Showing papers by "Keith A. Cengel published in 2022"

Forging Forward in Photodynamic Therapy.

Abstract: In 1978, a Cancer Research article by Dougherty and colleagues reported the first large-scale clinical trial of photodynamic therapy (PDT) for treatment of 113 cutaneous or subcutaneous lesions associated with ten different kinds of malignancies. In classic applications, PDT depends on excitation of a tissue-localized photosensitizer with wavelengths of visible light to damage malignant or otherwise diseased tissues. Thus, in this landmark article, photosensitizer (hematoporphyrin derivative) dose, drug-light interval, and fractionation scheme were evaluated for their therapeutic efficacy and normal tissue damage. From their observations came early evidence of the mechanisms of PDT's antitumor action, and in the decades since this work, our knowledge of these mechanisms has grown to build an understanding of the multifaceted nature of PDT. These facets are comprised of multiple cell death pathways, together with antivascular and immune stimulatory actions that constitute a PDT reaction. Mechanism-informed PDT protocols support the contribution of PDT to multimodality treatment approaches. Moreover, guided by an understanding of its mechanisms, PDT can be applied to clinical needs in fields beyond oncology. Undoubtedly, there still remains more to learn; new modes of cell death continue to be elucidated with relevance to PDT, and factors that drive PDT innate and adaptive immune responses are not yet fully understood. As research continues to forge a path forward for PDT in the clinic, direction is provided by anchoring new applications in mechanistically grounded protocol design, as was first exemplified in the landmark work conducted by Dougherty and colleagues. See related article by Dougherty and colleagues, Cancer Res 1978;38:2628-35.

Transient expansion and myofibroblast conversion of adipogenic lineage precursors mediate bone marrow repair after radiation

Abstract: Radiation causes a collapse of bone marrow cells and elimination of microvasculature. To understand how bone marrow recovers after radiation, we focused on mesenchymal lineage cells that provide a supportive microenvironment for hematopoiesis and angiogenesis in bone. We recently discovered a nonproliferative subpopulation of marrow adipogenic lineage precursors (MALPs) that express adipogenic markers with no lipid accumulation. Single-cell transcriptomic analysis revealed that MALPs acquire proliferation and myofibroblast features shortly after radiation. Using an adipocyte-specific Adipoq-Cre, we validated that MALPs rapidly and transiently expanded at day 3 after radiation, coinciding with marrow vessel dilation and diminished marrow cellularity. Concurrently, MALPs lost most of their cell processes, became more elongated, and highly expressed myofibroblast-related genes. Radiation activated mTOR signaling in MALPs that is essential for their myofibroblast conversion and subsequent bone marrow recovery at day 14. Ablation of MALPs blocked the recovery of bone marrow vasculature and cellularity, including hematopoietic stem and progenitors. Moreover, VEGFa deficiency in MALPs delayed bone marrow recovery after radiation. Taken together, our research demonstrates a critical role of MALPs in mediating bone marrow repair after radiation injury and sheds light on a cellular target for treating marrow suppression after radiotherapy.

Radiomic Phenotypes for Improving Early Prediction of Survival in Stage III Non-Small Cell Lung Cancer Adenocarcinoma after Chemoradiation

Abstract: Simple Summary Personalized therapy of non-small cell lung cancer (NSCLC) relies heavily on histopathological analyses that require invasive biopsies that have relatively high costs, provide limited assessment of tumor heterogeneity and are associated with potentially life-threatening complications. This retrospective study is aimed at evaluating the potential benefit of using predictive models that integrate radiomic features extracted from computed tomography (CT) images and commonly assessed clinical predictors to characterize the overall survival (OS) of stage III NSCLC adenocarcinoma patients receiving chemoradiation. Different than previous studies, our proposed approach explicitly accounts for CT parameter heterogeneity, such as presence or lack of intravenous contrast material and differences in CT scanner vendors through feature harmonization. Using a relatively homogeneous population of 110 patients, our results demonstrate that radiomic biomarkers derived using feature harmonization significantly improved the prediction of OS in our cohort when combined with Eastern Cooperative Oncology Group (ECOG) status and age at diagnosis, suggesting their potential in assisting clinical decision making.) upon the baseline model (C-score = 0.65, CI = (0.57, 0.73)). Our results suggest that harmonized radiomic phenotypes can significantly improve OS prediction in stage III NSCLC after chemoradiation. Abstract We evaluate radiomic phenotypes derived from CT scans as early predictors of overall survival (OS) after chemoradiation in stage III primary lung adenocarcinoma. We retrospectively analyzed 110 thoracic CT scans acquired between April 2012−October 2018. Patients received a median radiation dose of 66.6 Gy at 1.8 Gy/fraction delivered with proton (55.5%) and photon (44.5%) beam treatment, as well as concurrent chemotherapy (89%) with carboplatin-based (55.5%) and cisplatin-based (36.4%) doublets. A total of 56 death events were recorded. Using manual tumor segmentations, 107 radiomic features were extracted. Feature harmonization using ComBat was performed to mitigate image heterogeneity due to the presence or lack of intravenous contrast material and variability in CT scanner vendors. A binary radiomic phenotype to predict OS was derived through the unsupervised hierarchical clustering of the first principal components explaining 85% of the variance of the radiomic features. C-scores and likelihood ratio tests (LRT) were used to compare the performance of a baseline Cox model based on ECOG status and age, with a model integrating the radiomic phenotype with such clinical predictors. The model integrating the radiomic phenotype (C-score = 0.69, 95% CI = (0.62, 0.77)) significantly improved (p<0.005) upon the baseline model (C-score = 0.65, CI = (0.57, 0.73)). Our results suggest that harmonized radiomic phenotypes can significantly improve OS prediction in stage III NSCLC after chemoradiation.

Real-time PDT dose dosimetry for pleural photodynamic therapy

Abstract: PDT dose is the product of the photosensitizer concentration and the light fluence in the target tissue. For improved dosimetry during plural photodynamic therapy (PDT), an eight-channel PDT dose dosimeter was developed to measure both the light fluence and the photosensitizer concentration simultaneously from eight different sites in the pleural cavity during PDT. An isotropic detector with bifurcated fibers was used for each channel to ensure detected light was split equally to the photodiode and spectrometer. The light fluence rate distribution is monitored using an IR navigation system. The navigation system allows 2D light fluence mapping throughout the whole pleural cavity rather than just the selected points. The fluorescence signal is normalized by the light fluence measured at treatment wavelength. We have shown that the absolute photosensitizer concentration can be obtained by applying optical properties correction and linear spectral fitting to the measured fluorescence data. The detection limit and the optical property correction factor of each channel were determined and validated using tissue-simulating phantoms with known varying concentration of Photofrin. Tissue optical properties are determined using an absorption spectroscopy probe immediately before PDT at the same sites. The combination of 8-channel PDT dosimeter system and IR navigation system, which can calculate light fluence rate in the pleural cavity in real-time, providing a mean to determine the distribution of PDT dose on the entire pleural cavity to investigate the heterogeneity of PDT dose on the pleural cavity.

Evaluation of Detector Position and Light Fluence Distribution Using an Infrared Navigation System during Pleural Photodynamic Therapy †

Abstract: Photodynamic therapy (PDT) has been used to treat malignant pleural mesothelioma. Current practice involves delivering light to a prescribed light fluence with a point source, monitored by eight isotropic detectors inside the pleural cavity. An infrared (IR) navigation system was used to track the location of the point source throughout the treatment. The recorded data were used to reconstruct the pleural cavity and calculate the light fluence to the whole cavity. An automatic algorithm was developed recently to calculate the detector positions based on recorded data within an hour. This algorithm was applied to patient case studies and the calculated results were compared to the measured positions, with an average difference of 2.5 cm. Calculated light fluence at calculated positions were compared to measured values. The differences between the calculated and measured light fluence were within 14% for all cases, with a fixed scattering constant and a dual correction method. Fluence‐surface histogram (FSH) was calculated for photofrin‐mediated PDT to be able to cover 80% of pleural surface area to 50 J cm−2(83.3% of 60 J cm−2). The study demonstrates that it will be possible to eliminate the manual measurement of the detector positions, reducing the patient's time under anesthesia.

A single-center retrospective cohort study of perioperative systemic chemotherapy in diffuse malignant peritoneal mesothelioma

Abstract: Background Diffuse malignant peritoneal mesothelioma (DMPM) is a rare variant of malignant mesothelioma, representing 10–15% of malignant mesothelioma cases. The preferred therapeutic approach is cytoreductive surgery (CRS) accompanied by hyperthermic intraperitoneal chemotherapy (HIPEC); the role of systemic chemotherapy is not well established. While some limited retrospective studies report worse outcomes with neoadjuvant chemotherapy, our institution has favored the use of neoadjuvant chemotherapy for symptom relief and surgical optimization. The aim of our study was to assess the outcomes of patients receiving neoadjuvant chemotherapy, compared to those receiving adjuvant or no perioperative chemotherapy. Patients and methods We conducted a single-center retrospective cohort study of treatment-naïve, non-papillary DMPM patients seen at our institution between 1/1/2009 and 9/1/2019. We explored the effect of type of systemic therapy on clinical outcomes and estimated median overall survival (mOS) using Kaplan-Meier curves. Hazard ratios (HR) calculated by Cox proportional hazard model were used to estimate effect of the exposures on overall survival. Results 47 patients were identified with DMPM (median age at diagnosis 61.2 years, 76.6% epithelioid histology, 74.5% white race, 55.3% known asbestos exposure). CRS was performed in 53.2% of patients (25/47); 76.0% of surgical patients received HIPEC (19/25). The majority received systemic chemotherapy (37/47, 78.7%); among patients receiving both CRS and chemotherapy, neoadjuvant chemotherapy was more common than adjuvant chemotherapy (12 neoadjuvant, 8 adjuvant). Overall mOS was 84.1 months. Among neoadjuvant patients, 10/12 underwent surgery, and 2 were lost to follow-up; the majority (9/10) had clinically stable or improved disease during the pre-operative period. There were numerical more issues with chemotherapy with the adjuvant patients (4/8: 2 switches in platinum agent, 2 patients stopped therapy) than with the neoadjuvant patients (2/10: 1 switch in platinum agent, 1 delay due to peri-procedural symptoms). Neoadjuvant chemotherapy was not associated with worse mOS compared to adjuvant chemotherapy (mOS NR vs 95.1 mo, HR 0.89, 95% CI 0.18–4.5, p = 0.89). Conclusions When used preferentially, the use of neoadjuvant chemotherapy in DMPM patients was not associated with worse outcomes compared to adjuvant chemotherapy. It was well-tolerated and did not prevent surgical intervention.

In vivo spectroscopic evaluation of human tissue optical properties and hemodynamics during HPPH-mediated photodynamic therapy of pleural malignancies

Abstract: Abstract. Significance Dosimetry for photodynamic therapy is dependent on multiple parameters. Critically, in vivo tissue optical properties and hemodynamics must be determined carefully to calculate the total delivered light dose. Aim Spectroscopic analysis of diffuse reflectance measurements of tissues taken during a clinical trial of 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a-mediated photodynamic therapy for pleural malignancies. Approach Diffuse reflectance measurements were taken immediately before and after photodynamic therapy. Measurements were analyzed with a nonlinearly constrained multiwavelength, multi-distance algorithm to extract tissue optical properties, tissue oxygen saturation, StO2, and total hemoglobin concentration (THC). Results A total of 25 patients were measured, 23 of which produced reliable fits for optical property extraction. For all tissue types, StO2 ranged through [24, 100]% and [22, 97]% for pre-photodynamic therapy (PDT) and post-PDT conditions, respectively. Mean THC ranged through [ 69,152 ] μM and [ 48,111 ] μM, for pre-PDT and post-PDT, respectively. Absorption coefficients, μa, ranged through [ 0.024 , 3.5 ] cm − 1 and [ 0.039 , 3 ] cm − 1 for pre-PDT and post-PDT conditions, respectively. Reduced scattering coefficients, μs′, ranged through [ 1.4 , 73.4 ] cm − 1 and [ 1.2 , 64 ] cm − 1 for pre-PDT and post-PDT conditions, respectively. Conclusions There were similar pre- and post-PDT tissue optical properties and hemodynamics. The high variability in each parameter for all tissue types emphasizes the importance of these measurements for accurate PDT dosimetry.

A phenomenological model of proton FLASH oxygen depletion effects depending on tissue vasculature and oxygen supply

Abstract: Introduction Radiation-induced oxygen depletion in tissue is assumed as a contributor to the FLASH sparing effects. In this study, we simulated the heterogeneous oxygen depletion in the tissue surrounding the vessels and calculated the proton FLASH effective-dose-modifying factor (FEDMF), which could be used for biology-based treatment planning. Methods The dose and dose-weighted linear energy transfer (LET) of a small animal proton irradiator was simulated with Monte Carlo simulation. We deployed a parabolic partial differential equation to account for the generalized radiation oxygen depletion, tissue oxygen diffusion, and metabolic processes to investigate oxygen distribution in 1D, 2D, and 3D solution space. Dose and dose rates, particle LET, vasculature spacing, and blood oxygen supplies were considered. Using a similar framework for the hypoxic reduction factor (HRF) developed previously, the FEDMF was derived as the ratio of the cumulative normoxic-equivalent dose (CNED) between CONV and UHDR deliveries. Results Dynamic equilibrium between oxygen diffusion and tissue metabolism can result in tissue hypoxia. The hypoxic region displayed enhanced radio-resistance and resulted in lower CNED under UHDR deliveries. In 1D solution, comparing 15 Gy proton dose delivered at CONV 0.5 and UHDR 125 Gy/s, 61.5% of the tissue exhibited ≥20% FEDMF at 175 μm vasculature spacing and 18.9 μM boundary condition. This percentage reduced to 34.5% and 0% for 8 and 2 Gy deliveries, respectively. Similar trends were observed in the 3D solution space. The FLASH versus CONV differential effect remained at larger vasculature spacings. A higher FLASH dose rate showed an increased region with ≥20% FEDMF. A higher LET near the proton Bragg peak region did not appear to alter the FLASH effect. Conclusion We developed 1D, 2D, and 3D oxygen depletion simulation process to obtain the dynamic HRF and derive the proton FEDMF related to the dose delivery parameters and the local tissue vasculature information. The phenomenological model can be used to simulate or predict FLASH effects based on tissue vasculature and oxygen concentration data obtained from other experiments.

Association Between Cardiovascular Substructure Dose and Death Without Progression after Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer

Abstract:

Purpose/Objective(s)

Prior work has focused on associations between radiotherapy dose to cardiovascular (CV) substructures and either overall survival (OS) or cardiac events. Death without progression (DWP) is a potentially more specific endpoint than OS for understanding radiation toxicity and easier to record than cardiac events. We assessed associations of CV substructure dose with DWP and OS after chemoradiation (CRT) for locally advanced NSCLC (LA-NSCLC).

Materials/Methods

We retrospectively reviewed records of 187 patients with LA-NSCLC who received definitive CRT (median 66.6 Gy) from 2008-2016 at a single institution. CV substructures, including both atria (BA), right atrium, left atrium (LA), both ventricles (BV), right ventricle (RV), left ventricle, pericardium, aorta, superior vena cava, and pulmonary artery, were defined on radiation simulation scans using a deep learning auto-segmentation model. Dose-volume histogram (DVH) metrics to CV substructures (mean dose, volume receiving ≥5 Gy [V5], V30, V50), whole heart, lung, and esophagus were extracted. DWP was modelled with Fine-Gray method; disease progression was a competing event. OS was modelled with Cox regression. For each CV substructure, associations between each DVH metric and DWP and OS were assessed, and the candidate DVH metric with the lowest p value was promoted to multivariable analysis. Multivariable models with the same baseline covariates but different DVH metrics were generated and ranked by Akaike information criterion (AIC) to select "best" models. Cutpoint analyses were done with Contal and O'Quigley method.

Results

98 patients (52%) received proton therapy and 89 (48%) received photon therapy (68/89 intensity-modulated radiation therapy). At median follow-up of 28.8 months, 143 (76%) patients had died; overall, 25 (13%) experienced DWP. Causes of DWP included respiratory failure due to heart failure, COPD, pneumonia, or aspiration (n=10), out-of-hospital cardiopulmonary arrest (n=4), undifferentiated sepsis (n=2), probable radiation pneumonitis (n=1), esophagopleural fistula (n=1), and unknown (n=7). On multivariable analysis for DWP, best model included RV mean dose (AIC 222); 2^nd best included BV V5 (AIC 231). 3-year cumulative incidence of DWP was 21.3% vs 5.6% for RV mean dose ≥5.5 Gy vs <5.5 Gy (p=0.001). On multivariable analysis for OS, best model included LA V5 (AIC 1277.8); 2^nd best included BA V5 (AIC 1278.5). 3-year OS was 25.6% vs 46.3% for LA V5 ≥74.5% vs <74.5% (p=0.002). Associations were stronger among and driven by the photon subgroup. Proton therapy delivered lower dose to multiple CV substructures (e.g., RV mean dose, median 0.03 Gy vs 7.7 Gy; and LA V5, median 46.1% vs 78.1%; both p<0.0001).

Conclusion

Radiation dose to CV substructures showed different associations with DWP and OS. These results suggest DWP may be a meaningful endpoint for understanding CRT toxicity in LA-NSCLC.

Cardiac Substructure Dose and Cardiac Events Following Proton- vs. Photon-Based Chemoradiotherapy for Non-Small Cell Lung Cancer

Abstract:

Purpose/Objective(s)

Radiotherapy plays a critical role in treating locally advanced non-small cell lung cancer (LA-NSCLC) but is known to have deleterious effects on the heart. We hypothesized that dose to specific cardiovascular substructures – the great vessels, atria, ventricles, and left anterior descending coronary artery - may be lower with proton- versus photon-based radiotherapy, and that dose to certain substructures may be higher among those who experience post-chemoradiation (CRT) cardiac events.

Materials/Methods

In this single institution retrospective review, we created two cohorts from a larger number of patients treated with definitive CRT for LA-NSCLC. We matched 26 patients who experienced cardiac events after CRT to 26 patients who did not experience cardiac events after CRT, based on age, sex, cardiovascular comorbidity, and radiation modality (proton vs photon). In each group, half the patients were treated with proton therapy, and the other half with photon therapy. The cardiac events included acute coronary syndrome (ACS), coronary artery disease (CAD), myocardial infarction (MI), heart failure, and atrial fibrillation/flutter. For each patient, the whole heart and ten cardiac substructures on the radiation therapy planning computerized tomography (CT) scan were contoured. Dosimetric comparisons were made between the proton and photon cohorts, and between those who experienced cardiac events and those who did not.

Results

The mean whole heart dose in the patients receiving proton therapy was significantly lower than the mean heart dose in the patients receiving photon therapy (median 7.36 Gy vs 13.75 Gy, p=0.032). Other structures that had significantly lower mean dose when treated with protons were the left ventricle (median 0.364 Gy vs 4.68 Gy, p=0.0004), right ventricle (median 0.433 Gy vs 10.56 Gy, p<0.0001), and the LAD (median 1.19 Gy vs 12.27 Gy p=0.0002). There was no significant difference in whole heart dose or any cardiac substructure dose between those patients who experienced post-treatment cardiac events and those who did not (p>0.05 for all). Mean whole heart dose correlated with mean dose to each substructure except the aortic arch and the superior vena cava. Amongst all the associations, the strongest correlation was seen between the left ventricle and the left anterior descending artery (Spearman rho = .908).

Conclusion

Proton therapy may have a significant effect on sparing individual cardiac substructures from excess radiation dose when compared to photon therapy. In our analysis, there was no significant difference in heart dose or dose to any cardiac substructure between patients who experienced post-treatment cardiac events. Further research needs to be done to understand clinical significance of the association between cardiac substructure dose and post-treatment cardiac events.

Abstract 3304: Gene expression profiling of full-thickness skin after FLASH proton radiotherapy

Abstract: Purpose: To investigate the transcriptomic changes induced by FLASH proton radiotherapy (F-PRT) that could be responsible for the protection of normal epithelial tissues by radiation-induced toxicities as have been previously shown by us and others. Methods: C57BL/6J mice received 30 Gy of F-PRT or S-PRT to the hind leg at respective dose rates of 69-124 Gy/sec or 0.39-0.65 Gy/sec. RNA sequencing was performed using full-thickness leg skin at 5 days after radiation revealing major pathways regulated by F-PRT and S-PRT. In an endeavor to identify the full repertoire of cells and gene expression profiles that are involved in the sparing effects of FLASH PRT, we expanded our studies to include single-cell RNA sequencing (sc-RNA seq) and examined additional time points such as Day 2 and Day 10 after radiation. Single-cell transcriptome libraries were generated on a 10X Genomics Chromium system. Datasets were acquired from cell samples derived and sequenced from pooled skin samples of three mice per group. Skin from the sequenced mice was also embedded for spatial analysis of gene expression. Results: RNA sequencing revealed that F-PRT uniquely upregulates almost four times more genes compared to S-PRT (F-PRT-uniquely upregulated 489 genes vs S-PRT-uniquely upregulated 129 genes). Also, F-PRT uniquely downregulated 178 genes, compared to the 125 genes uniquely downregulated by S-PRT. GO analysis demonstrates that the keratinization and apoptosis pathways are uniquely upregulated by S-PRT, whereas F-PRT uniquely upregulates genes involved in vascular development pathway. During submission of the abstract, analysis of sc-RNA seq samples was pending. Conclusion: Our comprehensive studies inform on the transcriptomic profiling of skin cell populations that are affected by F-PRT vs S-PRT; this insight will further spur discoveries on the biology of FLASH radiotherapy effects. Citation Format: Anastasia Velalopoulou, Ilias V. Karagounis, Giorgos Skoufos, Ioannis I. Verginadis, Michele Kim, Khayrullo Shoniyozov, Artemis G. Hatzigeorgiou, Eric Diffenderfer, Lei Dong, James Metz, Constantinos Koumenis, Keith A. Cengel, Amit Maity, Theresa M. Busch. Gene expression profiling of full-thickness skin after FLASH proton radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3304.

Clinical activity of pembrolizumab monotherapy in diffuse malignant peritoneal mesothelioma.

Abstract: 8557 Background: Among patients with malignant mesothelioma, pembrolizumab has demonstrated activity in diffuse pleural mesothelioma (DPM), with limited data available for those with diffuse malignant peritoneal mesothelioma (DMPM). DMPM represents a clinically distinct entity from DPM and disease specific outcomes data is needed. We present real world data on the efficacy of pembrolizumab in DMPM. Methods: In this retrospective study, we identified patients with DMPM treated with pembrolizumab at two tertiary care cancer centers between 1/1/2009 and 1/1/2021. Clinicopathologic features were annotated. Median progression free survival (mPFS) and median overall survival (mOS) were calculated using Kaplan-Meier curves. Best overall response rate (BOR) was determined using RECIST 1.1 criteria. Association of partial response with disease characteristics was evaluated using Fisher’s exact test. Results: We identified 24 patients with DMPM who received pembrolizumab (median age 62 years, 63% never smokers, 58% female, 75% had epithelioid histology). All patients received systemic chemotherapy prior to pembrolizumab (median prior lines of therapy: 3). BOR was 17% (3 partial responses, 10 stable disease, 5 progressive disease, 6 lost to follow-up). With a median follow up time of 29.2 months, mPFS was 4.9 months and mOS 20.9 months from pembrolizumab initiation. Three patients experienced PFS of > 2 years. Among the 14 patients who underwent next generation sequencing of tumor tissue, there were 8 somatic BAP1 alterations. Among the 17 patients tested for PDL1, 6 had positive PDL1 expression (1-80%). There was no association between partial response and presence of a BAP1 somatic alteration (p = 0.453), PDL1 positivity (p = 0.7) or non-epithelioid histology (p = 0.55). Conclusions: Pembrolizumab is active in a PDL1 unselected cohort of patients with DMPM. The overall response rate of 17% and mPFS of 4.9 months in this 75% epithelioid histology cohort warrants further investigation to identify those most likely to respond to immunotherapy, especially among epithelioid histology.