Susanta K. Hui

Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS).

We have reviewed the studies on radiation-induced vascular changes in human and experimental tumors reported in the last several decades. Although the reported results are inconsistent, they can be generalized as follows. In the human tumors treated with conventional fractionated radiotherapy, the morphological and functional status of the vasculature is preserved, if not improved, during the early part of a treatment course and then decreases toward the end of treatment. Irradiation of human tumor xenografts or rodent tumors with 5–10 Gy in a single dose causes relatively mild vascular damages, but increasing the radiation dose to higher than 10 Gy/fraction induces severe vascular damage resulting in reduced blood perfusion. Little is known about the vascular changes in human tumors treated with high-dose hypofractionated radiation such as stereotactic body radiotherapy (SBRT) or stereotactic radiosurgery (SRS). However, the results for experimental tumors strongly indicate that SBRT or SRS of human tumors with doses higher than about 10 Gy/fraction is likely to induce considerable vascular damages and thereby damages the intratumor microenvironment, leading to indirect tumor cell death. Vascular damage may play an important role in the response of human tumors to high-dose hypofractionated SBRT or SRS.

Bone Marrow Adipose Tissue Is an Endocrine Organ that Contributes to Increased Circulating Adiponectin during Caloric Restriction

The adipocyte-derived hormone adiponectin promotes metabolic and cardiovascular health. Circulating adiponectin increases in lean states such as caloric restriction (CR), but the reasons for this paradox remain unclear. Unlike white adipose tissue (WAT), bone marrow adipose tissue (MAT) increases during CR, and both MAT and serum adiponectin increase in many other clinical conditions. Thus, we investigated whether MAT contributes to circulating adiponectin. We find that adiponectin secretion is greater from MAT than WAT. Notably, specific inhibition of MAT formation in mice results in decreased circulating adiponectin during CR despite unaltered adiponectin expression in WAT. Inhibiting MAT formation also alters skeletal muscle adaptation to CR, suggesting that MAT exerts systemic effects. Finally, we reveal that both MAT and serum adiponectin increase during cancer therapy in humans. These observations identify MAT as an endocrine organ that contributes significantly to increased serum adiponectin during CR and perhaps in other adverse states.

A framework for deformable image registration validation in radiotherapy clinical applications

Quantitative validation of deformable image registration (DIR) algorithms is extremely difficult because of the complexity involved in constructing a deformable phantom that can duplicate various clinical scenarios. The purpose of this study is to describe a framework to test the accuracy of DIR based on computational modeling and evaluating using inverse consistency and other methods. Three clinically relevant organ deformations were created in prostate (distended rectum and rectal gas), head and neck (large neck flexion), and lung (inhale and exhale lung volumes with variable contrast enhancement) study sets. DIR was performed using both B‐spline and diffeomorphic demons algorithms in the forward and inverse direction. A compositive accumulation of forward and inverse deformation vector fields was done to quantify the inverse consistency error (ICE). The anatomical correspondence of tumor and organs at risk was quantified by comparing the original RT structures with those obtained after DIR. Further, the physical characteristics of the deformation field, namely the Jacobian and harmonic energy, were computed to quantify the preservation of image topology and regularity of spatial transformation obtained in DIR. The ICE was comparable in prostate case but the B‐spline algorithm had significantly better anatomical correspondence for rectum and prostate than diffeomorphic demons algorithm. The ICE was 6.5 mm for demons algorithm for head and neck case when compared to 0.7 mm for B‐spline. Since the induced neck flexion was large, the average Dice similarity coefficient between both algorithms was only 0.87, 0.52, 0.81, and 0.67 for tumor, cord, parotids, and mandible, respectively. The B‐spline algorithm accurately estimated deformations between images with variable contrast in our lung study, while diffeomorphic demons algorithm led to gross errors on structures affected by contrast variation. The proposed framework offers the application of known deformations on any image datasets, to evaluate the overall accuracy and limitations of a DIR algorithm used in radiation oncology. The evaluation based on anatomical correspondence, physical characteristics of deformation field, and image characteristics can facilitate DIR verification with the ultimate goal of implementing adaptive radiotherapy. The suitability of application of a particular evaluation metric in validating DIR is dependent on the clinical deformation observed. PACS numbers: 87.57 nj, 87.55‐x,87.55 Qr

Helical tomotherapy as a means of delivering accelerated partial breast irradiation.

A novel treatment approach utilizing helical tomotherapy for partial breast irradiation for patients with early-stage breast cancer is described. This technique may serve as an alternative to high dose-rate (HDR) interstitial brachytherapy and standard linac-based approaches. Through helical tomotherapy, highly conformal irradiation of target volumes and avoidance of normal sensitive structures can be achieved. Unlike HDR brachytherapy, it is noninvasive. Unlike other linac-based techniques, it provides image-guided adaptive radiotherapy along with intensity modulation. A treatment planning CT scan was obtained as usual on a post-lumpectomy patient undergoing HDR interstitial breast brachytherapy. The patient underwent catheter placement for HDR treatment and was positioned prone on a specially designed position-supporting mattress during C T. The planning target volume (PTV) was defined as the lumpectomy bed plus a 20 mm margin. The prescription dose was 34 Gy (10 fx of 3.4 Gy) in both the CT based HDR and on the tomotherapy plan. Cumulative dose-volume histograms (DVHs) were generated and analyzed for the target, lung, heart, skin, pectoralis muscle, and chest wall for both HDR brachytherapy and helical tomotherapy. Dosimetric coverage of the target with helical tomotherapy was conformal and homogeneous. “Hot spots” (≥150% isodose line) were present around implanted dwell positions in brachytherapy plan whereas no isodose lines higher than 109% were present in the helical tomotherapy plan. Similar dose coverage was achieved for lung, pectoralis muscle, heart, chest wall and breast skin with the two methods. We also compared our results to that obtained using conventional linac-based three dimensional (3D) conformal accelerated partial breast irradiation. Dose homogeneity is excellent with 3D conformal irradiation, and lung, heart and chest wall dose is less than for either HDR brachytherapy or helical tomotherapy but skin and pectoral muscle doses were higher than with the other techniques. Our results suggest that helical tomotherapy can serve as an effective means of delivering accelerated partial breast irradiation and may offer superior dose homogeneity compared to HDR brachytherapy.

Indirect Tumor Cell Death After High-Dose Hypofractionated Irradiation: Implications for Stereotactic Body Radiation Therapy and Stereotactic Radiation Surgery.

PURPOSE The purpose of this study was to reveal the biological mechanisms underlying stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). METHODS AND MATERIALS FSaII fibrosarcomas grown subcutaneously in the hind limbs of C3H mice were irradiated with 10 to 30 Gy of X rays in a single fraction, and the clonogenic cell survival was determined with in vivo--in vitro excision assay immediately or 2 to 5 days after irradiation. The effects of radiation on the intratumor microenvironment were studied using immunohistochemical methods. RESULTS After cells were irradiated with 15 or 20 Gy, cell survival in FSaII tumors declined for 2 to 3 days and began to recover thereafter in some but not all tumors. After irradiation with 30 Gy, cell survival declined continuously for 5 days. Cell survival in some tumors 5 days after 20 to 30 Gy irradiation was 2 to 3 logs less than that immediately after irradiation. Irradiation with 20 Gy markedly reduced blood perfusion, upregulated HIF-1α, and increased carbonic anhydrase-9 expression, indicating that irradiation increased tumor hypoxia. In addition, expression of VEGF also increased in the tumor tissue after 20 Gy irradiation, probably due to the increase in HIF-1α activity. CONCLUSIONS Irradiation of FSaII tumors with 15 to 30 Gy in a single dose caused dose-dependent secondary cell death, most likely by causing vascular damage accompanied by deterioration of intratumor microenvironment. Such indirect tumor cell death may play a crucial role in the control of human tumors with SBRT and SRS.

Water-fat MRI for assessing changes in bone marrow composition due to radiation and chemotherapy in gynecologic cancer patients.

To assess the feasibility of using fat‐fraction imaging for measuring marrow composition changes over large regions in patients undergoing cancer therapy.

Helical tomotherapy targeting total bone marrow - first clinical experience at the University of Minnesota.

Total body irradiation (TBI) has been widely utilized as part of the conditioning regimen for hematopoietic cell transplantation [1]. However, with traditional TBI techniques the entire body is irr...

Prevention of bone growth defects, increased bone resorption and marrow adiposity with folinic acid in rats receiving long-term methotrexate.

The underlying pathophysiology for bone growth defects in paediatric cancer patients receiving high dose methotrexate chemotherapy remains unclear and currently there are no standardized preventative treatments for patients and survivors. Using a model in young rats, we investigated damaging effects of long-term treatment with methotrexate on growth plate and metaphyseal bone, and the potential protective effects of antidote folinic acid. This study demonstrated that chronic folinic acid supplementation can prevent methotrexate-induced chondrocyte apoptosis and preserve chondrocyte columnar arrangement and number in the growth plate. In the metaphysis, folinic acid supplementation can preserve primary spongiosa heights and secondary spongiosa trabecular volume by preventing osteoblasts from undergoing apoptosis and suppressing methotrexate-induced marrow adiposity and osteoclast formation. Systemically, plasma of folinic acid supplemented rats, in comparison to plasma from rats treated with MTX alone, contained a significantly lower level of IL-1β and suppressed osteoclast formation in vitro in normal bone marrow cells. The importance of IL-1β in supporting plasma-induced osteoclast formation was confirmed as the presence of an anti-IL-1β neutralizing antibody attenuated the ability of the plasma (from MTX-treated rats) in inducing osteoclast formation. Findings from this study suggest that folinic acid supplementation during chronic methotrexate treatment can alleviate growth plate and metaphyseal damages and therefore may be potentially useful in paediatric patients who are at risk of skeletal growth suppression due to chronic methotrexate chemotherapy.

Assessing prostate, bladder and rectal doses during image guided radiation therapy - Need for plan adaptation?

The primary application of Image‐Guided Radiotherapy (IGRT) in the treatment of localized prostate cancer has been to assist precise dose delivery to the tumor. With the ability to use in‐room Computed Tomography (CT) imaging modalities, the prostate, bladder and rectum can be imaged before each treatment and the actual doses delivered to these organs can be tracked using anatomy of the day. This study evaluates the dosimetric uncertainties caused by interfraction organ variation during IGRT for 10 patients using kilovoltage cone beam CT (kvCBCT) on the Elekta Synergy system and megavoltage CT (MVCT) on the TomoTherapy Hi·Art System. The actual delivered doses to the prostate, bladder and rectum were based on dose recomputation using CT anatomy of the day. The feasibility of dose calculation accuracy in kvCBCT images from the Elekta Synergy system was investigated using the ComTom phantom. Additionally, low contrast resolution, image uniformity, and spatial resolution between the three imaging modalities of kilovoltage CT (kvCT), kvCBCT and MVCT images, were quantitatively evaluated using the Catphan 600 phantom. The Planned Adaptive software was used on the TomoTherapy Hi·Art system to construct a cumulative Dose Volume Histogram (DVH), incorporating anatomical information provided by the daily MVCT scans. The cumulative DVH was examined to identify large deviation (10% or greater) between the planned and delivered mean doses. The study proposes a framework that applies the cumulative DVH to evaluate and adapt plans that are based on actual delivered doses. Due to the large deviation in CT number (›300 HU) between the kvCBCT images and the kvCT, a direct dose recomputation on the kvCBCT images from the Elekta Synergy system was found to be inaccurate. The maximum deviation to the prostate was only 2.7% in our kvCBCT study, when compared to the daily prescribed dose. However, there was a large daily variation in rectum and bladder doses based on the anatomy of the day. The maximum variation in rectum and bladder volumes receiving the percentage of prescribed dose was 12% and 40%, respectively. We have shown that by using Planned Adaptive software on the TomoTherapy Hi·Art system, plans can be adapted based on the image feedback from daily MVCT scans to allow the actual delivered doses to closely track the original planned doses. PACS number: 87.53.Tf

Validation of marrow fat assessment using noninvasive imaging with histologic examination of human bone samples

PURPOSE The marrow composition throughout the body is heterogeneous and changes with age. Due to heterogeneity, invasive biopsies of the iliac crest do not truly represent the complete physiological status, impeding the clinical effectiveness of this method. Therefore, we aim to provide verification for an in vivo imaging technique using co-registered histologic examinations for assessment of marrow adiposity. METHODS Five recently expired (i.e. <24h) human cadavers were scanned with a dual source CT (DECT) scanner in order to measure marrow fat in the lumbar vertebrae. These donors were also imaged using water-fat MRI (wfMRI) which was used to estimate the fraction of yellow marrow. After imaging, lumbar columns were excised and the superior and inferior aspects of 21 vertebrae were removed. The remaining center section was processed for histological examination to find the ratio of adipocyte volume per tissue volume (AV/TV). RESULTS Results of DECT and wfMRI had a high correlation (r = 0.88). AV/TV ranged from 0.18 to 0.75 with a mean (SD) of 0.36 (0.18). Inter-evaluator reliability for AV/TV was r > 0.984. There were similar correlations between AV/TV and the imaging modalities, DECT-derived MF and wfMRI (r = 0.802 and 0.772, respectively). CONCLUSIONS A high MF variation was seen among the 25 vertebrae imaged. Both DECT and wfMRI have a good correlation with the histologic adipocyte proportion and can be used to measure MF. This makes longitudinal studies possible without painful, less-effective, invasive biopsies.