Publications by authors named "Eugene J Koay"

135 Publications

Expansion of Candidate HPV-Specific T Cells in the Tumor Microenvironment during Chemoradiotherapy Is Prognostic in HPV16 Cancers.

Cancer Immunol Res 2022 Jan 19. Epub 2022 Jan 19.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Human papillomavirus (HPV) infection causes 600,000 new cancers worldwide each year. HPV-related cancers express the oncogenic proteins E6 and E7, which could serve as tumor-specific antigens. It is not known whether immunity to E6 and E7 evolves during chemoradiotherapy or affects survival. Using T cells from 2 HPV16 patients, we conducted functional T-cell assays to identify candidate HPV-specific T cells and common T-cell receptor motifs, which we then analyzed across 86 patients with HPV-related cancers. The HPV-specific clones and E7-related T-cell receptor motifs expanded in the tumor microenvironment over the course of treatment, whereas non-HPV-specific T cells did not. In HPV16 patients, improved recurrence-free survival was associated with HPV-responsive T-cell expansion during chemoradiotherapy.
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http://dx.doi.org/10.1158/2326-6066.CIR-21-0119DOI Listing
January 2022

PIONEER-Panc: a platform trial for phase II randomized investigations of new and emerging therapies for localized pancreatic cancer.

BMC Cancer 2022 Jan 3;22(1):14. Epub 2022 Jan 3.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1220 Holcombe Boulevard, MS97, Houston, TX, 77030, USA.

Background: Personalized and effective treatments for pancreatic ductal adenocarcinoma (PDAC) continue to remain elusive. Novel clinical trial designs that enable continual and rapid evaluation of novel therapeutics are needed. Here, we describe a platform clinical trial to address this unmet need.

Methods: This is a phase II study using a Bayesian platform design to evaluate multiple experimental arms against a control arm in patients with PDAC. We first separate patients into three clinical stage groups of localized PDAC (resectable, borderline resectable, and locally advanced disease), and further divide each stage group based on treatment history (treatment naïve or previously treated). The clinical stage and treatment history therefore define 6 different cohorts, and each cohort has one control arm but may have one or more experimental arms running simultaneously. Within each cohort, adaptive randomization rules are applied and patients will be randomized to either an experimental arm or the control arm accordingly. The experimental arm(s) of each cohort are only compared to the applicable cohort specific control arm. Experimental arms may be added independently to one or more cohorts during the study. Multiple correlative studies for tissue, blood, and imaging are also incorporated.

Discussion: To date, PDAC has been treated as a single disease, despite knowledge that there is substantial heterogeneity in disease presentation and biology. It is recognized that the current approach of single arm phase II trials and traditional phase III randomized studies are not well-suited for more personalized treatment strategies in PDAC. The PIONEER Panc platform clinical trial is designed to overcome these challenges and help advance our treatment strategies for this deadly disease.

Trial Registration: This study is approved by the Institutional Review Board (IRB) of MD Anderson Cancer Center, IRB-approved protocol 2020-0075. The PIONEER trial is registered at the US National Institutes of Health (ClinicalTrials.gov) NCT04481204 .
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http://dx.doi.org/10.1186/s12885-021-09095-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8722115PMC
January 2022

Novel Use of Low-Dose Radiotherapy to Modulate the Tumor Microenvironment of Liver Metastases.

Front Immunol 2021 15;12:812210. Epub 2021 Dec 15.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Despite multiple therapeutic approaches, the presence of liver metastases carries a guarded prognosis, urgently necessitating further clinical and scientific research to develop curative interventions. The liver is an immunoprivileged organ that suppresses the effectiveness of immunotherapies in patients with hepatic metastases. Cancer immunotherapies have been successfully bolstered by low-dose radiotherapy (LDRT), which is capable of reprogramming the tumor microenvironment (TME) from an immunosuppressive to an immunostimulatory one. Likewise, LDRT may be able to revoke the immune privilege enjoyed by the liver, permitting successful immunotherapies there. Here, we first review challenges that face the treatment of liver metastases. We next outline emerging preclinical and clinical evidence supporting enhanced systemic tumor control of LDRT in the context of cancer immunotherapy. Finally, we will discuss the rationale of combining liver-directed LDRT with immunostimulatory strategies to overcome immune resistance and achieve better clinical response. This notion is supported by a recent case study in which a patient who had progressed following T cell therapy experienced a complete response after LDRT to the liver.
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http://dx.doi.org/10.3389/fimmu.2021.812210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714746PMC
December 2021

Benchmarking Outcomes after Ablative Radiotherapy for Molecularly Characterized Intrahepatic Cholangiocarcinoma.

J Pers Med 2021 Dec 1;11(12). Epub 2021 Dec 1.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

We have previously shown that ablative radiotherapy (A-RT) with a biologically effective dose (BED) ≥ 80.5 Gy for patients with unresectable intrahepatic cholangiocarcinoma (ICC) is associated with longer survival. Despite recent large-scale sequencing efforts in ICC, outcomes following RT based on genetic alterations have not been described. We reviewed records of 156 consecutive patients treated with A-RT for unresectable ICC from 2008 to 2020. For 114 patients (73%), next-generation sequencing provided molecular profiles. The overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS) were estimated using the Kaplan-Meier method. Univariate and multivariable Cox analyses were used to determine the associations with the outcomes. The median tumor size was 7.3 (range: 2.2-18.2) cm. The portal vein thrombus (PVT) was present in 10%. The RT median BED was 98 Gy (range: 81-144 Gy). The median (95% confidence interval) follow-up was 58 (42-104) months from diagnosis and 39 (33-74) months from RT. The median OS was 32 (29-35) months after diagnosis and 20 (16-24) months after RT. The one-year OS, LC, and intrahepatic DMFS were 73% (65-80%), 81% (73-87%), and 34% (26-42%). The most common mutations were in (25%), (22%), (19%), and (13%). Upon multivariable analysis, the factors associated with death included worse performance status, larger tumor, metastatic disease, higher CA 19-9, PVT, satellitosis, and and mutations. mutation was associated with local failure. Further investigation into the prognostic value of individual mutations and combinations thereof is warranted.
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http://dx.doi.org/10.3390/jpm11121270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8703854PMC
December 2021

Stereotactic Versus Conventional Radiation Therapy for Patients With Pancreatic Cancer in the Modern Era.

Adv Radiat Oncol 2021 Nov-Dec;6(6):100763. Epub 2021 Jul 29.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Patients with pancreatic cancer often receive radiation therapy before undergoing surgical resection. We compared the clinical outcomes differences between stereotactic body radiation therapy (SBRT) and 3-dimensional (3D)/intensity-modulated radiation therapy (IMRT).

Methods And Materials: We retrospectively collected data from the University of Texas MD Anderson Cancer Center. Patients with borderline resectable/potentially resectable or locally advanced pancreatic cancer receiving neoadjuvant SBRT (median, 36.0 Gy/5fx), 3D conformal radiation (median, 50.4 Gy/28 fx) or IMRT (median, 50.4 Gy/28 fx) were included. Overall survival (OS) and progression-free survival were analyzed using Cox regression.

Results: In total, 104 patients were included in our study. Fifty-seven patients (54.8%) were treated with SBRT, and 47 patients (45.2%) were treated with 3D/IMRT. Patients in the SBRT group were slightly older (median age: 70.3 vs 62.7 in the 3D/IMRT group). Both groups had similar proportions of patients with locally advanced pancreatic cancer (SBRT: 30, 52.6%; 3D/IMRT: 24, 51.1%). All patients were treated with chemotherapy. Patients in the SBRT group underwent more surgical resection compared with the 3D/IMRT group (38.6% vs 23.4%, respectively). At a median follow-up of 22 months, a total of 60 patients (57.7%) died: 25 (25/57, 43.9%) in the SBRT group, and 35 (35/47, 74.5%) in the 3D/IMRT group. Median OS was slightly higher in the SBRT group (29.6 months vs 24.1 months in the 3D/IMRT group). On multivariable Cox regression, the choice of radiation therapy technique was not associated with differences in OS (adjusted hazard ratios [aHR] = 0.5; 95% confidence interval [CI], 0.2%-1.3%,  = .18). Moreover, patients that underwent surgical resection had better OS (aHR = 0.3, 95% CI, 0.1%-0.8%,  = .01). Furthermore, progression-free survival was also similar between patients treated with SBRT and those treated with 3D/IMRT (aHR = 0.9, 95% CI, 0.5%-1.8%,  = .81).

Conclusions: SBRT was associated with similar clinical outcomes compared with conventional radiation techniques, despite being delivered over a shorter period of time which would spare patients prolonged treatment burden. Future prospective data are still needed to better assess the role of SBRT in patients with pancreatic cancer.
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http://dx.doi.org/10.1016/j.adro.2021.100763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655391PMC
July 2021

Prognostic impact of lymphopenia and neutrophil-lymphocyte ratio for patients with anal squamous cell carcinoma.

J Gastrointest Oncol 2021 Oct;12(5):2412-2422

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Outcomes after definitive chemoradiation for squamous cell carcinoma are generally favorable. However, biomarkers to further yield prognostic information are desired. Treatment-related lymphopenia as well as an elevated baseline neutrophil-lymphocyte ratio have been associated with worse survival in several cancer types. We evaluated absolute lymphocyte count and neutrophil-lymphocyte ratio at baseline and at treatment-related nadir in patients with anal cancer for associations with oncologic endpoints.

Methods: We conducted a retrospective analysis of 428 consecutive patients with non-metastatic anal cancer treated with definitive, intensity-modulated radiation therapy-based chemoradiation. We analyzed absolute neutrophil and lymphocyte counts at several timepoints: pretreatment, weekly during treatment, and in the six weeks following treatment completion. Neutrophil-lymphocyte ratio was calculated at baseline and treatment-related nadir. We estimated oncologic endpoints using life tables and compared them using the log-rank test. We conducted univariate and multivariable time-to-event analyses using Cox proportional hazards.

Results: Median absolute lymphocyte count at baseline and nadir were 1.80 [interquartile range (IQR), 1.45-2.32] k/µL and 0.26 (IQR, 0.18-0.36) k/µL, respectively, and 31% developed treatment-related grade 4 lymphopenia. Median neutrophil-lymphocyte ratio at baseline and nadir were 2.34 (IQR, 1.68-3.30) and 8.80 (IQR, 5.86-12.68), respectively. Estimates of overall survival, local failure-free survival, distant metastasis-free survival (DMFS), and freedom from colostomy at 5 years were 87%, 86%, 82%, and 88%, respectively. Baseline and nadir absolute lymphocyte count were not associated with selected outcomes on univariate analysis. On multivariable analysis, factors independently associated with death included T3-T4 disease, HIV-positive status, treatment break, and baseline neutrophil-lymphocyte ratio >3. Baseline neutrophil-lymphocyte ratio showed a trend toward association with distant progression or death (P=0.07). The 5-year overall survival estimates for patients with baseline neutrophil-lymphocyte ratios ≤3 and >3 were 92.3% and 80.6%, respectively.

Conclusions: Lymphopenia during and after chemoradiation for anal cancer is common but does not appear to be associated with worse survival, recurrence, or metastases. However, elevated baseline neutrophil-lymphocyte ratio was independently associated with overall survival, local recurrence-free survival, and DMFS. Further studies are needed to determine the clinical utility of baseline neutrophil-lymphocyte ratio to guide treatment and follow-up.
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http://dx.doi.org/10.21037/jgo-21-323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576202PMC
October 2021

Early prediction of clinical response to checkpoint inhibitor therapy in human solid tumors through mathematical modeling.

Elife 2021 11 9;10. Epub 2021 Nov 9.

Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, United States.

Background: Checkpoint inhibitor therapy of cancer has led to markedly improved survival of a subset of patients in multiple solid malignant tumor types, yet the factors driving these clinical responses or lack thereof are not known. We have developed a mechanistic mathematical model for better understanding these factors and their relations in order to predict treatment outcome and optimize personal treatment strategies.

Methods: Here, we present a translational mathematical model dependent on three key parameters for describing efficacy of checkpoint inhibitors in human cancer: tumor growth rate (), tumor-immune infiltration (), and immunotherapy-mediated amplification of anti-tumor response (). The model was calibrated by fitting it to a compiled clinical tumor response dataset (n = 189 patients) obtained from published anti-PD-1 and anti-PD-L1 clinical trials, and then validated on an additional validation cohort (n = 64 patients) obtained from our in-house clinical trials.

Results: The derived parameters and were both significantly different between responding versus nonresponding patients. Of note, our model appropriately classified response in 81.4% of patients by using only tumor volume measurements and within 2 months of treatment initiation in a retrospective analysis. The model reliably predicted clinical response to the PD-1/PD-L1 class of checkpoint inhibitors across multiple solid malignant tumor types. Comparison of model parameters to immunohistochemical measurement of PD-L1 and CD8+ T cells confirmed robust relationships between model parameters and their underlying biology.

Conclusions: These results have demonstrated reliable methods to inform model parameters directly from biopsy samples, which are conveniently obtainable as early as the start of treatment. Together, these suggest that the model parameters may serve as early and robust biomarkers of the efficacy of checkpoint inhibitor therapy on an individualized per-patient basis.

Funding: We gratefully acknowledge support from the Andrew Sabin Family Fellowship, Center for Radiation Oncology Research, Sheikh Ahmed Center for Pancreatic Cancer Research, GE Healthcare, Philips Healthcare, and institutional funds from the University of Texas M.D. Anderson Cancer Center. We have also received Cancer Center Support Grants from the National Cancer Institute (P30CA016672 to the University of Texas M.D. Anderson Cancer Center and P30CA072720 the Rutgers Cancer Institute of New Jersey). This research has also been supported in part by grants from the National Science Foundation Grant DMS-1930583 (ZW, VC), the National Institutes of Health (NIH) 1R01CA253865 (ZW, VC), 1U01CA196403 (ZW, VC), 1U01CA213759 (ZW, VC), 1R01CA226537 (ZW, RP, WA, VC), 1R01CA222007 (ZW, VC), U54CA210181 (ZW, VC), and the University of Texas System STARS Award (VC). BC acknowledges support through the SER Cymru II Programme, funded by the European Commission through the Horizon 2020 Marie Skłodowska-Curie Actions (MSCA) COFUND scheme and the Welsh European Funding Office (WEFO) under the European Regional Development Fund (ERDF). EK has also received support from the Project Purple, NIH (U54CA210181, U01CA200468, and U01CA196403), and the Pancreatic Cancer Action Network (16-65-SING). MF was supported through NIH/NCI center grant U54CA210181, R01CA222959, DoD Breast Cancer Research Breakthrough Level IV Award W81XWH-17-1-0389, and the Ernest Cockrell Jr. Presidential Distinguished Chair at Houston Methodist Research Institute. RP and WA received serial research awards from AngelWorks, the Gillson-Longenbaugh Foundation, and the Marcus Foundation. This work was also supported in part by grants from the National Cancer Institute to SHC (R01CA109322, R01CA127483, R01CA208703, and U54CA210181 CITO pilot grant) and to PYP (R01CA140243, R01CA188610, and U54CA210181 CITO pilot grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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http://dx.doi.org/10.7554/eLife.70130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629426PMC
November 2021

External Beam Radiation Therapy for Primary Liver Cancers: An ASTRO Clinical Practice Guideline.

Pract Radiat Oncol 2022 Jan-Feb;12(1):28-51. Epub 2021 Oct 21.

Department of Radiation Oncology, Weill Cornell, New York, New York.

Purpose: This guideline provides evidence-based recommendations for the indications and technique-dose of external beam radiation therapy (EBRT) in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC).

Methods: The American Society for Radiation Oncology convened a task force to address 5 key questions focused on the indications, techniques, and outcomes of EBRT in HCC and IHC. This guideline is intended to cover the definitive, consolidative, salvage, preoperative (including bridge to transplant), and adjuvant settings as well as palliative EBRT for symptomatic primary lesions. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength.

Results: Strong recommendations are made for using EBRT as a potential first-line treatment in patients with liver-confined HCC who are not candidates for curative therapy, as consolidative therapy after incomplete response to liver-directed therapies, and as a salvage option for local recurrences. The guideline conditionally recommends EBRT for patients with liver-confined multifocal or unresectable HCC or those with macrovascular invasion, sequenced with systemic or catheter-based therapies. Palliative EBRT is conditionally recommended for symptomatic primary HCC and/or macrovascular tumor thrombi. EBRT is conditionally recommended as a bridge to transplant or before surgery in carefully selected patients. For patients with unresectable IHC, consolidative EBRT with or without chemotherapy should be considered, typically after systemic therapy. Adjuvant EBRT is conditionally recommended for resected IHC with high-risk features. Selection of dose-fractionation regimen and technique should be based on disease extent, disease location, underlying liver function, and available technologies.

Conclusions: The task force has proposed recommendations to inform best clinical practices on the use of EBRT for HCC and IHC with strong emphasis on multidisciplinary care. Future studies should focus on further defining the role of EBRT in the context of liver-directed and systemic therapies and refining optimal regimens and techniques.
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http://dx.doi.org/10.1016/j.prro.2021.09.004DOI Listing
January 2022

Development of a MicroRNA Signature Predictive of Recurrence and Survival in Pancreatic Ductal Adenocarcinoma.

Cancers (Basel) 2021 Oct 15;13(20). Epub 2021 Oct 15.

Department of Radiation Oncology, City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA.

Background: Optimal patient selection for radiotherapy in pancreatic ductal adenocarcinoma (PDAC) is unestablished. Molecular profiling may select patients at high risk for locoregional recurrence (LRR) who would benefit from radiation.

Methods: We included resectable pancreatic cancer (R-PDAC) patients, divided into training and validation cohorts, treated among three institutions with surgery and adjuvant chemotherapy, and borderline resectable or locally advanced pancreatic cancer (BR/LA-PDAC) patients treated with chemotherapy with or without radiation at the primary study institution. We isolated RNA from R-PDAC surgical specimens. Using NanoString, we identified miRNAs differentially expressed between normal and malignant pancreatic tissue. ElasticNet regression identified two miRNAs most predictive of LRR in the training cohort, miR-181b/d and miR-575, which were used to generate a risk score (RS). We evaluated the association of the median-dichotomized RS with recurrence and overall survival (OS).

Results: We identified 183 R-PDAC and 77 BR/LA-PDAC patients with median follow up of 37 months treated between 2001 and 2014. On multivariable analysis of the R-PDAC training cohort ( = 90), RS was associated with worse LRR (HR = 1.34; 95%CI 1.27-11.38; = 0.017) and OS (HR = 2.89; 95%CI 1.10-4.76; = 0.027). In the R-PDAC validation cohort, RS was associated with worse LRR (HR = 2.39; 95%CI 1.03-5.54; = 0.042), but not OS ( = 0.087). For BR/LA-PDAC, RS was associated with worse LRR (HR = 2.71; 95%CI 1.14-6.48; = 0.025), DR (HR = 1.93; 95%CI 1.10-3.38; = 0.022), and OS (HR = 1.97; 95%CI 1.17-3.34; = 0.011). Additionally, after stratifying by RS and receipt of radiation in BR/LA-PDAC patients, high RS patients who did not receive radiation had worse LRR ( = 0.018), DR ( 0.006), and OS ( < 0.001) compared to patients with either low RS or patients who received radiation, irrespective of RS.

Conclusions: RS predicted worse LRR and OS in R-PDAC and worse LRR, DR, and OS in BR/LA-PDAC. This may select patients who would benefit from radiation and should be validated prospectively.
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http://dx.doi.org/10.3390/cancers13205168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534163PMC
October 2021

Current Landscape and Future Directions of Biomarkers for Immunotherapy in Hepatocellular Carcinoma.

J Hepatocell Carcinoma 2021 24;8:1195-1207. Epub 2021 Sep 24.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Hepatocellular carcinoma (HCC) is the most common liver cancer and one of the leading causes of cancer-related deaths in the world. Multiple immunotherapeutic approaches have been investigated to date, and immunotherapy has become the new standard of care therapy in HCC. However, the current role of immunotherapy in HCC remains non-curative. Given this context, a high priority for oncology is understanding the biomarkers that predict clinical response to immunotherapy, have the potential to improve patient selection to maximize the clinical benefit, and spare unnecessary toxicity. In this review, we summarize the key predictive and prognostic biomarkers investigated in immunotherapy clinical trials in HCC and the emerging biomarkers to serve as a roadmap for future clinical trials. Biomarkers from tumoral tissues including PDL-1 expression, tissue infiltrating lymphocytes, tumor mutational burden (TMB) and specific immune signatures, and from peripheral blood including neutrophil-to-lymphocytes ratio, platelet-to-lymphocytes ratio, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and specific cytokines, along with gut microbiota are among the studied biomarkers to date in the HCC era. More integrative approaches, including mathematical biomarkers to predict immunotherapy outcomes, are yet to be studied in HCC.
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http://dx.doi.org/10.2147/JHC.S322289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478438PMC
September 2021

Factors associated with complex oral treatment device usage in patients with head and neck cancer.

Clin Transl Radiat Oncol 2021 Sep 8;30:78-83. Epub 2021 Aug 8.

Department of Radiation Oncology, Division of Radiation Oncology, MD Anderson Cancer Center, Houston, TX, United States.

Purpose: The objective was to identify clinical and epidemiological factors associated with utilization of a complex oral treatment device (COTD), which may decrease toxicity in patients undergoing radiation therapy for head and neck cancer (HNC).

Materials And Methods: We retrospectively reviewed data from 1992 to 2013 in the Surveillance, Epidemiology, and End Results (SEER)-Medicare databases to analyze COTD usage during intensity-modulated radiation therapy (IMRT) for patients diagnosed with cancer of the tongue, floor of mouth, nasopharynx, tonsil, or oropharynx. Patients with a radiation simulation and complex treatment device code within 4 weeks before the first IMRT claim were identified as meeting COTD usage criteria. Demographic, regional, tumor, and treatment data were analyzed.

Results: Out of 4511 patients who met eligibility criteria, 1932 patients (42.8%) did not utilize a COTD while 2579 (57.2%) met usage criteria. COTD utilization increased over time (36.36% usage in 1992 vs. 67.44% usage in 2013, ). Patients less likely to receive a COTD included those aged 86 years or older compared to those aged 66-70 (OR = 0.713, 95% CI: 0.528-0.962), male patients (OR = 0.817, 95% CI: 0.710-0.941), non-Hispanic Black patients compared to non-Hispanic White patients (OR = 0.750, 95% CI: 0.582-0.966), and Louisiana residents (OR = 0.367, 95% CI: 0.279-0.483). Cancer site, grade, stage, or function of IMRT had no significant association with COTD usage.

Conclusions: This study serves as the first known SEER-Medicare review of COTD utilization. Despite an increase in COTD usage over time, our results indicate age, gender, and geographic disparities are associated with utilization. Further research and development into methods that increase availability of COTDs may help increase utilization in specific patient populations.
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http://dx.doi.org/10.1016/j.ctro.2021.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365308PMC
September 2021

GRP78 expression and prognostic significance in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant therapy versus surgery first.

Pancreatology 2021 Oct 18;21(7):1378-1385. Epub 2021 Aug 18.

Department of Anatomical Pathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. Electronic address:

Background: Glucose-regulated protein 78 (GRP78) plays an essential role in protein folding, transportation, and degradation, thus regulates ER homeostasis and promotes cell survival, proliferation and invasion. GRP78 expression in PDAC patients who received neoadjuvant therapy has not been reported.

Methods: This retrospective study of resected PDAC patients included 125 patients treated with neoadjuvant therapy (NAT) and 140 patients treated with surgery first (SF). The expression of GRP78 was evaluated by immunohistochemistry on tissue microarrays and the results were correlated with clinicopathologic parameters and survival.

Results: GRP78 expression was higher in SF patients compared to NAT patients (P < 0.001). In SF cohort, the median disease-free survival (DFS) and overall survival (OS) for patients with GRP78-positive tumors were 11.2 months and 25.0 months, respectively, compared to DFS of 52.1 months (P = 0.008) and OS of 69.5 months (P = 0.02) for those with GRP78-negative tumors. GRP78 expression correlated with higher frequency of recurrent/metastasis (P = 0.045). In NAT cohort, GRP78 expression correlated with shorter OS (P = 0.03), but not DFS (P = 0.08). GRP78 expression was an independent prognosticator for both DFS (P = 0.02) and OS (P = 0.049) in SF cohort and was an independent prognosticator for OS (P = 0.03), but not for DFS (P = 0.06) in NAT cohort by multivariate analysis.

Conclusions: Our study showed that GRP78 expression in NAT cohort is lower than that in SF cohort. GRP78 expression correlated with shorter survival in both SF and NAT patients. Our findings suggest that targeting GRP78 may help to improve the prognosis in PDAC patients.
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http://dx.doi.org/10.1016/j.pan.2021.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541920PMC
October 2021

Dosimetric Uncertainties Resulting From Interfractional Anatomic Variations for Patients Receiving Pancreas Stereotactic Body Radiation Therapy and Cone Beam Computed Tomography Image Guidance.

Int J Radiat Oncol Biol Phys 2021 12 13;111(5):1298-1309. Epub 2021 Aug 13.

Department of Radiation Physics, UT-MD Anderson Cancer Center; Graduate School of Biomedical Sciences, UT-MD Anderson Cancer Center, Houston, TX. Electronic address:

Purpose: To estimate the effects of interfractional anatomic changes on dose to organs at risk (OARs) and tumors, as measured with cone beam computed tomography (CBCT) image guidance for pancreatic stereotactic body radiation therapy.

Methods And Materials: We evaluated 11 patients with pancreatic cancer whom were treated with stereotactic body radiation therapy (33-40 Gy in 5 fractions) using daily CT-on-rails (CTOR) image guidance immediately before treatment with breath-hold motion management. CBCT alignment was simulated in the treatment planning software by aligning the original planning CT to each fractional CTOR image set via fiducial markers. CTOR data sets were used to calculate fractional doses after alignment by applying the rigid shift of the planning CT and CTOR image sets to the planning treatment isocenter and recalculating the fractional dose. Accumulated dose to the gross tumor volume (GTV), tumor vessel interface, duodenum, small bowel, and stomach were calculated by summing the 5 fractional absolute dose-volume histograms into a single dose-volume histogram for comparison with the original planned dose.

Results: Four patients had a GTV D100% of at least 1.5 Gy less than the fractional planned value in several fractions; 4 patients had fractional underestimation of duodenum dose by 1.0 Gy per fraction. The D1.0 cm <35 Gy constraint was violated for at least 1 OAR in 3 patients, with either the duodenum (n = 2) or small bowel (n = 1) D1.0 cm being higher on the accumulated dose distribution (P = .01). D100% was significantly lower according to accumulated dose GTV (P = .01) and tumor vessel interface (P = .02), with 4 and 2 patients having accumulated D100%  ≥4 Gy lower than the planned value for the GTV and tumor vessel interface, respectively.

Conclusions: For some patients, CBCT image guidance based on fiducial alignment may cause large dosimetric uncertainties for OARs and target structures, according to accumulated dose.
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http://dx.doi.org/10.1016/j.ijrobp.2021.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8651043PMC
December 2021

Detection of vessel bifurcations in CT scans for automatic objective assessment of deformable image registration accuracy.

Med Phys 2021 Oct 25;48(10):5935-5946. Epub 2021 Aug 25.

Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Purpose: Objective assessment of deformable image registration (DIR) accuracy often relies on the identification of anatomical landmarks in image pairs, a manual process known to be extremely time-expensive. The goal of this study is to propose a method to automatically detect vessel bifurcations in images and assess their use for the computation of target registration errors (TREs).

Materials And Methods: Three image datasets were retrospectively analyzed. The first dataset included 10 pairs of inhale/exhale phases from lung 4DCTs and full inhale and exhale breath-hold CT scans from 10 patients presenting with chronic obstructive pulmonary disease, with 300 corresponding landmarks available for each case (DIR-Lab). The second dataset included six pairs of inhale/exhale phases from lung 4DCTs (POPI dataset), with 100 pairs of landmarks for each case. The third dataset included 28 pairs of pre/post-radiotherapy liver contrast-enhanced CT scans, each with five manually picked vessel bifurcation correspondences. For all images, the vasculature was autosegmented by computing and thresholding a vesselness image. Images of the vasculature centerline were computed, and bifurcations were detected based on centerline voxel neighbors' count. The vasculature segmentations were independently registered using a Demons algorithm between representations of their surface with distance maps. Detected bifurcations were considered as corresponding when distant by less than 5 mm after vasculature DIR. The selected pairs of bifurcations were used to calculate TRE after registration of the images considering three algorithms: rigid registration, Anaconda, and a Demons algorithm. For comparison with the ground truth, TRE values calculated using the automatically detected correspondences were interpolated in the whole organs to generate TRE maps. The performance of the method in automatically calculating TRE after image registration was quantified by measuring the correlation with the TRE obtained when using the ground truth landmarks.

Results: The median Pearson correlation coefficients between ground truth TRE and corresponding values in the generated TRE maps were r = 0.81 and r = 0.67 for the lung and liver cases, respectively. The correlation coefficients between mean TRE for each case were r = 0.99 and r = 0.64 for the lung and liver cases, respectively.

Conclusion: For lungs or liver CT scans DIR, a strong correlation was obtained between TRE calculated using manually picked or landmarks automatically detected with the proposed method. This tool should be particularly useful in studies requiring assessing the reliability of a high number of DIRs.
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http://dx.doi.org/10.1002/mp.15163DOI Listing
October 2021

CEA as a blood-based biomarker in anal cancer.

Oncotarget 2021 May 25;12(11):1037-1045. Epub 2021 May 25.

Department of Hematology/Oncology, Vanderbilt Ingram Cancer Center, Nashville, TN, USA.

Background: The clinical utility of a blood-based biomarker in squamous cell carcinoma of the anus (SCCA) is unknown. We analyzed carcinoembryonic antigen (CEA), a commonly employed assay for patients with colorectal adenocarcinoma, as a serum biomarker for patients with biopsy-proven SCCA.

Materials And Methods: Medical records from 219 patients with biopsy-proven SCCA at the University of Texas MD Anderson Cancer Center were reviewed under an IRB-approved protocol from 2013 to 2020 to assess for correlations between CEA levels and corresponding clinical and pathologic characteristics.

Results: The mean CEA among subgroups by clinical status at the time of presentation to our institution was highest among those patients with metastatic SCCA to visceral organs (M-V, 20.7 ng/mL), however this finding was not statistically significant by ANOVA ( = .74). By clinical subgroup, the percentage of patients with an abnormally elevated CEA was highest in those patients with metastatic disease to lymph nodes (M-L, 41.2%) followed by recurrent/unresectable SCCA (36.8%), and metastatic SCCA to visceral organs (M-V, 35.2%), and was statistically significant between groups (Fisher's exact test = .02). Using RECIST criteria for tumor progression and disease response, the mean change in CEA for patients with progression was an increase in 19 ng/mL, compared to a change of -7.3 ng/mL in those with disease response ( = .004). We likewise assessed whether CEA levels were associated with survival outcomes for all patients with metastatic SCCA, and found no correlation between CEA and likelihood for survival in a ROC analysis (multivariate, age-adjusted analysis for CEA cutoff of 8, HR = 1.01, 95% CI 0.52-1.96).

Conclusions: Despite interesting patterns of abnormally high CEA in SCCA patients with advanced disease, and correlation of increased CEA with disease progression (and conversely decreased CEA with disease response), CEA is not associated with survival outcomes in SCCA, and is not a clinically relevant biomarker in this disease.
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http://dx.doi.org/10.18632/oncotarget.27959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169063PMC
May 2021

Magnetic Resonance Guided Radiation Therapy for Pancreatic Adenocarcinoma, Advantages, Challenges, Current Approaches, and Future Directions.

Front Oncol 2021 11;11:628155. Epub 2021 May 11.

Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, United States.

Introduction: Pancreatic adenocarcinoma (PAC) has some of the worst treatment outcomes for any solid tumor. PAC creates substantial difficulty for effective treatment with traditional RT delivery strategies primarily secondary to its location and limited visualization using CT. Several of these challenges are uniquely addressed with MR-guided RT. We sought to summarize and place into context the currently available literature on MR-guided RT specifically for PAC.

Methods: A literature search was conducted to identify manuscript publications since September 2014 that specifically used MR-guided RT for the treatment of PAC. Clinical outcomes of these series are summarized, discussed, and placed into the context of the existing pancreatic literature. Multiple international experts were involved to optimally contextualize these publications.

Results: Over 300 manuscripts were reviewed. A total of 6 clinical outcomes publications were identified that have treated patients with PAC using MR guidance. Successes, challenges, and future directions for this technology are evident in these publications. MR-guided RT holds theoretical promise for the treatment of patients with PAC. As with any new technology, immediate or dramatic clinical improvements associated with its use will take time and experience. There remain no prospective trials, currently publications are limited to small retrospective experiences. The current level of evidence for MR guidance in PAC is low and requires significant expansion. Future directions and ongoing studies that are currently open and accruing are identified and reviewed.

Conclusions: The potential promise of MR-guided RT for PAC is highlighted, the challenges associated with this novel therapeutic intervention are also reviewed. Outcomes are very early, and will require continued and long term follow up. MR-guided RT should not be viewed in the same fashion as a novel chemotherapeutic agent for which dosing, administration, and toxicity has been established in earlier phase studies. Instead, it should be viewed as a novel procedural intervention which must be robustly tested, refined and practiced before definitive conclusions on the potential benefits or detriments can be determined. The future of MR-guided RT for PAC is highly promising and the potential implications on PAC are substantial.
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http://dx.doi.org/10.3389/fonc.2021.628155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144850PMC
May 2021

Integration of Systemic and Liver-Directed Therapies for Locally Advanced Hepatocellular Cancer: Harnessing Potential Synergy for New Therapeutic Horizons.

J Natl Compr Canc Netw 2021 May 1;19(5):567-576. Epub 2020 Oct 1.

1Department of Radiation Oncology.

Treatment options in locally advanced hepatocellular carcinoma (HCC) have evolved considerably over the past few years with the recent approval of multiple systemic therapies and significant advances in locoregional therapy. Given the poor prognosis for patients with unresectable HCC, there is significant interest in rationally designed combination therapies. This article reviews the treatment options available to patients with locally advanced HCC and discusses the rationale, ongoing trials, and future prospects for combining locoregional and systemic therapy in both the definitive and neoadjuvant settings.
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http://dx.doi.org/10.6004/jnccn.2021.7037DOI Listing
May 2021

Is the worst of the COVID-19 global pandemic yet to come? Application of financial mathematics as candidate predictive tools.

Transl Psychiatry 2021 05 20;11(1):299. Epub 2021 May 20.

Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX, USA.

The Elliott Wave principle is a time-honored, oft-used method for predicting variations in the financial markets. It is based on the notion that human emotions drive financial decisions. In the fight against the COVID-19 global pandemic, human emotions are similarly decisive, for instance in that they determine one's willingness to be vaccinated, and/or to follow preventive measures including the personal wearing of masks, the application of social distancing protocols, and frequent handwashing. On this basis, we postulated that the Elliott Wave Principle may similarly be used to predict the future evolution of the COVID-19 pandemic. We demonstrated that this method reproduces the data pattern for various countries and the world (daily new cases). Potential scenarios were then extrapolated, from the best-case corresponding to a rapid, full vaccination of the population, to the utterly disastrous case of slow vaccination, and poor adherence to preventive protocols.
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http://dx.doi.org/10.1038/s41398-021-01429-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134815PMC
May 2021

A Machine Learning Model Approach to Risk-Stratify Patients With Gastrointestinal Cancer for Hospitalization and Mortality Outcomes.

Int J Radiat Oncol Biol Phys 2021 09 29;111(1):135-142. Epub 2021 Apr 29.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Purpose: Patients with gastrointestinal (GI) cancer frequently experience unplanned hospitalizations, but predictive tools to identify high-risk patients are lacking. We developed a machine learning model to identify high-risk patients.

Methods And Materials: In the study, 1341 consecutive patients undergoing GI (abdominal or pelvic) radiation treatment (RT) from March 2016 to July 2018 (derivation) and July 2018 to January 2019 (validation) were assessed for unplanned hospitalizations within 30 days of finishing RT. In the derivation cohort of 663 abdominal and 427 pelvic RT patients, a machine learning approach derived random forest, gradient boosted decision tree, and logistic regression models to predict 30-day unplanned hospitalizations. Model performance was assessed using area under the receiver operating characteristic curve (AUC) and prospectively validated in 161 abdominal and 90 pelvic RT patients using Mann-Whitney rank-sum test. Highest quintile of risk for hospitalization was defined as "high-risk" and the remainder "low-risk." Hospitalizations for high- versus low-risk patients were compared using Pearson's χ test and survival using Kaplan-Meier log-rank test.

Results: Overall, 13% and 11% of patients receiving abdominal and pelvic RT experienced 30-day unplanned hospitalization. In the derivation phase, gradient boosted decision tree cross-validation yielded AUC = 0.823 (abdominal patients) and random forest yielded AUC = 0.776 (pelvic patients). In the validation phase, these models yielded AUC = 0.749 and 0.764, respectively (P < .001 and P = .002). Validation models discriminated high- versus low-risk patients: in abdominal RT patients, frequency of hospitalization was 39% versus 9% in high- versus low-risk groups (P < .001) and 6-month survival was 67% versus 92% (P = .001). In pelvic RT patients, frequency of hospitalization was 33% versus 8% (P = .002) and survival was 86% versus 92% (P = .15) in high- versus low-risk patients.

Conclusions: In patients with GI cancer undergoing RT as part of multimodality treatment, machine learning models for 30-day unplanned hospitalization discriminated high- versus low-risk patients. Future applications will test utility of models to prompt interventions to decrease hospitalizations and adverse outcomes.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.019DOI Listing
September 2021

Impact of Fiducial Marker Placement Before Stereotactic Body Radiation Therapy on Clinical Outcomes in Patients With Pancreatic Cancer.

Adv Radiat Oncol 2021 Mar-Apr;6(2):100621. Epub 2020 Nov 23.

University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Localized pancreatic cancer is commonly treated with stereotactic body radiation therapy (SBRT), which often requires the placement of fiducial markers. We compared the clinical outcomes of patients with and without fiducial markers.

Methods And Materials: We retrospectively collected data on patients with pancreatic cancer treated with neoadjuvant SBRT at a single institution. Patients were divided into 2 groups based on the placement of a fiducial marker. Local recurrence was the primary outcome. Time to event endpoints were analyzed using COX regression.

Results: We included 96 patients with unresectable pancreatic cancer: 46 patients (47.9%) did not have a fiducial marker, and 50 patients (52.1%) had a fiducial placed. Patients in the fiducial group were older and had more locally advanced pancreatic cancer compared with those who did not have a fiducial placed. Most patients in both groups (92.7%) received chemotherapy before SBRT treatment. SBRT was delivered to a median of 36 Gy over 5 fractions in the no-fiducial group, and 38 Gy over 5 fractions in the fiducial group. At a median follow-up of 20 months, local recurrence was similar irrespective of fiducial placement (adjusted hazard ratio [aHR] 0.6, 95% CI 0.3-1.3, = .59). Furthermore, no difference in overall survival was noted between the 2 groups (aHR 0.8, 95% CI 0.3-1.9, = .65). In patients who eventually underwent surgery post-SBRT, no difference in surgical margins ( = .40) or lymphovascular invasion ( = .76) was noted between the 2 groups. No patient developed acute pancreatitis after fiducial placement.

Conclusions: Our data suggest that the use of fiducial markers does not negatively affect clinical outcomes in patients with localized pancreatic cancer. Prospective confirmation of our results is still needed.
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http://dx.doi.org/10.1016/j.adro.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071717PMC
November 2020

Oncogenic Recruits an Expansive Transcriptional Network through Mutant p53 to Drive Pancreatic Cancer Metastasis.

Cancer Discov 2021 Aug 10;11(8):2094-2111. Epub 2021 Apr 10.

Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the tumor suppressor in nearly 70% of patients. Most alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis, yet the extent of direct cooperation between effectors and mutant p53 remains largely undefined. We show that oncogenic effectors activate CREB1 to allow physical interactions with mutant p53 that hyperactivate multiple prometastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the prometastatic, pioneer transcription factor , activating its transcriptional network while promoting WNT/β-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced and β-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic and mutant p53 to mitigate metastasis. SIGNIFICANCE: Oncogenic and mutant p53 are the most commonly mutated oncogene and tumor suppressor gene in human cancers, yet direct interactions between these genetic drivers remain undefined. We identified a cooperative node between oncogenic effectors and mutant p53 that can be therapeutically targeted to undermine cooperation and mitigate metastasis..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338884PMC
August 2021

Radiation-Associated Lymphopenia and Outcomes of Patients with Unresectable Hepatocellular Carcinoma Treated with Radiotherapy.

J Hepatocell Carcinoma 2021 3;8:57-69. Epub 2021 Mar 3.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: The immune system plays a crucial role in cancer surveillance. Previous studies have shown that lymphopenia associated with radiotherapy (RT) portends a poor prognosis. We sought to differentiate the effects of proton and photon RT on changes in absolute lymphocyte count (ALC) for patients with hepatocellular carcinoma (HCC).

Patients And Methods: Patients with HCC treated with definitive RT from 2006 to 2016 were studied. Serial ALCs were graded according to CTCAE v4.0. Overall survival (OS), disease-free survival, and distant metastasis-free survival were analyzed using the Kaplan-Meier method. Univariable and multivariable Cox-proportional hazards analyses were used to identify predictors of OS. A cohort analysis matched for treatment volume was performed to investigate differences in ALC dynamics between photon and proton therapy.

Results: Of 143 patients identified, the median age was 66 (range, 19-90) years. The treatment modality was photon in 103 (72%) and proton in 40 (28%). Median follow-up was 17 months (95% confidence interval, 13-25 months). The median time to ALC nadir after initiation of RT was 17 days with a median relative decrease of 67%. Those who received proton RT had a higher median ALC nadir (0.41 vs 0.32 k/µL, p=0.002) and longer median OS (33 vs 13 months, p=0.002) than those who received photon RT. Matched cohort analyses revealed a larger low-dose liver volume in the photon group, which correlated with lower ALC. On multivariable Cox analysis, Grade 3 or higher lymphopenia prior to or after RT, portal venous tumor thrombus, larger planning target volumes, Child-Pugh (CP) Class B, and increased CP score after RT were associated with a higher risk of death, whereas the use of proton therapy was associated with lower risk.

Conclusion: Grade 3 or higher lymphopenia may be associated with poorer outcomes in patients receiving RT for HCC. Protons may mitigate lymphopenia compared with photons, potentially due to reduced dose exposure of sites of lymphopoiesis.
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http://dx.doi.org/10.2147/JHC.S282062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937383PMC
March 2021

Implementation of a stereotactic body radiotherapy program for unresectable pancreatic cancer in an integrated community academic radiation oncology satellite network.

Clin Transl Radiat Oncol 2021 Mar 12;27:147-151. Epub 2021 Feb 12.

Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, United States.

With increasing interest in stereotactic body radiotherapy (SBRT) for unresectable pancreatic cancer, quality improvement (QI) initiatives to develop integrated clinical workflows are crucial to ensure quality assurance (QA) when introducing this challenging technique into radiation practices.

Materials/methods: In 2017, we used the Plan, Do, Study, Act (PDSA) QI methodology to implement a new pancreas SBRT program in an integrated community radiation oncology satellite. A unified integrated information technology infrastructure was used to virtually integrate the planned workflow into the community radiation oncology satellite network (P - Plan/D - Do). This workflow included multiple prospective quality assurance (QA) measures including multidisciplinary evaluation, prospective scrutiny of radiation target delineation, prospective radiation plan evaluation, and monitoring of patient outcomes. Institutional review board approval was obtained to retrospectively study and report outcomes of patients treated in this program (S - Study).

Results: There were 12 consecutive patients identified who were treated in this program from 2017 to 2020 with a median follow-up of 27 months. The median survival was 13 months, median local failure free survival was 12 months and median progression free survival was 6 months from SBRT. There were no acute or late Common Terminology Criteria for Adverse Effects (CTCAE) version 5 toxicities ≥ Grade 3.

Conclusion: We report the successful implementation of a community pancreas SBRT program involving multiple prospective QA measures, providing the groundwork to safely expand access to pancreas SBRT in our community satellite network (A - Act).
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http://dx.doi.org/10.1016/j.ctro.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907676PMC
March 2021

Do Pandemics Obey the Elliott Wave Principle of Financial Markets?

medRxiv 2021 Jan 22. Epub 2021 Jan 22.

Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, Texas, USA.

The Elliott Wave principle is a time-honored, oft-used method for predicting variations in the financial markets. It is based on the notion that human emotions drive financial decisions. In the fight against COVID-19, human emotions are similarly decisive, for instance in that they determine one's willingness to be vaccinated, and/or to follow preventive measures including the wearing of masks, the application of social distancing protocols, and frequent handwashing. On this basis, we postulated that the Elliott Wave Principle may similarly be used to predict the future evolution of the COVID-19 pandemic. We demonstrated that this method reproduces the data pattern especially well for USA (daily new cases). Potential scenarios were then extrapolated, from the best-case corresponding to a rapid, full vaccination of the population, to the utterly disastrous case of slow vaccination, and poor adherence to preventive protocols.
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http://dx.doi.org/10.1101/2021.01.21.21250273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836128PMC
January 2021

Automated Contouring of Contrast and Noncontrast Computed Tomography Liver Images With Fully Convolutional Networks.

Adv Radiat Oncol 2021 Jan-Feb;6(1):100464. Epub 2020 May 16.

Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: The deformable nature of the liver can make focal treatment challenging and is not adequately addressed with simple rigid registration techniques. More advanced registration techniques can take deformations into account (eg, biomechanical modeling) but require segmentations of the whole liver for each scan, which is a time-intensive process. We hypothesize that fully convolutional networks can be used to rapidly and accurately autosegment the liver, removing the temporal bottleneck for biomechanical modeling.

Methods And Materials: Manual liver segmentations on computed tomography scans from 183 patients treated at our institution and 30 scans from the Medical Image Computing & Computer Assisted Intervention challenges were collected for this study. Three architectures were investigated for rapid automated segmentation of the liver (VGG-16, DeepLabv3 +, and a 3-dimensional UNet). Fifty-six cases were set aside as a final test set for quantitative model evaluation. Accuracy of the autosegmentations was assessed using Dice similarity coefficient and mean surface distance. Qualitative evaluation was also performed by 3 radiation oncologists on 50 independent cases with previously clinically treated liver contours.

Results: The mean (minimum-maximum) mean surface distance for the test groups with the final model, DeepLabv3 +, were as follows: μ: 0.99 mm (0.47-2.2), μ: 1.12 mm (0.41-2.87), and μ: 1.48 mm (0.82-3.96). The qualitative evaluation showed that 30 of 50 autosegmentations (60%) were preferred to manual contours (majority voting) in a blinded comparison, and 48 of 50 autosegmentations (96%) were deemed clinically acceptable by at least 1 reviewing physician.

Conclusions: The autosegmentations were preferred compared with manually defined contours in the majority of cases. The ability to rapidly segment the liver with high accuracy achieved in this investigation has the potential to enable the efficient integration of biomechanical model-based registration into a clinical workflow.
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http://dx.doi.org/10.1016/j.adro.2020.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807136PMC
May 2020

CT features predictive of nodal positivity at surgery in pancreatic cancer patients following neoadjuvant therapy in the setting of dual energy CT.

Abdom Radiol (NY) 2021 06 20;46(6):2620-2627. Epub 2021 Jan 20.

Department of Abdominal Radiology, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.

Purpose: Evaluate utility of dual energy CT iodine material density images to identify preoperatively nodal positivity in pancreatic cancer patients who underwent neoadjuvant therapy.

Methods: This IRB approved retrospective study evaluated 62 patients between 2012 and 2016 with proven pancreatic ductal adenocarcinoma, who underwent neoadjuvant therapy, tumor resection and both baseline and preoperative assessment with pancreatic multiphasic rapid switching dual energy CT. Three radiologists in consensus identified on imaging nodes > 0.5 cm in short axis, evaluated nodal morphology, size and on each phase density in HU, and concentrations on iodine material density images normalized to the aorta.

Results: Of 62 patients, 33 were N0, 20 N1, and 9 N2. Total of 145 lymph nodes were evaluated, with average number of nodes per anatomic site ranging from 1.3 (body tumors) to 5 (uncinate) versus average of 24 and 30 nodes recovered respectively at surgery. Most (N = 44) were pancreatic head tumors. For all patients, regardless of site of primary tumor, the minimum measured iodine value of all of a patient's measured nodes taken as a group on preoperative studies, as normalized to the aorta, was significant at P = 0.041 value in differentiating N0 from N1/2 and ROC analysis showed an AUC of 0.67. With a cutoff of 0.2857, sensitivity was 0.78 and specificity was 0.58, with values < 0.2857 indicative of N1/2. Node morphology and changes in nodal size weren't statistically significant.

Conclusion: The dual energy based minimum normalized iodine value of all nodes in the surgical field on preoperative studies has modest utility in differentiating N0 from N1/2, and generally outperformed conventional features for identifying nodal metastases.
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http://dx.doi.org/10.1007/s00261-020-02917-5DOI Listing
June 2021

A mathematical model for the quantification of a patient's sensitivity to checkpoint inhibitors and long-term tumour burden.

Nat Biomed Eng 2021 04 4;5(4):297-308. Epub 2021 Jan 4.

Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX, USA.

A large proportion of patients with cancer are unresponsive to treatment with immune checkpoint blockade and other immunotherapies. Here, we report a mathematical model of the time course of tumour responses to immune checkpoint inhibitors. The model takes into account intrinsic tumour growth rates, the rates of immune activation and of tumour-immune cell interactions, and the efficacy of immune-mediated tumour killing. For 124 patients, four cancer types and two immunotherapy agents, the model reliably described the immune responses and final tumour burden across all different cancers and drug combinations examined. In validation cohorts from four clinical trials of checkpoint inhibitors (with a total of 177 patients), the model accurately stratified the patients according to reduced or increased long-term tumour burden. We also provide model-derived quantitative measures of treatment sensitivity for specific drug-cancer combinations. The model can be used to predict responses to therapy and to quantify specific drug-cancer sensitivities in individual patients.
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http://dx.doi.org/10.1038/s41551-020-00662-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669771PMC
April 2021

Imaging-Based Subtypes of Pancreatic Ductal Adenocarcinoma Exhibit Differential Growth and Metabolic Patterns in the Pre-Diagnostic Period: Implications for Early Detection.

Front Oncol 2020 2;10:596931. Epub 2020 Dec 2.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Background: Previously, we characterized subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed-tomography (CT) scans, whereby conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we hypothesized that these imaging-based subtypes would exhibit different growth-rates and distinctive metabolic effects in the period prior to PDAC diagnosis.

Materials And Methods: Retrospectively, we evaluated 55 patients who developed PDAC as a second primary cancer and underwent serial pre-diagnostic (T0) and diagnostic (T1) CT-scans. We scored the PDAC tumors into high and low delta on T1 and, serially, obtained the biaxial measurements of the pancreatic lesions (T0-T1). We used the Gompertz-function to model the growth-kinetics and estimate the tumor growth-rate constant (α) which was used for tumor binary classification, followed by cross-validation of the classifier accuracy. We used maximum-likelihood estimation to estimate initiation-time from a single cell (10 mm) to a 10 mm tumor mass. Finally, we serially quantified the subcutaneous-abdominal-fat (SAF), visceral-abdominal-fat (VAF), and muscles volumes (cm) on CT-scans, and recorded the change in blood glucose (BG) levels. T-test, likelihood-ratio, Cox proportional-hazards, and Kaplan-Meier were used for statistical analysis and p-value <0.05 was considered significant.

Results: Compared to high delta tumors, low delta tumors had significantly slower average growth-rate constants (0.024 month vs. 0.088 month, p<0.0001) and longer average initiation-times (14 years vs. 5 years, p<0.0001). α demonstrated high accuracy (area under the curve (AUC)=0.85) in classifying the tumors into high and low delta, with an optimal cut-off of 0.034 month. Leave-one-out-cross-validation showed 80% accuracy in predicting the delta-class (AUC=0.84). High delta tumors exhibited accelerated SAF, VAF, and muscle wasting (p <0.001), and BG disturbance (p<0.01) compared to low delta tumors. Patients with low delta tumors had better PDAC-specific progression-free survival (log-rank, p<0.0001), earlier stage tumors (p=0.005), and higher likelihood to receive resection after PDAC diagnosis (p=0.008), compared to those with high delta tumors.

Conclusion: Imaging-based subtypes of PDAC exhibit distinct growth, metabolic, and clinical profiles during the pre-diagnostic period. Our results suggest that heterogeneous disease biology may be an important consideration in early detection strategies for PDAC.
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http://dx.doi.org/10.3389/fonc.2020.596931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738633PMC
December 2020

Predictive Modeling for Voxel-Based Quantification of Imaging-Based Subtypes of Pancreatic Ductal Adenocarcinoma (PDAC): A Multi-Institutional Study.

Cancers (Basel) 2020 Dec 5;12(12). Epub 2020 Dec 5.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Previously, we characterized qualitative imaging-based subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed tomography (CT) scans. Conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we developed a quantitative classification of this imaging-based subtype (quantitative delta; q-delta). Retrospectively, baseline pancreatic protocol CT scans of three cohorts (cohort#1 = 101, cohort#2 = 90 and cohort#3 = 16 [external validation]) of patients with PDAC were qualitatively classified into high and low delta. We used a voxel-based method to volumetrically quantify tumor enhancement while referencing normal-pancreatic-parenchyma and used machine learning-based analysis to build a predictive model. In addition, we quantified the stromal content using hematoxylin- and eosin-stained treatment-naïve PDAC sections. Analyses revealed that PDAC quantitative enhancement values are predictive of the qualitative delta scoring and were used to build a classification model (q-delta). Compared to high q-delta, low q-delta tumors were associated with improved outcomes, and the q-delta class was an independent prognostic factor for survival. In addition, low q-delta tumors had higher stromal content and lower cellularity compared to high q-delta tumors. Our results suggest that q-delta classification provides a clinically and biologically relevant tool that may be integrated into ongoing and future clinical trials.
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http://dx.doi.org/10.3390/cancers12123656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762105PMC
December 2020

Clinicopathological correlation of radiologic measurement of post-therapy tumor size and tumor volume for pancreatic ductal adenocarcinoma.

Pancreatology 2021 Jan 14;21(1):200-207. Epub 2020 Nov 14.

Department of Anatomical Pathology, University of Texas, MD Anderson Cancer Center, 515 Holcombe Blvd, Houston, TX, 77030, USA; Department of Translational Molecular Pathology, University of Texas MD, Anderson Cancer Center, 515 Holcombe Blvd, Houston, TX, 77030, USA. Electronic address:

Objectives: Tumor size measurement is critical for accurate tumor staging in patients with pancreatic ductal adenocarcinoma (PDAC). However, accurate tumor size measurement is challenging in patients who received neoadjuvant therapy before resection, due to treatment-induced fibrosis and tumor invasion beyond the grossly identified tumor area. In this study, we evaluated the correlation between the tumor size and tumor volume measured on post-therapy computed tomography (CT) scans and the pathological measurement. Also, we investigated the correlation between these measurements and clinicopathological parameters and survival.

Materials And Methods: Retrospectively, we evaluated 343 patients with PDAC who received neoadjuvant therapy, followed by pancreaticoduodenectomy and had pre-operative pancreatic protocol CT imaging. We measured the longest tumor diameter (RadL) and the radiological tumor volume (RadV) on the post-therapy CT scan, then we categorized RadL into four radiologic tumor stages (RTS) based on the current AJCC staging (8th edition) protocol and RadV based on the median. Pearson correlation or Spearman's coefficient (δ), T-test and ANOVA was used to test the correlation between the radiological and pathological measurement. Chi-square analysis was used to test the correlation with the tumor pathological response, lymph-node metastasis and margin status and Kaplan-Meier and Cox-proportional hazard for survival analysis. P-value < 0.05 was considered significant.

Results: As a continuous variable, RadL showed a positive linear correlation with the post-therapy pathologic tumor size in the overall patient population (Pearson correlation coefficient: 0.72, P < 0.001) and RadV (δ: 0.63, p < 0.0001). However, there was no correlation between RadL and pathologic tumor size in patients with ypT0 and those with pathologic tumor size of ≤1.0 cm. Post-therapy RTS and RadV group correlated with ypT stage, tumor response grades using either CAP or MDA grading system, distance of superior mesenteric artery margin and tumor recurrence/metastasis.

Conclusion: Although RadL tends to understage ypT in PDAC patients who had no radiologically detectable tumor or small tumors (RTS0 or RTS1), radiologic measurement of post-therapy tumor size may be used as a marker for the pathologic tumor staging and tumor response to neoadjuvant therapy.
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http://dx.doi.org/10.1016/j.pan.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855532PMC
January 2021
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