial technique and placed to irradiate the tumor volume with the margin. The sources were removed two to three weeks following implantation. A complete response was observed in 89% of treated lesions (n = 72) and a partial response in 10% (n = 8). The two-year actuarial local recurrence-free survival was 77% [95% CI 63-87]. Variables, including recurrent versus non-recurrent lesions, baseline tumor size, or histology, did not impact long-term outcomes. Twenty-seven percent of patients developed related acute grade 2 or higher toxicities, which resolved with conservative measures. No grade 2 or higher late toxicities were observed. These data support the favorable safety profile of Alpha DaRT, which is currently being explored in a pivotal US trial.

Extra domain-A fibronectin is necessary for the development of nasal remodeling in chronic allergen-induced rhinitis.

BACKGROUND: Extra domain A-containing fibronectin (EDA-FN) is necessary for the development of allergen-induced lower airway fibrosis. The pathogenesis of fibrosis in allergic rhinitis has not been well studied. OBJECTIVES: To determine whether EDA-fibronectin is necessary for the development of nasal remodeling in a murine model of chronic allergic rhinitis and in human allergic rhinitis. METHODS: EDA(-/-) and wild-type (WT) C57Bl/6 mice were sensitized intraperitoneally and then challenged with inhaled ovalbumin (OVA) or saline for 2 and 5 weeks. Clinical signs of rhinitis and histological analysis of nasal tissue were evaluated. Immunohistological staining for EDA-FN was performed in human tissue of inferior nasal conchae from patients with allergic rhinitis and controls. RESULTS: After 2 weeks of allergen exposure, only goblet cell hyperplasia and perivascular eosinophilia were observed. After 5 weeks, goblet cell number, thickening of the subepithelial layer, and extent and area of collagen deposition were increased in the nasal tissue of WT OVA (ovalbumin)-challenged mice as compared with saline controls (P < .0001, P < .0001, P = .018, and P = .03, respectively). Clinical signs of rhinitis were observed only in WT OVA-challenged mice. In the EDA(-/-) mice exposed to OVA, collagen deposition, collagen area, and subepithelial thickness showed no increase and were similar to saline control mice, whereas goblet cell hyperplasia was similar to WT OVA-challenged mice. EDA-FN expression was prominent in inferior conchae from patients with allergic rhinitis but was absent in control patients. CONCLUSION: EDA-containing fibronectin is necessary for the development of nasal tissue fibrotic remodeling process in both murine and human allergic rhinitis.

Maxillary air density measurements for differentiating between acute and chronic rhinosinusitis.

OBJECTIVE: Maxillary sinus air-fluid levels and sinus opacification may appear similar in cases of acute and chronic rhinosinusitis. Our aim was to evaluate whether air density analysis in addition to air-fluid level can be used as a metric to differentiate between cases of acute and chronic rhinosinusitis. SUBJECTS AND METHODS: A prospective study of three patient groups (n = 73) who underwent sinus CT was performed. A study group composed of 23 patients with clinical acute rhinosinusitis was compared with two different control groups (one with chronic rhinosinusitis and the other with healthy sinuses) with 25 patients in each. In each case air density within the maxillary sinus was measured using a region of interest of 1 cm(2), 0.5 cm away from the sinus wall. The mean and SD of air density of each maxillary sinus were calculated from five sequential CT slices. We compared the results of each group using a paired Student t test and analysis of variance. RESULTS: Mean air density was significantly higher in the acutely inflamed sinuses compared with chronic sinusitis and healthy aerated sinuses (-846.6 vs -980 and -975.8 HU, respectively; p < 0.05). Sinus air density SD was greater in the acutely inflamed sinus than in chronic sinusitis and healthy sinuses (78.3 vs 17.9 and 6.8 HU, respectively; p < 0.05). CONCLUSION: Increased sinus air density and heterogeneity may help differentiate acute from chronic rhinosinusitis.

A Comparison of Outcomes in Medullary Thyroid Carcinoma Patients With and Without a Preoperative Diagnosis: A Multicenter Retrospective Cohort Study.

Background: Cytological limitations pose a challenge to preoperative diagnosis of medullary thyroid carcinoma (MTC) and therefore, a significant subset of patients is only diagnosed postoperatively. The objective of this study was to investigate the impact of knowledge of a preoperative MTC diagnosis on disease management and outcomes. Methods: Multicenter, retrospective, cohort study of MTC patients treated in Israel from January 2000 to June 2021. We compared cohorts of patients according to the presence or absence of a preoperative MTC diagnosis. Results: Ninety-four patients with histologically confirmed MTC were included (mean age 56.2 ± 14.3 years, 43% males). Fifty-three patients (56%) had a preoperative MTC diagnosis (preop-Dx group), and 41 (44%) were confirmed only postoperatively (no-Dx group). The extent of surgical resection, including completion procedures, was as follows: total thyroidectomy in 83% versus 100% (p = 0.002), central lymph node dissection (LND) in 46% versus 98% (p < 0.001), ipsilateral lateral LND in 36% versus 79% (p < 0.001), and contralateral lateral LND in 17% versus 28% (NS), in the no-Dx versus the preop-Dx group, respectively. Pathology confirmed a smaller median tumor size of 16 ± 17.4 mm versus 23 ± 14.0 mm (p = 0.09), a higher proportion of micro-MTC (size ≤10 mm) 32% versus 15% (p = 0.03), and a higher rate of co-occurrence of follicular cell-derived carcinoma 24% versus 4% (p = 0.003), in the no-Dx compared to the preop-Dx group, respectively. The rates of extrathyroidal and extranodal tumor extension were not significantly different between the groups. At the last follow-up, the biochemical cure was attained in 55% [CI 0.38-0.71] compared to 64% [CI 0.50-0.77] of the no-Dx and the preop-Dx group, respectively (p = 0.41). After the exclusion of patients with micro-MTC, biochemical cure was more commonly achieved in the preop-Dx group (33% [CI 0.14-0.52] vs. 62% [CI 0.46-0.77], p = 0.04). Preop-Dx patients had improved overall survival compared to the no-Dx group (log-rank p = 0.04) over a median follow-up of 82 months (interquartile range [IQR] 30-153). Conclusions: Preoperatively, the diagnosis of MTC is often missed. An accurate preoperative diagnosis of MTC may enable guideline-concordant surgical treatment and ultimately contribute to an overall survival benefit in MTC patients.

Double trouble: A cohort study of re-irradiation and laryngectomy - Severity of and risk for pharyngocutaneous fistula.

OBJECTIVES: Pharyngocutaneous fistula (PCF) is a devastating complication of laryngectomy. Different factors, principally previous irradiation, increases the risk for PCF formation. The current study objectives is to investigate the potential negative effect of re-irradiation on fistula development. Materilas and methods This is a single, referral, medical center retrospective, cohort study, conducted between the years 2011-2021. Electronic medical files, surgical notes, laboratory records and radiation plan (dose and time interval in case of re-irradiation) were examined. Main outcomes and measures Risk and predictors associated with PCF formation. Risk and severity of PCF in the setting of re-irradiation. RESULTS: Overall, 27 laryngectomized patients were investigated, of whom 21 patients had single radiation (pre or post-operative radiation) and the other 6 patients had two radiation treatments (before and after laryngectomy). The fistula rate was 33.33% (7/21) in the single radiation compared (p = 0.14) to 66.66% (4/6) in the re-irradiation group of patients (including late-onset fistulas). All single radiation PCF were self-limited, whereas, 3 out of 4 fistulas in the re-irradiation group were longstanding or permanent. In the re-irradiation group of patients, a shorter time interval between the first and second radiation treatments was demonstrated among those with fistula formation compared to patients with uneventful laryngectomy (p = 0.08). CONCLUSION: Re-irradiation and especially a brief interval between the radiation treatments is associated with a severe PCF.

Sentinel Lymph Node Identification in Cutaneous Head & Neck Cancer - Lymphoscintigraphy Late Phase.

OBJECTIVE: Sentinel node (SN) biopsy following lymphoscintography is recommended for high-risk cutaneous malignancies. Herein, we investigate different lymphoscintography phases, focusing on the importance of the late static phase and the resultant discovery of distal echelon solitary positive sentinel nodes that would otherwise have been overlooked. METHODS: In this retrospective cohort study, conducted in a tertiary referral medical center, we assessed SN localization and time from tracer injection to SN identification on lymphoscintigraphy. Findings on scan were compared with SN found in the surgical field, and with the final pathological investigation. RESULTS: Seventy-three patients, undergoing SN biopsy for head and neck skin malignancies, were investigated. Most patients were male (n = 50). The average age was 65.7 (±15.7) years and the average follow-up time was 29.1 (±22.4) months. Overall, 101 SNs were histologically investigated, demonstrating 7 positive SN. Eleven patients (15%) benefited from the late lymphoscintigraphy phase. In four studies, an SN was identified only in the late static phase, one of which was positive for the disease. In seven patients, SN was identified in the early phase with additional, different, SN on the late phase, one of which was positive for the disease. Comparing the yield (positive SNs) of early versus late phases, demonstrated the same importance (p = 0.275). CONCLUSIONS: The late lymphoscintigraphy phase has a crucial role in high-risk HN cutaneous cancer. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:2164-2168, 2022.