Intratumoral retrograde microdialysis treatment of high-grade glioma with cisplatin.

PURPOSE: This study evaluates the application of a microdialysis technique for interstitial chemotherapy using cisplatin in high-grade glioma. METHOD: An in vitro study demonstrated that cisplatin can be administered through retrograde microdialysis and defined the recovery for cisplatin. In a subsequent phase I study, 1-4 microdialysis catheters were implanted in tumor tissue, brain adjacent to tumor (BAT) tissue, and subcutaneous tissue in 10 patients with recurrent high-grade glioma. Cisplatin was administered continuously in daily doses between 0.3 and 3.9 mg for 4 to12 days. Microdialysis samples were continuously collected and analyzed for glucose metabolites, glutamate, glycerol, and cisplatin concentrations. Treatment tolerability was evaluated through clinical monitoring. Quality of life was assessed using the EORTC-QLQ-C30 questionnaire for up to 3 months after treatment. RESULTS: This in vitro study showed that cisplatin could be administrated with a recovery of 41-97%, depending on flowrate, type of catheter, and cisplatin concentration. During the treatment, patients were exposed to a total dose of 1.2-36.8 mg cisplatin. The concentration of cisplatin in BAT, serum, and subcutaneous tissue was close to detection level in all but two patients. A transient neurologic deterioration due to edema was commonly observed, but no systemic side effects were recorded. After onset of treatment, concentrations of glutamate and glycerol were significantly increased in tumor tissue but not in BAT, with a peak after 3 days, and consistent for the rest of the treatment. Five of the patients survived between 153 and 492 days after treatment. CONCLUSION: This phase I study demonstrates that retrograde microdialysis can be used to administer cisplatin interstitially into high-grade glioma tissue. A high cytotoxicity was detected in tumor tissue, but not in the surrounding brain. Retrograde microdialysis appears to be a clinically useful method for intratumoral drug administration in high-grade glioma.

Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma.

BACKGROUND: High-grade gliomas are associated with poor prognosis. Tumour heterogeneity and invasiveness create challenges for effective treatment and use of systemically administrated drugs. Furthermore, lack of functional predictive response-assays based on drug efficacy complicates evaluation of early treatment responses. METHODS: We used microdialysis to deliver cisplatin into the tumour and to monitor levels of metabolic compounds present in the tumour and non-malignant brain tissue adjacent to tumour, before and during treatment. In parallel, we collected serum samples and used multivariate statistics to analyse the metabolic effects. RESULTS: We found distinct metabolic patterns in the extracellular fluids from tumour compared to non-malignant brain tissue, including high concentrations of a wide range of amino acids, amino acid derivatives and reduced levels of monosaccharides and purine nucleosides. We found that locoregional cisplatin delivery had a strong metabolic effect at the tumour site, resulting in substantial release of glutamic acid, phosphate, and spermidine and a reduction of cysteine levels. In addition, patients with long-time survival displayed different treatment response patterns in both tumour and serum. Longer survival was associated with low tumour levels of lactic acid, glyceric acid, ketoses, creatinine and cysteine. Patients with longer survival displayed lower serum levels of ketohexoses, fatty acid methyl esters, glycerol-3-phosphate and alpha-tocopherol, while elevated phosphate levels were seen in both tumour and serum during treatment. CONCLUSION: We highlight distinct metabolic patterns associated with high-grade tumour metabolism, and responses to cytotoxic cisplatin treatment.

Gray-level invariant Haralick texture features.

Haralick texture features are common texture descriptors in image analysis. To compute the Haralick features, the image gray-levels are reduced, a process called quantization. The resulting features depend heavily on the quantization step, so Haralick features are not reproducible unless the same quantization is performed. The aim of this work was to develop Haralick features that are invariant to the number of quantization gray-levels. By redefining the gray-level co-occurrence matrix (GLCM) as a discretized probability density function, it becomes asymptotically invariant to the quantization. The invariant and original features were compared using logistic regression classification to separate two classes based on the texture features. Classifiers trained on the invariant features showed higher accuracies, and had similar performance when training and test images had very different quantizations. In conclusion, using the invariant Haralick features, an image pattern will give the same texture feature values independent of image quantization.

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial.

INTRODUCTION: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ. PATIENTS AND METHODS: Patients, after surgery for GBM or AA, age ≤60 years and performance status (PS) 0-2, were randomized to either 2-3 cycles of TMZ, 200 mg/m2 days 1-5 every 28 days, followed by RT 60 Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75 mg/m2 was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety. RESULTS: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24-60) and 89 (62%) were male. PS was 0-1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p = .76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p = .022). For patients with GBM, no difference in survival was observed (p = .10). MGMT and IDH status affected outcome. CONCLUSIONS: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.

Haralick texture features from apparent diffusion coefficient (ADC) MRI images depend on imaging and pre-processing parameters.

In recent years, texture analysis of medical images has become increasingly popular in studies investigating diagnosis, classification and treatment response assessment of cancerous disease. Despite numerous applications in oncology and medical imaging in general, there is no consensus regarding texture analysis workflow, or reporting of parameter settings crucial for replication of results. The aim of this study was to assess how sensitive Haralick texture features of apparent diffusion coefficient (ADC) MR images are to changes in five parameters related to image acquisition and pre-processing: noise, resolution, how the ADC map is constructed, the choice of quantization method, and the number of gray levels in the quantized image. We found that noise, resolution, choice of quantization method and the number of gray levels in the quantized images had a significant influence on most texture features, and that the effect size varied between different features. Different methods for constructing the ADC maps did not have an impact on any texture feature. Based on our results, we recommend using images with similar resolutions and noise levels, using one quantization method, and the same number of gray levels in all quantized images, to make meaningful comparisons of texture feature results between different subjects.

A Retrospective Evaluation of Bevacizumab Treatment in Patients with Progressive Malignant Glioma in Northern Sweden.

BACKGROUND/AIM: Overall survival for glioblastoma patients is short. Standard treatment is surgery followed by radiochemotherapy and adjuvant temozolomide. The aim of this study was to evaluate the outcome for all patients with progressive disease treated with bevacizumab-based treatment combinations in the northern region of Sweden. PATIENTS AND METHODS: This was a single-center retrospective analysis after bevacizumab-based second-line treatment for malignant glioma. All patients treated with bevacizumab, between 2007 and 2011 in our Center were retrospectively evaluated. RESULTS: Progression-free survival after the start of bevacizumab-based treatment was 20 weeks and overall survival was 31 weeks. Treatment was well tolerated, but 9% of patients (n=6) suffered from serious adverse events. In 68% of patients, a ≥25% decrease in contrast enhancement was seen at best response. CONCLUSION: Results from this retrospective study are comparable with earlier phase-II studies and motivate randomized trials of bevacizumab-based treatment in the second-line setting.

Effect of Increased Radiotoxicity on Survival of Patients with Non-small Cell Lung Cancer Treated with Curatively Intended Radiotherapy.

AIM: To elucidate the impact of different forms of radiation toxicities (esophagitis, radiation pneumonitis, mucositis and hoarseness), on the survival of patients treated with curatively intended radiotherapy for non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Data were individually collected retrospectively for all patients diagnosed with NSCLC subjected to curatively intended radiotherapy (≥50 Gy) in Sweden during the time period 1990 to 2000. RESULTS: Esophagitis was the only radiation-induced toxicity with an impact on survival (hazard ratio=0.83, p=0.016). However, in a multivariate model, with clinical- and treatment-related factors taken into consideration, the impact of esophagitis on survival was no longer statistically significant (hazard ratio=0.88, p=0.17). CONCLUSION: The effect on survival seen in univariate analysis may be related to higher radiation dose and to the higher prevalence of chemotherapy in this group. The results do not suggest that the toxicities examined have any detrimental effect on overall survival.

Accuracy of inverse treatment planning on substitute CT images derived from MR data for brain lesions.

BACKGROUND: In this pilot study we evaluated the performance of a substitute CT (s-CT) image derived from MR data of the brain, as a basis for optimization of intensity modulated rotational therapy, final dose calculation and derivation of reference images for patient positioning. METHODS: S-CT images were created using a Gaussian mixture regression model on five patients previously treated with radiotherapy. Optimizations were compared using D max, D min, D median and D mean measures for the target volume and relevant risk structures. Final dose calculations were compared using gamma index with 1%/1 mm and 3%/3 mm acceptance criteria. 3D geometric evaluation was conducted using the DICE similarity coefficient for bony structures. 2D geometric comparison of digitally reconstructed radiographs (DRRs) was performed by manual delineation of relevant structures on the s-CT DRR that were transferred to the CT DRR and compared by visual inspection. RESULTS: Differences for the target volumes in optimization comparisons were small in general, e.g. a mean difference in both D min and D max within ±0.3%. For the final dose calculation gamma evaluations, 100% of the voxels passed the 1%/1 mm criterion within the PTV. Within the entire external volume between 99.4% and 100% of the voxels passed the 3%/3 mm criterion. In the 3D geometric comparison, the DICE index varied between approximately 0.8-0.9, depending on the position in the skull. In the 2D DRR comparisons, no appreciable visual differences were found. CONCLUSIONS: Even though the present work involves a limited number of patients, the results provide a strong indication that optimization and dose calculation based on s-CT data is accurate regarding both geometry and dosimetry.

Brain tumors in Sweden: data from a population-based registry 1999-2012.

BACKGROUND: The Swedish brain tumor registry has, since it was launched in 1999, provided significant amounts of data on histopathological diagnoses and on important aspects of surgical and medical management of these patients. The purpose is mainly quality control, but also as a resource for research. METHODS: Three Swedish healthcare regions, constituting 40% of the Swedish population, have had an almost complete registration. The following parameters are registered: diagnosis according to SNOMED/WHO classification, symptoms, performance status, pre- and postoperative radiology, tumor size and localization, extent of surgery and occurrence of postoperative complications, postoperative treatment, such as radiotherapy and/or chemotherapy, other treatments, complications and toxicity, occurrence of reoperation/s, participation in clinical trials, multidisciplinary conferences and availability of a contact nurse. RESULTS: Surgical radicality has been essentially constant, whereas the use of early (within 72 hours) postoperative CT and MRI has increased, especially for high-grade glioma, which is a reflection of quality of surgery. Survival of patients with high-grade glioma has increased, especially in the age group 60-69. Patients aged 18-39 years had a five-year survival of 40%. Waiting times for the pathological report has been slightly prolonged. Geographical differences do exist for some of the variables. CONCLUSION: Population-based registration is valuable for assessment of clinical management, which could have impact on patient care. As a result of short survival and/or the propensity to affect cognitive functions this patient group has considerable difficulties to make their voices heard in society. We therefore believe that a report like the present one can contribute to the spread of knowledge and increase the awareness for this patient group among caregivers and policy makers.

ADC texture--an imaging biomarker for high-grade glioma?

PURPOSE: Survival for high-grade gliomas is poor, at least partly explained by intratumoral heterogeneity contributing to treatment resistance. Radiological evaluation of treatment response is in most cases limited to assessment of tumor size months after the initiation of therapy. Diffusion-weighted magnetic resonance imaging (MRI) and its estimate of the apparent diffusion coefficient (ADC) has been widely investigated, as it reflects tumor cellularity and proliferation. The aim of this study was to investigate texture analysis of ADC images in conjunction with multivariate image analysis as a means for identification of pretreatment imaging biomarkers. METHODS: Twenty-three consecutive high-grade glioma patients were treated with radiotherapy (2 Gy/60 Gy) with concomitant and adjuvant temozolomide. ADC maps and T1-weighted anatomical images with and without contrast enhancement were collected prior to treatment, and (residual) tumor contrast enhancement was delineated. A gray-level co-occurrence matrix analysis was performed on the ADC maps in a cuboid encapsulating the tumor in coronal, sagittal, and transversal planes, giving a total of 60 textural descriptors for each tumor. In addition, similar examinations and analyses were performed at day 1, week 2, and week 6 into treatment. Principal component analysis (PCA) was applied to reduce dimensionality of the data, and the five largest components (scores) were used in subsequent analyses. MRI assessment three months after completion of radiochemotherapy was used for classifying tumor progression or regression. RESULTS: The score scatter plots revealed that the first, third, and fifth components of the pretreatment examinations exhibited a pattern that strongly correlated to survival. Two groups could be identified: one with a median survival after diagnosis of 1099 days and one with 345 days, p = 0.0001. CONCLUSIONS: By combining PCA and texture analysis, ADC texture characteristics were identified, which seems to hold pretreatment prognostic information, independent of known prognostic factors such as age, stage, and surgical procedure. These findings encourage further studies with a larger patient cohort.

CT substitutes derived from MR images reconstructed with parallel imaging.

PURPOSE: Computed tomography (CT) substitute images can be generated from ultrashort echo time (UTE) MRI sequences with radial k-space sampling. These CT substitutes can be used as ordinary CT images for PET attenuation correction and radiotherapy dose calculations. Parallel imaging allows faster acquisition of magnetic resonance (MR) images by exploiting differences in receiver coil element sensitivities. This study investigates whether non-Cartesian parallel imaging reconstruction can be used to improve CT substitutes generated from shorter examination times. METHODS: The authors used gridding as well as two non-Cartesian parallel imaging reconstruction methods, SPIRiT and CG-SENSE, to reconstruct radial UTE and gradient echo (GE) data into images of the head for 23 patients. For each patient, images were reconstructed from the full dataset and from a number of subsampled datasets. The subsampled datasets simulated shorter acquisition times by containing fewer radial k-space spokes (1000, 2000, 3000, 5000, and 10,000 spokes) than the full dataset (30,000 spokes). For each combination of patient, reconstruction method, and number of spokes, the reconstructed UTE and GE images were used to generate a CT substitute. Each CT substitute image was compared to a real CT image of the same patient. RESULTS: The mean absolute deviation between the CT number in CT substitute and CT decreased when using SPIRiT as compared to gridding reconstruction. However, the reduction was small and the CT substitute algorithm was insensitive to moderate subsampling (≥ 5000 spokes) regardless of reconstruction method. For more severe subsampling (≤ 3000 spokes), corresponding to acquisition times less than a minute long, the CT substitute quality was deteriorated for all reconstruction methods but SPIRiT gave a reduction in the mean absolute deviation of down to 25 Hounsfield units compared to gridding. CONCLUSIONS: SPIRiT marginally improved the CT substitute quality for a given number of radial spokes as compared to gridding. However, the increased reconstruction time of non-Cartesian parallel imaging reconstruction is difficult to motivate from this improvement. Because the CT substitute algorithm was insensitive to moderate subsampling, data for a CT substitute could be collected in as little as minute and reconstructed with gridding without deteriorating the CT substitute quality.

Improved quality of computed tomography substitute derived from magnetic resonance (MR) data by incorporation of spatial information--potential application for MR-only radiotherapy and attenuation correction in positron emission tomography.

BACKGROUND: Estimation of computed tomography (CT) equivalent data, i.e. a substitute CT (s-CT), from magnetic resonance (MR) images is a prerequisite both for attenuation correction of positron emission tomography (PET) data acquired with a PET/MR scanner and for dose calculations in an MR-only radiotherapy workflow. It has previously been shown that it is possible to estimate Hounsfield numbers based on MR image intensities, using ultra short echo-time imaging and Gaussian mixture regression (GMR). In the present pilot study we investigate the possibility to also include spatial information in the GMR, with the aim to improve the quality of the s-CT. MATERIAL AND METHODS: MR and CT data for nine patients were used in the present study. For each patient, GMR models were created from the other eight patients, including either both UTE image intensities and spatial information on a voxel by voxel level, or only UTE image intensities. The models were used to create s-CT images for each respective patient. RESULTS: The inclusion of spatial information in the GMR model improved the accuracy of the estimated s-CT. The improvement was most pronounced in smaller, complicated anatomical regions as the inner ear and post-nasal cavities. CONCLUSIONS: This pilot study shows that inclusion of spatial information in GMR models to convert MR data to CT equivalent images is feasible. The accuracy of the s-CT is improved and the spatial information could make it possible to create a general model for the conversion applicable to the whole body.

Treatment planning of intracranial targets on MRI derived substitute CT data.

BACKGROUND: The use of magnetic resonance imaging (MRI) as a complement to computed tomography (CT) in the target definition procedure for radiotherapy is increasing. To eliminate systematic uncertainties due to image registration, a workflow based entirely on MRI may be preferable. In the present pilot study, we investigate dose calculation accuracy for automatically generated substitute CT (s-CT) images of the head based on MRI. We also produce digitally reconstructed radiographs (DRRs) from s-CT data to evaluate the feasibility of patient positioning based on MR images. METHODS AND MATERIALS: Five patients were included in the study. The dose calculation was performed on CT, s-CT, s-CT data without inhomogeneity correction and bulk density assigned MRI images. Evaluation of the results was performed using point dose and dose volume histogram (DVH) comparisons, and gamma index evaluation. RESULTS: The results demonstrate that the s-CT images improve the dose calculation accuracy compared to the method of non-inhomogeneity corrected dose calculations (mean improvement 2.0% points) and that it performs almost identically to the method of bulk density assignment. The s-CT based DRRs appear to be adequate for patient positioning of intra-cranial targets, although further investigation is needed on this subject. CONCLUSION: The s-CT method is very fast and yields data that can be used for treatment planning without sacrificing accuracy.

Evaluation of an attenuation correction method for PET/MR imaging of the head based on substitute CT images.

OBJECT: The aim of this study was to evaluate MR-based attenuation correction of PET emission data of the head, based on a previously described technique that calculates substitute CT (sCT) images from a set of MR images. MATERIALS AND METHODS: Images from eight patients, examined with (18)F-FLT PET/CT and MRI, were included. sCT images were calculated and co-registered to the corresponding CT images, and transferred to the PET/CT scanner for reconstruction. The new reconstructions were then compared with the originals. The effect of replacing bone with soft tissue in the sCT-images was also evaluated. RESULTS: The average relative difference between the sCT-corrected PET images and the CT-corrected PET images was 1.6% for the head and 1.9% for the brain. The average standard deviations of the relative differences within the head were relatively high, at 13.2%, primarily because of large differences in the nasal septa region. For the brain, the average standard deviation was lower, 4.1%. The global average difference in the head when replacing bone with soft tissue was 11%. CONCLUSION: The method presented here has a high rate of accuracy, but high-precision quantitative imaging of the nasal septa region is not possible at the moment.

Uncertainty estimation in dynamic contrast-enhanced MRI.

Using dynamic contrast-enhanced MRI (DCE-MRI), it is possible to estimate pharmacokinetic (PK) parameters that convey information about physiological properties, e.g., in tumors. In DCE-MRI, errors propagate in a nontrivial way to the PK parameters. We propose a method based on multivariate linear error propagation to calculate uncertainty maps for the PK parameters. Uncertainties in the PK parameters were investigated for the modified Kety model. The method was evaluated with Monte Carlo simulations and exemplified with in vivo brain tumor data. PK parameter uncertainties due to noise in dynamic data were accurately estimated. Noise with standard deviation up to 15% in the baseline signal and the baseline T1 map gave estimated uncertainties in good agreement with the Monte Carlo simulations. Good agreement was also found for up to 15% errors in the arterial input function amplitude. The method was less accurate for errors in the bolus arrival time with disagreements of 23%, 32%, and 29% for K(trans) , ve , and vp , respectively, when the standard deviation of the bolus arrival time error was 5.3 s. In conclusion, the proposed method provides efficient means for calculation of uncertainty maps, and it was applicable to a wide range of sources of uncertainty.

Synergistic killing of glioblastoma stem-like cells by bortezomib and HDAC inhibitors.

BACKGROUND: The malignant brain tumour glioblastoma is a devastating disease that remains a therapeutic challenge. MATERIALS AND METHODS: Effects of combinations of the US Food and Drug Administation (FDA) approved proteasome inhibitor bortezomib and the histone deacetylase (HDAC) inhibitors vorinostat, valproic acid and sodium phenylbutyrate were studied on primary glioblastoma stem cell lines and conventional glioblastoma cell lines. Cell survival, proliferation and death were analyzed by fluorometric microculture cytotoxicity assay (FMCA), propidium iodide labeling and flow cytometry, and cell cloning through limiting dilution and live-cell bright-field microscopy. RESULTS: Bortezomib and the HDAC inhibitors showed synergistic cell killing at clinically relevant drug concentrations, while the conventional cell lines cultured in serum-containing medium were relatively resistant to the same treatments. CONCLUSION: These findings of synergistic glioblastoma stem cell killing by bortezomib and three different FDA-approved HDAC inhibitors confirm and expand previous observations on co-operative effects between these classes of drugs.

Voxel-wise uncertainty in CT substitute derived from MRI.

PURPOSE: In an earlier work, we demonstrated that substitutes for CT images can be derived from MR images using ultrashort echo time (UTE) sequences, conventional T2 weighted sequences, and Gaussian mixture regression (GMR). In this study, we extend this work by analyzing the uncertainties associated with the GMR model and the information contributions from the individual imaging sequences. METHODS: An analytical expression for the voxel-wise conditional expected absolute deviation (EAD) in substitute CT (s-CT) images was derived. The expression depends only on MR images and can thus be calculated along with each s-CT image. The uncertainty measure was evaluated by comparing the EAD to the true mean absolute prediction deviation (MAPD) between the s-CT and CT images for 14 patients. Further, the influence of the different MR images included in the GMR model on the generated s-CTs was investigated by removing one or more images and evaluating the MAPD for a spectrum of predicted radiological densities. RESULTS: The largest EAD was predicted at air-soft tissue and bone-soft tissue interfaces. The EAD agreed with the MAPD in both these regions and in regions with lower EADs, such as the brain. Two of the MR images included in the GMR model were found to be mutually redundant for the purpose of s-CT generation. CONCLUSIONS: The presented uncertainty estimation method accurately predicts the voxel-wise MAPD in s-CT images. Also, the non-UTE sequence previously used in the model was found to be redundant.