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Biomedical subjects

G T Wolf

Publications and source records attributed to G T Wolf.

At least 19 recordsLinked to original sources
PubMed2007

Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma.

Like many epithelial tumors, head and neck squamous cell carcinoma (HNSCC) contains a heterogeneous population of cancer cells. We developed an immunodeficient mouse model to test the tumorigenic potential of different populations of cancer cells derived from primary, unmanipulated human HNSCC samples. We show that a minority population of CD44(+) cancer cells, which typically comprise <10% of the cells in a HNSCC tumor, but not the CD44(-) cancer cells, gave rise to new tumors in vivo. Immunohistochemistry revealed that the CD44(+) cancer cells have a primitive cellular morphology and costain with the basal cell marker Cytokeratin 5/14, whereas the CD44(-) cancer cells resemble differentiated squamous epithelium and express the differentiation marker Involucrin. The tumors that arose from purified CD44(+) cells reproduced the original tumor heterogeneity and could be serially passaged, thus demonstrating the two defining properties of stem cells: ability to self-renew and to differentiate. Furthermore, the tumorigenic CD44(+) cells differentially express the BMI1 gene, at both the RNA and protein levels. By immunohistochemical analysis, the CD44(+) cells in the tumor express high levels of nuclear BMI1, and are arrayed in characteristic tumor microdomains. BMI1 has been demonstrated to play a role in self-renewal in other stem cell types and to be involved in tumorigenesis. Taken together, these data demonstrate that cells within the CD44(+) population of human HNSCC possess the unique properties of cancer stem cells in functional assays for cancer stem cell self-renewal and differentiation and form unique histological microdomains that may aid in cancer diagnosis.

Animals↗
PubMed2006

Correlation between initial and early follow-up CT perfusion parameters with endoscopic tumor response in patients with advanced squamous cell carcinomas of the oropharynx treated with organ-preservation therapy.

BACKGROUND AND PURPOSE: Current organ-preservation regimens for upper aerodigestive tract squamous cell carcinoma (SCCA) require endoscopic procedures under general anesthesia to evaluate the tumor response. The purpose of our study was to determine whether CT perfusion (CTP) parameters correlate with response to induction chemotherapy as assessed by endoscopy under general anesthesia. METHODS: Nine patients with advanced (stage 3 or 4) SCCA of the oropharynx were enrolled in a nested phase 2 prospective trial in which induction chemotherapy was used to assess the tumor response. Patients underwent direct laryngoscopy and CTP before and 3 weeks after one cycle of induction chemotherapy. The outcome variables were the surgeon's estimate of tumor volume during endoscopy with biopsy under anesthesia and CTP parameters (capillary permeability (CP), blood volume (BV), blood flow (BF), and mean transit time (MTT)). Wilcoxon rank sum analysis was used to correlate the baseline values of BF and BV with response to induction chemotherapy. Comparison of agreement between the reduction in tumor volume and change in CTP parameters was performed by using kappa estimates. RESULTS: Seven of 9 patients demonstrated > or =50% tumor volume reduction, representing positive response to induction chemotherapy. In the responder group, the following changes in mean pre- and postinduction chemotherapy values were noted: mean BF, 114.2 mL/100 g /min (preinduction) to 45.1 mL/100 g/min (postinduction); mean BV, 5.11 mL/100 g to 3.1 mL/100 g; mean CP, 25.6 mL/100 g /min (preinduction) to 18.3 mL/100 g / min (postinduction); mean MTT, 4.9 seconds (preinduction) to 8.0 seconds (postinduction). In the nonresponder group, the following changes were noted: mean BF, 56.9 mL/100 g/min to 75.9 mL/100 g/min; mean, BV 2.7 mL/100 g to 4.71 mL/100 g; mean CP, 24.1 mL/100 g/min to 23.7 mL/100 g/min; mean MTT, 4.3 seconds to 5.34 seconds. Higher baseline (pretherapy) values of BV showed significant correlation with endoscopic tumor response (P < .05). Reduction in the BV (by >/=20%) on follow-up studies also showed substantial agreement with clinical response as assessed with endoscopy (kappa = 0.73). The agreement between decreased BF, decreased CP, and increased MTT and clinical response was fair (kappa = 0.37). CONCLUSION: These preliminary results show that deconvolution-based CTP technique offers potential for noninvasive monitoring of response to induction chemotherapy in patients with oropharyngeal cancers. Percentage reduction of BV is significantly correlated to endoscopic response to induction chemotherapy, though we acknowledge that the data correspond to short-term outcomes and long-term durability of response cannot be established. Nevertheless, validation of the use of deconvolution CTP parameters as predictors of tumor response may permit replacement of an invasive diagnostic procedure conducted under anesthesia currently used to assess response with noninvasive perfusion CT imaging.

Aged↗
PubMed2001

Conformal re-irradiation of recurrent and new primary head-and-neck cancer.

PURPOSE: To review the outcome of head-and-neck cancer patients re-irradiated using conformal radiation. PATIENTS AND METHODS: From 1983 to 1999, 60 patients with recurrent or new primary head-and-neck cancer received re-irradiation at the University of Michigan. Twenty patients were excluded due to the planned cumulative radiation dose being less than 100 Gy (18) and absence of prior radiation details (2), leaving 40 patients. Thirty-five patients were re-irradiated for unresectable disease, while 4 patients received adjuvant re-irradiation for high-risk disease. Thirty-eight patients had recurrences from previously treated cancer (19 regional, 14 local, 5 regional and local), and 2 patients had new primary tumors. The median time from the first course of radiation to re-irradiation was 21 months. Thirty-one patients (78%) were re-irradiated with curative intent, whereas 9 were treated with palliative intent. Re-irradiation was delivered using conformal techniques in the majority of patients and with concurrent chemotherapy in 14 patients. The median re-irradiation dose was 60 Gy. The median cumulative dose received was 121 Gy. Five patients (13%) did not complete their prescribed course of re-irradiation. RESULTS: The median survival following completion of re-irradiation was 12.5 months. The 1- and 2-year actuarial survival rates were 51.1% and 32.6%, respectively. On multivariate analysis, palliative intent of treatment, tumor bulk, and tumor site other than nasopharynx or larynx were associated with worse survival. The patients treated for unresectable disease did no worse than those treated adjuvantly. The median times to relapse-free survival, local-regional recurrence (LRR)-free survival, and ultimate LRR-free survival (allowing for surgical salvage) were 3.9 months, 7.8 months, and 8.7 months, respectively. Seven patients (18%) are presently alive with no evidence of disease, with a median follow-up of 49.9 months (range 3.3-78.9). Severe radiation-induced complications were seen in 7 patients (18%). Two other patients developed orocutaneous fistulas in the presence of tumor recurrence. Moderate fibrosis and trismus were common. CONCLUSION: Despite the use of conformal techniques, the prognosis of patients treated with re-irradiation is poor, and complications are not infrequent. A subset of patients is salvageable, and high-dose re-irradiation should be considered in selected patients.

Adolescent↗
PubMed2001

Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study.

PURPOSE: To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level. PATIENTS AND METHODS: Twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. Tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured. RESULTS: Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m(2)/wk, 150 mg/m(2)/wk, and 50 mg/m(2)/wk. No DLT was observed at 10 mg/m(2)/wk. The rate of endoscopy- and biopsy-assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m(2) (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m(2). CONCLUSION: A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m(2), which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio.

Adult↗
PubMed2001

Sentinel node localization in oral cavity and oropharynx squamous cell cancer.

OBJECTIVE: To evaluate the feasibility and predictive ability of the sentinel node localization technique for patients with squamous cell carcinoma of the oral cavity or oropharynx and clinically negative necks. DESIGN: Prospective, efficacy study comparing the histopathologic status of the sentinel node with that of the remaining neck dissection specimen. SETTING: Tertiary referral center. PATIENTS: Patients with T1 or T2 disease and clinically negative necks were eligible for the study. Nine previously untreated patients with oral cavity or oropharyngeal squamous cell carcinoma were enrolled in the study. INTERVENTIONS: Unfiltered technetium Tc 99m sulfur colloid injections of the primary tumor and lymphoscintigraphy were performed on the day before surgery. Intraoperatively, the sentinel node(s) was localized with a gamma probe and removed after tumor resection and before neck dissection. MAIN OUTCOME MEASURES: The primary outcome was the negative predictive value of the histopathologic status of the sentinel node for predicting cervical metastases. RESULTS: Sentinel nodes were identified in 9 previously untreated patients. In 5 patients, there were no positive nodes. In 4 patients, the sentinel nodes were the only histopathologically positive nodes. In previously untreated patients, the sentinel node technique had a negative predictive value of 100% for cervical metastasis. CONCLUSIONS: Our preliminary investigation shows that sentinel node localization is technically feasible in head and neck surgery and is predictive of cervical metastasis. The sentinel node technique has the potential to decrease the number of neck dissections performed in clinically negative necks, thus reducing the associated morbidity for patients in this group.

Adult↗
PubMed2001

Conservation laryngeal surgery for malignant tumors of the larynx and pyriform sinus.

Conservation surgery for cancers of the larynx and pyriform sinus is an expansive and complicated subject. A great deal of technical expertise and clinical judgement are required for appropriate surgical and oncologic outcomes. In the appropriate setting, surgery continues to play an important role in voice preservation for patients with laryngeal and hypopharyngeal carcinoma. Perhaps most importantly, options for organ preservation surgery have expanded, and the number of patients requiring total laryngectomy as primary surgical management has decreased. The medical surgical decision making is complex and requires precise delineation of tumor extent, careful patient evaluation, and thorough interdisciplinary discussion to select an optimal course of treatment for the individual patient.

Humans↗
PubMed2001

Clinical experience with HLA-B7 plasmid DNA/lipid complex in advanced squamous cell carcinoma of the head and neck.

OBJECTIVE: To investigate the safety and efficacy of alloantigen plasmid DNA therapy in patients with advanced head and neck squamous cell carcinoma using Allovectin-7 (Vical Inc, San Diego, Calif), a DNA/lipid complex designed to express the class I major histocompatibility complex antigen HLA-B7. DESIGN: Multi-institutional prospective trial. SETTING: Academic medical setting. PATIENTS: A total of 69 patients were enrolled in 3 sequential clinical trials: a single-center phase 1 trial and 2 multicenter phase 2 trials. Eligibility criteria included unresectable squamous cell carcinoma that failed conventional therapy, Karnofsky performance status score of 70 or greater, and no concurrent anticancer or immunosuppressive therapies. INTERVENTION: Patients received 2 biweekly intratumoral injections of 10 microg (phase 1 and first phase 2 trials) or 100 microg (second phase 2 trial) of Allovectin-7 followed by 4 weeks of observation. Patients with stable or responding disease after the observation period were given a second treatment cycle identical to the first. MAIN OUTCOME MEASURES: Patients were assessed for toxic effects, and tumor size was measured after cycles 1 (at 6 weeks) and 2 (at 16 weeks). RESULTS: Allovectin-7 treatment was well tolerated, with no grade 3 or 4 drug-related toxic effects. Of 69 patients treated, 23 (33%) had stable disease or a partial response after the first cycle of treatment and proceeded to the second cycle. After the second cycle, 6 patients had stable disease, 4 had a partial response, and 1 had a complete response. Responses persisted for 21 to 106 weeks. CONCLUSIONS: Intratumoral plasmid DNA immunotherapy for head and neck cancer with Allovectin-7 is safe, and further investigations are planned in patients with less advanced disease, where it could potentially improve patient survival and reduce the need for radical high-morbidity treatments.

Adult↗
PubMed2001

Options for preserving the larynx in patients with advanced laryngeal and hypopharyngeal cancer.

The introduction of newer surgical and combined-modality approaches to organ preservation in patients with advanced laryngeal or hypopharyngeal cancer is the most exciting clinical frontier in head and neck cancer treatment today. The use of these techniques at other sites, the exploration of improved methods for patient selection and tumor assessment, and the development of newer combination regimens will need to be rigorously studied in future clinical trials. In all these efforts, the major focus must remain on improving survival. This article reviews the latest developments in organ-preservation strategies and techniques for patients with advanced laryngeal or hypopharyngeal cancer.

Antineoplastic Agents↗
PubMed2000

Pain, quality of life, and spinal accessory nerve status after neck dissection.

OBJECTIVE: To assess quality of life (QOL) in patients with head and neck cancer who underwent neck dissection and to compare QOL scores for patients in whom the spinal accessory nerve (CN XI) was resected or preserved. SETTING AND DESIGN AND OUTCOMES MEASURES: Three hundred ninety-seven patients who had undergone treatment for head and neck cancer completed the University of Michigan Head and Neck Quality of Life (HNQOL) instrument, the Medical Outcomes Study SF-12 General Health Survey, and questions on "pain despite pain medications" and headaches. RESULTS: Of the 397 patients, 222 had no neck dissection, 46 had neck dissections resecting CN XI, and 129 had dissection sparing CN XI. Of the latter group, 68 patients had dissections sparing level V and 61 dissections included level V. Age, sex, primary site distribution, and T stage were not different between the groups. Patients who had neck dissections sparing CN XI had better scores on the HNQOL pain domain (P = .002), had less shoulder or neck pain (P = .003), and took pain medications less frequently (P = .0004) compared with patients who had neck dissections sacrificing CN XI. When CN XI was preserved, patients who had no level V dissection had better pain domain scores (P = .03) and eating domain scores (P = .007) on the HNQOL, had less shoulder or neck pain (P = .006), and had less physical problems (P = .03) than patients who had level V dissected. On multivariate analysis, pain-related QOL scores after neck dissection were significantly better (P < .01) if patients had dissections with preservation of CN XI and if level V was not dissected. CONCLUSION: Neck dissections sparing CN XI are associated with better pain scores on the HNQOL, less shoulder and neck pain, and less need for medications. When CN XI is spared, not dissecting level V of the neck is associated with better HNQOL pain scores, less shoulder or neck pain, and fewer physical problems.

Accessory Nerve↗
PubMed2000

Neoadjuvant therapy for organ preservation in head and neck cancer.

OBJECTIVES/HYPOTHESIS: We designed two sequential trials of induction chemotherapy followed by definitive radiation in patients with potentially resectable head and neck cancer to determine whether organ preservation is feasible without apparent compromise of survival Study Design Both trials were Phase II studies. METHODS: Two clinical trials were conducted sequentially at the University of Michigan. Fifty-two patients enrolled in the first study and were treated with a planned three cycles of carboplatin and 5-fluorouracil. Patients who achieved at least 50% reduction in the size of the primary tumor received definitive radiation therapy, to a dose of 6600 to 7380 cGy. Patients with minimal response or progression had immediate salvage surgery. Thirty-seven patients enrolled in the second trial, in which the chemotherapy consisted of carboplatin, 5-fluororuracil, and leukovorin. Responders were treated with accelerated radiation therapy, to a total dose of 7120 cGy delivered in 41 fractions over 5.5 weeks. RESULTS: Toxicity and response were similar in both trials; therefore, the results are reported first separately and then combined for all 89 patients. Tumor sites included: oropharynx, 55 patients; hypopharynx, 34 patients. Eighty-three percent of patients tolerated all three cycles of chemotherapy and toxicity was mild. Response to chemotherapy was: 48% complete response at the primary tumor site, and 34% partial response at the primary tumor site. Initial organ preservation at individual tumor sites was: oropharynx, 58%; hypopharynx, 59%. Median survival was 28 months, and survival at 3 and 5 years was 40% and 24%, respectively. CONCLUSIONS: These two regimens were well tolerated, and survival did not appear to be compromised by organ preservation treatment compared with historical controls. This approach warrants further investigation, particularly in those patients for whom surgery could be functionally debilitating.

Adult↗
PubMed1999

Predictive markers for response to chemotherapy, organ preservation, and survival in patients with advanced laryngeal carcinoma.

OBJECTIVE: A systematic retrospective study of the largest randomized trial of induction chemotherapy and radiation for advanced laryngeal cancer was undertaken to determine whether specific tumor or biologic factors were predictive of chemotherapy response, organ preservation, or survival. METHODS: The variables analyzed included clinical and histologic factors, immunohistochemical expression of proliferating cell nuclear antigen and p53, and adjusted DNA index measurements. Variables were evaluated for correlation with outcomes of tumor response, organ preservation, and survival. RESULTS: Multivariate analysis revealed that the best predictor of complete response to induction chemotherapy was low T class. The full multivariate model for predicting larynx preservation in patients treated with induction chemotherapy plus radiation shows that T class, p53 overexpression, and elevated proliferating cell nuclear antigen index were independent predictors of successful organ preservation. CONCLUSIONS: These predictive markers should be included in future clinical trials of advanced laryngeal cancer to determine their usefulness prospectively.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Health impact of head and neck cancer.

A multidimensional Head and Neck Quality of Life (HNQOL) instrument and a general health status measure were administered to 397 patients with head and neck cancer. Scores for the 4 domains of the HNQOL (communication, eating, pain, and emotional well-being) were calculated. Patient demographics, comorbidities, clinical characteristics, treatment data, disability status, and a global "overall bother" score were assessed. When compared with the US population aged 55 to 64 years, the group had significantly worse scores in the 8 health domains of the SF-36. Patients' overall bother scores from the head and neck cancer treatment correlated best with the HNQOL emotion domain (r = 0.71) and the HNQOL pain domain (r = 0.63), and least with the patients' perception of their response to treatment (r = 0.39). Pain, eating, emotion, physical component summary score, age, and an interaction term between eating and emotion were significant predictors for overall bother. Of the 217 patients who were working before the diagnosis of cancer, 74 (34. 1%) reported that they had become disabled. Patients who had more than 1 type of treatment were 5.9 times more likely to report themselves as disabled (odds ratio [OR] = 5.94, P < 0.01), even after adjusting for age, emotion score, and physical component summary score, which were other factors that predicted disability.

Comorbidity↗
PubMed1999

Expression of major histocompatibility complex antigens in squamous cell carcinomas of the head and neck: effects of interferon gene transfer.

The effect of retroviral-mediated interferon-gamma (IFN-gamma) gene transfer on major histocompatibility complex (MHC) class I and II antigen expression was investigated in 13 head and neck squamous carcinoma cell lines. Six cell lines exhibited increased MHC class I expression, and 10 exhibited increased MHC class II expression after IFN-gamma gene transfer. Differences in MHC antigen expression between parental and transduced cell lines were significant (P = 0. 002) only for cell lines that upregulated MHC class II expression. After incubation in medium containing 100 U/mL recombinant IFN-gamma, or in medium from IFN-gamma retrovirus-transduced NIH 3T3 cells, 12 cell lines significantly upregulated MHC class I expression, and 9 significantly upregulated MHC class II expression. Only cell lines that exhibited increased MHC class II expression after retroviral transduction also upregulated class II expression with exogenous IFN-gamma treatment. Thus some head and neck squamous carcinoma cell lines can upregulate MHC class I and II expression after exogenous application of either IFN-gamma or IFN-gamma retroviral transduction. These are promising findings for head and neck cancer immunotherapy and gene therapy.

Adult↗
PubMed1999

Head and neck cancer: detection of recurrence with three-dimensional principal components analysis at dynamic FDG PET.

Fully automated principal components analysis (PCA) was applied to dynamic 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomographic (PET) images obtained in 15 patients with previously treated head and neck cancer. PCA with time-activity curves incorporated kinetic information about FDG uptake, which improved tissue characterization on FDG PET images. The combination of standardized uptake value and PCA image sets likely will improve the reliability of tumor detection in head and neck cancers.

Adult↗