Prevalence of trauma history and symptoms in patients who have received vaginal brachytherapy as part of their endometrial cancer treatment.

OBJECTIVE: Vaginal brachytherapy (VBT) is an essential component of curative intent treatment for many patients with endometrial cancer. The prevalence of trauma history in this population is unknown and important to understand considering VBT requires patients to have an instrument vaginally inserted while in the vulnerable lithotomy position. We aim to identify patients treated with intracavitary VBT and collect survey data to assess trauma endpoints. METHODS: We retrospectively identified patients with endometrial cancer who underwent intracavitary VBT at our institution between 01/2017 and 08/2022. Patients were mailed and/or electronically mailed a survey that included demographics, psychosocial background, and validated trauma surveys to be filled out as they relate to their trauma experiences prior to VBT and again considering any trauma symptomatology related to VBT. Electronic medical record review was performed. Descriptive statistics as well as multivariate analysis were performed. RESULTS: 206 patients met inclusion criteria, 66 (32.1%) of whom returned the survey and were included for analysis. Thirty-two percent of patients self-reported a personal history of any prior mental health diagnosis. Eighty-eight percent of patients screened positive for a history of trauma exposure, 23% endorsed symptoms of PTSD related to their VBT experience, and 5% screened positive for a likely PTSD diagnosis from VBT. CONCLUSION: A majority of included patients had a history of trauma exposure prior to VBT. In a subset of patients, VBT re-induced trauma and was considered to be an independent traumatic event. This study highlights the importance of practicing trauma informed care, particularly in this patient population.

MRI-guided Real-time Online Gated Stereotactic Body Radiation Therapy for Liver Tumors.

BACKGROUND: Liver tumors are commonly encountered in oncology. The study aimed to assess the impact of magnetic resonance imaging (MRI)-guided stereotactic body radiation therapy (SBRT) (MRgSBRT) on disease-related outcomes and the toxicity profile. METHODS: Patients who received MRgSBRT from 2019 to 2021 for primary and metastatic liver tumors were included in this analysis. The protocol for treatment simulation included Gadoxetate disodium injection followed by a single-dimensional post-exhale MRI (0.35-T MRI linear accelerator) and computed tomography simulation. The patient demographics and treatment-related outcomes were assessed. The time-to-event curves were analyzed for freedom from local progression (FFLP) and overall survival (OS). RESULTS: A total of 35 patients were eligible for analysis with a median age of 70 years (range 25 to 95). The median follow-up was 19.4 months (range 1 to 37 mo). The one-year OS was 77.7%, with an estimated 3 years of 47.9%. Patients with the locally controlled disease had a better median OS of 27.8 months (95% CI [23.8-31.6]) compared with 13.5 months (95% CI [5.6-21.3], P =0.007) in patients with local disease progression. The 1-year FFLP was 95.6%, and 3-year estimated FFLP was 87.1%. Patients who received a radiation dose of biologically equivalent dose≥100 Gy had FFLP of 30.9 months (95% CI [28.7-33.1]) compared with 13.3 months (95% CI [5.3-21.3], P =0.004) in patients who received <100 Gy biologically equivalent dose. CONCLUSION: MRI-guided SBRT provides optimal local control, associated with improved OS in a heavily morbid, pretreated older cohort of patients with reasonable safety profiles.

Prostate segmentation accuracy using synthetic MRI for high-dose-rate prostate brachytherapy treatment planning.

Objective. Both computed tomography (CT) and magnetic resonance imaging (MRI) images are acquired for high-dose-rate (HDR) prostate brachytherapy patients at our institution. CT is used to identify catheters and MRI is used to segment the prostate. To address scenarios of limited MRI access, we developed a novel generative adversarial network (GAN) to generate synthetic MRI (sMRI) from CT with sufficient soft-tissue contrast to provide accurate prostate segmentation without MRI (rMRI).Approach. Our hybrid GAN, PxCGAN, was trained utilizing 58 paired CT-MRI datasets from our HDR prostate patients. Using 20 independent CT-MRI datasets, the image quality of sMRI was tested using mean absolute error (MAE), mean squared error (MSE), peak signal-to-noise ratio (PSNR) and structural similarity index (SSIM). These metrics were compared with the metrics of sMRI generated using Pix2Pix and CycleGAN. The accuracy of prostate segmentation on sMRI was evaluated using the Dice similarity coefficient (DSC), Hausdorff distance (HD) and mean surface distance (MSD) on the prostate delineated by three radiation oncologists (ROs) on sMRI versus rMRI. To estimate inter-observer variability (IOV), these metrics between prostate contours delineated by each RO on rMRI and the prostate delineated by treating RO on rMRI (gold standard) were calculated.Main results. Qualitatively, sMRI images show enhanced soft-tissue contrast at the prostate boundary compared with CT scans. For MAE and MSE, PxCGAN and CycleGAN have similar results, while the MAE of PxCGAN is smaller than that of Pix2Pix. PSNR and SSIM of PxCGAN are significantly higher than Pix2Pix and CycleGAN (p < 0.01). The DSC for sMRI versus rMRI is within the range of the IOV, while the HD for sMRI versus rMRI is smaller than the HD for the IOV for all ROs (p ≤ 0.03).Significance. PxCGAN generates sMRI images from treatment-planning CT scans that depict enhanced soft-tissue contrast at the prostate boundary. The accuracy of prostate segmentation on sMRI compared to rMRI is within the segmentation variation on rMRI between different ROs.

Multi-institutional Development and Validation of Contouring Guidelines for Para-aortic Elective Nodal Irradiation in Prostate Cancer Based on Patterns of Involvement on Targeted Molecular Imaging Positron Emission Tomography/Computed Tomography.

PURPOSE: Molecular imaging better identifies anatomic regions of metastatic spread of prostate cancer compared with conventional imaging, resulting in para-aortic (PA) nodal metastases being increasingly identified. Consequently, some radiation oncologists electively treat the PA lymph node region in patients with gross or high risk of PA nodal involvement. The anatomic locations of at-risk PA lymph nodes for prostate cancer are unknown. Our objective was to use molecular imaging to develop guidelines for the optimal delineation of the PA clinical target volume (CTV) in patients with prostate cancer. METHODS AND MATERIALS: We conducted a multi-institutional retrospective cohort study of patients with prostate cancer undergoing 18F-fluciclovine or 18F-DCFPyL prostate-specific membrane antigen positron emission tomography (PET)/computed tomography (CT). Images of patients with PET-positive PA nodes were imported into the treatment planning system, avid nodes were contoured, and measurements were taken in relation to anatomic landmarks. A contouring guideline that encompassed the location of ≥95% of PET-positive PA nodes was created using descriptive statistics and then validated in an independent data set. RESULTS: Five hundred fifty-nine patients had molecular PET/CT imaging in the development data set (78% 18F-fluciclovine, 22% prostate-specific membrane antigen). Seventy-six patients (14%) had evidence of PA nodal metastasis. We determined that expanding the CTV to 1.8 cm left of the aorta, 1.4 cm right of the inferior vena cava (IVC), 7 mm posterior to the aorta/IVC or to the vertebral body, and superiorly to the T11/T12 vertebral interface, with the anterior border 4 mm anterior to the aorta/IVC and inferior border at the bifurcation of the aorta/IVC, resulted in coverage of ≥95% of PET-positive PA nodes. When the guideline was used in the independent validation data set (246 patients with molecular PET/CT imaging, of whom 31 had PA nodal metastasis), 97% of nodes were encompassed, thereby validating our guideline. CONCLUSIONS: We used molecular PET/CT imaging to determine the anatomic locations of PA metastases to develop contouring guidelines for creating a prostate cancer PA CTV. Although the optimal patient selection and clinical benefits of PA radiation therapy remain uncertain, our results will aid in delineating the optimal target when PA radiation therapy is pursued.

Tailored Mentorship for the Underrepresented and Allies in Radiation Oncology: The Association of Residents in Radiation Oncology Equity and Inclusion Subcommittee Mentorship Experience.

PURPOSE: There are limited opportunities for mentorship for underrepresented in medicine (URM) trainees and physicians in radiation oncology (RO). The purpose of this study was to create and evaluate a formal mentorship program open to URMs and allies with interests in diversity, equity, and inclusion. METHODS AND MATERIALS: A mentorship program incorporating a virtual platform was designed by the Association of Residents in Radiation Oncology Equity and Inclusion Subcommittee. It was structured to include 6 sessions over 6 months with matched mentor-mentee pairs based on responses to a publicized online interest form. A compilation of evidence-based guidelines was provided to optimize the mentorship relationship. Linked pre- and postprogram surveys were administered to collect demographic data, define baseline goals and level of support, and evaluate program satisfaction. RESULTS: Thirty-five mentor-mentee pairs were matched; 31 mentees completed the preprogram survey and 17 completed the postprogram survey. Preprogram, only 3 mentees (9.7%) reported satisfaction with current mentorship and 5 (16%) reported mechanisms or mentorship in place at their program to support URMs. On the postprogram survey, mentees reported high satisfaction with areas of mentorship, mentor attributes, and the program overall. Opportunities for improvement include implementation of mechanisms to enhance communication with mentor-mentee pairs and maintain longitudinal engagement. CONCLUSIONS: In the first tailored mentorship program in RO for URMs and those with diversity, equity, and inclusion interests, our results demonstrate that there is self-reported interest for better mentorship for URMs in RO, and that a nationwide structured mentorship program can address participants' goals with high satisfaction. Program expansion could provide URMs and allies in RO more opportunities for career development and promote a greater sense of community and inclusion within the field.

Preliminary Approach to Implementing a COVID-19 Thoracic Radiation Therapy Program.

The value of low-dose whole thoracic radiation therapy (LD-WTRT) for SARS-CoV-2 (COVID-19) pneumonia is unknown. Should ongoing clinical trials demonstrate that LD-WTRT proves effective for COVID-19 pneumonia recovery, widespread rapid implementation will be helpful globally. Our aim was to outline a pragmatic process for safe and efficient administration of LD-WTRT to patients with COVID-19 pneumonia that could be implemented successfully in a community hospital setting based on participation in the PreVent clinical trial of LD-WTRT.

Radiotherapy and Immunotherapy Promote Tumoral Lipid Oxidation and Ferroptosis via Synergistic Repression of SLC7A11.

A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities, including radiotherapy. Here, we demonstrate that radiotherapy induces tumor-cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor-cell ferroptosis. Mechanistically, IFNγ derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently, yet synergistically, suppresses SLC7A11, a unit of the glutamate-cystine antiporter xc-, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy. SIGNIFICANCE: This article describes ferroptosis as a previously unappreciated mechanism of action for radiotherapy. Further, it shows that ferroptosis is a novel point of synergy between immunotherapy and radiotherapy. Finally, it nominates SLC7A11, a critical regulator of ferroptosis, as a mechanistic determinant of synergy between radiotherapy and immunotherapy.This article is highlighted in the In This Issue feature, p. 1631.

Volumetric 18 F-FDG-PET parameters as predictors of locoregional failure in low-risk HPV-related oropharyngeal cancer after definitive chemoradiation therapy.

BACKGROUND: We sought to investigate the prognostic value of volumetric positron emission tomography (PET) parameters in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) and a ≤10 pack-year smoking history treated with chemoradiation. METHODS: A total of 142 patients were included. Maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis (TLG) of the primary tumor, involved regional lymph nodes, and total lesion were calculated. Cox proportional hazard modeling was used to evaluate associations of clinical and PET parameters with locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), and overall survival (OS). RESULTS: On univariate analysis, volumetric PET parameters were significantly associated with all endpoints, and 8th edition American Joint Committee on Cancer/Union Internationale Contre le Cancer staging was significantly associated with DMFS and OS. On multivariate analysis, total lesion TLG was significantly associated with LRFFS, while staging was most significantly prognostic for DMFS and OS. CONCLUSION: Volumetric PET parameters are uniquely prognostic of LRFFS in low-risk HPV-related OPSCC and may be useful for directing de-intensification strategies.

Active shortening protects against stretch-induced force deficits in human skeletal muscle.

Skeletal muscle contraction results from molecular interactions of myosin "crossbridges" with adjacent actin filament binding sites. The binding of myosin to actin can be "weak" or "strong," and only strong binding states contribute to force production. During active shortening, the number of strongly bound crossbridges declines with increasing shortening velocity. Forcibly stretching a muscle that is actively shortening at high velocity results in no apparent negative consequences, whereas stretch of an isometrically (fixed-length) contracting muscle causes ultrastructural damage and a decline in force-generating capability. Our working hypothesis is that stretch-induced damage is uniquely attributable to the population of crossbridges that are strongly bound. We tested the hypothesis that stretch-induced force deficits decline as the prevailing shortening velocity is increased. Experiments were performed on permeabilized segments of individual skeletal muscle fibers obtained from human subjects. Fibers were maximally activated and allowed either to generate maximum isometric force (Fo), or to shorten at velocities that resulted in force maintenance of ≈50% Fo or ≈2% Fo For each test condition, a rapid stretch equivalent to 0.1 × optimal fiber length was applied. Relative to prestretch Fo, force deficits resulting from stretches applied during force maintenance of 100, ≈50, and ≈2% Fo were 23.2 ± 8.6, 7.8 ± 4.2, and 0.3 ± 3.3%, respectively (means ± SD, n = 20). We conclude that stretch-induced damage declines with increasing shortening velocity, consistent with the working hypothesis that the fraction of strongly bound crossbridges is a causative factor in the susceptibility of skeletal muscle to stretch-induced damage.NEW & NOTEWORTHY Force deficits caused by stretch of contracting muscle are most severe when the stretch is applied during an isometric contraction, but prevented if the muscle is shortening at high velocity when the stretch occurs. This study indicates that velocity-controlled modulation of the number of strongly bound crossbridges is the basis for the observed relationship between stretch-induced muscle damage and prevailing shortening velocity.

Simvastatin reduces fibrosis and protects against muscle weakness after massive rotator cuff tear.

BACKGROUND: Chronic rotator cuff tears are a common source of shoulder pain and disability, and patients with chronic cuff tears often have substantial weakness, fibrosis, inflammation, and fat accumulation. Identifying therapies to prevent the development of these pathologic processes will likely have a positive impact on clinical outcomes. Simvastatin is a drug with demonstrated anti-inflammatory and antifibrotic effects in many tissues but had not previously been studied in the context of rotator cuff tears. We hypothesized that after the induction of a massive supraspinatus tear, simvastatin would protect muscles from a loss of force production and fibrosis. METHODS: We measured changes in muscle fiber contractility, histology, and biochemical markers of fibrosis and fatty infiltration in rats that received a full-thickness supraspinatus tear and were treated with either carrier alone or simvastatin. RESULTS: Compared with vehicle-treated controls, simvastatin did not have an appreciable effect on muscle fiber size, but treatment did increase muscle fiber specific force by 20%. Simvastatin also reduced collagen accumulation by 50% but did not affect triglyceride content of muscles. Several favorable changes in the expression of genes and other markers of inflammation, fibrosis, and regeneration were also observed. CONCLUSIONS: Simvastatin partially protected muscles from the weakness that occurs as a result of chronic rotator cuff tear. Fibrosis was also markedly reduced in simvastatin-treated animals. Whereas further studies are necessary, statin medication could potentially help improve outcomes for patients with rotator cuff tears.

Inhibition of 5-LOX, COX-1, and COX-2 increases tendon healing and reduces muscle fibrosis and lipid accumulation after rotator cuff repair.

BACKGROUND: The repair and restoration of function after chronic rotator cuff tears are often complicated by muscle atrophy, fibrosis, and fatty degeneration of the diseased muscle. The inflammatory response has been implicated in the development of fatty degeneration after cuff injuries. Licofelone is a novel anti-inflammatory drug that inhibits 5-lipoxygenase (5-LOX), as well as cyclooxygenase (COX)-1 and COX-2 enzymes, which play important roles in inducing inflammation after injuries. While previous studies have demonstrated that nonsteroidal anti-inflammatory drugs and selective inhibitors of COX-2 (coxibs) may prevent the proper healing of muscles and tendons, studies about bone and cartilage have demonstrated that drugs that inhibit 5-LOX concurrently with COX-1 and COX-2 may enhance tissue regeneration. HYPOTHESIS: After the repair of a chronic rotator cuff tear in rats, licofelone would increase the load to failure of repaired tendons and increase the force production of muscle fibers. STUDY DESIGN: Controlled laboratory study. METHODS: Rats underwent supraspinatus release followed by repair 28 days later. After repair, rats began a treatment regimen of either licofelone or a vehicle for 14 days, at which time animals were euthanized. Supraspinatus muscles and tendons were then subjected to contractile, mechanical, histological, and biochemical analyses. RESULTS: Compared with controls, licofelone-treated rats had a grossly apparent decrease in inflammation and increased fibrocartilage formation at the enthesis, along with a 62% increase in the maximum load to failure and a 51% increase in peak stress to failure. Licofelone resulted in a marked reduction in fibrosis and lipid content in supraspinatus muscles as well as reduced expression of several genes involved in fatty infiltration. Despite the decline in fibrosis and fat accumulation, muscle fiber specific force production was reduced by 23%. CONCLUSION: The postoperative treatment of cuff repair with licofelone may reduce fatty degeneration and enhance the development of a stable bone-tendon interface, although decreases in muscle fiber specific force production were observed, and force production in fact declined. CLINICAL RELEVANCE: This study demonstrates that the inhibition of 5-LOX, COX-1, and COX-2 modulates the healing process of repaired rotator cuff tendons. Although further studies are necessary, the treatment of patients with licofelone after cuff repair may improve the development of a stable enthesis and enhance postoperative outcomes.

Aging-associated exacerbation in fatty degeneration and infiltration after rotator cuff tear.

BACKGROUND: Rotator cuff tears are one of the most common musculoskeletal complaints and a substantial source of morbidity in elderly patients. Chronic cuff tears are associated with muscle atrophy and an infiltration of fat to the area, a condition known as "fatty degeneration." To improve the treatment of cuff tears in elderly patients, a greater understanding of the changes in the contractile properties of muscle fibers and the molecular regulation of fatty degeneration is essential. METHODS: Using a full-thickness, massive supraspinatus and infraspinatus tear model in elderly rats, we measured fiber contractility and determined changes in fiber type distribution that develop 30 days after tear. We also measured the expression of messenger RNA and micro-RNA transcripts involved in muscle atrophy, lipid accumulation, and matrix synthesis. We hypothesized that a decrease in specific force of muscle fibers, an accumulation of type IIb fibers, and an upregulation in atrophic, fibrogenic, and inflammatory gene expression would occur in torn cuff muscles. RESULTS: Thirty days after the tear, we observed a reduction in muscle fiber force and an induction of RNA molecules that regulate atrophy, fibrosis, lipid accumulation, inflammation, and macrophage recruitment. A marked accumulation of advanced glycation end products and a significant accretion of macrophages in areas of fat accumulation were observed. CONCLUSIONS: The extent of degenerative changes in old rats was greater than that observed in adults. In addition, we identified that the ectopic fat accumulation that occurs in chronic cuff tears does not occur by activation of canonical intramyocellular lipid storage and synthesis pathways.