October, 2024 Publications from the Department of Human Oncology

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in more than 71,000 patients each year in the United States, with nearly 16,000 associated deaths. One significant hurdle in the treatment of HNSCC is acquired and intrinsic resistance to existing therapeutic agents. Over the past several decades, the University of Wisconsin has formed a multidisciplinary team to move basic scientific discovery along the translational spectrum to impact the lives of HNSCC patients. In this review, we outline key discoveries made throughout the years at the University of Wisconsin to deepen our understanding of therapeutic resistance in HNSCC and how a strong, interdisciplinary team can make significant advances toward improving the lives of these patients by combatting resistance to established therapeutic modalities. We are profoundly grateful to the many scientific teams worldwide whose groundbreaking discoveries, alongside evolving clinical paradigms in head and neck oncology, have been instrumental in making our work possible.

PMID:39457986 | PMC:PMC11508784 | DOI:10.3390/jcm13206036

BACKGROUND: HPV- associated squamous cell carcinoma (SCC) is uncommon in non-oropharynx sites and not well characterized. This study aims to investigate uncommon phenotypes of HPV-associated head and neck carcinoma, the prevalence and morphologic spectrum of HPV-associated SCC in the oral cavity, larynx and hypopharynx.

METHOD: P16 immunostaining and HPV E6/7 in situ hybridization (ISH) were performed on tissue microarrays comprised of SCCs from different anatomic sites: oropharynx (n = 270), hypopharynx (n = 52), oral cavity (n = 95) and larynx (n = 123). Tumors were classified as HPV-associated based on a positive E6/7 ISH testing. RNA sequencing was performed on several selected cases.

RESULT: 66% oropharynx SCCs (OPSCCs) were HPV-associated; all were p16/HPV testing concordant except one which was p16 negative. The p16-/HPV + OPSCC resembled similar gene expression signature with p16+/HPV + OPSCCs by transcriptome analysis. 6/95 (6%) oral cavity SCCs were HPV-associated, all from male patients and 5/6 (83%) arose from the floor of mouth. Morphologically, 3/6 (50%) showed keratinizing SCC and 5/6 (83%) demonstrated HPV-associated squamous dysplasia in adjacent mucosa. 1/123 (less than 1%) larynx SCCs and 0/52 hypopharynx SCCs were HPV-associated.

CONCLUSION: Although uncommon, p16 negative HPV-associated OPSCC can occur, emphasizing the importance of judicious HPV testing. The morphology of HPV-associated oral cavity SCCs may deviate from prototypic nonkeratinizing SCC, making them difficult to recognize. Presence of HPV-associated squamous dysplasia could serve as a morphologic clue.

PMID:39436498 | PMC:PMC11496466 | DOI:10.1007/s12105-024-01707-5

INTRODUCTION: Lactate is a pivotal molecule with diverse functions in the metabolic reprogramming of cancer cells. Beyond its role in metabolism, lactate exerts a modulatory effect within the tumor microenvironment; it is utilized by stromal cells and has been implicated in the suppression of the immune response against the tumor.

METHODS: Using in vitro assays (including flow cytometry, live-cell imaging and metabolic analyses), the impact of lactate dehydrogenase inhibitors (LDHIs) on melanoma cells were assessed. The therapeutic potential of LDHIs with immune checkpoint inhibitors (ICIs) were tested in vivo in murine models of melanoma tumors.

RESULTS: A potent anti-proliferative effect (via both cell cycle alterations and enhanced apoptosis) of LDHIs, Oxamate (Oxa) and methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (NHI-2), was found upon treatment of melanoma cell lines. Using a combination of Oxa and NHI-2, a synergistic effect to inhibit proliferation, glycolysis, and ATP production was observed. Metabolic analysis revealed significant alteration in glycolysis and oxidative phosphorylation, while metabolite profiling emphasized consequential effects on lactate metabolism and induced energy depletion by LDHIs. Detection of increased RANTES and MCP-1, with Oxa and NHI-2 treatment, prompted the consideration of combining LDHIs with ICIs. In vivo studies using a murine B78 melanoma tumor model revealed a significant improvement in treatment efficacy when LDHIs were combined with ICIs.

CONCLUSIONS: These findings propose the potential of targeting lactate metabolism to enhance the efficacy of ICI treatments in patients with melanoma.

PMID:39435293 | PMC:PMC11491500 | DOI:10.3389/fonc.2024.1428802

NRG Oncology's Developmental Therapeutics and Radiation Therapy Subcommittee assembled an interdisciplinary group of investigators to address barriers to successful early phase clinical trials of novel combination therapies involving radiation. This Policy Review elucidates some of the many challenges associated with study design for early phase trials combining radiotherapy with novel systemic agents, which are distinct from drug-drug combination development and are often overlooked. We also advocate for potential solutions that could mitigate or eliminate some of these barriers, providing examples of specific clinical trial designs that could help facilitate efficient and effective evaluation of novel drug-radiotherapy combinations.

PMID:39362260 | PMC:PMC11778933 | DOI:10.1016/S1470-2045(24)00264-X

In preclinical studies, p53 loss of function impacts chemotherapy response, but this has not been consistently validated clinically. We trained a TP53-loss phenocopy gene expression signature from pan-cancer clinical samples in the TCGA. In vitro, the TP53-loss phenocopy signature predicted chemotherapy response across cancer types. In a clinical dataset of 3003 breast cancer samples treated with neoadjuvant chemotherapy, the TP53-loss phenocopy samples were 56% more likely to have a pathologic complete response (pCR), with a significant association between TP53-loss phenocopy and pCR in both ER positive and ER negative tumors. In an independent clinical validation in the I-SPY2 trial (N = 987), we confirmed the association with neoadjuvant chemotherapy pCR and found higher rates of chemoimmunotherapy response in TP53-loss phenocopy tumors compared to non-TP53-loss phenocopy tumors (64% vs. 28%). The TP53-loss phenocopy signature predicts chemotherapy response across cancer types in vitro, and in a proof-of-concept clinical validation is associated with neoadjuvant chemotherapy response across multiple clinical breast cancer cohorts.

PMID:39358429 | PMC:PMC11447220 | DOI:10.1038/s41698-024-00722-7

PURPOSE: Magnetic resonance (MR)-guided radiation therapy enables online adaptation to address intra- and interfractional changes. To address the need of high-fidelity synthetic computed tomography (synCT) required for dose calculation, we developed a conditional generative adversarial network for synCT generation from low-field MR imaging in the brain.

METHODS AND MATERIALS: Simulation MR-CT pairs from 12 patients with glioma imaged with a head and neck surface coil and treated on a 0.35T MR-linac were prospectively included to train the model consisting of a 9-block residual network generator and a PatchGAN discriminator. Four-fold cross-validation was implemented. SynCT was quantitatively evaluated against real CT using mean absolute error (MAE), peak signal-to-noise ratio (PSNR), and structural similarity index measure (SSIM). Dose was calculated on synCT applying original treatment plan. Dosimetric performance was evaluated by dose-volume histogram metric comparison and local 3-dimensional gamma analysis. To demonstrate utilization in treatment adaptation, longitudinal synCTs were generated for qualitative evaluation, and 1 offline adaptation case underwent 2 comparative plan evaluations. Secondary validation was conducted with 9 patients on a different MR-linac using a high-resolution brain coil.

RESULTS: Our model generated high-quality synCTs with MAE, PSNR, and SSIM of 70.9 ± 10.4 HU, 28.4 ± 1.5 dB, and 0.87 ± 0.02 within the field of view, respectively. Underrepresented postsurgical anomalies challenged model performance. Nevertheless, excellent dosimetric agreement was observed with the mean difference between real and synCT dose-volume histogram metrics of -0.07 ± 0.29 Gy for target D95 and within [-0.14, 0.02] Gy for organs at risk. Significant differences were only observed in the right lens D0.01cc with negligible overall difference (<0.13 Gy). Mean gamma analysis pass rates were 92.2% ± 3.0%, 99.2% ± 0.7%, and 99.9% ± 0.1% at 1%/1 mm, 2%/2 mm, and 3%/3 mm, respectively. Secondary validation yielded no significant differences in synCT performance for whole-brain MAE, PSNR, and SSIM with comparable dosimetric results.

CONCLUSIONS: Our conditional generative adversarial network model generated high-fidelity brain synCTs from low-field MR imaging with excellent dosimetric performance. Secondary validation suggests great promise of implementing synCTs to facilitate robust dose calculation for online adaptive brain MR-guided radiation therapy.

PMID:39357787 | PMC:PMC11875202 | DOI:10.1016/j.ijrobp.2024.09.046

Sinonasal neoplasms are a remarkably heterogeneous group, reflecting the numerous tissue types present in the nasal cavity and paranasal sinuses. These entities can be relatively benign (ie, respiratory epithelial adenomatoid hamartoma) or can be exceedingly aggressive (ie, NUT carcinoma). Certain sinonasal tumors have a propensity to spread through local invasion and destruction, while others have a high likelihood of perineural spread. The genetic and molecular mechanisms underlying sinonasal tumor behavior have recently become better understood, and new tumor types have been described using these genetic and molecular data. This has prompted an expansion in the number of tumors included in the World Health Organization fifth edition classification system for head and neck tumors, along with a new classification structure. Radiologists' familiarity with this classification structure is crucial to understanding the expected behavior of these tumors and to collaboration with the multidisciplinary cancer care board in making decisions for optimal patient care. ©RSNA, 2024.

PMID:39264836 | DOI:10.1148/rg.240035

PURPOSE: To determine if patient-specific IMRT quality assurance can be measured on any matched treatment delivery system (TDS) for patient treatment delivery on another.

METHODS: Three VMAT plans of varying complexity were created for each available energy for head and neck, SBRT lung, and right chestwall anatomical sites. Each plan was delivered on three matched Varian TrueBeam TDSs to the same Scandidos Delta4 Phantom+ diode array with only energy-specific device calibrations. Dose distributions were corrected for TDS output and then compared to TPS calculations using gamma analysis. Round-robin comparisons between measurements from each TDS were also performed using point-by-point dose difference, median dose difference, and the percent of point dose differences within 2% of the mean metrics.

RESULTS: All plans had more than 95% of points passing a gamma analysis using 3%/3 mm criteria with global normalization and a 20% threshold when comparing measurements to calculations. The tightest gamma analysis criteria where a plan still passed > 95% were similar across delivery systems-within 0.5%/0.5 mm for all but three plan/energy combinations. Median dose deviations in measurement-to-measurement comparisons were within 0.7% and 1.0% for global and local normalization, respectively. More than 90% of the point differences were within 2%.

CONCLUSION: A set of plans spanning available energies and complexity levels were delivered by three matched TDSs. Comparisons to calculations and between measurements showed dose distributions delivered by each TDS using the same DICOM RT-plan file meet tolerances much smaller than typical clinical IMRT QA criteria. This demonstrates each TDS is modeled to a similar accuracy by a common class (shared) beam model. Additionally, it demonstrates that dose distributions from one TDS show small differences in median dose to the others. This is an important validation component of the common beam model approach, allowing for operational improvements in the clinic.

PMID:39250771 | PMC:PMC11466462 | DOI:10.1002/acm2.14492

PMID:39244349 | DOI:10.1016/j.ijrobp.2024.02.059

PMID:39244347 | DOI:10.1016/j.ijrobp.2024.01.209

Multi-energy computed tomography (MECT) offers the opportunity for advanced visualization, detection, and quantification of select elements (e.g., iodine) or materials (e.g., fat) beyond the capability of standard single-energy computed tomography (CT). However, the use of MECT requires careful consideration as substantially different hardware and software approaches have been used by manufacturers, including different sets of user-selected or hidden parameters that affect the performance and radiation dose of MECT. Another important consideration when designing MECT protocols is appreciation of the specific tasks being performed; for instance, differentiating between two different materials or quantifying a specific element. For a given task, it is imperative to consider both the radiation dose and task-specific image quality requirements. Development of a quality control (QC) program is essential to ensure the accuracy and reproducibility of these MECT applications. Although standard QC procedures have been well established for conventional single-energy CT, the substantial differences between single-energy CT and MECT in terms of system implementations, imaging protocols, and clinical tasks warrant QC tests specific to MECT. This task group was therefore charged with developing a systematic QC program designed to meet the needs of MECT applications. In this report, we review the various MECT approaches that are commercially available, including information about hardware implementation, MECT image types, image reconstruction, and postprocessing techniques that are unique to MECT. We address the requirements for MECT phantoms, review representative commercial MECT phantoms, and offer guidance regarding homemade MECT phantoms. We discuss the development of MECT protocols, which must be designed carefully with proper consideration of MECT technology, imaging task, and radiation dose. We then outline specific recommended QC tests in terms of general image quality, radiation dose, differentiation and quantification tasks, and diagnostic and therapeutic applications.

PMID:39072826 | DOI:10.1002/mp.17322

BACKGROUND: Cardiac applications in radiation therapy are rapidly expanding including magnetic resonance guided radiation therapy (MRgRT) for real-time gating for targeting and avoidance near the heart or treating ventricular tachycardia (VT).

PURPOSE: This work describes the development and implementation of a novel multi-modality and magnetic resonance (MR)-compatible cardiac phantom.

METHODS: The patient-informed 3D model was derived from manual contouring of a contrast-enhanced Coronary Computed Tomography Angiography scan, exported as a Stereolithography model, then post-processed to simulate female heart with an average volume. The model was 3D-printed using Elastic50A to provide MR contrast to water background. Two rigid acrylic modules containing cardiac structures were designed and assembled, retrofitting to an MR-safe programmable motor to supply cardiac and respiratory motion in superior-inferior directions. One module contained a cavity for an ion chamber (IC), and the other was equipped with multiple interchangeable cavities for plastic scintillation detectors (PSDs). Images were acquired on a 0.35 T MR-linac for validation of phantom geometry, motion, and simulated online treatment planning and delivery. Three motion profiles were prescribed: patient-derived cardiac (sine waveform, 4.3 mm peak-to-peak, 60 beats/min), respiratory (cos4 waveform, 30 mm peak-to-peak, 12 breaths/min), and a superposition of cardiac (sine waveform, 4 mm peak-to-peak, 70 beats/min) and respiratory (cos4 waveform, 24 mm peak-to-peak, 12 breaths/min). The amplitude of the motion profiles was evaluated from sagittal cine images at eight frames/s with a resolution of 2.4 mm × 2.4 mm. Gated dosimetry experiments were performed using the two module configurations for calculating dose relative to stationary. A CT-based VT treatment plan was delivered twice under cone-beam CT guidance and cumulative stationary doses to multi-point PSDs were evaluated.

RESULTS: No artifacts were observed on any images acquired during phantom operation. Phantom excursions measured 49.3 ± 25.8%/66.9 ± 14.0%, 97.0 ± 2.2%/96.4 ± 1.7%, and 90.4 ± 4.8%/89.3 ± 3.5% of prescription for cardiac, respiratory, and cardio-respiratory motion profiles for the 2-chamber (PSD) and 12-substructure (IC) phantom modules respectively. In the gated experiments, the cumulative dose was <2% from expected using the IC module. Real-time dose measured for the PSDs at 10 Hz acquisition rate demonstrated the ability to detect the dosimetric consequences of cardiac, respiratory, and cardio-respiratory motion when sampling of different locations during a single delivery, and the stability of our phantom dosimetric results over repeated cycles for the high dose and high gradient regions. For the VT delivery, high dose PSD was <1% from expected (5-6 cGy deviation of 5.9 Gy/fraction) and high gradient/low dose regions had deviations <3.6% (6.3 cGy less than expected 1.73 Gy/fraction).

CONCLUSIONS: A novel multi-modality modular heart phantom was designed, constructed, and used for gated radiotherapy experiments on a 0.35 T MR-linac. Our phantom was capable of mimicking cardiac, cardio-respiratory, and respiratory motion while performing dosimetric evaluations of gated procedures using IC and PSD configurations. Time-resolved PSDs with small sensitive volumes appear promising for low-amplitude/high-frequency motion and multi-point data acquisition for advanced dosimetric capabilities. Illustrating VT planning and delivery further expands our phantom to address the unmet needs of cardiac applications in radiotherapy.

PMID:39042362 | PMC:PMC11798577 | DOI:10.1002/mp.17315

There is a rising interest in developing and utilizing arc delivery techniques with charged particle beams, e.g., proton, carbon or other ions, for clinical implementation. In this work, perspectives from the European Society for Radiotherapy and Oncology (ESTRO) 2022 physics workshop on particle arc therapy are reported. This outlook provides an outline and prospective vision for the path forward to clinically deliverable proton, carbon, and other ion arc treatments. Through the collaboration among industry, academic, and clinical research and development, the scientific landscape and outlook for particle arc therapy are presented here to help our community understand the physics, radiobiology, and clinical principles. The work is presented in three main sections: (i) treatment planning, (ii) treatment delivery, and (iii) clinical outlook.

PMID:39009306 | DOI:10.1016/j.radonc.2024.110434