Middle ear effusion and newborn hearing screening.

PURPOSE: Middle ear effusion (MEE) is one of the reasons for screening failure and may require prolonged follow-up due to conductive hearing loss. We aimed to examine at 1-year follow-up, the fate of MEE. METHODS: From medical charts, computerized data were collected retrospectively of newborns born in the years 2012-2013 in Rambam Health Care Campus, Haifa city, Israel, who failed the Universal Newborn Hearing Screening (UNHS), and follow-up hearing evaluation data were extracted. RESULTS: Of 9527 newborns born in 2012-2013 in our institution, 144 [1.5%] failed the UNHS, and 46 were eventually diagnosed with conductive hearing loss caused by MEE. Spontaneous MEE clearance was recorded in 12 [26%], while 26 [57%] patients had persistent effusion that required further follow-up (10 [22%] required insertion of ventilation tubes and 16 [35%] were referred for further follow-up); 8 [17%] were lost to follow-up. CONCLUSION: Congenital MEE causing conductive hearing loss and UNHS failure is persistent and resolves at lower rates than non-congenital MEE.

Psychometric testing of the Skull Base Inventory health-related quality of life questionnaire in a multi-institutional study of patients undergoing open and endoscopic surgery.

PURPOSE: The skull base inventory (SBI) was developed to better assess health-related quality of life (HR-QOL) in patients with anterior and central skull base neoplasms treated by endoscopic and open approaches. The primary objective of this study was to prospectively assess the psychometric properties of the SBI. METHODS: This study is part of a multi-center study of patients undergoing endoscopic and open procedures completed between 2012 and 2018. Participants were eligible if they were over 18 years of age; had benign or malignant anterior, antero-lateral, or central skull base tumors; and required either an open or endoscopic skull base surgical approach. In order to assess the psychometric properties of the SBI, patients completed the instrument at six time points (preoperative, 2 weeks, 3 months, 6 months, 12 months postoperative). Patients also completed the Anterior Skull Base (ASB) questionnaire and the Sinonasal Outcome Test (SNOT-22) to allow comparison to the SBI. RESULTS: One hundred and eighty-seven patients were included across five centers, with 121 having an endoscopic procedure. Internal consistency (Cronbach's alpha = 0.95) and test-retest at 12 months and 12 months plus 2 weeks (intraclass correlation > 0.90) were excellent. Concurrent validity was demonstrated by very strong correlation between total SBI scores and ASB scores (r = 0.810 to 0.869, p < 0.001) and moderate correlation between nasal domain SBI scores and SNOT-22 scores (r = - 0.616 to - 0.738, p < 0.001). Convergent validity was demonstrated by moderate correlation between change in SBI scores and global QOL change (rs = 0.4942, p < 0.001). The minimally important clinical difference (global HR-QOL change of "a little better" or "a little worse") was 6.0. CONCLUSION: The SBI questionnaire is reliable and valid for patients treated by both endoscopic and open approaches and can be used for assessment of HR-QOL in these settings.

RET, a targetable driver of pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) remains a deadly disease, affecting about 40,000 individuals in the United States annually. We aimed to characterize the role of RET as a co-driver of pancreas tumorigenesis. To assess the role of RET as a co-driver of PDA, we generated a novel triple mutant transgenic mouse based on the cre-activated p53R172H gene and a constitutively active RET M919T mutant (PRC). Survival analysis was performed using Kaplan-Meier analysis. Study of human PDA specimens and Pdx-1-Cre/KrasG12D /p53R172H (KPC) mice revealed that RET is upregulated during pancreas tumorigenesis, from inception through precursor lesions, to invasive cancer. We demonstrated that activation of RET is capable of inducing invasive pancreatic carcinomas in the background of the P53 inactivation mutation. Compared to KPC mice, PRC animals had distinct phenotypes, including longer latency to tumor progression, longer survival, and the presence of multiple macrometastases. Enhanced activation of the MAPK pathway was observed as early as the PanIN 2 stage. Sequencing of the exonic regions of KRAS in PRC-derived PDA cells revealed no evidence of KRAS mutations. RET can be an essential co-driver of pancreatic tumorigenesis in conjugation with KRAS activity. These data suggest that RET may be a potential target in the treatment of PDA.

The role of adjuvant treatment in early-stage oral cavity squamous cell carcinoma: An international collaborative study.

BACKGROUND: Up to half of patients with oral cavity squamous cell carcinoma (OCSCC) have stage I to II disease. When adequate resection is attained, no further treatment is needed; however, re-resection or radiotherapy may be indicated for patients with positive or close margins. This multicenter study evaluated the outcomes and role of adjuvant treatment in patients with stage I to II OCSCC. METHODS: Overall survival (OS), disease-specific survival, local-free survival, and disease-free survival rates were calculated with Kaplan-Meier analysis. RESULTS: Of 1257 patients with T1-2N0M0 disease, 33 (2.6%) had positive margins, and 205 (16.3%) had close margins. The 5-year OS rate was 80% for patients with clear margins, 52% for patients with close margins, and 63% for patients with positive margins (P < .0001). In a multivariate analysis, age, depth of invasion, and margins were independent predictors of outcome. Close margins were associated with a >2-fold increase in the risk of recurrence (P < .0001). The multivariate analysis revealed that adjuvant treatment significantly improved the outcomes of patients with close/positive margins (P = .002 to .03). CONCLUSIONS: Patients with stage I to II OCSCC and positive/close margins have poor long-term outcomes. For this population, adjuvant treatment may be associated with improved survival. Cancer 2018;124:2948-55. © 2018 American Cancer Society.

Contemporary Treatment Approaches to Sinonasal Mucosal Melanoma.

Sinonasal mucosal melanoma (SNMM) is a rare oncological entity that comprises most head and neck mucosal melanomas. SNMM has distinctive genetic background, different from cutaneous melanoma. Survival outcomes among SNMM patients are poor; while there is no clear consensus on the optimal management of SNMM, the primary treatment modality is generally considered to be wide surgical excision, and radiation therapy (RT) is often used in the postoperative adjuvant setting to improve locoregional control. Systemic therapies have demonstrated little or no survival benefit, and most SNMM patients die of distant metastatic disease. Owing to the rarity of the disease, the literature describing treatment approaches for SNMM is lacking and largely limited to isolated case reports and retrospective series. Here, we describe contemporary diagnostic and therapeutic approaches to SNMM based on the most recent molecular and outcome data.

[SURGICAL TREATMENT OF LOCALLY ADVANCED WELL DIFFERENTIATED THYROID CARCINOMA].

AIMS: We aimed to better define the most appropriate therapeutic protocol for this type of tumor. BACKGROUND: The incidence of well-differentiated thyroid carcinoma is rising and the mortality from the disease remains low for patients with early disease. Nevertheless, the survival of patients with advanced disease has not improved during the last four decades and a controversy still exists in the literature regarding the optimal treatment in patients with locally advanced (T4) differentiated thyroid carcinoma. METHODS: Meta-analysis of the literature and our institutional experience, in treating patients with advanced papillary/follicular thyroid carcinoma. The main outcome measures were overall survival (OS) and disease-specific survival (DSS). RESULTS: The study group consisted of 38 patients with locally advanced thyroid carcinoma (T4). Regional spread to nodal metastases was present in 25 (65.7%) patients. Tracheal invasion was diagnosed in 29 (76.3%), of those 10 (26.3%) patients had airway obstruction. Recurrent laryngeal nerve (RLN) paralysis was revealed with clinical evidence during diagnosis in 23 (60.5%) patients. The 5-years OS was 66% and DSS was 87%. Multivariate analysis of outcome showed that undifferentiated carcinoma foci and vocal cord paralysis were associated with significantly reduced 5-years OS, and vocal cord paralysis was the only independent prognostic variable for DSS. Male gender and adjuvant radioactive iodine treatment were significant prognostic variables for disease free survival but not OS or DSS. CONCLUSIONS: Surgical resection remains the mainstay of treatment for locally advanced differentiated thyroid cancers. Foci of poorly differentiated cells, vocal cord paralysis and male gender are associated with poor prognosis. Radioactive iodine treatment improved local control but did not not affect OS. These patients should be managed by a multidisciplinary team in university centers specializing in treating complicated cancer patients.

Gemcitabine resistance in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) ranks fourth among cancer related deaths. The disappointing 5-year survival rate of below 5% stems from drug resistance to all known therapies, as well as from disease presentation at a late stage when PDA is already metastatic. Gemcitabine has been the cornerstone of PDA treatment in all stages of the disease for the last two decades, but gemcitabine resistance develops within weeks of chemotherapy initiation. From a mechanistic perspective, gemcitabine resistance may result from alterations in drug metabolism until the point that the cytidine analog is incorporated into the DNA, or from mitigation of gemcitabine-induced apoptosis. Both of these drug resistance modalities can be either intrinsic to the cancer cell, or influenced by the cancer microenvironment. Mechanisms of intrinsic gemcitabine resistance are difficult to tackle, as many of the genes that drive the carcinogenic process itself also interfere with gemcitabine-induced apoptosis. In this regard, recent understanding of the involvement of microRNAs in gemcitabine resistance may offer new opportunities to overcome intrinsic gemcitabine resistance. The characteristically fibrotic and immune infiltrated stroma of PDA that accompanies tumor inception and expansion is a lush ground for treatments aimed at targeting tumor microenvironment-mediated drug resistance. In the last couple of years, drugs interfering with tumor microenvironment have matured to clinical trials. Although drugs inducing 'stromal depletion' have yet failed to improve survival, they have greatly increased our understanding of tumor microenvironment-mediated drug resistance. In this review we summarize the current knowledge on intrinsic and environment-mediated gemcitabine resistance, and discuss the impact of these pathways on patient screening, and on future treatments aimed to potentiate gemcitabine activity.

Paracrine regulation of glioma cells invasion by astrocytes is mediated by glial-derived neurotrophic factor.

It was suggested that the brain microenvironment plays a role in glioma progression. Here we investigate the mechanism by which astrocytes which are abundant in glioma tumors, promote cancer cell invasion. In this study, we evaluated the effects of astrocytes on glioma biology both in vitro and in vivo and determined the downstream paracrine effect of glial-derived neurotrophic factor (GDNF) on tumor invasion. Astrocytes-conditioned media (ACM) significantly increased human and murine glioma cells migration compared to controls. This effect was inhibited when the activity of GDNF on glioma cells was blocked by RET-Fc chimera or anti-GDNF Ab and by small interfering RNA directed against GDNF expression by astrocytes. Glioma cells incubated with ACM led to time dependent phosphorylation of the GDNF receptor, RET and downstream activation of AKT. Tumor migration and GDNF-RET-AKT activation was inhibited by the RET small-molecule inhibitor pyrazolopyrimidine-1 (PP1) and by the AKT inhibitor LY294002. Finally, blocking of RET by PP1 or knockout of the RET coreceptor GFRα1 in glioma cells reduced the size of brain tumors in immunocompetent mice. We suggest a mechanism by which astrocytes attracted to the glioma tumors facilitate brain invasion by secretion of GDNF and activation of RET/GFRα1 receptors expressed by the cancer cells.

Elective neck dissection in patients with head and neck adenoid cystic carcinoma: an international collaborative study.

BACKGROUND: Adenoid cystic carcinoma (ACC) accounts for 3-5 % of all head and neck malignancies. Investigations of outcomes from elective neck dissection (END) for patients with ACC are sparse. This study aimed to assess the impact of END on the survival of patients with ACC. METHODS: This retrospective multicentered study investigated 270 patients who underwent neck dissection. A multivariate analysis assessed associations of clinical and histopathologic characteristics with survival outcomes. RESULTS: The primary tumor sites included the oral cavity in 250 patients (55 %), the major salivary glands in 133 patients (29 %), the sinonasal mucosa in 68 patients (15 %), and the larynx in six patients (1 %). The overall rate of occult nodal metastases among the patients who underwent END was 17 % (38/226). The highest incidence of occult nodal metastases was with the oral cavity (66 %). The 5-year overall survival (72 and 79 % for patients with or without END, respectively) and disease-specific survival (74 and 81 % for patients with or without END, respectively) were similar in the two groups. The subgroup analysis of patients according to the primary site showed no significant impact of END on outcome. In the multivariate analysis, primary site, T classification, and N classification were the only variables associated with outcome. CONCLUSIONS: The incidence of occult neck metastases among patients with ACC is 17 %. The highest incidence of occult metastases is with the oral cavity. Statistical analysis showed no survival advantage for patients who underwent END compared with those who did not.

An orthotopic mouse model of laryngeal squamous cell carcinoma.

OBJECTIVE: This study aimed to create a reliable and reproducible orthotopic mouse model of laryngeal malignancy that recapitulates its biologic behavior, local invasiveness, and spread as seen in patients. METHODS: Via direct laryngoscopy, human squamous cell carcinoma line FaDu (ATCC HTB-43) was implanted in the larynx (supraglottis and glottis) in nu/nu mice (n = 31). Animals were monitored with direct laryngoscopy and ultrasound for tumor growth and survival. Specimens of larynxes, neck lymphatics, livers, and lungs were removed for histopathologic evaluation to assess tumor extension, thyroid cartilage invasion, and nodal spread. RESULTS: Thirty-one successful direct laryngoscopies were performed. Supraglottic and glottic tumor uptake was 100% and 25%, respectively. Median survival for the animals with supraglottic tumors was 35 days. Histopathologic evaluation revealed pre-epiglottic extension, paraglottic extension, thyroid cartilage invasion, and lymph node metastasis. CONCLUSION: We describe the first orthotopic model for laryngeal cancer. Our model faithfully recapitulates the phenotype and malignant behavior that reproduces its natural biologic behavior as seen in laryngeal cancer patients. This model offers an opportunity to identify and specifically target therapy for larynx squamous cell carcinoma.

Outcome of patients undergoing salvage surgery for recurrent nasopharyngeal carcinoma: a meta-analysis.

BACKGROUND: The common treatment of primary patients with nasopharyngeal carcinoma is chemotherapy and radiotherapy. Surgery is reserved as salvage procedure for recurrent or persistent disease. Nevertheless, information on the outcome of these patients and the role of adjuvant reirradiation treatment is scarce. METHODS: We conducted a meta-analysis to identify prognostic factors associated with outcomes of patients with recurrent nasopharyngeal carcinoma treated by salvage surgery. RESULTS: The study group consisted of 779 patients from 17 published studies who met the inclusion criteria. The primary tumor classification at recurrence was T1-2 in 83 % of patients and T3-4 in 16.6 %. Regional lymph node metastases were present in 88 patients. The 5-year overall survival and local recurrence-free survival rates of the entire cohort were 51.2 and 63.4 %, respectively, with a distant metastases rate of 11.3 %. The 5-year overall survival was 63 % in patients receiving surgery and adjuvant radiotherapy compared to 39 % in patients receiving surgery alone (P = 0.05). Independent predictors of outcome on multivariate analysis were sex, N classification, surgical approach (endoscopic vs. open), adjuvant treatment, and margin status. Both endoscopic surgery and reirradiation were independent predictors of improved survival. CONCLUSIONS: More than half of the patients with recurrent disease can be salvaged by surgery. Margins status, and N and T classification are significant predictors of outcome. Multivariate analysis revealed that endoscopic surgery offers better outcome than open surgery for T3/4 disease in selected patients, and adjuvant reirradiation offers an additional survival advantage over surgery alone.

Next Directions in the Neuroscience of Cancers Arising outside the CNS.

SUMMARY: The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer neuroscience for malignancies arising outside of the central nervous system.

Primary Tumor Staging for Oral Cancer and a Proposed Modification Incorporating Perineural Invasion: An International Multicenter Study.

The objective of this study is to determine if the incorporation of perineural invasion (PNI) into the T-classification would improve the prognostic performance of TNM-8. An international, multicenter study of 1049 patients with oral cavity squamous cell carcinoma that were treated from 1994 to 2018 is performed. Various classification models are developed within each T-category and evaluated using the Harrel-concordance index (C-index), Akaike-information criterion (AIC), and visual inspection. Stratification into distinct prognostic categories, with internal validation, is performed using bootstrapping analysis (SPSS and R-software). Through multivariate analysis, PNI is significantly associated with disease-specific survival (p < 0.001). PNI integration into the staging system results in a significantly improved model compared with the current T category alone (lower AIC, p < 0.001). The PNI-integrated model is superior in predicting differential outcomes between T3 and T4 patients. A new model for T-classification of oral cavity squamous cell carcinoma is proposed, which is based on incorporating PNI into the staging system. These data can be used for future evaluations of the TNM staging system.

Beta-Blocker Use Is Associated With Worse Relapse-Free Survival in Patients With Head and Neck Cancer.

PURPOSE: Although beta-blockers (BBs) have been hypothesized to exert a beneficial effect on cancer survival through inhibition of beta-adrenergic signaling pathways, clinical data on this issue have been inconsistent. We investigated the impact of BBs on survival outcomes and efficacy of immunotherapy in patients with head and neck squamous cell carcinoma (HNSCC), non-small-cell lung cancer (NSCLC), melanoma, or squamous cell carcinoma of the skin (skin SCC), independent of comorbidity status or cancer treatment regimen. METHODS: Patients (N = 4,192) younger than 65 years with HNSCC, NSCLC, melanoma, or skin SCC treated at MD Anderson Cancer Center from 2010 to 2021 were included. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were calculated. Kaplan-Meier and multivariate analyses adjusting for age, sex, TNM staging, comorbidities, and treatment modalities were performed to assess the effect of BBs on survival outcomes. RESULTS: In patients with HNSCC (n = 682), BB use was associated with worse OS and DFS (OS: adjusted hazard ratio [aHR], 1.67; 95% CI, 1.06 to 2.62; P = .027; DFS: aHR, 1.67; 95% CI, 1.06 to 2.63; P = .027), with DSS trending to significance (DSS: aHR, 1.52; 95% CI, 0.96 to 2.41; P = .072). Negative effects of BBs were not observed in the patients with NSCLC (n = 2,037), melanoma (n = 1,331), or skin SCC (n = 123). Furthermore, decreased response to cancer treatment was observed in patients with HNSCC with BB use (aHR, 2.47; 95% CI, 1.14 to 5.38; P = .022). CONCLUSION: The effect of BBs on cancer survival outcomes is heterogeneous and varies according to cancer type and immunotherapy status. In this study, BB intake was associated with worse DSS and DFS in patients with head and neck cancer not treated with immunotherapy, but not in patients with NSCLC or skin cancer.

Endoscopic Septoplasty Versus Traditional Septoplasty for Treating Deviated Nasal Septum: A Prospective, Randomized Controlled Trial.

IMPORTANCE: This is the first randomized study to compare the quality of life of patients undergoing endoscopic septoplasty compared to traditional trans-nasal trans-speculum (TNTS) septoplasty. OBJECTIVE: To assess the clinical outcomes and quality of life results of endoscopic versus TNTS septoplasty in patients with septal deviation and nasal obstruction. DESIGN: A prospective, randomized controlled trial comparing 2 approaches of septoplasty: endoscopic and TNTS septoplasty performed in a single institution during the years 2016 to2017. The follow-up time was 3 months. SETTING: A single institution study in a tertiary health-care referral center. PARTICIPANTS: Patients who underwent primary surgery for repairing deviated nasal septum due to nasal obstruction, were older than 18 years old, and were eligible for study inclusion. Sixty-five patients were enrolled in this study, 34 in the endoscopic arm and 31 in the TNTS septoplasty arm. The overall follow-up rate was 94% at the first visit (2 weeks) and 92% at the last visit (12 weeks). Thus, the final cohort consisted of 60 patients, 30 in each study arm. The patients ranged in age from 18 to 71 years (mean 27 years) old. MAIN OUTCOMES AND MEASURES: The primary outcome was the Sino-Nasal Outcome Test-22 (SNOT-22) score. Secondary outcomes were the Short Form 36 (SF36) QOL score and complication rates. Both questionnaires were administered at 2 weeks and 3 months following surgery. RESULTS: Sixty patients completed this study, 30 in each study arm. Sino-Nasal Outcome Test-22 scores were improved after 3 months, with no difference between the study arms. There were no cases of septal perforation or profound bleeding requiring repeated surgery. CONCLUSIONS AND RELEVANCE: Endoscopic septoplasty and TNTS show similar results for treatment of nasal septum deviation. Trial Registration: Traditional Septoplasty versus Endoscopic Septoplasty for Treating Deviated Nasal Septum, NCT02653950. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0005ZOR&selectaction=Edit&uid=U00021YC&ts=2&cx=-2w7hot.

Can Tonsillectomy Be Safely Performed by Residents? A Comparative Retrospective Study.

OBJECTIVE: To assess whether a surgeon's level of training is associated with outcomes in pediatric tonsillectomy. DESIGN: A retrospective cohort study of the outcomes of pediatric tonsillectomies performed between 2006 and 2016 by senior surgeons versus resident surgeons under the supervision of senior surgeons. SETTING: An otolaryngology department in a tertiary academic hospital. PATIENTS: Children younger than 18 years who underwent bilateral tonsillectomy with or without adenoidectomy. MAIN OUTCOME MEASURES: Intraoperative bleeding, initiation of oral intake, and intraoperative and postoperative complications. RESULTS: Of 785 children, 397 (50.5%) were operated on by a resident surgeon and 388 (49.5%) by a senior surgeon. Patient demographics and surgical techniques were similar between the groups. The mean surgical time was 33.2 minutes in the residents' group and 27.1 minutes in the seniors' group (P = .032). The groups were similar in intraoperative bleeding, while same-day initiation of oral intake was 71% for children in the residents' group versus 61% in the seniors' group (P = .28). Reports of postoperative bleeding necessitating readmission and revised operations were similar for both groups (3.0% and 0.7%, respectively, in the residents' group; and 2.5% and 1.0%, respectively, in the seniors' group). CONCLUSION: Children undergoing tonsillectomy showed similar short-term outcomes, whether the operations were performed by a senior surgeon or a resident surgeon supervised by an attending surgeon. This study demonstrates the safety of pediatric tonsillectomy performed by resident surgeons supervised by attending physicians.

Long-Term Quality of Life after Endoscopic Pituitary Adenoma Surgery with Nasoseptal Flap Reconstruction.

INTRODUCTION: Endoscopic endonasal transsphenoidal surgery (EETS) on the pituitary gland is considered safe and efficacious. The nasoseptal flap (NSF) is sometimes used to prevent or repair postoperative cerebrospinal fluid (CSF) leaks. Few investigators have quantified long-term quality-of-life (QOL) outcomes regarding sinonasal measures after EETS, with or without involvement of the NSF. This study assesses whether the septal flap affects sinonasal QOL outcomes for patients receiving EETS for pituitary adenoma. METHODS AND MATERIALS: This is a retrospective study of patients who underwent EETS between 2013 and 2018. A total of 62 adults completed the Sinonasal Outcome Test-22 (SNOT-22) at least one year after the surgery. Outcome measures were compared between patients who underwent EETS with and without septal flap reconstruction. RESULTS: For the entire cohort, there were 14 patients (22.6%) who had septal flap reconstruction and 48 patients (77.4%) who did not. Patient demographics, tumor characteristics, surgical outcomes, and duration between surgery and completion of the questionnaire were similar for both groups. The mean SNOT-22 scores in the no reconstruction (NR) group and the nasoseptal flap reconstruction (NSFR) group were similar (P=0.9). In terms of SNOT-22 subdomains (rhinologic symptoms, extranasal rhinologic symptoms, ear/facial symptoms, psychological dysfunction, and sleep dysfunction), no significant differences were found when comparing the groups. CONCLUSION: As compared with no reconstructive involvement, NSF utilization does not affect the QOL and nasal symptoms of patients undergoing EETS.

Future directions in preclinical and translational cancer neuroscience research.

Recent advances in cancer neuroscience necessitate the systematic analysis of neural influences in cancer as potential therapeutic targets in oncology. Here, we outline recommendations for future preclinical and translational research in this field.