Advanced oropharyngeal carcinoma treated with surgery and radiotherapy: oncologic outcome and functional assessment.

INTRODUCTION/PURPOSE: Surgery and postoperative radiotherapy (XRT) is a standard therapy for locally advanced resectable oropharyngeal carcinoma. This maximizes local-regional control, but does not address the potential for occult distant metastases. Additionally, some patients may suffer poor functional outcome after this intensive local therapy. This report reviews our institutional experience with modern radical surgery and XRT for this disease. METHODS: A retrospective chart review was performed on 51 consecutive patients treated from 1991 to 1997 at the University of Pennsylvania with radical surgery and postoperative XRT. This study included patients with locally advanced, stage III/IV (exclusive of T1-2N1) squamous carcinoma of the oropharynx. All patients had a good performance status (ECOG 0-1). Patients who received adjuvant chemotherapy were excluded. No patient had gross residual disease after surgery; the median XRT dose was 63.7 Gy. Survival, local-regional control (LRC), and freedom from distant metastases (DM) were calculated actuarially. In patients who remained free of disease, functional status was determined using the List Performance Status Scale (PSS). RESULTS: With a median follow-up in surviving patients of 34 months, the 3-year actuarial overall survival was 51%. The 3-year LRC was 73%, and the freedom from DM was 69%. The most significant factor predicting for failure was the number of pathologically positive nodes (P <.001 for survival and DM; P =.003 for LRC). In 29 patients who were evaluable for the List PSS, the mean normalcy-of-diet score was 48; the mean eating-in-public score was 53; and the mean understandability-of-speech score was 75. There was a trend toward better PSS scores in patients with T1-2 tumors versus T3-4 tumors, although this did not reach statistical significance. CONCLUSIONS: Surgery and postoperative XRT offer relatively good LRC and moderate overall survival rates. Results, however, remain suboptimal, particularly with respect to the risk of DM and the functional outcome. These data provide a baseline for comparison with maturing results from multimodality trials in which radical surgery is not used in all patients with locally advanced oropharyngeal carcinoma.

Internal jugular vein versus external jugular vein anastamosis: implications for successful free tissue transfer.

BACKGROUND: Microvascular free flaps are becoming the reconstructive option of choice for many head and neck defects. Many previous studies have examined factors predicting free flap survival. No study has compared differences in free flap survival when anastomosed to the internal or external jugular systems. METHODS: Retrospective review of all free flaps performed at an academic medical center by a single head and neck microvascular surgeon during the period July 1995 to December 1999. Flaps were closely monitored postoperatively and taken back to the operating room urgently for arterial insufficiency or venous congestion. RESULTS: On hundred fifty-six free flaps were performed during this time period. Sixty-five free flaps were anastomosed to the external jugular (EJ) vein and 86 to the IJ system (62 to the proximal common facial vein, 17 end-side on the IJ, and 7 to other branches). Five had either two venous anastomoses or were anastomosed to other veins and were excluded from statistical analysis. Six (4%) vascular thromboses occurred; 5 were venous and 1 arterial. Success by group was 99% for IJ anastomosis (1 arterial thrombosis) and 92% for EJ anastomosis (5 venous thromboses, p =.03). Urgent anastomotic revision and reperfusion salvaged 5 of the 6 flaps (overall success 99%). CONCLUSIONS: Although the overall success rate (96% success with 99% success with salvage) is comparable to other large series, microvascular free flaps anastomosed to the external jugular vein failed at a significantly higher rate than those anastomosed to the IJ system. This suggests that the IJ system should be used as a recipient vessel when feasible.

Economic consequences of diagnostic imaging for vocal cord paralysis.

RATIONALE AND OBJECTIVES: The purpose of this retrospective study was to estimate the economic consequences of evaluating suspected vocal cord paralysis with magnetic resonance (MR) imaging and computed tomography (CT). MATERIALS AND METHODS: Reports from MR imaging (n = 30) or CT (n = 19) studies of the neck in 49 patients were retrospectively reviewed for causes of vocal cord paralysis. The patients were divided into high-suspicion (n = 20) and low-suspicion (n = 29) groups, based on the presence or absence of a clinically detectable abnormality other than vocal cord immobility. Clinic and inpatient charts were examined to determine the work-up in all cases. The Medicare Resource-based Relative Value Scale was used to estimate the costs of most procedures. RESULTS: The high-clinical-suspicion group included nine true-positive, four false-positive, seven true-negative, and no false-negative cases. Further work-up was performed in seven true-positive, three false-positive, and one true-negative cases. The total cost of immediate diagnostic work-up in these 20 patients, including MR imaging and/or CT, was $20,737 ($2,304 per true-positive case). The low-suspicion group included two true-positive, nine false-positive, 18 true-negative, and no false-negative cases. Further work-up was performed in both true-positive, four false-positive, and two true-negative cases. The total cost of immediate diagnostic work-up in these 29 patients was $21,698, (mean, $748; $10,849 per true-positive case). CONCLUSION: The average cost of finding space-occupying lesions in patients with vocal cord paralysis is more than 4.5 times higher in patients without suspicious antecedent clinical findings than in those with such a history. The benefits of obtaining negative findings and of detecting a small number of space-occupying lesions should be weighed against the costs of such examinations and of additional work-up for false-positive findings.

Phase I study of paclitaxel given by seven-week continuous infusion concurrent with radiation therapy for locally advanced squamous cell carcinoma of the head and neck.

PURPOSE: Paclitaxel is one of the most active agents for squamous cell carcinoma of the head and neck (SCCHN) and an in vitro radiosensitizer. The dose-response relationship for paclitaxel may depend more on exposure duration than on peak concentration. This National Cancer Institute-sponsored phase I trial was designed to determine the feasibility of combining continuous-infusion (CI) paclitaxel with concurrent radiation therapy (RT). PATIENTS AND METHODS: Patients with previously untreated stage IVA/B SCCHN were eligible. Primary end points were determination of the maximum-tolerated dose, dose-limiting toxicity, and pharmacokinetics for paclitaxel given by CI (24 hours a day, 7 days a week for 7 weeks) during RT (70 Gy/7 weeks). RESULTS: Twenty-seven patients were enrolled and assessable for toxicity. Nineteen of the patients who completed > or = 70 Gy were assessable for response. Grade 3 skin and mucosal acute reactions occurred at 10.5 mg/m(2)/d, but uninterrupted treatment was possible in five of six patients. At 17 mg/m(2)/d, skin toxicity required a 2-week treatment break for all three patients. The mean paclitaxel serum concentration at dose levels > or = 6.5 mg/m(2)/d exceeded that reported to achieve in vitro radiosensitization. Initial locoregional control was achieved in 14 (58%) of 24 of patients treated to 70 Gy, and control persisted in nine (38%). CONCLUSION: CI paclitaxel with concurrent RT is a feasible and tolerable regimen for patients with advanced SCCHN and good performance status. Preliminary response and survival data are encouraging and suggest that further study is indicated. The recommended phase II dose of paclitaxel by CI is 10.5 mg/m(2)/d with RT for SCCHN.

Backside first in head and neck surgery?: preventing pressure ulcers in extended length surgeries.

BACKGROUND: The operating room (OR) presents a high-risk environment for pressure injury. We designed a project to improve performance in the prevention of intraoperative pressure ulcers in extended length head and neck surgeries for malignancies (ELS) using a fluid mattress (RIK) intraoperatively. METHODS: A descriptive design was used to monitor performance improvement in this underrecognized aspect of patient care. A fluid, pressure-reducing OR mattress (RIK) was compared with the use of a standard foam OR mattress (Skytron). A convenience group of 36 consecutive patients, undergoing ELS, was included in the project. Patients were evaluated for presence or absence of a pressure ulcer immediately and 72 hours postoperatively. RESULTS: Patient groups were demographically and surgically comparable at a clinical level. Pressure ulcer incidence before intervention was 21% (4 of 19). This declined to 0% after intervention. CONCLUSIONS: Intraoperative pressure ulcers are a costly complication. Presence of a pressure ulcer extends time in the sick role and disrupts desired aesthetic outcomes. Use of a pressure-reducing device achieved the performance improvement objective. Implications for future research and current care are discussed.

Pilot study of organ preservation multimodality therapy for locally advanced resectable oropharyngeal carcinoma.

The purpose of this study was to determine the early efficacy and toxicity of a new multimodality organ-preservation regimen for locally advanced, resectable oropharyngeal squamous cell carcinoma (SCC). Patients with T3-4N0-3M0 or T2N2-3M0 oropharyngeal SCC were eligible for this Phase II study. Patients needed the physiologic reserve for surgery and technically resectable tumors. Induction carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) x 2 cycles (q21 days) were given. Objective responders received definitive radiotherapy (XRT), 70 Gy/7 weeks with concurrent weekly paclitaxel. Initially, the dose of paclitaxel was 50 mg/m2/week; because of mucosal toxicity it was reduced to 30 mg/m2/week. Patients with N2-3 disease received post-XRT neck dissection and 2 more cycles of "adjuvant" chemotherapy. In the first 22 patients, the neutropenic fever rate was 27%. Although there has been no grade IV-V toxicity from induction therapy, grade II-III toxicity resulted in an unacceptable delay in starting XRT in 14% of patients. The response rate to induction chemotherapy was 91%. Grade III mucositis occurred in all patients during concurrent chemoradiotherapy. One patient died of pneumonia during concurrent chemoradiotherapy after receiving 26 Gy and 3 doses of paclitaxel 50 mg/m2. No dose-limiting toxicity occurred in 15 patients treated with concurrent paclitaxel 30 mg/m2/week. Actuarial overall survival at 18 months is 82%; local-regional control is 86%. To date, distant metastases have not developed in any patients. This regimen has intense but acceptable acute toxicity. The maximum tolerated dosage of weekly paclitaxel during standard continuous-course XRT is confirmed to be 30 mg/m2/week. The treatment efficacy of this regimen (response rate and short-term local-regional and distant control) is encouraging. Accrual continues to obtain long-term toxicity, efficacy, and quality-of-life data.

Major salivary gland imaging.

The algorithm for imaging the salivary glands depends on the clinical scenario with which the patient presents to the clinician. Because of the importance of identifying small calculi in the gland or salivary duct as the cause of the symptom complex, nonenhanced computed tomography is often the best initial study for the evaluation of the painful gland. If an infiltrative neoplasm is highly suspected, nonenhanced and enhanced magnetic resonance (MR) imaging may be superior in demonstrating perineural, meningeal, and skull base invasion. Sialography is reserved for the evaluation of chronic sialadenitides unrelated to sialolithiasis. Thin-section MR techniques for MR sialography may soon replace conventional sialography.

Detection of hypoxia in human squamous cell carcinoma by EF5 binding.

Localization and quantitation of 2-nitroimidazole drug binding in low pO2 tumors is a technique that can allow the assessment of hypoxia as a predictive assay. EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] is such a drug, and it has been shown to be predictive of radiation response in rodent tumors. Using fluorescence immunohistochemical techniques, we provide data on the presence, distribution, and levels of EF5 binding as a surrogate for hypoxia in human head and neck and uterine cervix squamous cell cancers (SCCs). Six patients with SCC were studied. Four patients had head and neck tumors, and two had uterine cervix cancers. The incubation of fresh tissue cubes in EF3 under hypoxic conditions ("reference binding") demonstrated that all tumors were capable of binding drug, and that this binding varied by a factor of 2.9-fold (174.5-516.1) on an absolute fluorescence scale. In the five patients treated at the lowest drug doses (9 mg/kg), in situ binding was quantitatable. For all six patients, the maximum rate of in situ binding varied by a factor of 6.7 between the lowest and highest binding tumor (24.8-160.3) on an absolute fluorescence scale. In tumors with high binding regions, intratumoral heterogeneity was large, extending from minimal fluorescence (<1%) up to 88.6% of reference binding. In tumors with minimal binding, there was little intratumoral heterogeneity. These studies demonstrate substantial heterogeneity of in situ binding between and within individual squamous cell tumors.

Coimmunization with IFN-gamma or IL-2, but not IL-13 or IL-4 cDNA can enhance Th1-type DNA vaccine-induced immune responses in vivo.

As we explore the potential improvements to the current DNA vaccine strategies, it may be desirable to investigate methods to improve the level of resulting immune responses. One strategy is the use of cytokine cDNA as molecular adjuvants for DNA-based vaccines. Codelivery of these molecular adjuvants consisting of expression plasmid encoding for cytokines with DNA vaccine constructs is an effective method to modulate the magnitude and direction (humoral or cellular) of the immune responses. We have previously reported on the immunomodulatory effects of codelivering cDNA for interleukin-2 (IL-2) and IL-4 as molecular adjuvants for DNA-based vaccines. In this report, we extend these finding and compare the immunomodulatory effects of IL-2 and IL-4 with those of cDNA for prototypical Thl-type cytokine interferon-y (IFN-gamma) and Th2-type cytokine IL-13. We observed that distinct antigen-specific immune modulation can be achieved by the coinjection of IFN-gamma or IL-13 genes with DNA immunogen cassettes. We observed that IFN-gamma is a strong driver of Thl immune responses. Furthermore, in contrast to previous reports on their similarities in biologic activities, IL-13 and IL-4 cDNA coimmunizations modulated vaccine-induced immune responses differently in this model. Overall, these results further support the potential utility of this strategy as an important tool for the development of vaccines and immune therapies.

Macrophage colony-stimulating factor can modulate immune responses and attract dendritic cells in vivo.

Studies have indicated that professional APCs in the periphery, such as dendritic cells and macrophages, play an important role in initiating DNA vaccine-specific immune responses. To engineer the immune response induced by DNA vaccines in vivo we investigated the modulatory effects of codelivering growth factor genes for the hematopoietic APCs along with DNA vaccines. Specifically, we examined the effects on the antigen-specific immune responses following the codelivery of the gene expression cassettes for M-CSF, G-CSF, and GM-CSF along with HIV-1 DNA immunogen constructs. We observed that coimmunization with GM-CSF increased the antibody response and resulted in a significant enhancement of lymphoproliferative response. Furthermore, among all coinjection combinations, we found that M-CSF coinjections resulted in a high level of CTL enhancement. This enhancement of CTL responses observed from the coinjection with M-CSF was CD8+ T cell dependent and was associated with the presence of CD11c+ cells at the site of injection and with the antigen-specific induction of the beta-chemokine MIP-1beta, suggesting a role for this chemokine in CTL induction. These results suggest that hematopoietic growth factors should be further studied as potential adjuvants for in vivo modulators of immune responses.

Effects of external beam radiation on the allograft dermal implant.

OBJECTIVE: The purpose of this study was to define the effects of external beam radiation (EBR) on AlloDerm (LifeCell Corp) through the analysis of graft thickness, fibroblast recellularization, and neovascularization as a function of time. METHODS AND MATERIAL: Thirty-six male Sprague-Dawley rats (n = 36) were randomly assigned to 1 of 4 groups (A, B, C, and D). AlloDerm was implanted subcutaneously into the hind legs of each rat, and 20 Gy of EBR was administered to one side. Grafts harvested 1, 2, 4, and 12 weeks after radiation were subjected to blinded histologic analysis. RESULTS: In groups A, B, and C, the irradiated grafts showed a significant decrease in recellularization versus nonirradiated (P < 0.001). At 12 weeks (group D), recellularization equalized, but neovascularization was significantly less (P = 0.048) in the irradiated group. Graft thickness was unaffected. CONCLUSIONS: In the rat model, EBR of the implanted AlloDerm graft hinders recellularization in the early posttreatment period. However, EBR did not adversely affect graft thickness, recellularization or ultimate graft survival.

Clinical care pathways: decreasing resource utilization in head and neck surgical patients.

In this era of decreasing reimbursement, health systems have been forced to become more efficient and decrease resource utilization to remain financially viable. One of the methods of internal cost control has been the use of clinical pathways. Given the complexity of treatment of head and neck cancer patients, clinical pathways can help to standardize decision making and introduce uniformity in resource utilization. The objective of this study is to compare resource utilization and outcomes before and after implementation of a clinical pathway for head and neck surgical patients. We observed significant decreases in hospital costs as well as shorter lengths of stay after pathway implementation. It is our belief that a uniform management tool is beneficial in this complex disease.

Detection of recurrent head and neck squamous cell carcinomas after radiation therapy with 2-18F-fluoro-2-deoxy-D-glucose positron emission tomography.

OBJECTIVES/HYPOTHESIS: Fluorodeoxyglucose positron emission tomography (FDG-PET) has been proposed as a sensitive method to diagnose and stage various malignancies. We assessed the efficacy of FDG-PET imaging in distinguishing tumor persistence/recurrence from posttreatment changes following radiation therapy for squamous carcinomas of the head and neck STUDY DESIGN: Retrospective analysis of FDG-PET results compared with biopsy results or outcome, or both. METHODS: Twenty-eight patients who had undergone radiation therapy with or without surgery for treatment of squamous cell carcinoma were studied with FDG-PET imaging. There was clinical suspicion for recurrence in each patient, but no obvious mass or lesion to biopsy was found on physical examination or anatomic imaging. The results of FDG-PET imaging were compared with those of biopsy or clinical follow-up of at least 6 months, or both. RESULTS: FDG-PET imaging was positive in 13 patients, and the presence of active disease was confirmed in 12. Two thirds of the 12 received further cancer treatment. There were 15 negative FDG-PET images. Thirteen of these were confirmed true-negative images, but two studies were false-negative images. The sensitivity and specificity of FDG-PET were 86% and 93%, respectively, with positive and negative predictive values of 92% and 87%, respectively. The overall accuracy was 89%. CONCLUSION: FDG-PET imaging is a useful modality to distinguish tumor persistence/recurrence from radiation-induced tissue changes in the neck following treatment for head and neck cancer. FDG-PET can identify patients who may benefit from further treatment, and may lead to improved outcome for individual patients.

Nerve cell adhesion molecule expression in squamous cell carcinoma of the head and neck: a predictor of propensity toward perineural spread.

OBJECTIVE: To evaluate head and neck squamous cell carcinomas (SCCAs) for the expression of nerve cell adhesion molecule (N-CAM). We propose that expression of N-CAM by tumor cells may be associated with perineural invasion in SCCA of the head and neck. METHODS: Seventy-six archived specimens of histologically proven SCCA were analyzed by immunohistochemistry for the expression of N-CAM. Positive and negative controls were used to assess staining. Two sections of each specimen were reviewed for the presence of perineural invasion. A retrospective chart review was performed for each patient that corresponded to the above specimens. RESULTS: Perineural invasion was present in 28 (37%) of the 76 patients evaluated for the expression of N-CAM. N-CAM expression was demonstrated in 38 (50%) of the 76 specimens. The incidence of N-CAM expression was significantly associated with perineural invasion (P = .002). There was no significant association between the presence of staining or the presence of perineural invasion and the incidence of locoregional recurrence, distant metastasis, or survival status; however, the mean follow-up was only 13.6 months (range, 1-49 mo). CONCLUSION: There is a positive correlation between the presence of N-CAM expression and perineural invasion in SCCA of the head and neck. The expression of this adhesion molecule by tumor cells may facilitate both homophilic cell-to-cell and heterophilic cell-to-substrate adhesion, thereby enabling the tumor cells to use the perineural tissues or neural cells, or both as a conduit for perineural spread.

Malignant tumors of the nose and paranasal sinuses: hospital of the University of Pennsylvania experience 1990-1997.

We reviewed our experience with sinonasal malignancies, which comprise less than 1% of all cancers, in order to determine the spectrum of disease and outcome after treatment. The medical records of 48 patients with sinonasal malignancies treated between 1990-1997 were reviewed for epidemiologic characteristics, tumor location and histology, treatment modalities, and tumor recurrence. Mean age was 58.5 years and 46% were male. Multiple sites of origin were common, including maxillary sinus (83%), ethmoid sinus (35%), and nasal cavity (40%). The histologic spectrum included squamous cell carcinoma (46%), adenoid cystic carcinoma (6%), and miscellaneous others (48%). Treatment included surgery and adjuvant radiotherapy (XRT) (58%), surgery alone (27%), XRT and chemotherapy (6%), surgery and chemotherapy (4%), and XRT alone (4%). Mean follow-up was 15 months (range 2-58). Recurrence was evident in nine patients (19%), 3 (33%) of whom had prior treatment before presenting to HUP. Of the six who recurred after initial treatment at HUP, five (83.3%) were treated with surgery and XRT and one (16.7%) was treated with surgery alone. Of the three that recurred after undergoing attempts at salvage (prior treatment and then treatment at HUP), one had received surgery alone followed by surgery and XRT, one had surgery and XRT followed by surgery and one had XRT followed by surgery alone. Our experience reveals surgery and XRT to be the modality of choice, particularly for advanced tumors, whereas surgery alone may be sufficient for small, well localized tumors. Neoadjuvant chemotherapy may offer improved local control; the future role of endoscopic surgery warrants further investigation.

Seven-week continuous-infusion paclitaxel concurrent with radiation therapy for locally advanced non-small cell lung and head and neck cancers.

The goal of these National Cancer Institute-sponsored phase I trials is to determine the feasibility, toxicity, and pharmacokinetics of continuous-infusion (24 hr/d, 7 d/wk, 7 weeks total) intravenous paclitaxel combined with standard, curative-intent thoracic radiation therapy (XRT) for previously untreated, locally advanced non-small cell lung cancer and squamous cell cancer of the head and neck (HNSCC). Eligible patients have locally advanced (T4NXM0 or TXN2-3M0) non-small cell lung cancer ineligible for potentially curative surgical resection or locally advanced HNSCC with an expected 5-year survival rate of less than 25%, as well as a good performance status, adequate hematologic, hepatic, and renal function, and no distant metastases. Non-small cell lung cancer patients receive a total tumor dose of 64.8 Gy megavoltage XRT in 7 weeks at 1.8 Gy once daily, 5 d/wk. Patients with HNSCC receive 70 Gy megavoltage XRT in 7 weeks at 2 Gy once daily, 5 d/wk. Paclitaxel is delivered by continuous intravenous infusion starting 48 hours before XRT and continuing for its duration. The dose of paclitaxel is escalated in cohorts of three patients in a standard phase I design. To date, 49 patients have been entered on both studies and 43 are evaluable for toxicity. Paclitaxel dose is currently at the 17 mg/m2/d dose level, with no dose-limiting toxicity thus far. Clinical outcomes suggest significant activity for this combination. This therapy is feasible and has been well-tolerated through current dose levels. Dose escalation is ongoing.

CD86 (B7-2) can function to drive MHC-restricted antigen-specific CTL responses in vivo.

Activation of T cells requires both TCR-specific ligation by direct contact with peptide Ag-MHC complexes and coligation of the B7 family of ligands through CD28/CTLA-4 on the T cell surface. We recently reported that coadministration of CD86 cDNA along with DNA encoding HIV-1 Ags i.m. dramatically increased Ag-specific CTL responses. We investigated whether the bone marrow-derived professional APCs or muscle cells were responsible for the enhancement of CTL responses following CD86 coadministration. Accordingly, we analyzed CTL induction in bone marrow chimeras. These chimeras are capable of generating functional viral-specific CTLs against vaccinia virus and therefore represent a useful model system to study APC/T cell function in vivo. In vaccinated chimeras, we observed that only CD86 + Ag + MHC class I results in 1) detectable CTLs following in vitro restimulation, 2) detectable direct CTLs, 3) enhanced IFN-gamma production in an Ag-specific manner, and 4) dramatic tissue invasion of T cells. These results support that CD86 plays a central role in CTL induction in vivo, enabling non-bone marrow-derived cells to prime CTLs, a property previously associated solely with bone marrow-derived APCs.

Intracellular adhesion molecule-1 modulates beta-chemokines and directly costimulates T cells in vivo.

The potential roles of adhesion molecules in the expansion of T cell-mediated immune responses in the periphery were examined using DNA immunogen constructs as model antigens. We coimmunized cDNA expression cassettes encoding the adhesion molecules intracellular adhesion molecule-1 (ICAM-1), lymphocyte function associated-3 (LFA-3), and vascular cell adhesion molecule-1 (VCAM-1) along with DNA immunogens, and we analyzed the resulting antigen-specific immune responses. We observed that antigen-specific T-cell responses can be enhanced by the coexpression of DNA immunogen and adhesion molecules ICAM-1 and LFA-3. Coexpression of ICAM-1 or LFA-3 molecules along with DNA immunogens resulted in a significant enhancement of T-helper cell proliferative responses. In addition, coimmunization with pCICAM-1 (and more moderately with pCLFA-3) resulted in a dramatic enhancement of CD8-restricted cytotoxic T-lymphocyte responses. Although VCAM-1 and ICAM-1 are similar in size, VCAM-1 coimmunization did not have any measurable effect on cell-mediated responses. These results suggest that ICAM-1 and LFA-3 provide direct T-cell costimulation. These observations are further supported by the finding that coinjection with ICAM-1 dramatically enhanced the level of interferon-gamma (IFN-gamma) and beta-chemokines macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and regulated on activation normal T-cell expression and secreted (RANTES) produced by stimulated T cells. Through comparative studies, we observed that ICAM-1/LFA-1 T-cell costimulatory pathways are independent of CD86/CD28 pathways and that they may synergistically expand T-cell responses in vivo.

Cytokine molecular adjuvants modulate immune responses induced by DNA vaccine constructs for HIV-1 and SIV.

DNA or nucleic acid immunization has been shown to induce both antigen-specific cellular and humoral immune responses in vivo. Moreover, immune responses induced by DNA immunization can be enhanced and modulated by the use of molecular adjuvants. To further engineer the immune response in vivo, we investigated the induction and regulation of immune responses from the codelivery of Thl cytokines (interleukin-2 [IL-2] and IL-12), Th2 cytokines (IL-4 and IL-10), and granulocyte-macrophage colony-stimulating factor (GM-CSF) genes along with a DNA vaccine construct encoding for simian immunodeficiency virus (SIV) gag/pol proteins. We observed that coinjection with IL-2, IL-4, IL-10, and GM-CSF resulted in increased levels of antigen-specific antibodies. In addition, we found that coinjection with cytokine genes drove the immune responses toward a more Thl or Th2 phenotype. We also observed that coadministration of IL-2, IL-12, and GM-CSF genes resulted in a dramatic enhancement of Th proliferation responses. Moreover, coimmunization with IL-12 genes resulted in a dramatic enhancement of antigen-specific cytotoxic T lymphocyte (CTL) responses. These results support the potential utility of molecular adjuvants in DNA vaccine regimens.

A phase I trial of 96-hour paclitaxel infusion plus accelerated radiotherapy of unrespectable head and neck cancer.

PURPOSE: To determine the maximum tolerated dose (MTD) of paclitaxel given as a 96-hour continuous infusion during Weeks 1 and 5 of an accelerated radiotherapy schedule for the definitive treatment of advanced (nonmetastatic) unresectable squamous cell carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: Thirteen patients with Stage IV SCCHN were enrolled. Radiotherapy consisted of 70-72 Gy over 6 weeks, with a fractionation scheme of 2 Gy q.d. for 4 weeks followed by 1.6 Gy b.i.d. for 2 weeks, with no planned interruptions. Paclitaxel was administered over a 96-hour continuous infusion during Weeks 1 and 5 of radiotherapy at the following dose levels: Dose Level 1: 40 mg/m(2)/96-hours (3 patients); Dose Level 2: 80 mg/m(2)/96-hrs (5 patients); Dose Level 3: 120 mg/m(2)/96-hours (2 patients); and Dose Level 2A: 100 mg/m(2)/96-hours (3 patients). RESULTS: The MTD of Paclitaxel was 100 mg/m(2)/96-hours. All but one patient (who experienced progressive disease after receiving 61 Gy and both cycles of paclitaxel) completed therapy as planned. Dose-limiting toxicity occurred in both patients enrolled at Dose Level 3, with one patient experiencing Grade 4 diffuse moist desquamation and the other patient experiencing Grade 4 mucositis and febrile neutropenia. Thus, Dose Level 2A was opened and no dose limiting toxicity was noted. Grade 3 non-dose limiting mucositis and dermatitis occurred at all paclitaxel dose levels. There were no treatment-related deaths. All Grade 3 and 4 toxicities were reversible. Complete responses were seen in 8 of 13 patients, 4 patients achieved partial responses, and 1 patient had no response/progressive disease. CONCLUSIONS: Infusional paclitaxel over 96 hours during Weeks 1 and 5 of this accelerated radiotherapy schedule is feasible. The MTD of paclitaxel in this protocol was 100 mg/m(2)/96-hours. Dose-limiting toxicities were primarily enhanced epithelial reactions, but febrile neutropenia also occurred. All patients develop non-dose limiting Grade 3 skin and mucosal reactions, reflecting the high treatment intensity. This regimen merits further investigation.