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David E Schuller

Publications and source records attributed to David E Schuller.

At least 19 recordsLinked to original sources
PubMed2006

Epigenetic regulation of the tumor suppressor gene TCF21 on 6q23-q24 in lung and head and neck cancer.

The identification of tumor suppressor genes has classically depended on their localization within recurrent regions of loss of heterozygosity. According to Knudson's two-hit hypothesis, the remaining allele is lost, either genetically or, more recently identified, through epigenetic events. To date, retrospective analyses have determined promoter methylation as a common alternative alteration in cancer cells to silence cancer-related genes. Here we report an application of restriction landmark genomic scanning that allows for DNA methylation profiling along a region of recurrent loss of heterozygosity at chromosome 6q23-q24. This approach resulted in the identification of a tumor suppressor gene, TCF21, which is frequently lost in human malignancies. We demonstrate that TCF21 is expressed in normal lung airway epithelial cells and aberrantly methylated and silenced in the majority of head and neck squamous cell carcinomas and non-small-cell lung cancers analyzed. TCF21 is known to regulate mesenchymal cell transition into epithelial cells, a property that has been shown to be deficient in carcinomas. We further demonstrate that exogenous expression of TCF21 in cells that have silenced the endogenous TCF21 locus resulted in a reduction of tumor properties in vitro and in vivo.

Animals↗
PubMed2006

Intensification regimen for advanced-stage resectable hypopharyngeal carcinoma.

OBJECTIVE: To determine feasibility, compliance, long-term survival, and disease control rates in the intensification regimen for advanced resectable hypopharyngeal carcinoma. DESIGN: Prospective, nonrandomized, controlled phase 2 trial with a median follow-up period of 89 months (range, 3.4-140.0 months). SETTING: Cancer center at a state university. PATIENTS: Thirty-two patients (age range, 44-79 years; median age, 59 years) with advanced (69% stage IV, 31% stage III) resectable hypopharyngeal carcinoma. INTERVENTIONS: Combination of surgery, radiation therapy, and chemotherapy (cisplatin and paclitaxel) along with intraoperative radiation therapy. MAIN OUTCOME MEASURES: Compliance, long-term survival, and locoregional and systemic disease control rates and functional outcome. RESULTS: The protocol compliance rate was 62% (20 of 32 patients), and the overall 5-year survival rate was 56%. Local recurrence occurred in 3 patients (9%). The systemic disease control rate was 91% (29 of 32 patients). Total laryngectomy was required in 15 patients (47%); preservation of the larynx was possible in 17 patients (53%). Only 3 (13%) of 6 patients were percutaneous endoscopic gastrostomy tube dependent in the long-term follow-up. CONCLUSIONS: The intensification regimen described in this study accomplished excellent long-term survival and disease control rates in patients with advanced resectable hypopharyngeal carcinoma. The future plan is to proceed with a phase 3 trial if the single-institutional experience at The Ohio State University can be duplicated in a multi-institutional phase 2 study.

Adult↗
PubMed2006

Long-term results of a multimodal intensification regimen for previously untreated advanced resectable squamous cell cancer of the oral cavity, oropharynx, or hypopharynx.

BACKGROUND: Long-term disease control of an intensified treatment regimen for previously untreated stage III and IV resectable oral cavity, oropharyngeal, or hypopharyngeal squamous cell carcinoma was analyzed. METHODS: Forty-three patients with previously untreated, advanced stage, resectable squamous carcinomas of the oral cavity, oropharynx, or hypopharynx were enrolled in a prospective phase II institutional clinical trial at a tertiary care National Cancer Institute-designated comprehensive cancer center. It includes preoperative accelerated hyperfractionated radiotherapy with concurrent cisplatin followed immediately by surgery and intraoperative radiotherapy, and completed with early postoperative weekly paclitaxel, two additional cisplatin cycles, and concurrent once-daily radiotherapy beginning on day 28 after surgery. RESULTS: Forty-three patients enrolled in the study. Protocol compliance was 53%. The range of time at risk was 10.4 to 56.23 months (median, 45 months). The locoregional (93%) and systemic (91%) disease control rates were excellent. Overall long-term survival was 79%. CONCLUSIONS: An intensive treatment regimen that improves compliance and long-term disease control is clearly feasible for this patient population.

Adult↗
PubMed2006

p16 gene alterations in locally advanced squamous cell carcinoma of the head and neck.

We previously documented the presence of mutations/deletions in the tumor suppressor gene p16 in squamous cell carcinoma of the head and neck (SCCHN). However, the association of these p16 alterations with clinical outcome is unknown. In this study, RNA was isolated from 19 frozen SCCHN from 19 patients who were previously enrolled in the OSU intensification regimen 2. Quantitative real-time RT-PCR and direct sequencing analysis was then performed on the specimens to detect p16 gene alterations. Clinical outcome for each patient was updated and correlated with the p16 alterations found. Five tumor specimens were found to have no or very low expression of p16 when compared with normal tissue. The remaining 14 tumor samples demonstrated overexpression of p16 relative to the level of expression in normal tissue. Sequence analysis of the p16 RT-PCR product from these specimens allowed identification of mutational changes in the coding sequence of p16 in four of the SCCHN specimens. Subsequent analysis of clinical outcome associated with locoregional/distant failure demonstrated no correlation with either altered expression of p16 or mutational status of p16. Results from this study indicate that p16 alterations are frequently found in this cohort of SCCHN. However, p16 alterations alone do not appear to be associated with clinical outcome.

Adult↗
PubMed2005

Somatic acquisition and signaling of TGFBR1*6A in cancer.

CONTEXT: TGFBR1*6A is a common polymorphism of the type I transforming growth factor beta receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown. OBJECTIVES: To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3-amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells. DESIGN, SETTING, AND PATIENTS: Tumor and germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A. MAIN OUTCOME MEASURES: TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-beta-dependent cell proliferation. RESULTS: TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-beta growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells. CONCLUSIONS: TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-beta. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-beta signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer.

Activin Receptors, Type I↗
PubMed2005

Organ preservation for advanced resectable cancer of the base of tongue and hypopharynx: a Southwest Oncology Group Trial.

PURPOSE: The Southwest Oncology Group designed a phase II trial for patients with base of tongue or hypopharyngeal cancer to evaluate the complete histologic response rate at the primary site after induction chemotherapy followed by chemoradiotherapy for responders. Secondary end points were the rate of organ preservation and the need for salvage surgery. PATIENTS AND METHODS: Fifty-nine eligible patients were enrolled; 37 had base of tongue cancer, and 22 had hypopharynx cancer. Forty-two percent had stage III disease, and 58% had stage IV disease. Induction chemotherapy was two cycles of cisplatin 100 mg/m(2) and fluorouracil 1,000 mg/m(2)/d for 5 days. Patients who had a greater than 50% response at the primary site were treated with radiation 72Gy and concurrent cisplatin 100 mg/m(2) for three cycles. Patients with less than partial response at the primary had immediate salvage surgery. RESULTS: Forty-five patients (76%) had a greater than 50% response at the primary after induction chemotherapy; 43 went on to receive definitive chemoradiotherapy. Thirty-two patients (54%) achieved a histologic complete response at the primary site, and an additional nine patients had a complete clinical response, but biopsy was not done. Seventy-five percent of patients did not require surgery at the primary tumor site. The 3-year overall survival was 64%. The 3-year progression-free survival with organ preservation was 52%. CONCLUSION: Patients with base of tongue or hypopharyngeal cancer treated with this regimen of induction chemotherapy followed by definitive chemoradiotherapy have a good rate of organ preservation without compromise of survival.

Adult↗
PubMed2005

Intraoperative single fraction high-dose-rate brachytherapy for head and neck cancers.

PURPOSE: To report on the use of single fraction high-dose-rate brachytherapy in delivering localized intraoperative radiation therapy to sites in the head and neck region inaccessible to intraoperative electron beam radiotherapy (IOERT). METHODS AND MATERIALS: After maximal surgical resection, 7.5-20 Gy intraoperative high-dose-rate brachytherapy (IOHDR) was delivered to 65 patients using custom-made surface applicators. RESULTS: The 1-, 3-, and 5-year local control rates for the entire group were 77%, 69%, and 59%, respectively. The 1-, 3-, and 5-year overall survival rates were 83%, 63%, and 42%, respectively, with a median overall survival of 50 months. There were no major intraoperative or postoperative complications. CONCLUSIONS: IOHDR can be used to treat selected locally advanced head and neck tumors arising at sites inaccessible to IOERT or at institutions not using IOERT. A prospective multi-institutional study with a larger number of patients treated with IOHDR is needed to firmly establish the efficacy of IOHDR in this population group.

Adolescent↗
PubMed2004

Disease control, survival, and functional outcome after multimodal treatment for advanced-stage tongue base cancer.

BACKGROUND: Surgical resection and postoperative radiation for advanced-stage malignancies of the oral cavity, oropharynx, and hypopharynx result in a dismal overall survival of 38%. Patients with carcinoma of the tongue base frequently have advanced disease at the time of presentation, and combined-modality therapy is usually required to achieve cure. Because of the poor survival rates with advanced malignancies with standard therapy, new and innovative approaches continue to be developed in an attempt to have a greater impact on disease control, patient survival, and functional outcome after therapy. This study examines functional outcome, survival, and disease control in patients receiving an intensified treatment regimen with concomitant chemoradiotherapy, surgery, and intraoperative radiotherapy for previously untreated, resectable, stage III and IV squamous cell carcinoma (SCC) of the tongue base. METHODS: Forty patients with previously untreated, resectable, stage III and IV squamous cell carcinoma of the tongue base were treated in one of three sequential phase II intensification regimens (IRs). Treatment consisted of perioperative, hyperfractionated radiotherapy (9.1 Gy) with concurrent cisplatin followed by surgical resection with intraoperative radiotherapy boost (7.5 Gy). Postoperative treatment involved concurrent chemoradiotherapy (40 Gy to the primary site and upper neck and 45 Gy to the supraclavicular areas) with cisplatin with or without paclitaxel. Locoregional and distant disease control, 2-year overall, and disease-specific survival rates were calculated. The Performance Status Scale (PSS) for Head and Neck Cancer Patients was administered to 25 of the surviving patients. The effects of the method of surgical reconstruction, surgery involving the mandible and/or larynx, and early versus advanced T stage on PSS score were evaluated with the Wilcoxon rank-sum test. RESULTS: Median follow-up in months for IR1, IR2, and IR3 were 83.6, 75.2, and 26.8. The locoregional control rate was 100%, and the rate of distant metastases was 7.5% for all patients. Two-year overall and disease-specific survival rates for the entire study population were 74.7% and 93.6%, respectively. Mean PSS scores by subscales Eating in Public, Understandability of Speech, and Normalcy of Diet were 55 (range, 0-100), 73 (range, 25-100), and 49 (range, 0-100), respectively. PSS scores were significantly higher in patients with primary closure of the surgical defect, no mandibular surgery, and early T-stage lesions. CONCLUSIONS: Although functional outcome may be decreased by certain surgical interventions and advanced T stage, the high rate of locoregional and distant disease control and excellent 2-year disease-specific survival supports an aggressive treatment regimen for advanced tongue base cancer.

Adult↗
PubMed2004

Role of the physician versus the patient in the detection of recurrent disease following treatment for head and neck cancer.

OBJECTIVES/HYPOTHESIS: Objective evidence supporting current National Comprehensive Cancer Network guidelines regarding surveillance of patients treated for head and neck cancer is presently lacking. The study examines the relative role of current surveillance methods on disease detection in this patient population. STUDY DESIGN: Prospective nonrandomized study. METHODS: Clinical information was prospectively collected in a standardized format during 3645 encounters with patients with head and neck cancer over an 18-month period. Data pertaining to visit history, symptom history, patient findings, physician findings, and disease status for each encounter were reviewed. RESULTS: Of 3645 visits, disease recurrence or new primary tumor was documented in 180 encounters (5%). Salvage therapy was thought to be feasible in at least 65% of cases. Of these 180 recurrences or new primaries, there were 142 patients (79%) who had identified new symptoms or physical findings, or both, before the physician's examination. Most commonly reported was the presence of a neck mass (38%), progressive pain (27%), or other visible lesion or ulcer (14%). Patients with recurrence represented nearly 40% of all patients reporting new symptoms or findings (142 of 367). Conversely, recurrence was rare in the absence of reported symptoms or findings (1.2%). Surprisingly, despite patients reporting new symptoms or findings, physician evaluation most commonly occurred at the patient's routine surveillance visit rather than an earlier time point (104 of 142 [73%]). CONCLUSION: Self-diagnosis of recurrent or new primary disease is extremely common by virtue of symptoms or findings noted by patients before interaction with the clinician. However, presence of symptoms or findings did not motivate the patients to seek earlier medical attention. In the absence of such symptoms, physician diagnosis of recurrence is uncommon. Given the significant social and economic impact involved in surveillance of patients with head and neck cancer, further prospective study to optimize the method and frequency of this type of clinical activity is warranted and planned.

Head and Neck Neoplasms↗
PubMed2003

AIDS-related Kaposi's sarcoma cells rapidly internalize endostatin, which co-localizes to tropomysin microfilaments and inhibits cytokine-mediated migration and invasion.

AIDS-related Kaposi's sarcoma (KS) is the most common HIV-related malignancy. In some respects, KS is analogous to other angioproliferative diseases, in that KS lesions are highly vascularized and promoted by inflammatory cytokines. However, unlike other cancers or inflammatory mediated vascular diseases, KS is unique in that the KS lesional cells both express and respond to the complete angiogenic cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Therefore, the angiogenic phenotype, which is crucial for cancer progression, is inherent to KS tumor cells. Due to the recognized importance of angiogenesis in cancer progression, numerous angiostatic agents are being investigated as potential therapeutic agents. One such agent is endostatin, which is a 20-kDa carboxyl-terminal fragment of collagen XVIII that has demonstrated potent angiostatic activities at both the in vivo and in vitro levels. Since endostatin is recognized as a potent angiostatic agent, the majority of in vitro endostatin studies have evaluated its effects on endothelial cells. Although KS cells are speculated to arise from endothelial cell precursors and KS lesions are highly vascularized, no previous studies have investigated endostatin-KS cell interactions. This present study evaluated endostatin's effects on KS tumor cell: (i) signal transduction (endostatin internalization and transcription factor activation), and (ii) migration and invasion (functional activity assays and tropomysin co-localization). Our results show that KS cells rapidly internalize endostatin and that endostatin initiates activation of the transcription activating factors nuclear factor-kappaB (NF-kappaB) and activating protein 1 (AP-1). Our data also show that internalized endostatin co-localizes to tropomysin microfilaments and acts to inhibit KS cell migration and invasion in response to the clinically relevant angiogenic cytokines VEGF and bFGF. As a consequence of its combined angiostatic and antitumorigenic activities, endostatin could provide dual therapeutic benefits for patients with mucocutaneous KS.

Acquired Immunodeficiency Syndrome↗
PubMed2003

An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer.

PURPOSE: The Head and Neck Intergroup conducted a phase III randomized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer. PATIENTS AND METHODS: Eligible patients were randomly assigned between arm A (the control), single daily fractionated radiation (70 Gy at 2 Gy/d); arm B, identical radiation therapy with concurrent bolus cisplatin, given on days 1, 22, and 43; and arm C, a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy, 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle. Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and, if necessary, as salvage therapy on all three treatment arms. Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test. RESULTS: Between 1992 and 1999, 295 patients were entered on this trial. This did not meet the accrual goal of 362 patients and resulted in premature study closure. Grade 3 or worse toxicity occurred in 52% of patients enrolled in arm A, compared with 89% enrolled in arm B (P <.0001) and 77% enrolled in arm C (P <.001). With a median follow-up of 41 months, the 3-year projected overall survival for patients enrolled in arm A is 23%, compared with 37% for arm B (P =.014) and 27% for arm C (P = not significant). CONCLUSION: The addition of concurrent high-dose, single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival, although it also increases toxicity. The loss of efficacy resulting from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery.

Adult↗
PubMed2002

Multimodal intensification therapy for previously untreated advanced resectable squamous cell carcinoma of the oral cavity, oropharynx, or hypopharynx.

BACKGROUND: An intensified treatment regimen for previously untreated Stage III and IV resectable oral cavity, oropharyngeal, or hypopharyngeal squamous cell carcinoma was analyzed to assess disease control, patient compliance, and toxicity. METHODS: Forty three patients with previously untreated, advanced, resectable squamous cell carcinoma of the oral cavity, oropharynx, or hypopharynx were enrolled in a prospective Phase II institutional clinical trial at a tertiary care comprehensive cancer center. This regimen was a continuum of multimodal treatment in a contracted time interval. It included preoperative slightly accelerated hyperfractionated radiotherapy with concurrent cisplatin, followed immediately with surgery and intraoperative radiotherapy, and completed with early postoperative weekly paclitaxel (beginning on Day 6 after surgery), two additional cisplatin cycles, and concurrent once daily radiotherapy beginning on Day 28 after surgery. RESULTS: The current trial was designed to reduce the toxicity of the systemic therapy while maintaining or improving locoregional/distant disease control and patient compliance. There were 43 patients enrolled, and the range of time at risk was 2.6 to 24.7 months (median, 14.6 months). Of the 43 registered patients, 43 were evaluable. The locoregional (100%) and systemic (93%) disease control rates were excellent, with low rates of patient noncompliance (21%) and reduced levels of toxicity. CONCLUSIONS: An intensive treatment regimen that improves disease control and treatment compliance is clearly feasible for this patient population. Future plans include modifications to continue to reduce toxicity and expansion to a multi-center Phase II trial to determine if the single institutional results can be duplicated.

Adult↗
PubMed2002

Maxillary removal and reinsertion in pediatric patients.

OBJECTIVE: To examine outcomes after the maxillary removal and reinsertion (MRR) approach for the treatment of anterior cranial base tumors in pediatric patients. DESIGN: Eligible patients were identified by medical record review. Consenting patients were studied via rhinoscopy, fiberoptic endoscopy, standard facial photographs, and cephalometric radiographs. SETTING: A tertiary care otolaryngology clinic. PATIENTS: Inclusion criteria were age younger than 16 years at time of initial procedure and a follow-up period of at least 6 months. Nine patients were eligible, and 5 enrolled. All were male patients (mean age, 13.8 years; age range, 11-15 years) treated for juvenile nasopharyngeal angiofibroma. MAIN OUTCOME MEASURES: History and examination were performed to evaluate occlusion, vision, facial growth, and tumor status. Cephalograms were used to calculate 3 standard cephalometric measurements: sella to A point, basion to A point, and condylion to A point. Cephalograms were examined for plate migration and bony resorption. RESULTS AND CONCLUSIONS: No major long-term complications were identified in the patients after MRR. Cephalometric analysis revealed minor abnormalities in 2 children, but no plate migration or bony resorption was identified in the removed and reinserted maxillae. No abnormal development patterns were detected on physical examination or when cephalometric measurements were compared with age- and race-matched normative data. Although further study is warranted, MRR seems safe and effective for treatment of pediatric patients with anterior cranial base tumors.

Angiofibroma↗
PubMed2002

Simple predictors of survival in head and neck squamous cell carcinoma.

OBJECTIVE: To develop a simple prognostic survival rule from easily obtained characteristics of patients undergoing potentially curative resection of head and neck squamous cell carcinoma using classification and regression trees. DESIGN: Inception cohort. SETTING: Tertiary care center. PATIENTS: Consecutive patients undergoing resection lasting at least 2 hours, from July 1993 through June 1997. MAIN OUTCOME MEASURE: Survival, age, TNM tumor stage, functional class, systolic and diastolic blood pressure, body mass index, and serum albumin concentration were evaluated as predictors. RESULTS: Four hundred six patients were followed up for 5 to 1446 days (median, 391 days), during which time 172 deaths occurred. Median survival was 687 days. Patients with TNM stage I, II, or III squamous cell carcinoma had a mean survival of 1068 days. Patients with TNM stage IV or recurrent disease were further stratified. Those with a serum albumin concentration less than 3.85 g/dL had a median survival of 404 days (95% confidence interval, 286-532 days), and those with an serum albumin concentration of 3.85 g/dL or above had a median survival of 625 days (95% confidence interval, 536-1032 days). A similar survival was found using age younger than 66.5 years as a predictor instead of serum albumin concentration less than 3.85 g/dL. CONCLUSIONS: At our institution, patients with stage I, II, or III squamous cell carcinoma had a mean survival of approximately 3 years. Those with stage IV or recurrent squamous cell carcinoma could be stratified by either serum albumin concentration or by age into 2 groups with a median survival of 1 or 2 years.

Adult↗
PubMedDate not supplied

Mohs micrographic surgery and the otolaryngologist.

OBJECTIVE: The purpose of this study was to provide an update and overview of the current indications for Mohs micrographic surgery (MMS) for cutaneous and upper aerodigestive tract malignancies. STUDY DESIGN: Literature review. METHODS: A comprehensive review of the literature from 1971 to present was completed by using the Medline data base. In addition, interviews were obtained with several otolaryngologists who had used the technique. RESULTS: MMS offers a superior alternative to standard excision in a variety of cutaneous malignancies. Overall, for the skin cancers likely to be encountered by the otolaryngologist, there is significant evidence that MMS offers increased rates of cure as well as tissue conservation. The role of MMS in upper aerodigestive tract malignancies continues to evolve and multiple issues must be addressed before its general application. CONCLUSIONS: When confronted with a difficult cutaneous malignancy, the otolaryngologist should consider MMS to optimize treatment results.

Carcinoma↗