Re-irradiation for recurrent glioblastoma multiforme: a critical comparison of different concepts.

PURPOSE: Purpose of this study was to investigate outcome and toxicity of re-irradiation for recurrent primary glioblastoma (rGBM). We evaluated a group of patients with rGBM and identical primary treatment comprising adjuvant radiotherapy (30â€¯× 2 Gy) with concurrent temozolomide (TMZ). METHODS: In this retrospective study of 46 patients, all received adjuvant or definitive normofractionated radiotherapy to a pretreated area, some with concurrent chemotherapy. Impact of different clinical, histological, or epidemiological factors on survival and radiation toxicity was reviewed. RESULTS: Of 46 patients, 40 completed the intended therapy. Overall survival (OS) was 20 months (range 6-72 months). Overall survival and progression-free survival after re-irradiation (OS2 and PFS2) were 9.5 and 3.4 months (range 2-40 and 0.7-44 months). Simultaneous systemic therapy improved PFS2 and OS2 (4.3 vs. 2.0, p < 0.001 and 12 vs. 4 months, p = 0.13, respectively). Therapy with TMZ or bevacizumab improved PFS2 vs. nitrosureas (6.6 vs. 2.9, p = 0.03 and 5.1 vs. 2.9 months, p = 0.035, respectively). TMZ also improved PFS2 and OS2 vs. all other systemic therapies (6.6 vs. 4, p < 0.001 and 17 vs. 10 months, p = 0.1). In a subgroup analysis for patients with methylation of the MGMT promoter, doses of >36 Gy as well as TMZ vs. no systemic therapy improved PFS2 (p = 0.045 and p = 0.03, respectively). 27.5% of all patients had no acute toxicity. Three patients with acute and four patients with late grade 3 toxicities were reported. CONCLUSION: Normofractionated radiotherapy is a feasible option for rGBM with a good toxicity profile. Simultaneously applied systemic therapy was associated with improved outcome. For MGMT promoter-methylated histology, higher radiation doses improved survival.

Engineering of clinical glioma treatment: prediction of pro-invasive molecular events in treated gliomas.

The diffusely infiltrative nature of malignant gliomas is the main obstacle to successful treatment approaches. Advanced simulation models of the in vivo response to therapy conditions are expected to improve malignant glioma treatment substantially. In parallel experiments, human malignant glioma cells underwent either radiation or chemotherapy treatment (chemotreatment) with temozolomide alone, or combined chemoradiation. Cells were treated according to diverse, clinically relevant, therapeutic algorithms. Quantitative 'real-time' polymerase chain reaction (PCR) measurements were performed for target genes, namely vascular endothelial growth factor, p53, and cyclooxygenase-2, which allow a comparative evaluation of pro-invasive molecular events in treated gliomas. The proof-of-principle study simulated variable intratumoural regional conditions. Pro-invasive molecular patterns were strongly dependent on the treatment algorithm, cellular density, and drug delivery. The highest pro-invasive potential was demonstrated for simulated peripheral regions under continued chemoradiation. This result strongly supports the clinical observations of increased aggressiveness and relatively poor response to second-line therapies in post-operatively chemoradiation-treated malignant gliomas at the time of relapse. Individualized and potentially the most effective treatment algorithms can be designed using established gene expression patterns applied on primary cell cultures obtained from individual patients. Individual drug toxicity and response to anti-cancer therapy can be predicted.

Initial experience with lung-MRI at 3.0T: Comparison with CT and clinical data in the evaluation of interstitial lung disease activity.

OBJECTIVES: We evaluated the feasibility of highfield lung-MRI at 3.0T. A comparison with Computed Tomography (CT) and clinical data regarding the assessment of inflammatory activity in patients with diffuse lung disease was performed. MATERIAL AND METHODS: Prospective evaluation of 21 patients (15 males, 6 females, 43-80 y) with diffuse lung diseases who underwent clinical work-up inclusive laboratory tests, lung-function tests and transbronchial biopsy. After routine helical CT (additional 12 HRCT) a lung-MRI (3.0 Intera, Philips Medical Systems, Best, The Netherlands) using a T2-weighted, cardiac and respiratory triggered Fast-Spinecho-Sequence (TE/TR=80/1500-2500 ms, 22 transverse slices, 7/2mm slice-thickness/-gap) was performed. A pneumologist classified the cases into two groups: A=temporary acute interstitial disease or chronic interstitial lung disease with acute episode or superimposed infection/B=burned out interstitial lung disease without activity. Two blinded CT-radiologists graded the cases in active/inactive disease on the basis of nine morphological criteria each. A third radiologist rated the MRI-cases as active/inactive, depending on the signal-intensities of lung tissues. RESULTS: The pneumologist classified 14 patients into group A and 7 patients into group B. Using CT, 6 cases were classified as active, 15 cases as inactive disease. With MRI 12 cases were classified as active and 9 cases as inactive. In the complete group of 21 patients MRI decisions and CT decisions respectively were false positive/false negative/correct in 2/4/15 respectively 0/8/13 cases. Correct diagnoses were obtained in 72% (MRI) respectively 62% (CT). In the subgroup of 12 cases including HRCT, MRI respectively CT were false positive/false negative/correct in 2/1/9 respectively 0/5/7 cases. Correct diagnoses were obtained in 75% (MRI) respectively 58% (CT). CONCLUSION: Highfield MRI of the lung is feasible and performed slightly better compared to CT in the determination of activity in patients with interstitial lung diseases.

Non-sufficient cell cycle control as possible clue for the resistance of human malignant glioma cells to clinically relevant treatment conditions.

OBJECTIVES: Human gliomas have a catastrophic prognosis with a median survival in the range of one year even after therapeutic treatment. Relatively high resistance towards apoptotic stimuli is the characteristic feature of malignant gliomas. Since cell cycle control has been shown to be the key mechanism controlling both apoptosis and proliferation, this study focuses on DNA damage analysis and protein expression patterns of essential cell cycle regulators P53 and P21waf1/cip1 in glioma under clinically relevant therapeutic conditions. MATERIAL AND METHODS: U87MG cell line, characterised by wild p53-phenotype relevant for the majority of primary malignant glioblastomas, was used. Glioma cells underwent either irradiation or temozolomide treatment alone, or combined radio/chemo treatment. DNA damage was analysed by the "Comet Assay". Expression rates of target proteins were analysed using "Western-Blot" technique. RESULTS AND CONCLUSIONS: "Comet Assay" demonstrated extensive DNA damage caused by temozolomide treatment alone and in combination with irradiation, correlating well with the low survival rate observed under these treatment conditions. In contrast, irradiation alone resulted in a relatively low DNA damage, correlating well with a high survival rate and indicating a poor therapeutic efficiency of irradiation alone. Unusually low up-regulation of P53 and P21waf1/cip1 expression patterns was produced by the hereby tested stressful conditions. A deficit in cell cycle control might be the clue to the high resistance of malignant glioma cells to established therapeutic approaches.

Parametrial and rectovaginal adenocarcinoma arising from endometriosis.

Malignant extragonadal tumors arising from endometriosis are rare. We report on two cases. A 41-year-old gravida 1, para 1 (G1P1), with adenocarcinoma of the right parametrium arising from endometriosis and a 51-year-old G1P1 with endometriosis-associated rectovaginal adenocarcinoma were treated. Treatment included radical surgery plus radiation therapy. While the former patient was doing well 2 years after the primary diagnosis, the latter suffered a local pelvic recurrence 2 years later. Although there are no randomized controlled studies, radical surgery followed by radiation therapy seems generally to be the treatment of choice. The analysis of PTEN in various forms of endometriosis and its malignant transformation may help in understanding the early steps of tumorigenesis.

Molecular imaging system for possible prediction of active retinopathy in patients with Diabetes mellitus.

OBJECTIVE: The deposition of advanced glycation end products is enhanced in Diabetes mellitus (DM) and has been linked to diabetic complications such as a microvascular disease. Glycated proteins have receptors on mononuclear blood cells (MBCs) and have been shown to generate reactive oxygen species altering gene expression and modifying cellular targets, such as endothelial cells. Retinal angiopathy is a frequently observed microvascular complication in DM-patients. Because of the central role of activated MBCs, we hypothesised a functional link between specific alterations in gene expression of MBCs, an increased activity of matrix proteases in serum, and the extent of retinal angiopathy in DM. MATERIAL AND METHODS: An appearance and proliferation index of diabetic retinopathy was evaluated in 38 DM-patients using fluorescein angiography. Alterations of gene transcription levels in MBCs were investigated using hybridisation of individual mRNA-pools to Atlas Array with a concomitant quantification of specific cDNAs by "Real-Time"-PCR. The activity of matrix metalloproteinases MMP-2 and MMP-9 in individual serum samples was measured by zymography combined with densitometric imaging system. RESULTS AND CONCLUSIONS: Hybridisation to Atlas Array of mRNA-pools isolated from MBCs revealed an enhanced expression of recoverin in DM-patients compared to the control group. "Real-Time"-PCR showed the highest recoverin levels in the DM-subgroup with a high proliferation index. MMP-2 activity was highly increased in 36% of all patients, and in 44, 44, and 19% of patients with proliferative retinopathy, advanced proliferative retinopathy, and no detectable proliferation respectively. In those 3 groups MMP-9 activity was highly increased in 56, 67, and 31% of patients respectively, and in 44% of all DM-patients. In contrast to patients with active proliferation, the simultaneous high activation of all three genes was not observed in patients without active proliferation. The ex vivo molecular imaging system developed in this work may be helpful for the prediction of active proliferative retinopathy in DM.

Expression of ABC-1 transporter is elevated in human glioma cells under irradiation and temozolomide treatment.

OBJECTIVE: Chemo-therapeutic treatment of glioma patients has minor success. Little is known about mechanisms of a pronounced resistance of gliomas towards actual therapies, yet. ABC-1 belongs to the group of transporters known to be involved in the export of hydrophobic substances and vascular regulation. This study investigates an effect of both temozolomide (TMZ) treatment and/or irradiation on the expression of the ABC-1 transporter in human U87-MG glioma cells. MATERIAL AND METHODS: In parallel experiments U87-MG cells underwent either irradiation (RT), chemo-treatment (CT) using TMZ, and combined chemo/radiation-treatment (CT/RT). After each treatment the cells were incubated either 2 or 24 hours at 37 degrees C and counted before protein analysis using Western-Blot technique. RESULTS AND CONCLUSIONS: An exponential growth of cellular density was observed for both untreated and irradiated cells being, however, about 2-times slower in irradiated compared to untreated cells. In contrast the density increase of chemo-treated cells as well as that of cells, which underwent the combined CT/RT treatment was of linear nature. ABC-1 expression was detected in untreated as well as treated cells. Increasing cell density and all kinds of treatment resulted in a considerably enhanced ABC-1 expression. CT treatment resulted in highly up-regulated ABC-1 expression especially in non-confluent cultures compared to untreated cells. Irradiation had a comparable or even higher inducible effect on the ABC-1 expression rates depending, however, on cell density. The highest expression rates were observed in cultures with high cellular density 2 hours after application of the combined treatment. Strong up-regulation of ABC-1 expression under both irradiation and chemo-treatment might be a clue to multidrug and irradiation cross-resistance mechanisms of malignant glioma cells converting the ABC-1 transporter into an attractive pharmacological target for a clinical breakthrough in the therapy of malignant gliomas.

Daily amifostine given concomitantly to chemoradiation in head and neck cancer. A pilot study.

BACKGROUND: In patients with loco-regionally advanced head and neck cancer conventionally fractionated radiotherapy alone results in poor loco-regional control and survival rates. Treatment intensification by simultaneous administration of cytotoxic drugs produces higher acute morbidity. Therefore chemical radioprotection of normal tissues may be of clinical benefit. PATIENTS AND METHODS: In a pilot study patients with advanced nonresectable head and neck cancer treated with conventionally fractionated radical radiotherapy (60 to 66 Gy total doses) and concomitantly given 5-fluorouracil as protracted venous infusion, 250 mg/sqm/24 h over the entire treatment period were given amifostine 300 mg absolutely before each fraction. Acute treatment related morbidity was scored according to CTC classification and loco-regional control and survival rates were estimated. Comparison was made with a historical control group of identical chemoradiation but without amifostine application. RESULTS: Chemoradiation induced oral mucositis was delayed and showed significant lower degrees at all 10 Gy increments (p < 0.05) except 60 Gy and over (p > 0.05). No significant toxicity was recorded with respect to blood pressure, serum calcium, potassium, hematologic parameters, emesis, nausea or body weight loss. Progression free survival and overall survival probability at 2 years were not statistically different in both cohorts. CONCLUSION: Amifostine given before each fraction of radiotherapy over 6 weeks has no cumulative toxicity, was well tolerated and may reduce treatment induced oral mucositis. No tumor protective effect was observed.