Richard H. Greiner

The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants

Point mutations constitute a major mode of oncogenic activation of the Met receptor tyrosine kinase. Met is aberrantly activated in many types of human malignancies and its deregulated activity is correlated with aggressive tumor traits such as abnormal proliferation and survival, leading to tumor growth, local invasion and metastasis. Here we report that the Met kinase inhibitor SU11274 differentially affects the kinase activity and subsequent signaling of various mutant forms of Met. Two Met variants tested, M1268T and H1112Y, were potently inhibited by 2 μM SU11274, while two other variants, L1213V and Y1248H, remained resistant under similar experimental conditions. Inhibition of the kinase altered cell proliferation, morphology and motility, while cells containing resistant mutants appeared unaffected by the compound. The basis for the sensitivity or resistance to SU11274 is discussed in terms of the position of the mutations predicted from a homology model.

Carcinoma of the parotid gland

BACKGROUND: The low incidence and heterogeneity of histiotypes of primary parotid carcinomas makes these tumors histologically and epidemiologically difficult to evaluate. The present study reviews a single institutions experience in the treatment of primary parotid carcinomas during the last 10 years. METHODS: The charts of 98 consecutive patients who had a primary parotid carcinoma and who received primary curative treatment were analyzed retrospectively. The tumors were grouped into high-grade and low-grade malignancies. The effect of treatment modalities on locoregional control, the incidence of locoregional recurrences and distant metastases, and survival rates are evaluated and compared between high- and low-grade malignancies. RESULTS: High- and low-grade malignant tumors were observed in 50 and 48 cases, respectively. Lymph node metastases were detected in 25 of 98 (25%) patients, of whom 8 of 22 (22%) clinically NO staged patients underwent elective neck dissection. In 24 of 26 resected facial nerves, a histologic tumor infiltration was confirmed, in 14 high-grade and 10 low-grade tumors. Local recurrence developed in 13 patients and was associated in 7 with high-grade and in 6 with low-grade tumors. All but 1 of the low-grade malignancies with local recurrence did not receive postoperative irradiation. Regional recurrence developed in 11 patients and distant metastases developed in 10, 3 in combination with a neck recurrence and 1 with a local recurrence. The survival rate at 5 years for low- and high-grade carcinomas was 87% and 56% and the disease-free survival rate 72% and 48%, respectively. CONCLUSIONS: The incidence of occult metastases in clinically N0-elective neck dissection was 22%. A routine elective neck dissection in all N0 parotid carcinomas is suggested. There is no statistically significant difference between low- and high-grade tumors as for the rate of local recurrence and, as all except one of the low-grade malignancies with local recurrence did not receive postoperative irradiation, postoperative irradiation is not only suggested for high-grade carcinomas but also for T2 to T4 low-grade carcinomas.

Significant correlation of hypoxia-inducible factor-1α with treatment outcome in cervical cancer treated with radical radiotherapy

PURPOSE In the early stages of cervical cancer treated with surgery alone, hypoxia-inducible factor-1alpha (hif-1alpha) expression is prognostic for overall survival. Because hypoxia plays an important role in radiation resistance, we investigated hif-1alpha expression in cervical cancer treated with local radical radiotherapy (RT). METHODS AND MATERIALS Between 1990 and 1998, 91 patients with squamous cell or adenocarcinoma of the uterine cervix were treated with external beam RT with and without brachytherapy. Biopsies from 78 patients were available for immunohistochemistry. The impact of the immunoreactivity of hif-1alpha in regard to survival end points was determined by univariate and multivariate analyses. Correlations with clinicopathologic characteristics were determined by cross-tabulations. RESULTS Hif-1alpha was expressed in 73 (94%) of 78 patients. It was closely linked to the pretreatment hemoglobin level (p = 0.04, r = -0.22, Spearman correlation test). The Kaplan-Meier curves showed a significantly shorter local progression-free survival (p = 0.04, log-rank) and overall survival (p = 0.01, log-rank) and a trend for shorter disease-free survival (p = 0.15) for patients with increased hif-1alpha expression. The multivariate analyses revealed hif-1alpha expression to be an independent factor for overall survival (p = 0.02). CONCLUSION Hif-1alpha is expressed in the vast majority of patients with advanced cervical cancer and had a prognostic significance. A weak but significant correlation was noted with pretreatment hemoglobin level.

Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter?

BackgroundHypoxia-inducible factor 1 alpha (hif-1α) furnishes tumor cells with the means of adapting to stress parameters like tumor hypoxia and promotes critical steps in tumor progression and aggressiveness. We investigated the role of hif-1α expression in patients with node-positive breast cancer.MethodsTumor samples from 77 patients were available for immunohistochemistry. The impact of hif-1α immunoreactivity on survival endpoints was determined by univariate and multivariate analyses, and correlations to clinicopathological characteristics were determined by cross-tabulations.Resultshif-1α was expressed in 56% (n = 43/77) of the patients. Its expression correlated with progesterone receptor negativity (P = 0.002). The Kaplan–Meier curves revealed significantly shorter distant metastasis-free survival (DMFS) (P = 0.04, log-rank) and disease-free survival (DFS) (P = 0.04, log-rank) in patients with increased hif-1α expression. The difference in overall survival (OS) did not attain statistical significance (5-year OS, 66% without hif-1α expression and 55% with hif-1α expression; P = 0.21). The multivariate analysis failed to reveal an independent prognostic value for hif-1α expression in the whole patient group. The only significant parameter for all endpoints was the T stage (T3/T4 versus T1/T2: DMFS, relative risk = 3.16, P = 0.01; DFS, relative risk = 2.57, P = 0.03; OS, relative risk = 3.03, P = 0.03). Restricting the univariate and multivariate analyses to T1/T2 tumors, hif-1α expression was a significant parameter for DFS and DMFS.Conclusionshif-1α is expressed in the majority of patients with node-positive breast cancer. It can serve as a prognostic marker for an unfavorable outcome in those with T1/T2 tumors and positive axillary lymph nodes.

Intratumoral microvessel density predicts local treatment failure of radically irradiated squamous cell cancer of the oropharynx

PURPOSE To determine the predictive value of intratumoral microvessel density (IMD), and of the expression of p53, vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1) for the radiocurability of patients with squamous cell cancer of the oropharynx. MATERIALS AND METHODS 139 patients with squamous cell cancer of the oropharynx were radically irradiated (median dose, 74 Gy) between 1991 and 1997. Biopsies from 100 patients were processed for immunohistochemistry. IMD was determined in hot spot areas of tissue stained with anti-CD31 at a magnification of x200. Staining for p53 was considered positive if more than 10% of the cell nuclei overexpressed the protein. Immunostaining of VEGF and TSP-1 was assessed semiquantitatively. RESULTS Increasing IMD (range, 54-282) was strongly correlated with incomplete remission of both the primary tumors (p = 0.01) and lymph node metastases (p = 0.02). Moreover, multivariate Cox regression analysis revealed local failure-free survival to decline with increasing IMD (IMD continuous: risk ratio = 1.01 per increase of 1 microvessel, p = 0. 0001; IMD categorical: </= 80: baseline, 81-110: risk ratio = 2.71, 111-130: risk ratio = 4.55, > 130: risk ratio = 13.01). Neither the expression of p53, nor that of VEGF or TSP-1 was associated with the treatment outcome or IMD, but VEGF and TSP-1 expression were positively correlated (p = 0.02). CONCLUSION IMD represents a powerful and independent predictive factor for local treatment failure in radically irradiated patients with squamous cell cancer of the oropharynx.

Esthesioneuroblastoma: irradiation alone and surgery alone are not enough

PURPOSE To evaluate the long-term outcome of patients with esthesioneuroblastoma treated with neoadjuvant or definitive radiotherapy (RT). METHODS AND MATERIALS Between 1980 and 2001, 28 patients with histologically confirmed esthesioneuroblastoma underwent RT, with a median dose of 60 Gy (range 38-73). The median age was 58 years (range 16-85). According to the Kadish classification, 4 patients had Stage A, 8 Stage B, and 16 Stage C tumors. Radical resection was performed in 13 cases, in 9 before RT and in 4 after RT because of stable or progressive disease. The outcome analyses included the median age (58 years), Kadish stage, skull base penetration, intraorbital extension, resection status, and total dose (<or=60 vs. >60 Gy). RESULTS After a mean follow-up of 68 months, 54% of patients were free of tumor progression. The 5- and 10-year local progression-free survival rate was 81% and 51%, respectively, and the disease-free survival rate was 70% and 25%, respectively. Four of ten deaths (4/10) were intercurrent, resulting in a cause-specific survival of 77% and 69% at 5 and 10 years, respectively. Radical resection offered significantly better local progression-free survival and disease-free survival (p <0.02). Skull base penetration (p <0.04), intraorbital extension (p <0.04), and Kadish C stage (p <0.06) were important for impaired disease-free survival. CONCLUSION Despite doses up to 73 Gy, radical RT cannot replace radical resection, which classifies esthesioneuroblastoma as rather radioresistant. Because of its biology and the high rates of late recurrence, we recommend a radical strategy with resection, high-dose RT, and simultaneous chemotherapy. We are aware that some tumors qualify for palliative treatment only.

Prevalence and clinical impact of Met Y1253D-activating point mutation in radiotherapy-treated squamous cell cancer of the oropharynx

Aberrant signalling through the hepatocyte growth factor/scatter factor receptor Met has been implicated in various aspects of the development of human cancer including the promotion of tumour invasion, angiogenesis and metastasis. Moreover, experimental data indicate that activation of the Met receptor may be involved in cellular resistance towards antineoplastic treatments such as chemotherapy and ionizing radiation. We determined the prevalence and clinical impact of the Met-activating mutation Y1253D in patients with squamous cell cancer of the oropharynx treated by radical radiotherapy. To screen archival tissue for the presence of a low-abundance point mutation, we developed a sensitive screening method using real-time polymerase chain reaction along with peptide nucleic acid-based DNA clamping and melting curve analysis. By this approach, Met Y1253D was detected in tumours of 15 out of 138 patients (10.9%). Both univariate and multivariate survival analysis revealed Met Y1253D to be significantly associated with impaired local tumour control. Our results provide evidence that the Met-activating mutation Y1253D is present in a notable subset of patients with oropharyngeal cancer and indicate that it may interfere with radioresponsiveness of these tumours, supporting the notion of aberrant Met signalling as a potential target for radiosensitization.

Late acute thrombotic occlusion after endovascular brachytherapy and stenting of femoropopliteal arteries

OBJECTIVES The aim of this article is to underline the importance of this complication after endovascular brachytherapy (EVBT) and intravascular stenting of the femoropopliteal arteries occurring in a running randomized trial. BACKGROUND Endovascular brachytherapy has been proposed as a promising treatment modality to reduce restenosis after angioplasty. However, the phenomenon of late acute thrombotic occlusion (LATO) in patients receiving EVBT after stenting is of major concern. METHODS In an ongoing prospective multicenter trial, patients were randomized to undergo EVBT (iridium 192; 14 Gy at a depth of the radius of the vessel +2 mm) after percutaneous recanalization of femoropopliteal obstructions. Of the 204 patients who completed the six months follow-up, 94 were randomized to EVBT. RESULTS Late acute thrombotic occlusion occurred exclusively in 6 of 22 patients (27%) receiving EVBT after intravascular stenting and always in concomitance with reduction of antithrombotic drug prevention (clopidogrel). Conversely, none of the 13 patients with stents and without EVBT (0%; p < 0.05) and none of the 72 patients (0%; p < 0.01) undergoing EVBT after simple balloon angioplasty presented LATO. CONCLUSIONS Late thrombotic occlusion occurs not only in patients undergoing EVBT after percutaneous coronary recanalization but also after stenting of the femoropopliteal arteries and may compromise the benefits of endovascular radiation. The fact that all our cases with LATO occurred concomitantly with stopping clopidogrel may indicate a possible rebound mechanism. An intensive and prolonged antithrombotic prevention is probably indicated in these patients.

MRI of Merkel Cell Carcinoma: Histologic Correlation and Review of the Literature

OBJECTIVE The objective of this study was to determine the MRI characteristics of Merkel cell carcinoma, with an emphasis on histologic correlation. MATERIALS AND METHODS The demographic information about 15 patients from our institution and their MRI examinations were retrospectively reviewed by three musculoskeletal radiologists by consensus for lesion location and intrinsic characteristics. The study group was composed of three women and 12 men who ranged in age from 48 to 87 years, with a mean age of 75 years. Histology results of resected specimens were reviewed in all cases and were correlated with imaging. RESULTS MRI showed skin thickening, subcutaneous reticular stranding (n = 9, 60%); multiple anatomically aligned subcutaneous soft-tissue masses, representing lymphatic tumor nodules (n = 5, 33%); lymph node enlargement with fine, compressed, retained fatty tissue (n = 5, 33%); nodal necrosis (n = 1); and perifascial and intramuscular metastases (n = 2). Histology confirmed the lymphatic nature of the soft-tissue Merkel cell tumors. CONCLUSION Patients with Merkel cell tumors may present at imaging with subcutaneous lymphatic reticular stranding, multiple subcutaneous masses, and lymph node metastases. Often there is massive lymph node enlargement with fine, compressed, retained fatty tissue.

Endovascular brachytherapy after femoropopliteal balloon angioplasty fails to show robust clinical benefit over time.

Purpose: To determine if the short-term efficacy of adjunctive endovascular brachytherapy (EVBT) is maintained over time in patients undergoing balloon angioplasty (BA) of femoropopliteal atherosclerotic lesions. Methods: To evaluate the long-term clinical and angiographic outcome of EVBT, 147 consecutive patients (82 men; mean age 70.8±8.5 years) with 147 treated limbs were randomized to BA with (n=72, 49%) or without (n=75, 51%) adjunctive EVBT (12 or 14-Gy from an 192Ir source, no centering, a 5-mm reference depth). Sixty-eight (46%) limbs were treated for de novo and 79 (54%) for recurrent femoropopliteal lesions. Clinical follow-up at 1, 3, 6, and 12 months and annually thereafter included evaluation of symptoms, ankle-brachial index (ABI), and intra-arterial angiography for new/worsening symptoms or at follow-up between 2 and 5 years. Sustained clinical success was defined as improvement in ABI ≥0.1 and/or of symptoms without repeated target lesion revascularization. Angiographic restenosis was defined as ≥50% diameter reduction. Subgroup analysis was performed for de novo versus recurrent lesions. Results: Mean clinical follow-up was 32.3±21.5 months. Angiographic follow-up was available in 83 (56%) patients (41 BA and 42 BA+EVBT) at a mean 31.8±20.7 months. Cumulative sustained clinical success rates at 1, 2, and 3 years, respectively, were 84.3%, 82.1%, and 76.4% after BA versus 82.4%, 69.8%, and 67.5% after BA+EVBT (p=0.26 by log-rank). Although the proportion of patients undergoing follow-up angiography was moderate, the freedom from angiographic restenosis at 1, 2, and 3 years was 70.7%, 63.1%, and 47.1% after BA versus 82.7%, 64.3%, and 64.3% after BA+EVBT (p=0.16 by log-rank). No differences were found between BA and BA+EVBT outcomes in patients with de novo versus recurrent femoropopliteal lesions. Conclusion: The seemingly beneficial short-term effects of BA+EVBT are not sustained in the longer term, with no robust clinical improvement after angioplasty of atherosclerotic de novo or recurrent femoropopliteal lesions at up to 5 years.