Perfusion Magnetic Resonance Imaging Changes in Normal Appearing Brain Tissue after Radiotherapy in Glioblastoma Patients may Confound Longitudinal Evaluation of Treatment Response.

BACKGROUND: The aim of this study was assess acute and early delayed radiation-induced changes in normal-appearing brain tissue perfusion as measured with perfusion magnetic resonance imaging (MRI) and the dependence of these changes on the fractionated radiotherapy (FRT) dose level. PATIENTS AND METHODS: Seventeen patients with glioma WHO grade III-IV treated with FRT were included in this prospective study, seven were excluded because of inconsistent FRT protocol or missing examinations. Dynamic susceptibility contrast MRI and contrast-enhanced 3D-T1-weighted (3D-T1w) images were acquired prior to and in average (standard deviation): 3.1 (3.3), 34.4 (9.5) and 103.3 (12.9) days after FRT. Pre-FRT 3D-T1w images were segmented into white- and grey matter. Cerebral blood volume (CBV) and cerebral blood flow (CBF) maps were calculated and co-registered patient-wise to pre-FRT 3D-T1w images. Seven radiation dose regions were created for each tissue type: 0-5 Gy, 5-10 Gy, 10-20 Gy, 20-30 Gy, 30-40 Gy, 40-50 Gy and 50-60 Gy. Mean CBV and CBF were calculated in each dose region and normalised (nCBV and nCBF) to the mean CBV and CBF in 0-5 Gy white- and grey matter reference regions, respectively. RESULTS: Regional and global nCBV and nCBF in white- and grey matter decreased after FRT, followed by a tendency to recover. The response of nCBV and nCBF was dose-dependent in white matter but not in grey matter. CONCLUSIONS: Our data suggest that radiation-induced perfusion changes occur in normal-appearing brain tissue after FRT. This can cause an overestimation of relative tumour perfusion using dynamic susceptibility contrast MRI, and can thus confound tumour treatment evaluation.

Hypofractionated high-energy proton-beam irradiation is an alternative treatment for WHO grade I meningiomas.

BACKGROUND: Radiation treatment is commonly employed in the treatment of meningiomas. The aim of this study was to evaluate the effectiveness and safety of hypofractionated high-energy proton therapy as adjuvant or primary treatment for WHO grade I meningiomas. METHOD: A total of 170 patients who received irradiation with protons for grade I meningiomas between 1994 and 2007 were included in the study. The majority of the tumours were located at the skull base (n = 155). Eighty-four patients were treated post subtotal resection, 42 at tumour relapse and 44 with upfront radiotherapy after diagnosis based on the typical radiological image. Irradiation was given in a hypofractionated fashion (3-8 fractions, usually 5 or 6 Gy) with a mean dose of 21.9 Gy (range, 14-46 Gy). All patients were planned for follow-up with clinical controls and magnetic resonance imaging scans at 6 months and 1, 2, 3, 5, 7 and 10 years after treatment. The median follow-up time was 84 months. Age, gender, tumour location, Simpson resection grade and target volume were assessed as possible prognostic factors for post-irradiation tumour progression and radiation related complications. RESULTS: The actuarial 5- and 10-year progression-free survival rates were 93% and 85% respectively. Overall mortality rate was 13.5%, while disease-specific mortality was 1.7% (3/170 patients). Older patients and patients with tumours located in the middle cranial fossa had a lower risk for tumour progression. Radiation-related complications were seen in 16 patients (9.4%), with pituitary insufficiency being the most common. Tumour location in the anterior cranial fossa was the only factor that significantly increased the risk of complications. CONCLUSIONS: Hypofractionated proton-beam radiation therapy may be used particularly in the treatment of larger World Health Organisation grade I meningiomas not amenable to total surgical resection. Treatment is associated with high rates of long-term tumour growth control and acceptable risk for complications.

Long-term evaluation of the effect of hypofractionated high-energy proton treatment of benign meningiomas by means of (11)C-L-methionine positron emission tomography.

PURPOSE: To determine if (11)C-L-methionine PET is a useful tool in the evaluation of the long-term effect of proton beam treatment in patients with meningioma remnant. METHODS: Included in the study were 19 patients (4 men, 15 women) with intracranial meningioma remnants who received hypofractionated high-energy proton beam treatment. Patients were examined with (11)C-L-methionine PET and MRI prior to treatment and after 6 months, and 1, 2, 3, 5, 7 and 10 years. Temporal changes in methionine uptake ratio, meningioma volume, meningioma regrowth and clinical symptoms throughout the follow-up period were evaluated. RESULTS: In 17 patients the tumour volume was unchanged throughout the follow-up. The methionine uptake ratio on PET decreased over the years in most patients. In two patients the tumour remnant showed progression on MRI. In these patients, prior to the volume increase on MRI, the methionine uptake ratio increased. One patient experienced transient clinical symptoms and showed radiological evidence of a radiation-induced reaction close to the irradiated field. CONCLUSION: Proton beam treatment is a safe and effective treatment for achieving long-term growth arrest in meningioma remnants. Follow-up with (11)C-L-methionine PET may be a valuable adjunct to, but not a replacement for, standard radiological follow-up.

Positive correlation between occlusion rate and nidus size of proton beam treated brain arteriovenous malformations (AVMs).

BACKGROUND: Proton beam radiotherapy of arteriovenous malformations (AVM) in the brain has been performed in Uppsala since 1991. An earlier study based on the first 26 patients concluded that proton beam can be used for treating large and medium sized AVMs that were considered difficult to treat with photons due to the risk of side effects. In the present study we analyzed the result from treating the subsequent 65 patients. MATERIAL AND METHODS: A retrospective review of the patients' medical records, treatment protocols and radiological results was done. Information about gender, age, presenting symptoms, clinical course, the size of AVM nidus and rate of occlusion was collected. Outcome parameters were the occlusion of the AVM, clinical outcome and side effects. RESULTS: The rate of total occlusion was overall 68%. For target volume 0-2 cm(3) it was 77%, for 3-10 cm(3) 80%, for 11-15 cm(3) 50% and for 16-51 cm(3) 20%. Those with total regress of the AVM had significantly smaller target volumes (p < 0.009) higher fraction dose (p < 0.001) as well as total dose (p < 0.004) compared to the rest. The target volume was an independent predictor of total occlusion (p = 0.03). There was no difference between those with and without total occlusion regarding mean age, gender distribution or symptoms at diagnosis. Forty-one patients developed a mild radiation-induced brain edema and this was more common in those that had total occlusion of the AVM. Two patients had brain hemorrhages after treatment. One of these had no effect and the other only partial occlusion from proton beams. Two thirds of those presenting with seizures reported an improved seizure situation after treatment. CONCLUSION: Our observations agree with earlier results and show that proton beam irradiation is a treatment alternative for brain AVMs since it has a high occlusion rate even in larger AVMs.

PTPN6 expression is epigenetically regulated and influences survival and response to chemotherapy in high-grade gliomas.

The prognosis of high-grade glioma patients is poor, and the tumors are characterized by resistance to therapy. The aims of this study were to analyze the prognostic value of the expression of the protein tyrosine phosphatase non-receptor type 6 (PTPN6, also referred to as SHP1) in high-grade glioma patients, the epigenetic regulation of the expression of PTPN6, and the role of its expression in chemotherapy resistance in glioma-derived cells. PTPN6 expression was analyzed with immunohistochemistry in 89 high-grade glioma patients. Correlation between PTPN6 expression and overall survival was analyzed with Kaplan-Meier univariate analysis and Cox regression multivariate analysis. Differences in drug sensitivity to a panel of 16 chemotherapeutic drugs between PTPN6-overexpressing clones and control clones were analyzed in vitro with the fluorometric microculture cytotoxicity assay. Cell cycle analysis was done with Krishan staining and flow cytometry. Apoptosis was analyzed with a cell death detection ELISA kit as well as cleaved caspase-3 and caspase-9 Western blotting. Autophagy was analyzed with LC3B Western blotting. Methylation of the PTPN6 promoter was analyzed with bisulfite pyrosequencing, and demethylation of PTPN6 was done with decitabine treatment. The PTPN6 expression correlated in univariate analysis to poor survival for anaplastic glioma patients (p = 0.026). In glioma-derived cell lines, overexpression of PTPN6 caused increase resistance (p < 0.05) to the chemotherapeutic drugs bortezomib, cisplatin, and melphalan. PTPN6 expression did not affect bortezomib-induced cell cycle arrest, apoptosis, or autophagy. Low PTPN6 promoter methylation correlated to protein expression, and the protein expression was increased upon demethylation in glioma-derived cells. PTPN6 expression may be a factor contributing to poor survival for anaplastic glioma patients, and in glioma-derived cells, its expression is epigenetically regulated and influences the response to chemotherapy.

Haemangiopericytoma presenting with acute intracerebral haemorrhage--a case report and literature review.

BACKGROUND: Intracranial haemangiopericytoma (HPC), a rare malignant tumour, should be distinguished from meningioma and solitary fibrous tumour, which have been considered as separate entities since 1993, according to histopathology and clinical characteristics. METHODS: A PUBMED search for "Intracranial Haemangiopericytoma" yielded 176 articles, where 26 were of particular interest for this review article. CASE REPORT: Our patient, a 27-year-old man with HPC of grade III according to WHO, presents with an acute intracerebral haematoma, which is extremely rare. RESULTS: Surgery (total resection) is the primary treatment. Long-term close clinical and radiological follow-up is crucial due to the high rate of recurrence and tendency for development of metastasis. DISCUSSION: The effects of postoperative radiotherapy need further investigation. Besides neurosurgery, radiotherapy should always be considered in both patients with these highly malignant tumours (WHO grade III) and in patients with partial resection or inoperable cases (WHO grade II).

Magnetic resonance imaging detected radiation-induced changes in patients with proton radiation-treated arteriovenous malformations.

BACKGROUND: Treatment of intracranial arteriovenous malformations (AVMs) includes surgery, radiation therapy, endovascular occlusion, or a combination. Proton radiation therapy enables very focused radiation, minimizing dose to the surrounding brain. PURPOSE: To evaluate the presence of radiation-induced changes on post-treatment MRI in patients with AVMs treated with proton radiation and to compare these with development of symptoms and nidus obliteration. MATERIAL AND METHODS: Retrospective review of pre- and post-treatment digital subtraction angiography and MRI and medical records in 30 patients with AVMs treated with proton radiation. Patients were treated with two or five fractions; total radiation dose was 20-35 physical Gy. Vasogenic edema (minimal, perinidal, or severe), contrast enhancement (minimal or annular), cavitation and nidus obliteration (total, partial, or none) were assessed. RESULTS: 26 of 30 patients (87%) developed MRI changes. Vasogenic edema was seen in 25 of 30 (83%), abnormal contrast enhancement in 18 of 26 (69%) and cavitation in 5 of 30 (17%). Time from treatment to appearance of MRI changes varied between 5 and 25 months (median 7, mean 10). Seven patients developed new or deteriorating symptoms that required treatment with corticosteroids; all these patients had extensive MRI changes (severe vasogenic edema and annular contrast enhancement). Not all patients with extensive MRI changes developed symptoms. We found no relation between MRI changes and nidus obliteration. CONCLUSION: Radiation-induced MRI changes are seen in a majority of patients after proton radiation treatment of AVMs. Extensive MRI changes are associated with new or deteriorating symptoms.

Cancer of the parotid gland; long-term follow-up. A single centre experience on recurrence and survival.

BACKGROUND: The aim of the study was to investigate the results of treatment of malignant parotid gland tumours at a single centre during a 56 year period, focusing on tumour control and survival. PATIENTS AND METHODS: At Uppsala University Hospital, Sweden, 144 patients (73 male and 71 female) with parotid cancer were treated between 1948 and 2004. The mean and median ages were 62 and 65 years, respectively (range 16-89 years). Surgery was the primary treatment in 113 (78%) patients followed by radiotherapy in 81. Postoperative radiotherapy in doses of 64-66 Gy, where the intention was curative and delivered with either split course or not, was administered to a majority of patients after 1970. The split-course mode was practised between 1970 and 1989. The median follow-up time was 8.3 years for patients still alive. There were 57 (40%) relapses, of which 40 were local recurrences with 26 inside the treatment volume. RESULTS: The overall 5-year survival was 53%. The majority of tumour-related deaths appeared in the first 3-5 years after diagnosis. Age, co-morbidity, the presence of lymph node metastases, adenoid cystic carcinoma and extent of disease were important for outcome; gender, however, was not. We found no difference in the survival between patients following split course therapy versus continuous fractionation. No difference could be seen in the survival of patients treated in the 1970s versus the 1990s. CONCLUSIONS: Age, nodal engagement, a higher T-stage, adenoid cystic carcinoma histopathology, facial palsy and intercurrent disease worsen the outcome of patients, whereas gender does not. Treatment principles at our hospital have been surgery followed by radiotherapy since the early 1970s even though a split course technique was practised during a part of this period. Survival has not improved markedly. Thus, there is scope for improvement for this group of patients.

Boron neutron capture therapy (BNCT) for glioblastoma multiforme: a phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA).

BACKGROUND AND PURPOSE: To evaluate the efficacy and safety of boron neutron capture therapy (BNCT) for glioblastoma multiforme (GBM) using a novel protocol for the boronophenylalanine-fructose (BPA-F) infusion. PATIENT AND METHODS: This phase II study included 30 patients, 26-69 years old, with a good performance status of which 27 have undergone debulking surgery. BPA-F (900 mg BPA/kg body weight) was given i.v. over 6h. Neutron irradiation started 2h after the completion of the infusion. Follow-up reports were monitored by an independent clinical research institute. RESULTS: The boron-blood concentration during irradiation was 15.2-33.7 microg/g. The average weighted absorbed dose to normal brain was 3.2-6.1 Gy (W). The minimum dose to the tumour volume ranged from 15.4 to 54.3 Gy (W). Seven patients suffered from seizures, 8 from skin/mucous problem, 5 patients were stricken by thromboembolism and 4 from abdominal disturbances in close relation to BNCT. Four patients displayed 9 episodes of grade 3-4 events (WHO). At the time for follow-up, minimum ten months, 23 out of the 29 evaluable patients were dead. The median time from BNCT treatment to tumour progression was 5.8 months and the median survival time after BNCT was 14.2 months. Following progression, 13 patients were given temozolomide, two patients were re-irradiated, and two were re-operated. Patients treated with temozolomide lived considerably longer (17.7 vs. 11.6 months). The quality of life analysis demonstrated a progressive deterioration after BNCT. CONCLUSION: Although, the efficacy of BNCT in the present protocol seems to be comparable with conventional radiotherapy and the treatment time is shorter, the observed side effects and the requirement of complex infrastructure and higher resources emphasize the need of further phase I and II studies, especially directed to improve the accumulation of (10)B in tumour cells.

Dynamic contrast-enhanced magnetic resonance imaging may act as a biomarker for vascular damage in normal appearing brain tissue after radiotherapy in patients with glioblastoma.

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a promising perfusion method and may be useful in evaluating radiation-induced changes in normal-appearing brain tissue. PURPOSE: To assess whether radiotherapy induces changes in vascular permeability (Ktrans) and the fractional volume of the extravascular extracellular space (Ve) derived from DCE-MRI in normal-appearing brain tissue and possible relationships to radiation dose given. MATERIAL AND METHODS: Seventeen patients with glioblastoma treated with radiotherapy and chemotherapy were included; five were excluded because of inconsistencies in the radiotherapy protocol or early drop-out. DCE-MRI, contrast-enhanced three-dimensional (3D) T1-weighted (T1W) images and T2-weighted fluid attenuated inversion recovery (T2-FLAIR) images were acquired before and on average 3.3, 30.6, 101.6, and 185.7 days after radiotherapy. Pre-radiotherapy CE T1W and T2-FLAIR images were segmented into white and gray matter, excluding all non-healthy tissue. Ktrans and Ve were calculated using the extended Kety model with the Parker population-based arterial input function. Six radiation dose regions were created for each tissue type, based on each patient's computed tomography-based dose plan. Mean Ktrans and Ve were calculated over each dose region and tissue type. RESULTS: Global Ktrans and Ve demonstrated mostly non-significant changes with mean values higher for post-radiotherapy examinations in both gray and white matter compared to pre-radiotherapy. No relationship to radiation dose was found. CONCLUSION: Additional studies are needed to validate if Ktrans and Ve derived from DCE-MRI may act as potential biomarkers for acute and early-delayed radiation-induced vascular damages. No dose-response relationship was found.

Clinical impact of positron emission tomography (PET) with (18F)fluorodeoxyglucose (FDG) in head and neck tumours.

CONCLUSION: PET plays an important role in staging, on suspicion of recurrence and for detection of occult primary tumours in the head and neck. OBJECTIVE: Since 1998 we have used positron emission tomography (PET) with (18F)fluorodeoxyglucose (FDG) to assess selected patients. This procedure has often helped in making decisions on staging and treatment. PATIENTS AND METHODS: The case records of the first 80 patients (104 PET examinations) were studied retrospectively. RESULTS: A total of 39 examinations were performed for staging. PET detected all primary tumours except two (stage T1), and staging was adjusted after 13%. In all, 33 PET examinations were performed on suspicion of recurrent tumour. In 52% of these PET determined further treatments; in 21% PET had a direct impact on the surgical planning. In 18 patients with metastases from an occult primary tumour, PET detected 39% of those tumours; in 22% it was the sole modality to do so. No recurrences or second primary tumours were detected when PET was used for follow-up of clinically cured patients. Results were similar when squamous cell carcinomas (SCCs) were considered alone as compared to the complete material. The mean standardized uptake value (SUV) was higher for cases deemed tumour-positive than in negative cases.

Potential outcomes of modalities and techniques in radiotherapy for patients with hypopharyngeal carcinoma.

BACKGROUND AND PURPOSE: To determine potential improvements in treatment outcome for patients with hypopharyngeal carcinoma, T4N0M0, using proton and intensity modulated photon radiotherapy (IMRT) compared to a standard 3D conformal radiotherapy treatment (3D-CRT) in terms of local tumour control probability, TCP, and normal tissue complication probability (NTCP) for the spinal cord and the parotid glands using. PATIENTS AND METHODS: Using the three-dimensional treatment-planning system, Helax-TMS, 5 patients were planned with protons, IMRT, and 3D-CRT plans. The prescribed dose used was 30 fractions x 2.39 Gy for the protons and IMRT and 35 fractions x 2.00 Gy for 3D-CRT. The treatment plans were evaluated using dose volume data and dose response models were used to calculate TCP and NTCP. The target volumes were delineated to spare the parotid glands. A dose escalation was made for protons and IMRT using NTCP constraints to the spinal cord. RESULTS: On average, protons and IMRT increase TCP by 17% compared to 3D-CRT. For the spinal cord NTCP values are zero for all methods and patients. Average NTCP values for the parotid glands were >90% for 3D-CRT and significantly lower for protons and IMRT varying from 43-65%. The average parotid gland dose was 33 Gy for the protons, 38 Gy for IMRT and 48 Gy for 3D-CRT. CONCLUSIONS: Protons and IMRT gave a significant TCP increase compared to 3D-CRT while no significant difference between protons and IMRT was found. Protons generally show lower non-target tissue doses, which indicates a possibility for further dose escalation. Large individual dose differences between protons and IMRT for parotid glands indicate that some patients may benefit more from protons and others from IMRT.

On the issue of early and aggressive treatment in grade 2 gliomas.

PURPOSE: To study the effects of surgery and timing of radiotherapy on patient survival in grade 2 gliomas. METHODS: One hundred and eighty-nine patients with diffuse astrocytomas, oligoastrocytomas, and oligodendrogliomas, World Health Organization grade 2, treated between 1982 and 2000 were identified. The impact of treatment given and clinical parameters were studied in univariate- and multivariate survival analyses. RESULTS: Median survival for the whole patient sample was 6.4 years and the 5-year survival rate was 60%. Macroscopic total resection was beneficial in the univariate analysis (P=0.03) but not when adjusting for confounders. Early subtotal resection did not prolong survival. Early radiotherapy was associated with a shorter survival time compared to delayed or no irradiation (P=0.004). However, this difference was mainly due to an unequal distribution of prognostic factors and was not significant in the multivariate analysis. The most important predictors for long survival time were young age ( P<0.001), oligodendroglioma histology ( P<0.001), and small tumour size ( P=0.02). CONCLUSIONS: Early conventional treatment with surgery and radiotherapy had no positive effect on patient survival. This opens up the possibility of trying and evaluating other first-line treatment regimens in this disease.

Cellular retention of radioactivity and increased radiation dose. Model experiments with EGF-dextran.

Targeting of tumor cells with radiolabeled biomolecules is a possible approach to inactivate disseminated tumor cells. However, rapid degradation of the biomolecules after cellular internalization and subsequent excretion of the radioactivity is a problem. We studied the possibility of using dextran as a carrier of radionuclides to improve the intracellular retention. An EGF-dextran conjugate, aimed for targeting of tumor cells overexpressing the EGF-receptor, was used as model. Retention tests were performed with (125)I on different parts: [(125)I]-EGF-dextran-[(125)I], [(125)I]-EGF-dextran and EGF-dextran-[(125)I]. Comparisons were made with [(125)I]-EGF. The radiolabeled compounds were incubated with cultured glioma cells for different times. The cellular retention of radioactivity was then measured for up to 24 h. Expected radiation doses at the cellular level were calculated assuming that (131)I, instead of (125)I, was coupled to EGF and EGF-dextran. The results indicated that the EGF-part of the conjugate was degraded and the EGF-attached radioactivity was rapidly excreted, whereas radioactivity on dextran was retained intracellularly to a high degree, i.e. 70-80% of the radioactivity bound to dextran was still cell-associated after 24 h. The retention after 24 h was significantly higher (p < 0.001) when the radioactivity was on the dextran instead of the EGF-part. The radiolabeled EGF-dextran had a notably high specific radioactivity; up to 11 MBq/microg. There was potential for at least hundred times increased radiation dose per receptor interaction when the radioactivity was on the dextran part. The advantage with radioactivity on the dextran part was the high cellular retention and the high specific radioactivity (higher than previously reported for other residualizing labels) without severe loss of receptor specific binding. Thus, dextran seems suitable as a carrier of radionuclides aimed for therapy and gives potential for a highly increased radiation dose.

Radiation treatment of T1-T4 squamous cell carcinoma of the larynx: a retrospective analysis and long-term follow-up of 135 patients.

PURPOSE: To evaluate the long-term outcome of radiation therapy for patients with histologically verified squamous cell glottic carcinoma. PATIENTS AND METHODS: A retrospective study was performed on patients who had received radiation treatment at the Department of Oncology, Uppsala University, Uppsala, Sweden, between 1978 and 1987 Patients with a documented follow-up for at least five years, or to time of death, were studied. Radiation treatment was delivered utilising daily fractions of 1.8-20 over 6-7 weeks, totalling 60-70 Gy. Patients whose tumours were not controlled by radiation therapy, or whose tumours recurred, were offered surgical intervention. RESULTS: The study included 135 patients. Five-year survival rates adjusted to death due to laryngeal carcinoma were: T1, 95%; T2, 87%; T3, 72% and T4, 25%. CONCLUSION: Primary radiotherapy achieves a high rate of cure for T1-T2 laryngeal carcinoma. Tumour-related morbidity and death continued beyond the standard five-year follow-up, especially for patients with T1/T2 laryngeal carcinomas.

[177Lu]Bz-DTPA-EGF: Preclinical characterization of a potential radionuclide targeting agent against glioma.

Patients with glioblastoma multiforme have a poor prognosis due to recurrences originating from spread cells. The use of radionuclide targeting might increase the chance of inactivating single tumor cells with minimal damage to surrounding healthy tissue. As a target, overexpressed epidermal growth factor receptors (EGFR) may be used. A natural ligand to EGFR, the epidermal growth factor (EGF) is an attractive targeting agent due to its low molecular weight (6 kDa) and high affinity for EGFR. 177Lu (T(1/2) = 6.7 days) is a radionuclide well suited for treatment of small tumor cell clusters, since it emits relatively low-energy beta particles. The goal of this study was to prepare and preclinically evaluate both in vitro and in vivo the [177Lu]Bz-DTPA-EGF conjugate. The conjugate was characterized in vitro for its cell-binding properties, and in vivo for its pharmacokinetics and ability to target EGFR. [177Lu]Bz-DTPA-EGF bound to cultured U343 glioblastoma cells with an affinity of 1.9 nM. Interaction with EGFR led to rapid internalization, and more than 70% of the cell-associated radioactivity was internalized after 30 minutes of incubation. The retention of radioactivity was good, with more than 65% of the 177Lu still cell-associated after 2 days. Biodistribution studies of i.v. injected [177Lu]Bz-DTPA-EGF in NMRI mice demonstrated a rapid blood clearance. Most of the radioactivity was found in the liver and kidneys. The liver uptake was receptor-mediated, since it could be significantly reduced by preinjection of unlabeled EGF. In conclusion, [177Lu]Bz-DTPA-EGF seems to be a promising candidate for locoregional treatment of glioblastoma due to its high binding affinity, low molecular weight, and ability to target EGFR in vivo.

[(111)In]Bz-DTPA-hEGF: Preparation and in vitro characterization of a potential anti-glioblastoma targeting agent.

The overexpression of epidermal growth factor receptors, EGFR, in glioblastomas is well documented. Hence, the EGFR can be used as target structure for a specific targeting of glioblastomas. Both radiolabeled anti-EGFR antibodies and the natural ligand EGF are candidate agents for targeting. However, EGF, which has a rather low molecular weight (6 kDa), might have better tissue penetration properties through both normal tissue and tumors in comparison with anti-EGF antibodies and their fragments. The aim of this study was to prepare and evaluate in vitro an EGF-based antiglioma conjugate with residualizing label. Human recombinant EGF (hEGF) was coupled to isothiocyanate-benzyl-DTPA. The conjugate was purified from unreacted chelator using solid-phase extraction and labeled with (111)In. The labeling yield was 87% +/- 7%. The label was reasonably stable; the transchelation of (111)In to serum proteins was about 5% after incubation at 37 degrees C during 24 hours. The obtained [(111)In]benzyl-DTPA-hEGF conjugate was characterized in vitro using the EGFR expressing glioma cell line U343MGaCl2:6. The binding affinity, internalization, and retention of the conjugate were studied. The conjugate had receptor specific binding and the radioactivity was quickly internalized. The intracellular retention of radioactivity after interrupted incubation with conjugate was 71% +/- 1% and 59% +/- 1.5% at 24 and 45 hours, respectively. The dissociation constant was estimated to 2.0 nM. The results indicate that [(111)In]benzyl-DTPA-hEGF is a potential candidate for targeting glioblastoma cells, possibly using locoregional injection.

Time trends in T3 to T4 laryngeal cancer: a population-based long-term analysis.

BACKGROUND: A decline in laryngectomies and survival in laryngeal cancer has been reported, especially among patients with advanced tumors. METHODS: Of 1058 patients with laryngeal cancer diagnosed from 1978 to 2007 in the Uppsala-Örebro region in Sweden, 263 T3 to T4 tumors treated with curative intent were studied retrospectively. Two time periods were defined, 1978 to 1992 and 1993 to 2007. RESULTS: Glottic tumors decreased constituting 68.6% of cases in 1978 to 1992 and 47.9% in 1993 to 2007. Laryngectomies were performed in 38.8% and 34.5% in the corresponding time periods. The use of laryngectomy was not strongly prognostic. A decline in overall survival (OS) over time could only be identified for the first year of follow-up. Chemotherapy was only used in a minority of cases. CONCLUSION: The marked decrease of glottic site may mark a shift in etiology. Laryngectomy was not strongly associated with improved survival. The absence of improved survival calls for intensified research.