Age Stratification and Prognostic Factor Analysis in Pediatric Differentiated Thyroid Cancer.

OBJECTIVES: Differentiated thyroid cancer (DTC) is rare in the pediatric population. It remains unclear whether younger children are at greater risk of more aggressive disease. We aimed to identify prognostic factors for aggressive pediatric DTC and to define an appropriate age stratification. METHODS: This retrospective cohort study included all patients aged 18 years or less who were treated for DTC between 1985 and 2021 in a tertiary medical center and were followed up for a minimum of 1.5 years after treatment. RESULTS: Seventy-eight patients were included, all diagnosed with papillary thyroid carcinoma: 30 (38.5%) low-risk, 21 (26.9%) intermediate-risk, and 27 (34.6%) high-risk according to the American Thyroid Association (ATA) risk stratification. The mean duration of follow-up was 11.8 ± 7.8 years. No evidence of disease was documented in 52 patients (66.7%) at 1-year post-treatment and 64 patients (82.1%) at the end of follow-up. On analysis by age, evidence of disease at 1-year post-treatment was found in 66.7% of children younger than 11 years, compared to 25.4% of older children (p = 0.002). There was no significant difference by age in evidence of disease at the last follow-up (p = 0.453). Patients aged <11 years at diagnosis were associated with more aggressive disease features on histopathologic examination, metastatic disease, and high ATA risk level. Patients aged <8 years were associated with more frequent bilateral disease and extrathyroidal extension. CONCLUSION: Pediatric DTC patients who are younger than 11 years at diagnosis have more aggressive disease features and a lower early remission rate than older patients. Nevertheless, their long-term outcome is satisfactory. LEVEL OF EVIDENCE: 4-retrospective cohort study Laryngoscope, 134:4818-4825, 2024.

Evaluating Depth of Invasion as a Continuous Prognostic Factor in Oral Squamous Cell Carcinoma.

BACKGROUND: Depth of invasion (DOI) has a significant clinical impact on the staging system of oral squamous cell carcinoma (OSCC). We aimed to compare the prognostic impact of treating DOI as a continuous variable rather than a categorical one. METHODS: A retrospective review of 277 OSCC patients surgically treated in a tertiary care center from 2000 to 2020, with a minimum 2-year follow-up. The analyses were performed using Cox and logistic regression. RESULTS: DOI as a continuous variable significantly predicted mortality in both univariate (p < 0.001) and multivariate (p < 0.001) analyses. It was also a significant predictor of locoregional recurrence (multivariate p = 0.039) and occult lymph node metastasis (univariate p = 0.005, multivariate p = 0.04). Categorical analysis failed to demonstrate the same significance. CONCLUSIONS: DOI as a continuous factor rather than a categorical one is significantly associated with mortality, locoregional recurrence, and occult lymph node metastasis. This innovative approach promotes personalized risk stratification and better decision-making.

Management and prognosis of iatrogenic perforations of the cervical oesophagus and hypopharynx.

Objective: The study aimed to identify factors affecting the management and prognosis of iatrogenic cervical oesophageal and hypopharyngeal perforations (iCEHPs). Methods: We retrospectively analysed 24 patients treated for iCEHP between 2004 and 2021 at a tertiary university medical centre. Data on demographics, clinical features, imaging, management and outcomes were collected. Factors associated with primary management and patient outcome were assessed. Results: The most common management approach was surgical neck exploration (15 patients, 62.5%). Surgical management was used in 93% of uncontained perforations compared to 11% of contained perforations (p < 0.001). Surgically-treated patients had higher levels of C-reactive protein (CRP) than conservatively-treated patients (median, 18.3 vs 4.8 mg/dL; p = 0.001). Delayed diagnosis (≥ 24 hours) was associated with increased mortality (100 vs 5%; p = 0.011). The mortality rate was significantly higher in patients who had a history of neck irradiation than in patients who did not (67 vs 5%; p = 0.032). Conclusions: Early diagnosis of iCEHP improves outcomes. The appropriate management should be carefully selected on the basis of CRP level and imaging findings. Prior neck radiation is a poor prognostic factor.

The Incidence of Radiologic Evidence of Sinusitis Following Endoscopic Pituitary Surgery: A Multi-Center Study.

Background: Endoscopic endonasal skull base surgery has become a viable alternative to open procedures for the surgical treatment of benign and malignant lesions in the sinonasal and skull base regions. As in sinus surgery, skull base surgery may cause crusting and posterior rhinorrhea, particularly when a nasoseptal flap is required for skull base reconstruction. Post-operative radiological sinonasal findings have been reported previously with no clear correlation with intraoperative decision-making. As in open surgery, endoscopic surgery is not standardized and there is variability in the intervention to assist with exposure and skull base repair. These modifications, including middle turbinate resection, nasoseptal flap, fat graft, and maxillary antrostomy have the potential for nasal morbidity. The aim of this study was to evaluate whether specific interventions during surgery or specific patient and tumor characteristics harbor a more significant risk of causing nasal morbidity post-operatively, as demonstrated by post-operative imaging. Methods: A retrospective analysis of all patients who underwent endoscopic endonasal skull base surgery for pituitary lesions at two major referral centers was performed. Data on demographic, clinical, and pathological features were collected, and pre- and post-operative imaging studies (computed tomography (CT) and magnetic resonance imaging (MRI)) were reviewed and scored according to the Lund-Mackay (LM) scoring system. Results: The study included 183 patients. Radiographic evidence of sinusitis was observed in 30 patients (LM score > 4) in post-operative imaging studies. Patients who underwent middle turbinectomy or nasoseptal flap were found to have significantly higher LM scores on follow-up imaging. A nasoseptal flap was found to be associated with an average increase in LM score of 1.67 points and middle turbinectomy with an average increase of 2.21 points. There was no correlation between tumor size and findings that were compatible with sinusitis on post-operative imaging. Conclusions: The findings of the present study suggest that endoscopic endonasal skull base surgery is associated with radiological evidence of sinusitis. Nasoseptal flap reconstruction and middle turbinectomy were strongly associated with radiographic sinusitis and should be judiciously performed during surgery. A clinical correlation is needed for further recommendations.

Rethinking Surgical Margins: A New Approach to Predict Outcomes in Oral Squamous Cell Carcinoma.

OBJECTIVE: The traditional categorical division of surgical margins using a 5 mm cutoff in oral cavity squamous cell carcinoma (OCSCC) is controversial. The primary aim of this study was to investigate the presence of an optimal cutoff point or, alternatively, assess the potential improvement in predictive value by considering the surgical margins as a continuum. METHODS: Retrospective analysis of OCSCC patients at a tertiary medical center in 1995-2020. Clinical, pathological, and surgical data were evaluated for effect on survivability by regression analyses. RESULTS: The cohort included 266 patients (48.1% male, mean age 65.4 ± 17.7). Patient stratification by categorical margin status yielded no significant between-group differences in survival (p = 0.54). Significance was achieved when margin distance was reevaluated as a continuous variable (p = 0.0018). Similar results were shown in local control (categorical p = 0.59 vs. continuous p = 0.06). Multivariate model excluded possible confounders. A predictive model was created to provide a more accurate prediction of survival. CONCLUSIONS: The continuum spectrum of margin distance better predicts survival outcomes and locoregional control in OCSCC. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Management of laryngeal chondroradionecrosis: A single-center experience.

BACKGROUND: Laryngeal chondroradionecrosis (LCRN) is a rare but severe complication of radiation therapy. The study aimed to review the management of LCRN and evaluate the clinical benefit of hyperbaric oxygen therapy (HBOT). METHODS: We retrospectively analyzed all radiation-induced LCRN patients between 2006 and 2019 at a tertiary medical center. Diagnosis was based on signs and symptoms of Chandler's classification, imaging, and/or histopathology report. The primary outcome was improvement in Chandler's grade after HBOT. RESULTS: Of 678 irradiated laryngeal cancer patients, 29 (4.3%) were diagnosed with LCRN. The most common primary management was tracheostomy with intravenous steroids and antibiotics (59%). Ten patients received HBOT (34.5%), and six underwent total laryngectomy (21%). In HBOT-treated patients, Chandler's grade significantly improved from a median of 4 (range 2-4) to 2.5 (range 1-4; p = 0.005). CONCLUSIONS: HBOT may benefit in the management of patients with persistence and unresponsive symptoms of LCRN following radiation therapy for laryngeal SCC.

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.

Unleashing Natural IL18 Activity Using an Anti-IL18BP Blocker Induces Potent Immune Stimulation and Antitumor Effects.

Recombinant cytokines have limited anticancer efficacy mostly due to a narrow therapeutic window and systemic adverse effects. IL18 is an inflammasome-induced proinflammatory cytokine, which enhances T- and NK-cell activity and stimulates IFNγ production. The activity of IL18 is naturally blocked by a high-affinity endogenous binding protein (IL18BP). IL18BP is induced in the tumor microenvironment (TME) in response to IFNγ upregulation in a negative feedback mechanism. In this study, we found that IL18 is upregulated in the TME compared with the periphery across multiple human tumors and most of it is bound to IL18BP. Bound IL18 levels were largely above the amount required for T-cell activation in vitro, implying that releasing IL18 in the TME could lead to potent T-cell activation. To restore the activity of endogenous IL18, we generated COM503, a high-affinity anti-IL18BP that blocks the IL18BP:IL18 interaction and displaces precomplexed IL18, thereby enhancing T- and NK-cell activation. In vivo, administration of a surrogate anti-IL18BP, either alone or in combination with anti-PD-L1, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, the anti-IL18BP induced pronounced TME-localized immune modulation including an increase in polyfunctional nonexhausted T- and NK-cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL18BP using an Ab is a promising approach to harness cytokine biology for the treatment of cancer.

Extended cervical approach for retrosternal multinodular goiter.

Objective: Partial or total sternotomy is required for 10% of retrosternal goiter. This study reviewed our experience with an extended cervicotomic approach as an alternative surgical solution for retrosternal goiter. Methods: A retrospective study was performed on patients who underwent partial or total thyroidectomy for retrosternal goiter between 2014 and 2019 at a tertiary medical centre. Data on clinical, radiologic, and pathologic factors were analysed. Peri- and postoperative outcomes were compared between extended and standard cervical approaches to predict the need for an extended cervical approach. Results: The cohort included 265 patients, of whom 245 (92.4%) were treated by standard thyroidectomy. In 17 (6.4%), the standard approach proved insufficient, and the horizontal incision was extended to a T-shape to improve access. The remaining 3 patients required a sternotomy. Use of the extended cervical approach was significantly associated with clinical features such as male gender, diabetes, high body mass index and postoperative hypocalcaemia. Conclusions: The extended cervicotomic approach is an alternative surgical solution for retrosternal goiter, with no increased risk of significant post-operative complications.

The Clinical Behavior and Recurrence Patterns of Oral Cavity Cancer in Oral Lichen Planus Patients.

OBJECTIVES: Oral lichen planus (OLP) is a chronic inflammatory disorder involving epithelia with squamous differentiation. Although described as a potential malignant precursor, the characteristics of malignancies arising among these patients are not widely described. Our goal was to describe the patterns of disease recurrence of patients with oral cavity squamous cell carcinoma (OSCC) arising on the background of OLP. METHODS: A retrospective analysis of all surgically treated patients with OSCC at a university-affiliated tertiary care center between 2000 and 2020. RESULTS: Two hundred seventy-nine patients with OSCC treated surgically were included. Forty (14.3%) had OLP. The mean age of patients with OLP was 70.9 years compared with 64.3 years for non-OLP patients (p = 0.03). OLP patients had a significantly higher rate of disease recurrence, persistence, or multiple primary disease (70% vs. 33.9%, p < 0.001). The mean number of sequential oncologic events for each patient with recurrence was also significantly higher among OLP patients (1.86 vs. 1.36, p = 0.03), a difference explained by a higher rate of multiple primary presentations (0.71 vs. 0.28, p = 0.008). A significant difference in disease-free survival (DFS) was demonstrated between the groups as patients with OLP had a lower 5-year DFS (34.7% vs. 61.3%, log-rank p value <0.001). On multivariate analysis, OLP was significantly associated with multiple primary events (p < 0.001, Odds ratio = 7.42, 95% confidence interval 2.9-19). CONCLUSIONS: OSCC patients with OLP background demand close clinical follow-up, as multiple primary disease is significantly more common and the DFS is significantly lower among these patients. A thorough clinical evaluation for all oral cavity subsites is mandatory. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3146-3151, 2024.

Prognostic Significance of Regional Disease in Young Patients with Oral Cancer: A Comparative Study.

BACKGROUND: Regional metastases are considered the most important prognostic factor in OSCC patients. We aimed to investigate the impact of regional disease among different age groups with OSCC. METHODS: A retrospective comparison between patients 40 years old or younger, 41-69 years old, and 70 years or older treated for OSCC between 2000 and 2020 in a tertiary-care center. RESULTS: 279 patients were included. The mean age was 65 ± 17.7 and 133 were male (47.7%). Thirty-six (12.9%) were 40 years old or younger, 101 (36.2%) were 41-69 years and 142 (50.9%) were 70 years or older. Five-year overall survival and disease-specific survival (DSS) were significantly better among patients younger than 40 compared to the mid-age group and patients 70 years or older (76.7% vs. 69.4% vs.48.2%, Log-rank p < 0.001, and 76.7% vs. 75.3% vs. 46.5%, Log-rank p < 0.001, respectively). While an association between regional spread and overall survival and DSS was demonstrated among all age groups, the odds ratio (OR) for death of any cause and death of disease regarding cervical metastasis was much higher among patients younger than 40 compared with the 41-69 and 70+ age groups (death of any cause-OR = 23, p-value = 0.008, OR = 2.6, p-value = 0.026, OR = 2.4, p-value = 0.13, respectively. Death of disease-OR = 23, p-value = 0.008, OR = 2.3, p-value = 0.082, OR = 4.1, p-value = 0.001, respectively). In univariate  analysis, regional metastasis was associated with disease-free survival only among patients younger than 40 (p-value = 0.04). CONCLUSIONS: Regional metastases correspond with worse prognosis in young patients compared to older patients. These patients may benefit from a comprehensive treatment approach with close post-treatment follow-up. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:2212-2220, 2024.

Foregoing elective neck dissection for elderly patients with oral cavity squamous cell carcinoma.

OBJECTIVE: Elective neck dissection (END) improves outcomes among clinically node-negative patients with oral cavity squamous cell carcinoma (OCSCC). However, END is of questionable value, considering the potentially higher comorbidities and operative risks in elderly patients. METHODS: A retrospective review of all patients older than 65 years of age who were treated for OCSCC at a tertiary care centre between 2005 and 2020 was conducted. RESULTS: Fifty-three patients underwent primary tumour resection alone, and 71 had simultaneous END. Most primary tumours were located on the mobile tongue. The patients who did not undergo END had a higher mean age (81.2 vs. 75.1 years, P < 0.00001), significantly shorter surgeries, and shorter hospitalizations. Occult cervical metastases were found in 24% of the patients who underwent END. The two groups showed no significant differences in overall survival or recurrence rates. Similar results were shown in a subpopulation analysis of patients older than 75 years. CONCLUSION: Foregoing END in elderly patients with no clinical evidence of neck metastases did not result in lower survival rates or higher recurrence rates.

Salivary Gland Secretory Carcinoma; Review of 13 Years World-Wide Experience and Meta-Analysis.

OBJECTIVES: Secretory Carcinoma is a malignant salivary gland tumor, initially described in 2010. This rare tumor is associated with the translocation t(12;15) (p13;q25), resulting in the fusion gene ETV6-NTRK3. Since this tumor is quite rare, most publications describe only small cohorts of patients. We aimed to investigate the clinical, pathological, and prognostic features of this newly defined malignant entity. DATA SOURCES: Pubmed, Google Scholar, and Web of Science databases. REVIEW METHODS: All published articles between 2010 and 2023 were reviewed. Search terms included the terms "Mammary Analogue Secretory Carcinoma" and "Secretory Carcinoma". All articles published in English reporting on Secretory Carcinoma of salivary glands were retrieved. RESULTS: One-hundred and 12 retrospective articles reporting a total of 674 patients were included, with 52% males and a mean age of 44.9 ± 18.9. The event rate for patients with advanced-stage disease (Stage 3/4) at presentation was 24.1% (95% CI 17.6%-31.9%, I2 = 9.2%), 14.6% for regional metastases (95% CI 10.5%-20%, I2 = 12%), and the event rate of distant metastasis was 8.4% (95% CI 5.5%-12.7%, I2 = 4.2%). Adjuvant radiotherapy was administered for 30.3% of patients (95% CI 24.1%-37.2%, I2 = 21.5%). The recurrence rate was 19% (95% CI 15.1%-23.8%, I2 = 5%). Survival outcomes showed a 17.2% death of disease rate for Secretory Carcinoma patients (95% CI 13.5%-21.8%, I2 = 7.3%). CONCLUSIONS: Secretory Carcinoma is a rare and relatively newly defined entity arising in the parotid gland most commonly. Characterized as a low-grade tumor, the majority of patients are diagnosed at an early stage, without regional or distant disease, and the prognosis is relatively good. LEVEL OF EVIDENCE: NA Laryngoscope, 134:1716-1724, 2024.

The Value of Computed Tomography in Recurrent Laryngeal Cancer Following Organ Preservation Therapy.

AIM: This study aims to assess the accuracy of computed tomography (CT) in detecting recurrent laryngeal tumors after failed chemoradiation therapy (CRT). BACKGROUND: Local recurrence of laryngeal tumors following CRT has been reported in approximately 25%, yet it is often difficult to detect. METHODS: Ten patients with laryngeal cancer who failed CRT and subsequently underwent salvage total laryngectomy were included. The laryngeal subsites involved in the tumor were identified based on postoperative pathology. The corresponding preoperative CT scans were selected for review by seven experts (head-and-neck surgeons or radiologists) who scored the extent of tumor spread on each scan on a 5-point scale, from no tumor detected to clearly visible tumor. RESULTS: The rates of high tumor detectability (scores 4-5) varied according to laryngeal subsite, from 75% in the glottic region, to 45% in the subglottic region, and to 19% in the supraglottic region (P=0.01). The detectability rates were higher on scans performed 2 years or more after CRT. CONCLUSION: The CT evaluation of laryngeal cancer after CRT has limited value, particularly in the epiglottis and subglottis.

Long-term complications associated with the management of sinonasal malignancies: a single center experience.

Objective: The aim of this study was to review the long-term complications associated with treatment of patients with sinonasal malignancies (SNMs) and risk factors for these complications. Methods: A retrospective analysis of all patients treated for SNMs at a tertiary care center between 2001 and 2018. A total of 77 patients were included. The primary outcome measure was post-treatment long-term complications. Results: Overall, long-term complications were identified in 41 patients (53%), and the most common were sinonasal (22 patients, 29%) and orbital/ocular-related (18 patients, 23%). In a multivariate regression analysis, irradiation was the only significant predictor of long-term complications (p = 0.001, OR = 18.86, CI = 3.31-107.6). No association was observed between long-term complications and tumour stage, surgical modality, or radiation dose/modality. Mean radiation dose ≥ 50 Gy to the optic nerve was associated with grade ≥ 3 visual acuity impairment (100% vs 3%; p = 0.006). Radiation therapy for disease recurrence was associated with additional long-term complications (56% vs 11%; p = 0.04). Conclusions: Treatment of SNMs has substantial long-term complications, which are significantly associated with radiation therapy.

Cutaneous Squamous Cell Carcinoma in Immunocompromised Patients-A Comparison between Different Immunomodulating Conditions.

BACKGROUND: Immunosuppression is strongly associated with an increased risk of developing cutaneous squamous cell carcinoma (cSCC). Studies on solid organ transplant recipients (SOTR) and chronic lymphocytic leukemia (CLL) patients have already demonstrated higher rates of aggressive cSCC tumors in these populations compared to immunocompetent controls. Studies on other immunosuppressed patient groups are scarce. This study was aimed at assessing the effects of different immunomodulating conditions on patients diagnosed with cSCC. We sought to compare the clinical features, treatments, and survival rates among the different study groups, as well as outcomes to those of immunocompetent controls with cSCC. METHODS: A retrospective analysis of 465 cSCC patients, both immunosuppressed (IS) and immunocompetent controls. Etiologies for immunosuppression included SOTR, CLL, chronic kidney disease (CKD), psoriasis, rheumatoid arthritis (RA) and systemic lupus erythematous (SLE). RESULTS: Compared to the control group, IS patients demonstrated several significant differences. These include higher rates of positive resection margins, higher recurrence rates, and multiple SCC tumors. Patients in the IS group, who were also given immunomodulating agents, demonstrated even lower survival rates. Cox regression analysis demonstrated statistically significant decreased overall survival (OS) rates for IS patients compared to the controls (OR = 1.9, p = 0.031). SOTR patients tend to have multiple cSCC tumors (35%), with the highest number of primary tumors compared to controls (2.54 tumors per patient on average, p < 0.001), but also compared to all other IS groups. The average SCC lesion size in the SOTR group was the smallest, measuring at 13.5 mm, compared to the control group and all other IS groups. Decreased survival rates were seen on Cox regression analysis compared to controls (HR = 2.4, p = 0.001), but also to all other IS groups. CLL patients also had the highest rates of positive margins compared to controls (36% vs. 9%, p < 0.01) and to all other IS groups. They were also most likely to get adjuvant or definitive oncological treatments, either radiotherapy or chemotherapy, compared to controls (36% vs. 15%, p = 0.02) and to other IS groups. Patients in the CKD group demonstrated the highest rates for multiple cSCC (OR = 4.7, p = 0.001) and the worst rates of survival on Cox regression analysis (HR = 3.2, p = 0.001). Both rheumatoid arthritis and psoriasis patients demonstrated the shortest disease-free survival rates (2.9y ± 1.1, 2.3y ± 0.7, respectively), compared to controls (4.1y ± 2.8) and to all other IS groups. CONCLUSIONS: Among cSCC patients, immunosuppression due to SOTR, CLL, CKD, RA, and psoriasis is associated with worse outcomes compared to controls and other IS groups. These patients should be regarded as high-risk for developing aggressive cSCC tumors. This study is the first to assess and compare cSCC outcomes among multiple IS patient groups.

The Predictors of Persistent Posttracheostomy Tracheocutaneous Fistula and Successful Surgical Closure.

OBJECTIVE: Persistent tracheocutaneous fistula is a well-described complication of prolonged tracheostomy, with a prevalence of about 70% when decannulation is performed after more than 16 weeks. Predictors of its occurrence and outcome of treatment in adults remain unclear. The aim of the study was to describe our experience with the treatment of persistent posttracheostomy tracheocutaneous fistula in adults and to investigate factors associated with its formation and with the success of surgical closure. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary medical center. METHODS: Patients who underwent open-approach tracheostomy between 2000 and 2020 were identified by database review. Data on background, need for surgical closure, and the surgical outcome was collected from the medical files and analyzed statistically between groups. RESULTS: Of 516 patients identified, 127 with sufficient long-term follow-up data were included in the study. Compared to patients whose fistula closed spontaneously (n = 85), patients who required surgical closure (n = 42) had significantly higher rates of smoking, laryngeal or thyroid malignancy, and airway obstruction as the indication for tracheostomy, on both univariate and multivariate analysis. In a comparison of patients with successful (n = 29) or failed (n = 11) surgical closure, factors significantly associated with failure were prior radiotherapy and lower preoperative albumin level, on univariate analysis. CONCLUSION: Smoking, thyroid or laryngeal malignancy, and airway obstruction indication are risk factors for persistent posttracheostomy tracheocutaneous fistula. Patients should be closely followed after tracheostomy and referred for surgery if the fistula fails to close. Before surgery, careful evaluation of the patient's nutritional status and consideration of prior radiation treatment is mandatory.

Effect of Opioid Receptor Activation and Blockage on the Progression and Response to Treatment of Head and Neck Squamous Cell Carcinoma.

Recent studies suggest that opioids have a role in the progression of HNSCC mediated by mu opioid receptors (MOR), however, the effects of their activation or blockage remains unclear. Expression of MOR-1 was explored in seven HNSCC cell lines using Western blotting (WB). XTT cell proliferation and cell migration assays were performed on four selected cell lines (Cal-33, FaDu, HSC-2, and HSC-3), treated with opiate receptor agonist (morphine), antagonist (naloxone), alone and combined with cisplatin. All four selected cell lines display an increased cell proliferation and upregulation of MOR-1 when exposed to morphine. Furthermore, morphine promotes cell migration, while naloxone inhibits it. The effects on cell signaling pathways were analyzed using WB, demonstrating morphine activation of AKT and S6, key proteins in the PI3K/AKT/mTOR axis. A significant synergistic cytotoxic effect between cisplatin and naloxone in all cell lines is observed. In vivo studies of nude mice harboring HSC3 tumor treated with naloxone demonstrate a decrease in tumor volume. The synergistic cytotoxic effect between cisplatin and naloxone is observed in the in vivo studies as well. Our findings suggest that opioids may increase HNSCC cell proliferation via the activation of the PI3K/Akt/mTOR signaling pathway. Moreover, MOR blockage may chemo-sensitize HNSCC to cisplatin.

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.

The protective effect of aspirin-induced temporary threshold shift in an animal model of cisplatin-related ototoxicity.

PURPOSE: The purpose of this study was to evaluate whether induction of temporary threshold shift (TTS) with aspirin prior to cisplatin exposure can prevent or minimize cisplatin detrimental effects on hearing. METHODS: We randomly divided BALB mice into three groups: (1) cisplatin only, (2) aspirin only, and (3) combined aspirin/cisplatin. Cisplatin was administered as a single intraperitoneal injection of 14 mg/kg. Aspirin was administered for three weeks via intraperitoneal injection of 200 mg/kg sodium salicylate, twice daily. Air conduction thresholds were recorded using Auditory Brainstem Responses (ABR). Cochleae were harvested and cochlear hair cells were counted using a scanning electron microscope (SEM). RESULTS: Aspirin-induced TTS have reached an average of 30.05±16.9 dB after 2 weeks. At 60 days, cisplatin-only treated mice experienced an average threshold shifts of 50.7 dB at 4 kHz, 35.16 dB at 8 kHz, 70 dB at 16 kHz, 53.1 dB at 32 kHz. All threshold shifts were significantly worse than for cisplatin/aspirin treated mice with TTS of 11.85 dB at 4 kHz, 3.58 dB at 8 kHz, 16.58  dB at 16 kHz, 20.41 dB at 32 kHz (p < 0.01). Cochlear cell count with SEM has shown reduction in the number of both inner and outer hair cells in the mid-turn in cisplatin treated mice. CONCLUSION: Aspirin induced TTS can protect from cisplatin-induced ototoxicity. This beneficial effect was demonstrated by auditory thresholds as well as SEM. Larger pre-clinical and clinical studies are still needed to confirm these findings.