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Perineural invasion (PNI) is an ominous form of cancer progression along nerves associated with poor clinical outcome. Glial derived neurotrophic factor (GDNF) interacts with cancer cell RET receptors to enable PNI, but downstream events remain undefined. We demonstrate that GDNF leads to early activation of the GTPase Cdc42 in pancreatic cancer cells, but only delayed activation of RhoA and does not affect Rac1. Depletion of Cdc42 impairs pancreatic cancer cell chemotaxis toward GDNF and nerves. An siRNA library of guanine nucleotide exchange factors was screened to identify activators of Cdc42. ARHGEF7 (β-Pix) was required for Cdc42 activation and chemotaxis toward nerves, and also colocalizes with RET under GDNF stimulation. Cdc42 enables PNI in an in vitro dorsal root ganglia coculture model, and controls the directionality of migration but does not affect cell speed or cell viability. In contrast, Rac1 was necessary for cell speed but not directionality, while the RhoA was not necessary for either cell speed or directionality. Cdc42 was required for PNI in an in vivo murine sciatic nerve model. Depletion of Cdc42 significantly diminished the length of PNI, volume of PNI, and motor nerve paralysis resulting from PNI. Activated Cdc42 is expressed in human salivary ductal cancer cells invading nerves. These findings establish the GDNF–RET–β-Pix–Cdc42 pathway as a directional regulator of pancreatic cancer cell migration toward nerves, highlight the importance of directional migration in PNI, and offer novel targets for therapy. Implications: Cdc42 regulates cancer cell directional migration toward and along nerves in PNI.

Arteriovenous malformations are congenital vascular anomalies in which there is a direct communication between arteries and veins. Extracranial lesions in the head and neck are rare, and may not be detected until adolescence. We present a case of a 14-year-old male who presented with an expanding neck hematoma. After securing the airway, angioembolization was performed, followed by hematoma evacuation and surgical resection of the lesion. Imaging and histologic examination demonstrated an arteriovenous malformation (AVM) of the hyoid bone. While uncommon, AVMs must be considered in the evaluation of a pediatric neck mass, given the propensity for rapid deterioration.

Salivary gland neoplasms are relatively rare tumors with a wide range of biologic behavior. Early low-grade malignancies could be adequately treated with surgery alone, while larger locally advanced tumors will require adjuvant radiation therapy. The role of chemotherapy remains palliative. The goal of this article is to provide a critical review of recent literature on diagnosis and management of salivary neoplasms. How to cite this article Chernichenko N. Critical Update on Malignant Salivary Gland Neoplasms. Int J Head Neck Surg 2017;8(2):71-75.

Aim To examine the value of proton therapy in relation to other treatment modalities in head and neck cancer. Review Proton therapy has evolved into more sophisticated and costly intensity-modulated proton therapy and has resulted in even greater dose reduction to normal critical structures at risk as compared with photon therapy. Early clinical studies in head and neck cancers, especially for tumors of the skull base and paranasal sinuses, suggest that proton therapy is excellent in terms of local control and is comparable to intensity-modulated radiation therapy photons but with lower rates of morbidity. Results There are many potential advantages to radiation therapy with protons. While there are many single institution studies examining the added value of protons to photon therapy, the value of proton therapy must be examined in prospective randomized clinical studies and across many subsites of head and neck cancer. Additional evidence is necessary to guide efficient clinical practice, patient selection, and tumors that are most likely to benefit from this treatment modality and justify proton therapy use given its significant cost. How to cite this article Katsoulakis E, Chernichenko N, Schreiber D. Proton Therapy in the Treatment of Head and Neck Cancer. Int J Head Neck Surg 2017;8(2):45-48.

Nerves enable cancer progression, as cancers have been shown to extend along nerves through the process of perineural invasion, which carries a poor prognosis. Furthermore, the innervation of some cancers promotes growth and metastases. It remains unclear, however, how nerves mechanistically contribute to cancer progression. Here, we demonstrated that Schwann cells promote cancer invasion through direct cancer cell contact. Histological evaluation of murine and human cancer specimens with perineural invasion uncovered a subpopulation of Schwann cells that associates with cancer cells. Coculture of cancer cells with dorsal root ganglion extracts revealed that Schwann cells direct cancer cells to migrate toward nerves and promote invasion in a contact-dependent manner. Upon contact, Schwann cells induced the formation of cancer cell protrusions in their direction and intercalated between the cancer cells, leading to cancer cell dispersion. The formation of these processes was dependent on Schwann cell expression of neural cell adhesion molecule 1 (NCAM1) and ultimately promoted perineural invasion. Moreover, NCAM1-deficient mice showed decreased neural invasion and less paralysis. Such Schwann cell behavior reflects normal Schwann cell programs that are typically activated in nerve repair but are instead exploited by cancer cells to promote perineural invasion and cancer progression.

To describe the outcome of patients with poorly differentiated thyroid cancer (PDTC) presenting with gross extrathyroidal extension (ETE). After obtaining Institutional Review Board approval, we performed a retrospective review of a consecutive series of thyroid cancer patients treated by primary surgical resection with or without adjuvant therapy at Memorial Sloan-Kettering Cancer Center from 1986 to 2009. Out of 91 PDTC patients, 27 (30%) had gross ETE (T4a), and they formed the basis of our study. Of 27 patients, 52% were women. The median age was 70 years (range 27-87 years). Ten patients (37%) presented with distant metastases; four to bone, three to lung, and three to both bone and lung. All patients had extended total thyroidectomy, except two who had subtotal thyroidectomy. Twenty patients (74%) had central compartment neck dissection and 11 also had lateral neck dissection. Four patients had pN0, six (30%) pN1a, and 10 (50%) pN1b neck disease. Twenty-one patients (77%) had adjuvant therapy: 15 (55%) radioactive iodine (RAI) only, three (11%) postoperative external beam radiation (EBRT) only, and three (11%) had both RAI and EBRT. Overall survival (OS), disease-specific survival (DSS), local recurrence-free survival (LRFS), and regional recurrence-free survival (RRFS) were calculated by the Kaplan Meier method. The median follow-up time was 57 months (range 1-197 months). The 5 year OS and DSS were 47% and 49%, respectively. This poor outcome was due to distant metastatic disease; 10 patients had distant metastases at presentation and a further six developed distant metastases during follow-up. Locoregional control was good with 5-year LRFS and RRFS of 70% and 62%, respectively. Overall, eight patients (30%) had recurrences: two had distant alone, two regional, two regional and distant, one local and distant, and one had local, regional, and distant recurrence. Aggressive surgery in patients with PDTC showing gross ETE resulted in satisfactory locoregional control. Due to the small proportion of patients who received EBRT (22%), it is not possible to analyze its benefit on locoregional control. Of significance is the observation that the majority of patients (60%) who presented with or subsequently developed distant metastases eventually died of distant disease. New systemic therapies to target distant metastatic disease are required for improvements in outcome

The incidence of thyroid cancer in the United States has been increasing. The biologic behavior of well-differentiated thyroid cancer (WDTC) can vary from indolent tumor to an aggressive disease with invasion of critical structures and/or widespread distant metastasis. Therefore, the risk stratification is crucial in understanding the biology of thyroid cancer, its prognosis and appropriate therapeutic interventions. In fact, understanding the nuances of biological behavior of thyroid carcinomas lays the foundation for the idea of selective surgical management of this disease.

Electrical stimulation has been widely applied in medicine to combat microorganisms,1 enhance wound healing,2 and treat tumors,3 as well as promote strengthening and motor control of skeletal muscles.4,5 Common rehabilitation practice is to place electrodes on the skin to stimulate nerves supplying muscle groups of interest to increase strength.6,7 Neuromuscular electrical stimulation (NMES) has been used for decades on a wide array of muscle groups, but it was investigated for dysphagia rehabilitation in neurologically impaired patients in the late 1990s,8,9 and in 2002, the U.S. Food and Drug Administration (FDA) cleared a device for the treatment of dysphagia. Several meta-analyses have since evaluated the effect of NMES on swallowing rehabilitation and revealed a small but significant summary effect size.10,11 More recently, investigation of NMES has focused on its effects as an adjunct to traditional swallowing therapy in patients receiving treatment for locally advanced head and neck cancer.12 However, the FDA applies a general warning to all NMES devices to avoid stimulating over areas of malignancy.13,14 The concern is that applying electrical stimulation to the anterior neck may stimulate tumor growth if there is residual disease or recurrence following treatment. It is common practice to wait at least several months after radiation and/or surgical treatment before initiating NMES to minimize or resolve dysphagia. A drawback to delaying therapy is that by the time NMES has commenced, the patient typically has chronic dysphagia,15 making the condition more difficult to manage. If NMES in the setting of active malignancy proves not to enhance tumorigenic activity, then perhaps its benefit for dysphagia therapy can be enhanced by starting therapy earlier in the rehabilitation period. To our knowledge, there has never been an animal or human study investigating the effects of skin surface electrical stimulation (as in NMES) on an underlying malignancy, located deep to the skin surface but aligned with the location of electrical stimulation. Based on our review of the literature pertaining to electrodes inserted directly into tumors and resulting in tumor destruction,3, 16–21 we hypothesized that NMES will not increase underlying tumor burden.

We describe a case of benign inverted papilloma with intracranial extension treated with endoscopic resection combined with craniotomy. Intracranial involvement of inverted papilloma, in the absence of malignancy, is uncommon. We present an analysis of the literature identifying the characteristics and outcomes of benign intracranial inverted papilloma. PubMed database was searched using keywords intracranial, inverted or inverting, and papilloma. There are 17 reports of benign inverted papilloma with intracranial extension reported with a mean age of 49.2 years (range, 23 to 92 years), a female predominance, 22% of cases with an associated mucocele, and 60% recurrent disease. The most common sites of invasion are the frontal sinus or cribriform plate. The prognosis for benign intracranial inverted papilloma is dependent on the presence of dural invasion and the achievement of total resection. There are no reported recurrences after craniofacial resection with a mean follow-up of 7.9 years. Adjuvant radiation therapy has demonstrated benefit in cases of residual disease after resection. We expect that endoscopic resection, the standard treatment for sinonasal inverted papilloma, will be increasingly used in the presence of intracranial extension.

Objective The purpose of this study was to demonstrate the efficacy of arterial coupling. Study Design Retrospective data were collected in a consecutive series of 124 patients undergoing surgical resection of head and neck tumors followed by free tissue transfer (FTT). Methods and Measures The Unilink coupling device was used to perform arterial and venous anastomosis. Flap survival and thrombosis of the arterial anastomoses were determined. Results A total of 124 consecutive patients underwent a total of 127 microvascular FTTs. Reconstruction included 90 radial forearm, 26 fibula, 9 rectus abdominis, and 2 iliac crest myocutaneous free flaps. There were four (3.2%) complications related to arterial insufficiency in our series, three of which were salvageable. There were three (2.4%) flap failures, resulting in an overall free flap survival rate of 97.6 percent. Conclusion The flap survival with the Unilink Microvascular Anastomotic System is similar to that of standard suture techniques. Use of a coupler device is the preferred method in performing microvascular FTT at our institution.

The progression of HIV disease may be affected by co-infection with other viruses. This study investigates the prevalence of Epstein-Barr virus (EBV); cytomegalovirus (CMV); herpes simplex virus (HSV) types 1 and 2; hepatitis A, B, and C (HA, HB, HC); and tuberculosis in perinatally HIV-infected children. Electrochemiluminescence Immunoassay (EIA) against EBV, CMV, HSV 1 and 2, HAV HBV HCV, and skin testing with purified protein derivative was performed on 45 perinatally HIV-infected children. CMVwas positive in 51%, EBVin 93.3%, HSV-1 in 62.2%, HSV-2 in 48.9%, HAV in 15.6%, HBVand HCV in 6.7% and PPD in 0%. HSV-2 prevalence was higher in females and Hispanics. The prevalence of CMV, EBV HSV-1, and tuberculosis was equivalent to rates reported in the general population. Prevalence of HSV-2 was significantly higher than in the general population (p < 0.001). Higher rates of HSV-2 infection and hepatitis may be secondary to high maternal co-infection rate and subsequent vertical transmission.

The ability of cancer cells to invade along nerves is associated with aggressive disease and diminished patient survival rates. Perineural invasion (PNI) may be mediated by nerve secretion of glial cell line-derived neurotrophic factor (GDNF) attracting cancer cell migration through activation of cell surface Ret proto-oncogene (RET) receptors. GDNF family receptor (GFR)α1 acts as coreceptor with RET, with both required for response to GDNF. We demonstrate that GFRα1 released by nerves enhances PNI, even in the absence of cancer cell GFRα1 expression. Cancer cell migration toward GDNF, RET phosphorylation, and MAPK pathway activity are increased with exposure to soluble GFRα1 in a dose-dependent fashion. Dorsal root ganglia (DRG) release soluble GFRα1, which potentiates RET activation and cancer cell migration. In vitro DRG coculture assays of PNI show diminished PNI with DRG from GFRα1(+/-) mice compared with GFRα1(+/+) mice. An in vivo murine model of PNI demonstrates that cancer cells lacking GFRα1 maintain an ability to invade nerves and impair nerve function, whereas those lacking RET lose this ability. A tissue microarray of human pancreatic ductal adenocarcinomas demonstrates wide variance of cancer cell GFRα1 expression, suggesting an alternate source of GFRα1 in PNI. These findings collectively demonstrate that GFRα1 released by nerves enhances PNI through GDNF-RET signaling and that GFRα1 expression by cancer cells enhances but is not required for PNI. These results advance a mechanistic understanding of PNI and implicate the nerve itself as a key facilitator of this adverse cancer cell behavior.

Salivary gland carcinomas are relatively rare malignant tumors, accounting for less than 5% of all cancers of the head and neck.1 They encompass a wide spectrum of histologic abnormalities with varied biologic behavior. Initial therapy of localized disease consists of complete surgical excision. The risk of recurrence and metastasis is significantly higher in patients with locally advanced salivary carcinomas. Individuals with high-grade salivary carcinomas have a 5-year survival of roughly 40%; those with low-and intermediate-grade tumors have a 5-year survival of 85% to 90%.2,3 For these patients, complete surgical resection followed by postoperative radiation therapy is recommended.4 Unfortunately, patients with recurrent and/or unresectable disease have few effective treatment options. Clinical trials exploring the role of chemotherapy in the management of salivary gland carcinomas failed to show survival benefit.1 Chemotherapy, therefore, is generally reserved as a palliative measure for patients with symptoms and/or rapid disease progression. Clearly, novel therapies are needed to improve outcomes for patients with salivary carcinomas. Oncolytic viruses have emerged as versatile therapeutic agents that can selectively infect, replicate within, and ultimately lyse a host cancer cell. A variety of viruses have been reported5–7 to possess on-colytic antitumoral activity, including herpes simplex type 1, adenovirus, reovirus, vesicular stomatitis virus, measles virus, poliovirus, West Nile virus, and New-castle disease virus. Vaccinia virus, which is a double-stranded DNA member of the genus Orthopoxvirus, has many unique characteristics that make it an excellent tool in cancer treatment. In addition to its natural tropism for tumor tissues and its abilities for efficient entry, replication, and lysis, vaccinia virus has a remarkable safety record in its historical widespread human application as a vaccine for smallpox. The vaccinia replication cycle occurs exclusively in the cytoplasm, which eliminates the possibility of chromosomal integration.7 Furthermore, there are many Food and Drug Administration–approved antiviral agents available to limit viral spread and control the unlikely possibility of viral toxicity.8 Consequently, several recombinant vaccinia viruses have been constructed and studied in preclinical and clinical phase 1 settings.8,9 Recombinant, replication-competent vaccinia virus (GLV-1h68) has been reported10–16 as effective in breast cancer, thyroid cancer, mesothelioma, pancreatic cancer, prostate cancer, human hepatocellular carcinoma, and head and neck cancer models. The aim of this study was to assess the usefulness of GLV-1h68 as a therapeutic agent against salivary gland carcinoma in vitro and in vivo. Murine flank and orthotopic parotid tumor models were used.

To provide a critical review of recent literature on the role of tracheal resection in thyroid cancer.The current body of literature is centered on the controversy regarding how radical the extent of tracheal resection needs to be to achieve long-term control of thyroid carcinoma with tracheal invasion. Proponents of shave excision are guided by the reported survival outcomes comparable to segmental resections in a selected group of patients. Others believe that all patients should have a segmental sleeve resection to ensure clearance of transmural disease. Recent advances in microsurgical reconstruction may allow selected patients to undergo tracheal resection when a large tracheal defect is anticipated.Tracheal invasion by well differentiated carcinoma is a marker of a more aggressive tumor behavior, defining a subpopulation of patients at a greater risk of recurrence and death. The goal of surgical intervention in this scenario is complete resection with no gross residual disease. A well designed prospective multi-institutional trial, taking into account depth of invasion, risk group stratification, histology, presence of distant metastasis, radioactive iodine trapping ability, adjuvant treatment, and long-term survival data, is needed to compare the outcomes following more conservative shave excision and segmental tracheal resection.

Background Approximately one fourth of bone and soft-tissue sarcomas recur after prior treatment. GLV-1h68 is a recombinant, replication-competent vaccinia virus that has been shown to have oncolytic effects against many human cancer types. We sought to determine whether GLV-1h68 could selectively target and lyse a panel of human bone and soft-tissue sarcoma cell lines in vitro and in vivo . Methods GLV-1h68 was tested in a panel of four cell lines including: fibrosarcoma HT-1080, osteosarcoma U-2OS, fibrohistiocytoma M-805, and rhabdomyosarcoma HTB-82. Gene expression, infectivity, viral proliferation, and cytotoxicity were characterized in vitro . HT-1080 xenograft flank tumors grown in vivo were injected intratumorally with a single dose of GLV-1h68. Results All four cell lines supported robust viral transgene expression in vitro . At a multiplicity of infection (MOI) of five, GLV-1h68 was cytotoxic to three cell lines, resulting in >80% cytotoxicity over 7 d. In vivo , a single injection of GLV-1h68 into HT-1080 xenografts exhibited localized intratumoral luciferase activity peaking at d 2–4, with gradual resolution over 8 d and no evidence of spread to normal tissues. Treated animals exhibited near-complete tumor regression over a 28-d period without observed toxicity. Conclusion GLV-1h68 has potent direct oncolytic effects against human sarcoma in vitro and in vivo . Recombinant vaccinia oncolytic virotherapy could provide a new platform for the treatment of patients with bone and soft tissue sarcomas. Future clinical trials investigating oncolytic vaccinia as a therapy for sarcomas are warranted.

Objectives: The aim of this study was to identify the response of the cricopharyngeus muscle (CPM) to esophageal stimulation by intraluminal mechanical distension and intraluminal acid and bile perfusion. Methods: In 3 adult pigs, electromyographic (EMG) activity of the CPM was recorded at baseline and after esophageal stimulation at 3 levels: Proximal, middle, and distal. The esophagus was stimulated with 20-mL balloon distension and intraluminal perfusion of 40 mL 0.1N hydrochloric acid, taurocholic acid (pH 1.5), and chenodeoxycholic acid (pH 7.4) at the rate of 40 mL/min. The EMG spike density was defined as peak-to-peak spikes greater than 10 μV averaged over 10-ms intervals. Results: In all 3 animals, the spike density at baseline was 0. The spike densities increased after proximal and middle distensions to 15.2 ± 1.5 and 5.1 ± 1.2 spikes per 10 ms, respectively. No change in CPM EMG activity occurred after distal distension. The spike density following intraluminal perfusion with hydrochloric acid at the distal level was 10.1 ± 1.1 spikes per 10 ms. No significant change in CPM EMG activity occurred after acid perfusion at the middle and proximal levels. No change in CPM EMG activity occurred after intraluminal esophageal perfusion with either taurocholic acid or chenodeoxycholic acid. Conclusions: Proximal esophageal distension, as well as distal intraluminal acid perfusion, appeared to be important mechanisms in generation of CPM activity. Bile acids, on the other hand, failed to evoke such CPM activity. The data suggest that transpyloric refluxate may not be significant enough to evoke the CPM protective sphincteric function, thereby placing supraesophageal structures at risk of bile injury.

Objective: The purpose of this study is to demonstrate the success rate of using a coupling device for end-to-side venous anastomosis in patients undergoing free-tissue transfer (FTT) in head and neck reconstruction. Methods and Measures: Retrospective data were collected in consecutive series of 134 patients undergoing surgical resection of head and neck tumors followed by FTT. All microvascular FTTs were performed at Yale-New Haven Hospital between November 2001 and August 2007. The Unilink coupling device was used to perform arterial and venous anastomosis in this case series. Flap survival and thrombosis of the venous anastomoses were determined. Results: One hundred thirty-four consecutive patients underwent a total of 137 microvascular FTTs using a coupling device. In our series, a total of 173 end-to-side anastomoses were completed in 96 patients. Of these, 77 patients had both venous anastomoses, 17 underwent one end-to-side and one end-to-end anastomoses, and two patients had one venous anastomosis per patient performed in end-to-side fashion. Reconstruction included 76 radial forearm, 17 fibula, and three rectus abdominis free flaps. There were three vascular insufficiency related complications of which two were salvageable. There was one case of flap failure (1%), resulting in a free flap survival rate of 99%. Conclusion: This largest reported series of end-to-side venous anastomoses with an anastomotic coupling device demonstrates feasibility and efficacy of this technique in head and neck reconstruction.

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Perineural invasion (PNI) is the ability of cancer cells to invade in, around, and along nerves. PNI is widely recognized as an adverse pathologic feature of many malignancies. Glial-derived neurotrophic factor (GDNF) is secreted by nerve and glial cells, and is important in neural development. We previously showed that GDNF activation of the RET/GFR-alpha tyrosine kinase in cancer cells induces chemotaxis towards nerves and PNI. Cdc42 is a member of the Rho family of G proteins and a key regulator of cell polarity. We demonstrate here that GDNF-mediated activation of RET/GFR-alpha leads to activation of Cdc42 as a mediator of cancer cell chemotaxis and PNI. Exposure of MiaPaCa2 cells to GDNF or dorsal root ganglia (DRG) activates Cdc42. SiRNA inhibition of Cdc42 impairs MiaPaCa2 chemotaxis towards GDNF or DRG in Boyden chamber assays. SiRNA inhibition of RET decreases Cdc42 activity under GDNF stimulation and MiaPaCa2 chemotaxis. To study dynamic interactions between nerves and cancer cells in vitro, we used a DRG and cancer cell co-culture model of PNI in matrigel. Analysis of individual cell trajectories reveals that cell velocity remains unchanged, while directional migration is disrupted with shRNA inhibition of Cdc42. The disruption of directional response impairs the ability of shRNA Cdc42 MiaPaCa2 cells to migrate along neurites, as visualized by time lapse microscopy and measured by area of PNI. MRI imaging of live mice with sciatic nerves injected with shRNA Cdc42 MiaPaCa2 cells reveals significantly diminished length and volume of PNI as compared with injected shRNA control cancer cells when matched for equivalent overall tumor volume. Murine sciatic nerves injected with shRNA Cdc42 MiaPaCa2 cells exhibited preserved hindlimb and hind paw neurologic function, and diminished perineural invasion by histopathologic examination as compared with shRNA control MiaPaCa2. To identify potential activators of Cdc42 in this model, we performed a comprehensive siRNA screen of guanine nucleotide exchange factors (GEFs), identifying specific GEFs which are necessary for MiaPaCa2 migration towards DRG in Boyden chambers. We identified and validated six GEFs ([FLJ10521][1], DOCK9, ARHGEF7, RASGRF1, ARHGEF5, PLEKHG1) that impair chemotaxis without affecting proliferation. These findings provide novel insights into the molecular mechanisms underlying cancer cell perineural invasion. The RET-GEF-Cdc42 axis may be an attractive target for novel therapies that may potentially interrupt perineural invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 460. doi:1538-7445.AM2012-460 [1]: /lookup/external-ref?link_type=GENPEPT&access_num=FLJ10521&atom=%2Fcanres%2F72%2F8_Supplement%2F460.atom