Bryan Traughber

18F-FDG PET/CT for Monitoring of Treatment Response in Breast Cancer

Changes in tumor metabolic activity have been shown to be an early indicator of treatment effectiveness for breast cancer, mainly in the neoadjuvant setting. The histopathologic response at the completion of chemotherapy has been used as the reference standard for assessment of the accuracy of 18F-FDG PET in predicting a response during systemic treatment. Although a pathologic complete response (pCR) remains an important positive prognostic factor for an individual patient, a recent metaanalysis could validate pCR as a surrogate marker for patient outcomes only in aggressive breast cancer subtypes. For establishment of the clinical application of metabolic treatment response studies, larger series of specific breast cancer subtypes—including hormone receptor–positive, human epidermal growth factor receptor 2–positive, and triple-negative breast cancers—are necessary. In addition, thresholds for relative changes in 18F-FDG uptake to distinguish between responding and nonresponding tumors need to be validated for different systemic treatment approaches, with progression-free survival and overall survival as references. A PET-based treatment stratification is applicable clinically only if valid alternative therapies are available. Of note, patients who do not achieve a pCR might still benefit from neoadjuvant therapy enabling breast-conserving surgery. In the metastatic setting, residual tumor metabolic activity after the initiation of systemic therapy is an indicator of active disease, whereas a complete resolution of metabolic activity is predictive of a successful treatment response.

ACR Appropriateness Criteria® non-spine bone metastases.

Bone is one of the most common sites of metastatic spread of malignancy, with possible deleterious effects including pain, hypercalcemia, and pathologic fracture. External beam radiotherapy (EBRT) remains the mainstay for treatment of painful bone metastases. EBRT may be combined with other local therapies like surgery or with systemic treatments like chemotherapy, hormonal therapy, osteoclast inhibitors, or radiopharmaceuticals. EBRT is not commonly recommended for patients with asymptomatic bone metastases unless they are associated with a risk of pathologic fracture. For those who do receive EBRT, appropriate fractionation schemes include 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or a single 8 Gy fraction. Single fraction treatment maximizes convenience, while fractionated treatment courses are associated with a lower incidence of retreatment. The appropriate postoperative dose fractionation following surgical stabilization is uncertain. Reirradiation with EBRT may be safe and provide pain relief, though retreatment might create side effect risks which warrant its use as part of a clinical trial. All patients with bone metastases should be considered for concurrent management by a palliative care team, with patients whose life expectancy is less than six months appropriate for hospice evaluation. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria® Metastatic Epidural Spinal Cord Compression and Recurrent Spinal Metastasis.

Metastatic epidural spinal cord compression (MESCC) is an oncologic emergency and if left untreated, permanent paralysis will ensue. The treatment of MESCC is governed by disease, patient, and treatment factors. Patients preferences and goals of care are to be weighed into the treatment plan. Ideally, a patient with MESCC is evaluated by an interdisciplinary team promptly to determine the urgency of the clinical scenario. Treatment recommendations must take into consideration the risk-benefit profiles of surgical intervention and radiotherapy for the particular individuals circumstance, including neurologic status, performance status, extent of epidural disease, stability of the spine, extra-spinal disease status, and life expectancy. In patients with high spinal instability neoplastic score (SINS) or retropulsion of bone fragments in the spinal canal, surgical intervention should be strongly considered. The rate of development of motor deficits from spinal cord compression may be a prognostic factor for ultimate functional outcome, and should be taken into account when a treatment recommendation is made. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Generation of brain pseudo-CTs using an undersampled, single-acquisition UTE-mDixon pulse sequence and unsupervised clustering.

PURPOSE MR-based pseudo-CT has an important role in MR-based radiation therapy planning and PET attenuation correction. The purpose of this study is to establish a clinically feasible approach, including image acquisition, correction, and CT formation, for pseudo-CT generation of the brain using a single-acquisition, undersampled ultrashort echo time (UTE)-mDixon pulse sequence. METHODS Nine patients were recruited for this study. For each patient, a 190-s, undersampled, single acquisition UTE-mDixon sequence of the brain was acquired (TE = 0.1, 1.5, and 2.8 ms). A novel method of retrospective trajectory correction of the free induction decay (FID) signal was performed based on point-spread functions of three external MR markers. Two-point Dixon images were reconstructed using the first and second echo data (TE = 1.5 and 2.8 ms). R2(∗) images (1/T2(∗)) were then estimated and were used to provide bone information. Three image features, i.e., Dixon-fat, Dixon-water, and R2(∗), were used for unsupervised clustering. Five tissue clusters, i.e., air, brain, fat, fluid, and bone, were estimated using the fuzzy c-means (FCM) algorithm. A two-step, automatic tissue-assignment approach was proposed and designed according to the prior information of the given feature space. Pseudo-CTs were generated by a voxelwise linear combination of the membership functions of the FCM. A low-dose CT was acquired for each patient and was used as the gold standard for comparison. RESULTS The contrast and sharpness of the FID images were improved after trajectory correction was applied. The mean of the estimated trajectory delay was 0.774 μs (max: 1.350 μs; min: 0.180 μs). The FCM-estimated centroids of different tissue types showed a distinguishable pattern for different tissues, and significant differences were found between the centroid locations of different tissue types. Pseudo-CT can provide additional skull detail and has low bias and absolute error of estimated CT numbers of voxels (-22 ± 29 HU and 130 ± 16 HU) when compared to low-dose CT. CONCLUSIONS The MR features generated by the proposed acquisition, correction, and processing methods may provide representative clustering information and could thus be used for clinical pseudo-CT generation.

Role of Pluronic block copolymers in modulation of heat shock protein 70 expression

Purpose: The goal of this study was to evaluate the relationship between previously demonstrated thermosensitising effects of the block copolymer, Pluronic, and heat shock protein 70 (Hsp70) expression in an experimental colorectal cancer model in vitro and in vivo. Materials and methods: Rat colorectal carcinoma cells were treated with low-grade hyperthermia (43°C) alone or in combination with Pluronics L10 (3 mg/mL), L61 (0.3 mg/mL), or L64 (0.5 mg/mL) for 20 min. Adinosine triphosphate (ATP) levels and cell viability were determined using standard assays. Hsp70 expression was quantified by western blot for cells treated with L10, L61, and L64 at doses specified above and Pluronic P85 (10 mg/mL) alone and in combination with heat. BDIX rats with flank tumours were used to study the effect of L61 and hyperthermia on Hsp70 expression in vivo. Results: In vitro, treatment with L10, L61, and L64 plus low-grade hyperthermia lead to depletion of ATP levels to between 8 and 66% of untreated control after 24 h. Maximum expression of Hsp70 was observed at 9 h following hyperthermia alone. The combination of low-grade hyperthermia and Pluronic treatment reduced Hsp70 expression for up to 6 hours, and L10 appeared to completely inhibit the Hsp70 expression. In vivo, Hsp70 expression was increased 5 h after hyperthermia in BDIX rat tumour models and no Hsp70 expression was observed in L61 pre-treated and control groups. Conclusion: Pluronic effectively improves hyperthermic and low-grade hyperthermic treatment in part due to reduction of Hsp70 expression.

k-space sampling optimization for ultrashort TE imaging of cortical bone: Applications in radiation therapy planning and MR-based PET attenuation correction

PURPOSE The ultrashort echo-time (UTE) sequence is a promising MR pulse sequence for imaging cortical bone which is otherwise difficult to image using conventional MR sequences and also poses strong attenuation for photons in radiation therapy and PET imaging. The authors report here a systematic characterization of cortical bone signal decay and a scanning time optimization strategy for the UTE sequence through k-space undersampling, which can result in up to a 75% reduction in acquisition time. Using the undersampled UTE imaging sequence, the authors also attempted to quantitatively investigate the MR properties of cortical bone in healthy volunteers, thus demonstrating the feasibility of using such a technique for generating bone-enhanced images which can be used for radiation therapy planning and attenuation correction with PET/MR. METHODS An angularly undersampled, radially encoded UTE sequence was used for scanning the brains of healthy volunteers. Quantitative MR characterization of tissue properties, including water fraction and R2(∗) = 1/T2(∗), was performed by analyzing the UTE images acquired at multiple echo times. The impact of different sampling rates was evaluated through systematic comparison of the MR image quality, bone-enhanced image quality, image noise, water fraction, and R2(∗) of cortical bone. RESULTS A reduced angular sampling rate of the UTE trajectory achieves acquisition durations in proportion to the sampling rate and in as short as 25% of the time required for full sampling using a standard Cartesian acquisition, while preserving unique MR contrast within the skull at the cost of a minimal increase in noise level. The R2(∗) of human skull was measured as 0.2-0.3 ms(-1) depending on the specific region, which is more than ten times greater than the R2(∗) of soft tissue. The water fraction in human skull was measured to be 60%-80%, which is significantly less than the >90% water fraction in brain. High-quality, bone-enhanced images can be generated using a reduced sampled UTE sequence with no visible compromise in image quality and they preserved bone-to-air contrast with as low as a 25% sampling rate. CONCLUSIONS This UTE strategy with angular undersampling preserves the image quality and contrast of cortical bone, while reducing the total scanning time by as much as 75%. The quantitative results of R2(∗) and the water fraction of skull based on Dixon analysis of UTE images acquired at multiple echo times provide guidance for the clinical adoption and further parameter optimization of the UTE sequence when used for radiation therapy and MR-based PET attenuation correction.

A domain constrained deformable (DoCD) model for co-registration of pre- and post-radiated prostate MRI

External beam radiation treatment (EBRT) is a popular method for treating prostate cancer (CaP) involving destroying tumor cells with ionizing radiation. Following EBRT, biochemical failure has been linked with disease recurrence. However, there is a need for methods for evaluating early treatment related changes to allow for an early intervention in case of incomplete disease response. One method for looking at treatment evaluation is to detect changes in MRI markers on a voxel-by-voxel basis following treatment. Changes in MRI markers may be correlated with disease recurrence and complete or partial response. In order to facilitate voxel-by-voxel imaging related treatment changes, and also to evaluate morphologic changes in the gland post treatment, the pre- and post-radiated MRI must first be brought into spatial alignment via image registration. However, EBRT induces changes in the prostate volume and distortion to the internal anatomy of the prostate following radiation treatment. The internal substructures of the prostate, the central gland (CG) and peripheral zone (PZ), may respond to radiation differently, and their resulting shapes may change drastically. Biomechanical models of the prostate that have been previously proposed tend to focus on how external forces affect the surface of the prostate (not the internals), and assume that the prostate is a volume-preserving entity. In this work we present DoCD, a biomechanical model for automatically registering pre-, post-EBRT MRI with the aim of expressly modeling the (1) changes in volume, and (2) changes to the CG and PZ. DoCD was applied to a cohort of 30 patients and achieved a root mean square error of 2.994 mm, which was statistically significantly better a traditional biomechanical model which did not consider changes to the internal anatomy of the prostate (mean of 5.071 mm).

Preclinical evaluation of radiosensitizing activity of Pluronic block copolymers.

Abstract Purpose: Pluronic block copolymers are non-ionic surfactants with demonstrated sensitizing activity in chemotherapy and hyperthermia in various tumor cell lines. In the current study we investigated the potential activity of Pluronic as a radiosensitizing agent. Materials and methods: As a possible mechanism, the effect of Pluronic on Hsp70 and Hsp90 was examined. Gli36 human glioma cells were treated with radiation alone as well as with a combination treatment of Pluronic and radiation. Results: Clonogenic cell survival assays show that Pluronic has an elevated effect on radiosensitization (50% high, p < 0.01), even with radiation doses as low as 2 Gy. The Hsp90 level was reduced 24 h after the combined treatment in both in vitro and in vivo. Similarly, Hsp70 levels were also decreased 24 h post treatment. When Gli36 cells were exposed to Pluronic before and during irradiation, DNA DSB: double-strand breaks repair was reduced, and elevated apoptosis was also seen in tumor xenografts. Conclusion: Data suggest the potential use of L10 as a radiosensitizer. While the mechanism of sensitization requires additional investigation, the presented results indicate that the effect may be due, in part, to a decrease in Hsp90 and 70 levels and increased DNA damage.

Outcomes and toxicities in patients treated with definitive focal therapy for primary prostate cancer: systematic review

AIM This systematic review summarizes the clinical data on focal therapy (FT) when used alone as definitive therapy for primary prostate cancer (PCa). METHODS The protocol is detailed in the online PROSPERO database, registration No. CRD42014014765. Articles evaluating any form of FT alone as a definitive treatment for PCa in adult male patients were included. RESULTS Of 10,419 identified articles, 10,401 were excluded, and thus leaving 18 for analysis. In total, 2288 patients were treated using seven modalities. The outcomes of FT in PCa seem to be similar to those observed with whole gland therapy and with fewer side effects. CONCLUSION Further research, including prospective randomized trials, is warranted to elucidate the potential advantages of focal radiation techniques for treating PCa. Prospero Registration Number: CRD42014014765.

Preliminary Evaluation of Dedicated PET/MRI in Gastrointestinal Malignancy: Qualitative and Quantitative Comparison to PET/CT

ratio (T/M). Results: All patients completed their intended course of therapy. Median follow-up for all patients was 17 months (range 4.2-28 months). Four patients developed distant metastases; one patient developed local relapse 14 months post treatment, one patient had persistent FDG uptake on a 3 month post-treatment FDG-PET/CT and had confirmed pathologically persistent disease. The median tumor to muscle ratio was 1.35 (range 0.88-1.79). A T/M threshold of 1.35 was used as a cutoff threshold. 2/6 patients with T/M ratios above 1.35 had persistent disease/local relapse vs 0/2 patients with T/M ratios below 1.35. 4/6 patients with T/M ratios above 1.35 developed metastatic disease vs 1/2 patients with T/M ratios below 1.35 who developed metastatic disease. Conclusions: PET imaging with 18F Ef5 is feasible for patients with uterine cervical cancer. This is a small pilot study, and the utility of 18F EF5 and its predictive value need to be further investigated for this population.