Phase II study of the antiangiogenesis agent thalidomide in recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Thalidomide has been shown to have antiangiogenic effects in preclinical models as well as a significant antitumor effect in hematologic tumors such as multiple myeloma. The authors performed this Phase II study to determine the activity, toxicity profile, and antiangiogenic effect of thalidomide in patients with locoregionally recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS: Twenty-one patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with single-agent thalidomide. All patients had received radiation therapy, and most had undergone surgery (95%) and/or chemotherapy (90%). Thalidomide was initiated at 200 mg;3>daily and increased to a target dose of 1000 mg daily. Patients continued treatment until disease progression, unacceptable toxicity, or death occurred. RESULTS: All 21 patients eventually developed progressive disease. Median time to progression was 50 days (95% confidence interval, 28-70), with median overall survival time of 194 days (95% lower confidence boundary, 151), similar to the progression and survival times reported for this patient group with other agents. Thalidomide was generally well tolerated, with few patients experiencing Grades 3 to 4 toxicities. Serum vascular endothelial growth factor and basic fibroblast growth factor levels increased in six of seven patients, for whom paired serum samples were available and all of whom had progressive disease. CONCLUSIONS: In this heavily pretreated population of patients with advanced squamous cell carcinoma of the head and neck, thalidomide does not appear to have single-agent antitumor activity. Further evaluation of the mechanism of action of thalidomide is indicated. Potentially, future evaluations of thalidomide may be performed in combination with other antiangiogenic or cytotoxic agents in patients with earlier stage disease or in patients with minimal residual disease.

In vivo calibration of a femoral fixation device transducer for measuring anterior cruciate ligament graft tension: a study in an ovine model.

Toward developing a transducer for measuring in vivo tension in anterior cruciate ligament grafts in humans, the objectives of this study were to determine the following: (1) whether the calibration of a previously reported femoral fixation device transducer (FDT) (Ventura et al., 1998) is affected by the presence of the graft when implanted in the tibial metaphysis of an ovine model, (2) whether the FDT remains calibrated at 4 weeks postoperatively, and (3) whether the biological incorporation of the graft occurs prior to a change in the FDT calibration. The FDT was implanted in the hind limb of five sheep using an extra-articular procedure. Both the proximal common digital extensor tendon (i.e., graft) and a Teflon-coated wire were looped around the FDT inside a tunnel in the tibial metaphysis. The FDT was calibrated on three occasions using the loop of wire: once intraoperatively before graft insertion, once intraoperatively after graft insertion, and once postoperatively after the animals had been sacrificed at 4 weeks. Following sacrifice, the load transmitted to the FDT by the graft was also determined. The FDT exhibited linear calibration intraoperatively both before and after graft insertion with an average error relative to the calibration before insertion of the graft of -4.6 percent of full-scale load (150 N) and this average relative error was not significantly different from zero (p = 0.183). After 4 weeks of implantation, the average relative percent error was -5.0 percent and was not significantly different from zero (p = 0.434) indicating that the FDT remained calibrated in the in vivo environment. Because only 15 percent of the graft tension was transmitted to the FDT after 4 weeks, biological incorporation of the graft preceded the loss of calibration. In light of these findings, the FDT offers the capability of measuring the intra-articular ACL graft tension in vivo in animal models and possibly humans before the biological bond develops and also of monitoring the formation and maturation of the biological bond between a graft and bone tunnel.

Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer.

C225, a human-mouse chimerized monoclonal antibody directed against the epidermal growth factor receptor (EGFr), has a synergistic effect with cisplatin in xenograft models. To determine the tumor EGFr saturation dose with C225 and the fate of infused C225, we conducted a Phase Ib study with C225 in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck. Using tumor samples, we assessed tumor EGFr saturation by antibody using immunohistochemistry studies, the EGFr tyrosine kinase assay, and detection of the EGFr/C225 complex formation by immunoblot. Potential candidates were screened for EGFr expression in their tumors, and 12 patients who had high levels of EGFr expression and tumors easily accessible for repeated biopsies (pretherapy, 24 h after first C225 infusion, 24 h before third C225 infusion) were entered at three different dose levels of C225 with a fixed dose of cisplatin. The median value of tumor EGFr saturation increased to 95% at the higher dose levels. EGFr tyrosine kinase activity was significantly reduced after C225 infusion, and EGFr/C225 complexes were also detected at higher doses of C225. The loading dose of C225 at 400 mg/m(2) with a maintenance dose at 250 mg/m(2) achieved a high percentage of saturation of EGFr in tumor tissue, and these doses were recommended for Phases II or III clinical trials. Six (67%) of nine evaluable patients achieved major responses, including two (22%) complete responses. Mild to moderate degrees of allergic reaction and folliculitis-like skin reactions were demonstrated. We conclude that infused C225 binds and significantly saturates tumor EGFr, which may render a high degree of antitumor activity, and provides a novel mechanism for targeting cancer therapy for patients who have EGFr expression in their tumors.

Bone contusion patterns of the knee at MR imaging: footprint of the mechanism of injury.

Bone marrow contusions are frequently identified at magnetic resonance imaging after an injury to the musculoskeletal system. These osseous injuries may result from a direct blow to the bone, from compressive forces of adjacent bones impacting one another, or from traction forces that occur during an avulsion injury. The distribution of bone marrow edema is like a footprint left behind at injury, providing valuable clues to the associated soft-tissue injuries. Five contusion patterns with associated soft-tissue injuries occur in the knee: pivot shift injury, dashboard injury, hyperextension injury, clip injury, and lateral patellar dislocation. The classic bone marrow edema pattern seen following the pivot shift injury involves the posterolateral tibial plateau and the midportion of the lateral femoral condyle. Edema occurs in the anterior aspect of the proximal tibia following the dashboard injury. Hyperextension results in the "kissing" contusion pattern involving the anterior aspect of the proximal tibia and distal femur. The clip injury results in a prominent area of edema involving the lateral femoral condyle and a smaller area of edema involving the medial femoral condyle. Finally, lateral patellar dislocation results in edema involving the inferomedial patella and anterior aspect of the lateral femoral condyle. In many instances, the mechanism of injury can be determined by studying the distribution of bone marrow edema, which then enables one to predict with accuracy the specific soft-tissue abnormalities that are likely to be present.

Oblique meniscomeniscal ligament: another potential pitfall for a meniscal tear--anatomic description and appearance at MR imaging in three cases.

Three patients with an arthroscopically proved normal variant, the oblique meniscomeniscal ligament, underwent prospective magnetic resonance (MR) imaging of the knee. In the first case, the ligament was misinterpreted as a displaced flap tear of the posterior horn of the lateral meniscus. In the two subsequent cases, the ligament was identified correctly at MR imaging as the oblique meniscomeniscal ligament.

Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma.

PURPOSE: To assess the activity and toxicity profile of combined taxol (paclitaxel), ifosfamide, and platinum (cisplatin) (TIP) in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck. PATIENTS AND METHODS: Recurrent or metastatic head and neck SCC patients received paclitaxel 175 mg/m2 in a 3-hour infusion on day 1; ifosfamide 1,000 mg/m2 in a 2-hour infusion on days 1 through 3; mesna 600 mg/m2 on days 1 through 3; and cisplatin 60 mg/m2 on day 1, repeated every 3 to 4 weeks. All were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic hematopoietic growth factors were not permitted. RESULTS: Fifty-two patients were assessable for response and toxicity; 53 for survival (local-regional recurrence alone in 57% and distant metastasis with or without local-regional recurrence in 43%). Overall response rate was 58% (30 of 52) of patients; complete response rate was 17% (nine of 52) of patients, with six complete responses that continued for a median 15.7+ months. Median follow-up of all patients was 17.7 months. Median survival was 8.8 months (95% confidence interval [CI] 8.1 to 17.5 months). Toxicity was relatively well tolerated and caused no deaths. The most frequent moderate-to-severe toxicity (90% of patients) was transient grades 3 to 4 neutropenia; neutropenic fever occurred in 27%. Grade 3 peripheral neuropathy occurred in three patients, none had grade 4. Grade 3 mucositis occurred in only one patient, none had grade 4. CONCLUSION: TIP had major activity in this setting, with a 58% objective response rate, 17% complete response rate, durable complete responses (six of nine persisting), and relatively well-tolerated toxicity, with no toxic deaths. The activity of TIP, a novel taxol-cisplatin-based regimen, in recurrent or metastatic head and neck SCC should be confirmed in a phase III trial.

The effect of tibiotalar fixation on foot biomechanics.

Contact areas and peak pressures in the posterior facet of the subtalar and the talonavicular joints were measured in cadaver lower limbs for both the normal limb and after fixation of the tibiotalar joint. Six joints were fixed in neutral, in 5-7 degrees of varus and of valgus. Ten degrees of equinus angulation was also studied. Each position of fixation was tested independently. Neutral was defined as fixation without coronal or sagittal plane angulation compared with prefixation alignment of the specimen. When compared with normal unfused condition, peak pressures increased, and contact areas decreased in the subtalar joint for specimens fixed in neutral, varus, and valgus. However, the change in peak pressure for neutral fusion compared with normal control was not statistically significant (P > 0.07). Peak pressures for varus and valgus fixation were significantly different from normal (P < 0.001). Contact areas for all positions of fixation were significantly different from normal (P < 0.001). Coronal plane angulation, however, also resulted in significantly lower contact areas compared with neutral fixation (P < 0.001). Contact areas and peak pressures in the talonavicular joint did not appear to be substantially affected by tibiotalar fixation with coronal plane angulation. Equinus fixation qualitatively increased contact areas and peak pressures in the talonavicular and posterior facet of the subtalar joint. Neutral alignment of the tibiotalar joint in the coronal and sagittal planes altered subtalar and talonavicular joint contact characteristics the least compared with normal controls. Therefore, ankle fusion in the neutral position would be expected to most closely preserve normal joint biomechanics and may limit the progression of degenerative arthrosis of the subtalar joint.

Recent advances in paclitaxel-containing chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck.

Current chemotherapeutic approaches to recurrent or metastatic head and neck cancer have yielded response rates of 10% to 20% for single agents and 30% to 40% for combination chemotherapy. Median survival for patients with recurrent or metastatic disease treated with single agents or combination chemotherapy is between 4 and 6 months. Investigation of new drugs, therefore, has high priority among clinicians and researchers. One new agent that has been effective as single-agent therapy is paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). We tested the combination of paclitaxel, ifosfamide, and cisplatin in recurrent or metastatic head and neck cancer. The starting dose of paclitaxel was 175 mg/m2 as a 3-hour infusion on day 1, ifosfamide 1 g/m2 as a 2-hour infusion on days 1 to 3, and cisplatin 60 mg/m2 via 2-hour infusion on day 1. This schedule was repeated every 3 weeks. Sixty-five patients were entered into the study and 62 patients are currently evaluable for response and toxicity in the phase I and phase II portions of this study. We observed 10 (16%) complete responses and 24 (39%) partial responses. The overall response rate was 55% in phases I/II of this interim analysis. In the phase II part alone, we have observed eight (16%) complete responses and 22 (44%) partial responses to date among 50 evaluable patients. Median survival times were 8.9 months for all patients and 9.7 months for patients in the phase II part of the study. Preliminary results demonstrate significant antitumor activity in patients with recurrent or metastatic head and neck cancer. The paclitaxel/ifosfamide/cisplatin regimen was well tolerated. Chemotherapy with paclitaxel/ifosfamide/cisplatin should be tested as an induction regimen in patients with locally advanced head and neck cancer. It also warrants testing in a randomized setting to compare it with a standard regimen, such as the combination of 5-fluorouracil and cisplatin.