Unique approaches for testicular shielding during total-body irradiation for pediatric patients.

Total-body irradiation (TBI) has been used as a part of the conditioning regimen for patients undergoing hematopoietic stem cell transplantation for certain nonmalignant conditions such as sickle cell disease. Although effective, TBI can cause lasting side effects for pediatric patients. One of these potential side effects includes oligospermia or even permanent azoospermia. Although many investigators have studied ways to shield the testicles during the TBI for nonmalignant conditions, there is no set standard. We describe the technical aspects of effective techniques to shield the testicles of male pediatric patients undergoing TBI. We verified that our techniques reduced the testicular dose by approximately 80%-85% of the TBI prescription dose in four male pediatric patients, keeping the dose well below the documented doses that can cause permanent infertility and hypogonadism.

Clinical significance of serum apolipoproteins as a predictor of coronary heart disease risk in Korean men.

OBJECTIVE: Although serum apolipoprotein measurement is known to be associated with coronary heart disease (CHD) risk, there is only limited information about the clinical significance of lipid profiles such as ApoA, ApoB and A/B ratio in predicting CHD risk in Asians. Therefore, this cohort study was conducted to evaluate the longitudinal effects of baseline serum apolipoprotein measurements on CHD risk in Korean men. DESIGN: Initially, an intermediate and high Framingham risk score (FRS)-free cohort of 23 918 healthy Korean men was followed until 2010. FRS was calculated for each man and divided into three levels of risk <10% (low), 10-19% (intermediate) and ≥20% (high). More-than-a-moderate CHD risk group (participants with FRS ≥ 10%) and high CHD risk group (participants with FRS ≥ 20%) were defined as our two dependent variables. Cox proportional hazards models were performed. RESULTS: In the more-than-a-moderate CHD risk group, the total and average follow-up periods were 83340·2 and 3·48 person-years, respectively, and 3763 (15·7%) incident cases developed between 2006 and 2010. In the high CHD risk group, the total and average follow-up periods were 87868·8 and 3·67 person-years, respectively, and 344 (1·4%) incident cases developed between 2006 and 2010. Multivariate-adjusted analyses showed a strong statistically significant relationship between the quintile groups of apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA-1) and apolipoprotein B/apolipoprotein A-1 (ApoB/A-1) ratio and both the more-than-a-moderate CHD risk and high CHD risk. CONCLUSIONS: Serum ApoB, ApoA-1 and ApoB/A-1 ratio levels are independently associated with CHD risk in Korean men.

ACR Appropriateness Criteria® Recurrent Hodgkin Lymphoma.

This topic addresses the management of recurrent Hodgkin lymphoma. While autologous stem cell transplantation may be appropriate for select cases of recurrent disease following comprehensive combined-modality therapy, other options exist for patients treated with lower-dose therapy for early-stage disease. Additionally, innovative targeted therapies provide newer salvage options to consider. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the complex decision-making associated with the management of recurrent Hodgkin lymphoma.

Targeting S6K/NFκB/SQSTM1/Polθ signaling to suppress radiation resistance in prostate cancer.

In this study we have identified POLθ-S6K-p62 as a novel druggable regulator of radiation response in prostate cancer. Despite significant advances in delivery, radiotherapy continues to negatively affect treatment outcomes and quality of life due to resistance and late toxic effects to the surrounding normal tissues such as bladder and rectum. It is essential to develop new and effective strategies to achieve better control of tumor. We found that ribosomal protein S6K (RPS6KB1) is elevated in human prostate tumors, and contributes to resistance to radiation. As a downstream effector of mTOR signaling, S6K is known to be involved in growth regulation. However, the impact of S6K signaling on radiation response has not been fully explored. Here we show that loss of S6K led to formation of smaller tumors with less metastatic ability in mice. Mechanistically we found that S6K depletion reduced NFκB and SQSTM1 (p62) reporter activity and DNA polymerase θ (POLθ) that is involved in alternate end-joining repair. We further show that the natural compound berberine interacts with S6K in a in a hitherto unreported novel mode and that pharmacological inhibition of S6K with berberine reduces Polθ and downregulates p62 transcriptional activity via NFκB. Loss of S6K or pre-treatment with berberine improved response to radiation in prostate cancer cells and prevented radiation-mediated resurgence of PSA in animals implanted with prostate cancer cells. Notably, silencing POLQ in S6K overexpressing cells enhanced response to radiation suggesting S6K sensitizes prostate cancer cells to radiation via POLQ. Additionally, inhibition of autophagy with CQ potentiated growth inhibition induced by berberine plus radiation. These observations suggest that pharmacological inhibition of S6K with berberine not only downregulates NFκB/p62 signaling to disrupt autophagic flux but also decreases Polθ. Therefore, combination treatment with radiation and berberine inhibits autophagy and alternate end-joining DNA repair, two processes associated with radioresistance leading to increased radiation sensitivity.

DNA Dosimeter Measurement of Relative Biological Effectiveness for 160 kVp and 6 MV X Rays.

In this work, we developed a DNA dosimeter, consisting of 4-kb DNA strands attached to magnetic streptavidin beads and labeled with fluorescein, to detect double-strand breaks (DSBs). The purpose here was to evaluate whether the DNA dosimeter readings reflect the relative biological effects of 160 kVp and 6 MV X rays. AVarian 600 C/D linac (6 MV) and a Faxitron cabinet X-ray system (160 kVp), both calibrated using traceable methods, were used to deliver high- and low-energy photons, respectively, to DNA dosimeters and multiple cell lines (mNs-5, HT-22 and Daoy). The responses were fit versus dose, and were used to quantify the dose of low-energy photons that produced the same response as that of the high-energy photons, at doses of 3, 6 and 9 Gy. The equivalent doses were utilized to calculate the relative biological effectiveness (RBEDSB and RBEcell survival). Additionally, a neutral comet assay was performed to measure the amount of intracellular DNA DSB, and ultimately the RBEcomet assay. The results of this work showed 160-kVp photon RBE values and 95% confidence intervals of 1.12 ± 0.04 (mNS-5), 1.16 ± 0.06 (HT-22), 1.25 ± 0.09 (Daoy) and 1.21 ± 0.24 (DNA dosimeter) at 9 Gy and 1.32 ± 0.16 (comet assay) at 3 Gy. Within the current error, the DNA dosimeter measured RBEDSB values in agreement with the RBEcell survival and assay from the cell survival and comet assay RBEcomet measurements. These results suggest that the DNA dosimeter can measure the changes in the radiobiological effects from different energy photons.

Delivery of four-dimensional radiotherapy with TrackBeam for moving target using an AccuKnife dual-layer MLC: dynamic phantoms study.

Respiratory motion has been considered a clinical challenge for lung tumor treatments due to target motion. In this study, we aimed to perform an experimental evaluation based on dynamic phantoms using MLC-based beam tracking. TrackBeam, a prototype real-time beam tracking system, has been assembled and evaluated in our clinic. TrackBeam includes an orthogonal dual-layer micro multi-leaf collimator (DmMLC), an on-board mega-voltage (MV) portal imaging device, and an image processing workstation. With a fiducial marker implanted in a moving target, the on-board imaging device can capture the motion. The TrackBeam workstation processes the online MV fluence and detects and predicts tumor motion. The DmMLC system then dynamically repositions each leaf to form new beam apertures based on the movement of the fiducial marker. In this study, a dynamic phantom was used for the measurements. Three delivery patterns were evaluated for dosimetric verification based on radiographic films: no-motion-lung-tumor (NMLT), three-dimensional conformal radiotherapy (3DCRT), and four-dimensional tracking radiotherapy (4DTRT). The displacement between the DmMLC dynamic beam isocenter and the fiducial marker was in the range of 0.5 mm to 1.5 mm. With radiographic film analysis, the planar dose histogram difference between 3DCRT and NLMT was 48.6% and 38.0% with dose difference tolerances of 10% and 20%. The planar dose histogram difference between 4DTRT and NLMT was 15.2% and 4.0% respectively. Based-on dose volume histogram analysis, 4DTRT reduces the mean dose for the surrounding tissue from 35.4 Gy to 19.5 Gy, reduces the relative volume of the total lung from 28% to 18% at V20, and reduces the amount of dose from 35.2 Gy to 15.0 Gy at D20. The experimental results show that MLC-based real-time beam tracking delivery provides a potential solution to respiratory motion control. Beam tracking delivers a highly conformal dose to a moving target, while sparing surrounding normal tissue.

Outcomes of patients undergoing radiation therapy for bladder cancer.

OBJECTIVES: To review our two institutional experiences regarding the historical referral patterns of bladder cancer patients to receive radiation therapy, characteristics of these referred patients, and their treatment outcomes. METHODS: A retrospective review was performed analyzing patients who underwent radiation therapy for bladder cancer from 2005 to 2015 (n = 69) at two regional referral institutions. The age-adjusted Charlson comorbidity index (AACCI) was calculated for each patient. Patients were divided into three groups: definitive concurrent chemoradiation (CCR), aggressive radiation (AR) alone ≥ 50 Gy, or palliative radiation alone (PR) < 50 Gy. Gastrointestinal (GI) and genitourinary (GU) acute toxicities were recorded. RESULTS: The median overall AACCI score was 7, which correlates to a two-year expected survival of 55% ± 11%. Thirty-five (50.7%) patients received CCR, 19 (27.5%) received AR, and 15 (21.7%) received PR. Patients presented with hematuria (n = 43, 62%), pain (n = 18, 26%), or obstruction (n = 12, 17%). Of symptomatic patients, treatment improved hematuria in 86%, pain in 75%, and obstruction in 42%. Twenty-two recurrences (32%) were identified at follow-up. Local, regional, and distant recurrences developed in 20%, 14%, and 17% of patients who received CCR. There were two grade 3 GU toxicities and one grade 3 GI toxicity; all grade 3 toxicities were in patients receiving CCR. CONCLUSIONS: Bladder preservation is possible with chemoradiation therapy; however, urologists rarely refer patients for consideration of chemoradiation. The limited patients who are referred for radiation generally have limited life expectancy, significant comorbidities, or have advanced disease amenable only to palliation. Palliative radiation improves symptoms with minimal toxicity.

DNA double-strand breaks as a method of radiation measurements for therapeutic beams.

PURPOSE: Many types of dosimeters are used to measure radiation dose and calibrate radiotherapy equipment, but none directly measure the biological effect of this dose. The purpose here is to create a dosimeter that can measure the probability of double-strand breaks (DSB) for DNA, which is directly related to the biological effect of radiation. METHODS: A DNA dosimeter, consisting of magnetic streptavidin beads attached to four kilobase pair DNA strands labeled with biotin and fluorescein amidite (FAM) on opposing ends, was suspended in phosphate-buffered saline (PBS). Fifty microliter samples were placed in plastic tubes inside a water tank setup and irradiated at the dose levels of 25, 50, 100, 150, and 200 Gy. After irradiation, the dosimeters were mechanically separated into beads (intact DNA) and supernatant (broken DNA/FAM) using a magnet. The fluorescence was read and the probability of DSB was calculated. This DNA dosimeter response was benchmarked against a Southern blot analysis technique for the measurement of DSB probability. RESULTS: For the DNA dosimeter, the probabilities of DSB at the dose levels of 25, 50, 100, 150, and 200 Gy were 0.043, 0.081, 0.149, 0.196, and 0.242, respectively, and the standard errors of the mean were 0.002, 0.003, 0.006, 0.005, and 0.011, respectively. For the Southern blot method, the probabilities of DSB at the dose levels of 25, 50, 100, 150, and 200 Gy were 0.053, 0.105, 0.198, 0.235, and 0.264, respectively, and the standard errors of the mean were 0.013, 0.024, 0.040, 0.044, and 0.063, respectively. CONCLUSIONS: A DNA dosimeter can accurately determine the probability of DNA double-strand break (DSB), one of the most toxic effects of radiotherapy, for absorbed radiation doses from 25 to 200 Gy. This is an important step in demonstrating the viability of DNA dosimeters as a measurement technique for radiation.