Navigating Breast Cancer Oligometastasis and Oligoprogression: Current Landscape and Future Directions.

PURPOSE: We examine the potential for curative approaches among metastatic breast cancer (MBC) patients by exploring the recent literature on local ablative therapies like surgery and stereotactic body radiation therapy (SBRT) in patients with oligometastatic (OM) breast cancer. We also cover therapies for MBC patients with oligoprogressive (OP) disease. KEY FINDINGS: Surgery and SBRT have been studied for OM and OP breast cancer, mainly in retrospective or non-randomized trials. While many studies demonstrated favorable results, a cooperative study and single-institution trial found no support for surgery/SBRT in OM and OP cases, respectively. CONCLUSION: While there is interest in applying local therapies to OM and OP breast cancer, the current randomized data does not back the routine use of surgery or SBRT, particularly when considering the potential for treatment-related toxicities. Future research should refine patient selection through advanced imaging and possibly explore these therapies specifically in patients with hormone receptor-positive or HER2-positive disease.

The Effect of State and Local Flavored Cigar Sales Restrictions, on Retail Sales of Large Cigars, Cigarillos, and Little Cigars in Massachusetts, California, Illinois, and New York.

INTRODUCTION: In 2009, the Family Smoking Prevention and Tobacco Control Act prohibited flavored cigarettes but allowed for flavored cigars. Since, there has been a 34% increase in youth cigar use and widened racial disparities. State and local jurisdictions have increasingly enacted flavored tobacco product sales restrictions. As more jurisdictions consider implementing flavor restrictions, it is important to understand their effect on tobacco markets that have high flavor proliferation, including the cigar market. AIMS AND METHODS: This study uses data from Truth Initiative's flavor policy database and NielsenIQ retailer scanners for California, Illinois, Massachusetts, and New York. We use a three-way fixed-effect model to assess the impact of the percentage of the population covered by a flavored cigar sales restriction on per capita unit sales of cigars. RESULTS: We find that population coverage by cigar sales restrictions was significantly associated with decreases in per capita cigar sales. More specifically, a 25% increase in the percentage of the population covered by a flavored cigar sales restriction was associated with a decrease in per capita all cigar sales of 15%-19%, 4%-10% for large cigars, 17%-21% for cigarillos, and 2%-41% for little cigars. CONCLUSION: Flavored cigar sales restrictions are an effective policy to reduce per capita cigar sales. The Food and Drug Administration (FDA)'s proposed product standards would increase population covered by a flavored cigar sales restriction to 100%, leading to potential significant reductions in cigar sales, especially little cigar, and cigarillo sales. This may also substantially reduce youth cigar use and racial disparities in cigar use. IMPLICATIONS: In April 2022, the U.S. FDA published a proposed rule to prohibit characterizing flavors in all cigars and menthol cigarettes. Besides this proposed rule, there has been little federal action to date to reduce sales of flavored cigars. However, as of March 31, 2022, Massachusetts and 333 localities across 10 states have enacted policies that restrict the sale of flavored cigars and other tobacco products. We find that population coverage by cigar sales restrictions is significantly associated with decreases in per capita cigar sales.

Oral nicotine marketing claims in direct-mail advertising.

BACKGROUND: Little is known regarding how oral nicotine products (eg, nicotine pouches, lozenges) are marketed to consumers, including whether potential implicit reduced harm claims are used. In the current study, we explored the marketing claims present in a sample of direct-mail oral nicotine advertisements sent to US consumers (March 2018-August 2020). METHODS: Direct-mail ads (n=50) were acquired from Mintel and dual-coded for the following claims: alternative to other tobacco products, ability to use anywhere, spit-free, smoke-free and product does not contain tobacco leaf. We merged the coded data with Mintel's volume estimate (number of mail pieces sent to consumers) and calculated the proportion of oral nicotine advertisements containing claims by category. RESULTS: Of the 38 million pieces of oral nicotine direct-mail sent to US consumers, most featured claims that the product could be used anywhere (84%, 31.8 million pieces); was an alternative to other tobacco products (69%, 26.1 million pieces); and did not contain tobacco leaf (eg, 'tobacco leaf-free', 'simple' approach of extracting nicotine from tobacco; 55%, 20.7 million pieces). A slightly smaller proportion contained claims that oral nicotine was 'spit-free' (52%, 19.8 million pieces) or 'smoke-free' (31%, 11.7 million pieces). CONCLUSION: Our results provide an early indication of marketing claims used to promote oral nicotine. The strategies documented, particularly the use of language to highlight oral nicotine is tobacco-free, may covey these products as lower-risk to consumers despite the lack of evidence or proper federal authorisation that oral nicotine products are a modified-risk tobacco product. Future research is needed to examine consumer perceptions of such claims.

Analysis of e-cigarette warning letters issued by the Food and Drug Administration in 2020 and 2021.

PURPOSE: This study analyses the Food and Drug Administration (FDA) warning letters sent to e-cigarette companies from 1 January 2020 to 9 September 2021. Study results can inform regulation of e-cigarettes. METHODOLOGY: Warning letters retrieved from FDA's website were coded for company type (retailer, manufacturer or distributor), location (domestic or international), infractions listed (PMTA (premarket tobacco product application), selling to minors, advertising to youth or packaging violation/mislabelling), product type (e-liquid, device or both), flavour (fruit, candy, tobacco, menthol/mint, concept flavour) and consequence (civil money penalties, product seizure and injunction, product detention and refusal of entry to the USA, no-tobacco-sales order, criminal prosecution). RESULTS: Of 303 coded letters (126 from 2020 and 177 from 2021), 97.4% were sent to small online retailers. Overall, 94.1% of the companies cited were located within the USA, 75.2% of the infractions were identified by reviewing a company's website and 70.5% were PMTA violations. In 2020, 55.6% of infractions were PMTA violations; in 2021, nearly all infractions were PMTA violations. The letters cited 880 products; 92.2% of which were e-liquid products, with 32.4% fruit and 31.1% concept flavours. DISCUSSION: Warning letters targeted small online retailers rather than large e-cigarette brands or products most used by youth: pod mods and disposables. The focus of these enforcement actions comprises a small share of the market and the impact on use was likely minimal. With PMTA decisions pending for the largest brands of e-cigarettes, the FDA should use its enforcement powers to target manufacturers, distributors and sellers of the tobacco products that have the greatest impact on youth and products that provide no public health benefit.

The interplay between chromosome stability and cell cycle control explored through gene-gene interaction and computational simulation.

Chromosome stability models are usually qualitative models derived from molecular-genetic mechanisms for DNA repair, DNA synthesis, and cell division. While qualitative models are informative, they are also challenging to reformulate as precise quantitative models. In this report we explore how (A) laboratory experiments, (B) quantitative simulation, and (C) seriation algorithms can inform models of chromosome stability. Laboratory experiments were used to identify 19 genes that when over-expressed cause chromosome instability in the yeast Saccharomyces cerevisiae To better understand the molecular mechanisms by which these genes act, we explored their genetic interactions with 18 deletion mutations known to cause chromosome instability. Quantitative simulations based on a mathematical model of the cell cycle were used to predict the consequences of several genetic interactions. These simulations lead us to suspect that the chromosome instability genes cause cell-cycle perturbations. Cell-cycle involvement was confirmed using a seriation algorithm, which was used to analyze the genetic interaction matrix to reveal an underlying cyclical pattern. The seriation algorithm searched over 10(14) possible arrangements of rows and columns to find one optimal arrangement, which correctly reflects events during cell cycle phases. To conclude, we illustrate how the molecular mechanisms behind these cell cycle events are consistent with established molecular interaction maps.

Suppression of lung adenocarcinoma progression by Nkx2-1.

Despite the high prevalence and poor outcome of patients with metastatic lung cancer the mechanisms of tumour progression and metastasis remain largely uncharacterized. Here we modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS and inactivation of the p53 pathway, using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras(LSL-G12D/+);p53(flox/flox) mice initiates lung adenocarcinoma development. Although tumours are initiated synchronously by defined genetic alterations, only a subset becomes malignant, indicating that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK2-related homeobox transcription factor Nkx2-1 (also called Ttf-1 or Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1 negativity is pathognomonic of high-grade poorly differentiated tumours. Gain- and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1-regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically restricted chromatin regulator Hmga2. Whereas focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability and increased metastatic proclivity. Thus, the oncogenic and suppressive functions of Nkx2-1 in the same tumour type substantiate its role as a dual function lineage factor.

Grade 5 Radiation Necrosis After Whole-Brain Radiation Therapy.

Whole-brain radiation treatment is often considered for patients with leptomeningeal disease. There are limited reports of the development of radiation necrosis after whole-brain radiation treatment and fewer associating the presence of germline mutations with risk. We present a case report to highlight the need for consideration of radiosensitizing mutations when recommending radiation therapy.

Omission of adjuvant radiotherapy in low-risk elderly males with breast cancer.

PURPOSE: Randomized clinical trials demonstrate that lumpectomy + hormone therapy (HT) without radiation therapy (RT) yields equivalent survival and acceptable local-regional outcomes in elderly women with early-stage, node-negative, hormone-receptor positive (HR +) breast cancer. Whether these data apply to men with the same inclusion criteria remains unknown. METHODS: The National Cancer Database was queried for male patients ≥ 65 years with pathologic T1-2N0 (≤ 3 cm) HR + breast cancer treated with breast-conserving surgery with negative margins from 2004 to 2019. Adjuvant treatment was classified as HT alone, RT alone, or HT + RT. Male patients were matched with female patients for OS comparison. Survival analysis was performed using Cox regression and Kaplan - Meier method. Inverse probability of treatment weighting (IPTW) was applied to adjust for confounding. RESULTS: A total of 523 patients met the inclusion criteria, with 24.4% receiving HT, 16.3% receiving RT, and 59.2% receiving HT + RT. The median follow-up was 6.9 years (IQR: 5.0-9.4 years). IPTW-adjusted 5-yr OS rates in the HT, RT, and HT + RT cohorts were 84.0% (95% CI 77.1-91.5%), 81.1% (95% CI 71.1-92.5%), and 93.0% (95% CI 90.0-96.2%), respectively. On IPTW-adjusted MVA, relative to HT, receipt of HT + RT was associated with improvements in OS (HR: 0.641; p = 0.042). RT alone was not associated with improved OS (HR: 1.264; p = 0.420). CONCLUSION: Among men ≥ 65 years old with T1-2N0 HR + breast cancer, RT alone did not confer an OS benefit over HT alone. Combination of RT + HT demonstrated significant improvements in OS. De-escalation of treatment through omission of either RT or HT at this point should be done with caution.

Cannabis and vaping nicotine: An exploration of risk factors using a nationally representative sample of youth and young adults.

BACKGROUND: Given that cannabis and e-cigarettes are among the most commonly used substances among young people, there is a need to identify risk factors for concurrent cannabis consumption and nicotine vaping among youth and young adults. METHODS: Data were obtained from the Truth Longitudinal Cohort, collected from September 2020 to March 2021, among a cohort aged 15-24 years (N = 6379). Chi-square tests were conducted to detect differences in sample characteristics by dual use status (never e-cigarette and never cannabis users, never cannabis and former/noncurrent e-cigarette users, never e-cigarette and former/noncurrent cannabis users, former/noncurrent e-cigarette and cannabis users, current e-cigarette only users, current cannabis only users, and concurrent cannabis and e-cigarette dual users). Multinomial logistic regression was used to determine key demographic variables predicting dual use status. RESULTS: Household tobacco use (Relative Risk Ratio, RRR = 4.93), higher sensation seeking (RRR = 3.98), and mental health score (RRR = 2.58) were associated with higher risk of dual use. Being 15-17 years (RRR = 0.22), being female (RRR = 0.59) and having parents with an education level of some college or more (RRR = 0.64) were associated with lower risk of dual use. CONCLUSION: Findings suggest the need to carefully monitor cannabis and vaping nicotine among young people. The identification of risk factors provides additional guidance for prevention and treatment efforts, suggesting the need to address use of both substances and target those most at risk.

Intra-fractional geometric and dose/volume metric variations of magnetic resonance imaging-guided stereotactic radiotherapy of prostate bed after radical prostatectomy.

Background and purpose: Magnetic Resonance Imaging (MRI)-guided Stereotactic body radiotherapy (SBRT) treatment to prostate bed after radical prostatectomy has garnered growing interests. The aim of this study is to evaluate intra-fractional anatomic and dose/volume metric variations for patients receiving this treatment. Materials and methods: Nineteen patients who received 30-34 Gy in 5 fractions on a 0.35T MR-Linac were included. Pre- and post-treatment MRIs were acquired for each fraction (total of 75 fractions). The Clinical Target Volume (CTV), bladder, rectum, and rectal wall were contoured on all images. Volumetric changes, Hausdorff distance, Mean Distance to Agreement (MDA), and Dice similarity coefficient (DSC) for each structure were calculated. Median value and Interquartile range (IQR) were recorded. Changes in target coverage and Organ at Risk (OAR) constraints were compared and evaluated using Wilcoxon rank sum tests at a significant level of 0.05. Results: Bladder had the largest volumetric changes, with a median volume increase of 48.9 % (IQR 28.9-76.8 %) and a median MDA of 5.1 mm (IQR 3.4-7.1 mm). Intra-fractional CTV volume remained stable with a median volume change of 1.2 % (0.0-4.8 %). DSC was 0.97 (IQR 0.94-0.99). For the dose/volume metrics, there were no statistically significant changes observed except for an increase in bladder hotspot and a decrease of bladder V32.5 Gy and mean dose. The CTV V95% changed from 99.9 % (IQR 98.8-100 %) to 99.6 % (IQR 93.9-100 %). Conclusion: Despite intra-fractional variations of OARs, CTV coverage remained stable during MRI-guided SBRT treatments for the prostate bed.

Identifying predictors of on-table adaptation for pancreas stereotactic body radiotherapy (SBRT).

Purpose: To identify any clinical or dosimetric parameters that predict which individuals may benefit from on-table adaptation during pancreas stereotactic body radiotherapy (SBRT) with MRI-guided radiotherapy. Methods and materials: This was a retrospective study of patients undergoing MRI-guided SBRT from 2016 to 2022. Pre-treatment clinical variables and dosimetric parameters on the patient's simulation scan were recorded for each SBRT course, and their ability to predict for on-table adaptation was analyzed using ordinal logistic regression. The outcome measure was number of fractions adapted. Results: Sixty-three SBRT courses consisting of 315 fractions were analyzed. Median prescription dose was 40 Gy in five fractions (range, 33-50 Gy); 52% and 48% of courses were prescribed ≤40 Gy and >40 Gy, respectively. The median minimum dose delivered to 95% (D95) of the gross tumor volume (GTV) and planning target volume (PTV) was 40.1 Gy and 37.0 Gy, respectively. Median number of fractions adapted per course was three, with 58% (183 out of 315) total fractions adapted. On univariable analysis, the prescription dose (>40 Gy vs ≤40 Gy), GTV volume, stomach V20 and V25, duodenum V20 and dose maximum, large bowel V33 and V35, GTV dose minimum, PTV dose minimum, and gradient index were significant determinants for adaptation (all p < 0.05). On multivariable analysis, only the prescription dose was significant (adjusted odds ratio 19.7, p = 0.005), but did not remain significant after multiple test correction (p = 0.08). Conclusions: The likelihood of needing on-table adaptation could not be reliably predicted a priori using pre-treatment clinical characteristics, dosimetry to nearby organs at risk, or other dosimetric parameters based on the patient's anatomy at the time of simulation, suggesting the critical importance of day-to-day variations in anatomy and increasing access to adaptive technology for pancreas SBRT. A higher (ablative) prescription dose was associated with increased use of adaptation.

Differential Distribution of Brain Metastases from Non-Small Cell Lung Cancer Based on Mutation Status.

Non-small cell lung cancer (NSCLC) has a high rate of brain metastasis. The purpose of this study was to assess the differential distribution of brain metastases from primary NSCLC based on mutation status. Brain MRI scans of patients with brain metastases from primary NSCLC were retrospectively analyzed. Brain metastatic tumors were grouped according to mutation status of their primary NSCLC and the neuroimaging features of these brain metastases were analyzed. A total of 110 patients with 1386 brain metastases from primary NSCLC were included in this study. Gray matter density at the tumor center peaked at ~0.6 for all mutations. The median depths of tumors were 7.9 mm, 8.7 mm and 9.1 mm for EGFR, ALK and KRAS mutation groups, respectively (p = 0.044). Brain metastases for the EGFR mutation-positive group were more frequently located in the left cerebellum, left cuneus, left precuneus and right precentral gyrus. In the ALK mutation-positive group, brain metastases were more frequently located in the right middle occipital gyrus, right posterior cingulate, right precuneus, right precentral gyrus and right parietal lobe. In the KRAS mutation-positive patient group, brain metastases were more frequently located in the posterior left cerebellum. Our study showed differential spatial distribution of brain metastases in patients with NSCLC according to their mutation status. Information regarding distribution of brain metastases is clinically relevant as it could be helpful to guide treatment planning for targeted therapy, and for predicting prognosis.

68Ga-PSMA PET/CT-Based Atlas for Prostate Bed Recurrence After Radical Prostatectomy: Clinical Implications for Salvage Radiation Therapy Contouring Guidelines.

The aim of this study was to analyze the patterns of prostate bed (PB) recurrence in prostate cancer patients experiencing prostate-specific antigen (PSA) persistence (BCP) or biochemical recurrence (BCR) after radical prostatectomy using 68Ga-PSMA-11 PET/CT (68Ga-PSMA PET) in relation to the Radiation Therapy Oncology Group (RTOG) clinical target volumes (CTVs). Methods: This single-center, retrospective analysis included patients with BCP or BCR after radical prostatectomy and PB recurrence on 68Ga-PSMA PET. The PB recurrences were delineated by nuclear medicine physicians, the CTVs by radiation oncologists contouring guidelines on the 68Ga-PSMA PET, respectively, masked from each other. The coverage of the 68Ga-PSMA PET recurrence was categorized as PSMA recurrence completely covered, partially covered, or not covered by the RTOG-based CTV. Further, we evaluated the differences in PSMA recurrence patterns among patients with different 68Ga-PSMA PET staging (miTNM). Mann-Whitney U tests, the chi-square test, and Spearman (ρ) correlation analysis were used to investigate associations between CTV coverage and 68Ga-PSMA PET-based tumor volume, serum PSA levels, miTNM, and rectal/bladder involvement. Results: A total of 226 patients were included in the analysis; 127 patients had PSMA recurrence limited to the PB (miTrN0M0), 30 had pelvic nodal disease (miTrN1M0), 32 had extrapelvic disease (miTrN0M1), and 37 had both pelvic nodal disease and extrapelvic disease (miTrN1M1). In the miTrN0M0 cohort, the recurrence involved the rectal and bladder walls in 12 of 127 (9%) and 4 of 127 (3%), respectively. The PSMA-positive PB recurrences were completely covered by the CTV in 68 of 127 patients (53%), partially covered in 43 of 127 (34%), and not covered in 16 of 127 (13%). Full coverage was associated with a smaller tumor volume (P = 0.043), a lack of rectal/bladder wall involvement (P = 0.03), and lower miTNM staging (P = 0.035) but not with lower serum PSA levels (P = 0.979). Conclusion: Our study suggests that 68Ga-PSMA PET can be a valuable tool for guiding salvage radiation therapy (SRT) planning directed to the PB in the setting of postoperative BCR or BCP. These data should be incorporated into the redefinition of PB contouring guidelines.

Inhibition of RRM2 radiosensitizes glioblastoma and uncovers synthetic lethality in combination with targeting CHK1.

Glioblastoma (GBM) is an aggressive malignant primary brain tumor. Radioresistance largely contributes to poor clinical outcomes in GBM patients. We targeted ribonucleotide reductase subunit 2 (RRM2) with triapine to radiosensitize GBM. We found RRM2 is associated with increasing tumor grade, is overexpressed in GBM over lower grade gliomas and normal tissue, and is associated with worse survival. We found silencing or inhibition of RRM2 by siRNA or triapine sensitized GBM cells to ionizing radiation (IR) and delayed resolution of IR-induced γ-H2AX nuclear foci. In vivo, triapine and IR reduced tumor growth and increased mouse survival. Intriguingly, triapine led to RRM2 upregulation and CHK1 activation, suggesting a CHK1-dependent RRM2 upregulation following RRM2 inhibition. Consistently, silencing or inhibition of CHK1 with rabusertib abolished the triapine-induced RRM2 upregulation. Accordingly, combining rabusertib and triapine resulted in synthetic lethality in GBM cells. Collectively, our results suggest RRM2 is a promising therapeutic target for GBM, and targeting RRM2 with triapine sensitizes GBM cells to radiation and independently induces synthetic lethality of GBM cells with CHK1 inhibition. Our findings suggest combining triapine with radiation or rabusertib may improve therapeutic outcomes in GBM.

The role of adaptive planning in margin-reduced, MRI-guided stereotactic body radiotherapy to the prostate bed following radical prostatectomy: Post-hoc analysis of a phase II clinical trial.

BACKGROUND AND PURPOSE: We examined the interfractional variations of clinical target volumes (CTVs), planning target volumes (PTVs), and organs-at-risk (OARs) in patients receiving MRI-guided stereotactic body radiotherapy (SBRT) to the prostate bed and evaluated the potential role of adaptive planning. MATERIALS AND METHODS: 31 patients received 30-34 Gy in five fractions to the prostate bed on a phase II clinical trial. OARs, CTVs, and PTVs were retrospectively contoured on daily pretreatment MRIs (n = 155). Geometric comparisons were made between initial planning contours and daily pretreatment contours. Predicted treatment plans for each fraction were evaluated using the following constraints: CTV V95%>93%, PTV V95%>90%, bladder Dmax < 36.7 Gy, bladder V32.5 Gy < 35%, rectum Dmax < 36.7 Gy, rectum V27.5 Gy < 45%, rectum 32.5 Gy < 30%, and rectal wall V24Gy < 50%. Adaptive planning was simulated for all fractions that failed to meet these criteria. Plans were then re-evaluated. RESULTS: Median change in volume was 0.48% for CTV, -24.5% for bladder, and 6.95% for rectum. Median DSC was 0.89 for CTV, 0.79 for bladder, and 0.76 for rectum. 145/155 fractions (93.5%) met CTV V95%>93%. 75/155 fractions (48.4%) failed at least one OAR dose constraint. Overall, 83/155 fractions (53.5%) met criteria for adapting planning. This affected 24/31 patients (77.4%). Following adaptive planning, all fractions met CTV V95%>93% and PTV V95%>90% and 120/155 fractions (77.4%) met all OAR constraints. CONCLUSION: Due to significant interfractional variations in anatomy, a majority of fractions failed to meet both target volume and OAR constraints. However, adaptive planning was effective in overcoming these anatomic changes. Adaptive planning should be routinely considered in prostate bed SBRT.

Brief Report: Severe Pneumonitis After Combined Thoracic Radiotherapy and Osimertinib.

Introduction: Osimertinib is an effective treatment for metastatic NSCLC. Occasionally, thoracic radiation therapy (TRT) is delivered to patients receiving osimertinib to treat residual or progressing pulmonary tumors. Anecdotal reports suggest that the delivery of TRT in combination with osimertinib may be associated with a high risk of severe pneumonitis. Methods: A retrospective study was performed at a single academic medical center in the United States to investigate the incidence of severe pneumonitis among patients treated with combined TRT and osimertinib between June 2016 and December 2021. Baseline patient characteristics, tumor size and location, and dosimetric parameters were evaluated. The highest grade of radiation pneumonitis that developed within 6 months of treatment was scored in accordance with the Common Terminology Criteria for Adverse Events version 5.0. Results: A total of 16 patients were identified who were treated with combined TRT and osimertinib. All had a diagnosis of metastatic NSCLC. Treatment-related grade greater than or equal to 2 pneumonitis developed in 56%, grade greater than or equal to 3 in 37.5%, and grade 4 in 6.3%; no patient developed grade 5 pneumonitis. Median time to any-grade pneumonitis was 29 days (1-84 d); all patients had symptom resolution with expectant management or oral steroid therapies. All patients discovered to have grade greater than or equal to 3 pneumonitis (n = 6) received TRT to tumors located within 2 cm of the proximal bronchial tree, including tumors abutting the proximal bronchial tree (n = 2) and within the mediastinum (n = 1). Conclusions: The combination of TRT with osimertinib was associated with a high rate of severe pneumonitis that required oral steroid medications. Larger studies are needed to validate these findings and to understand the clinical and treatment factors that influence this risk and how they can be mitigated.

Quality-of-Life Outcomes and Toxicity Profile Among Patients With Localized Prostate Cancer After Radical Prostatectomy Treated With Stereotactic Body Radiation: The SCIMITAR Multicenter Phase 2 Trial.

PURPOSE: Postoperative radiation therapy (RT) is an underused standard-of-care intervention for patients with prostate cancer and recurrence/adverse pathologic features after radical prostatectomy. Although stereotactic body RT (SBRT) is a well-studied and convenient option for definitive treatment, data on the postprostatectomy setting are extremely limited. The purpose of this study was to evaluate short-term physician-scored genitourinary (GU) and gastrointestinal (GI) toxicities and patient-reported outcomes after postprostatectomy SBRT. METHODS AND MATERIALS: The SCIMITAR trial was a phase 2, dual-center, open-label, single-arm trial that enrolled patients with postoperative prostate-specific antigen >0.03 ng/mL or adverse pathologic features. Coprimary endpoints were 4-year biochemical recurrence-free survival, physician-scored acute and late GU and GI toxicities by the Common Terminology Criteria for Adverse Events (version 4.03) scale, and patient-reported quality-of-life (QOL) outcomes, as represented by the Expanded Prostate Cancer Index-26 and the International Prostate Symptom Score. Patients received SBRT 30 to 34 Gy/5 fractions to the prostate bed ± bed boost ± pelvic nodes with computed tomography (CTgRT) or magnetic resonance imaging guidance (MRgRT) in a nonrandomized fashion. Physician-scored toxicities and patient-reported QOL outcomes were collected at baseline and at 1, 3, and 6 months of follow-up. Univariable and multivariable analyses were performed to evaluate predictors of toxicities and QOL outcomes. RESULTS: One hundred participants were enrolled (CTgRT, n = 69; MRgRT, n = 31). The median follow-up was 29.5 months (CTgRT: 33.3 months, MRgRT: 22.6 months). The median (range) prostate bed dose was 32 (30-34) Gy. Acute and late grade 2 GU toxicities were both 9% while acute and late grade 2 GI toxicities were 5% and 0%, respectively. Three patients had grade 3 toxicity (n = 1 GU, n = 2 GI). No patient receiving MRgRT had grade 3 GU or grade ≥2 GI toxicity. Compared with CTgRT, MRgRT was associated with a 30.5% (95% confidence interval, 11.6%-49.5%) reduction in any-grade acute GI toxicity (P = .006). MRgRT was independently associated with improved any-grade GI toxicity and improved bowel QOL. CONCLUSIONS: Postprostatectomy SBRT was well tolerated at short-term follow-up. MRgRT may decrease GI toxicity. Longer toxicity and/or efficacy follow-up and randomized studies are needed.

Dosimetric Effects of Air Cavities for MRI-Guided Online Adaptive Radiation Therapy (MRgART) of Prostate Bed after Radical Prostatectomy.

PURPOSE: To evaluate dosimetric impact of air cavities and their corresponding electron density correction for 0.35 tesla (T) Magnetic Resonance-guided Online Adaptive Radiation Therapy (MRgART) of prostate bed patients. METHODS: Three 0.35 T MRgRT plans (anterior-posterior (AP) beam, AP-PA beams, and clinical intensity modulated radiation therapy (IMRT)) were generated on a prostate bed patient's (Patient A) planning computed tomography (CT) with artificial rectal air cavities of various sizes (0-3 cm, 0.5 cm increments). Furthermore, two 0.35 T MRgART plans ('Deformed' and 'Override') were generated on a prostate bed patient's (Patient B) daily magnetic resonance image (MRI) with artificial rectal air cavities of various sizes (0-3 cm, 0.5 cm increments) and on five prostate bed patient's (Patient 1-5) daily MRIs (2 MRIs: Fraction A and B) with real air cavities. For each MRgART plan, daily MRI electron density map was obtained by deformable registration with simulation CT. In the 'Deformed' plan, a clinical IMRT plan is calculated on the daily MRI with electron density map obtained from deformable registration only. In the 'Override' plan, daily MRI and simulation CT air cavities are manually corrected and bulk assigned air and water density on the registered electron density map, respectively. Afterwards, the clinical IMRT plan is calculated. RESULTS: For the MRgRT plans, AP and AP-PA plans' rectum/rectal wall max dose increased with increasing air cavity size, where the 3 cm air cavity resulted in a 20%/17% and 13%/13% increase, relative to no air cavity, respectively. Clinical IMRT plan was robust to air cavity size, where dose change remained less than 1%. For the MRgART plans, daily MRI electron density maps, obtained from deformable registration with simulation CT, was unable to accurately produce electron densities reflecting the air cavities. However, for the artificial daily MRI air cavities, dosimetric change between 'Deformed' and 'Override' plan was small (<4%). Similarly, for the real daily MRI air cavities, clinical constraint changes between 'Deformed' and 'Override' plan was negligible and did not lead to change in clinical decision for adaptive planning except for two fractions. In these fractions, the 'Override' plan indicated that the bladder max dose and rectum V35.7 exceeded the constraint, while the 'Deformed' plan showed acceptable dose, although the absolute difference was only 0.3 Gy and 0.03 cc, respectively. CONCLUSION: Clinical 0.35 T IMRT prostate bed plans are dosimetrically robust to air cavities. MRgART air cavity electron density correction shows clinically insignificant change and is not warranted on low-field systems.

Ensemble learning and tensor regularization for cone-beam computed tomography-based pelvic organ segmentation.

PURPOSE: Cone-beam computed tomography (CBCT) is a widely accessible low-dose imaging approach compatible with on-table patient anatomy observation for radiotherapy. However, its use in comprehensive anatomy monitoring is hindered by low contrast and low signal-to-noise ratio and a large presence of artifacts, resulting in difficulty in identifying organ and structure boundaries either manually or automatically. In this study, we propose and develop an ensemble deep-learning model to segment post-prostatectomy organs automatically. METHODS: We utilize the ensemble logic in various modules during the segmentation process to alleviate the impact of low image quality of CBCT. Specifically, (1) semantic attention was obtained from an ensemble 2.5D You-only-look-once detector to consistently define regions of interest, (2) multiple view-specific two-stream 2.5D segmentation networks were developed, using auxiliary high-quality CT data to aid CBCT segmentation, and (3) a novel tensor-regularized ensemble scheme was proposed to aggregate the estimates from multiple views and regularize the spatial integrity of the final segmentation. RESULTS: A cross-validation study achieved Dice similarity coefficient and mean surface distance of 0.779 ± $\pm$ 0.069 and 2.895 ± $\pm$ 1.496 mm for the rectum, and 0.915 ± $\pm$ 0.055 and 1.675 ± $\pm$ 1.311 mm for the bladder. CONCLUSIONS: The proposed ensemble scheme manages to enhance the geometric integrity and robustness of the contours derived from CBCT with light network components. The tensor regularization approach generates organ results conforming to anatomy and physiology, without compromising typical quantitative performance in Dice similarity coefficient and mean surface distance, to support further clinical interpretation and decision making.

Technical note: Air bubble-induced performance degradation in automatic rectum segmentation from cone-beam CT.

PURPOSE: Cone-beam computed tomography (CBCT) is widely used for daily anatomy monitoring and can be a potential source to support adaptation. However, low image quality and artifacts limit CBCT's clinical utility. Peristalsis and air bubbles can cause severe artifacts in pelvic CBCT. We have observed that severe air bubble-induced Feldkamp artifacts in the rectum may contribute to low automatic segmentation accuracy. MATERIALS AND METHODS: In this study, air bubbles within the rectum were extracted and automatic rectum segmentation performance was measured in Dice similarity coefficient (DSC). A Gaussian mixture model (GMM) was used to characterize their correlation, and an expectation-maximization (EM) approach was used to solve the corresponding parameter estimation and decouple the impact from air bubbles versus other image attributes based on cluster memberships. Postprostatectomy patient data with high variability in air bubble size and shape were used in this study to reveal the regression relationship. RESULTS: GMM identified two distinct correlative relations between the air-bubble severity in the rectum and the rectum prediction DSC: one showed strong negative dependency of segmentation performance on air bubble presence, and the other one had mild-to-moderate dependency that suggested another group of contributing factors influencing rectum segmentation, such as the inconsistent presence of fiducial seeds and shape extremes. CONCLUSION: The presence of severe air bubbles contributes semilinearly to performance degradation in automatic rectum segmentation. A good correction mechanism may boost the accuracy and consistency of pelvic segmentation.