Walter T. Lee

Risk factors for hypopharyngeal/upper esophageal stricture formation after concurrent chemoradiation

Concurrent chemoradiation therapy has been demonstrated to be effective as an organ‐sparing treatment for select advanced head and neck squamous cell carcinoma (HNSCC). However, this treatment modality is not without side effects. One side effect is the formation of upper esophageal strictures. As concurrent chemoradiation treatment is used more frequently, it is important to identify risk factors associated with stricture formation.

3D computed tomographic analysis of frontal recess anatomy in patients without frontal sinusitis

OBJECTIVE: Describe frontal sinus pneumatization in patients with no history of frontal sinus disease. STUDY DESIGN AND METHODS: All 1-mm axial sinus CT scans performed from 2001 through 2003 were eligible for review on a CBYON Suite workstation (CBYON, Mountain View, CA). Exclusion criteria included frontal sinusitis, sinonasal polyposis, age < 18 years, sinus malignancy, fibroosseous lesions, maxillofacial trauma, congenital anomaly, and sinus surgery. RESULTS: A total of 50 patients met the inclusion criteria. The prevalence of each structure was: agger nasi cell (89%), type 1 frontal cell (37%), type 2 frontal cell (19%), type 3 frontal cell (8%), type 4 frontal cell (0%), supraorbital ethmoid cell (62%), suprabullar cell (15%), frontal bullar cell (9%), interfrontal septal cell (14%), and recessus terminalis (22%). CONCLUSIONS: This study describes frontal pneumatization in patients without a history of conditions that influence frontal pneumatization. The results characterize normal frontal recess/sinus pneumatization patterns.

Comparative analysis of antigen loading strategies of dendritic cells for tumor immunotherapy.

Dendritic cells (DCs) loaded with antigens can effectively stimulate host immune responses to syngeneic tumors, but there is considerable controversy as to which forms of antigen-loading are most immunogenic. Here, the authors compared immunotherapeutic reactivities of DCs loaded with a variety of antigen preparations. Because DC maturation stages affect their capacities of antigen processing and presentation, two DC populations were used for the current analysis: in vivo Flt-3 ligand-induced mature DCs and in vitro bone marrow-derived DCs, which were less mature. To facilitate a direct comparison, the LacZ gene-transduced B16 melanoma model system was used, where β-galactosidase served as the surrogate tumor-rejection antigen. DC loading strategies included pulsing with the β-galactosidase protein, H-2Kb restricted peptide, tumor cell lysate, and irradiated tumor cells and fusion of DCs with tumor cells. Our results demonstrated that electrofusion of DCs and tumor cells generated a therapeutic vaccine far superior to other methods of DC loading. For the treatment of 3-day established pulmonary tumor nodules, a single intranodal vaccination plus IL-12 resulted in a significant reduction of metastatic nodules, while other DC preparations were only marginally effective. Immunotherapy mediated by the fusion cells was tumor antigen-specific. Consistent with their therapeutic activity, fusion hybrids were the most potent stimulators to induce specific IFN-γ secretion from immune T cells. Furthermore, fusion cells also stimulated a small amount of IL-10 production from immune T cells. However, this IL-10 secretion was also induced by other DC preparations and did not correlate with in vivo therapeutic reactivity.

Sentinel Node Biopsy for Head and Neck Melanoma A Systematic Review

Objective. This systematic review was conducted to examine the test performance of sentinel node biopsy in head and neck melanoma, including the identification rate and false-negative rate. Data Sources. PubMed, EMBASE, ASCO, and SSO database searches were conducted to identify studies fulfilling the following inclusion criteria: sentinel node biopsy was performed, lesions were located on the head and neck, and recurrence data for both metastatic and nonmetastatic patients were reported. Review Methods. Dual-blind data extraction was conducted. Primary outcomes included identification rate and test performance based on completion neck dissection or nodal recurrence. Results. A total of 3442 patients from 32 studies published between 1990 and 2009 were reviewed. Seventy-eight percent of studies were retrospective and 22% were prospective. Trials varied from 9 to 755 patients (median 55). Mean Breslow depth was 2.53 mm. Median sentinel node biopsy identification rate was 95.2%. More than 1 basin was reported in 33.1% of patients. A median of 2.56 sentinel nodes per patient were excised. Sentinel node biopsy was positive in 15% of patients. Subsequent completion neck dissection was performed in almost all of these patients and revealed additional positive nodes in 13.67%. Median follow-up was 31 months. Across all studies, predictive value positive for nodal recurrence was 13.1% and posttest probability negative was 5%. Median false-negative rate for nodal recurrence was 20.4%. Conclusion. Sentinel node biopsy of head and neck melanoma is associated with an increased false-negative rate compared with studies of non–head and neck lesions. Positive sentinel node status is highly predictive of recurrence.

Paired Toll-like receptor agonists enhance vaccine therapy through induction of interleukin-12.

Minimal requirements for generating effective immunity include the delivery of antigenic (signal 1) and costimulatory (signal 2) signals to T lymphocytes. Recently, a class of third signals, often delivered by antigen-presenting dendritic cells, has been shown to greatly enhance immune responses, especially against tumors. Among signal 3 factors, interleukin (IL)-12 is particularly effective and can be conditionally induced by agonists of Toll-like transmembrane receptors (TLR). In this study, we assessed the therapeutic effect of adjuvant TLR agonist administration upon the capacity of dendritic cell (DC)-tumor electrofusion hybrids to eradicate established MCA205 sarcomas in syngeneic mice. Paired, but not solitary combinations of polyinosine:polycytadilic acid (P[I:C]; TLR3 agonist) and CpG DNA (ODN1826l; TLR9 agonist) stimulated IL-12 secretion from DCs in vitro and synergized with vaccination to achieve potent tumor rejection. Therapeutic effects, however, required coadministration of paired TLR agonists and DC-tumor fusion hybrids. The administration of TLR agonists alone or with fusion vaccine induced transient splenomegaly but without apparent toxicity. The therapeutic effects of this immunization regimen were significantly abrogated through the neutralization of IL-12p70, indicating that production of this third signal was essential to the observed tumor regression. These results show the profound functional consequences of TLR cooperativity and further highlight the critical role of IL-12 in antitumor immunity.

Results of ansa to recurrent laryngeal nerve reinnervation

Objective We sought to describe the results of ansa cervicalis to recurrent laryngeal nerve (ansa-RLN) reinnervation for unilateral vocal fold paralysis. Study Design A chart review was performed on patients undergoing ansa-RLN reinnervation for unilateral vocal cord paralysis at a tertiary care center. Patient perceptions of preoperative and postoperative voice quality was surveyed. Acoustic and visual parameters were assessed from videostroboscopy. Results From a total of 25 study patients, 15 patients underwent both preoperative and postoperativ video stroboscopies. In stroboscopies within 6 months, the average improvement in overall severity, roughness, and breathiness was 69, 79, and 100 percent, respectively. In stroboscopies after 6 months, the average improvement in overall severity, roughness, and breathiness was 63, 66, and 100 percent, respectively. Postoperatively, all patients had reinnervation of the vocal fold. Conclusions Voice outcomes were improved in patients with preoperative and postoperative stroboscopies. Significance Ansa-RLN reinnervation should be considered as a treatment for unilateral vocal fold paralysis.

HPV status-independent association of alcohol and tobacco exposure or prior radiation therapy with promoter methylation of FUSSEL18, EBF3, IRX1, and SEPT9, but not SLC5A8, in head and neck squamous cell carcinomas.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with more than half a million people being diagnosed with the disease annually. Within the last 2 decades, the human papillomavirus (HPV) has been found to be associated with this malignancy. More recently, HPV‐infected HNSCC has been found to exhibit higher levels of global DNA methylation. In a recent study, we identified five tumor suppressive genes (IRX1, EBF3, SLC5A8, SEPT9, and FUSSEL18) as frequently methylated in HNSCC biopsies using a global methylation analysis via restriction landmark genomic scanning. In this study, we verify these genes as valid methylation markers in two separate sets of HNSCC specimens. By using the available clinical information linked to the patient specimens, we found a strong association between promoter methylation of FUSSEL18, IRX1, and EBF3 and prior radiation therapy (P < 0.0001) irrespective of HPV status. Also, promoter methylation of FUSSEL18 and SEPTIN9 was found to correlate significantly with exposure to alcohol and tobacco (P = 0.021). Importantly, in this study, we preliminarily show a trend between HPV16 positivity and specific target gene hypermethylation of IRX1, EBF3, SLC5A8, and SEPT9. If replicated in a larger study, the HPV status may be a patient selection biomarker when determining the most efficacious treatment modality for these different subsets of patients (e.g., inclusion or exclusion of epigenetic therapies). Equally notable and independent of HPV status, hypermethylation of the promoters of a subset of these genes in recurrences especially in the setting of prior radiation or in the setting of alcohol and tobacco use might help guide adjunctive inclusion or exclusion or epigenetic therapy.

Reproductive Potential of Men with Obstructive Azoospermia Undergoing Percutaneous Sperm Retrieval and Intracytoplasmic Sperm Injection According to the Cause of Obstruction

PURPOSE We evaluated the retrieval rates and reproductive outcomes of percutaneous sperm retrieval according to the cause of obstructive azoospermia. MATERIALS AND METHODS We retrospectively studied the records of 146 men with obstructive azoospermia who underwent sperm retrieval for intracytoplasmic sperm injection. Patients were grouped by the cause of obstruction, including 32 with congenital bilateral absence of the vas deferens, 59 with vasectomy and 55 with obstruction due to post-infection disease. Sperm were retrieved percutaneously from the epididymis or testis. We compared retrieval rates and intracytoplasmic sperm injection outcomes, including neonatal results, in the groups of men with obstructive azoospermia. RESULTS The success of sperm retrieval was similar among the etiology groups, including 100% for congenital bilateral absence of the vas deferens, 96.6% for vasectomy and 96.3% for previous infection. Significantly fewer men in the congenital bilateral absence of the vas deferens group needed testicular aspiration compared to those in the post-infection and vasectomy groups (3.1% vs 23.6% and 30.5%, respectively, p <0.001). Sperm cryopreservation was possible in 26.7% of the cases and did not significantly differ among the groups. Live birth rates after sperm injection were similar in the congenital (34.4%), vasectomy (32.2%) and previous infection (36.4%) groups. Birth parameters, prematurity and low birth weight rates were comparable among the groups. CONCLUSIONS Percutaneous sperm retrieval is an effective method to retrieve sperm in men with obstructive azoospermia irrespective of the cause of obstruction. The chance of achieving a live birth and the profile of neonates born after sperm injection do not seem to be related to the cause of obstruction.

A non-oncogenic HPV 16 E6/E7 vaccine enhances treatment of HPV expressing tumors

Human papillomaviruses (HPVs) are the causative factor for >90% of cervical cancers and 25% of head and neck cancers. The incidence of HPV positive (+) head and neck squamous cell carcinomas has greatly increased in the last 30 years. E6 and E7 are the two key viral oncoproteins that induce and propagate cellular transformation. An immune response generated during cisplatin/radiation therapy improves tumor clearance of HPV(+) cancers. Augmenting this induced response during therapy with an adenoviral HPV16 E6/E7 vaccine improves long-term survival in pre-clinical models. Here, we describe the generation of an HPV16 E6/E7 construct, which contains mutations that render E6/E7 non-oncogenic, while preserving antigenicity. These mutations do not allow E6/E7 to degrade p53, pRb, PTPN13, or activate telomerase. Non-oncogenic E6/E7 (E6Δ/E7Δ) expressed as a stable integrant, or in the [E1-, E2b-] adenovirus, lacks the ability to transform human cells while retaining the ability to induce an HPV-specific immune response. Moreover, E6Δ/E7Δ plus chemotherapy/radiation statistically enhances clearance of established HPV(+) cancer in vivo.

Use of In Situ Hybridization to Detect Human Papillomavirus in Head and Neck Squamous Cell Carcinoma Patients Without a History of Alcohol or Tobacco Use

CONTEXT Head and neck squamous cell carcinoma is commonly associated with tobacco and alcohol use. There are, however, a group of patients without a significant history of tobacco or alcohol use, and the etiology of these tumors is incompletely understood. OBJECTIVE To examine tumors in this subpopulation for association with human papillomavirus (HPV) using newly available in situ hybridization probes. DESIGN Between October 2004 and October 2005, 22 patients who did not use alcohol or tobacco were included. Formalin-fixed, paraffin-embedded tissue sections were used to perform in situ hybridization using newly available probe sets (Ventana Medical Systems, Tucson, Ariz). The slides were examined for the presence of integrated HPV using light microscopy. Positive and negative xenograft controls were run with the assay. Results.-The mean age of the patients was 64 years. There were 14 men and 8 women. The most common anatomic sites included tongue (n = 8), tonsil (n = 7), and larynx (n = 7). All cases and controls were successfully stained. Only 2 cases were positive for high-risk HPV, and both demonstrated an integrated pattern. Both cases were tumors of the tonsil. No cases were positive for low-risk HPV. CONCLUSIONS These results demonstrate that the new probe sets for HPV can be used very efficiently in clinical pathology material of head and neck squamous cell carcinoma. Our data show that high-risk HPV is an uncommon finding in head and neck squamous cell carcinoma from patients who do not have a history of tobacco or alcohol use; low-risk HPV was not seen in any case.