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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.

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

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.