Faculty Bibliography

BACKGROUND:Financial toxicity (FT) from cancer treatment significantly impacts the quality of life among breast cancer patients. The study aimed to assess the longitudinal associations between FT and symptom burden in Chinese breast cancer patients. METHODS:This prospective cohort study was conducted from November 2022 to March 2024. Participants were recruited from four Grade-A public hospitals across different areas of China using convenience sampling. FT was assessed using the Comprehensive Score for Financial Toxicity, with higher scores indicating better financial well-being. Symptom burden was measured with the BCPT (Breast Cancer Prevention Trial) Eight Symptom Scale and the Memorial Symptom Assessment Scale-Short Form Psychological Subscales, with higher scores indicating greater psychological symptom burden. Assessments were conducted at baseline (T1), 3 months (T2), 6 months (T3), and 12 months (T4) post-surgery. RESULTS:Among 378 participants (all women; mean [SD] age, 48.9 [9.97] years), a moderate negative association was found between physical symptom burden and FT (r = -0.498 to -0.411) and between psychological symptom burden and FT (r = -0.493 to -0.392). Random Intercept Cross-lagged Panel Model demonstrated that FT negatively predicted the subsequent physical symptom burden (r = -0.166 to -0.122, p < 0.05). Physical symptom burden at T1 and T3 also negatively predicted the subsequent FT (r = -0.294 to -0.186, p < 0.05). Additionally, psychological symptom burden negatively predicted FT at the subsequent time point (r = -0.116 to -0.069, p < 0.05). CONCLUSIONS:This study found vicious associations between FT and symptom burden in breast cancer patients. Future interventions addressing FT should incorporate the monitoring and management of symptom burden.

PURPOSE/UNASSIGNED:We evaluated prostate volume changes during stereotactic body radiation therapy (SBRT) using serial MRI, identifying variables associated with prostatic swelling and their correlation with acute toxicity. METHODS/UNASSIGNED:Fifty-two patients with localized prostate cancer, androgen deprivation therapy naive, underwent SBRT to 40 Gy in five fractions on an MRI-Linear Accelerator with dominant intraprostatic lesion boosts to 45 Gy when present. Whole prostate (WP) and transition zone (TZ) measurements were assessed on the pre-treatment T2 MRI obtained for daily adaptation. Volumes were calculated using the ellipsoid formula. Non-transition zone (nonTZ) measures = WP values - TZ values. Transition zone index (TZI) = TZ volume/WP volume. Acute toxicity and International Prostate Symptom Scores (IPSS) were recorded. RESULTS/UNASSIGNED:Prostate volume increased significantly over the first four fractions, peaking at fraction 4 with mean percent and absolute changes of 21 % and 7.8 cc, respectively. Standardized TZ measures were strongly associated with WP volume (β per SD 10.60-12.78; all p < 0.001), whereas the only nonTZ dimension weakly associated was anteroposterior (β per SD 1.78). Each standard deviation increase in baseline TZ parameters doubled to tripled the odds of significant swelling (≥10 cc) (all p ≤ 0.011). The interaction of baseline TZI with later fractions was significantly associated with swelling (fraction 4: β = 12.06, p = 0.020; fraction 5: β = 10.96, p = 0.036), but not baseline TZI alone. Neither Grade 2+ genitourinary toxicity nor IPSS changes were associated with prostate measures or TZI. CONCLUSIONS/UNASSIGNED:Prostate volume significantly increases during SBRT, primarily corresponding with TZ volumetric changes. Baseline TZ measurements most strongly predict high-volume swelling. Acute toxicity was not associated with volumetric change.

Non-small cell lung cancer (NSCLC) patients with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti-PD-1. Here, we conducted an in vivo CRISPR screen that identified HDAC1 as a target to reverse anti-PD-1 resistance driven by loss of STK11 and developed TNG260, a potent small-molecule inhibitor of the CoREST complex with selectivity exceeding previously generated inhibitors in this class in preclinical studies. Treatment with TNG260 led to increased expression of immunomodulatory genes in STK11-deficient cancer cells. When combined with anti-PD-1, TNG260 induced immune-mediated stasis and/or regression in STK11-deficient syngeneic tumor models and autochthonous NSCLC models. In the tumors of patients with STK11-deficient cancers on a clinical trial (NCT05887492), treatment with a combination of TNG260 and pembrolizumab increased intratumoral histone acetylation, PD-L1 tumor proportion scores, and T cell infiltration into the tumor microenvironment. This study illustrates a promising treatment strategy for addressing immune evasion in STK11-mutant NSCLC patients.

PURPOSE/OBJECTIVE:To evaluate the degree and rate of bladder filling during magnetic resonance imaging-guided linear accelerator (MRL) prostate stereotactic body radiotherapy (SBRT), and to determine the association of degree of bladder filling with intra-fractional prostatic motion requiring positional shifts during therapy. The impact of bladder filling on post-treatment target and normal tissue dosimetry was also evaluated. METHODS:Sixty-two consecutive prostate SBRT patients treated on the MRL with an empty bladder and a five-fraction regimen were evaluated. Bladder filling patterns during each treatment session and the frequency of required shifts to address intra-fractional prostate motion were studied. During each fraction, three MR image acquisitions were obtained: an immediate baseline T2-weighted sequence, a verification sequence after the plan was generated prior to treatment delivery, and a sequence post-treatment. Bladder filling rates were evaluated at these time points for each fraction and across the five treatment fractions. Multivariate analysis identified variables associated with increased bladder filling rates and the likelihood of positional target adjustments of the prostate during real-time adaptive planning. Post-treatment MR structures were used to recalculate plans for analysis of intra-fractional dosimetric variations in target and normal tissue doses. RESULTS:The median baseline bladder volume at fraction 1 was 88 cc (range 35-245), increasing to 138 cc (range 55-340) at verification MR and 156 cc (range 69-475) post-treatment. Bladder volume increases from baseline to verification MR and from verification MR to post-treatment MR were consistent across the cohort. Multivariate analysis identified the use of alpha receptor blockers during treatment (beta - 17.36 mL; 95 % CI - 32.97, -1.74; p = 0.030) and lower baseline bladder volume (beta 11.62 mL; 95 % CI 4.20, 19.05; p = 0.002) as significant factors in limiting both absolute bladder volume and the rate of bladder filling during adaptive SBRT fractions. Conversely, the need for a positional target shift at verification MR was associated with larger bladder volume (OR 1.20; 95 % CI 0.98, 1.46; p = 0.075) and high International Prostate Symptom Score (OR 5.42; 95 % CI 1.34, 21.89; p = 0.018). Post-treatment dosimetric analysis revealed no notable compromises to prostate target coverage (D95Gy median -0.19 Gy, IQR 0.49) or normal tissue constraints. CONCLUSIONS:This analysis of bladder filling dynamics in patients undergoing prostate SBRT with real-time adaptive planning demonstrated predictable bladder filling patterns using an empty bladder regimen. Dose-volume constraints were consistently achieved for both target volumes and normal tissues. The finding that alpha receptor blockers reduced the rate of bladder filling during treatment fractions may have implications for improving treatment consistency and patient comfort in real-time adaptive planning workflows.

OBJECTIVE:Identify how surgical resection of pancreatic ductal adenocarcinoma (PDAC) affects systemic minimal residual disease (MRD). METHODS:Pancreatic tumors were generated by orthotopic implantation of tumor cells into the pancreas of immunocompetent mice. Tumor resection was carried out via distal pancreatectomy and splenectomy. Liver metastases and microenvironment immune changes were analyzed in resected vs. non-resected mice. RESULTS:Resection was accompanied by proliferative expansion of liver metastases and an increase in hepatic metastatic burden. Postoperative immune changes predominantly manifested as a time-dependent increase in eosinophils and decrease in neutrophils. The postoperative hepatic eosinophilia was protective of further metastatic progression. The parenchymal findings were detectable in the circulation, and the trends observed in the mouse model modeled those seen in PDAC patients postoperatively. CONCLUSION/CONCLUSIONS:Collectively, we describe a preclinical resection model that offers a means to investigate MRD. Using this model, we delineated effects of surgical resection on metastatic outgrowth and uncovered a protective link between the postoperative hepatic eosinophilia and further metastatic progression.

KRAS is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with G12C mutation and advanced our understanding of its function. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V transgenic mouse model. We explore the therapeutic potential of KRASG12V degradation and characterize its impact on the tumor microenvironment (TME). Our study reveals that degrading KRASG12V abolishes lung and pancreatic tumors in mice and causes a robust inhibition of KRAS-regulated cancer intrinsic signaling. Importantly, targeted degradation of KRASG12V reprograms the TME towards a stimulatory milieu and drives antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides important insights into the impact of degrading KRASG12V on both tumor progression and immune response, highlighting degraders as a powerful strategy for targeting KRAS mutant cancers.

PURPOSE/OBJECTIVE:To commission a beam model in ClearCalc (Radformation Inc.) for use as a secondary dose calculation algorithm and to implement its use into an adaptive workflow for an MR-linear accelerator. METHODS:A beam model was developed using commissioning data for an Elekta Unity MR-linear accelerator and entered into ClearCalc. The beam model consisted of absolute dose calculation settings, output factors, percent depth-dose (PDD) curves, mutli-leaf collimator (MLC) transmission and dose leaf gap error, and cryostat corrections. Beam profiles were hard-coded by the manufacturer into the beam model and were compared with Monaco-derived profiles. The beam model was tested by comparing point doses in a homogenous phantom obtained through measurements using an ionization chamber in water, Monaco, and ClearCalc for various field sizes, source-surface distances (SSDs), and point locations. Additional testing including point dose verification for test plans using a heterogeneous phantom and patient plans. Post clinical implementation, performance of ClearCalc was evaluated for the first 41 patients treated, which included 215 adaptive plans. RESULTS:PDDs generated using ClearCalc fell within 1.2% of measurements. Field profile comparison between ClearCalc and Monaco showed an average pass rate of 98% using a 3%/3 mm gamma criteria. Measured cryostat corrections used in the beam model showed a maximum deviation from unity of 1.4%. Point dose and field monitor units (MUs) comparisons in a homogenous phantom (N = 22), heterogeneous phantoms (N = 22), and patient plans (N = 57) all passed with a threshold of 5%/5MU. Clinically, ClearCalc was implemented as a physics check post adaptive planning completed prior to beam delivery. Point dose and field MUs showed good agreement at a 5%/5MU threshold for prostate stereotactic body radiation therapy (SBRT), pelvic lymph nodes, rectum, and prostate and lymph node plans. DISCUSSION/CONCLUSIONS:This work demonstrated commissioning and clinical implementation of ClearCalc into an adaptive planning workflow. No primary or adaptive plan failures were reported with proper beam model testing.

Tumor-educated platelets (TEPs) are a potential method of liquid biopsy for the diagnosis and monitoring of cancer. However, the mechanism underlying tumor education of platelets is not known, and transcripts associated with TEPs are often not tumor-associated transcripts. We demonstrated that direct tumor transfer of transcripts to circulating platelets is an unlikely source of the TEP signal. We used CDSeq, a latent Dirichlet allocation algorithm, to deconvolute the TEP signal in blood samples from patients with glioblastoma. We demonstrated that a substantial proportion of transcripts in the platelet transcriptome are derived from nonplatelet cells, and the use of this algorithm allows the removal of contaminant transcripts. Furthermore, we used the results of this algorithm to demonstrate that TEPs represent a subset of more activated platelets, which also contain transcripts normally associated with nonplatelet inflammatory cells, suggesting that these inflammatory cells, possibly in the tumor microenvironment, transfer transcripts to platelets that are then found in circulation. Our analysis suggests a useful and efficient method of processing TEP transcriptomic data to enable the isolation of a unique TEP signal associated with specific tumors.

PURPOSE/UNASSIGNED:Cardiac radioablation is an emerging therapy for recurrent ventricular tachycardia. Electrophysiology (EP) data, including electroanatomic maps (EAM) and electrocardiographic imaging (ECGI), provide crucial information for defining the arrhythmogenic target volume. The absence of standardized workflows and software tools to integrate the EP maps into a radiation planning system limits their use. This study developed a comprehensive software tool to enable efficient utilization of the mapping for cardiac radioablation treatment planning. METHODS AND MATERIALS/UNASSIGNED:After the scar area is outlined on the mapping surface, the tool extracts and extends the annotated patch into a closed surface and converts it into a structure set associated with the anatomic images. The tool then exports the structure set and the images as The Digital Imaging and Communications in Medicine Standard in Radiotherapy for a radiation treatment planning system to import. Overlapping the scar structure on simulation CT, a transmural target volume is delineated for treatment planning. RESULTS/UNASSIGNED:The tool has been used to transfer Ensite NavX EAM data into the Varian Eclipse treatment planning system in radioablation on 2 patients with ventricular tachycardia. The ECGI data from CardioInsight was retrospectively evaluated using the tool to derive the target volume for a patient with left ventricular assist device, showing volumetric matching with the clinically used target with a Dice coefficient of 0.71. CONCLUSIONS/UNASSIGNED:HeaRTmap smoothly fuses EP information from different mapping systems with simulation CT for accurate definition of radiation target volume. The efficient integration of EP data into treatment planning potentially facilitates the study and adoption of the technique.