67 results on '"Colbert LE"'
Search Results
2. Protocol for culturing patient-derived organoids of cervical cancer.
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Wang R, Harris T, Negrón-Figueroa D, Lo D, Judge A, Walters D, Jiang B, and Colbert LE
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- Humans, Female, Culture Media, Conditioned, Tumor Cells, Cultured, Organoids cytology, Organoids pathology, Organoids metabolism, Uterine Cervical Neoplasms pathology, Cell Culture Techniques methods
- Abstract
Herein, we present a protocol for culturing patient-derived organoids (PDOs) of cervical cancer that includes workflows for tumor biopsy/resection tissue and cytobrush-sampled cells. We describe steps for PDO culture initiation, including rinsing, gentle dissociation, Lymphoprep separation, and cell assessment, as well as seeding cells from surgical and cytobrush tissue digestion. We then provide guidance on PDO maintenance and passage and techniques for producing conditioned medium. Overall, this protocol serves as a valuable guide for establishing and maintaining cervical cancer PDOs. For complete details on the use and execution of this protocol, please refer to Colbert et al.
1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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3. Genomic Biomarkers Predict Response to Combined ATR Inhibition and Radiotherapy.
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Schrank BR and Colbert LE
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- Humans, Biomarkers, Tumor genetics, Neoplasms genetics, Neoplasms radiotherapy, Neoplasms drug therapy, Animals, Genomics methods, Mice, Chemoradiotherapy methods, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Ataxia Telangiectasia Mutated Proteins genetics, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use
- Abstract
For decades, chemoradiosensitization with checkpoint kinase inhibitors has been proposed but largely unexplored. A recent study reports that the novel ataxia telangiectasia and Rad3-related kinase inhibitor RP-3500 synergizes with radiation to control Atm-/- tumors in vivo. RP-3500 did not radiosensitize wild-type or Brca-1-deficient tumors, highlighting the need for a genotype-tailored approach. See related article by Ng et al., p. 5643., (©2024 American Association for Cancer Research.)
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- 2024
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4. Human Papilloma Virus Circulating Cell-Free DNA Kinetics in Cervical Cancer Patients Undergoing Definitive Chemoradiation.
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Seo A, Xiao W, Gjyshi O, Yoshida-Court K, Wei P, Swanson D, Cisneros Napravnik T, Grippin A, Venkatesan AM, Jacobsen MC, Fuentes DT, Lynn E, Sammouri J, Jhingran A, Joyner M, Lin LL, Colbert LE, Gillison ML, and Klopp AH
- Abstract
Purpose: The human papillomavirus (HPV) is a significant cause of cervical cancer. We hypothesized that detecting viral cell-free HPV DNA (cfDNA) before, during, and after chemoradiation (chemoRT) could provide insights into disease extent, clinical staging, and treatment response., Experimental Design: Sixty-six patients with locally advanced cervical cancer were enrolled between 2017 and 2023. 49 received standard-of-care (SOC) treatment and 17 participated in a clinical trial combining a therapeutic HPV vaccine (PDS0101; IMMUNOCERV). Plasma was collected at baseline, weeks 1, 3, and 5 of chemoRT, and 3-4 months after chemoRT. HPV cfDNA was quantified using droplet digital PCR targeting the HPV E6/E7 oncogenes of 13 high-risk types. MRI was performed at baseline and before brachytherapy., Results: The median follow-up was 23 months, with recurrence-free survival (RFS) of 78.4% at 2 years. Baseline nodal disease extent correlated with HPV cfDNA levels. HPV cfDNA levels peaked in week 1 of radiation and decreased through treatment. Patients receiving the PDS0101 vaccine had a higher rate of undetectable HPV type 16 cfDNA compared to SOC. HPV cfDNA clearance correlated with better 2-yr RFS (92.9% vs. 30%, log-rank p=0.0067). The strongest predictor of RFS was HPV cfDNA clearance in follow-up achieving a concordance index (CI) 0.83, which improved when combined with MRI response (CI 0.88)., Conclusions: HPV cfDNA levels change dynamically during chemoRT. HPV cfDNA at follow-up predicts RFS. Delivery of therapeutic HPV vaccine with chemoRT was linked to rapid HPV cfDNA decline. Monitoring HPV cfDNA during and after chemoRT may guide tailoring of personalized treatment.
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- 2024
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5. Correction: Immune environment and antigen specificity of the T cell receptor repertoire of malignant ascites in ovarian cancer.
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Yoshida-Court K, Karpinets TV, Mitra A, Solley TN, Dorta-Estremera S, Sims TT, Delgado Medrano AY, Alam MBE, Ahmed-Kaddar M, Lynn EJ, Sastry KJ, Zhang J, Futreal A, Nick A, Lu K, Colbert LE, and Klopp AH
- Abstract
[This corrects the article DOI: 10.1371/journal.pone.0279590.]., (Copyright: © 2024 Yoshida-Court et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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6. Mechanisms by Which the Intratumoral Microbiome May Potentiate Immunotherapy Response.
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Negrón-Figueroa D and Colbert LE
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- Humans, Tumor Microenvironment immunology, Immunotherapy methods, Microbiota, Neoplasms immunology, Neoplasms therapy, Neoplasms microbiology
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- 2024
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7. Intratumoral microbiome of adenoid cystic carcinomas and comparison with other head and neck cancers.
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Karpinets TV, Mitani Y, Chang CC, Wu X, Song X, Flores II, McDaniel LK, Hoballah YM, Veguilla FJ, Ferrarotto R, Colbert LE, Ajami NJ, Jenq RR, Zhang J, Futreal AP, and El-Naggar AK
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- Humans, Female, Male, Middle Aged, Aged, Adult, Bacteria classification, Bacteria genetics, Bacteria isolation & purification, Carcinoma, Adenoid Cystic microbiology, Carcinoma, Adenoid Cystic pathology, Microbiota, Head and Neck Neoplasms microbiology, Head and Neck Neoplasms pathology, RNA, Ribosomal, 16S genetics
- Abstract
Adenoid cystic carcinoma (ACC) is a rare, usually slow-growing yet aggressive head and neck malignancy. Despite its clinical significance, our understanding of the cellular evolution and microenvironment in ACC remains limited. We investigated the intratumoral microbiomes of 50 ACC tumor tissues and 33 adjacent normal tissues using 16S rRNA gene sequencing. This allowed us to characterize the bacterial communities within the ACC and explore potential associations between the bacterial community structure, patient clinical characteristics, and tumor molecular features obtained through RNA sequencing. The bacterial composition in the ACC was significantly different from that in adjacent normal salivary tissue, and the ACC exhibited diverse levels of species richness. We identified two main microbial subtypes within the ACC: oral-like and gut-like. Oral-like microbiomes, characterized by increased diversity and abundance of Neisseria, Leptotrichia, Actinomyces, Streptococcus, Rothia, and Veillonella (commonly found in healthy oral cavities), were associated with a less aggressive ACC-II molecular subtype and improved patient outcomes. Notably, we identified the same oral genera in oral cancer and head and neck squamous cell carcinomas. In both cancers, they were part of shared oral communities associated with a more diverse microbiome, less aggressive tumor phenotype, and better survival that reveal the genera as potential pancancer biomarkers for favorable microbiomes in ACC and other head and neck cancers. Conversely, gut-like intratumoral microbiomes, which feature low diversity and colonization by gut mucus layer-degrading species, such as Bacteroides, Akkermansia, Blautia, Bifidobacterium, and Enterococcus, were associated with poorer outcomes. Elevated levels of Bacteroides thetaiotaomicron were independently associated with significantly worse survival and positively correlated with tumor cell biosynthesis of glycan-based cell membrane components., (© 2024. The Author(s).)
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- 2024
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8. Single-fraction radiation retreatment for bone metastases: role of a rapid access clinic.
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Kim M, Maldonado JA, Pandey P, El Alam MB, Kouzy R, Christopherson K, Minsky BD, Nugyen QN, Grosshans D, Lin LL, Mitchell MP, Klopp AH, Lee PP, Bird J, Satcher R, Lewis VO, Lin PP, Tang C, Koong AC, Moon B, and Colbert LE
- Abstract
Objectives: This study investigates retreatment rates in single-fraction radiation therapy (SFRT) for painful bone metastasis in patients with limited life expectancy. We compared retreatment-free survival (RFS) in patients from a rapid access bone metastases clinic (RABC) and non-RABC patients, identifying factors associated with retreatment., Methods: In this observational study, we analysed RABC patients who received SFRT between April 2018 and November 2019, using non-RABC SFRT patients as a comparison group. Patients with prior or perioperative radiation therapy (RT) were excluded. The primary endpoint was same-site and any-site retreatment with RT or surgery. Patient characteristics were compared using χ
2 and Student's t-tests, with RFS estimates based on a multistate model considering death as a competing risk using Aalen-Johansen estimates., Results: We identified 151 patients (79 RABC, 72 non-RABC) with 225 treatments (102 RABC, 123 non-RABC) meeting eligibility criteria. Of the 22 (10.8%) same-site retreatments, 5 (22.7%) received surgery, 14 (63.6%) received RT and 3 (13.6%) received both RT and surgery. We found no significant differences in any-site RFS (p=0.97) or same-site RFS (p=0.11)., Conclusions: RFS is high and similar comparable in the RABC and non-RABC cohorts. Retreatment rates are low, even in patients with low Eastern Cooperative Oncology Group scores., Competing Interests: Competing interests: PPLee reports personal fees and non-financial support from Viewray, Inc., grants, personal fees and non-financial support from AstraZeneca, Inc., personal fees and non-financial support from Varian, Inc, outside the submitted work. PPLin reports book royalties from Springer Nature, outside the submitted work., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2024
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9. Exploratory analysis of the cervix tumoral HPV antigen-specific T-cell repertoire during chemoradiation and after brachytherapy.
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Manzar GS, Alam MBE, Lynn EJ, Karpinets TV, Harris T, Lo D, Yoshida-Court K, Napravnik TC, Sammouri J, Lin D, Andring LM, Bronk J, Wu X, Sims TT, Mathew G, Schmeler KM, Eifel PJ, Jhingran A, Lin LL, Joyner MM, Zhang J, Futreal A, Klopp AH, and Colbert LE
- Subjects
- Female, Humans, Cervix Uteri, T-Lymphocytes, Prospective Studies, Neoplasm Recurrence, Local, Receptors, Antigen, T-Cell, Tumor Microenvironment, Uterine Cervical Neoplasms radiotherapy, Papillomavirus Infections complications, Brachytherapy methods
- Abstract
Background: Chemoradiation (CRT) may modulate the immune milieu as an in-situ vaccine. Rapid dose delivery of brachytherapy has unclear impact on T-cell repertoires. HPV-associated cancers express viral oncoproteins E6/E7, which enable tracking antigen/tumor-specific immunity during CRT., Methods: Thirteen cervical cancer patients on a multi-institutional prospective protocol from 1/2020-1/2023 underwent standard-of-care CRT with pulsed-dose-rate brachytherapy boost (2 fractions). Cervix swabs at various timepoints underwent multiplex DNA deep sequencing of the TCR-β/CDR3 region with immunoSEQ. Separately, HPV-responsive T-cell clones were also expanded ex vivo. Statistical analysis was via Mann-Whitney-U., Results: TCR productive clonality, templates, frequency, or rearrangements increased post-brachytherapy in 8 patients. Seven patients had E6/E7-responsive evolution over CRT with increased productive templates (ranges: 1.2-50.2 fold-increase from baseline), frequency (1.2-1.7), rearrangements (1.2-40.2), and clonality (1.2-15.4). Five patients had HPV-responsive clonal expansion post-brachytherapy, without changes in HPV non-responsive clones. Epitope mapping revealed VDJ rearrangements targeting cervical cancer-associated antigens in 5 patients. The only two patients with disease recurrence lacked response in all metrics. A lack of global TCR remodeling correlated with worse recurrence-free survival, p = 0.04., Conclusion: CRT and brachytherapy alters the cervical cancer microenvironment to facilitate the expansion of specific T-cell populations, which may contribute to treatment efficacy., (Copyright © 2023 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)
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- 2024
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10. Comparing long-term sexual dysfunction across different uterine cancer treatment modalities.
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Yoder AK, Lakomy DS, Wu J, Andring LM, Corrigan KL, Fellman B, Jhingran A, Klopp AH, Colbert LE, Soliman PT, Frumovitz MM, Peterson SK, and Lin LL
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- Humans, Female, Hot Flashes radiotherapy, Hot Flashes etiology, Cross-Sectional Studies, Brachytherapy methods, Uterine Neoplasms radiotherapy, Sexual Dysfunction, Physiological etiology
- Abstract
Introduction: The objective of this study was to assess differences in long-term sexual and menopausal side effects after uterine cancer treatment among treatment modalities., Methods and Materials: This is a cross-sectional study that examined women treated for uterine cancer from 2006-2018. Eligible women included those who underwent a hysterectomy/bilateral salpino-oophorectemy alone (HS), with brachytherapy (BT), or with external beam radiation therapy (EBRT). A noncancer cohort of women who underwent a hysterectomy/BSO for benign indications were also identified (non-CA). To compare outcomes, we utilized a shortened form of the female sexual function index (FSFI) and the menopause survey, which consists of 3 subscales: hot flashes, vaginal symptoms, and urinary symptoms. Demographic, comorbidity, and other treatment variables were collected. Survey totals were compared across cohorts using ANOVA tests and logistic regression., Results: A total of 284 women completed the Menopause Survey (Non-CA 64, HS 60, BT 69, EBRT 91); 116 women reported sexual activity in the last 4 weeks and completed the FSFI (NC 32, HS 21, BT 31, EBRT 32). The mean FSFI score for the entire cohort was 11.4 (SD 4.16), which indicates poor sexual function. There was no significant difference between any cohort in the overall FSFI score (p = 0.708) or in any of the FSFI subscales (all p > 0.05). On univariate analysis, BT was associated with fewer menopausal hot flashes and vaginal symptoms compared to the non-CA cohort (p < 0.05), which did not persist on multivariable analysis., Conclusion: There was no significant difference in sexual dysfunction or menopausal symptoms in those treated for uterine cancer with or without adjuvant radiation. Most patients reported poor sexual function., (Copyright © 2023 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)
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- 2024
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11. Management and long-term clinical outcomes of patients with stage IVA cervical cancer with bladder involvement.
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Sammouri J, Venkatesan AM, Lin LL, Jhingran A, Klopp AH, Joyner MM, Eifel PJ, and Colbert LE
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- Female, Humans, Urinary Bladder, Pelvis, Retrospective Studies, Uterine Cervical Neoplasms radiotherapy, Uterine Cervical Neoplasms etiology, Brachytherapy adverse effects
- Abstract
Objective: To describe the long-term outcomes of patients with stage IVA cervical cancer, a rare and deadly disease for which long-term toxicity data are scarce, to guide clinician counseling and survivorship support., Methods: In a retrospective review of a prospectively maintained database, we identified 76 patients with stage IVA cervical cancer with biopsy- or MRI-proven bladder mucosal involvement who received definitive radiotherapy (external beam radiotherapy [EBRT] alone or EBRT plus brachytherapy) with or without chemotherapy at our institution between 2000 and 2020. We used Kaplan-Meier modeling to estimate recurrence-free survival (RFS) and overall survival (OS) and used proportional hazard modeling to identify clinical variables associated with recurrence or survival. We performed actuarial competing risk modeling for severe late toxicity (grades 3 to 5, occurring >6 months of follow-up) and vesicovaginal fistulae (VVF), censoring for pelvic recurrence and death, and made comparisons between potential predictors using Gray's test and binary logistic regression., Results: The median follow-up time was 76 months (interquartile range 58-91). The median OS duration was 35 months (range, 18-not reached), and the 2- and 5-year OS rates were 53.6% and 40.9%, respectively. OS and RFS did not differ significantly between patients who received EBRT alone (N = 18) or EBRT plus brachytherapy (N = 49). Current smoking was a strong predictor of severe late toxicity, whose incidence was 14% at 2 years and 17% at 10 years. The VVF incidence was 24% at 2 years and 32% at 10 years., Conclusion: Patients with stage IVA cervical cancer, even those who receive EBRT alone, can have long-term survival. These patients should be followed closely for late radiation-related toxicity., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)
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- 2024
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12. Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial.
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Taniguchi CM, Frakes JM, Aguilera TA, Palta M, Czito B, Bhutani MS, Colbert LE, Abi Jaoude J, Bernard V, Pant S, Tzeng CD, Kim DW, Malafa M, Costello J, Mathew G, Rebueno N, Koay EJ, Das P, Ludmir EB, Katz MHG, Wolff RA, Beddar S, Sawakuchi GO, Moningi S, Slack Tidwell RS, Yuan Y, Thall PF, Beardsley RA, Holmlund J, Herman JM, and Hoffe SE
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- Humans, Male, Female, Aged, Bayes Theorem, Double-Blind Method, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Adenocarcinoma radiotherapy, Adenocarcinoma drug therapy, Pancreatic Neoplasms radiotherapy, Pancreatic Neoplasms drug therapy, Radiosurgery adverse effects, Carcinoma, Pancreatic Ductal radiotherapy, Carcinoma, Pancreatic Ductal drug therapy
- Abstract
Background: Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma., Methods: In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete., Findings: Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT., Interpretation: SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results., Funding: Galera Therapeutics., Competing Interests: Declaration of interests CMT reports grant or contracts with US National Institutes of Health (NIH and CPRIT), licenses with Xerient Pharmaceuticals for licensed or individual patent for radioprotection of the upper gastrointestinal tract, and consulting fees with Phebry. JMF reports consultant and advisory board roles for Viewray, and payment for presentations for Boston Scientific. TAA reports an unfunded study steering committee role for Galera Therapeutics (Galera). MP reports research support to their institution from Merck and Varian, royalties to serve as section editor for cholangiocarcinoma, consulting fees from Voxelmetric and Syntactx, a speakers honorarium for Oakstone CME, advisory board participation for Varian, and an unpaid ASTRO Education Committee role. BC reports royalties from Springer, honoraria for Varian-Educational and Oakstone, and a leadership or fiduciary role with the National Comprehensive Cancer Network. MSB reports funding from Galera, institution grants or contracts from Nanobiotix, Silenseed, Trisalis, Artidis, SUC2, CPRIT, AstraZeneca, Merck, Siemens Medical, and Boston Scientific (Augmenix) and consulting fees from Oncosil and Strapax. SP reports consulting or advisory roles for Zymeworks, Ipsen, Novartis, Janssen, Boehringer Ingelheim, and AskGene Pharma, and institutional research funding from Mirati Therapeutics, Lilly, Xencor, Novartis, Rgenix, Bristol-Myers Squibb, Astellas Pharma, Framewave, 4D Pharma, Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Biosciences, Elicio Therapeutics, Bionte, Ipsen, Zymeworks, Pfizer, ImmunoMET, Immuneering, and Amal Therapeutics. C-WDT reports an institution-sponsored research agreement with Sirtex, and individual and institutional honoraria from PanTher. DWK reports grants or contracts from Bold Therapeutics, and payment or honoraria from AstraZeneca. JC reports travel expense money from Galera. EJK reports research grants and contracts from NIH, US Department of Defense, Cancer Prevention and Research Institute of Texas, and Artidis, royalties or licenses from Taylor and Francis, and Kallisio, consulting fees from Kallisio, AstraZeneca, RenovoRx, MD Anderson Physician Network, MJH Life Sciences, and Quantum Aurea Capital, honoraria from Northwestern University and Amplity, a patent pending for 3D oral stents, scientific and medical advisory board roles for Cholangiocarcinoma Foundation, and stock or stock options with Quantum Aurea Capital. PD reports consulting fees from the American Society for Radiation Oncology, payment or honoraria from American Society for Clinical Oncology, Conveners, Physicians Education Resource, Imedex, and Bayer. RAW reports royalties from McGraw-Hill. GOS reports a research agreement with Artios Pharma. RSST reports institutional funding from Galera and NIH National Cancer Institute (NCI). YY reports personal fees from AbbVie, Amgen, Bexion Pharmaceuticals, BeyondSpring Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Bristol Myers Squibb, Century Therapeutics, Enliven Therapeutics, Repare Therapeutics, Servier Pharmaceuticals, Starpax Pharmaceuticals, and Vertex Pharmaceuticals during the conduct of the study. PFT reports research funding from NIH NCI. RAB is an employee and officer of, reports receiving compensation from, and holds equity in the sponsor, Galera, residual royalties resulting from the acquisition of Confluence from Aclaris Therapeutics, stock or stock options with Galera, Euclises, Aclaris Therapeutics, and Novocure, and patents for methods for treatment of diseases, (US Pat 10,493,081, 2019 issued to Galera); a patent methods for treatment of diseases (US Pat 9,149,483, 2015 issued to Galera). JH was an employee and officer of, reports receiving compensation from, and holds equity in the sponsor, Galera. JMH reports research funding to their institution and support for attending a meeting from Canopy Cancer Collective, royalties or licenses from Springer, stock or stock options with Histosonics, and consulting fees from Histosonics and Boston Scientific. SEH is an employee of MyCareGorithm and has her own limited liability company, Beyond the White Coat. She has received travel assistance from ViewRay, stock options from Rittenhouse, and her institution received research funding from ViewRay and Galera. LEC, JAJ, VB, MM, GM, NR, EBL, MHGK, SB, and SM declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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13. Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.
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Colbert LE, El Alam MB, Wang R, Karpinets T, Lo D, Lynn EJ, Harris TA, Elnaggar JH, Yoshida-Court K, Tomasic K, Bronk JK, Sammouri J, Yanamandra AV, Olvera AV, Carlin LG, Sims T, Delgado Medrano AY, Napravnik TC, O'Hara M, Lin D, Abana CO, Li HX, Eifel PJ, Jhingran A, Joyner M, Lin L, Ramondetta LM, Futreal AM, Schmeler KM, Mathew G, Dorta-Estremera S, Zhang J, Wu X, Ajami NJ, Wong M, Taniguchi C, Petrosino JF, Sastry KJ, Okhuysen PC, Martinez SA, Tan L, Mahmud I, Lorenzi PL, Wargo JA, and Klopp AH
- Subjects
- Female, Humans, Lactic Acid metabolism, Lactobacillus genetics, Lactobacillus metabolism, Tumor Microenvironment, Uterine Cervical Neoplasms radiotherapy, Microbiota
- Abstract
Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types., Competing Interests: Declaration of interests L.E.C. reports grants from American Society for Clinical Oncology, Radiology Society of North America, National Institutes of Health, and MD Anderson Cancer Center during the conduct of the study. A.J. reports personal fees from Genentech during the conduct of the study, as well as personal fees from Genentech outside the submitted work. L.L. reports other support from AstraZeneca and Pfizer, and grants from NCI outside the submitted work. J.A.W. reports other support from Micronoma during the conduct of the study, as well as other support from Imedex, Dava Oncology, Illumina, and PeerView outside the submitted work. P.O. reports Faculty grant/research support from Merck Sharp and Dohme Corp, Deinove Pharmaceuticals, Summit Pharmaceuticals, Melinta Pharmaceuticals, and Napo Pharmaceutical, in addition to consultant work with Napo Pharmaceutical, Ferring Pharmaceutical, Summit Pharmaceutical, and SNIPR Biome Company, all outside of the submitted work., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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14. Serial Genotyping of the Human Papillomavirus in Cervical Cancer: An Insight Into Virome Dynamics During Chemoradiation Therapy.
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Sammouri J, Wong MC, Lynn EJ, El Alam MB, Lo DK, Lin D, Harris TH, Karpinets TV, Court K, Napravnik TC, Wu X, Zhang J, Klopp AH, Ajami NJ, and Colbert LE
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- Humans, Female, Human Papillomavirus Viruses, Prospective Studies, Genotype, Virome, Papillomaviridae genetics, DNA, Viral analysis, Uterine Cervical Neoplasms pathology, Papillomavirus Infections complications
- Abstract
Purpose: Human papillomavirus (HPV) is the primary driver of cervical cancer. Although studies in other malignancies correlated peripheral blood DNA clearance with favorable outcomes, research on the prognostic value of HPV clearance in gynecologic cancers using intratumoral HPV is scarce. We aimed to quantify the intratumoral HPV virome in patients undergoing chemoradiation therapy (CRT) and associate this with clinical characteristics and outcomes., Methods and Materials: This prospective study enrolled 79 patients with stage IB-IVB cervical cancer undergoing definitive CRT. Cervical tumor swabs collected at baseline and week 5 (end of intensity modulated radiation therapy) were sent for shotgun metagenome sequencing and processed via VirMAP, a viral genome sequencing and identification tool for all known HPV types. The data were categorized into HPV groups (16, 18, high risk [HR], and low risk [LR]). We used independent t tests and Wilcoxon signed-rank to compare continuous variables and χ
2 and Fisher exact tests to compare categorical variables. Kaplan-Meier survival modeling was performed with log-rank testing. HPV genotyping was verified using quantitative polymerase chain reaction to validate VirMAP results using receiver operating characteristic curve and Cohen's kappa., Results: At baseline, 42%, 12%, 25%, and 16% of patients were positive for HPV 16, HPV 18, HPV HR, and HPV LR, respectively, and 8% were HPV negative. HPV type was associated with insurance status and CRT response. Patients with HPV 16+ and other HPV HR+ tumors were significantly more likely to have a complete response to CRT versus patients with HPV 18 and HPV LR/HPV-negative tumors. Overall HPV viral loads predominantly decreased throughout CRT, except for HPV LR viral load., Conclusions: Rarer, less well-studied HPV types in cervical tumors are clinically significant. HPV 18 and HPV LR/negative tumors are associated with poor CRT response. This feasibility study provides a framework for a larger study of intratumoral HPV profiling to predict outcomes in patients with cervical cancer., (Copyright © 2023. Published by Elsevier Inc.)- Published
- 2023
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15. HPV-related anal cancer is associated with changes in the anorectal microbiome during cancer development.
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Elnaggar JH, Huynh VO, Lin D, Hillman RT, Abana CO, El Alam MB, Tomasic KC, Karpinets TV, Kouzy R, Phan JL, Wargo J, Holliday EB, Das P, Mezzari MP, Ajami NJ, Lynn EJ, Minsky BD, Morris VK, Milbourne A, Messick CA, Klopp AH, Futreal PA, Taniguchi CM, Schmeler KM, and Colbert LE
- Subjects
- Humans, Female, Prospective Studies, Cross-Sectional Studies, Tumor Microenvironment, Papillomavirus Infections, Anus Neoplasms, Carcinoma, Squamous Cell complications, Microbiota
- Abstract
Background: Squamous cell carcinoma of the anus (SCCA) is a rare gastrointestinal cancer. Factors associated with progression of HPV infection to anal dysplasia and cancer are unclear and screening guidelines and approaches for anal dysplasia are less clear than for cervical dysplasia. One potential contributing factor is the anorectal microbiome. In this study, we aimed to identify differences in anal microbiome composition in the settings of HPV infection, anal dysplasia, and anal cancer in this rare disease., Methods: Patients were enrolled in two prospective studies. Patients with anal dysplasia were part of a cross-sectional cohort that enrolled women with high-grade lower genital tract dysplasia. Anorectal tumor swabs were prospectively collected from patients with biopsy-confirmed locally advanced SCCA prior to receiving standard-of-care chemoradiotherapy (CRT). Patients with high-grade lower genital tract dysplasia without anal dysplasia were considered high-risk (HR Normal). 16S V4 rRNA Microbiome sequencing was performed for anal swabs. Alpha and Beta Diversity and composition were compared for HR Normal, anal dysplasia, and anal cancer., Results: 60 patients with high-grade lower genital tract dysplasia were initially enrolled. Seven patients had concurrent anal dysplasia and 44 patients were considered HR Normal. Anorectal swabs from 21 patients with localized SCCA were included, sequenced, and analyzed in the study. Analysis of weighted and unweighted UniFrac distances demonstrated significant differences in microbial community composition between anal cancer and HR normal (p = 0.018). LEfSe identified that all three groups exhibited differential enrichment of specific taxa. Peptoniphilus (p=0.028), Fusobacteria (p=0.0295) , Porphyromonas (p=0.034) , and Prevotella (p=0.029) were enriched in anal cancer specimens when compared to HR normal., Conclusion: Although alpha diversity was similar between HR Normal, dysplasia and cancer patients, composition differed significantly between the three groups. Increased anorectal Peptoniphilus, Fusobacteria , Porphyromonas , and Prevotella abundance were associated with anal cancer. These organisms have been reported in various gastrointestinal cancers with roles in facilitating the proinflammatory microenvironment and neoplasia progression. Future work should investigate a potential role of microbiome analysis in screening for anal dysplasia and investigation into potential mechanisms of how these microbial imbalances influence the immune system and anal carcinogenesis., Competing Interests: CT is on the clinical advisory board of Accuracy, has a patent for oral amifostine as a radioprotectant of the upper gastrointestinal tract issued, licensed, and with royalties paid from Xerient Pharmaceuticals and a pending patent for prolyl hydroxylase inhibitors as a radioprotectant of the gastrointestinal tract, was the lead principal investigator of a multicenter trial testing the effects of high-dose stereotactic body radiation therapy with the radiomodulator, GC4419, and is a paid consultant for Phebra Pty, Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elnaggar, Huynh, Lin, Hillman, Abana, El Alam, Tomasic, Karpinets, Kouzy, Phan, Wargo, Holliday, Das, Mezzari, Ajami, Lynn, Minsky, Morris, Milbourne, Messick, Klopp, Futreal, Taniguchi, Schmeler and Colbert.)
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- 2023
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16. Cervicovaginal Microbiota Profiles in Precancerous Lesions and Cervical Cancer among Ethiopian Women.
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Teka B, Yoshida-Court K, Firdawoke E, Chanyalew Z, Gizaw M, Addissie A, Mihret A, Colbert LE, Napravnik TC, El Alam MB, Lynn EJ, Mezzari M, Anuja J, Kantelhardt EJ, Kaufmann AM, Klopp AH, and Abebe T
- Abstract
Although high-risk human papillomavirus infection is a well-established risk factor for cervical cancer, other co-factors within the local microenvironment may play an important role in the development of cervical cancer. The current study aimed to characterize the cervicovaginal microbiota in women with premalignant dysplasia or invasive cervical cancer compared with that of healthy women. The study comprised 120 Ethiopian women (60 cervical cancer patients who had not received any treatment, 25 patients with premalignant dysplasia, and 35 healthy women). Cervicovaginal specimens were collected using either an Isohelix DNA buccal swab or an Evalyn brush, and ribosomal RNA sequencing was used to characterize the cervicovaginal microbiota. Shannon and Simpson diversity indices were used to evaluate alpha diversity. Beta diversity was examined using principal coordinate analysis of weighted UniFrac distances. Alpha diversity was significantly higher in patients with cervical cancer than in patients with dysplasia and in healthy women ( p < 0.01). Beta diversity was also significantly different in cervical cancer patients compared with the other groups (weighted UniFrac Bray-Curtis, p < 0.01). Microbiota composition differed between the dysplasia and cervical cancer groups. Lactobacillus iners was particularly enriched in patients with cancer, and a high relative abundance of Lactobacillus species was identified in the dysplasia and healthy groups, whereas Porphyromonas , Prevotella , Bacteroides , and Anaerococcus species predominated in the cervical cancer group. In summary, we identified differences in cervicovaginal microbiota diversity, composition, and relative abundance between women with cervical cancer, women with dysplasia, and healthy women. Additional studies need to be carried out in Ethiopia and other regions to control for variation in sample collection.
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- 2023
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17. Impact of Treatment Modality on Quality of Life Among Uterine Cancer Survivors.
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Yoder AK, Lakomy DS, Wu J, Andring LM, Fellman B, Colbert LE, Jhingran A, Klopp AH, Soliman P, Peterson SK, and Lin LL
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- Humans, Female, Quality of Life, Cross-Sectional Studies, Radiotherapy, Adjuvant, Neoplasm Staging, Cancer Survivors, Uterine Neoplasms radiotherapy, Uterine Neoplasms pathology, Endometrial Neoplasms radiotherapy, Endometrial Neoplasms surgery, Brachytherapy
- Abstract
Aims: Our understanding of the impact of adjuvant therapy on longitudinal quality of life (QoL) following surgery for patients with uterine cancer is limited. The purpose of this study was to compare QoL in patients who have undergone surgery with or without radiation therapy for uterine cancer., Materials and Methods: This was a cross-sectional cohort study that examined women treated for uterine cancer at MD Anderson Cancer Center from 2006 to 2017. Participants included those who underwent hysterectomy/bilateral salphingo-oophorectomy alone, with brachytherapy or external beam radiation therapy (EBRT). A non-cancer cohort of women who underwent a hysterectomy/bilateral salphingo-oophorectomy for benign indications was also identified (non-CA). To compare QoL we used the Functional Assessment of Cancer Therapy - Endometrial survey (FACT-En), a validated survey used to assess QoL. The survey has five subscales: physical, social, emotional, functional and an endometrial cancer-specific subscale. Cohorts were compared using ANOVA tests., Results: In total, 309 women responded to the questionnaire (hysterectomy/bilateral salphingo-oophorectomy 64, brachytherapy 77, EBRT 96, non-CA 72). The median time from surgery to survey completion was 6.7 years. The mean total FACT-En score for the entire cohort was 144 [standard deviation 22]. Overall QoL was different between cohorts, with the EBRT cohort reporting the lowest QoL (mean 139.4 [21.6]) and the brachytherapy cohort the highest (150.6 [18.2], P = 0.006). Among patients who had undergone cancer treatment, the EBRT cohort reported the worst endometrial-specific QoL (53.5 [8.6]), while again the brachytherapy group reported the highest score (57.5 [6.1], P = 0.007)., Conclusions: QoL differences in women who have undergone different treatments for uterine cancer may persist years after treatment. In women with endometrial cancer who require adjuvant therapy, brachytherapy does not appear to have any long-term detriments on QoL., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)
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- 2023
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18. Circulating neutrophils and tumor-associated myeloid cells function as a powerful biomarker for response to chemoradiation in locally advanced cervical cancer.
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Gjyshi O, Grippin A, Andring L, Jhingran A, Lin LL, Bronk J, Eifel PJ, Joyner MM, Sastry JK, Yoshida-Court K, Solley TN, Napravnik TC, O'Hara MP, Hegde VL, Colbert LE, and Klopp AH
- Abstract
Purpose: The immune system's role in mediating the cytotoxic effects of chemoradiotherapy remains not completely understood. The integration of immunotherapies into treatment will require insight into features and timing of the immune microenvironment associated with treatment response. Here, we investigated the role of circulating neutrophils and tumor-associated myeloid cells (TSAMs) as potential agents and biomarkers for disease-related outcomes in locally advanced cervical cancer (LACC)., Material and Methods: Hematologic parameters for two LACC patient cohorts, a retrospective clinical and a prospective translational cohort, were obtained at baseline, weekly during chemoradiotherapy for the retrospective cohort, biweekly during chemoradiotherapy for the prospective cohort, and at the first follow-up visit for both cohorts (mean 14.7 weeks, range 8.1-25.1 weeks for the prospective cohort and 5.3 weeks with a range of 2.7-9.0 weeks for the retrospective cohort). In both cohorts, baseline as well as mean and lowest on-treatment values for platelets, hemoglobin, absolute neutrophil count (ANC), and absolute lymphocyte count (ALC) were analyzed for correlations with disease-related outcomes. In the prospective cohort, circulating myeloid cells were isolated from peripheral blood mononuclear cells (PBMCs), and TSAMs were isolated from tumor tissue via a novel serial cytobrush sampling assay. The samples were analyzed by flow cytometry., Results: In both cohorts, the only hematologic parameter significantly associated with survival was elevated on-treatment mean ANC (mANC), which was associated with lower local failure-free and overall survival rates in the retrospective and prospective cohorts, respectively. mANC was not associated with a difference in distant metastases. CD11b
+ CD11c- TSAMs, which act as a surrogate marker for intratumoral neutrophils, steadily decreased during the course of chemoRT and nadier'd at week 5 of treatment. Conversely, circulating myeloid cells identified from PBMCs steadily increased through week 5 of treatment. Regression analysis confirmed an inverse relationship between circulating myeloid cells and TSAMs at this time point., Conclusions: These findings identify on-treatment mean neutrophil count as a predictor of disease-related outcomes, suggest that neutrophils contribute to chemoradiation treatment resistance, and demonstrate the importance of techniques to measure intratumoral immune activity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)- Published
- 2023
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19. Immune environment and antigen specificity of the T cell receptor repertoire of malignant ascites in ovarian cancer.
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Yoshida-Court K, Karpinets TV, Mitra A, Solley TN, Dorta-Estremera S, Sims TT, Delgado Medrano AY, El Alam MB, Ahmed-Kaddar M, Lynn EJ, Sastry KJ, Zhang J, Futreal A, Nick A, Lu K, Colbert LE, and Klopp AH
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- Humans, Female, Carcinoma, Ovarian Epithelial metabolism, Receptors, Antigen, T-Cell, CD8-Positive T-Lymphocytes, Immunity, Ascites metabolism, Ovarian Neoplasms metabolism
- Abstract
We evaluated the association of disease outcome with T cell immune-related characteristics and T cell receptor (TCR) repertoire in malignant ascites from patients with high-grade epithelial ovarian cancer. Ascitic fluid samples were collected from 47 high-grade epithelial ovarian cancer patients and analyzed using flow cytometry and TCR sequencing to characterize the complementarity determining region 3 TCR β-chain. TCR functions were analyzed using the McPAS-TCR and VDJ databases. TCR clustering was implemented using Grouping of Lymphocyte Interactions by Paratope Hotspots software. Patients with poor prognosis had ascites characterized by an increased ratio of CD8+ T cells to regulatory T cells, which correlated with an increased productive frequency of the top 100 clones and decreased productive entropy. TCRs enriched in patients with an excellent or good prognosis were more likely to recognize cancer antigens and contained more TCR reads predicted to recognize epithelial ovarian cancer antigens. In addition, a TCR motif that is predicted to bind the TP53 neoantigen was identified, and this motif was enriched in patients with an excellent or good prognosis. Ascitic fluid in high-grade epithelial ovarian cancer patients with an excellent or good prognosis is enriched with TCRs that may recognize ovarian cancer-specific neoantigens, including mutated TP53 and TEAD1. These results suggest that an effective antigen-specific immune response in ascites is vital for a good outcome in high-grade epithelial ovarian cancer., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yoshida-Court et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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20. An Automated Treatment Planning Framework for Spinal Radiation Therapy and Vertebral-Level Second Check.
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Netherton TJ, Nguyen C, Cardenas CE, Chung C, Klopp AH, Colbert LE, Rhee DJ, Peterson CB, Howell R, Balter P, and Court LE
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- Automation, Humans, Retrospective Studies, Spine diagnostic imaging, Radiotherapy Planning, Computer-Assisted methods, Tomography, X-Ray Computed methods
- Abstract
Purpose: Complicating factors such as time pressures, anatomic variants in the spine, and similarities in adjacent vertebrae are associated with incorrect level treatments of the spine. The purpose of this work was to mitigate such challenges by fully automating the treatment planning process for diagnostic and simulation computed tomography (CT) scans., Methods and Materials: Vertebral bodies are labeled on CT scans of any length using 2 intendent deep-learning models-mirroring 2 different experts labeling the spine. Then, a U-Net++ architecture was trained, validated, and tested to contour each vertebra (n = 220 CT scans). Features from the CT and auto-contours were input into a random forest classifier to predict whether vertebrae were correctly labeled. This classifier was trained using auto-contours from cone beam computed tomography, positron emission tomography/CT, simulation CT, and diagnostic CT images (n = 56 CT scans, 751 contours). Auto-plans were generated via scripting. Each model was combined into a framework to make a fully automated clinical tool. A retrospective planning study was conducted in which 3 radiation oncologists scored auto-plan quality on an unseen patient cohort (n = 60) on a 5-point scale. CT scans varied in scan length, presence of surgical implants, imaging protocol, and metastatic burden., Results: The results showed that the uniquely designed convolutional neural networks accurately labeled and segmented vertebral bodies C1-L5 regardless of imaging protocol or metastatic burden. Mean dice-similarity coefficient was 85.0% (cervical), 90.3% (thoracic), and 93.7% (lumbar). The random forest classifier predicted mislabeling across various CT scan types with an area under the curve of 0.82. All contouring and labeling errors within treatment regions (11 of 11), including errors from patient plans with atypical anatomy (eg, T13, L6) were detected. Radiation oncologists scored 98% of simulation CT-based plans and 92% of diagnostic CT-based plans as clinically acceptable or needing minor edits for patients with typical anatomy. On average, end-to-end treatment planning time of the clinical tool was less than 8 minutes., Conclusions: This novel method to automatically verify, contour, and plan palliative spine treatments is efficient and effective across various CT scan types. Furthermore, it is the first to create a clinical tool that can automatically verify vertebral level in CT images., (Published by Elsevier Inc.)
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- 2022
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21. Feasibility of a novel non-invasive swab technique for serial whole-exome sequencing of cervical tumors during chemoradiation therapy.
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Bronk JK, Kapadia C, Wu X, Chapman BV, Wang R, Karpinets TV, Song X, Futreal AM, Zhang J, Klopp AH, and Colbert LE
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- Feasibility Studies, Female, High-Throughput Nucleotide Sequencing methods, Humans, Mutation, Exome Sequencing, Exome, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms therapy
- Abstract
Background: Clinically relevant genetic predictors of radiation response for cervical cancer are understudied due to the morbidity of repeat invasive biopsies required to obtain genetic material. Thus, we aimed to demonstrate the feasibility of a novel noninvasive cervical swab technique to (1) collect tumor DNA with adequate throughput to (2) perform whole-exome sequencing (WES) at serial time points over the course of chemoradiation therapy (CRT)., Methods: Cervical cancer tumor samples from patients undergoing chemoradiation were collected at baseline, at week 1, week 3, and at the completion of CRT (week 5) using a noninvasive swab-based biopsy technique. Swab samples were analyzed with whole-exome sequencing (WES) with mutation calling using a custom pipeline optimized for shallow whole-exome sequencing with low tumor purity (TP). Tumor mutation changes over the course of treatment were profiled., Results: 216 samples were collected and successfully sequenced for 70 patients (94% of total number of tumor samples collected). A total of 33 patients had a complete set of samples at all four time points. The mean mapping rate was 98% for all samples, and the mean target coverage was 180. Estimated TP was greater than 5% for all samples. Overall mutation frequency decreased during CRT but mapping rate and mean target coverage remained at >98% and >180 reads at week 5., Conclusion: This study demonstrates the feasibility and application of a noninvasive swab-based technique for WES analysis which may be applied to investigate dynamic tumor mutational changes during treatment to identify novel genes which confer radiation resistance., Competing Interests: The authors have declared that no competing interests exist.
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- 2022
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22. Longitudinal Changes in Bone Mineral Measurements Inside and Outside Radiation Fields Used for Cervical Cancer Treatment.
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Wu J, Lakomy DS, Fellman BM, Salcedo MP, Sood AK, Jhingran A, Klopp AH, Iyer RB, Jimenez C, Colbert LE, Eifel PJ, Schmeler KM, and Lin LL
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- Absorptiometry, Photon methods, Adult, Aged, Aged, 80 and over, Bone Density, Female, Humans, Middle Aged, Minerals, Prospective Studies, Young Adult, Uterine Cervical Neoplasms diagnostic imaging, Uterine Cervical Neoplasms radiotherapy
- Abstract
Purpose: We compared the magnitude of changes in bone mineral density (BMD), within and outside the radiation field, among women who received pelvic radiation therapy (RT) with or without chemotherapy for cervical cancer., Methods and Materials: In this secondary analysis of a prospective study, we analyzed serial computed tomography scans and dual-energy x-ray absorptiometry scans from 78 patients who received definitive RT or chemoradiation therapy (CRT) for cervical cancer at a single institution from 2008 to 2015. BMD values at L1, L2, L3, and L4 were measured. We compared changes in BMD within the radiation field (ie, at L4) with those outside the field (ie, at L1). Linear mixed models were also used to examine the effect of RT on changes in BMD over time and covariate adjustment., Results: The median age of the 78 patients was 45.5 years (range, 23-88 years); all received RT and 76 (97%) received concurrent CRT. Treatment was associated with significant declines in BMD in all 4 lumbar vertebral bodies over time (P < .05), with nadir at 3 months for L4 and at 1 year for L1. Pairwise comparisons at 3 months and 2 years after treatment indicated that BMD in L4 (within the RT field) had improved (P = .037), but BMD in L1 (outside the RT field) was no different at 3 months and 2 years., Conclusions: Significant BMD declines were observed in all lumbar vertebral bodies immediately after RT. However, in-field vertebral bodies reached nadir BMD earlier than those located outside the RT field. Our results suggest that treatment and patient-related factors other than RT may contribute to declines in BMD after treatment for cervical cancer. Routine bone density screening and post-RT therapy with hormones may be beneficial for selected patients who receive CRT for cervical cancer., (Copyright © 2022 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)
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- 2022
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23. Metagenomes of rectal swabs in larger, advanced stage cervical cancers have enhanced mucus degrading functionalities and distinct taxonomic structure.
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Karpinets TV, Wu X, Solley T, El Alam MB, Sims TT, Yoshida-Court K, Lynn E, Ahmed-Kaddar M, Biegert G, Yue J, Song X, Sun H, Petrosino JF, Mezzari MP, Okhuysen P, Eifel PJ, Jhingran A, Lin LL, Schmeler KM, Ramondetta L, Ajami N, Jenq RR, Futreal A, Zhang J, Klopp AH, and Colbert LE
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- Female, Humans, Metabolic Networks and Pathways, Metagenome, Mucus, Gastrointestinal Microbiome genetics, Uterine Cervical Neoplasms
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Background: Gut microbiome community composition differs between cervical cancer (CC) patients and healthy controls, and increased gut diversity is associated with improved outcomes after treatment. We proposed that functions of specific microbial species adjoining the mucus layer may directly impact the biology of CC., Method: Metagenomes of rectal swabs in 41 CC patients were examined by whole-genome shotgun sequencing to link taxonomic structures, molecular functions, and metabolic pathway to patient's clinical characteristics., Results: Significant association of molecular functions encoded by the metagenomes was found with initial tumor size and stage. Profiling of the molecular function abundances and their distributions identified 2 microbial communities co-existing in each metagenome but having distinct metabolism and taxonomic structures. Community A (Clostridia and Proteobacteria predominant) was characterized by high activity of pathways involved in stress response, mucus glycan degradation and utilization of degradation byproducts. This community was prevalent in patients with larger, advanced stage tumors. Conversely, community B (Bacteroidia predominant) was characterized by fast growth, active oxidative phosphorylation, and production of vitamins. This community was prevalent in patients with smaller, early-stage tumors., Conclusions: In this study, enrichment of mucus degrading microbial communities in rectal metagenomes of CC patients was associated with larger, more advanced stage tumors., (© 2022. The Author(s).)
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- 2022
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24. Microbiome Dynamics During Chemoradiation Therapy for Anal Cancer.
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Lin D, El Alam MB, Jaoude JA, Kouzy R, Phan JL, Elnaggar JH, Resendiz B, Medrano AYD, Lynn EJ, Nguyen ND, Noticewala SS, Mathew GG, Holliday EB, Minsky BD, Das P, Morris VK, Eng C, Mezzari MP, Petrosino JF, Ajami NJ, Klopp AH, Taniguchi CM, and Colbert LE
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- Adult, Aged, Chemoradiotherapy adverse effects, Female, Humans, Male, Middle Aged, Prospective Studies, RNA, Ribosomal, 16S, Anus Neoplasms pathology, Carcinoma, Squamous Cell pathology, Microbiota
- Abstract
Purpose: Patients with localized squamous cell carcinoma of the anus (SCCA) who experience treatment toxicity or recurrences have few therapeutic options. Investigation into the microbiome's influence on treatment toxicity and its potential use as a predictive biomarker could improve these patients' outcomes. Our study presents the first longitudinal characterization of the SCCA tumor microbiome and its associations with treatment-related toxicities., Methods and Materials: This prospective cohort study included patients with nonmetastatic SCCA receiving standard-of-care chemoradiation therapy. Anorectal swabs of the tumor site were collected before, during, and after treatment. Patient-reported quality-of-life metrics were collected at similar time points. 16S rRNA gene sequencing was used to perform diversity and taxonomic characterization of the SCCA microbiome. Wilcoxon signed-rank tests were used to compare microbial diversity and abundance over time. Wilcoxon rank-sum tests were used to compare microbial profiles of high and low toxicity groups., Results: Twenty-two patients with SCCA were included in this study with a median age of 58.5 years (range, 39-77 years), and 18 (82%) were women. Alpha diversity remained relatively stable throughout chemoradiation therapy except for decreases in the Observed Features (P = .03) index at week 5 relative to baseline. Tumor microbial compositions changed significantly by the end of treatment (P = .03). Differential enrichment of bacteria at specific time points occurred during treatment, including the enrichment of Clostridia at follow-up (vs week 5, q = 0.019) and Corynebacterium at week 5 (vs baseline, q = 0.015; vs follow-up, q = 0.022). Patients experiencing high toxicity at week 5 had higher relative counts of Clostridia, Actinobacteria, and Clostridiales at baseline (P = .03 for all)., Conclusions: The tumor microbiome changes during and after chemoradiation therapy, and patient-reported toxicity levels are associated with patients' microbial profiles. Further studies into these microbial characterizations and toxicity associations will elucidate the tumor microbiome's role in predicting treatment-related outcomes for patients with SCCA., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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25. Long-term survival following definitive radiation therapy for recurrence or oligometastases in gynecological malignancies: A landmark analysis.
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Corrigan KL, Yoder A, De B, Lin L, Jhingran A, Joyner MM, Eifel PJ, Colbert LE, Lu KH, and Klopp AH
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- Carcinoma, Ovarian Epithelial, Disease-Free Survival, Female, Humans, Lymphatic Metastasis, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local radiotherapy, Retrospective Studies, Endometrial Neoplasms radiotherapy, Ovarian Neoplasms, Uterine Cervical Neoplasms pathology, Vaginal Neoplasms radiotherapy
- Abstract
Objective: Radiation therapy (RT) may improve outcomes for patients with oligometastatic cancer. We sought to determine if there are long-term survivors treated with definitive RT for recurrent or oligometastatic gynecological cancer (ROMGC), and to evaluate the clinical and disease characteristics of these patients., Methods: We performed a landmark analysis in 48 patients with ROMGC who survived for ≥5 years following definitive RT of their metastasis. Patient characteristics were extracted from the medical record. DFS was modeled using the Kaplan-Meier method., Results: This cohort included 20 patients (42%) with ovarian cancer, 16 (33%) with endometrial cancer, 11 (23%) with cervical cancer, and one (2%) with vaginal cancer. The sites of ROMGC were the pelvic (46%), para-aortic (44%), supraclavicular (7%), mediastinal (4%), axillary (4%) lymph nodes and the lung (5.5%). Median total RT dose and fractionation were 62.1 Gy and 2.1 Gy/fraction; one patient was treated with SBRT. 32 patients (67%) received chemoradiation; these patients had higher rates of median DFS than those treated with RT alone (93 vs. 34 months, P = 0.05). At median follow-up of 11.7 years, 11 (23%) patients had progression of disease. 20 (42%) patients had died, 9 (19%) died from non-gynecologic cancer and 8 (17%) from gynecologic cancer (three were unknown). 25 (52%) patients were alive and disease-free (10 initially had endometrial cancer [63% of these patients], eight had cervical cancer [73%], six had ovarian cancer [30%], one had vaginal cancer [100%])., Conclusions: Long-term survival is possible for patients treated with definitive RT for ROMG, however randomized data are needed to identify which patients derive the most benefit., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2022
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26. Expansion of Candidate HPV-Specific T Cells in the Tumor Microenvironment during Chemoradiotherapy Is Prognostic in HPV16 + Cancers.
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Colbert LE, El MB, Lynn EJ, Bronk J, Karpinets TV, Wu X, Chapman BV, Sims TT, Lin D, Kouzy R, Sammouri J, Biegert G, Delgado Medrano AY, Olvera A, Sastry KJ, Eifel PJ, Jhingran A, Lin L, Ramondetta LM, Futreal AP, Jazaeri AA, Schmeler KM, Yue J, Mitra A, Yoshida-Court K, Wargo JA, Solley TN, Hegde V, Nookala SS, Yanamandra AV, Dorta-Estremera S, Mathew G, Kavukuntla R, Papso C, Ahmed-Kaddar M, Kim M, Zhang J, Reuben A, Holliday EB, Minsky BD, Koong AC, Koay EJ, Das P, Taniguchi CM, and Klopp A
- Subjects
- Chemoradiotherapy, Female, Human papillomavirus 16, Humans, Papillomavirus E7 Proteins, Prognosis, Repressor Proteins, T-Lymphocytes, Tumor Microenvironment, Oncogene Proteins, Viral, Papillomavirus Infections, Uterine Cervical Neoplasms
- Abstract
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., (©2022 American Association for Cancer Research.)- Published
- 2022
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27. Biology of the Radio- and Chemo-Responsiveness in HPV Malignancies.
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Spiotto MT, Taniguchi CM, Klopp AH, Colbert LE, Lin SH, Wang L, Frederick MJ, Osman AA, Pickering CR, and Frank SJ
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- Apoptosis, Cell Line, Tumor, G2 Phase Cell Cycle Checkpoints, Humans, Papillomaviridae, Radiobiology, Tumor Microenvironment, Alphapapillomavirus, Head and Neck Neoplasms, Papillomavirus Infections complications
- Abstract
In multiple anatomic sites, patients with cancers associated with the Human Papillomavirus (HPV) experience better locoregional control and overall survival after radiotherapy and/or chemoradiotherapy than patients with HPV-negative cancers. These improved outcomes suggest that relatively unique biological features in HPV-positive cancers may increase sensitivity to DNA damaging agents as well as an impaired DNA damage response. This review will address potential biological mechanisms driving this increased sensitivity of HPV-positive cancer to radiation and/or chemotherapy. This review will discuss the clinical and preclinical observations that support the intrinsic radiosensitivity and/or chemosensitivity of HPV-positive cancers. Furthermore, this review will highlight the molecular mechanisms for increased radiation sensitivity using the classical "4 Rs" of radiobiology: repair, reassortment, repopulation, and reoxygenation. First, HPV-positive cancers have increased DNA damage due to increased oxidative stress and impaired DNA damage repair due to the altered activity TP53, p16, TIP60, and other repair proteins. Second, irradiated HPV-positive cancer cells display increased G2/M arrest leading to reassortment of cancer cells in more radiosensitive phases of the cell cycle. In addition, HPV-positive cancers have less radioresistant cancer stem cell subpopulations that may limit their repopulation during radiotherapy. Finally, HPV-positive cancers may also have less hypoxic tumor microenvironments that make these cancers more sensitive to radiation than HPV-negative cells. We will also discuss extrinsic immune and microenvironmental factors enriched in HPV-positive cancers that facilities responses to radiation. Therefore, these potential biological mechanisms may underpin the improved clinical outcomes often observed in these virally induced cancers., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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28. Diversity and composition of gut microbiome of cervical cancer patients: Do results of 16S rRNA sequencing and whole genome sequencing approaches align?
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Biegert G, El Alam MB, Karpinets T, Wu X, Sims TT, Yoshida-Court K, Lynn EJ, Yue J, Medrano AD, Petrosino J, Mezzari MP, Ajami NJ, Solley T, Ahmed-Kaddar M, Klopp AH, and Colbert LE
- Subjects
- Bacteria genetics, Biodiversity, DNA, Bacterial, Feces microbiology, Female, High-Throughput Nucleotide Sequencing methods, Humans, Metagenome, Metagenomics methods, Microbiota genetics, Middle Aged, Gastrointestinal Microbiome genetics, RNA, Ribosomal, 16S genetics, Uterine Cervical Neoplasms genetics, Whole Genome Sequencing methods
- Abstract
Background: Next generation sequencing has progressed rapidly, characterizing microbial communities beyond culture-based or biochemical techniques. 16S ribosomal RNA gene sequencing (16S) produces reliable taxonomic classifications and relative abundances, while shotgun metagenome sequencing (WMS) allows higher taxonomic and functional resolution at greater cost. The purpose of this study was to determine if 16S and WMS provide congruent information for our patient population from paired fecal microbiome samples., Results: Comparative indices were highly congruent between 16S and WMS. The most abundant genera for 16S and WMS data did not overlap. Overlap was observed at the Phylum level, as expected. However, relative abundances correlated poorly between the two methodologies (all P-value>0.05). Hierarchical clustering of both sequencing analyses identified overlapping enterotypes. Both approaches were in agreement with regard to demographic variables., Conclusion: Diversity, evenness and richness are comparable when using 16S and WMS techniques, however relative abundances of individual genera are not. Clinical associations with diversity and evenness metrics were similarly identified with WMS or 16S., (Copyright © 2021 Elsevier B.V. All rights reserved.)
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- 2021
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29. National Quality Measure Compliance for Palliative Bone Radiation Among Patients With Metastatic Non-Small Cell Lung Cancer.
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Grant SR, Smith BD, Colbert LE, Nguyen QN, Yu JB, Lin SH, and Chen AB
- Abstract
Background: There exists wide practice variability in palliative treatment schedules for bone metastases. In an effort to reduce variation and promote high-quality, cost-conscious care, the National Quality Forum (NQF) endorsed measure 1822 in 2012. This measure recommends the use of 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction for palliative radiation for bone metastases. We report on longitudinal compliance with this measure., Methods: Using the National Cancer Database, patients with metastatic thoracic non-small cell lung cancer diagnosed between 2004 and 2016 who received radiation therapy for bony sites of metastatic disease were identified. Treatment courses fitting 1 of the 4 recommended schedules under NQF 1822 were coded as compliant. Rates of compliance by patient, tumor, and treatment characteristics were analyzed., Results: A total of 42,685 patients met the criteria for inclusion. Among all patients, 60.2% of treatment courses were compliant according to NQF 1822. Compliance increased over time and was highest for treatments to the extremity (69.8%), lowest for treatments to the skull or head (48.8%), and higher for academic practice (67.1%) compared with community (56.0%) or integrated network facilities (61.2%). On multivariable analysis, predictors of NQF 1822 compliance included year of diagnosis after 2011, treatment to an extremity, or treatment at an academic facility. Of noncompliant treatment courses, extended fractionation (≥11 fractions) occurred in 62.6% and was more common before 2012, in community practice, and for treatments of the skull or head., Conclusions: Among patients treated for metastatic non-small cell lung cancer, compliance with NQF 1822 increased over time. Although extended fractionation constituted a majority of noncompliant treatment courses, a substantial proportion also involved shorter courses.
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- 2021
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30. A prospective study of the adaptive changes in the gut microbiome during standard-of-care chemoradiotherapy for gynecologic cancers.
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El Alam MB, Sims TT, Kouzy R, Biegert GWG, Jaoude JABI, Karpinets TV, Yoshida-Court K, Wu X, Delgado-Medrano AY, Mezzari MP, Ajami NJ, Solley T, Ahmed-Kaddar M, Lin LL, Ramondetta L, Jazaeri A, Jhingran A, Eifel PJ, Schmeler KM, Wargo J, Klopp AH, and Colbert LE
- Subjects
- Adult, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Bacteria drug effects, Bacteria isolation & purification, Bacteria radiation effects, Chemoradiotherapy adverse effects, Female, Humans, Middle Aged, Prospective Studies, Gastrointestinal Microbiome drug effects, Gastrointestinal Microbiome radiation effects, Genital Neoplasms, Female drug therapy, Genital Neoplasms, Female radiotherapy
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Background: A diverse and abundant gut microbiome can improve cancer patients' treatment response; however, the effect of pelvic chemoradiotherapy (CRT) on gut diversity and composition is unclear. The purpose of this prospective study was to identify changes in the diversity and composition of the gut microbiome during and after pelvic CRT., Materials and Methods: Rectal swabs from 58 women with cervical, vaginal, or vulvar cancer from two institutions were prospectively analyzed before CRT (baseline), during CRT (weeks 1, 3, and 5), and at first follow-up (week 12) using 16Sv4 rRNA gene sequencing of the V4 hypervariable region of the bacterial 16S rRNA marker gene. 42 of these patients received antibiotics during the study period. Observed operational taxonomic units (OTUs; representative of richness) and Shannon, Simpson, Inverse Simpson, and Fisher diversity indices were used to characterize alpha (within-sample) diversity. Changes over time were assessed using a paired t-test, repeated measures ANOVA, and linear mixed modeling. Compositional changes in specific bacteria over time were evaluated using linear discriminant analysis effect size., Results: Gut microbiome richness and diversity levels continually decreased throughout CRT (mean Shannon diversity index, 2.52 vs. 2.91; all P <0.01), but were at or near baseline levels in 60% of patients by week 12. Patients with higher gut diversity at baseline had the steepest decline in gut microbiome diversity. Gut microbiome composition was significantly altered during CRT, with increases in Proteobacteria and decreases in Clostridiales, but adapted after CRT, with increases in Bacteroides species., Conclusion: After CRT, the diversity of the gut microbiomes in this population tended to return to baseline levels by the 12 week follow-up period, but structure and composition remained significantly altered. These changes should be considered when designing studies to analyze the gut microbiome in patients who receive pelvic CRT for gynecologic cancers., Competing Interests: The authors have declared that no competing interests exist.
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- 2021
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31. Gut microbiome diversity is an independent predictor of survival in cervical cancer patients receiving chemoradiation.
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Sims TT, El Alam MB, Karpinets TV, Dorta-Estremera S, Hegde VL, Nookala S, Yoshida-Court K, Wu X, Biegert GWG, Delgado Medrano AY, Solley T, Ahmed-Kaddar M, Chapman BV, Sastry KJ, Mezzari MP, Petrosino JF, Lin LL, Ramondetta L, Jhingran A, Schmeler KM, Ajami NJ, Wargo J, Colbert LE, and Klopp AH
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- Adult, Aged, Antigens, CD metabolism, Antigens, Differentiation, T-Lymphocyte metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Female, Humans, Ki-67 Antigen metabolism, Lectins, C-Type metabolism, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Middle Aged, Prospective Studies, Time Factors, Treatment Outcome, Tumor Microenvironment, Uterine Cervical Neoplasms immunology, Uterine Cervical Neoplasms microbiology, Uterine Cervical Neoplasms mortality, Chemoradiotherapy adverse effects, Chemoradiotherapy mortality, Gastrointestinal Microbiome, Intestines microbiology, Uterine Cervical Neoplasms therapy
- Abstract
Diversity of the gut microbiome is associated with higher response rates for cancer patients receiving immunotherapy but has not been investigated in patients receiving radiation therapy. Additionally, current studies investigating the gut microbiome and outcomes in cancer patients may not have adjusted for established risk factors. Here, we sought to determine if diversity and composition of the gut microbiome was independently associated with survival in cervical cancer patients receiving chemoradiation. Our study demonstrates that the diversity of gut microbiota is associated with a favorable response to chemoradiation. Additionally, compositional variation among patients correlated with short term and long-term survival. Short term survivor fecal samples were significantly enriched in Porphyromonas, Porphyromonadaceae, and Dialister, whereas long term survivor samples were significantly enriched in Escherichia Shigella, Enterobacteriaceae, and Enterobacteriales. Moreover, analysis of immune cells from cervical tumor brush samples by flow cytometry revealed that patients with a high microbiome diversity had increased tumor infiltration of CD4+ lymphocytes as well as activated subsets of CD4 cells expressing ki67+ and CD69+ over the course of radiation therapy. Modulation of the gut microbiota before chemoradiation might provide an alternative way to enhance treatment efficacy and improve treatment outcomes in cervical cancer patients.
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- 2021
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32. Does a Custom Electronic Health Record Alert System Improve Physician Compliance With National Quality Measures for Palliative Bone Metastasis Radiotherapy?
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Grant SR, Smith BD, Pandey P, Maldonado JA, Kim M, Moon BS, and Colbert LE
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- Humans, Palliative Care, Bone Neoplasms radiotherapy, Bone Neoplasms secondary, Electronic Health Records, Physicians, Quality Indicators, Health Care
- Abstract
Purpose: In an effort to promote cost-conscious, high-quality, and patient-centered care in the palliative radiation of painful bone metastases, the National Quality Forum (NQF) formed measure 1822 in 2012, which recommends the use of one of the four dose-fractionation schemes (30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction). We investigated whether a custom electronic health record (EHR) alert system improved quality measure compliance among 88 physicians at a large academic center and institutional network., Methods: In March 2018, a multiphase alert system was embedded in a custom web-based EHR. Prior to a course of palliative bone radiation, the alert system notified the user of NQF 1822 recommendations and, once prescription was completed, either affirmed compliance or advised a change in treatment schedule. Rates of compliance were evaluated before and after implementation of alert system., Results: Of 2,399 treatment courses, 86.5% were compliant with NQF 1822 recommendations. There was no difference in rates of NQF 1822 compliance before or after implementation of the custom EHR alert (86.0% before March 2018 v 86.9% during and after March 2018, P = .551)., Conclusion: There was no change in rates of compliance following implementation of a custom EHR alert system designed to make treatment recommendations based on national quality measure guidelines. To be of most benefit, future palliative bone metastasis decision aids should leverage peer review, target a clear practice deficiency, center upon high-quality practice guidelines, and allow flexibility to reflect the diversity of clinical scenarios.
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- 2021
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33. Patient-Reported GI Outcomes in Patients With Anal Cancer Receiving Modern Chemoradiation.
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Kouzy R, Abi Jaoude J, Lin D, El Alam MB, Minsky BD, Koay EJ, Das P, Holliday EB, Klopp AH, Colbert LE, and Taniguchi CM
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- Antineoplastic Combined Chemotherapy Protocols, Chemoradiotherapy adverse effects, Fluorouracil adverse effects, Humans, Male, Middle Aged, Mitomycin therapeutic use, Patient Reported Outcome Measures, Anus Neoplasms drug therapy, Quality of Life
- Abstract
Purpose: Among patients with anal cancer, chemoradiotherapy is often associated with toxicities that diminish quality of life. We describe the GI-related patient-reported outcomes (PROs) of patients with anal cancer receiving chemoradiotherapy to improve patient-physician communication., Methods: We prospectively followed patients with nonmetastatic squamous cell carcinoma of the anal canal who received definitive chemoradiotherapy. Patients completed the bowel subdomain of the Expanded Prostate Cancer Index Composite (EPIC) questionnaire before treatment and at 4 subsequent timepoints. We used the paired Wilcoxon test to compare EPIC scores at different times., Results: The study included 21 patients; median age was 57 years. Most patients (52%) had T2 and either N0 or N1 disease (81%). Most patients (91%) received chemotherapy with cisplatin-fluorouracil and either intensity-modulated radiotherapy or volumetric modulated arc therapy. Compared with the patients' median overall summary score at baseline (66), their median score at 1 week (82) was higher ( P = .009), whereas their median score at 5 weeks (54) was lower ( P = .025). The patients' median overall summary score at baseline and at 3 months did not differ ( P = .919). Three months after radiotherapy, most patients reported minimal adverse effects compared with baseline., Conclusion: The GI-related PROs of patients with anal cancer tend to fluctuate during radiotherapy but return to baseline by 3 months, at which time most patients report few or no residual adverse effects. We provide a clear timeline of GI acute toxicity using sequential PRO measurements that will improve patient-physician communication regarding expectations for cancer treatment.
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- 2020
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34. Effect of Antibiotics on Gut and Vaginal Microbiomes Associated with Cervical Cancer Development in Mice.
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Karpinets TV, Solley TN, Mikkelson MD, Dorta-Estremera S, Nookala SS, Medrano AYD, Petrosino JF, Mezzari MP, Zhang J, Futreal PA, Sastry KJ, Colbert LE, and Klopp A
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- Animals, Bacteria genetics, Bacteria growth & development, Bacteria isolation & purification, Female, Mice, Uterine Cervical Neoplasms drug therapy, Uterine Cervical Neoplasms microbiology, Vagina drug effects, Anti-Bacterial Agents pharmacology, Bacteria classification, Gastrointestinal Microbiome, Uterine Cervical Neoplasms pathology, Vagina microbiology
- Abstract
Antibiotics affect microbial diversity in the gut, leading to dysbiosis and impaired immunity. However, the impact of antibiotics on microbial communities at other sites, such as vagina is less understood. It is also not clear whether changes induced by antibiotics in both microbiomes affect the development of cervical cancer. In this study, we utilized the murine model to evaluate these questions. We show that oral application of broad-spectrum antibiotics in mice changed not only diversity, but composition and sharing of gut and vaginal microbiomes in mice and influenced cervical cancer development in an orthotopic tumor model. Antibiotics decreased richness and diversity indexes in the gut but increased them in the vagina. Some beneficial taxa, such as Bacteroides, Ruminococcaceae , and Lachnospiraceae increased their abundance in the vagina while other pathogenic species, such as Proteobacteria , were decreased. As a result of the changes, mice with greater richness and diversity of the vaginal microbiome after antibiotics exposure were less likely developed tumors. No association between richness and diversity of the gut microbiome and tumor development was identified., (©2020 American Association for Cancer Research.)
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- 2020
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35. Evaluation of the Visibility and Artifacts of 11 Common Fiducial Markers for Image Guided Stereotactic Body Radiation Therapy in the Abdomen.
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Slagowski JM, Colbert LE, Cazacu IM, Singh BS, Martin R, Koay EJ, Taniguchi CM, Koong AC, Bhutani MS, Herman JM, and Beddar S
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- Artifacts, Humans, Phantoms, Imaging, Abdomen, Fiducial Markers, Radiotherapy, Image-Guided
- Abstract
Purpose: The purpose of this study was to quantitatively evaluate the visibility and artifacts of commercially available fiducial markers to optimize their selection for image guided stereotactic body radiation therapy., Methods and Materials: From 6 different vendors, we selected 11 fiducials commonly used in image guided radiation therapy. The fiducials varied in material composition (e.g., gold, platinum, carbon), shape (e.g., cylindrical, notched/linear, coiled, ball-like, step), and size measured in terms of diameter (0.28-1.0 mm) and length (3.0-20.0 mm). Each fiducial was centered in 4-mm bolus within a 13-cm-thick water-equivalent phantom. Fiducials were imaged with the use of a simulation computed tomography (CT) scanner, a CT-on-rails system, and an onboard cone beam CT system. Acquisition parameters were set according to clinical protocols. Visibility was assessed in terms of contrast (Δ Hounsfield unit [HU]) and the Michelson visibility metric. Artifacts were quantified in terms of relative standard deviation and relative streak artifacts level (rSAL). Twelve radiation oncologists ranked each fiducial in terms of clinical usefulness., Results: Contrast and artifacts increased with fiducial size. For CT imaging, maximum contrast (2722 HU) and artifacts (rSAL = 2.69) occurred for the largest-diameter (0.75 mm) platinum fiducial. Minimum contrast (551 HU) and reduced artifacts (rSAL = 0.65) were observed for the smallest-diameter (0.28 mm) gold fiducial. Carbon produced the least severe artifacts (rSAL = 0.29). The survey indicated that physicians preferred gold fiducials with a 0.35- to 0.43-mm diameter, 5- to 10-mm length, and coiled or cylindrical shape that balanced contrast and artifacts., Conclusions: We evaluated 11 different fiducials in terms of visibility and artifacts. The results of this study may assist radiation oncologists who seek to maximize contrast, minimize artifacts, or balance contrast versus artifacts by fiducial selection., (Copyright © 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)
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- 2020
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36. The Role of the Cervicovaginal and Gut Microbiome in Cervical Intraepithelial Neoplasia and Cervical Cancer.
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Sims TT, Colbert LE, and Klopp AH
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The microbiome, which refers to the microbiota within a host and their collective genomes, has recently been demonstrated to play a critical role in cancer progression, metastasis, and therapeutic response. The microbiome is known to affect host immunity, but its influence on human papilloma virus (HPV) gynecologic malignancies remains limited and poorly understood. To date, studies have largely focused on the cervicovaginal microbiome; however, there is growing evidence that the gut microbiome may interact and substantially affect therapeutic response in gynecologic cancers. Importantly, new developments in microbiome sequencing and advanced bioinformatics technologies have enabled rapid advances in our understanding of the gut and local tumor microbiota. In this review, we examine the evidence supporting the role of the microbiome in HPV-associated cervical intraepithelial neoplasia (CIN) and cervical cancer, explore characteristics that influence and shape the host microbiota that impact HPV-driven carcinogenesis, and highlight potential approaches and considerations for future and ongoing research of the microbiome's effect on HPV-associated cancer., Competing Interests: Conflicts of Interest: None., (© Innovative Healthcare Institute 2021.)
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- 2020
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37. Tumor microbial diversity and compositional differences among women in Botswana with high-grade cervical dysplasia and cervical cancer.
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Sims TT, Biegert GWG, Ramogola-Masire D, Ngoni K, Solley T, Ning MS, El Alam MB, Mezzari M, Petrosino J, Zetola NM, Schmeler KM, Colbert LE, Klopp AH, and Grover S
- Subjects
- Adult, Botswana, Carcinoma, Squamous Cell pathology, Clostridiales, Comamonadaceae, Female, Gardnerella, Humans, Lactobacillus, Microbiota, Middle Aged, Neoplasm Grading, Prospective Studies, Proteobacteria, Uterine Cervical Dysplasia pathology, Uterine Cervical Neoplasms pathology, Carcinoma, Squamous Cell microbiology, Cervix Uteri microbiology, Uterine Cervical Dysplasia microbiology, Uterine Cervical Neoplasms microbiology
- Abstract
Introduction: We characterized the cervical 16S rDNA microbiome of patients in Botswana with high-grade cervical dysplasia and locally advanced cervical cancer., Methods: This prospective study included 31 patients: 21 with dysplasia and 10 with cancer. The Shannon diversity index was used to evaluate alpha (intra-sample) diversity, while the UniFrac (weighted and unweighted) and Bray-Curtis distances were employed to evaluate beta (inter-sample) diversity. The relative abundance of microbial taxa was compared among samples using linear discriminant analysis effect size., Results: Alpha diversity was significantly higher in patients with cervical cancer than in patients with cervical dysplasia (P<0.05). Beta diversity also differed significantly (weighted UniFrac Bray-Curtis, P<0.01). Neither alpha diversity (P=0.8) nor beta diversity (P=0.19) varied by HIV status. The results of linear discriminant analysis effect size demonstrated that multiple taxa differed significantly between patients with cervical dysplasia vs cancer. Lachnospira bacteria (in the Clostridia class) were particularly enriched among cervical dysplasia patients, while Proteobacteria (members of the Firmicutes phyla and the Comamonadaceae family) were enriched in patients with cervical cancer., Discussion: The results of our study suggest that differences exist in the diversity and composition of the cervical microbiota between patients with cervical dysplasia and patients with cervical cancer in Botswana. Additional studies are warranted to validate these findings and elucidate their clinical significance among women living in sub-Saharan Africa, as well as other regions of the world., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2020
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38. Applying to Radiation Oncology Amid a Pandemic.
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Kouzy R, Abi Jaoude J, Yue J, Maldonado JA, Taniguchi CM, Ludmir EB, and Colbert LE
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- 2020
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39. Microbiome factors in HPV-driven carcinogenesis and cancers.
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Lin D, Kouzy R, Abi Jaoude J, Noticewala SS, Delgado Medrano AY, Klopp AH, Taniguchi CM, and Colbert LE
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- Female, Humans, Papillomavirus Infections pathology, Cell Transformation, Viral, Microbiota, Neoplasms metabolism, Neoplasms microbiology, Neoplasms virology, Papillomaviridae metabolism, Papillomavirus Infections metabolism
- Abstract
Competing Interests: The authors have declared that no competing interests exist.
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- 2020
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40. Cancer Research after COVID-19: Where Do We Go from Here?
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Colbert LE, Kouzy R, Abi Jaoude J, Ludmir EB, and Taniguchi CM
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- Betacoronavirus, Biomedical Research organization & administration, COVID-19, Clinical Trials as Topic, Humans, Laboratories, SARS-CoV-2, Biomedical Research trends, Coronavirus Infections, Neoplasms, Pandemics, Pneumonia, Viral
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- 2020
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41. Microbial Diversity and Composition Is Associated with Patient-Reported Toxicity during Chemoradiation Therapy for Cervical Cancer.
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Mitra A, Grossman Biegert GW, Delgado AY, Karpinets TV, Solley TN, Mezzari MP, Yoshida-Court K, Petrosino JF, Mikkelson MD, Lin L, Eifel P, Zhang J, Ramondetta LM, Jhingran A, Sims TT, Schmeler K, Okhuysen P, Colbert LE, and Klopp AH
- Subjects
- Adult, Aged, Biodiversity, Cohort Studies, Female, Humans, Middle Aged, Patient Reported Outcome Measures, Uterine Cervical Neoplasms drug therapy, Uterine Cervical Neoplasms radiotherapy, Chemoradiotherapy adverse effects, Gastrointestinal Microbiome radiation effects, Gastrointestinal Tract microbiology, Gastrointestinal Tract radiation effects, Safety, Uterine Cervical Neoplasms microbiology, Uterine Cervical Neoplasms therapy
- Abstract
Purpose: Patients receiving pelvic radiation for cervical cancer experience high rates of acute gastrointestinal (GI) toxicity. The association of changes in the gut microbiome with bowel toxicity from radiation is not well characterized., Methods and Materials: Thirty-five patients undergoing definitive chemoradiation therapy (CRT) underwent longitudinal sampling (baseline and weeks 1, 3, and 5) of the gut microbiome and prospective assessment of patient-reported GI toxicity. DNA was isolated from stool obtained at rectal examination and analyzed with 16S rRNA sequencing. GI toxicity was assessed with the Expanded Prostate Cancer Index Composite instrument to evaluate frequency, urgency, and discomfort associated with bowel function. Shannon diversity index was used to characterize alpha (within sample) diversity. Weighted UniFrac principle coordinates analysis was used to compare beta (between sample) diversity between samples using permutational multivariate analysis of variance. Linear discriminant analysis effect size highlighted microbial features that best distinguish categorized patient samples., Results: Gut microbiome diversity continuously decreased over the course of CRT, with the largest decrease at week 5. Expanded Prostate Cancer Index Composite bowel function scores also declined over the course of treatment, reflecting increased symptom burden. At all individual time points, higher diversity of the gut microbiome was linearly correlated with better patient-reported GI function, but baseline diversity was not predictive of eventual outcome. Patients with high toxicity demonstrated different compositional changes during CRT in addition to compositional differences in Clostridia species., Conclusions: Over time, increased radiation toxicity is associated with decreased gut microbiome diversity. Baseline diversity is not predictive of end-of-treatment bowel toxicity, but composition may identify patients at risk for developing high toxicity., (Copyright © 2020. Published by Elsevier Inc.)
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- 2020
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42. Outcomes of ICU Admission of Patients With Progressive Metastatic Gastrointestinal Cancer.
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Epstein AS, Yang A, Colbert LE, Voigt LP, Meadows J, Goldberg JI, and Saltz LB
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- Adenocarcinoma pathology, Adenocarcinoma therapy, Adult, Aged, Aged, 80 and over, Databases, Factual, Disease Progression, Female, Gastrointestinal Neoplasms pathology, Gastrointestinal Neoplasms therapy, Hospital Mortality, Humans, Male, Middle Aged, Neoplasm Metastasis, Retrospective Studies, Treatment Outcome, Adenocarcinoma mortality, Gastrointestinal Neoplasms mortality, Hospitalization statistics & numerical data, Intensive Care Units statistics & numerical data
- Abstract
Background: Data on the outcomes of intensive care unit (ICU) admissions for patients with advanced incurable chemoresistant solid tumor malignancies, and the benefits of subsequent/post-ICU anticancer treatments are limited but have end-of-life and ethical implications., Methods: An institutional database was queried to identify patients of the gastrointestinal (GI) medical oncology service of Memorial Sloan Kettering Cancer Center with ≥1 ICU admission during 2014. Records were reviewed for evidence of cancer control from cancer treatment after the ICU admission., Results: Twenty-eight patients who had progressed beyond at least first-line chemotherapy for metastatic GI adenocarcinoma were admitted to the ICU for sequelae of progressive clinical deterioration. The most frequent reasons for ICU admission were sepsis (39%) and acute respiratory failure (29%). Ten patients died in the ICU, 3 died during the same hospitalization after ICU discharge, and 15 were discharged from the hospital. Of these 15, the median survival from hospital discharge was 2.2 months and 6 received further chemotherapy but with no evidence of clinical benefit. Of these 6, 3 lived over 5 months but the treatment of 5 entailed recycling of previously ineffective chemotherapy agents (3) or those originally used in the adjuvant setting (2). Two of these patients received liver-directed therapy without benefit., Conclusions: Admissions to the ICU in this cancer population were associated with high morbidity and mortality and did not result in benefit from subsequent cancer treatment. These data can be used to help establish realistic expectations and care goals in previously treated patients having metastatic GI cancer with clinical deterioration.
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- 2020
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43. Immunotherapy and Radiation.
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Colbert LE and Jhingran A
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- Combined Modality Therapy, Humans, Neoplasms immunology, Immune Tolerance radiation effects, Immunotherapy, Neoplasms drug therapy, Neoplasms radiotherapy
- Abstract
Radiation is an essential tool in cancer therapy, both in the definitive and palliative setting. Radiation therapy can drive the cancer immune cycle via several mechanisms, but it also has immune suppressive effects that might be overcome via radiation/immunotherapy combination approaches. Understanding this underlying biology will lead to improved combination therapy approaches. Although clinical evidence of radiation and immunotherapy combination approaches in the metastatic setting to induce an abscopal response is limited, combination approaches in the oligometastatic and definitive setting are extremely promising.
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- 2020
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44. Top Concerns of Radiation Oncology Trainees in 2019: Job Market, Board Examinations, and Residency Expansion.
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Kahn J, Goodman CR, Albert A, Agarwal A, Jeans E, Tye K, Campbell SR, Marcrom S, and Colbert LE
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- Forecasting, Health Workforce statistics & numerical data, Humans, Radiation Oncologists supply & distribution, Societies, Medical, United States, Accreditation standards, Clinical Competence, Employment statistics & numerical data, Internship and Residency statistics & numerical data, Radiation Oncology statistics & numerical data, Radiation Oncology trends
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- 2020
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45. Gut microbial diversity and genus-level differences identified in cervical cancer patients versus healthy controls.
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Sims TT, Colbert LE, Zheng J, Delgado Medrano AY, Hoffman KL, Ramondetta L, Jazaeri A, Jhingran A, Schmeler KM, Daniel CR, and Klopp A
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- Aged, Feces microbiology, Female, Humans, Lymphatic Metastasis, Middle Aged, Neoplasm Staging, Prospective Studies, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms pathology, Gastrointestinal Microbiome genetics, Uterine Cervical Neoplasms microbiology
- Abstract
Objectives: The aim of this study was to characterize variation in the gut microbiome of women with locally advanced cervical cancer and compare it to healthy controls., Methods: We characterized the 16S rDNA fecal microbiome in 42 cervical cancer patients and 46 healthy female controls. Shannon diversity index (SDI) was used to evaluate alpha (within sample) diversity. Beta (between sample) diversity was examined using principle coordinate analysis (PCoA) of unweighted Unifrac distances. Relative abundance of microbial taxa was compared between samples using Linear Discriminant Analysis Effect Size (LEfSe)., Results: Within cervical cancer patients, bacterial alpha diversity was positively correlated with age (p = 0.22) but exhibited an inverse relationship in control subjects (p < 0.01). Alpha diversity was significantly higher in cervical cancer patients as compared to controls (p < 0.05), though stratification by age suggested this relationship was restricted to older women (>50 years; p < 0.01). Beta diversity (unweighted Unifrac; p < 0.01) also significantly differed between cervical cancer patients and controls. Based on age- and race-adjusted LEfSe analysis, multiple taxa significantly differed between cervical cancer patients and controls. Prevotella, Porphyromonas, and Dialister were significantly enriched in cervical cancer patients, while Bacteroides, Alistipes and members of the Lachnospiracea family were significantly enriched in healthy subjects., Conclusion: Our study suggests differences in gut microbiota diversity and composition between cervical cancer patients and controls. Associations within the gut microbiome by age may reflect etiologic/clinical differences. These findings provide rationale for further study of the gut microbiome in cervical cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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46. A Survey Study of Female Radiation Oncology Residents' Experiences to Inform Change.
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Osborn VW, Doke K, Griffith KA, Jones R, Lee A, Maquilan G, Masters AH, Albert AA, Dover LL, Puckett LL, Hentz C, Kahn JM, Colbert LE, Barry PN, and Jagsi R
- Subjects
- Burnout, Professional epidemiology, Career Mobility, Female, Humans, Internship and Residency statistics & numerical data, Pregnancy, Radiation Oncology statistics & numerical data, Self-Help Groups, Sexual Harassment statistics & numerical data, Social Support, Surveys and Questionnaires statistics & numerical data, Change Management, Internship and Residency organization & administration, Mentors statistics & numerical data, Radiation Oncology organization & administration, Sexism statistics & numerical data
- Abstract
Purpose: Women remain underrepresented at all levels within the field of radiation oncology. We sought to study current female residents' experiences and concerns to inform interventions to promote gender equity. Furthermore, we evaluated interest in a professional society specifically for women radiation oncologists., Methods and Materials: An anonymous 76-item survey was designed and distributed to current women residents in radiation oncology in 2017-2018. Analyses describe personal, program, and family characteristics and experiences before and after joining the field., Results: Of 170 female residents surveyed, 125 responded (74% response rate). Over one-quarter were in programs with ≤2 female residents (29%) and ≤2 female attendings (29%). One-third (34%) reported having children. Over half (51%) reported that lack of mentorship affected career ambitions. Over half (52%) agreed that gender-specific bias existed in their programs, and over a quarter (27%) reported they had experienced unwanted sexual comments, attention, or advances by a superior or colleague. Only 5% reported no symptoms of burnout. Almost all (95%) agreed that radiation oncology is perceived as family friendly; however, only 52% agreed that it actually is. An overwhelming majority (90%) expressed interest in joining a professional group for women in radiation oncology., Conclusions: In the first study to our knowledge to focus specifically on the experiences of women residents in radiation oncology, a number of areas for potential improvement were highlighted, including isolation and underrepresentation, mentorship needs, bias and harassment, and gender-based obstacles such as need for support during pregnancy and motherhood. These findings support the organization of groups such as the Society for Women in Radiation Oncology, which seeks to target these needs to promote gender equity., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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47. Selective EGLN Inhibition Enables Ablative Radiotherapy and Improves Survival in Unresectable Pancreatic Cancer.
- Author
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Fujimoto TN, Colbert LE, Huang Y, Molkentine JM, Deorukhkar A, Baseler L, de la Cruz Bonilla, Yu M, Lin D, Gupta S, Cabeceiras PK, Kingsley CV, Tailor RC, Sawakuchi GO, Koay EJ, Piwnica-Worms H, Maitra A, and Taniguchi CM
- Subjects
- Animals, Apoptosis, Female, Glycine pharmacology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pancreatic Neoplasms pathology, Pancreatic Neoplasms radiotherapy, Proto-Oncogene Proteins p21(ras) physiology, Radiation Injuries etiology, Radiation Injuries mortality, Radiotherapy adverse effects, Transcription Factors physiology, Tumor Suppressor Protein p53 physiology, Glycine analogs & derivatives, Hypoxia-Inducible Factor-Proline Dioxygenases antagonists & inhibitors, Isoquinolines pharmacology, Pancreatic Neoplasms mortality, Radiation Injuries prevention & control, Radiation-Protective Agents pharmacology, Radiotherapy mortality
- Abstract
When pancreatic cancer cannot be removed surgically, patients frequently experience morbidity and death from progression of their primary tumor. Radiation therapy (RT) cannot yet substitute for an operation because radiation causes fatal bleeding and ulceration of the nearby stomach and intestines before achieving tumor control. There are no FDA-approved medications that prevent or reduce radiation-induced gastrointestinal injury. Here, we overcome this fundamental problem of anatomy and biology with the use of the oral EGLN inhibitor FG-4592, which selectively protects the intestinal tract from radiation toxicity without protecting tumors. A total of 70 KPC mice with autochthonous pancreatic tumors received oral FG-4592 or vehicle control ± ablative RT to a cumulative 75 Gy administered in 15 daily fractions to a limited tumor field. Although ablative RT reduced complications from local tumor progression, fatal gastrointestinal bleeding was observed in 56% of mice that received high-dose RT with vehicle control. However, radiation-induced bleeding was completely ameliorated in mice that received high-dose RT with FG-4592 (0% bleeding, P < 0.0001 compared with vehicle). Furthermore, FG-4592 reduced epithelial apoptosis by half ( P = 0.002) and increased intestinal microvessel density by 80% compared with vehicle controls. EGLN inhibition did not stimulate cancer growth, as treatment with FG-4592 alone, or overexpression of HIF2 within KPC tumors independently improved survival. Thus, we provide a proof of concept for the selective protection of the intestinal tract by the EGLN inhibition to enable ablative doses of cytotoxic therapy in unresectable pancreatic cancer by reducing untoward morbidity and death from radiation-induced gastrointestinal bleeding. SIGNIFICANCE: Selective protection of the intestinal tract by EGLN inhibition enables potentially definitive doses of radiation therapy. This might allow radiation to be a surgical surrogate for unresectable pancreatic cancer. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/9/2327/F1.large.jpg., (©2019 American Association for Cancer Research.)
- Published
- 2019
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48. Brachytherapy Training Survey of Radiation Oncology Residents.
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Marcrom SR, Kahn JM, Colbert LE, Freese CM, Doke KN, Yang JC, Yashar CM, Luu M, and Kamrava M
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- Attitude, Career Choice, Fellowships and Scholarships, Female, Humans, Internet, Internship and Residency, Male, Radiosurgery, Societies, Medical, Surveys and Questionnaires, United States, Brachytherapy methods, Radiation Oncology education, Radiation Oncology methods
- Abstract
Purpose: As brachytherapy utilization rates decline, we sought to evaluate the state of brachytherapy training during radiation oncology residency., Methods and Materials: US radiation oncology residents in the Association of Residents in Radiation Oncology database were sent an online questionnaire regarding brachytherapy training. Survey questions addressed a wide array of topics, and responses were often given on a 1 to 5 Likert-type scale that reflected strength of opinion. Postgraduate year (PGY) 4/5 respondents' answers were analyzed. Descriptive statistics were generated, and rank correlation analyses (Kendall's τ coefficient and Wilcoxon signed-rank test) were used for comparisons., Results: The survey was completed by 145 of 567 residents (62% being PGY4/5). Of PGY4/5 respondents, 96% (86 of 90) believed learning brachytherapy during residency was important, and 72% (65 of 90) felt their program valued brachytherapy training. Resident brachytherapy comfort varied by site, decreasing as follows: gynecologic, prostate, breast, skin. The current intracavitary 15-case minimum was believed adequate by most, but only a minority believed the 5-case interstitial minimum was adequate. Most respondents (59%) believed that caseload was the greatest barrier to achieving independence in brachytherapy. Significant support exists for American Brachytherapy Society training courses and on-the-job education to enhance training, but enthusiasm about pursuing brachytherapy fellowship training was low. Most respondents expressed confidence in developing a brachytherapy practice (54%); however, this was significantly lower than the rate of those confident in developing a stereotactic body radiation therapy/stereotactic radiosurgery program (97%) (P < .001). Furthermore, there was an association between aggregate number of brachytherapy cases performed and resident confidence in starting a brachytherapy practice (τ = 0.37; P < .001)., Conclusions: Brachytherapy is an important component of residency training that is valued by residents and programs. Because caseload was the greatest perceived barrier in brachytherapy training, with confidence correlated with case volume, attempts should be made to expand opportunities for training experiences that are feasible to complete during residency., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2019
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49. Kinetics of Intratumoral Immune Cell Activation During Chemoradiation for Cervical Cancer.
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Dorta-Estremera S, Colbert LE, Nookala SS, Yanamandra AV, Yang G, Delgado A, Mikkelson M, Eifel P, Jhingran A, Lilie LL, Welsh J, Schmeler K, Sastry JK, and Klopp A
- Subjects
- Adult, Aged, Biopsy, CD11b Antigen metabolism, CD11c Antigen metabolism, CD3 Complex metabolism, CD8-Positive T-Lymphocytes cytology, Cell Proliferation, Cervix Uteri radiation effects, Dendritic Cells cytology, Female, Flow Cytometry, Humans, Kinetics, Lymphocyte Activation, Lymphocytes, Tumor-Infiltrating immunology, Middle Aged, Phenotype, Prospective Studies, Receptors, Antigen, T-Cell immunology, Tumor Microenvironment, Uterine Cervical Neoplasms immunology, Chemoradiotherapy, Immune System, Immunotherapy, Uterine Cervical Neoplasms drug therapy, Uterine Cervical Neoplasms radiotherapy
- Abstract
Purpose: Radiation therapy has direct cytotoxic effects on tumor-infiltrating lymphocytes, but it also has immune stimulatory effects that increase immune cell infiltration. The dynamics of these competing effects on immune cells at the site of the tumor are poorly characterized during chemoradiation treatment (CRT) because of the difficulty of obtaining consecutive tumor biopsies. We used a minimally invasive cervical cytobrushing method to analyze the kinetics of intratumoral immune cell changes in patients with cervical cancer during CRT., Methods and Materials: Cervical brushings were obtained from 20 patients with cervical cancer at baseline and during fractionated radiation therapy and cisplatin (weeks 1, 3, and 5). Matching peripheral blood mononuclear cells were obtained from 9 patients at the same time points. Cells were analyzed using multispectral flow cytometry to identify T cell and myeloid cell subsets and their activation status. Changes in immune cell subsets throughout treatment were calculated using matched-pair analysis with Wilcoxon rank sum test., Results: We observed a significant decline in CD3+ total T cells, as well as CD8+ and CD4+ T-cell subsets in the first week of treatment from baseline, followed by variable expansion at weeks 3 and 5. This coincided with higher levels of proliferating CD8+ T cells expressing Ki67 at week 3 of treatment. The percentages of activated CD8+ T cells expressing CD69 continuously increased over the course of treatment, whereas the percentage of activated CD11c+CD11b- dendritic cells was highest during the first week. Many of these changes were not observed in the blood., Conclusions: Our results identified immune dynamic changes during CRT, indicating that CRT may be immune activating at the site of the tumor. This study also suggests the importance of sequential analyses of the local tumor microenvironment in addition to peripheral blood., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2018
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50. Dose escalation for locally advanced pancreatic cancer: How high can we go?
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Colbert LE, Rebueno N, Moningi S, Beddar S, Sawakuchi GO, Herman JM, Koong AC, Das P, Holliday EB, Koay EJ, and Taniguchi CM
- Abstract
Purpose: There are limited treatment options for locally advanced, unresectable pancreatic cancer (LAPC) and no likelihood of cure without surgery. Radiation offers an option for local control, but radiation dose has previously been limited by nearby bowel toxicity. Advances in on-board imaging and treatment planning may allow for dose escalation not previously feasible and improve local control. In preparation for development of clinical trials of dose escalation in LAPC, we undertook a dosimetric study to determine the maximum possible dose escalation while maintaining known normal tissue constraints., Methods and Materials: Twenty patients treated at our institution with either SBRT or dose-escalated hypofractionated IMRT (DE-IMRT) were re-planned using dose escalated SBRT to 70 Gy in 5 fractions to the GTV and 40 Gy in 5 fractions to the PTV. Standard accepted organ at risk (OAR) constraints were used for planning. Descriptive statistics were generated for homogeneity, conformality, OAR's and GTV/PTV., Results: Mean iGTV coverage by 50 Gy was 91% (±0.07%), by 60 Gy was 61.3% (±0.08%) and by 70 Gy was 24.4% (±0.05%). Maximum PTV coverage by 70 Gy was 33%. Maximum PTV coverage by 60 Gy was 77.5%. The following organ at risk (OAR) constraints were achieved for 90% of generated plans: Duodenum V20 < 30 cc, V30 < 3 cc, V35 < 1 cc; Small Bowel V20 < 15 cc, V30 < 1 cc, V35 < 0.1 cc; Stomach V20 < 20 cc, V30 < 2 cc, V35 < 1 cc. V40 < 0.5 cc was achieved for all OAR., Conclusions: Dose escalation to 60 Gy is dosimetrically feasible with adequate GTV coverage. The identified constraints for OAR's will be used in ongoing clinical trials.
- Published
- 2018
- Full Text
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