Optic toxicity in radiation treatment of meningioma: a retrospective study in 213 patients.

In this retrospective evaluation, we correlated radiation dose parameters with occurrence of optical radiation-induced toxicities. 213 meningioma patients received radiation between 2000 and 2013. Radiation dose and clinical data were extracted from planning systems and patients' files. The range of follow-up period was 2-159 months (median 75 months). Median age of patients was 60 years (range 23-86). There were 163 female and 50 male patients. In 140 cases, at least one of the neuro-optic structures (optic nerves and chiasm) was inside the irradiated target volumes. We found 15 dry eye (7 %) and 24 cataract (11.2 %) cases. Median dose to affected lachrymal glands was 1.47 Gy and median dose to affected lenses was 1.05 Gy. Age and blood cholesterol level in patients with cataract were significantly higher. Patients with dry eye were significantly older. Only two patients with visual problems attributable to radiation treatment were seen. They did not have any risk factors. Maximum and median delivered doses to neuro-optic structures were not higher than 57.30 and 54.60 Gy respectively. Low percentages of cases with radiation induced high grade optic toxicities show that modern treatment techniques and doses are safe. In very few patients with optic side effects, doses to organs at risk were higher than the defined constraint doses. This observation leads to the problem of additional risk factors coming into play. The role of risk factors and safety of higher radiation doses in high grade meningiomas should be investigated in more comprehensive studies.

Simultaneous integrated vs. sequential boost in VMAT radiotherapy of high-grade gliomas.

BACKGROUND: In 20 patients with high-grade gliomas, we compared two methods of planning for volumetric-modulated arc therapy (VMAT): simultaneous integrated boost (SIB) vs. sequential boost (SEB). The investigation focused on the analysis of dose distributions in the target volumes and the organs at risk (OARs). METHOD: After contouring the target volumes [planning target volumes (PTVs) and boost volumes (BVs)] and OARs, SIB planning and SEB planning were performed. The SEB method consisted of two plans: in the first plan the PTV received 50 Gy in 25 fractions with a 2-Gy dose per fraction. In the second plan the BV received 10 Gy in 5 fractions with a dose per fraction of 2 Gy. The doses of both plans were summed up to show the total doses delivered. In the SIB method the PTV received 54 Gy in 30 fractions with a dose per fraction of 1.8 Gy, while the BV received 60 Gy in the same fraction number but with a dose per fraction of 2 Gy. RESULTS: All of the OARs showed higher doses (Dmax and Dmean) in the SEB method when compared with the SIB technique. The differences between the two methods were statistically significant in almost all of the OARs. Analysing the total doses of the target volumes we found dose distributions with similar homogeneities and comparable total doses. CONCLUSION: Our analysis shows that the SIB method offers advantages over the SEB method in terms of sparing OARs.

Quantitative assessment of hypoxia subtypes in microcirculatory supply units of malignant tumors using (immuno-)fluorescence techniques.

BACKGROUND AND PURPOSE: Hypoxia is a characteristic of tumors, is known to increase aggressiveness, and causes treatment resistance. Traditional classification suggests two types of hypoxia: chronic and acute. Acute hypoxia is mostly caused by transient disruptions in perfusion, while chronic hypoxia is caused by diffusion limitations. This classification may be insufficient in terms of pathogenetic and pathophysiological mechanisms. Therefore, we quantified hypoxia subtypes in tumors based on (immuno-)fluorescent marker distribution patterns in microcirculatory supply units (MCSUs). MATERIAL AND METHODS: Cryosections from hSCC lines (SAS, FaDu, UT-SCC-5, UT-SCC-14, UT-SCC-15) were analyzed. Hypoxia was identified by pimonidazole, perfusion by Hoechst 33342, and endothelial cells by CD31. The following patterns were identified in vital tumor tissue: (1) normoxia: Hoechst 33342 fluorescence around microvessels, no pimonidazole, (2) chronic hypoxia: Hoechst 33342 fluorescence around microvessels, pimonidazole distant from microvessels, (3) acute hypoxia: no Hoechst 33342 fluorescence around microvessels, pimonidazole in immediate vicinity of microvessels, and (4) hypoxemic hypoxia: Hoechst 33342 fluorescence and pimonidazole directly around microvessels. RESULTS: Quantitative assessment of MCSUs show predominance for normoxia in 4 out of 5 tumor lines (50.1-72.8%). Total hypoxia slightly prevails in UT-SCC-15 (56.9%). Chronic hypoxia is the dominant subtype (65.4-85.9% of total hypoxia). Acute hypoxia only accounts for 12.9-29.8% and hypoxemic hypoxia for 1.2-6.4% of total hypoxia. The fraction of perfused microvessels ranged from 82.5-96.6%. CONCLUSION: Chronic hypoxia is the prevailing subtype in MCSUs. Acute hypoxia and hypoxemic hypoxia account for only a small fraction. This approach enables assessment and recognition of different hypoxia subtypes including hypoxemic hypoxia and may facilitate methods to (clinically) identify and eliminate hypoxia.

Modern management of rare brain metastases in adults.

Brain metastases (BM) represent the main cause of intracranial neoplasms in adults, while being relatively less common in children. Today, better treatment options of the primary malignancy lead to higher remission rates as well as prolonged stable clinical conditions. This may in part explain the increased incidence of BM. Morbidity and mortality rates in patients with malignancies deteriorate significantly in cases of metastatic involvement of the central nervous system. Nowadays, especially modern management using surgical, medical, and radiotherapeutic options for treatment of BM tends to improve survival rates and enhance quality of life. Nonetheless, almost all treatment options are considered as palliative. In this review, we outline current knowledge of the incidence, diagnostic facilities, and therapeutic management of rare BM, with consideration of the basic aspects of the primary malignancy.

A planning comparison of dynamic IMRT for different collimator leaf thicknesses with helical tomotherapy and RapidArc for prostate and head and neck tumors.

PURPOSE: A comparative analysis of the three most advanced intensity-modulated radiotherapy (IMRT) techniques currently commercially available was performed. Treatment plans made in rotational techniques (helical tomotherapy [HT] and RapidArc) were compared with sliding-window IMRT (dIMRT) on a conventional linear accelerator using different leaf thicknesses (2.5 mm, 5 mm, and 10 mm). The influence of the different planning techniques on the coverage of planning volume and sparing of organs at risk (OARs) was investigated. PATIENTS AND METHODS: Nine patients with localized prostate and nine patients with head and neck cancer were chosen for this study. Treatment planning was performed in Eclipse (Varian) and in Tomotherapy planning software. Treatment plans were compared according to target volume coverage and sparing OARs, as well as by conformity and homogeneity index. RESULTS: For both investigated tumor sites, the dosimetric effects of leaf widths between 2.5 mm, 5 mm and 10 mm were shown to be small in regard to target coverage. Tomotherapy plans had better target coverage (higher minimum dose). For prostate cancer, better sparing of bladder and rectum was achieved with RapidArc and dIMRT plans. For head and neck cancer, best sparing of parotid glands was achieved in HT plans. There was no significant difference (p > 0.05) in sparing of OARs between the dIMRT plans with different leaf widths neither for prostate cancer nor for head and neck cancer. CONCLUSION: For prostate and head and neck cases, all investigated IMRT techniques provide highly conformal treatment plans in terms of both target coverage and critical structure sparing.

Tumor shrinkage assessed by volumetric MRI in the long-term follow-up after stereotactic radiotherapy of meningiomas.

PURPOSE: To evaluate tumor volume reduction in the follow-up of meningiomas after fractionated stereotactic radiotherapy (FSRT) or linac radiosurgery (RS) by using magnetic resonance imaging (MRI). PATIENTS AND METHODS: In 59 patients with skull base meningiomas, gross tumor volume (GTV) was outlined on contrast-enhanced MRI before and median 50 months (range 11-92 months) after stereotactic radiotherapy. MRI was performed as an axial three-dimensional gradient-echo T1-weighted sequence at 1.6 mm slice thickness without gap (3D-MRI). Results were compared to the reports of diagnostic findings. RESULTS: Mean tumor size of all 59 meningiomas was 13.9 ml (0.8-62.9 ml) before treatment. There was shrinkage of the treated meningiomas in all but one patient. Within a median volumetric follow-up of 50 months (11-95 months), an absolute mean volume reduction of 4 ml (0-18 ml) was seen. The mean relative size reduction compared to the volume before radiotherapy was 27% (0-73%). Shrinkage measured by 3D-MRI was greater at longer time intervals after radiotherapy. The mean size reduction was 17%, 23%, and 30% (at < 24 months, 24-48 months, and 48-72 months). CONCLUSION: By using 3D-MRI in almost all patients undergoing radiotherapy of a meningioma, tumor shrinkage is detected. The data presented here demonstrate that volumetric assessment from 3D-MRI provides additional information to routinely used radiologic response measurements. After FSRT or RS, a mean size reduction of 25-45% can be expected within 4 years.

Prognostic scores in brain metastases from breast cancer.

BACKGROUND: Prognostic scores might be useful tools both in clinical practice and clinical trials, where they can be used as stratification parameter. The available scores for patients with brain metastases have never been tested specifically in patients with primary breast cancer. It is therefore unknown which score is most appropriate for these patients. METHODS: Five previously published prognostic scores were evaluated in a group of 83 patients with brain metastases from breast cancer. All patients had been treated with whole-brain radiotherapy with or without radiosurgery or surgical resection. In addition, it was tested whether the parameters that form the basis of these scores actually have a prognostic impact in this biologically distinct group of brain metastases patients. RESULTS: The scores that performed best were the recursive partitioning analysis (RPA) classes and the score index for radiosurgery (SIR). However, disagreement between the parameters that form the basis of these scores and those that determine survival in the present group of patients and many reported data from the literature on brain metastases from breast cancer was found. With the four statistically significant prognostic factors identified here, a 3-tiered score can be created that performs slightly better than RPA and SIR. In addition, a 4-tiered score is also possible, which performs better than the three previous 4-tiered scores, incl. graded prognostic assessment (GPA) score and basic score for brain metastases (BSBM). CONCLUSION: A variety of prognostic models describe the survival of patients with brain metastases from breast cancer to a more or less satisfactory degree. However, the standard brain metastases scores might not fully appreciate the unique biology and time course of this disease, e.g., compared to lung cancer. It appears possible that inclusion of emerging prognostic factors will improve the results and allow for development and validation of a consensus score for broad clinical application. The model that is based on the authors own patient group, which is not large enough to fully evaluate a large number of potential prognostic factors, is meant to illustrate this point rather than to provide the definitive score.

Disease presentation and outcome in young patients (<40 years) with brain metastases from malignant melanoma.

While elderly patients with brain metastases from malignant melanoma apparently have an unfavourable prognosis, little information is available on disease presentation and treatment outcome in youngest patients. Considering this, our experience with radiation therapy in this particular subset was evaluated. Our database with 48 melanoma patients contained three patients aged <40 years. All received whole-brain radiation therapy plus steroids and individual systemic measures according to the institutional policy. In one case, brain metastases were present already at first diagnosis of melanoma. The maximum interval to diagnosis of brain metastases was 21 months. All the patients were male and had multiple lesions (at least 6) plus extracranial metastases. None of them died from extracranial disease. The maximum survival was 5 months. Thus, our young patients with brain metastases did not achieve a better outcome than intermediate age groups. Whole-brain radiation therapy was not able to provide durable CNS control. Prospective studies on treatment intensification appear warranted.

Disease presentation and treatment outcome in very young patients with brain metastases from lung cancer.

BACKGROUND: While elderly patients with brain metastases from lung cancer appear to have an unfavorable prognosis, little information is available on disease presentation and treatment outcome in very young patients. PATIENTS AND METHODS: Retrospective evaluation of radiation therapy in this particular subpopulation. The database with 149 lung cancer patients contained 9 patients aged <40 years. The majority received whole-brain radiation therapy with 30 Gy in 10 fractions plus steroids, with or without other local or systemic measures according to the institutional policy. RESULTS: Five patients had small-cell histology. Median Karnofsky performance score was 70. In 6 cases, brain metastases were present already at first diagnosis. Eight patients had multiple lesions. Of 8 patients with complete follow-up, only 1 died from spread to the central nervous system (CNS), all others from extracranial disease. Maximum survival was 26 months (median 7 months). CONCLUSION: Very young patients with brain metastases did not achieve a better outcome than intermediate age groups. Radiation therapy was able to provide durable CNS control in nearly all patients, while systemic failures remained the leading cause of death. Prospective studies on treatment intensification and quality of life in these patients appear warranted.

Disease presentation and outcome in very young patients with brain metastases from breast cancer.

AIMS AND BACKGROUND: Little information is available on disease presentation and treatment outcome in very young patients with brain metastases from breast cancer. Therefore, we evaluated our results in this group. METHODS: In our database, 7/74 breast cancer patients treated for brain metastases were < 40 years old. All received whole-brain radiation therapy plus individual local or systemic measures. RESULTS: In patients with information available, tumors were poorly differentiated and metastatic to the axillary lymph nodes at primary diagnosis. All patients had extracranial metastases. Two died from their brain disease within 5 months. Five patients died from extracranial progression after 3-84 months (2 long-term survivors beyond 2 years, characterized by single brain lesions and high performance status). CONCLUSIONS: Very young patients did not achieve a better outcome than intermediate age groups. Whole-brain radiation therapy plus surgery or radiosurgery provided durable CNS control in most of the patients. Improved systemic therapy appears to represent the key to a better outcome.

Is whole-brain radiotherapy effective and safe in elderly patients with brain metastases?

OBJECTIVE: The outcome of whole-brain radiotherapy in elderly patients with brain metastases is not well documented. As the number of such patients is expected to increase, we evaluated our results. METHODS: Seventeen patients aged 75-82 years were identified for this retrospective analysis. The majority received 30 Gy in 10 fractions plus steroids (without other local or systemic measures). The median Karnofsky performance score (KPS) was 70. RESULTS: Symptomatic improvement was observed in 53%. Median survival of the responding patients was 4.5 months. However, median survival of the non-responding patients was 1.4 months only. All patients that survived for more than 4 months had a KPS > or =70 and metachronous brain metastases. None of the patients with KPS <70 survived for more than 2.2 months. None of the patients developed severe acute toxicity. One patient developed severe late neurotoxicity. CONCLUSIONS: Most elderly patients with brain metastases have an unfavourable prognosis. However, as in other populations, assessment of KPS and few other factors might guide the choice of treatment. Radiation therapy might lead to symptomatic responses in approximately half of the patients, but long-term survivors appear at risk of neurotoxicity. As promising results were published from a retrospective radiosurgery series, prospective trials appear warranted.

Evaluation of late neurologic adverse events in patients with brain metastases from non-small cell lung cancer.

AIM: The purpose of this prospective evaluation was to assess the late neurologic adverse events and Karnofsky performance status (KPS) in patients with at least two brain metastases from non-small cell lung cancer treated with whole-brain radiotherapy (WBRT) with or without sequential systemic chemotherapy. PATIENTS AND METHODS: All patients were required to have an initial KPS of at least 70%. During the first six months, the patients were re-examined every four weeks, later every 3 months or whenever the clinical condition worsened. Due to slow accrual, the protocol was closed prematurely in 2005. Sixteen adult patients (median age 56 years) treated with 10x3 Gy were studied. RESULTS: Late adverse events > or = grade 2 (CTC AE v3.0) in imaging-confirmed absence of progressive brain metastases developed in 3 patients after a median of 5 months. With a median overall survival of 7 months, the actuarial risk of late adverse events at that time was 0% after WBRT alone and 37% after WBRT and chemotherapy. Thus, larger studies assessing the impact of multimodal treatment are recommended.

Analysis of long-term survivors of glioblastoma multiforme in a single institution with aggressive local retreatment protocol.

UNLABELLED: Current treatment methods result in survival beyond 2 years in just a minority of adult patients with glioblastoma multiforme (GBM). Our institution has used an aggressive policy of local retreatment, including surgery and radiotherapy, at first relapse. Long-term survival (>2 years) after such an approach was evaluated. PATIENTS AND METHODS: A retrospective analysis was carried out of all patients with confirmed histological diagnosis of GBM at relapse. Patients with oligodendroglial component or progression from low-grade glioma were not included. RESULTS: Out of the 30 patients managed with aggressive local retreatment, 8 survived for more than 2 years, but no 5-year survivors were observed. All were younger than 60 years, had a good performance status, RPA class III or IV and a long interval to relapse. Those with the longest survival times had also received two different chemotherapy regimens. However, two of the patients were never treated with chemotherapy. Survival from retreatment was 5-17 months. CONCLUSION: When selecting patients on the basis of the factors associated with long-term survival, the same sequence of surgery, radiotherapy and chemotherapy that should be considered at first diagnosis might provide a moderate survival extension.

Quantitative Analysis of [18F]FMISO PET for Tumor Hypoxia: Correlation of Modeling Results with Immunohistochemistry.

PURPOSE: Quantitative evaluation of tumor hypoxia based on H-1-(3-[18F]fluoro-2-hydroxypropyl)-2-nitroimidazole ([18F]FMISO) positron emission tomography (PET) can deliver important information for treatment planning in radiotherapy. However, the merits and limitations of different analysis methods in revealing the underlying physiological feature are not clear. This study aimed to assess these quantitative analysis methods with the support of immunohistological data. PROCEDURES: Sixteen nude mice bearing xenografted human squamous cell carcinomas (FaDu or CAL-33) were scanned using 2-h dynamic [18F]FMISO PET. Tumors were resected and sliced, and the hypoxia marker pimonidazole was immunostained followed by H&E staining. The pimonidazole signal was segmented using a k-means clustering algorithm, and the hypoxic fraction (HF) was calculated as the hypoxic area/viable tumor-tissue-area ratio pooled over three tissue slices from the apical, center, and basal layers. PET images were analyzed using various methods including static analysis [standard uptake value (SUV), tumor-to-blood ratio (T/B), tumor-to-muscle ratio (T/M)] and kinetic modeling (Casciari αk A , irreversible and reversible two-tissue compartment k 3, Thorwarth w A k 3, Patlak K i , Logan V d , Cho K), and correlated with HF. RESULTS: No significant correlation was found for static analysis. A significant correlation between k 3 of the irreversible two-tissue compartment model and HF was observed (r = 0.61, p = 0.01). The correlation between HF and αk A of the Casciari model could be improved through reducing local minima by testing more sets of initial values (r = 0.59, p = 0.02) or by reducing the model complexity by fixing three parameters (r = 0.63, p = 0.0008). CONCLUSIONS: With support of immunohistochemistry data, this study shows that various analysis methods for [18F]FMISO PET perform differently for assessment of tumor hypoxia. A better fitting quality does not necessarily mean a higher physiological correlation. Hypoxia PET analysis needs to consider both the mathematical stability and physiological fidelity. Based on the results of this study, preference should be given to the irreversible two-tissue compartment model as well as the Casciari model with reduced parameters.

Matching the reaction-diffusion simulation to dynamic [18F]FMISO PET measurements in tumors: extension to a flow-limited oxygen-dependent model.

Positron-emission tomography (PET) with hypoxia specific tracers provides a noninvasive method to assess the tumor oxygenation status. Reaction-diffusion models have advantages in revealing the quantitative relation between in vivo imaging and the tumor microenvironment. However, there is no quantitative comparison of the simulation results with the real PET measurements yet. The lack of experimental support hampers further applications of computational simulation models. This study aims to compare the simulation results with a preclinical [18F]FMISO PET study and to optimize the reaction-diffusion model accordingly. Nude mice with xenografted human squamous cell carcinomas (CAL33) were investigated with a 2 h dynamic [18F]FMISO PET followed by immunofluorescence staining using the hypoxia marker pimonidazole and the endothelium marker CD 31. A large data pool of tumor time-activity curves (TAC) was simulated for each mouse by feeding the arterial input function (AIF) extracted from experiments into the model with different configurations of the tumor microenvironment. A measured TAC was considered to match a simulated TAC when the difference metric was below a certain, noise-dependent threshold. As an extension to the well-established Kelly model, a flow-limited oxygen-dependent (FLOD) model was developed to improve the matching between measurements and simulations. The matching rate between the simulated TACs of the Kelly model and the mouse PET data ranged from 0 to 28.1% (on average 9.8%). By modifying the Kelly model to an FLOD model, the matching rate between the simulation and the PET measurements could be improved to 41.2-84.8% (on average 64.4%). Using a simulation data pool and a matching strategy, we were able to compare the simulated temporal course of dynamic PET with in vivo measurements. By modifying the Kelly model to a FLOD model, the computational simulation was able to approach the dynamic [18F]FMISO measurements in the investigated tumors.

11C-methionine PET improves the target volume delineation of meningiomas treated with stereotactic fractionated radiotherapy.

PURPOSE: To evaluate the role of 11C-methionine positron emission tomography (MET-PET) in target volume delineation for meningiomas and to determine the interobserver variability. METHODS AND MATERIALS: Two independent observers performed treatment planning in 10 patients according to a prospective written protocol. In the first step, they used coregistered computed tomography (CT) and magnetic resonance imaging (MRI). In the second step, MET-PET was added to CT/MRI (image fusion based on mutual information). RESULTS: The correlation between gross tumor volume (GTVs) delineated by the two observers based on CT/MRI was r=0.855 (Spearman's correlation coefficient, p=0.002) and r=0.988 (p=0.000) when MET-PET/CT/MRI were used. The number of patients with agreement in more then 80% of the outlined volume increased with the availability of MET-PET from 1 in 10 to 5 in 10. The median volume of intersection between the regions delineated by two observers increased significantly from 69% (from the composite volume) to 79%, by the addition of MET-PET (p=0.005). The information of MET-PET was useful to delineate GTV in the area of cavernous sinus, orbit, and base of the skull. CONCLUSIONS: The hypothesis-generating findings of potential normal tissue sparing and reduced interobserver variability provide arguments for invasive studies of the correlation between MET-PET images and histologic tumor extension and for prospective trials of target volume delineation with CT/MRI/MET-PET image fusion.

Extensive local and systemic therapy in extraneural metastasized glioblastoma multiforme.

Cases of extracranial metastases of glioblastoma multiforme to sites such as bones, spleen, lung, liver and kidneys have been reported but available information about treatment of organ and bone metastases is extremely scarce. In this report a case of glioblastoma multiforme (GBM) of the temporal lobe with subsequent liver and bone metastases is described and the success of different chemotherapy regimens is discussed. Liver and bone metastases were effectively treated with temozolomide and later with carboplatin and docetaxel. Two years after first diagnosis symptomatic local recurrence occurred. Therefore a stereotactic fractionated radiotherapy was performed. As a result of relapse of liver metastases the patient received chemotherapy with adriamycin, cyclophosphamide and etoposide. Visceral metastases were stable, but nevertheless the patient died from local progression 3 years after first diagnosis. In conclusion, liver metastases of GBM can be effectively treated by chemotherapy. This case report suggests suitable substances which can be chosen according to clinical circumstances.

Treatment of unresectable glioblastoma multiforme.

Uncertainty exists about the adequate treatment of adult patients with unresectable, primary, biopsy-proven glioblastoma multiforme (GBM), because the different options for this group of patients have not been evaluated in randomized clinical trials to date. Usually, these patients are lumped together in studies of radiotherapy or combined modality treatment with patients who have undergone extensive surgical resection, although they represent an unfavorable subgroup. This fact led us to review the recently published results for combined radio- and chemotherapy and to compare them with historical data. Management with best supportive care after biopsy resulted in a median survival time of 3 months. Median survival in a historical series of radiotherapy was of the order of 6-7 months and 2-year survival was less than 10%. Combined treatment consistently resulted in a 2-year survival rate of 10-18%. However, the median survival in contemporary series is highly variable, still ranging from 5 to 13 months. Even with the same regimen, large differences in outcome were observed (median survival 5 vs. 9.4 months). In a large randomized trial of radiotherapy vs. radiotherapy plus temozolomide, the subgroup with biopsy only did not benefit significantly from combined treatment. With different radiochemotherapy approaches, the median survival was approximately 5 months in recursive partitioning analysis (RPA) class VI, but 8-14 months in classes IV and V Thus, careful patient selection is necessary to avoid overtreatment in prognostically unfavorable groups with unresectable GBM. In patients qualifying for lengthy regimens of radio-chemotherapy, prospective randomized trials should study whether simultaneous radio- and chemotherapy is superior to radiotherapy alone and, if so, what are the effects of addition of either upfront chemotherapy orpostradiation chemotherapy. Recent data suggest that class prediction models, based on defined molecular profiles, and assessment of MGMT promoter methylation might contribute to improved patient stratification and decision making.

Radiotherapy-induced lung toxicity: risk factors and prevention strategies.

Radiotherapy-induced lung toxicity might compromise the success of current efforts regarding lung cancer treatment intensification. Compounds which prevent lung toxicity without affecting the radiosensitivity of the tumor can contribute to improvement of cure rates. Basic research on radiotherapy-induced lung reactions significantly improved our understanding of the molecular and cellular mechanisms underlying acute radiation pneumonitis and the tissue remodelling leading to lung fibrosis. Identification of mediators such as various adhesion molecules, cytokines and growth factors in this process allows for innovative intervention studies. This review summarizes translational research data as well as clinical strategies for response modification and prediction.

Preclinical evaluation of parametric image reconstruction of [18F]FMISO PET: correlation with ex vivo immunohistochemistry.

Compared to indirect methods, direct parametric image reconstruction (PIR) has the advantage of high quality and low statistical errors. However, it is not yet clear if this improvement in quality is beneficial for physiological quantification. This study aimed to evaluate direct PIR for the quantification of tumor hypoxia using the hypoxic fraction (HF) assessed from immunohistological data as a physiological reference. Sixteen mice with xenografted human squamous cell carcinomas were scanned with dynamic [18F]FMISO PET. Afterward, tumors were sliced and stained with H&E and the hypoxia marker pimonidazole. The hypoxic signal was segmented using k-means clustering and HF was specified as the ratio of the hypoxic area over the viable tumor area. The parametric Patlak slope images were obtained by indirect voxel-wise modeling on reconstructed images using filtered back projection and ordered-subset expectation maximization (OSEM) and by direct PIR (e.g., parametric-OSEM, POSEM). The mean and maximum Patlak slopes of the tumor area were investigated and compared with HF. POSEM resulted in generally higher correlations between slope and HF among the investigated methods. A strategy for the delineation of the hypoxic tumor volume based on thresholding parametric images at half maximum of the slope is recommended based on the results of this study.