[Show abstract][Hide abstract] ABSTRACT: Cellular communities in living tissues act in concert to establish intricate microenvironments, with complexity difficult to recapitulate in vitro. We report a method for docking numerous cellularized hydrogel shapes (100-1,000 µm in size) into hydrogel templates to construct 3D cellular microenvironments. Each shape can be uniquely designed to contain customizable concentrations of cells and molecular species, and can be placed into any spatial configuration, providing extensive compositional and geometric tunability of shape-coded patterns using a highly biocompatible hydrogel material. Using precisely arranged hydrogel shapes, we investigated migratory patterns of human mesenchymal stem cells and endothelial cells. We then developed a finite element gradient model predicting chemotactic directions of cell migration in micropatterned cocultures that were validated by tracking ∼2,500 individual cell trajectories. This simple yet robust hydrogel platform provides a comprehensive approach to the assembly of 3D cell environments.
Proceedings of the National Academy of Sciences 03/2013; 110(12). DOI:10.1073/pnas.1300569110 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
To examine the therapeutic effects of an attenuated, replication-competent vaccinia virus (GLV-1h68) against a panel of 5 human salivary gland carcinoma cell lines.
The susceptibility of 5 salivary gland carcinoma cell lines to infection and oncolysis by GLV-1h68 was assessed in vitro and in vivo.
All 5 cell lines were susceptible to viral infection, transgene expression, and cytotoxic reactions. Three cell lines were exquisitely sensitive to infection by very low doses of GLV-1h68. Orthotopic parotid tumors exhibited more aggressive behavior compared with flank tumors. A single intratumoral injection of GLV-1h68 induced significant tumor regression without observed toxic effects in flank and parotid tumor models; controls demonstrated rapid tumor progression.
These promising results demonstrate significant oncolytic activity by an attenuated vaccinia virus for infecting and lysing salivary gland carcinomas, supporting future clinical trials.
JAMA Otolaryngology - Head and Neck Surgery 02/2013; 139(2):173-82. DOI:10.1001/jamaoto.2013.1360 · 1.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Perineural invasion (PNI) by cancer cells is an ominous clinical event that is associated with increased local recurrence and poor prognosis. Although radiation therapy (RT) may be delivered along the course of an invaded nerve, the mechanisms through which radiation may potentially control PNI remain undefined.
An in vitro co-culture system of dorsal root ganglia (DRG) and pancreatic cancer cells was used as a model of PNI. An in vivo murine sciatic nerve model was used to study how RT to nerve or cancer affects nerve invasion by cancer.
Cancer cell invasion of the DRG was partially dependent on DRG secretion of glial-derived neurotrophic factor (GDNF). A single 4 Gy dose of radiation to the DRG alone, cultured with non-radiated cancer cells, significantly inhibited PNI and was associated with decreased GDNF secretion but intact DRG viability. Radiation of cancer cells alone, co-cultured with non-radiated nerves, inhibited PNI through predominantly compromised cancer cell viability. In a murine model of PNI, a single 8 Gy dose of radiation to the sciatic nerve prior to implantation of non-radiated cancer cells resulted in decreased GDNF expression, decreased PNI by imaging and histology, and preservation of sciatic nerve motor function.
Radiation may impair PNI through not only direct effects on cancer cell viability, but also an independent interruption of paracrine mechanisms underlying PNI. RT modulation of the nerve microenvironment may decrease PNI, and hold significant therapeutic implications for RT dosing and field design for patients with cancers exhibiting PNI.
PLoS ONE 06/2012; 7(6):e39925. DOI:10.1371/journal.pone.0039925 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: First bite syndrome (FBS) refers to facial pain characterized by a severe cramping or spasm in the parotid region with the first bite of each meal that diminishes over the next several bites.1, 2 It is a potential sequela of surgery involving the infratemporal fossa (ITF), parapharyngeal space (PPS), and/or deep lobe of the parotid gland. The incidence, risk factors, treatment options, and outcomes of FBS are poorly understood. We hypothesized that certain clinical and tumor variables independently predict the development of FBS.
Retrospective cohort study.
We reviewed the records of 499 patients (mean age, 50 years; range, 12-81 years) undergoing surgery of the deep lobe of the parotid gland, PPS, and/or ITF between 1992 and 2010. Minimum follow-up time was 3 months (median, 39 months). Patient, tumor, and FBS characteristics were analyzed. Incidence was calculated using the Kaplan-Meier method. Univariate analyses and multivariate logistic regression were used to identify independent risk factors for FBS. Patients developing FBS were interviewed to assess the efficacy of various treatment modalities.
FBS developed in 45 patients (incidence, 9.6%), at a mean time of 97 (range, 6-877) days from surgery. On multivariate analysis, three variables were significant independent risk factors for FBS: sympathetic chain sacrifice (odds ratio [OR], 4.7; P = .008), PPS dissection (OR, 8.7; P = .001), and resection of only the deep lobe of the parotid gland (OR, 4.2; P = .002). FBS developed in 48.6% of patients undergoing sympathetic chain sacrifice, 22.4% of patients undergoing PPS dissection, 38.4% of patients undergoing isolated deep lobe parotid resection, and 0.8% of patients undergoing total parotidectomy. Partial resolution of FBS symptoms occurred in 69% and complete resolution in 12%. Of 45 FBS patients, 15 (33%) underwent at least one type of treatment for symptomatic relief. No treatment consistently provided effective symptomatic relief.
The strongest independent risk factors for FBS are PPS dissection, deep lobe of parotid resection, and sympathetic chain sacrifice. Patients undergoing surgery with dissection and/or manipulation in these anatomical sites and structures should be thoroughly counseled about the risk of developing FBS.
The Laryngoscope 06/2012; 122(8):1773-8. DOI:10.1002/lary.23372 · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective The optimal type of neck dissection in head and neck squamous cell carcinoma (SCC) with clinical cervical metastases has not been determined. The following study was performed to determine the rate of regional control with selective neck dissection (SND) in these patients. Study Design Case series with planned data collection. Settings Single institution, cancer center. Methods and Subjects Patients with cervical lymph node metastases from mucosal cancers of the head and neck who were treated with SND from 2000 to 2010 were selected. Demographics, tumor characteristics, extent of neck dissection, adjuvant treatments, locoregional control, and survival were recorded. Recurrence in the neck and disease-specific survival (DSS) were primary and secondary end points. Results One hundred eight patients underwent SND. Sixty-nine (64%) were male. Median age was 62 (20-89) years. The most common primary site was the oral cavity (71.3%). Ninety-five (88%) received adjuvant treatment. Median follow-up was 21 months. Six patients (5.5%) had isolated recurrence in the dissected neck. Patients with N2C disease had poorer neck recurrence-free survival. At the end of study, 64 (59.3%) patients had no evidence of disease, and 23 (21.3%) had died of disease. Two-year DSS was 76.9%. Number of positive nodes (P = .026) and positive surgical margins (P = .001), among others, were predictors of poorer DSS. Conclusion In a highly selected group of patients with cervical lymph node metastases from head and neck SCC, selective neck dissection is effective in controlling the disease in the neck when performed in the setting of a multimodality treatment, including adjuvant radiotherapy or radiochemotherapy.
Otolaryngology Head and Neck Surgery 04/2012; 147(4):707-15. DOI:10.1177/0194599812444852 · 2.02 Impact Factor