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Biomedical subjects

Paul M Harari

Publications and source records attributed to Paul M Harari.

At least 19 recordsLinked to original sources
PubMed2007

Planned postradiotherapy neck dissection: Rationale and clinical outcomes.

OBJECTIVES: In this study, we examine pathology results and clinical outcome for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) who present with advanced neck disease and undergo planned postradiotherapy neck dissection. STUDY DESIGN: Review of all patients with SCCHN treated with primary radiation (or chemoradiation) and postradiotherapy neck dissection at the University of Wisconsin between 1992 to 2005 was performed. One hundred seven neck dissections were identified in 93 patients, 79 unilateral and 14 bilateral. All major treatment and outcome parameters were examined with particular emphasis on the postradiotherapy neck dissection. RESULTS: Thirty of 107 neck dissection specimens (28%) showed evidence of residual carcinoma on pathologic review. The mean number of lymph nodes identified at neck dissection for the entire cohort was 21 per specimen (range, 1-60) with 1.3 nodes per positive neck dissection demonstrating residual carcinoma. No correlation was found between the type of neck dissection performed and the presence of residual nodal disease. Eighty-two evaluated patients (93%) remain free of regional disease recurrence, whereas six patients have subsequently manifested neck recurrence. Four of the six patients who developed regional recurrence showed residual carcinoma in their neck dissection specimen. Five of these patients underwent comprehensive neck dissection (levels I-V); one underwent selective neck dissection (<levels I-V). CONCLUSION: Approximately one-fourth of the patients in this series showed pathologic evidence of residual carcinoma in the neck at the time of postradiotherapy neck dissection. The majority of these cases showed microscopic residual carcinoma in a single lymph node. Although in the early postradiotherapy setting, we cannot accurately predict the viability and growth potential of microscopic residual carcinoma in lymph nodes, these findings, combined with the modest overall morbidity of selective neck dissection, suggest that planned postradiotherapy neck dissection should be strongly considered for patients presenting with advanced neck disease. This remains a prevailing clinical practice at our institution.

Aged↗
PubMed2006

Impact of conventional radiotherapy on health-related quality of life and critical functions of the head and neck.

PURPOSE: Head-and-neck radiotherapy is associated with significant morbidities. Our purpose was to document impact of morbidities by use of multiple objective measures and health-related quality of life (HR-QOL). METHODS AND MATERIALS: Ten head-and-neck cancer patients were evaluated before receiving conventional head-and-neck radiotherapy and at 1 month and 6 months after treatment. We evaluated weight, saliva production, diet, swallow function, auditory function, and HR-QOL. RESULTS: After radiotherapy, weight was reduced in 89% of subjects. Salivary function was significantly reduced and did not resolve by 6 months. Diet impairment and abnormalities in swallowing function persisted at 6 months. Perception of physical functioning was reduced after treatment, and swallowing, coughing, and dry-mouth symptoms increased. Very few changes were observed in auditory function. CONCLUSIONS: Conventional head-and-neck radiotherapy is associated with substantial functional deficits and diminished HR-QOL. Deficits reported here can serve as a baseline for comparison with results derived from new radiotherapy-treatment techniques.

Aged↗
PubMed2006

Augmentation of radiation response with the vascular targeting agent ZD6126.

PURPOSE: To examine the antivascular and antitumor activity of the vascular targeting agent ZD6126 in combination with radiation in lung and head-and-neck (H and N) cancer models. The overall hypothesis was that simultaneous targeting of tumor cells (radiation) and tumor vasculature (ZD6126) might enhance tumor cell killing. METHODS AND MATERIALS: A series of in vitro studies using human umbilical vein endothelial cells (HUVEC) and in vivo studies in athymic mice bearing human lung (H226) and H and N (squamous cell carcinoma [SCC]1, SCC6) tumor xenografts treated with ZD6126 and/or radiation were performed. RESULTS: ZD6126 inhibited the capillary-like network formation in HUVEC. Treatment of HUVEC with ZD6126 resulted in cell cycle arrest in G2/M, with decrease of cells in S phase and proliferation inhibition in a dose-dependent manner. ZD6126 augmented the cell-killing effect of radiation and radiation-induced apoptosis in HUVEC. The combination of ZD6126 and radiation further decreased tumor vascularization in an in vivo Matrigel angiogenesis assay. In tumor xenografts, ZD6126 enhanced the antitumor activity of radiation, resulting in tumor growth delay. CONCLUSIONS: These preclinical studies suggest that ZD6126 can augment the radiation response of proliferating endothelial H and N and lung cancer cells. These results complement recent reports suggesting the potential value of combining radiation with vascular targeting/antiangiogenic agents.

Angiogenesis Inhibitors↗
PubMed2006

Enhancing the antitumor activity of ErbB blockade with histone deacetylase (HDAC) inhibition.

Molecular inhibition of the ErbB signaling pathway represents a promising cancer treatment strategy. Preclinical studies suggest that enhancement of antitumor activity can be achieved by maximizing ErbB signaling inhibition. Using cDNA microarrays, we identified histone deacetylase (HDAC) inhibitors as having strong potential to enhance the effects of anti-ErbB agents. Studies using a 20,000 element (20K) cDNA microarray demonstrate decreased transcript expression of ErbB1 (epidermal growth factor receptor) and ErbB2 in DU145 (prostate) and ErbB2 in SKBr3 (breast) cancer cell lines. Additional changes in the DU145 gene expression profile with potential interaction to ErbB signaling include down-regulation of caveolin-1 and hypoxia inducible factor 1-alpha (HIF1-alpha), and up-regulation of gelsolin, p19(INK4D) and Nur77. Findings were validated using real time RT-PCR and Western blot analysis. Enhanced proliferative inhibition, apoptosis induction and signaling inhibition were demonstrated when combining HDAC inhibition with ErbB blockade. These results suggest that used cooperatively, anti-ErbB agents and HDAC inhibitors may offer a promising strategy of dual targeted therapy. Additionally, microarray data suggest that the beneficial interaction of these agents may not derive solely from modulation of ErbB expression, but may result from effects on other oncogenic processes including angiogenesis, invasion and cell cycle kinetics.

Apoptosis↗
PubMed2006

Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.

BACKGROUND: We conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck. METHODS: Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy. The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety. RESULTS: The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (hazard ratio for locoregional progression or death, 0.68; P=0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P=0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P=0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups. CONCLUSIONS: Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. (ClinicalTrials.gov number, NCT00004227.)

Adult↗
PubMed2006

Biologic basis for combining drugs with radiation.

Concurrent administration of radiation and chemotherapy has emerged as a dominant form of cancer treatment. Nevertheless, our understanding of the specific mechanisms of interaction between radiation and chemotherapy is still evolving. Biological evidence gained in experimental cell lines and tumors suggests that cisplatin lesions cause repair inhibition of radiation-induced DNA damage affecting both homologous recombination and nonhomologous end joining. In the case of 5-fluorouracil (5-FU), the crucial event in the radiosensitisation process appears to be inappropriate progression through S-phase in the presence of bound drug affecting both DNA repair and cell cycle. In similar fashion, data with gemcitabine suggest that radiosensitization arises through progression into S-phase causing depletion of 2'-deoxyadenosine 5'-triphosphate pools, which leads to misincorporation and misrepair of incorrect bases in irradiated cells. As the new molecular-targeted agents become increasingly available to complement established radiation and chemoradiation treatment regimens, new concepts of drug-radiation interaction are evolving that require innovative thinking regarding the manner in which radiation and drugs cooperate and how clinical trials are best performed.

Biological Phenomena↗
PubMed2006

Radiation combined with EGFR signal inhibitors: head and neck cancer focus.

Molecular inhibition of epidermal growth factor receptor (EGFR) signaling represents one of the most promising current arenas for the advancement of molecularly targeted cancer therapies. A series of EGFR inhibitors from both the monoclonal antibody (mAb) and tyrosine kinase inhibitor (TKI) class have shown clear clinical activity in the treatment of several common human cancers. Three EGFR inhibitors have recently gained Food and Drug Administration (FDA) approval for cancer therapy in the United States including the mAb cetuximab (Erbitux) and the small-molecule TKIs gefitinib (Iressa) and erlotinib (Tarceva). The rapidly expanding preclinical and clinical data contributing to these FDA approvals validate a central role of the EGFR as an important molecular target in epithelial malignancies. Indeed, one of the more striking clinical results in this field has been recently achieved by combining an EGFR inhibitor (cetuximab) with radiation in the treatment of advanced head and neck cancer patients. Nevertheless, the overall clinical gains realized to date with the EGFR inhibitors are modest for the global cancer population. Much remains to be learned regarding the rational integration of EGFR inhibitors into cancer treatment regimens as well as methods to optimize the selection of patients most likely to benefit from EGFR inhibitor strategies.

Antibodies, Monoclonal↗
PubMed2006

Radiation and new molecular agents, part II: targeting HDAC, HSP90, IGF-1R, PI3K, and Ras.

Current research efforts in cancer therapeutics include the development of novel inhibitory agents that target molecular pathways involved in tumor growth and progression. Ultimately, many of these agents may prove most efficacious when combined with conventional cytotoxic therapies, including radiation therapy. Elucidation of the biologic pathways underlying radiation response has identified several targets involved in radiation resistance, providing rationale for combining these agents with radiation. Agents targeting single pathways, including EGFR, IGF-1R, PI3K, and Ras, have been studied alone and in combination with radiation. Although this strategy is increasingly supported by preclinical and clinical data, the single-target approach may be limited by such factors as tumor heterogeneity and genetic instability. Emerging approaches include multipathway-targeted therapy by either combining target-specific agents or using single agents that target multiple pathways, including HDAC and HSP90 inhibitors. These approaches reviewed herein hold promise for improved radiation therapy efficacy and, ultimately, improved patient outcome.

Antineoplastic Agents↗
PubMed2006

Introduction.

Explore the source record for details and available documents.

Combined Modality Therapy↗
PubMed2006

Clinical implementation of adaptive helical tomotherapy: a unique approach to image-guided intensity modulated radiotherapy.

Image-guided IMRT is a revolutionary concept whose clinical implementation is rapidly evolving. Methods of executing beam intensity modulation have included individually designed compensators, static multi-leaf collimators (MLC), dynamic MLC, and sequential (serial) tomotherapy. We have developed helical tomotherapy as an innovative solution to overcome some of the limitations of other IMRT systems. The unique physical design of helical tomotherapy allows the realization of the concepts of adaptive radiotherapy and conformal avoidance. In principle, these advances should improve normal tissue sparing and permit dose reconstruction and verification, thereby allowing significant biologically effective dose escalation. Recent radiobiological findings can be translated into altered fractionation schemes that aim to improve the local control and long-term survival. This strategy is being tested at the University of Wisconsin using helical tomotherapy with its highly precise delivery and verification system along with meticulous and practical forms of immobilization. Innovative techniques such optical guidance, respiratory gating, and ultrasound assessments are being designed and tailored for helical tomotherapy use. The intrinsic capability of helical tomotherapy for megavoltage CT (MVCT) imaging for IMRT image-guidance is being optimized. The unique features of helical tomotherapy might allow implementation of image-guided IMRT that was previously impossible or impractical. Here we review the technological, physical, and radiobiological rationale for the ongoing and upcoming clinical trials that will use image-guided IMRT in the form of helical tomotherapy; and we describe our plans for testing our hypotheses in a rigorous prospective fashion.

Humans↗
PubMed2006

Clinical advancement of EGFR inhibitors in cancer therapy.

The epidermal growth factor receptor (EGFR) represents one of the most promising molecular targets in cancer therapeutics. An array of EGFR inhibitory drugs have been developed that are progressing rapidly in oncology clinical trials. This chapter provides an overview of EGFR inhibitors and key clinical trial results that are helping to define a future role for these molecular agents in cancer treatment.

Clinical Trials as Topic↗
PubMed2006

EGFR-targeting monoclonal antibodies in head and neck cancer.

The epidermal growth factor (EGF) and its receptor were discovered nearly 40 years ago. Over the past decade interruption of this pathway has been exploited in the treatment of various solid tumors. Antibodies that interfere with ligand binding to and dimerization of the EGFR (and small molecules that inhibit the EGFR tyrosine kinase) are anti-proliferative, radiosensitizing, and synergistic with DNA-damaging cytotoxic agents. Proposed mechanisms of radio- and chemosensitization include enhanced apoptosis, interference with DNA repair and angiogenesis, receptor depletion from the cell surface and antibody-dependent cell-mediated cytotoxicity. This article provides the reader with a comprehensive review of EGFR-targeting antibodies under development for the treatment of head and neck squamous cell cancer (HNSCC) and also summarizes relevant clinical data in this disease with small molecule EGFR inhibitors. One of the monoclonal antibodies, cetuximab, recently received full FDA approval for the treatment of patients with locoregionally advanced (with radiation) or metastatic HNSCC (as a single agent). Regulatory approval followed reporting of a large international study in which the addition of cetuximab to definitive radiation therapy in HNSCC resulted in statistically significant improvements in locoregional control and overall survival. Results of the pivotal trial, other clinical data supporting the regulatory approval, and a preview of the next generation of clinical trials are presented. Considerable work remains to be done, particularly to enhance our understanding of factors that may predict for favorable response to EGFR inhibitor therapy and to evaluate the impact of integrating anti-EGFR therapies into complex chemoradiation programs delivered with curative intent.

Antibodies, Monoclonal↗
PubMed2005

Angiogenesis and radiation response modulation after vascular endothelial growth factor receptor-2 (VEGFR2) blockade.

The formation of new blood vessels (angiogenesis) represents a critical factor in the malignant growth of solid tumors and metastases. Vascular endothelial cell growth factor (VEGF) and its receptor VEGFR2 represent central molecular targets for antiangiogenic intervention, because of their integral involvement in endothelial cell proliferation and migration. In the current study, we investigated in vitro and in vivo effects of receptor blockade on various aspects of the angiogenic process using monoclonal antibodies against VEGFR2 (cp1C11, which is human specific, and DC101, which is mouse specific). Molecular blockade of VEGFR2 inhibited several critical steps involved in angiogenesis. VEGFR2 blockade in endothelial cells attenuated cellular proliferation, reduced cellular migration, and disrupted cellular differentiation and resultant formation of capillary-like networks. Further, VEGFR2 blockade significantly reduced the growth response of human squamous cell carcinoma xenografts in athymic mice. The growth-inhibitory effect of VEGFR2 blockade in tumor xenografts seems to reflect antiangiogenic influence as demonstrated by vascular growth inhibition in an in vivo angiogenesis assay incorporating tumor-bearing Matrigel plugs. Further, administration of VEGFR2-blocking antibodies in endothelial cell cultures, and in mouse xenograft models, increased their response to ionizing radiation, indicating an interactive cytotoxic effect of VEGFR2 blockade with radiation. These data suggest that molecular inhibition of VEGFR2 alone, and in combination with radiation, can enhance tumor response through molecular targeting of tumor vasculature.

Animals↗
PubMed2005

Modulation of radiation response by histone deacetylase inhibition.

PURPOSE: Histone deacetylase (HDAC) inhibitors, which modulate chromatin structure and gene expression, represent a class of anticancer agents that hold particular potential as radiation sensitizers. In this study, we examine the capacity of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) to modulate radiation response in human tumor cell lines and explore potential mechanisms underlying these interactions. METHODS AND MATERIALS: Cell proliferation: Exponentially growing tumor cells were incubated in medium containing 0-10 microM of SAHA for 72 h. Cells were fixed/stained with crystal violet to estimate cell viability. Apoptosis: Caspase activity was analyzed by fluorescence spectroscopy using a fluorescein labeled pan-caspase inhibitor. Cells were harvested after 48 h of exposure to SAHA (1.0 microM), radiation (6 Gy), or the combination. Whole cell lysates were evaluated for poly(ADP-ribose) polymerase (PARP) cleavage by western blot analysis. Radiation survival: Cells were exposed to varying doses of radiation +/- 3 days pretreatment with SAHA (0.75-1.0 microM). After incubation intervals of 14-21 days, colonies were stained with crystal violet and manually counted. Immunocytochemistry: Cells were grown and treated in chamber slides. At specified times after treatment with SAHA, cells were fixed in paraformaldehyde, permeabilized in methanol, and probed with primary and secondary antibody solutions. Slides were analyzed using an epifluorescent microscope. RESULTS: SAHA induced a dose-dependent inhibition of proliferation in human prostate (DU145) and glioma (U373vIII) cancer cell lines. Exposure to SAHA enhanced radiation-induced apoptosis as measured by caspase activity (p < 0.05) and PARP cleavage. The impact of SAHA on radiation response was further characterized using clonogenic survival analysis, which demonstrated that treatment with SAHA reduced tumor survival after radiation exposure. We identified several oncoproteins and DNA damage repair proteins (epidermal growth factor receptor, AKT, DNA-PK, and Rad51) that show differential expression after exposure to SAHA. These proteins may contribute to mechanistic synergy between HDAC inhibition and radiation response. CONCLUSION: These preclinical results suggest that treatment with the HDAC inhibitor SAHA can enhance radiation-induced cytotoxicity in human prostate and glioma cells. We are examining the capacity of HDAC inhibitors to modulate radiation response and tumor control in animal xenograft model systems to strengthen the rationale for future clinical trial exploration.

Apoptosis↗
PubMed2005

Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva).

Erlotinib (Tarceva) is an orally available HER1 (epidermal growth factor receptor, EGFR) tyrosine kinase inhibitor advancing through clinical trials for the treatment of a range of human malignancies. In this study, we examine the capacity of erlotinib to modulate radiation response and investigate specific mechanisms underlying these interactions in human tumor cell lines and xenografts. The impact of erlotinib on cell cycle kinetics was analyzed using flow cytometry, and the impact on apoptosis was evaluated via fluorescein-labeled pan-caspase inhibition and poly(ADP-ribose) polymerase cleavage. Radiation-induced EGFR autophosphorylation and Rad51 expression were examined by Western blot analysis. Radiation survival was analyzed using a clonogenic assay and assessment of in vivo tumor growth was done using a mouse xenograft model system. Microarray studies were carried out using 20 K human cDNA microarray and select genes were validated using quantitative reverse transcription-PCR (RT-PCR). Independently, erlotinib and radiation induce accumulation of tumor cells in G(1) and G(2)-M phase, respectively, with a reduction of cells in S phase. When combined with radiation, erlotinib promotes a further reduction in S-phase fraction. Erlotinib enhances the induction of apoptosis, inhibits EGFR autophosphorylation and Rad51 expression following radiation exposure, and promotes an increase in radiosensitivity. Tumor xenograft studies confirm that systemic administration of erlotinib results in profound tumor growth inhibition when combined with radiation. cDNA microarray analysis assessing genes differentially regulated by erlotinib following radiation exposure identifies a diverse set of genes deriving from several functional classes. Validation is confirmed for several specific genes that may influence radiosensitization by erlotinib including Egr-1, CXCL1, and IL-1beta. These results identify the capacity of erlotinib to enhance radiation response at several levels, including cell cycle arrest, apoptosis induction, accelerated cellular repopulation, and DNA damage repair. Preliminary microarray data suggests additional mechanisms underlying the complex interaction between EGFR signaling and radiation response. These data suggest that the erlotinib/radiation combination represents a strategy worthy of further examination in clinical trials.

Animals↗
PubMed2005

The impact of daily setup variations on head-and-neck intensity-modulated radiation therapy.

PURPOSE: Intensity-modulated radiation therapy (IMRT) in the treatment of head-and-neck (H&N) cancer provides the opportunity to diminish normal tissue toxicity profiles and thereby enhance patient quality of life. However, highly conformal treatment techniques commonly establish steep dose gradients between tumor and avoidance structures. Daily setup variations can therefore significantly compromise the ultimate precision of idealized H&N IMRT delivery. This study provides a detailed analysis regarding the potential impact of daily setup variations on the overall integrity of H&N IMRT. METHODS AND MATERIALS: A series of 10 patients with advanced H&N cancer were prospectively enrolled in a clinical trial to examine daily H&N radiation setup accuracy. These patients were treated with conventional shrinking field design using three-dimensional treatment planning techniques (not IMRT). Immobilization and alignment were performed using modern H&N practice techniques including conventional thermoplastic masking, baseplate fixation to the treatment couch, three-point laser alignment, and weekly portal film evaluation. After traditional laser alignment, setup accuracy was assessed daily for each patient by measuring 3 Cartesian and 3 angular deviations from the specified isocenter using a high-precision, optically guided patient localization system, which affords submillimeter setup accuracy. These positional errors were then applied to a distinct series of 10 H&N IMRT plans for detailed analysis regarding the impact of daily setup variation (without optical guidance) on the ultimate integrity of IMRT plans over a 30-day treatment course. Dose-volume histogram (DVH), equivalent uniform dose (EUD), mean total dose (mTd), and maximal total dose (MTD) for normal structures were analyzed for IMRT plans with and without incorporation of daily setup variation. RESULTS: Using conventional H&N masking and laser alignment for daily positioning, the mean setup error in any single dimension averaged 3.33 mm. However, when all six degrees of freedom were accounted for, using the optically guided patient localization system, the mean composite vector offset was 6.97 mm with a standard deviation of 3.63 mm. Superimposition of mean offset vectors on idealized H&N IMRT treatment plans enabled evaluation of resultant shifts in DVH, EUD, mTd, and MTD calculations. Partial geographic tumor miss (GTV underdosing) and normal tissue overdosing was common when these mean positional offsets were incorporated. The decrease in EUD for defined tumor volumes ranged up to 21% when the largest offset histories were applied, and 3-14% for plans when the least and median offset histories were applied. CONCLUSION: The successful implementation of H&N IMRT requires accurate and reproducible treatment delivery over a 6- to 7-week treatment course. The adverse impact of daily setup variation, which occurs routinely with conventional H&N masking techniques, may be considerably greater than recognized. Isocenter verification checks on two-dimensional orthogonal films may not sufficiently alert the clinician to the magnitude of three-dimensional offset vectors and the resultant impact on the quality of overall IMRT delivery. Unrecognized geographic miss and resultant target underdose may occur. Similarly, selected normal structures such as parotid glands may receive higher doses than intended. The results of this study suggest that more rigorous immobilization techniques than conventional masking and routine patient setup tracking methodologies are important for the accurate monitoring and successful delivery of high-quality IMRT for H&N cancer.

Aged↗