Prospective study of exclusive strontium-/yttrium-90 beta-irradiation of primary and recurrent pterygia with no prior surgical excision. Clinical outcome of long-term follow-up.

PURPOSE: To evaluate the consecutive treatment results regarding pterygium recurrence and the efficacy of exclusive strontium-/yttrium-90 beta-irradiation for primary and recurrent pterygia and to analyze the functional outcome. PATIENTS AND METHODS: Between October 1974 and December 2005, 58 primary and 21 recurrent pterygia were exclusively treated with strontium-/yttrium-90 beta-irradiation with doses ranging from 3,600 to 5,500 cGy. The follow-up time was 46.6 +/- 26.7 months, with a median of 46.5 months. RESULTS: The treatment led to a size reduction in all pterygia (p < 0.0001). Neither recurrences nor side effects were observed during therapy and follow-up in this study. Best-corrected visual acuity increased (p = 0.0064). Corneal astigmatism was reduced in recurrent pterygia (p = 0.009). CONCLUSION: Exclusive strontium-/yttrium-90 beta-irradiation of pterygia is a very efficient and well-tolerated treatment, with remarkable aesthetic and rehabilitative results in comparison to conventional treatments, especially for recurrent lesions which have undergone prior surgical excision.

Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer.

BACKGROUND: We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer. METHODS: After undergoing surgery with curative intent, 167 patients were randomly assigned to receive radiotherapy alone (66 Gy over a period of 6 1/2 weeks) and 167 to receive the same radiotherapy regimen combined with 100 mg of cisplatin per square meter of body-surface area on days 1, 22, and 43 of the radiotherapy regimen. RESULTS: After a median follow-up of 60 months, the rate of progression-free survival was significantly higher in the combined-therapy group than in the group given radiotherapy alone (P=0.04 by the log-rank test; hazard ratio for disease progression, 0.75; 95 percent confidence interval, 0.56 to 0.99), with 5-year Kaplan-Meier estimates of progression-free survival of 47 percent and 36 percent, respectively. The overall survival rate was also significantly higher in the combined-therapy group than in the radiotherapy group (P=0.02 by the log-rank test; hazard ratio for death, 0.70; 95 percent confidence interval, 0.52 to 0.95), with five-year Kaplan-Meier estimates of overall survival of 53 percent and 40 percent, respectively. The cumulative incidence of local or regional relapses was significantly lower in the combined-therapy group (P=0.007). The estimated five-year cumulative incidence of local or regional relapses (considering death from other causes as a competing risk) was 31 percent after radiotherapy and 18 percent after combined therapy. Severe (grade 3 or higher) adverse effects were more frequent after combined therapy (41 percent) than after radiotherapy (21 percent, P=0.001); the types of severe mucosal adverse effects were similar in the two groups, as was the incidence of late adverse effects. CONCLUSIONS: Postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications.

Increased invasive potential and up-regulation of MMP-2 in MDA-MB-231 breast cancer cells expressing the beta3 integrin subunit.

Integrins are a family of transmembrane adhesion receptors that might transduce signals from the extracellular matrix into the inside of cells after ligand binding. In order to investigate whether beta3 integrins expressed in tumor cells might mediate such outside-in signaling, human MDA-MB-231 breast cancer cells that were stably transfected with either beta3 integrin or mock-transfected were investigated in a matrigel degradation assay and a grafting experiment was performed on the developing chicken chorioallantoic membrane (CAM). After cultivation on matrigel for time periods between one and five days, more matrigel was digested in the wells in which beta3 integrin expressing cells were incubated than in wells of mock-transfected cells. Furthermore, extracts of beta3 integrin expressing cells contained higher levels of MMP-2 protein as determined by immunoblotting and more MMP-2 associated gelatinase activity as detected by zymography than extracts of mock-transfected cells. Matrigel degradation and gelatinase activity as well as MMP-2 expression were elevated when beta3 integrin expressing cells were incubated in the presence of the RGD peptide (mimicking an integrin ligand). After grafting on 10 day-old embryonic chicken CAM for three to five days, beta3 integrin expressing cells assembled in spheroids showed higher rates of spreading on the CAM surface and CAM invasion as well as a significant MMP-2 up-regulation compared to mock-transfected cells. The results from the in vivo and in vitro experiments allow the conclusion that the presence of beta3 integrin in MDA-MB-231 breast cancer cells induced an increased MMP-2 expression and activity that might contribute to the enhanced invasive potential observed.

Breast cancer and human papillomavirus (HPV) infection: no evidence of a viral etiology in a group of Swiss women.

There are controversial data on the meaning of viral induction of breast cancer. The aim of this study was to investigate the presence of human papillomavirus (HPV) DNA in patients with breast carcinoma and the correlation of viral infection with disease outcome. Paraffin-embedded sections from 81 patients with breast cancer were analyzed for HPV DNA by polymerase chain reaction (PCR) using the SPF1/2 primers covering about 40 different low-, intermediate- and high-risk types. We found all samples were negative for HPV DNA. Our analysis could not support a role of HPV in breast carcinoma. Controversial published data indicate a need for further, larger epidemiologic studies.

Impact of viral E2-gene status on outcome after radiotherapy for patients with human papillomavirus 16-positive cancer of the uterine cervix.

PURPOSE: Integration of high-risk papillomavirus DNA has been considered an important step in oncogenic progression to cervical carcinoma. Disruption of the human papillomavirus (HPV) genome within the E2 gene is frequently a consequence. This study investigated the influence of episomal viral DNA on outcome in patients with advanced cervical cancer treated with primary radiotherapy. METHODS AND MATERIALS: Paraffin-embedded biopsies of 82 women with locally advanced cervical cancer could be analyzed for HPV infection by multiplex polymerase chain reaction (PCR) by use of SPF1/2 primers. E2-gene intactness of HPV-16-positive samples was analyzed in 3 separate amplification reactions by use of the E2A, E2B, E2C primers. Statistical analyses (Kaplan-Meier method; log-rank test) were performed for overall survival (OS), disease-free survival (DFS), local progression-free survival (LPFS), and distant metastases-free survival (DMFS). RESULTS: Sixty-one (75%) of 82 carcinomas were HPV positive, 44 of them for HPV-16 (72%). Seventeen of the 44 HPV-16-positive tumors (39%) had an intact E2 gene. Patients with a HPV-16-positive tumor and an intact E2 gene showed a trend for a better DFS (58% vs. 38%, p = 0.06) compared with those with a disrupted E2 gene. A nonsignificant difference occurred regarding OS (87% vs. 66%, p = 0.16) and DMFS (57% vs. 48%, p = 0.15). CONCLUSION: E2-gene status may be a promising new target, but more studies are required to elucidate the effect of the viral E2 gene on outcome after radiotherapy in HPV-positive tumors.

Daily organ tracking in intensity-modulated radiotherapy of prostate cancer using an electronic portal imaging device with a dose saving acquisition mode.

BACKGROUND AND PURPOSE: Daily use of conventional electronic portal imaging devices (EPID) for organ tracking is limited due to the relatively high dose required for high quality image acquisition. We studied the use of a novel dose saving acquisition mode (RadMode) allowing to take images with one monitor unit per image in prostate cancer patients undergoing intensity-modulated radiotherapy (IMRT) and tracking of implanted fiducial gold markers. PATIENTS AND METHODS: Twenty five patients underwent implantation of three fiducial gold markers prior to the planning CT. Before each treatment of a course of 37 fractions, orthogonal localization images from the antero-posterior and from the lateral direction were acquired. Portal images of both the setup procedure and the five IMRT treatment beams were analyzed. RESULTS: On average, four localization images were needed for a correct patient setup, resulting in four monitor units extra dose per fraction. The mean extra dose delivered to the patient was thereby increased by 1.2%. The procedure was precise enough to reduce the mean displacements prior to treatment to < o =0.3 mm. CONCLUSIONS: The use of a new dose saving acquisition mode enables to perform daily EPID-based prostate tracking with a cumulative extra dose of below 1 Gy. This concept is efficiently used in IMRT-treated patients, where separation of setup beams from treatment beams is mandatory.

Postoperative radiation therapy for T1 and T2 primary parotid carcinoma: is it useful?

OBJECTIVE: The benefit of postoperative radiation for advanced primary parotid carcinoma has been reported previously, whereas studies to evaluate the usefulness of postoperative radiation for T1 and T2 parotid carcinomas have never been performed. STUDY DESIGN AND SETTING: Retrospective analysis on 58 previously untreated patients with T1 and T2 parotid carcinomas. In 34 patients, postoperative radiation was included in the treatment protocol and in 24 patients, no postoperative radiation was applied. RESULTS: A local recurrence was observed in 8 of 24 (33%) patients without and in 1 of 34 (3%) patients with postoperative radiation (P < 0.5). The 5-year actuarial and disease-free survival rate was 83% and 70% for patients without postoperative radiation and 93% and 92% for patients with postoperative radiation. CONCLUSION AND SIGNIFICANCE: Local recurrence was less often observed in patients with postoperative radiation. Nevertheless, prospective randomized studies are needed to confirm the usefulness of postoperative radiation in early carcinomas. EBM RATING: B-3b.

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.

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 microM 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.

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.

Long term results of non-surgical, exclusive strontium-/yttrium-90 beta-irradiation of pterygia.

BACKGROUND AND PURPOSE: To evaluate long term results and to demonstrate safety and efficacy of non-surgical, exclusive strontium-/yttrium-90 beta irradiation of non-operated pterygia. PATIENTS AND METHODS: Between March 1977 and April 1999, 43 patients with 54 primary pterygia were treated with an exclusive strontium-/yttrium-90 beta-irradiation up to a total dose of 50 Gy divided in four fractions with one week apart. All patients were referred from the same ophthalmologist. The average follow-up were 112(+/-88 months (range, 12-321 months), median 96 months. RESULTS: The patients were referred with early symptomatic manifestations of pterygia with a mean horizontal diameter of 1.6+/-0.7 mm (range, 0.5-4.5 mm), which shrank to a mean diameter of 0.9+/-0.6 mm (range, 0-2.5 mm) after irradiation (P<0.005). There was a reduction of size in every pterygium, none of the 54 pterygia developed a recurrent growth and there were no patient with any late side effect. Following the strontium-/yttrium-90 application the process came up with an obliteration of the vessels, which resulted in a grey, thin and avascular pannus. CONCLUSIONS: Strontium-/yttrium-90 beta-irradiation as an exclusive, non-surgical treatment for early pterygia provides a significant reduction of the size of the irradiated pterygia, is a safe and effective therapy to prevent a recurrence and can be performed without late side effects.

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

BACKGROUND: Hypoxia-inducible factor 1 alpha (hif-1alpha) 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-1alpha expression in patients with node-positive breast cancer. METHODS: Tumor samples from 77 patients were available for immunohistochemistry. The impact of hif-1alpha immunoreactivity on survival endpoints was determined by univariate and multivariate analyses, and correlations to clinicopathological characteristics were determined by cross-tabulations. RESULTS: hif-1alpha 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-1alpha expression. The difference in overall survival (OS) did not attain statistical significance (5-year OS, 66% without hif-1alpha expression and 55% with hif-1alpha expression; P = 0.21). The multivariate analysis failed to reveal an independent prognostic value for hif-1alpha 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-1alpha expression was a significant parameter for DFS and DMFS. CONCLUSIONS: hif-1alpha 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.

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 (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.

Significant correlation of hypoxia-inducible factor-1alpha 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.

Expression of transforming growth factor-alpha, epidermal growth factor receptor and platelet-derived growth factors A and B in oropharyngeal cancers treated by curative radiation therapy.

BACKGROUND AND PURPOSE: Epidermal growth factor receptor (EGFR) has been implicated in cellular responses to ionizing radiation and represents a major target for current radiosensitizing strategies. We wished to ascertain whether a correlation existed between the expression of EGFR, transforming growth factor-alpha (TGFalpha) and platelet-derived growth factors A and B (PDGF-A and PDGF-B) and treatment outcome in a group of patients with oropharyngeal cancer who had undergone curative radiation therapy. We also assessed the relationship existing between each of the aforementioned proteins and intratumoral microvessel densities (IMD) which have been previously reported (Int J Radiat Oncol Biol Phys 2000;48:17-25. MATERIALS AND METHODS: Pretherapeutic tumor biopsies from 95 patients were immunohistochemically stained and their immunoreactivities evaluated semi-quantitatively. The statistical analyses included Cox regression for calculating risk ratios of survival endpoints and logistic regression for determining odds ratios for the development of distant metastasis. RESULTS: Local tumor control as well as disease-free and overall survival were independent of protein expression levels, whereas combined TGFalpha and EGFR immunoreactivities were closely related to IMD (P = 0.003). The expression levels of these two proteins were also correlated to each other (P = 0.015). Expression of PDGF-B occurred in 54% of cases and was associated with an increase in the risk of developing distant metastasis (P = 0.011). CONCLUSIONS: Tumoral levels of TGFalpha, EGFR and PDGF-A/B are not predictive of radioresponsiveness in oropharyngeal cancers. The association between IMD and immunoreactivity for TGFalpha and EGFR indicates the involvement of these proteins in the promotion of angiogenesis in these tumors. PDGF-B should be further evaluated as a prognostic marker for squamous cell cancer of the head and neck.

Long-term follow-up of concurrent radiotherapy and chemotherapy for locally advanced cervical cancer: 12-Year survival after radiochemotherapy.

Recently randomized trials show an overall survival advantage of 30% for cisplatin-based chemotherapy given concurrently with radiation therapy. Current data do not allow to conclude which drugs could be best combined with cisplatin. Here we report the very long-term results of a prospective phase II trial of concurrent radiochemotherapy in advanced cancer of the cervix. Psychological impact has been evaluated with long-term survivors. Patient with squamous cell carcinoma of the cervix FIGO stage IIB, III or IVA received a concomitant chemotherapy with cisplatin, fluorouracil and mitomycin C and radiotherapy. From June 1988 to September 1990, 22 of 23 patients were eligible. The overall response rate was 82%. All 22 patients treated showed acute hematological toxicity and two patients developed severe late bowel toxicity. Ten patients (45%) were alive after a median observation time of 145.5 months. Intolerance to certain food and vaginal changes due to radiotherapy remain problematic. The lack of improvement compared to cisplatin alone and late bowel toxicity do not support the use of mitomycin C in the combination of the concurrent treatment of chemoradiation. The psychological impact of this treatment should not be minimized. Most problems tend to diminish with time with the exception of intestinal side effects and vaginal changes.

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 institution's 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.

Differential inhibition sensitivities of MET mutants to the small molecule inhibitor SU11274.

Point mutations emerge as one of the rate-limiting steps in tumor response to small molecule inhibitors of protein kinases. Here we characterized the response of the MET mutated variants, V1110I, V1238I, V1206L and H1112L to the small molecule SU11274. Our results reveal a distinct inhibition pattern of the four mutations with IC(50) values for autophosphorylation inhibition ranging between 0.15 and 1.5muM. Differences were further seen on the ability of SU11274 to inhibit phosphorylation of downstream MET transducers such as AKT, ERK, PLCgamma and STAT3 and a variety of MET-dependent biological endpoints. In all the assays, H1112L was the most sensitive to SU11274, while V1206L was less affected under the used concentration range. The differences in responses to SU11274 are discussed based on a structural model of the MET kinase domain.

Prevention of radiochemotherapy-induced toxicity with amifostine in patients with malignant orbital tumors involving the lacrimal gland: a pilot study.

BACKGROUND: To use amifostine concurrently with radiochemotherapy (CT-RT) or radiotherapy (RT) alone in order to prevent dry eye syndrome in patients with malignancies located in the fronto-orbital region. METHODS: Five patients (2 males, 3 females) with diagnosed malignancies (Non-Hodgkin B-cell Lymphoma, neuroendocrine carcinoma) involving the lacrimal gland, in which either combined CT-RT or local RT were indicated, were prophylactically treated with amifostine (500 mg sc). Single RT fraction dose, total dose and treatment duration were individually adjusted to the patient's need. Acute and late adverse effects were recorded using the RTOG score. Subjective and objective dry eye assessment was performed for the post-treatment control of lacrimal gland function. RESULTS: All patients have completed CT-RT or RT as indicated. The median total duration of RT was 29 days (range, 23 - 39 days) and the median total RT dose was 40 Gy (range, 36 - 60 Gy). Median lacrimal gland exposure was 35.9 Gy (range, 16.8 - 42.6 Gy). Very good partial or complete tumor remission was achieved in all patients. The treatment was well tolerated without major toxic reactions. Post-treatment control did not reveal in any patient either subjective or objective signs of a dry eye syndrome. CONCLUSION: The addition of amifostine to RT/CT-RT of patients with tumors localized in orbital region was found to be associated with absence of dry eye syndrome.