Guenther Gruber

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.

Boost radiotherapy in young women with ductal carcinoma in situ: a multicentre, retrospective study of the Rare Cancer Network

BACKGROUND Outcome data in young women with ductal carcinoma in situ (DCIS) are rare. The benefits of boost radiotherapy in this group are also unknown. We aimed to assess the effect of boost radiotherapy in young patients with DCIS. METHODS We included 373 women from 18 institutions who met the following inclusion criteria: having tumour status Tis and nodal status (N)0, age 45 years or younger at diagnosis, and having had breast-conserving surgery. 57 (15%) patients had no radiotherapy after surgery, 166 (45%) had radiotherapy without boost (median dose 50 Gy [range 40-60]), and 150 (40%) had radiotherapy with boost (60 Gy [53-76]). The primary outcome was local relapse-free survival. FINDINGS Median follow-up was 72 months (range 1-281). 55 (15%) patients had local relapse. Local relapse-free survival at 10 years was 46% (95% CI 24-67) for patients given no radiotherapy, 72% (61-83) for those given radiotherapy without boost, and 86% (78-93) for those given radiotherapy and boost (difference between all three groups, p<0.0001). Age, margin status, and radiotherapy dose were significant predictors of local relapse-free survival. Compared with patients who had no radiotherapy, those who had radiotherapy had a decreased risk of local relapse (without boost, hazard ratio 0.33 [95% CI 0.16-0.71], p=0.004; with boost, 0.15 [0.06-0.36], p<0.0001). INTERPRETATION In the absence of randomised trials, boost radiotherapy should be considered in addition to surgery for breast-conserving treatment for DCIS.

Tumor Recovery by Angiogenic Switch from Sprouting to Intussusceptive Angiogenesis after Treatment with PTK787/ZK222584 or Ionizing Radiation

Inhibitors of angiogenesis and radiation induce compensatory changes in the tumor vasculature both during and after treatment cessation. To assess the responses to irradiation and vascular endothelial growth factor-receptor tyrosine kinase inhibition (by the vascular endothelial growth factor tyrosine kinase inhibitor PTK787/ZK222854), mammary carcinoma allografts were investigated by vascular casting; electron, light, and confocal microscopy; and immunoblotting. Irradiation and anti-angiogenic therapy had similar effects on the tumor vasculature. Both treatments reduced tumor vascularization, particularly in the tumor medulla. After cessation of therapy, the tumor vasculature expanded predominantly by intussusception with a plexus composed of enlarged sinusoidal-like vessels containing multiple transluminal tissue pillars. Tumor revascularization originated from preserved alpha-smooth muscle actin-positive vessels in the tumor cortex. Quantification revealed that recovery was characterized by an angiogenic switch from sprouting to intussusception. Up-regulated alpha-smooth muscle actin-expression during recovery reflected the recruitment of alpha-smooth muscle actin-positive cells for intussusception as part of the angio-adaptive mechanism. Tumor recovery was associated with a dramatic decrease (by 30% to 40%) in the intratumoral microvascular density, probably as a result of intussusceptive pruning and, surprisingly, with only a minimal reduction of the total microvascular (exchange) area. Therefore, the vascular supply to the tumor was not severely compromised, as demonstrated by hypoxia-inducible factor-1alpha expression. Both irradiation and anti-angiogenic therapy cause a switch from sprouting to intussusceptive angiogenesis, representing an escape mechanism and accounting for the development of resistance, as well as rapid recovery, after cessation of therapy.

Postoperative Proton Radiotherapy for Localized and Locoregional Breast Cancer: Potential for Clinically Relevant Improvements?

PURPOSE To study the potential reduction of dose to organs at risk (OARs) with intensity-modulated proton radiotherapy (IMPT) compared with intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) photon radiotherapy for left-sided breast cancer patients. METHODS AND MATERIALS Comparative treatment-planning was performed using planning computed tomography scans of 20 left-sided breast cancer patients. For each patient, three increasingly complex locoregional volumes (planning target volumes [PTVs]) were defined: whole breast (WB) or chest wall (CW) = (PTV1), WB/CW plus medial-supraclavicular (MSC), lateral-supraclavicular (LSC), and level III axillary (AxIII) nodes = (PTV2) and WB/CW+MSC+LSC+AxIII plus internal mammary chain = (PTV3). For each patient, 3D-CRT, IMRT, and IMPT plans were optimized for PTV coverage. Dose to OARs was compared while maintaining target coverage. RESULTS All the techniques met the required PTV coverage except the 3D-CRT plans for PTV3-scenario. All 3D-CRT plans for PTV3 exceeded left-lung V20. IMPT vs. 3D-CRT: significant dose reductions were observed for all OARs using IMPT for all PTVs. IMPT vs. IMRT: For PTV2 and PTV3, low (V5) left lung and cardiac doses were reduced by a factor >2.5, and cardiac doses (V22.5) were by a factor of >20 lower with IMPT compared with IMRT. CONCLUSIONS When complex-target irradiation is needed, 3D-CRT often compromises the target coverage and increases the dose to OARs; IMRT can provide better results but will increase the integral dose. The benefit of IMPT is based on improved target coverage and reduction of low doses to OARs, potentially reducing the risk of late-toxicity. These results indicate a potential role of proton-radiotherapy for extended locoregional irradiation in left breast cancer.

Outcome and prognostic factors in olfactory neuroblastoma: a rare cancer network study.

PURPOSE To assess the outcome in patients with olfactory neuroblastoma (ONB). METHODS AND MATERIALS Seventy-seven patients treated for nonmetastatic ONB between 1971 and 2004 were included. According to Kadish classification, there were 11 patients with Stage A, 29 with Stage B, and 37 with Stage C. T-classification included 9 patients with T1, 26 with T2, 16 with T3, 15 with T4a, and 11 with T4b tumors. Sixty-eight patients presented with N0 (88%) disease. RESULTS Most of the patients (n = 56, 73%) benefited from surgery (S), and total excision was possible in 44 patients (R0 in 32, R1 in 13, R2 in 11). All but five patients benefited from RT, and chemotherapy was given in 21 (27%). Median follow-up period was 72 months (range, 6-315). The 5-year overall survival (OS), disease-free survival (DFS), locoregional control, and local control were 64%, 57%, 62%, and 70%, respectively. In univariate analyses, favorable factors were Kadish A or B disease, T1-T3 tumors, no nodal involvement, curative surgery, R0/R1 resection, and RT-dose 54 Gy or higher. Multivariate analysis revealed that the best independent factors predicting the outcome were T1-T3, N0, R0/R1 resection, and total RT dose (54 Gy or higher). CONCLUSION In this multicenter retrospective study, patients with ONB treated with R0 or R1 surgical resection followed by at least 54-Gy postoperative RT had the best outcome. Novel strategies including concomitant chemotherapy and/or higher dose RT should be prospectively investigated in this rare disease for which local failure remains a problem.

Microbeam Radiation-Induced Tissue Damage Depends on the Stage of Vascular Maturation

PURPOSE To explore the effects of microbeam radiation (MR) on vascular biology, we used the chick chorioallantoic membrane (CAM) model of an almost pure vascular system with immature vessels (lacking periendothelial coverage) at Day 8 and mature vessels (with coverage) at Day 12 of development. METHODS AND MATERIALS CAMs were irradiated with microplanar beams (width, ∼25 μm; interbeam spacing, ∼200 μm) at entrance doses of 200 or 300 Gy and, for comparison, with a broad beam (seamless radiation [SLR]), with entrance doses of 5 to 40 Gy. RESULTS In vivo monitoring of Day-8 CAM vasculature 6 h after 200 Gy MR revealed a near total destruction of the immature capillary plexus. Conversely, 200 Gy MR barely affected Day-12 CAM mature microvasculature. Morphological evaluation of Day-12 CAMs after the dose was increased to 300 Gy revealed opened interendothelial junctions, which could explain the transient mesenchymal edema immediately after irradiation. Electron micrographs revealed cytoplasmic vacuolization of endothelial cells in the beam path, with disrupted luminal surfaces; often the lumen was engorged with erythrocytes and leukocytes. After 30 min, the capillary plexus adopted a striated metronomic pattern, with alternating destroyed and intact zones, corresponding to the beam and the interbeam paths within the array. SLR at a dose of 10 Gy caused growth retardation, resulting in a remarkable reduction in the vascular endpoint density 24 h postirradiation. A dose of 40 Gy damaged the entire CAM vasculature. CONCLUSIONS The effects of MR are mediated by capillary damage, with tissue injury caused by insufficient blood supply. Vascular toxicity and physiological effects of MR depend on the stage of capillary maturation and appear in the first 15 to 60 min after irradiation. Conversely, the effects of SLR, due to the arrest of cell proliferation, persist for a longer time.

Prognosis of dermal lymphatic invasion with or without clinical signs of inflammatory breast cancer

It is still an open debate whether tumor emboli in dermal lymphatics without inflammatory signs represent a similar bad prognosis like inflammatory breast cancer. We evaluated the prognostic role of dermal lymphatic invasion (DLI) in breast cancer with (DLI + ID) or without (DLI w/o ID) inflammatory disease (ID). From August 1988 to January 2000, 42 patients with DLI were irradiated. Twenty‐five were classified as pT4, 13 out of them as pT4d (inflammatory disease); the 17 remaining patients had 1 T1c, 12 T2 and 4 T3 cancers with DLI. Axillary dissection revealed node‐positive disease in 39/41 patients (median, 9 positive nodes). Thirty‐eight out of 42 patients received adjuvant systemic treatment(s). After a mean follow‐up of 33 months, 22/42 patients (52%) are disease‐free. The actuarial 3‐year disease‐free survival is 50% (DLI w/o ID, 61%; DLI + ID, 31%; p < 0.03); the corresponding overall survival was 69% (DLI w/o ID, 87%; DLI + ID, 37%; p = 0.005). The presence or absence of ID was the only significant parameter for all endpoints in multivariate analyses. Dissemination occurred in 19 (45%), local relapse in 7 (n = 17%) and regional failure in 4 (10%). Nine patients (21%) had contralateral breast cancer/relapse. Despite the same histopathologic presentation, DLI w/o ID offered a significantly better disease‐free survival and overall survival than ID. The finding of dermal lymphatic tumor invasion predicts a high probability for node‐positive disease.

The Synergistic Action of a VEGF-Receptor Tyrosine-Kinase Inhibitor and a Sensitizing PDGF-Receptor Blocker Depends upon the Stage of Vascular Maturation

Objective: To investigate the effects of tyrosine‐kinase inhibitors of vascular endothelial growth factor (VEGF) and platelet‐derived growth factor (PDGF)‐receptors on non‐malignant tissue and whether they depend upon the stage of vascular maturation.

Prospective study on exclusive, nonsurgical strontium-/yttrium-90 irradiation of pterygia.

Purpose:Prospective study to evaluate consecutive treatment results and to demonstrate safety and efficacy of nonsurgical, exclusive strontium-/yttrium-90 β-irradiation of nonoperated pterygia.Patients and Methods:Between November 1999 and March 2002, 20 patients with 21 primary pterygia and six patients with recurrent pterygia after former surgery were treated with exclusive strontium-/yttrium-90 irradiation up to a total dose of 3,600 cGy (six fractions) and 4,800 cGy (eight fractions), respectively. All patients were referred from a single institution. The mean follow-up is 35.6 ± 7.3 months (range 24–48 months).Results:Prior to irradiation the mean horizontal diameter of all pterygia was 2.6 mm and shrank to a mean diameter of 1.6 mm after treatment (p = 0.0011, Student’s t-test). The treatment led to a reduction in size of all 21 primary and all six recurrent pterygia. Visual acuity reached a value of 0.73 before and 0.82 after treatment. This improvement was not significant in Student’s t-test (p = 0.12). The visual acuity did not decrease in any patient, complications were not observed, and in none of the 27 pterygia a recurrence developedConclusion:Exclusive strontium-/yttrium-90 irradiation of the early and moderately advanced pterygium is a very efficient and very well-tolerated method of treatment. As to the therapeutic management, it is suggested to apply β-irradiation prior to the development of an astigmatism-relevant pterygium, which requires excision.Ziel:Prospektive Studie zur klinischen Evaluation der Wirksamkeit und Sicherheit der ausschließlichen Strontium-/Yttrium-90-Bestrahlung des nicht operierten Pterygiums.Patienten und Methodik:Zwischen November 1999 und März 2002 wurden 20 Patienten mit 21 primären Pterygien und sechs Patienten mit sechs nach Exzision rezidivierenden Pterygien mit einer ausschließlichen Strontium-/Yttrium-90-Bestrahlung, Gesamtdosis 3600 cGy (sechs Fraktionen) bzw. 4800 cGy (acht Fraktionen), behandelt. Die Patienten waren von einer einzigen Institution zugewiesen worden. Die durchschnittliche Nachbeobachtungszeit liegt bei 35,6 ± 7,3 Monaten (Bereich: 24–48 Monate).Ergebnisse:Der durchschnittliche Durchmesser der Pterygien betrug vor der Bestrahlung 2,6 mm und nahm nach Bestrahlung signifikant auf 1,6 mm ab (p = 0,0011, Student-t-Test). Alle 27 Pterygien—sowohl die 21 primären als auch die sechs rezidivierenden—nahmen nach der Bestrahlung an Ausdehnung und Größe ab. Die durchschnittliche Sehschärfe lag vor der Bestrahlung bei 0,73 und nach der Bestrahlung bei 0,82. Die Verbesserung war im Student-t-Test (p = 0,12) nicht signifikant. Kein Auge entwickelte nach der Behandlung eine Verminderung der Sehschärfe; es trat keine Komplikation auf, und bei keinem der 27 Pterygien musste ein Rezidiv festgestellt werden.Schlussfolgerung:Die ausschließliche Strontium-/Yttrium-90-Bestrahlung des frühen und mäßig fortgeschrittenen Pterygiums ist eine sehr effiziente und sehr gut tolerierte therapeutische Methode. Hinsichtlich des Behandlungsmanagements empfiehlt es sich, die β-Bestrahlung vor der Entwicklung eines astigmatismusrelevanten Pterygiums zu applizieren, welches eine Exzision indiziert.