Feasibility and efficacy of active breathing coordinator assisted deep inspiration breath hold technique for treatment of locally advanced breast cancer.

BACKGROUND: Active breathing coordinator (ABC)-assisted deep inspiration breath hold (DIBH) is an important organ sparing radiation therapy (RT) technique for left-sided breast cancer patients. Patients with advanced breast cancer undergoing chest wall and regional nodal irradiation often require a field matching technique. While field matching has been demonstrated to be safe and effective in free breathing patients, its safety and accuracy in DIBH/ABC use has not been previously reported. PURPOSE: To report the accuracy, feasibility, and safety of field matching with ABC/DIBH for patients receiving breast/chest wall irradiation with nodal irradiation using a three-field technique. METHODS: From December 2012 to May 2018, breast cancer patients undergoing ABC/DIBH-based RT at a single institution were reviewed. For each fraction, the amount of overlap/gap between the supraclavicular and the tangential field were measured and recorded. Patient characteristics, including acute and delayed skin toxicities, were analyzed. RESULTS: A total of 202 patients utilized ABC/DIBH and 4973 fractions had gap/overlap measurements available for analysis. The average gap/overlap measured at junction was 0.28 mm ± 0.99 mm. A total of 72% of fractions had no measurable gap/overlap (0 mm), while 5.6% had an overlap and 22.7% a gap. There was no significant trend for worsening or improvement of gap/overlap measurements with increasing fraction number per patient. OSLD measurements were compared to the planned dose. The median dose 1 cm above the junction was 106% ± 7% of planned dose (range 94%-116%). One centimeter below the junction, the median dose was 114% ± 11% of planned dose (range 95%-131%). At the junction, the median dose was 106% ± 16.3% of planned dose (range 86%-131%). Acute skin toxicity was similar to historically reported values (grade 3, 5.4%, grade 4, 0%). CONCLUSION: ABC-assisted DIBH is a safe and technically feasible method of delivering RT in the setting of complex matching field technique for breast and regional nodal treatments.

In vivo quantification of myocardial stiffness in hypertensive porcine hearts using MR elastography.

PURPOSE: To determine alteration in left ventricular (LV) myocardial stiffness (MS) with hypertension (HTN). Cardiac MR elastography (MRE) was used to estimate MS in HTN induced pigs and MRE-derived MS measurements were compared against LV pressure, thickness and circumferential strain. MATERIALS AND METHODS: Renal-wrapping surgery was performed to induce HTN in eight pigs. LV catheterization (to measure pressure) and cardiac MRI (1.5 Tesla; gradient echo-MRE and tagging) was performed pre-surgery at baseline (Bx), and post-surgery at month 1 (M1) and month 2 (M2). Images were analyzed to estimate LV-MS, thickness, and circumferential strain across the cardiac cycle. The associations between end-diastolic (ED) and end-systolic (ES) MS and (i) mean LV pressure; (ii) ED and ES thickness, respectively; and (iii) circumferential strain were evaluated using Spearman's correlation method. RESULTS: From Bx to M2, mean pressure, MRE-derived stiffness, and thickness increased while circumferential strain decreased significantly (slope test, P ≤ 0.05). Both ED and ES MS had significant positive correlation with (i) mean pressure (ED MS: ρ = 0.56; P = 0.005 and ES MS: ρ = 0.45; P = 0.03); (ii) ED thickness ( ρ = 0.73; P < 0.0001) and ES thickness ( ρ = 0.84; P < 0.0001), respectively; but demonstrated a negative trend with circumferential strain (ED MS: ρ = 0.31 and ES MS: ρ = 0.37). CONCLUSION: This study demonstrated that, in a HTN porcine model, MRE-derived MS increased with increase in pressure and thickness. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:813-820.

In vivo magnetic resonance elastography to estimate left ventricular stiffness in a myocardial infarction induced porcine model.

PURPOSE: To estimate change in left ventricular (LV) end-systolic and end-diastolic myocardial stiffness (MS) in pigs induced with myocardial infarction (MI) with disease progression using cardiac magnetic resonance elastography (MRE) and to compare it against ex vivo mechanical testing, LV circumferential strain, and magnetic resonance imaging (MRI) relaxometry parameters (T1 , T2 , and extracellular volume fraction [ECV]). MATERIALS AND METHODS: MRI (1.5T) was performed on seven pigs, before surgery (Bx), and 10 (D10), and 21 (D21) days after creating MI. Cardiac MRE-derived MS was measured in infarcted region (MIR) and remote region (RR), and validated against mechanical testing-derived MS obtained postsacrifice on D21. Circumferential strain and MRI relaxometry parameters (T2 , T1 , and ECV) were also obtained. Multiparametric analysis was performed to determine correlation between cardiac MRE-derived MS and 1) strain, 2) relaxometry parameters, and 3) mechanical testing. RESULTS: Mean diastolic (D10: 5.09 ± 0.6 kPa; D21: 5.45 ± 0.7 kPa) and systolic (D10: 5.72 ± 0.8 kPa; D21: 6.34 ± 1.0 kPa) MS in MIR were significantly higher (P < 0.01) compared to mean diastolic (D10: 3.97 ± 0.4 kPa; D21: 4.12 ± 0.2 kPa) and systolic (D10: 5.08 ± 0.6 kPa; and D21: 5.16 ± 0.6 kPa) MS in RR. The increase in cardiac MRE-derived MS at D21 (MIR) was consistent and correlated strongly with mechanical testing-derived MS (r(diastolic) = 0.86; r(systolic) = 0.89). Diastolic MS in MIR demonstrated a negative correlation with strain (r = 0.58). Additionally, cardiac MRE-derived MS demonstrated good correlations with post-contrast T1 (r(diastolic) = -0.549; r(systolic) = -0.741) and ECV (r(diastolic) = 0.548; r(systolic) = 0.703), and no correlation with T2 . CONCLUSION: As MI progressed, cardiac MRE-derived MS increased in MIR compared to RR, which significantly correlated with mechanical testing-derived MS, T1 and ECV. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:1024-1033.

Measuring age-dependent myocardial stiffness across the cardiac cycle using MR elastography: A reproducibility study.

PURPOSE: To assess reproducibility in measuring left ventricular (LV) myocardial stiffness in volunteers throughout the cardiac cycle using MR elastography (MRE) and to determine its correlation with age. METHODS: Cardiac MRE (CMRE) was performed on 29 normal volunteers, with ages ranging from 21 to 73 years. For assessing reproducibility of CMRE-derived stiffness measurements, scans were repeated per volunteer. Wave images were acquired throughout the LV myocardium, and were analyzed to obtain mean stiffness during the cardiac cycle. CMRE-derived stiffness values were correlated to age. RESULTS: Concordance correlation coefficient revealed good interscan agreement with rc of 0.77, with P-value < 0.0001. Significantly higher myocardial stiffness was observed during end-systole (ES) compared with end-diastole (ED) across all subjects. Additionally, increased deviation between ES and ED stiffness was observed with increased age. CONCLUSION: CMRE-derived stiffness is reproducible, with myocardial stiffness changing cyclically across the cardiac cycle. Stiffness is significantly higher during ES compared with ED. With age, ES myocardial stiffness increases more than ED, giving rise to an increased deviation between the two.

Impact of SOD-Mimetic Manganoporphyrins on Spin Trapping of Superoxide and Related Artifacts.

The superoxide dismutase (SOD)-mimetic effectiveness of [meso-tetrakis (R)porphyrinato]manganese with R = 1,3-di-N-ethylimidazolium-2-yl (Mn-TDEIP), 1,3-di-N-methylimidazolium-2-yl (Mn-TDMIP), 1,3-di-N-propylimidazolium-2-yl (Mn-TDPIP), N-ethyl-2-pyridyl (Mn-T2EPyP), 4-sulphonatophenyl (Mn-TSP), 1-methyl-4-pyridyl (Mn-T4PyP), 4-carboxyphenyl (Mn-TBAP), and ß-octabromomeso-tetrakis(4-carboxyphenyl porphyrinato)manganese (MnBr8TBAP) was compared with Cu, Zn SOD. Superoxide generated by reaction of xanthine oxidase with hypoxanthine was trapped with 5-tert-butoxycarbonyl-5-methyl-1-pyrroline N-oxide (BMPO), forming BMPO-OOH, which was monitored by electron paramagnetic resonance. Manganoporphyrins with redox potentials ranging from -0.190 to 0.346 V relative to the standard hydrogen electrode were selected for this study. With 0.1 µM manganoporphyrins and 20 mM BMPO, the effectiveness of the manganoporphyrins in inhibiting formation of BMPO-OOH increases in the order Mn-TSP < Mn-TBAP < MnBr8TBAP < Mn-T4PyP < Mn-T2EPyP < Mn-TDEIP ~ Mn-TDMIP ~ Mn-TDPIP ~ Cu, Zn SOD. However, at higher concentrations of manganoporphyrin and BMPO, a BMPO-OH signal was observed. The formation of BMPO-OH was not inhibited by catalase or dimethylsulfoxide, which demonstrated that it was not produced from hydroxyl radical. The artifactual formation of BMPO-OH is attributed to oxidation of the water adduct of BMPO by the manganoporphyrins or decomposition of BMPO-OOH. Although spin trapping is an effective method for evaluating SOD-mimetic efficacy, caution must be exercised to ensure that artifact signals are not interpreted improperly.

Expanded Radiosurgery Capabilities Utilizing Gamma Knife Icon™.

The indications and techniques for the treatment of intracranial lesions continue to evolve with the advent of novel technologies. The Gamma Knife Icon™ (GK Icon™) is the most recent model available from Elekta, providing a frameless solution for stereotactic radiosurgery. At our institution, 382 patients with 3,213 separate intracranial lesions have been treated with frameless stereotactic radiotherapy using the GK Icon. The wide range of diagnoses include brain metastases, meningiomas, arteriovenous malformations, acoustic neuromas, pituitary adenomas, and several other histologies. The ability to perform both frame and frameless treatments on the GK Icon has significantly increased our daily volume by almost 50% on a single machine. Although the frameless approach allows one to take advantage of the precision in radiosurgery, the intricacies regarding treatment with this frameless system are not well established. Our initial experience will help to serve as a guide to those wishing to implement this novel technology in their practice.

Changing equipoise in the landscape of radiation for oligometastatic lung cancer.

There is growing interest in exploring use of local therapies in the management of oligometastatic non-small cell lung cancer (NSCLC) to provide durable local and distant disease control. Prospective phase II studies have incorporated local therapy (predominantly stereotactic ablative radiotherapy or SABR) to both primary and metastatic sites. For patients who received these treatments, median progression-free survival (PFS) and overall survival (OS) exceeded that of historical controls treated with systemic therapy alone (9.7-23.5 and 13.5-41.2 months, respectively). Additionally, three trials randomized oligometastatic NSCLC patients to standard of care systemic therapy regimens vs. local consolidative therapy (LCT) plus standard of care systemic therapy (or observation) and all demonstrated a significant improvement in PFS, with two showing OS benefits to date. Notably, a majority of these trials selected patients with at least stable disease after completion of systemic therapy for local therapy and defined the oligometastatic state as one with no more than five metastatic sites spread across three organs. For patients with oligometastatic NSCLC, there are many important factors that should drive use and timing of local therapy, including metastatic presentation sequence (synchronous vs. metachronous), extent of disease (number and distribution of sites), and quality of life goals. The referenced clinical trials accrued patients prior to the approval of immunotherapy for metastatic NSCLC, so the benefits of any local therapy in this setting remain uncertain. To ultimately clarify the role of local therapy in oligometastatic NSCLC in the era of improving systemic therapy efficacy (i.e., immunotherapy and targeted therapy combinations with cytotoxics), we recommend enrollment in in phase III studies with OS endpoints (i.e., NRG LU 002 and SARON) whenever possible. These and other important issues associated with local therapy for oligometastatic NSCLC are reviewed in this paper.

Financial Toxicity and Cancer Therapy: A Primer for Radiation Oncologists.

The diagnosis and treatment of cancer places patients at risk for serious financial consequences, which are detrimental to overall health and well-being. The concept of financial toxicity (FT) describes monetary and health implications related to the financial burden of receiving care. To investigate this important area, the authors first explore aspects of the modern American health care insurance system that relate to cancer care. Then they summarize relevant literature across multiple domains of FT that include monetary, functional, and patient-reported measures. The authors conclude by making simple recommendations to begin addressing FT in clinical practice.

Prostate brachytherapy procedural training: incorporation of related procedures in resident training and competency assessment.

PURPOSE: Inadequate procedural training is of increasing concern in resident training, especially in prostate brachytherapy (PB). Transperineal rectal spacer placement (TRSP) requires many of the same proficiencies as PB. This work describes the assessment of teaching techniques focusing on developing critical competencies for PB using related clinical procedures (TRSP). MATERIAL AND METHODS: For PB and TRSP, key competencies were identified: 9 for PB and 7 for TRSP; 4 are shared between PB and TRSP. "Comfort level" with these procedures was assessed prior to and following participation in TRSP. RESULTS: 8 of 12 trainees at our institution participated in TRSP procedures. 2 of these trainees had prior experience with PB or related procedures and were excluded. Trainees self-reported "comfort levels" between 0 and 3 for four competency domains. Initial median comfort (MC) level for competency domains relevant to PB included: patient positioning (median 1, range 0-2), transrectal ultrasound imaging (median 1, range 0-1), fiducial placement (median 1, range 0-1), and hydrodissection (median 0, range 0-1). Median number of TRSP procedures performed by assessed trainees during the analysis period was 4 (range 1-6). Following TRSP procedure training, MC level increased: 2 points for patient positioning (median 3, range 1-3; p < 0.01), 1.5 points for transrectal ultrasound imaging (median 2.5, range 1.3, p < 0.001); 1 point for fiducial placement (median score 2, range 1-3; p < 0.001); and 1.5 points for hydrodissection (median score 2, range 1-3; p < 0.001). CONCLUSIONS: Increasing trainee involvement in related procedures to develop core competencies may help facilitate increased comfort with common skills critical to the independent performance of PB.

Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer.

: Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH-, i.e., intravenous infusions of ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH- decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (H2O2)-mediated mechanism. In this study, we demonstrate that P-AscH- radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH-, while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH- in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH- during the radiotherapy "beam on." Specifically, treatment with P-AscH- increased median overall survival compared with our institutional average (21.7 vs. 12.7 months, P = 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH--treated subjects was also greater than our institutional average (13.7 vs. 4.6 months, P < 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH- in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH- efficacy is warranted in a phase II clinical trial. SIGNIFICANCE: These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma.

Safety and efficacy of concurrent immune checkpoint inhibitors and hypofractionated body radiotherapy.

Integration of hypofractionated body radiotherapy (H-RT) into immune checkpoint inhibitor (ICI) therapy may be a promising strategy to improve the outcomes of ICIs, although sufficient data is lacking regarding the safety and efficacy of this regimen. We, hereby, reviewed the safety and efficacy of this combination in 59 patients treated with H-RT during or within 8 weeks of ICI infusion and compared results with historical reports of ICI treatment alone. Most patients had RCC or melanoma. Median follow-up was 11 months. Most patients received either Nivolumab alone or with Ipilimumab; 83% received stereotactic RT and 17% received conformal H-RT. Any grade adverse events (AEs) were reported in 46 patients, and grade 3-4 in 12 patients without any treatment-related grade 5 toxicity. The most common grade 3 AEs were fatigue and pneumonitis. Grade 3-4 toxicities were higher with ICI combination and with simultaneous ICIs. Overall, most any-grade or grade ≥3 AE rates did not differ significantly from historically reported rates with single-agent or multi-agent ICIs. Toxicity did not correlate with H-RT site, dose, fraction number, tumor type, or ICI and H-RT sequencing. Median progression-free survival was 6.5 months. Objective response rate (ORR) was 26%; 10% had complete response (CR). Median duration of response was 9.4 ± 4.6 months. H-RT of lung lesions was more likely to achieve CR than other sites. H-RT of bone lesions had a lower ORR than non-bone H-RT. In conclusion, combining body H-RT with ICIs is safe and promising. Prospective validation is warranted.

Magnetic resonance elastography of the pancreas: Measurement reproducibility and relationship with age.

PURPOSE: To determine magnetic resonance elastography (MRE)-derived stiffness of pancreas in healthy volunteers with emphasis on: 1) short term and midterm repeatability; and 2) variance as a function of age. METHODS: Pancreatic MRE was performed on 22 healthy volunteers (age range:20-64years) in a 3T-scanner. For evaluation of reproducibility of stiffness estimates, the scans were repeated per volunteer on the same day (short term) and one month apart (midterm). MRE wave images were analyzed using 3D inversion to estimate the stiffness of overall pancreas and different anatomic regions (i.e., head, neck, body, and tail). Concordance and Spearman correlation tests were performed to determine reproducibility of stiffness measurements and relationship to age. RESULTS: A strong concordance correlation (ρc=0.99; p-value<0.001) was found between short term and midterm repeatability pancreatic stiffness measurements. Additionally, the pancreatic stiffness significantly increased with age with good Spearman correlation coefficient (all ρ>0.81; p<0.001). The older age group (>45yrs) had significantly higher stiffness compared to the younger group (≤45yrs) (p<0.001). No significant difference (p>0.05) in stiffness measurements was observed between different anatomical regions of pancreas, except neck stiffness was slightly lower (p<0.012) compared to head and overall pancreas at month 1. CONCLUSION: MRE-derived pancreatic stiffness measurements are highly reproducible in the short and midterm and increase linearly with age in healthy volunteers. Further studies are needed to examine these effects in patients with various pancreatic diseases to understand potential clinical applications.

Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer.

Pharmacological ascorbate (AscH(-)) selectively induces cytotoxicity in pancreatic cancer cells vs normal cells via the generation of extracellular hydrogen peroxide (H2O2), producing double-stranded DNA breaks and ultimately cell death. Catalytic manganoporphyrins (MnPs) can enhance ascorbate-induced cytotoxicity by increasing the rate of AscH(-) oxidation and therefore the rate of generation of H2O2. We hypothesized that combining MnPs and AscH(-) with the chemotherapeutic agent gemcitabine would further enhance pancreatic cancer cell cytotoxicity without increasing toxicity in normal pancreatic cells or other organs. Redox-active MnPs were combined with AscH(-) and administered with or without gemcitabine to human pancreatic cancer cell lines, as well as immortalized normal pancreatic ductal epithelial cells. The MnPs MnT2EPyP (Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl) porphyrin pentachloride) and MnT4MPyP (Mn(III)tetrakis(N-methylpyridinium-4-yl) porphyrin pentachloride) were investigated. Clonogenic survival was significantly decreased in all pancreatic cancer cell lines studied when treated with MnP + AscH(-) + gemcitabine, whereas nontumorigenic cells were resistant. The concentration of ascorbate radical (Asc(•-), an indicator of oxidative flux) was significantly increased in treatment groups containing MnP and AscH(-). Furthermore, MnP + AscH(-) increased double-stranded DNA breaks in gemcitabine-treated cells. These results were abrogated by extracellular catalase, further supporting the role of the flux of H2O2. In vivo growth was inhibited and survival increased in mice treated with MnT2EPyP, AscH(-), and gemcitabine without a concomitant increase in systemic oxidative stress. These data suggest a promising role for the use of MnPs in combination with pharmacologic AscH(-) and chemotherapeutics in pancreatic cancer.

Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation.

Renewed interest in using pharmacological ascorbate (AscH-) to treat cancer has prompted interest in leveraging its cytotoxic mechanism of action. A central feature of AscH- action in cancer cells is its ability to act as an electron donor to O2 for generating H2O2. We hypothesized that catalytic manganoporphyrins (MnP) would increase AscH- oxidation rates, thereby increasing H2O2 fluxes and cytotoxicity. Three different MnPs were tested (MnTBAP, MnT2EPyP, and MnT4MPyP), exhibiting a range of physicochemical and thermodynamic properties. Of the MnPs tested, MnT4MPyP exerted the greatest effect on increasing the rate of AscH- oxidation as determined by the concentration of ascorbate radical [Asc•-] and the rate of oxygen consumption. At concentrations that had minimal effects alone, combining MnPs and AscH- synergized to decrease clonogenic survival in human pancreatic cancer cells. This cytotoxic effect was reversed by catalase, but not superoxide dismutase, consistent with a mechanism mediated by H2O2. MnPs increased steady-state concentrations of Asc•- upon ex vivo addition to whole blood obtained either from mice infused with AscH- or patients treated with pharmacologic AscH-. Finally, tumor growth in vivo was inhibited more effectively by combining MnT4MPyP with AscH-. We concluded that MnPs increase the rate of oxidation of AscH- to leverage H2O2 flux and ascorbate-induced cytotoxicity.