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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.

Sinonasal mucosal melanoma (SNMM) is a rare tumor, comprising less than 10% of sinonasal malignancies. SNMM most frequently occurs in the nasal cavity (70%) and maxillary sinus (14%), typically as black patches. Overall, SNMM harbors a very poor prognosis; 5-year survival is less than 30%. Nasal cavity tumors confer a better prognosis than sinus melanoma. The primary management for SNMM is surgery, when feasible, followed by adjuvant radiotherapy. Recent studies suggest that immunotherapy may confer survival benefit to patients with advanced disease. The multidisciplinary team approach has been shown to optimize treatment, reduce costs, and minimize adverse events, while maximizing the chances for cure.

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.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.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.Congenital MEE causing conductive hearing loss and UNHS failure is persistent and resolves at lower rates than non-congenital MEE.

BACKGROUND Differentiated thyroid cancers often require radioiodine treatment followed by posttreatment scan. We aimed in this study to assess the utility of the posttreatment radioiodine scan in this population. METHODS An analysis of patients who received radioiodine treatment at Rambam Campus, during 2006-2013. Scans showing remnant normal thyroid tissue were considered as normal. Positive uptake was defined as uptake in the lateral neck or distant sites. RESULTS A total of 455 patients were analyzed, 68% had T1-T2 and 28% had positive lymph nodes. Positive uptake in the lateral neck was recorded in 52 (11.4%) and in distant sites in 41 (9%) patients. Tracheal invasion, esophageal invasion, nerve invasion, and N1b classification were associated with a positive scan (P

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.

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.

Neuro-glial activation is a recently identified hallmark of growing cancers. Targeting tumor hyperinnervation in preclinical and small clinical trials has yielded promising antitumor effects, highlighting the need of systematic analysis of neural influences in cancer (NIC). Here, we outline the strategies translating these findings from bench to the clinic.

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 .

In oral cavity SCCs, tumor margin status is an important prognostic factor. Achieving negative margins depends primarily on the surgeon skills and the accuracy of intraoperative margin assessment. Tumor margin of less than 5 mm is considered as close margin, while ≥5 mm is defined as negative margin. In patients with early-stage SCC of the oral cavity, close margins were associated with over twofold increase in the risk of recurrence, compared with negative margins. Patients with positive/close margins are amenable to adjuvant radiation or chemoradiation therapy. The utility of specimen-driven margin analysis is associated with a higher rate of negative margins than the traditional patient-driven margin analysis. Specimen-driven margin analysis can prevent escalation of adjuvant treatment in up to 30% of the patients.

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 2-fold increase in the risk of recurrence (P

Background The mainstay of treatment in adenoid cystic carcinoma (ACC) of the head and neck is surgical resection with negative margins. The purpose of this study was to define the margin status that associates with survival outcomes of ACC of the head and neck. Methods We conducted univariate and multivariate analyses of international data. Results Data of 507 patients with ACC of the head and neck were analyzed; negative margins defined as ≥5 mm were detected in 253 patients (50%). On multivariate analysis, the hazard ratios (HRs) of positive margin status were 2.68 (95% confidence interval [CI], 1.2-6.2; p = .04) and 2.63 (95% CI, 1.1-6.3; p = .03) for overall survival (OS) and disease-specific survival (DSS), respectively. Close margins had no significant impact on outcome, with HRs of 1.1 (95% CI, 0.4-3.0; p = .12) and 1.07 (95% CI, 0.3-3.4; p = .23) for OS and DSS, respectively, relative with negative margins. Conclusion In head and neck ACC, positive margins are associated with the worst outcome. Negative or close margins are associated with improved outcome, regardless of the distance from the tumor. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1008-1014, 2017.

Objective Adenoidectomy can be performed using the cold method (mainly adenoid curettes) or the hot method (suction diathermy). Both techniques have similar intra and postoperative outcomes. However, the long-term clinical outcome of improving sleep disorder symptoms has not been well established. The objective of this study was to compare outcomes of hot method and cold method adenoidectomy one year following the surgery. Study design A prospective, randomized, single-blinded study of children under age 16 years who underwent adenoidectomy during the years 2014–2017. Patients were randomized to hot or cold adenoidectomy techniques. Setting A tertiary health care referral center. Subjects and methods The final analysis included 58 children, mean age 5.9 years (range 1.2–15). The primary outcome was change in the Pediatric Sleep Questionnaire (PSQ) scores one month and one year after surgery. The secondary outcome was complication rate. Results Clinical and demographic parameters were similar between the patients in the hot method group (n = 30) and the cold method group (n = 28). Adenoid size and estimated bleeding were similar between the groups. At one month after surgery, PSQ score was improved by a mean + 0.31 in the hot method group compared to +0.32 in the cold method group (p = 0.54). Improvement in PSQ scores was greater following hot than cold adenoidectomy at one year after surgery (+0.31 points vs. +0.22 points, p = 0.009). Conclusion Hot adenoidectomy is associated with better outcome than the cold technique, as reflected by PSQ scores one year after the surgery.

Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory to RAI, heralding a poor prognosis. RAI-refractory (RAI-R) cancer cells result from the loss of thyroid differentiation features, such as iodide uptake and organification. This loss of differentiation features correlates with the degree of mitogen-activated protein kinase (MAPK) activation, which is higher in tumors with BRAF (B-Raf proto-oncogene) mutations than in those with RTK (receptor tyrosine kinase) or RAS (rat sarcoma) mutations. Hence, inhibition of the mitogen-activated protein kinase kinase-1 and -2 (MEK-1 and -2) downstream of RAF (rapidly accelerated fibrosarcoma) could sensitize RAI refractivity in thyroid cancer. However, a significant hurdle is the development of secondary tumor resistance (escape mechanisms) to these drugs through upregulation of tyrosine kinase receptors or another alternative signaling pathway. The sodium iodide symporter (NIS) is a plasma membrane glycoprotein, a member of solute carrier family 5A (SLC5A5), located on the basolateral surfaces of the thyroid follicular epithelial cells, which mediates active iodide transport into thyroid follicular cells. The mechanisms responsible for NIS loss of function in RAI-R thyroid cancer remains unclear. In a study of patients with recurrent thyroid cancer, expression levels of specific ribosomal machinery—namely PIGU (phosphatidylinositol glycan anchor biosynthesis class U), a subunit of the GPI (glycosylphosphatidylinositol transamidase complex—correlated with RAI avidity in radioiodine scanning, NIS levels, and biochemical response to RAI treatment. Here, we review the proposed mechanisms for RAI refractivity and the management of RAI-refractive metastatic, recurrent thyroid cancer. We also describe novel targeted systemic agents that are in use or under investigation for RAI-refractory disease, their mechanisms of action, and their adverse events.

Background: Foreign body aspiration (FBA) is a major cause of morbidity and mortality in children. It is a preventable event that predominates in preschool age. The signs and symptoms mimic respiratory diseases common in the same age-group. We compared FBA in infants to FBA in older children. Methods: Retrospective analysis of all the cases of suspected FBA of children under the age of 18 years hospitalized at one medical center during 2002 to 2016. We analyzed the data according to age: up to 1 year (infants) and 1 to 18 years. Results: One hundred seventy-five children with suspected FBA were admitted; of whom, 27 (15%) were infants and 148 (85%) were older children (age 1-18 years). For the 2 age groups, adults witnessed 85% and 73%, respectively, of the incidents ( P = .4). In the neonate group, 48% presented with normal X-ray findings compared to only 20% in the older group; 15% of the older group had a positive chest X-ray for a foreign body, while none had such in the infants’ group ( P = .01). For the 2 age groups, the majority of the FBs found were from organic origin. About half of the patients were diagnosed and managed within 24 hours of the aspiration event. In 10%, repeated bronchoscopy was performed due to a retained FB remnant. In a multivariate analysis, signs and symptoms ( P < .05), location of the FB ( P < .001), and witnessed aspiration ( P < .001) were independent prognostic factors for the length of hospitalization. Conclusion: Foreign body aspiration is not uncommon in young infants; the management is challenging due to small airways, the need to use smaller bronchoscopes, and the lack of working channel forces in pediatric bronchoscopes.

The local extension of cancer cells along nerves is a frequent clinical finding for various tumours. Traditionally, nerve invasion was assumed to occur via the path of least resistance; however, recent animal models and human studies have revealed that cancer cells have an innate ability to actively migrate along axons in a mechanism called neural tracking. The tendency of cancer cells to track along nerves is supported by various cell types in the perineural niche that secrete multiple growth factors and chemokines. We propose that the perineural niche should be considered part of the tumour microenvironment, describe the molecular cues that facilitate neural tracking and suggest methods for its inhibition.

Background A positive margin is among the most significant factors that affects the outcome in head and neck squamous cell carcinoma (SCC). The purpose of this study was to compare the negative margin rates between 2 methods of intraoperative margin assessment in patients with oral cavity SCC. Methods A prospective, randomized controlled trial comparing 2 methods of intraoperative margin assessment: specimen-driven margins and patient-driven margins. Results The final analysis included 71 patients, 20 (29%) in the patient-driven margin arm. Frozen section analysis revealed positive/close surgical margins that led to an extension of the surgical resection in 22 of 51 patients (43%) in the specimen-driven margin arm, and 2 of 20 patients (10%) in the patient-driven margin arm (p = .01). After final pathological analysis, the wide negative margin rate was 84% in the specimen-driven margin arm, compared to 55% in the patient-driven margin arm (p = .02). Extension of the surgical resection prevented escalation of adjuvant treatment in 19 patients (38%) in the specimen-driven margin arm and 10% in the patient-driven margin arm. Conclusion Specimen derived margin assessment led to significant improvement in the rate of negative margins. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1803–E1809, 2016

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.

Pancreas cancer cells have a tendency to invade along nerves. Such cancerous nerve invasion (CNI) is associated with poor outcome; however, the exact mechanism that drives cancer cells to disseminate along nerves is unknown. Immunohistochemical analysis of human pancreatic ductal adenocarcinoma (PDAC) specimens showed overexpression of the L1 cell adhesion molecule (L1CAM) in cancer cells and in adjacent Schwann cells (SC) in invaded nerves. By modeling the neural microenvironment, we found that L1CAM secreted from SCs acts as a strong chemoattractant to cancer cells, through activation of MAP kinase signaling. L1CAM also upregulated expression of metalloproteinase-2 (MMP-2) and MMP-9 by PDAC cells, through STAT3 activation. Using a transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we show that treatment with anti-L1CAM Ab significantly reduces CNI in vivo. We provide evidence of a paracrine response between SCs and cancer cells in the neural niche, which promotes cancer invasion via L1CAM secretion.

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.

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.

We aimed to better define the most appropriate therapeutic protocol for this type of tumor.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.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).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.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.

The evolution of surgical oncologic technology has moved toward reducing patient morbidity without compromising oncologic resection. In head and neck surgery, organ-preserving techniques have paved the way for the development of transoral approaches that remove tumors of the upper aerodigestive tract without external incisions and potentially spare patients adjuvant treatment. The introduction of robotic-assisted surgery and transoral robotic surgery (TORS) reflects progression of the current transoral techniques to the upper aerodigestive tract. This chapter reviews the evolution of robotic-assisted surgery. We discuss its applications in head and neck surgery and early oncologic and functional outcomes, training of surgeons, costs, and future directions.

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.

Objective Chordoma is a locally aggressive tumor. The aim of this study was to assess the efficacy of different surgical approaches and adjuvant radiation modalities used to treat these patients. Design Meta-analysis. Main Outcome Measures Overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS). Results The 5-year OS and PFS rates of the whole cohort (n = 467) were 86% and 65.7%, respectively. The 5-year DSS for patients who underwent open surgery and endoscopic surgery was 45% and 49%, respectively (p = 0.8); PFS was 94% and 79%, respectively (p = 0.11). The 5-year OS of patients treated with surgery followed by adjuvant radiotherapy was 90% compared with 70% of those treated by surgery alone (p = 0.24). Patients undergoing partial resection without adjuvant radiotherapy had a 5-year OS of 41% and a DSS of 45%, significantly lower than in the total-resection group (p = 0.0002 and p = 0.01, respectively). The complication rates were similar in the open and endoscopic groups. Conclusions Patients undergoing total resection have the best outcome; adjuvant radiation therapy improves the survival of patients undergoing partial resection. In view of the advantages of minimally invasive techniques, endoscopic surgery appears an appropriate surgical approach for this disease.

Tumor spread along nerves, a phenomenon known as perineurial invasion, is common in various cancers including pancreatic ductal adenocarcinoma (PDAC). Neural invasion is associated with poor outcome, yet its mechanism remains unclear. Using the transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we investigated the mechanism of neural invasion in PDAC. To detect tissue-specific factors that influence neural invasion by cancer cells, we characterized the perineurial microenvironment using a series of bone marrow transplantation (BMT) experiments in transgenic mice expressing single mutations in the Cx3cr1, GDNF and CCR2 genes. Immunolabeling of tumors in KPC mice of different ages and analysis of human cancer specimens revealed that RET expression is upregulated during PDAC tumorigenesis. BMT experiments revealed that BM-derived macrophages expressing the RET ligand GDNF are highly abundant around nerves invaded by cancer. Inhibition of perineurial macrophage recruitment, using the CSF-1R antagonist GW2580 or BMT from CCR2-deficient donors, reduced perineurial invasion. Deletion of GDNF expression by perineurial macrophages, or inhibition of RET with shRNA or a small-molecule inhibitor, reduced perineurial invasion in KPC mice with PDAC. Taken together, our findings show that RET is upregulated during pancreas tumorigenesis and its activation induces cancer perineurial invasion. Trafficking of BM-derived macrophages to the perineurial microenvironment and secretion of GDNF are essential for pancreatic cancer neural spread.

Background Radioactive iodine (RAI) is the mainstay of treatment for differentiated thyroid carcinoma (DTC). Nevertheless, the mechanism of RAI resistance that occurs in many patients with DTC remains unknown. We aimed to elucidate the role of post-translational regulation of radioiodine uptake. Methods We analyzed the expression pattern of the ribosomal glycosylphosphatidylinositol transamidase (GPIT) complex in freshly excised tumors from 10 patients with DTC. We used functional RAI uptake assays to assess the role of GPIT in iodine uptake both in vivo and in vitro. The effects of MEK inhibition on the GPIT subunit PIGU and the sodium iodide symporter (NIS) were assessed in three DTC cell lines and in four human DTC biopsies. We used a multivariable logistic regression model to study the role of PIGU in the response to RAI treatment in advanced DTC. All statistical tests were two-sided. Results Expression profiling of different GPIT complex subunits revealed statistically significantly lower expression of PIGU in papillary carcinomas than in matched normal thyroid tissue (P < .001). Expression of PIGU in the K1 human papillary carcinoma cell line resulted in a robust increase in NIS glycosylation and trafficking to the cell membrane, accompanied by a robust increase in I125 uptake both in vitro (465 200 ± 56 343 vs 1236 ± 156 counts per million, P < .001) and in vivo (128 945 ± 28 556 vs 7963 ± 192 counts per million, P < .001, n = 5 mice per group). Treatment with the MEK inhibitors U0126 and PD302 rescued PIGU expression. Finally, the PIGU expression levels in tumors of 18 patients with recurrent DTC were associated with a biochemical response to RAI treatment (hazard ratio = 8.06, 95% confidence interval = 3.72 to 12.3, P = .001). Conclusions We showed that downregulation of PIGU in DTC determines NIS function and RAI avidity. This represents a novel mechanism for RAI resistance.

One way that solid tumors disseminate is through neural invasion. This route is well-known in cancers of the head and neck, prostate, and pancreas. These neurotropic cancer cells have a unique ability to migrate unidirectionally along nerves towards the central nervous system (CNS). The dorsal root ganglia (DRG)/cancer cell model is a three dimensional (3D) in vitro model frequently used for studying the interaction between neural stroma and cancer cells. In this model, mouse or human cancer cell lines are grown in ECM adjacent to preparations of freshly dissociated cultured DRG. In this article, the DRG isolation protocol from mice, and implantation in petri dishes for co-culturing with pancreatic cancer cells are demonstrated. Five days after implantation, the cancer cells made contact with the DRG neurites. Later, these cells formed bridgeheads to facilitate more extensive polarized, neurotropic migration of cancer cells.

Head and neck malignancies have the propensity to invade nerves. Perineural tumor invasion is common, with some series reporting rates of 30 to 100%. Squamous cell carcinoma and adenoid cystic carcinoma are the most commonly involved tumors. The most commonly involved nerves are the trigeminal (cranial nerve [CN] V) and facial (CN VII) and their branches. Neural spread away from a tumor is encountered less often and usually causes specific symptoms such as pain, muscle weakness, and atrophy, depending on the involved nerves. While clinical symptoms and physical examination may suggest the presence of neural invasion, specific imaging modalities such as fat-suppressed T1-weighted magnetic resonance images, should be utilized to identify perineural tumor spread in its early phases. Perineural tumor spread should be considered and addressed in the treatment planning of patients with head and neck or skull base cancers as it can influence the extent of surgery, and the dosage and fields of radiation therapy. In the current review, we discuss the clinical course of perineural tumor spread and its therapeutic implications.

One way that solid tumors disseminate is through neural invasion. This route is well-known in cancers of the head and neck, prostate, and pancreas. These neurotropic cancer cells have a unique ability to migrate unidirectionally along nerves towards the central nervous system (CNS). The dorsal root ganglia (DRG)/cancer cell model is a three dimensional (3D) in vitro model frequently used for studying the interaction between neural stroma and cancer cells. In this model, mouse or human cancer cell lines are grown in ECM adjacent to preparations of freshly dissociated cultured DRG. In this article, the DRG isolation protocol from mice, and implantation in petri dishes for co-culturing with pancreatic cancer cells are demonstrated. Five days after implantation, the cancer cells made contact with the DRG neurites. Later, these cells formed bridgeheads to facilitate more extensive polarized, neurotropic migration of cancer cells.

Differentiated thyroid carcinoma (DTC) comprises over 90% of thyroid tumors and includes papillary and follicular carcinomas. Patients with DTC have an excellent prognosis, with a 10-year survival rate of over 90%. However, the risk of recurrent tumor ranges between 5% and 30% within 10 years of the initial diagnosis. Cervical lymph node disease accounts for the majority of recurrences and in most cases is detected during follow-up by ultrasound or elevated levels of serum thyroglobulin. Recurrent disease is accompanied by increased morbidity. The mainstay of treatment of nodal recurrence is surgical management. We provide an overview of the literature addressing surgical management of recurrent or persistent lymph node disease in patients with DTC.

A positive margin is among the most significant factors that affects the outcome in head and neck squamous cell carcinoma (SCC). The purpose of this study was to compare the negative margin rates between 2 methods of intraoperative margin assessment in patients with oral cavity SCC.A prospective, randomized controlled trial comparing 2 methods of intraoperative margin assessment: specimen-driven margins and patient-driven margins.The final analysis included 71 patients, 20 (29%) in the patient-driven margin arm. Frozen section analysis revealed positive/close surgical margins that led to an extension of the surgical resection in 22 of 51 patients (43%) in the specimen-driven margin arm, and 2 of 20 patients (10%) in the patient-driven margin arm (p = .01). After final pathological analysis, the wide negative margin rate was 84% in the specimen-driven margin arm, compared to 55% in the patient-driven margin arm (p = .02). Extension of the surgical resection prevented escalation of adjuvant treatment in 19 patients (38%) in the specimen-driven margin arm and 10% in the patient-driven margin arm.Specimen derived margin assessment led to significant improvement in the rate of negative margins. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1803-E1809, 2016.

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.

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.

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. We conducted a meta-analysis to identify prognostic factors associated with outcomes of patients with recurrent nasopharyngeal carcinoma treated by salvage surgery. 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. 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.

Cancerous neural invasion (CNI) is a well-known route of cancer spread in head and neck cancer. Patients with CNI suffer from severe morbidity due to neuropathic pain and most succumb to cancer within months. The exact mechanism that drives cancer cells to disseminate along nerves remained to be defined. The overall objective of our research was to identify candidate proteins and host cells that contribute to CNI. L1 cell adhesion molecule (L1cam) is a 200kDa transmembrane glycoprotein of the immunoglobulin superfamily. In many human cancers, L1cam is constitutively over-expressed, and its expression is generally associated with poor prognosis and metastases formation. Immunohistochemical analysis of the neural niche in human cancer specimens showed overexpression of L1cam in both cancer cells and Schwann cells. To address the role of L1cam in vitro, we used the Dorsal Root Ganglia. Treatment of Cancer Cells with Anti L1cam mAb resulted in a significant reduction in CNI of cancer cells. Next, we used Schwann cells conditioned media (SCCM) to study the role of soluble Schwann cells derived L1cam. Immunopercipitation of L1cam in SCCM resulted in a significant reduction in L1cam concentration and led to reduced cancer cell migration, invasion, and motility. To study the role of SCCM as a chemo attractant to cancer cells we utilized a modified in-vitro nerve invasion assay that consists of 3 layers Fibroblasts-ECM-Schwann. In this model blocking the activity of L1cam in Schwann cells inhibited the cancer cells invasion through these layers. Finally, in-vivo studies in transgenic mice treated with L1cam mAb triweekly, showed a significant reduction in CNI in the tumors compared to the control group. Taken together, our results identify a paracrine interaction between Schwann cells in the neural niche and the cancer cells promotes perineural invasion via L1cam secretion. Citation Format: Shorook Na’ara, Ziv Gil, Moran Amit. Paracrine interactions between Schwann cells and cancer cells promotes perineural invasion via L1cam secretion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5072.

Radioactive iodine (RAI) treatment has a significant role in the management of differentiated thyroid carcinoma after surgical treatment. Although there is significant variability between patients, in response to RAI treatment, the mechanism responsible for this phenomenon is unknown. PIGU is an endoplasmic reticulum protein and a component of the GPIT complex, which plays a crucial role in post-translational modification of proteins such as sodium iodide symporter (NIS). Immunohistochemical analysis revealed significantly lower expression of PIGU in papillary carcinomas compared to matched normal thyroid tissue (P Citation Format: MORAN AMIT, shorook Na’ara, Tomer Charas, Ziv gil. PIGU modulates radioactive iodine uptake in differentiated thyroid cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2879.

Introduction: Perineural invasion of cancer cells (CPNI) is found in most patients with pancreatic adenocarcinomas (PDAs). Although the presence of M2 macrophages in the perineural environment has been associated with shortened survival rates in PDA patients, the mechanism underlying this phenomenon has not been elucidated. It has been suggested that secretion of the RET ligand glial-derived neurotrophic factor (GDNF) by M2 macrophages causes cancerous RET-expressing cells to migrate along affected nerves. This concept, however, has not been demonstrated in vivo. This study was aimed at understanding the contribution of macrophages to perineural invasion for in vivo models of PDA, and to characterize the role of the GDNF-RET axis in this unique microenvironmental niche. Methods: Immunohistochemical analysis of PDA specimens of a novel Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, revealed that CD163+ (M2) endoneurial macrophages (EMΦs) predominate the endoneural space of invaded nerves. In a bone marrow transplant (BMT) from CX3CRGFP/+ mice, a 23- fold increase in the recruitment of GFP+ macrophages to the perineural space was witnessed as compared to GFP- cells, indicating recruitment of bone marrow- derived macrophages to the perineural niche, rather than resident tissue macrophages. A BMT from CCR2-/- mice lacking macrophage recruitment capacity resulted in a 6-fold decrease of the invasion severity score, and a 2.5-fold decrease in perineural invasion index. Analysis by fluorescence microscopy indicated that EMΦs expressed higher levels of GDNF compared to EMΦs in premalignant lesion and normal controls. In order to differentiate between the contributions of GDNF secreted by nerves to the invasion presses and its secretion from recruited M2 macrophages, we performed a BMT from GDNF+/- mice. The BMT led to a 1.5-fold improvement in both the invasion severity score and the perineural invasion index. Similarly, mice treated with PP1, a RET receptor inhibitor, caused a 1.5-fold decrease in the invasion severity score, and a 1.3-fold decrease in the perineural invasion index. Finally, xenografts of PDAC cells, in which RET was silenced using siRNA, resulted in a 3.5-fold decrease in the invasion severity score and a 3.2-fold decrease in the perineural invasion index. Discussion: Taken together, our results suggest a paracrine response between bone marrow-derived tumor-associated EMΦs and PDA cells. This loop probably orchestrates the formation of cancer nerve invasion. Further studies using novel transgenic animal models aimed at specifying the specific molecular signals that induce disease invasion and proliferation in the perineural microenvironment are needed. Citation Format: Moran Amit, Shorook Na'ara, Yoav Binenbaum, Ziv Gil. Marrow-derived macrophages mediate invasion of pancreatic adenocarcinoma by RET activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2355. doi:10.1158/1538-7445.AM2015-2355