Oana Craciunescu

Pulsatile blood flow effects on temperature distribution and heat transfer in rigid vessels

The effect of blood velocity pulsations on bioheat transfer is studied. A simple model of a straight rigid blood vessel with unsteady periodic flow is considered. A numerical solution that considers the fully coupled Navier-Stokes and energy equations is used for the simulations. The influence of the pulsation rate on the temperature distribution and energy transport is studied for four typical vessel sizes: aorta, large arteries, terminal arterial branches, and arterioles. The results show that: the pulsating axial velocity produces a pulsating temperature distribution; reversal of flow occurs in the aorta and in large vessels, which produces significant time variation in the temperature profile. Change of the pulsation rate yields a change of the energy transport between the vessel wall and fluid for the large vessels. For the thermally important terminal arteries (0.04-1 mm), velocity pulsations have a small influence on temperature distribution and on the energy transport out of the vessels (8 percent for the Womersley number corresponding to a normal heart rate). Given that there is a small difference between the time-averaged unsteady heat flux due to a pulsating blood velocity and an assumed nonpulsating blood velocity, it is reasonable to assume a nonpulsating blood velocity for the purposes of estimating bioheat transfer.

Feasibility of optimizing the dose distribution in lung tumors using fluorine‐18‐fluorodeoxyglucose positron emission tomography and single photon emission computed tomography guided dose prescriptions

The information provided by functional images may be used to guide radiotherapy planning by identifying regions that require higher radiation dose. In this work we investigate the dosimetric feasibility of delivering dose to lung tumors in proportion to the fluorine-18-fluorodeoxyglucose activity distribution from positron emission tomography (FDG-PET). The rationale for delivering dose in proportion to the tumor FDG-PET activity distribution is based on studies showing that FDG uptake is correlated to tumor cell proliferation rate, which is shown to imply that this dose delivery strategy is theoretically capable of providing the same duration of local control at all voxels in tumor. Target dose delivery was constrained by single photon emission computed tomography (SPECT) maps of normal lung perfusion, which restricted irradiation of highly perfused lung and imposed dose-function constraints. Dose-volume constraints were imposed on all other critical structures. All dose-volume/function constraints were considered to be soft, i.e., critical structure doses corresponding to volume/function constraint levels were minimized while satisfying the target prescription, thus permitting critical structure doses to minimally exceed dose constraint levels. An intensity modulation optimization methodology was developed to deliver this radiation, and applied to two lung cancer patients. Dosimetric feasibility was assessed by comparing spatially normalized dose-volume histograms from the nonuniform dose prescription (FDG-PET proportional) to those from a uniform dose prescription with equivalent tumor integral dose. In both patients, the optimization was capable of delivering the nonuniform target prescription with the same ease as the uniform target prescription, despite SPECT restrictions that effectively diverted dose from high to low perfused normal lung. In one patient, both prescriptions incurred similar critical structure dosages, below dose-volume/function limits. However, in the other patient, critical structure dosage from the nonuniform dose prescription exceeded dose-volume/function limits, and greatly exceeded that from the uniform dose prescription. Strict compliance to dose-volume/ function limits would entail reducing dose proportionality to the FDG-PET activity distribution, thereby theoretically reducing the duration of local control. Thus, even though it appears feasible to tailor lung tumor dose to the FDG-PET activity distribution, despite SPECT restrictions, strict adherence to dose-volume/function limits could compromise the effectiveness of functional image guided radiotherapy.

Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: A review of the randomised data

Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation.

Concurrent Stereotactic Radiosurgery and Bevacizumab in Recurrent Malignant Gliomas: A Prospective Trial

PURPOSE Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG. METHODS AND MATERIALS Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status. RESULTS One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months. CONCLUSIONS Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach.

Prospective Trial of Synchronous Bevacizumab, Erlotinib, and Concurrent Chemoradiation in Locally Advanced Head and Neck Cancer

Purpose: We assessed the safety and efficacy of synchronous VEGF and epidermal growth factor receptor (EGFR) blockade with concurrent chemoradiation (CRT) in locally advanced head and neck cancer (HNC). Experimental Design: Newly diagnosed patients with stage III/IV HNC received a 2-week lead-in of bevacizumab and/or erlotinib, followed by both agents with concurrent cisplatin and twice daily radiotherapy. Safety was assessed using Common Toxicity Criteria version 3.0. The primary efficacy endpoint was clinical complete response (CR) rate after CRT. Results: Twenty-nine patients enrolled on study, with 27 completing therapy. Common grade III toxicities were mucositis (n = 14), dysphagia (n = 8), dehydration (n = 7), osteoradionecrosis (n = 3), and soft tissue necrosis (n = 2). Feeding tube placement was required in 79% but no patient remained dependent at 12-month posttreatment. Clinical CR after CRT was 96% [95% confidence interval (CI), 82%–100%]. Median follow-up was 46 months in survivors, with 3-year locoregional control and distant metastasis-free survival rates of 85% and 93%. Three-year estimated progression-free survival, disease-specific survival, and overall survival rates were 82%, 89%, and 86%, respectively. Dynamic contrast enhanced MRI (DCE-MRI) analysis showed that patients who had failed had lower baseline pretreatment median Ktrans values, with subsequent increases after lead-in therapy and 1 week of CRT. Patients who did not fail had higher median Ktrans values that decreased during therapy. Conclusions: Dual VEGF/EGFR inhibition can be integrated with CRT in locally advanced HNC, with efficacy that compares favorably with historical controls albeit with an increased risk of osteoradionecrosis. Pretreatment and early DCE-MRI may prospectively identify patients at high risk of failure. Clin Cancer Res; 18(5); 1404–14. ©2012 AACR.

A phase I/II study of neoadjuvant liposomal doxorubicin, paclitaxel, and hyperthermia in locally advanced breast cancer.

Purpose: The prognosis for locally advanced breast cancer (LABC) patients continues to be poor, with an estimated five-year survival of only 50–60%. Preclinical data demonstrates enhanced therapeutic efficacy with liposomal encapsulation of doxorubicin combined with hyperthermia (HT). Therefore this phase I/II study was designed to evaluate the safety and efficacy of a novel neoadjuvant combination treatment of paclitaxel, liposomal doxorubicin, and hyperthermia. Materials and methods: Eligible patients received four cycles of neoadjuvant liposomal doxorubicin (30–75 mg/m2), paclitaxel (100–175 mg/m2), and hyperthermia. They subsequently underwent either a modified radical mastectomy or lumpectomy with axillary node dissection followed by radiation therapy and then eight cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy. Results: Forty-seven patients with stage IIB-III LABC were enrolled and 43 patients were evaluable. Fourteen patients (33%) had inflammatory breast cancer. Combined (partial + complete) clinical response rate was 72% and combined pathological response rate was 60%. Four patients achieved a pathologically complete response. Sixteen patients were eligible for breast-conserving surgery. The cumulative equivalent minutes (CEM 43) at T90 (tenth percentile of temperature distribution) was significantly greater for those with a pathological response. Four-year disease-free survival was 63% (95% CI, 46%–76%) and the four-year overall survival was 75% (95% CI, 58–86%). Conclusions: Neoadjuvant therapy using paclitaxel, liposomal doxorubicin and hyperthermia is a feasible and well tolerated treatment strategy in patients with LABC. The thermal dose parameter CEM 43 T90 was significantly correlated with attaining a pathological response.

Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer

Abstract Purpose: Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population. Patients and methods: This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21–35 days, followed immediately by chest wall MLHT for 1 hour at 40–42 °C. In the first trial 18 subjects received LTLD at 20, 30, or 40 mg/m2; in the second trial, 11 subjects received LTLD at 40 or 50 mg/m2. Results: The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256 mg/m2 of prior anthracyclines and a median dose of 61 Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50 mg/m2, with seven subjects (24%) developing reversible grade 3–4 neutropenia and four (14%) reversible grade 3–4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30–66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses. Conclusion: LTLD at 50 mg/m2 and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population.

Evaluation of antioxidant and cytoprotective activities of Arnica montana L. and Artemisia absinthium L. ethanolic extracts

BackgroundArnica montana L. and Artemisia absinthium L. (Asteraceae) are medicinal plants native to temperate regions of Europe, including Romania, traditionally used for treatment of skin wounds, bruises and contusions. In the present study, A. montana and A. absinthium ethanolic extracts were evaluated for their chemical composition, antioxidant activity and protective effect against H2O2-induced oxidative stress in a mouse fibroblast-like NCTC cell line.ResultsA. absinthium extract showed a higher antioxidant capacity than A. montana extract as Trolox equivalent antioxidant capacity, Oxygen radical absorbance capacity and 2,2-diphenyl-1-picrylhydrazyl free radical-scavenging activity, in correlation with its flavonoids and phenolic acids content. Both plant extracts had significant effects on the growth of NCTC cells in the range of 10–100 mg/L A. montana and 10–500 mg/L A. absinthium. They also protected fibroblast cells against hydrogen peroxide-induced oxidative damage, at the same doses. The best protection was observed in cell pre-treatment with 10 mg/L A. montana and 10–300 mg/L A. absinthium, respectively, as determined by Neutral red and lactate dehydrogenase assays. In addition, cell pre-treatment with plant extracts, at these concentrations, prevented morphological changes induced by hydrogen peroxide. Flow-cytometry analysis showed that pre-treatment with A. montana and A. absinthium extracts restored the proportion of cells in each phase of the cell cycle.ConclusionsA. montana and A. absinthium extracts, rich in flavonoids and phenolic acids, showed a good antioxidant activity and cytoprotective effect against oxidative damage in fibroblast-like cells. These results provide scientific support for the traditional use of A. montana and A. absinthium in treatment of skin disorders.

Accuracy of real time noninvasive temperature measurements using magnetic resonance thermal imaging in patients treated for high grade extremity soft tissue sarcomas

PURPOSE To establish accuracy of real time noninvasive temperature measurements using magnetic resonance thermal imaging in patients treated for high grade extremity soft tissue sarcomas. METHODS Protocol patients with advanced extremity sarcomas were treated with external beam radiation therapy and hyperthermia. Invasive temperature measures were compared to noninvasive magnetic resonance thermal imaging (MRTI) at 1.5 T performed during hyperthermia. Volumetric temperature rise images were obtained using the proton resonance frequency shift (PRFS) technique during heating in a 140 MHz miniannular phased array applicator. MRTI temperature changes were compared to invasive measurements of temperature with a multisensor fiber optic probe inside a #15 g catheter in the tumor. Since the PRFS technique is sensitive to drifts in the primary imaging magnetic field, temperature change distributions were corrected automatically during treatment using temperature-stable reference materials to characterize field changes in 3D. The authors analyzed MRT images and compared, in evaluable treatments, MR-derived temperatures to invasive temperatures measured in extremity sarcomas. Small regions of interest (ROIs) were specified near each invasive sensor identified on MR images. Temperature changes in the interstitial sensors were compared to the corresponding ROI PRFS-based temperature changes over the entire treatment and over the steady-state period. Nonevaluable treatments (motion/imaging artifacts, noncorrectable drifts) were not included in the analysis. RESULTS The mean difference between MRTI and interstitial probe measurements was 0.91 degrees C for the entire heating time and 0.85 degrees C for the time at steady state. These values were obtained from both tumor and normal tissue ROIs. When the analysis is done on just the tumor ROIs, the mean difference for the whole power on time was 0.74 degrees C and during the period of steady state was 0.62 degrees C. CONCLUSIONS The data show that for evaluable treatments, excellent correlation (deltaT < 1 degrees C) of MRTI-ROI and invasive measurements can be achieved, but that motion and other artifacts are still serious challenges that must be overcome in future work.

DCE-MRI Parameters Have Potential to Predict Response of Locally Advanced Breast Cancer Patients to Neoadjuvant Chemotherapy and Hyperthermia: A Pilot Study

Combined therapies represent a staple of modern medicine. For women treated with neoadjuvant chemotherapy (NA ChT) for locally advanced breast cancer (LABC), early determination of whether the patient will fail to respond can enable the use of alternative, more beneficial therapies. This is even more desirable when the combined therapy includes hyperthermia (HT), an efficient way to improve drug delivery, however, more costly and time consuming. There is data showing that this goal can be achieved using magnetic resonance imaging (MRI) with contrast agent (CA) enhancement. This work for the first time proposes combining the information extracted from pre-treatment MR imaging into a morpho-physiological tumour score (MPTS) with the hypothesis that this score will increase the prognostic efficacy, compared to each of its MR-derived components: morphological (derived from the shape of the tumour enhancement) and physiological (derived from the CA enhancement variance dynamics parameters). The MPTS was correlated with response as determined by both pathologic residual tumour and MRI imaging, and was shown to have potential to predict response. The MPTS was extracted from pre-treatment MRI parameters, so independent of the combined therapy used. Purpose: To use a novel morpho-physiological tumour score (MPTS) generated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict response to treatment. Materials and methods: A protocol was designed to acquire DCE-MRI images of 20 locally advanced breast cancer (LABC) patients treated with neoadjuvant chemotherapy (NA ChT) and hyperthermia (HT). Imaging was done over 30 min following bolus injection of gadopentetate-based contrast agent. Parametric maps were generated by fitting the signal intensity to a double exponential curve and were used to derive a morphological characterisation of the lesions. Enhancement-variance dynamics parameters, wash-in and wash-out parameters (WiP, WoP), were extracted. The morphological characterisation and the WiP and WoP were combined into a MPTS with the intent of achieving better prognostic efficacy. The MPTS was correlated with response to NA therapy as determined by pathological residual tumour and MRI imaging. Results: The contrast agent in all tumours typically peaked in the first 1–4 min. The tumours’ WiP and WoP varied considerably. The MPTS was highly correlated with whether the patients had a pathological response. This scoring system has a specificity of 78% and a sensitivity of 91% for predicting response to NA chemotherapy. The kappa was 0.69 with a 95% confidence interval of [0.38, 1] and a p-value of 0.002. Conclusions: This pilot study shows that the MPTS derived using pre-treatment MRI images has the potential to predict response to NA ChT and HT in LABC patients. Further prospective studies are needed to confirm the validity of these results.