Publications by authors named "Shruti Jolly"

105 Publications

Use and Outcomes of SBRT for Early Stage NSCLC Without Pathologic Confirmation in the Veterans Health Care Administration.

Adv Radiat Oncol 2021 Jul-Aug;6(4):100707. Epub 2021 Apr 20.

Center for Clinical Management Research, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan.

Purpose: Stereotactic body radiation therapy (SBRT) use has increased among patients without pathologic confirmation (PC) of lung cancer. Empirical SBRT without PC raises concerns about variation in workup and patient selection, but national trends have not been well described. In this study, we assessed patterns of empirical SBRT use, workup, and causes of death among a large national non-small cell lung cancer (NSCLC) cohort.

Methods And Materials: We identified 2221 patients treated with SBRT for cT1-T2aN0M0 NSCLC in the Veterans Affairs health care system from 2008 to 2015. We reviewed their pretreatment workup and assessed associations between absence of PC and clinical and demographic factors. We compared causes of death between PC and non-PC groups and used Cox proportional hazards modeling to compare overall survival and lung cancer specific survival (LCSS) between these groups.

Results: Treatment without PC varied from 0% to 61% among Veterans Affairs medical centers, with at least 5 cases of stage I NSCLC. Overall, 14.9% of patients were treated without PC and 8.8% did not have a biopsy attempt. Ten percent of facilities were responsible for almost two-thirds (62%) of cases of treatment without PC. Of non-PC patients, 95.5% had positron emission tomography scans, 40.6% had biopsy procedures attempted, and 12.7% underwent endobronchial ultrasound. Non-PC patients were more likely to have cT1 tumors and live outside the histoplasmosis belt. Age, sex, smoking status, and Charlson comorbidity index were similar between groups. Lung cancer was the most common cause of death in both groups. Overall survival was similar between groups, whereas non-PC patients had better LCSS (hazard ratio = 0.77,  = .031).

Conclusions: Empirical SBRT use varied widely among institutions and appropriate radiographic workup was consistently used in this national cohort. Future studies should investigate determinants of variation and reasons for higher LCSS among non-PC patients.
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http://dx.doi.org/10.1016/j.adro.2021.100707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361048PMC
April 2021

Predictors of Pneumonitis After Conventionally Fractionated Radiotherapy for Locally Advanced Lung Cancer.

Int J Radiat Oncol Biol Phys 2021 Jul 24. Epub 2021 Jul 24.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.

Purpose: Multiple factors influence the risk of developing pneumonitis after radiation therapy (RT) for lung cancer, but few resources exist to guide clinicians in predicting risk in an individual patient treated with modern techniques. We analyzed toxicity data from a state-wide consortium to develop an integrated pneumonitis risk model.

Methods And Materials: All patients (N = 1302) received conventionally fractionated RT for stage II-III non-small cell lung cancer between April 2012 and July 2019. Pneumonitis occurring within 6 months of treatment was graded by local practitioners and collected prospectively from 27 academic and community clinics participating in a state-wide quality consortium. Pneumonitis was modeled as either grade ≥2 (G2+) or grade ≥3 (G3+). Logistic regression models were fit to quantify univariable associations with dose and clinical factors, and stepwise Akaike information criterion-based modeling was used to build multivariable prediction models.

Results: The overall rate of pneumonitis of any grade in the 6 months following RT was 16% (208 cases). Seven percent of cases (n = 94) were G2+ and <1% (n = 11) were G3+. Adjusting for incomplete follow-up, estimated rates for G2+ and G3+ were 14% and 2%, respectively. In univariate analyses, gEUD, V5, V10, V20, V30, and mean lung dose (MLD) were positively associated with G2+ pneumonitis risk, whereas current smoking status was associated with lower odds of pneumonitis. G2+ pneumonitis risk of ≥22% was independently predicted by MLD of ≥20 Gy, V20 of ≥35%, and V5 of ≥75%. In multivariate analyses, the lung V5 metric remained a significant predictor of G2+ pneumonitis, even when controlling for MLD, despite their close correlation. For G3+ pneumonitis, MLD and V20 were statistically significant predictors. Number of patient comorbidities was an independent predictor of G3+, but not G2+ pneumonitis.

Conclusions: We present an analysis of pneumonitis risk after definitive RT for lung cancer using a large, prospective dataset. We incorporate comorbidity burden, smoking status, and dosimetric parameters in an integrated risk model. These data may guide clinicians in assessing pneumonitis risk in individual patients.
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http://dx.doi.org/10.1016/j.ijrobp.2021.07.1691DOI Listing
July 2021

Genetic Variations in the Transforming Growth Factor-β1 Pathway May Improve Predictive Power for Overall Survival in Non-small Cell Lung Cancer.

Front Oncol 2021 7;11:599719. Epub 2021 Jul 7.

Department of Radiation Oncology, Case Western Reserve University Comprehensive Cancer Center, Cleveland, OH, United States.

Transforming growth factor-β1 (TGF-β1), a known immune suppressor, plays an important role in tumor progression and overall survival (OS) in many types of cancers. We hypothesized that genetic variations of single nucleotide polymorphisms (SNPs) in the TGF-β1 pathway can predict survival in patients with non-small cell lung cancer (NSCLC) after radiation therapy. Fourteen functional SNPs in the TGF-β1 pathway were measured in 166 patients with NSCLC enrolled in a multi-center clinical trial. Clinical factors, including age, gender, ethnicity, smoking status, stage group, histology, Karnofsky Performance Status, equivalent dose at 2 Gy fractions (EQD2), and the use of chemotherapy, were first tested under the univariate Cox's proportional hazards model. All significant clinical predictors were combined as a group of predictors named "Clinical." The significant SNPs under the Cox proportional hazards model were combined as a group of predictors named "SNP." The predictive powers of models using Clinical and Clinical + SNP were compared with the cross-validation concordance index (C-index) of random forest models. Age, gender, stage group, smoking, histology, and EQD2 were identified as significant clinical predictors: Clinical. Among 14 SNPs, BMP2:rs235756 (HR = 0.63; 95% CI:0.42-0.93; = 0.022), SMAD9:rs7333607 (HR = 2.79; 95% CI 1.22-6.41; = 0.015), SMAD3:rs12102171 (HR = 0.68; 95% CI: 0.46-1.00; = 0.050), and SMAD4: rs12456284 (HR = 0.63; 95% CI: 0.43-0.92; = 0.016) were identified as powerful predictors of SNP. After adding SNP, the C-index of the model increased from 84.1 to 87.6% at 24 months and from 79.4 to 84.4% at 36 months. Genetic variations in the TGF-β1 pathway have the potential to improve the prediction accuracy for OS in patients with NSCLC.
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http://dx.doi.org/10.3389/fonc.2021.599719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294034PMC
July 2021

A situational awareness Bayesian network approach for accurate and credible personalized adaptive radiotherapy outcomes prediction in lung cancer patients.

Phys Med 2021 Jul 4;87:11-23. Epub 2021 Jun 4.

Department of Radiation Oncology, The University of Michigan, Ann Arbor, MI, USA.

Purpose: A situational awareness Bayesian network (SA-BN) approach is developed to improve physicians' trust in the prediction of radiation outcomes and evaluate its performance for personalized adaptive radiotherapy (pART).

Methods: 118 non-small-cell lung cancer patients with their biophysical features were employed for discovery (n = 68) and validation (n = 50) of radiation outcomes prediction modeling. Patients' important characteristics identified by radiation experts to predict individual's tumor local control (LC) or radiation pneumonitis with grade ≥ 2 (RP2) were incorporated as expert knowledge (EK). Besides generating an EK-based naïve BN (EK-NBN), an SA-BN was developed by incorporating the EK features into pure data-driven BN (PD-BN) methods to improve the credibility of LC or / and RP2 prediction. After using area under the free-response receiver operating characteristics curve (AU-FROC) to assess the joint prediction of these outcomes, their prediction performances were compared with a regression approach based on the expert yielded estimates (EYE) penalty and its variants.

Results: In addition to improving the credibility of radiation outcomes prediction, the SA-BN approach outperformed the EYE penalty and its variants in terms of the joint prediction of LC and RP2. The value of AU-FROC improves from 0.70 (95% CI: 0.54-0.76) using EK-NBN, to 0.75 (0.65-0.82) using a variant of EYE penalty, to 0.83 (0.75-0.93) using PD-BN and 0.83 (0.77-0.90) using SA-BN; with similar trends in the validation cohort.

Conclusions: The SA-BN approach can provide an accurate and credible human-machine interface to gain physicians' trust in clinical decision-making, which has the potential to be an important component of pART.
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http://dx.doi.org/10.1016/j.ejmp.2021.05.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284560PMC
July 2021

Contemporary Practice Patterns for Palliative Radiation Therapy of Bone Metastases: Impact of a Quality Improvement Project on Extended Fractionation.

Pract Radiat Oncol 2021 May 26. Epub 2021 May 26.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. Electronic address:

Purpose: Radiation therapy effectively palliates bone metastases, although variability exists in practice patterns. National recommendations advocate against using extended fractionation (EF) with courses greater than 10 fractions. We previously reported EF use of 14.8%. We analyzed practice patterns within a statewide quality consortium to assess EF use in a larger patient population after implementation of a quality measure focused on reducing EF.

Methods And Materials: Patients treated for bone metastases within a statewide radiation oncology quality consortium were prospectively enrolled from March 2018 through October 2020. The EF quality metric was implemented March 1, 2018. Data on patient, physician, and facility characteristics; fractionation schedules; and treatment planning and delivery techniques were collected. Multivariable binary logistic regression was used to assess EF.

Results: Twenty-eight facilities enrolled 1445 consecutive patients treated with 1934 plans. The median number of treatment plans per facility was 52 (range, 7-307). Sixty different fractionation schedules were used. EF was delivered in 3.4% of plans. Initially, EF use was lower than expected and remained low over time. Significant predictors for EF use included complicated metastasis (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.04-4.02; P = .04), lack of associated central nervous system or visceral disease (OR, 2.27; 95% CI, 1.2-4.2; P = .01), nonteaching versus teaching facilities (OR, 8.97; 95% CI, 2.1-38.5; P < .01), and treating physicians with more years in practice (OR, 12.82; 95% CI, 3.9-42.4; P < .01).

Conclusions: Within a large, prospective population-based data set, fractionation schedules for palliative radiation therapy of bone metastases remain highly variable. Resource-intensive treatments including EF persist, although EF use was low after implementation of a quality measure. Complicated metastases, lack of central nervous system or visceral disease, and treatment at nonteaching facilities or by physicians with more years in practice significantly predict use of EF. These results support ongoing efforts to more clearly understand and address barriers to high-value radiation approaches in the palliative setting.
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http://dx.doi.org/10.1016/j.prro.2021.05.002DOI Listing
May 2021

New Therapies and Biomarkers: Are We Ready for Personalized Treatment in Small Cell Lung Cancer?

Am Soc Clin Oncol Educ Book 2021 Mar;41:1-10

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

Small cell lung cancer (SCLC) is an aggressive form of lung cancer with a 5-year survival rate of less than 7%. In contrast to non-small cell lung cancer, SCLC has long been treated as a homogeneous disease without personalized treatment options. In recent years, the incorporation of immunotherapy into the treatment paradigm has brought moderate benefit to patients with SCLC; however, more effective therapies are urgently needed. In this article, we describe the current treatment standards and emerging therapeutic approaches for the treatment of SCLC. We also discuss promising biomarkers in SCLC and the recently discovered four subtypes of SCLC, each with its unique therapeutic vulnerability. Lastly, we discuss the advances in radiation therapy for the treatment of SCLC.
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http://dx.doi.org/10.1200/EDBK_320673DOI Listing
March 2021

Investigating the SPECT Dose-Function Metrics Associated With Radiation-Induced Lung Toxicity Risk in Patients With Non-small Cell Lung Cancer Undergoing Radiation Therapy.

Adv Radiat Oncol 2021 May-Jun;6(3):100666. Epub 2021 Feb 7.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

Purpose: Dose to normal lung has commonly been linked with radiation-induced lung toxicity (RILT) risk, but incorporating functional lung metrics in treatment planning may help further optimize dose delivery and reduce RILT incidence. The purpose of this study was to investigate the impact of the dose delivered to functional lung regions by analyzing perfusion (Q), ventilation (V), and combined V/Q single-photon-emission computed tomography (SPECT) dose-function metrics with regard to RILT risk in patients with non-small cell lung cancer (NSCLC) patients who received radiation therapy (RT).

Methods And Materials: SPECT images acquired from 88 patients with locally advanced NSCLC before undergoing conventionally fractionated RT were retrospectively analyzed. Dose was converted to the nominal dose equivalent per 2 Gy fraction, and SPECT intensities were normalized. Regional lung segments were defined, and the average dose delivered to each lung region was quantified. Three functional categorizations were defined to represent low-, normal-, and high-functioning lungs. The percent of functional lung category receiving ≥20 Gy and mean functional intensity receiving ≥20 Gy (iV) were calculated. RILT was defined as grade 2+ radiation pneumonitis and/or clinical radiation fibrosis. A logistic regression was used to evaluate the association between dose-function metrics and risk of RILT.

Results: By analyzing V/Q normalized intensities and functional distributions across the population, a wide range in functional capability (especially in the ipsilateral lung) was observed in patients with NSCLC before RT. Through multivariable regression models, global lung average dose to the lower lung was found to be significantly associated with RILT, and Q and V iV were correlated with RILT when using ipsilateral lung metrics. Through a receiver operating characteristic analysis, combined V/Q low-function receiving ≥20 Gy (low-functioning V/Q) in the ipsilateral lung was found to be the best predictor (area under the curce: 0.79) of RILT risk.

Conclusions: Irradiation of the inferior lung appears to be a locational sensitivity for RILT risk. The multivariable correlation between ipsilateral lung iV and RILT, as well as the association of low-functioning V/Q and RILT, suggest that irradiating low-functioning regions in the lung may lead to higher toxicity rates.
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http://dx.doi.org/10.1016/j.adro.2021.100666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010578PMC
February 2021

A Multi-Institutional Analysis of Adjuvant Chemotherapy and Radiation Sequence in Women With Stage IIIC Endometrial Cancer.

Int J Radiat Oncol Biol Phys 2021 08 5;110(5):1423-1431. Epub 2021 Mar 5.

Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Purpose: Our purpose was to evaluate the effect of sequence and type of adjuvant therapy for patients with stage IIIC endometrial carcinoma (EC) on outcomes.

Methods And Materials: In a multi-institutional retrospective cohort study, patients with stage IIIC EC who had surgical staging and received both adjuvant chemotherapy and radiation therapy (RT) were included. Adjuvant treatment regimens were classified as adjuvant chemotherapy followed by sequential RT (upfront chemo), which was predominant sequence; RT with concurrent chemotherapy followed by chemotherapy (concurrent); systemic chemotherapy before and after RT (sandwich); adjuvant RT followed by chemotherapy (upfront RT); or chemotherapy concurrent with vaginal cuff brachytherapy alone (chemo-brachy). Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method.

Results: A total of 686 eligible patients were included with a median follow-up of 45.3 months. The estimated 5-year OS and RFS rates were 74% and 66%, respectively. The sequence and type of adjuvant therapy were not correlated with OS or RFS (adjusted P = .68 and .84, respectively). On multivariate analysis, black race, nonendometrioid histology, grade 3 tumor, stage IIIC2, and presence of adnexal and cervical involvement were associated with worse OS and RFS (all P < .05). Regardless of the sequence of treatment, the most common site of first recurrence was distant metastasis (20.1%). Vaginal only, pelvic only, and paraortic lymph node (PALN) recurrences occurred in 11 (1.6%),15 (2.2 %), and 43 (6.3 %) patients, respectively. Brachytherapy alone was associated with a higher rate of PALN recurrence (15%) compared with external beam radiation therapy (5%) P < .0001.

Conclusions: The sequence and type of combined adjuvant therapy did not affect OS or RFS rates. Brachytherapy alone was associated with a higher rate of PALN recurrence, emphasizing the role of nodal radiation for stage IIIC EC. The vast proportion of recurrences were distant despite systemic chemotherapy, highlighting the need for novel regimens.
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http://dx.doi.org/10.1016/j.ijrobp.2021.02.055DOI Listing
August 2021

Mapping lung ventilation through stress maps derived from biomechanical models of the lung.

Med Phys 2021 Feb 23;48(2):715-723. Epub 2020 Dec 23.

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

Purpose: Most existing computed tomography (CT)-ventilation imaging techniques are based on deformable image registration (DIR) of different respiratory phases of a four-dimensonal CT (4DCT) scan of the lung, followed by the quantification of local breathing-induced changes in Hounsfield Units (HU) or volume. To date, only moderate correlations have been reported between these CT-ventilation metrics and standard ventilation imaging modalities for adaptive lung radiation therapy. This study evaluates the use of stress maps derived from biomechanical model-based DIR as an alternative CT-ventilation metric.

Materials And Methods: Six patients treated for lung cancer with conventional radiation therapy were retrospectively analyzed. For each patient, a 4DCT scan and Tc-99m SPECT-V image acquired for treatment planning were collected. Biomechanical model-based DIR was applied between the inhale and exhale phase of the 4DCT scans and stress maps were calculated. The voxel-wise correlation between the reference SPECT-V image and map of the maximum principal stress was measured with a Spearman correlation coefficient. The overlap between high (above the 75th percentile) and low (below the 25th percentile) functioning volumes extracted from the reference SPECT-V and the stress maps was measured with Dice similarity coefficients (DSC). The results were compared to those obtained when using two classical CT-ventilation metrics: the change in HU and Jacobian determinant.

Results: The mean Spearman correlation coefficients were: 0.37 ± 18 and 0.39 ± 13 and 0.59 ± 0.13 considering the changes in HU, Jacobian and maximum principal stress, respectively. The corresponding mean DSC coefficients were 0.38 ± 0.09, 0.37 ± 0.07 and 0.52 ± 0.07 for the high ventilation function volumes and 0.48 ± 0.13, 0.44 ± 0.09 and 0.52 ± 0.07 for the low ventilation function volumes.

Conclusion: For presenting a significantly stronger and more consistent correlation with standard SPECT-V images than previously proposed CT-ventilation metrics, stress maps derived with the proposed method appear to be a promising tool for incorporation into functional lung avoidance strategies.
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http://dx.doi.org/10.1002/mp.14643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444226PMC
February 2021

Particle Beam Therapy for Cardiac-Sparing Radiotherapy in Non-Small Cell Lung Cancer.

Semin Radiat Oncol 2021 Apr;31(2):112-119

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI. Electronic address:

Radiation therapy plays an integral role in the treatment of all stages of non-small cell lung cancer. Survival outcomes are improving, but radiation therapy remains associated with long-term toxicity. Recently, it has become evident that the heart is an important organ at risk for treatment-related morbidity. In this review, we discuss the hypothesis that particle radiation therapy offers superior dosimetry compared with photon-based treatment, and that this comparative advantage translates into clinically meaningful cardiac toxicity reduction with similar local tumor control. We discuss the evidence in non-small cell lung cancer to date, the ongoing prospective trials that may provide additional insight, and the opportunities to optimally integrate particle therapy into future prospective investigation.
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http://dx.doi.org/10.1016/j.semradonc.2020.11.005DOI Listing
April 2021

Weighted-Support Vector Machine Learning Classifier of Circulating Cytokine Biomarkers to Predict Radiation-Induced Lung Fibrosis in Non-Small-Cell Lung Cancer Patients.

Front Oncol 2020 1;10:601979. Epub 2021 Feb 1.

Department of Clinical Oncology, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.

Background: Radiation-induced lung fibrosis (RILF) is an important late toxicity in patients with non-small-cell lung cancer (NSCLC) after radiotherapy (RT). Clinically significant RILF can impact quality of life and/or cause non-cancer related death. This study aimed to determine whether pre-treatment plasma cytokine levels have a significant effect on the risk of RILF and investigate the abilities of machine learning algorithms for risk prediction.

Methods: This is a secondary analysis of prospective studies from two academic cancer centers. The primary endpoint was grade≥2 (RILF2), classified according to a system consistent with the consensus recommendation of an expert panel of the AAPM task for normal tissue toxicity. Eligible patients must have at least 6 months' follow-up after radiotherapy commencement. Baseline levels of 30 cytokines, dosimetric, and clinical characteristics were analyzed. Support vector machine (SVM) algorithm was applied for model development. Data from one center was used for model training and development; and data of another center was applied as an independent external validation.

Results: There were 57 and 37 eligible patients in training and validation datasets, with 14 and 16.2% RILF2, respectively. Of the 30 plasma cytokines evaluated, SVM identified baseline circulating CCL4 as the most significant cytokine associated with RILF2 risk in both datasets ( = 0.003 and 0.07, for training and test sets, respectively). An SVM classifier predictive of RILF2 was generated in Cohort 1 with CCL4, mean lung dose (MLD) and chemotherapy as key model features. This classifier was validated in Cohort 2 with accuracy of 0.757 and area under the curve (AUC) of 0.855.

Conclusions: Using machine learning, this study constructed and validated a weighted-SVM classifier incorporating circulating CCL4 levels with significant dosimetric and clinical parameters which predicts RILF2 risk with a reasonable accuracy. Further study with larger sample size is needed to validate the role of CCL4, and this SVM classifier in RILF2.
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http://dx.doi.org/10.3389/fonc.2020.601979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883680PMC
February 2021

Integrative Oncology Education: An Emerging Competency for Oncology Providers.

Curr Oncol 2021 02 10;28(1):853-862. Epub 2021 Feb 10.

Department of Family Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

A growing number of cancer patients use complementary and alternative therapies during and after conventional cancer treatment. Patients are often reluctant to discuss these therapies with their oncologist, and oncologists may have limited knowledge and confidence on how to advise patients on the appropriate use. Integrative oncology is a patient-centered, evidence-informed field that utilizes mind-body practices, lifestyle modifications and/or natural products interwoven with conventional cancer treatment. It prioritizes safety and best available evidence to offer appropriate interventions alongside conventional care. There are few opportunities for oncologists to learn about integrative oncology. In this commentary, we highlight the Integrative Oncology Scholars (IOS) program as a means to increase competency in this growing field. We provide an overview of several integrative oncology modalities that are taught through this program, including lifestyle modifications, physical activity, and mind-body interventions. We conclude that as more evidence is generated in this field, it will be essential that oncology healthcare providers are aware of the prevalent use of these modalities by their patients and cancer centers include Integrative Oncology trained physicians and other healthcare professionals in their team to discuss and recommend evidence-based integrative oncology therapies alongside conventional cancer treatments to their patients.
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http://dx.doi.org/10.3390/curroncol28010084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985783PMC
February 2021

In Reply to Hasan et al.

Int J Radiat Oncol Biol Phys 2020 12 18;108(5):1391-1392. Epub 2020 Nov 18.

University of Michigan, Department of Radiation Oncology, Ann Arbor, Michigan.

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http://dx.doi.org/10.1016/j.ijrobp.2020.06.034DOI Listing
December 2020

Extracellular vesicles on demand (EVOD) chip for screening and quantification of cancer-associated extracellular vesicles.

Biosens Bioelectron 2020 Nov 23;168:112535. Epub 2020 Aug 23.

Department of Chemical Engineering and Biointerface Institute, University of Michigan, 2800 Plymouth Road, NCRC B10-A184, Ann Arbor, MI, 48109, USA; Roger Cancer Center, University of Michigan, 1500 E Medical Center Dr. Ann Arbor, 48109, USA. Electronic address:

While significant advancements have been made in cancer therapeutics and treatments, early disease detection and diagnosis remains critical to ensuring favorable outcomes for patients. To that end, we propose a microfluidic based approach to the sensitive detection of an intriguing cancer biomarker, extracellular vesicles (EVs). Our extracellular vesicles on demand (EVOD) chip utilizes a catalyst-free click chemistry to rapidly and specifically isolate EVs of interest. This specific isolation is followed by subsequent dithiothreitol release of the isolated EVs for downstream functional analysis. This joint isolation and release provide a powerful tool for the screening and quantification of EVs of interest. By incorporating antibodies against cancer associated surface proteins into the click-chemistry, we were able to selectively recover cancer-associated exosomes, allowing for important insights into patient disease. This platform was also tested using non-small cell lung cancer (NSCLC) patient samples, where anti-epidermal growth factor receptor (EGFR) assisted platform were able to selectively isolate and release 76% more exosomes from NSCLC patients than from healthy donors. This matches the previously reported higher EGFR expression commonly found in NSCLC EVs. Through its rapid isolation kinetics and adaptability in marker targeting, the EVOD device provides a highly versatile liquid biopsy platform for clinicians to use in the fight against cancer.
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http://dx.doi.org/10.1016/j.bios.2020.112535DOI Listing
November 2020

Executive summary of the American Radium Society® Appropriate Use Criteria for management of uterine carcinosarcoma.

Gynecol Oncol 2020 08 29;158(2):460-466. Epub 2020 May 29.

Stritch School of Medicine, Loyola University Chicago, IL, United States of America.

Objective: Uterine carcinosarcomas (UCS) represent a rare but aggressive subset of endometrial cancers, comprising <5% of uterine malignancies. To date, limited prospective trials exist from which evidence-based management of this rare malignancy can be developed.

Methods: The American Radium Society Appropriate Use Criteria presented in this manuscript are evidence-based guidelines developed by a multidisciplinary expert panel for management of women with UCS. An extensive analysis of current medical literature from peer-reviewed journals was performed. A well-established methodology (modified Delphi) was used to rate the appropriate use of imaging and treatment procedures for the management of UCS. These guidelines are intended for the use of all practitioners who desire information about the management of UCS.

Results: The majority of patients with UCS will present with advanced extra uterine disease, with 10% presenting with metastatic disease. They have worse survival outcomes when compared to uterine high-grade endometrioid adenocarcinomas. The primary treatment for non-metastatic UCS is complete surgical staging with total hysterectomy, salpingo-oophorectomy and lymph node staging. Patients with UCS appear to benefit from adjuvant multimodality therapy to reduce the chance of tumor recurrence with the potential to improve overall survival.

Conclusion: Women diagnosed with uterine UCS should undergo complete surgical staging. Adjuvant multimodality therapies should be considered in the treatment of both early- and advanced stage patients. Long-term surveillance is indicated as many of these women may recur. Prospective clinical studies of women with UCS are necessary for optimal management.
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http://dx.doi.org/10.1016/j.ygyno.2020.04.683DOI Listing
August 2020

Central Airway Toxicity After High Dose Radiation: A Combined Analysis of Prospective Clinical Trials for Non-Small Cell Lung Cancer.

Int J Radiat Oncol Biol Phys 2020 11 26;108(3):587-596. Epub 2020 May 26.

Department of Radiation Oncology, University Hospitals/Seidman Cancer Center and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio; Department of Clinical Oncology, Hong Kong University Shenzhen Hospital and Queen Mary Hospital, Hong Kong University Li Ka Shing Medical School, Hong Kong, China. Electronic address:

Purpose: To study the dosimetric risk factors for radiation-induced proximal bronchial tree (PBT) toxicity in patients treated with radiation therapy for non-small cell lung cancer (NSCLC).

Methods And Materials: Patients with medically inoperable or unresectable NSCLC treated with conventionally fractionated 3-dimensional conformal radiation therapy (3DCRT) in prospective clinical trials were eligible for this study. Proximal bronchial tree (PBT) and PBT wall were contoured consistently per RTOG 1106 OAR-Atlas. The dose-volume histograms (DVHs) of physical prescription dose (DVHp) and biological effective dose (α/β = 2.5; DVH2.5) were generated, respectively. The primary endpoint was PBT toxicities, defined by CTCAE 4.0 under the terminology of bronchial stricture/atelectasis.

Results: Of 100 patients enrolled, with a median follow-up of 64 months (95% confidence interval [CI], 50-78), 73% received 70 Gy or greater and 17% developed PBT toxicity (grade 1, 8%; grade 2, 6%; grade 3, 0%; and grade 4, 3%). The median time interval between RT initiation and onset of PBT toxicity was 8.4 months (95% CI, 4.7-44.1). The combined DVHs showed that no patient with a PBT maximum physical dose <65 Gy developed any PBT toxicity. Cox proportional hazards analysis and receiver operating characteristic analysis demonstrated that V75 of PBT was the most significant dosimetric parameter for both grade 1+ (P = .035) and grade 2+ (P = .037) PBT toxicities. The dosimetric thresholds for V75 of PBT were 6.8% and 11.9% for grade 1+ and grade 2+ PBT toxicity, respectively.

Conclusions: V75 of PBT appeared be the most significant dosimetric parameter for PBT toxicity after conventionally fractionated thoracic 3DCRT. Constraining V75 of PBT can limit clinically significant PBT toxicity.
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http://dx.doi.org/10.1016/j.ijrobp.2020.05.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074530PMC
November 2020

Radiation-Induced Insufficiency Fractures After Pelvic Irradiation for Gynecologic Malignancies: A Systematic Review.

Int J Radiat Oncol Biol Phys 2020 11 19;108(3):620-634. Epub 2020 May 19.

University of Michigan, Department of Radiation Oncology, Ann Arbor, Michigan. Electronic address:

Purpose: To identify and define the incidence, risk factors, clinical characteristics, and treatment approaches to pelvic insufficiency fractures (PIFs) that develop as a consequence of pelvic radiation therapy for gynecologic malignancies.

Materials And Methods: A systematic literature review (PubMed and Embase indexed from January 1, 1980, to May 1, 2020) of studies describing PIFs that result from radiation therapy for gynecologic malignancies. A random-effects model weighted by the inverse variance was used to calculate the pooled crude incidence, actuarial incidence, and proportion of symptomatic PIFs, and to evaluate the relationship between PIF incidence and various risk factors.

Results: Thirty-eight studies describing PIFs following radiation therapy for gynecologic malignancies were reviewed. A meta-analysis of 6488 patients (37 studies) identified the crude incidence of PIF as 9.4% (95% confidence interval [CI] 6.8%-12.4%), and a meta-analysis of 2131 patients (9 studies) identified the 5-year actuarial incidence of PIF as 15.3% (95% CI 7.5%-25.0%). Factors that significantly correlated with increased risk of PIF development included evidence of osteoporosis (P < .001), postmenopausal state (P < .001), and history of diabetes mellitus (P = .005). Median time to PIF development ranged from 8 to 39 months after radiation therapy with the sacrum being the most frequent location for fracture development (60%). From 18 studies, 58.5% (95% CI 50.6%-66.2%) of PIFs were symptomatic, with pain as the most common presenting symptom of PIFs. Conservative management was used more than bone-directed therapies for treatment of PIFs (85% and 6% of patients, respectively).

Conclusions: PIFs cause significant morbidity in gynecologic cancer patients after radiation therapy. In this systematic review, we discuss the incidence and risk factors associated with PIF development as it relates to the different detection methods, radiation techniques, doses, and gynecologic cancers treated. Additional studies are needed to further define prevention and treatment approaches for insufficiency fractures.
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http://dx.doi.org/10.1016/j.ijrobp.2020.05.013DOI Listing
November 2020

Microfluidic device for high-throughput affinity-based isolation of extracellular vesicles.

Lab Chip 2020 05;20(10):1762-1770

Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.

Immunoaffinity based EV isolation technologies use antibodies targeting surface markers on EVs to provide higher isolation specificity and purity compared to existing approaches. One standing challenge for researchers is how to release captured EVs from the substrate to increase downstream and biological studies. The strong binding between the antibody and antigen or the antibody and substrate is commonly unbreakable without operating at conditions outside of the critical physiological range, making the release of EVs problematic. Additionally, immuno-affinity approaches are usually low-throughput due to their low flow velocity to ensure adequate time for antibody-antigen binding. To overcome these limitations, we modified the OncoBean chip, a previously reported circulating tumor cell isolation microfluidic device. The OncoBean chip is a radial flow microfluidic device with bean-shape microposts functionalized with biotin-conjugated EPCAM antibody through biotin-avidin link chemistry. It was demonstrated that the high surface area and varying shear rate provided by the bean-shaped posts and the radial flow design in the chip, enabled efficient capture of CTCs at high flow rate. We replace the anti-EPCAM with antibodies that recognize common EV surface markers to achieve high-throughput EV isolation. Moreover, by incorporating desthiobiotin-conjugated antibodies, EVs can be released from the device after capture, which offers a significant improvement over the existing isolation. The released EVs were found to be functional by confirming their uptake by cells using flow cytometry and fluorescent microscopy. We believe the proposed technology can facilitate both the study of EVs as cell-to-cell communicators and the further identification of EV markers.
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http://dx.doi.org/10.1039/c9lc01190kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328786PMC
May 2020

A Phase 1 Trial Assessing the Safety and Tolerability of a Therapeutic DNA Vaccination Against HPV16 and HPV18 E6/E7 Oncogenes After Chemoradiation for Cervical Cancer.

Int J Radiat Oncol Biol Phys 2020 07 7;107(3):487-498. Epub 2020 Mar 7.

Department of Radiation and Cellular Oncology, University of Chicago, Chicago Illinois.

Purpose: This study assessed the safety and tolerability of therapeutic immunization against the human papillomavirus (HPV) viral oncoproteins E6 and E7 in patients with cervical cancer after chemoradiation.

Methods And Materials: MEDI0457 (INO-3112) is a DNA-based vaccine targeting E6 and E7 of HPV-16/18 that is coinjected with an IL-12 plasmid followed by electroporation with the CELLECTRA 5P device. At 2 to 4 weeks after chemoradiation, patients with newly diagnosed stage IB1-IVA (cohort 1) or persistent/recurrent (cohort 2) cervical cancers were treated with 4 immunizations of MEDI0457 every 4 weeks. The primary endpoints were incidence of adverse events and injection site reactions. Immune responses against HPV antigens were measured by ELISpot for interferon-γ (IFNγ), enzyme-linked immunosorbent assay for antibody responses and multiplexed immunofluorescence for immune cells in cervical biopsy specimens.

Results: Ten patients (cohort 1, n = 7; cohort 2, n = 3) with HPV16 (n = 7) or HPV18 (n = 3) cervical cancers received MEDI0457 after chemoradiation. Treatment-related adverse events were all grade 1, primarily related to the injection site. Eight of 10 patients had detectable cellular or humoral immune responses against HPV antigens after chemoradiation and vaccination: 6 of 10 patients generated anti-HPV antibody responses and 6 of 10 patients generated IFNγ-producing T cell responses. At the completion of chemoradiation and vaccination, cervical biopsy specimens had detectable CD8 T cells and decreased PD-1CD8, PD-L1CD8, and PD-L1CD68 subpopulations. All patients cleared detectable HPV DNA in cervical biopsies by completion of chemoradiation and vaccination.

Conclusions: Adjuvant MEDI0457 is safe and well tolerated after chemoradiation for locally advanced or recurrent cervical cancers, supporting further investigation into combining tumor-specific vaccines with radiation therapy.
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http://dx.doi.org/10.1016/j.ijrobp.2020.02.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705948PMC
July 2020

Paired phase II trials evaluating cetuximab and radiotherapy for low risk HPV associated oropharyngeal cancer and locoregionally advanced squamous cell carcinoma of the head and neck in patients not eligible for cisplatin.

Head Neck 2020 08 27;42(8):1728-1737. Epub 2020 Jan 27.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

Background: Alternative therapeutic strategies are needed for localized oropharyngeal carcinoma. Cetuximab represents a potential option for those ineligible for cisplatin or, until recently, an agent for de-escalation in low risk HPV+ oropharyngeal carcinoma (OPSCC). Our objective was to define the toxicity and efficacy of cetuximab-radiotherapy.

Methods: We conducted paired phase II trials evaluating cetuximab-radiotherapy in two cohorts (a) low risk HPV+ OPSCC and (b) cisplatin ineligible. The mean follow-up was 48 months.

Results: Forty-two patients were enrolled in cohort A with a 2-year disease free survival (DFS) of 81%. Twenty-one patients were enrolled in cohort B prior to closure due to adverse outcomes with a 2-year DFS of 37%. Severe toxicities were seen in 60% of patients, 30% required enteral nutrition.

Conclusion: Among cisplatin ineligible patients, cetuximab treatment engendered poor outcomes. Rates of severe toxicities were on par with platinum-based regimens suggesting that cetuximab is not a benign treatment.
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http://dx.doi.org/10.1002/hed.26085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404812PMC
August 2020

Patient-reported financial toxicity and adverse medical consequences in head and neck cancer.

Oral Oncol 2020 02 23;101:104521. Epub 2019 Dec 23.

Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States; Department of Internal Medicine, Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI, United States. Electronic address:

Objectives: Financial toxicity (FT) is a significant barrier to high-quality cancer care, and patients with head and neck cancer (HNCA) are particularly vulnerable given their need for intensive support, daily radiotherapy (RT), and management of long-term physical, functional, and psychosocial morbidities following treatment. We aim to identify predictors of FT and adverse consequences in HNCA following RT.

Materials And Methods: We performed a prospective survey study of patients with HNCA seen in follow-up at an academic comprehensive cancer center (CCC) or Veterans Affairs hospital between 05/2016 and 06/2018. Surveys included validated patient-reported functional outcomes and the COST measure, a validated instrument for measuring FT.

Results: The response rate was 86% (n = 63). Younger age and lower median household income by county were associated with lower COST scores (i.e., worse FT) on multivariable analysis (p = .045 and p = .016, respectively). Patients with worse FT were more likely to skip clinic visits (RR (95% CI) 2.13 (1.23-3.67), p = .007), be noncompliant with recommended supplements or medications (1.24 (1.03-1.48), p = .02), and require supportive infusions (1.10 (1.02-1.20), p = .02). At the CCC, patients with worse FT were more likely to require feeding tubes (1.62 (1.14-2.31), p = .007). Overall, 36% reported that costs were higher than expected, 48% were worried about paying for treatment, and 33% reported at least a moderate financial burden from treatment.

Conclusion: HNCA patients experience substantial FT from their diagnosis and/or therapy, with potential implications for medical compliance, QOL, and survivorship care.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008081PMC
February 2020

A Pilot Study of Atezolizumab Plus Hypofractionated Image Guided Radiation Therapy for the Treatment of Advanced Non-Small Cell Lung Cancer.

Int J Radiat Oncol Biol Phys 2020 09 19;108(1):170-177. Epub 2019 Nov 19.

Department of Medicine, Hematology-Oncology, University of Michigan, Ann Arbor, Michigan. Electronic address:

Purpose: Preclinical data and subset analyses from immunotherapy clinical trials indicate that prior radiation therapy was associated with better progression-free survival and overall survival when combined with immune checkpoint inhibitors in patients with non-small cell lung cancer. We present a prospective study of hypofractionated image guided radiation therapy (HIGRT) to a single site of metastatic disease concurrently with atezolizumab in patients with metastatic non-small cell lung cancer.

Methods And Materials: Patients meeting eligibility criteria received 1200 mg of atezolizumab intravenously every 3 weeks with concurrent 3- or 5-fraction HIGRT starting no later than the second cycle. The 3-fraction regimen employed a minimum of 8 Gy per fraction compared with 6 Gy for the 5-fraction regimen. Imaging was obtained every 12 weeks to assess response.

Results: From October 2015 to February 2017, 12 patients were enrolled in the study (median age 64; range, 55-77 years). The best response by the Response Evaluation in Solid Tumors criteria was partial response in 3 and stable disease in 3, for a disease control rate of 50%. Five patients had a grade 3 immune-related adverse event, including choreoretinitis (n = 1), pneumonitis (n = 1), transaminitis (n = 1), fatigue (n = 1), and peripheral neuropathy (n = 1). The median progression-free survival was 2.3 months, and the median overall survival was 6.9 months (range, 0.4-not reached). There was no clear association between peripheral blood T cell repertoire characteristics at baseline, PD-L1, or tumor mutations and response or outcome. One long-term survivor exhibited oligoclonal T cell populations in a baseline tumor biopsy that were consistently detected in peripheral blood over the entire course of the study.

Conclusions: HIGRT plus atezolizumab resulted in an overall response rate of 25% and disease control rate of 50% in this pilot study. The incidence of grade 3 adverse events was similar to that of atezolizumab alone. Alhough it was a pilot study with limited sample size, the results generated hypotheses worthy of further investigation.
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http://dx.doi.org/10.1016/j.ijrobp.2019.10.047DOI Listing
September 2020

Interstitial High-Dose-Rate Gynecologic Brachytherapy: Clinical Workflow Experience From Three Academic Institutions.

Semin Radiat Oncol 2020 01;30(1):29-38

Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL.

An interstitial brachytherapy approach for gynecologic cancers is typically considered for patients with lesions exceeding 5 mm within tissue or that are not easily accessible for intracavitary applications. Recommendations for treating gynecologic malignancies with this approach are available through the American Brachytherapy Society, but vary based on available resources, staffing, and logistics. The intent of this manuscript is to share the collective experience of 3 academic centers that routinely perform interstitial gynecologic brachytherapy. Discussion points include indications for interstitial implants, procedural preparations, applicator selection, anesthetic options, imaging, treatment planning objectives, clinical workflows, timelines, safety, and potential challenges. Interstitial brachytherapy is a complex, high-skill procedure requiring routine practice to optimize patient safety and treatment efficacy. Clinics planning to implement this approach into their brachytherapy practice may benefit from considering the discussion points shared in this manuscript.
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http://dx.doi.org/10.1016/j.semradonc.2019.08.001DOI Listing
January 2020

A utility approach to individualized optimal dose selection using biomarkers.

Biom J 2020 03 6;62(2):386-397. Epub 2019 Nov 6.

Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.

In many settings, including oncology, increasing the dose of treatment results in both increased efficacy and toxicity. With the increasing availability of validated biomarkers and prediction models, there is the potential for individualized dosing based on patient specific factors. We consider the setting where there is an existing dataset of patients treated with heterogenous doses and including binary efficacy and toxicity outcomes and patient factors such as clinical features and biomarkers. The goal is to analyze the data to estimate an optimal dose for each (future) patient based on their clinical features and biomarkers. We propose an optimal individualized dose finding rule by maximizing utility functions for individual patients while limiting the rate of toxicity. The utility is defined as a weighted combination of efficacy and toxicity probabilities. This approach maximizes overall efficacy at a prespecified constraint on overall toxicity. We model the binary efficacy and toxicity outcomes using logistic regression with dose, biomarkers and dose-biomarker interactions. To incorporate the large number of potential parameters, we use the LASSO method. We additionally constrain the dose effect to be non-negative for both efficacy and toxicity for all patients. Simulation studies show that the utility approach combined with any of the modeling methods can improve efficacy without increasing toxicity relative to fixed dosing. The proposed methods are illustrated using a dataset of patients with lung cancer treated with radiation therapy.
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http://dx.doi.org/10.1002/bimj.201900030DOI Listing
March 2020

Isolation and Profiling of Circulating Tumor-Associated Exosomes Using Extracellular Vesicular Lipid-Protein Binding Affinity Based Microfluidic Device.

Small 2019 11 7;15(47):e1903600. Epub 2019 Oct 7.

Department of Chemical Engineering and Biointerface Institute, University of Michigan, 2800 Plymouth Road, NCRC B10-A184, Ann Arbor, MI, 48109, USA.

Extracellular vesicles (EVs) are emerging as a potential diagnostic test for cancer. Owing to the recent advances in microfluidics, on-chip EV isolation is showing promise with respect to improved recovery rates, smaller necessary sample volumes, and shorter processing times than ultracentrifugation. Immunoaffinity-based microfluidic EV isolation using anti-CD63 is widely used; however, anti-CD63 is not specific to cancer-EVs, and some cancers secrete EVs with low expression of CD63. Alternatively, phosphatidylserine (PS), usually expressed in the inner leaflet of the lipid bilayer of the cells, is shown to be expressed on the outer surface of cancer-associated EVs. A new exosome isolation microfluidic device ( ExoChip), conjugated with a PS-specific protein, to isolate cancer-associated exosomes from plasma, is presented. The device achieves 90% capture efficiency for cancer cell exosomes compared to 38% for healthy exosomes and isolates 35% more A549-derived exosomes than an anti-CD63-conjugated device. Immobilized exosomes are then easily released using Ca chelation. The recovered exosomes from clinical samples are characterized by electron microscopy and western-blot analysis, revealing exosomal shapes and exosomal protein expressions. The ExoChip facilitates the isolation of a specific subset of exosomes, allowing the exploration of the undiscovered roles of exosomes in cancer progression and metastasis.
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http://dx.doi.org/10.1002/smll.201903600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951813PMC
November 2019

A Validation Study on IDO Immune Biomarkers for Survival Prediction in Non-Small Cell Lung Cancer: Radiation Dose Fractionation Effect in Early-Stage Disease.

Clin Cancer Res 2020 01 30;26(1):282-289. Epub 2019 Aug 30.

Department of Radiation Oncology, University Hospitals Cleveland Medical Center/Seidman Cancer Center, Cleveland, Ohio.

Purpose: We recently reported that indoleamine 2, 3-dioxygenase (IDO) activity is significantly correlated with more distant metastasis and worse survival. The present study examined whether radiotherapy (RT) dose fractionation correlates with IDO-mediated immune activity in patients with early-stage NSCLC. Patients with newly diagnosed stage I-II NSCLC treated with either conventionally fractionated 3-dimensional conformal radiotherapy (3DCRT) or stereotactic body radiotherapy (SBRT) were analyzed. Levels of two key molecules associated with the IDO immune checkpoint, serum kynurenine and the kynurenine:tryptophan ratio (K:T ratio), were measured at pre-RT, during-RT, and 3-month post-RT. The relationship between disease control outcomes [overall survival (OS), progression free survival, and local/regional/distant failure rates] and absolute levels of these markers, as well as dynamic changes in their levels during RT, was studied.

Results: Fifty-six patients (SBRT = 28, 3DCRT = 28) with early-stage NSCLC were studied. In all patients, higher kynurenine post-RT was significantly associated with worse OS ([HR, 1.25; 95% confidence interval (CI), 1.01-1.55; = 0.044). No statistically significant differences in absolute kynurenine levels or the K:T ratio were observed in patients treated with 3DCRT or SBRT at any of the three time points. However, the absolute kynurenine levels rose significantly more post-RT in the 3DCRT patients with a median increase 0.721 ng/mL, compared to that of SBRT patients (0.115 ng/mL); = 0.022.

Conclusions: This study validated that elevated IDO activity correlated with worse survival outcomes in patients with early-stage NSCLC treated with definitive RT. Hypofractionated SBRT may have less immunosuppressive effect than 3DCRT, as measured by IDO.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1202DOI Listing
January 2020

Multiplex isolation and profiling of extracellular vesicles using a microfluidic DICE device.

Analyst 2019 Oct 29;144(19):5785-5793. Epub 2019 Aug 29.

Department of Chemical Engineering and Biointerface Institutes, University of Michigan, 2800 Plymouth Road, NCRC B10-A184, Ann Arbor, MI 48109, USA.

Profiling of extracellular vesicles (EVs) is an emerging area in the field of liquid biopsies because of their innate significance in diseases and abundant information reflecting disease status. However, unbiased enrichment of EVs and thorough profiling of EVs is challenging. In this paper, we present a simple strategy to immobilize and analyze EVs for multiple markers on a single microfluidic device and perform differentiated immunostaining-based characterization of extracellular vesicles (DICE). This device, composed of four quadrants with a single inlet, captures biotinylated EVs efficiently and facilitates multiplexed immunostaining to profile their extracellular proteins, allowing for a multiplexed approach for non-invasive cancer diagnostics in the future. From controlled sample experiments using cancer cell line derived EVs and specific fluorescence staining with lipophilic dyes, we identified that the DICE device is capable of isolating biotinylated EVs with 84.4% immobilization efficiency. We extended our study to profile EVs of 9 clinical samples from non-small cell lung cancer (NSCLC) patients and healthy donors and found that the DICE device successfully facilitates immunofluorescent staining for both the NSCLC patients and the healthy control. This versatile and simple method to profile EVs could be extended to EVs of any biological origin, promoting discoveries of the role of EVs in disease diagnostics and monitoring.
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http://dx.doi.org/10.1039/c9an01235dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774196PMC
October 2019

Cardiac Dose in Locally Advanced Lung Cancer: Results From a Statewide Consortium.

Pract Radiat Oncol 2020 Jan - Feb;10(1):e27-e36. Epub 2019 Aug 2.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

Purpose: The heart has been identified as a potential significant organ at risk in patients with locally advanced non-small cell lung cancer treated with radiation. Practice patterns and radiation dose delivered to the heart in routine practice in academic and community settings are unknown.

Methods And Materials: Between 2012 and 2017, 746 patients with stage III non-small cell lung cancer were treated with radiation within the statewide Michigan Radiation Oncology Quality Consortium (MROQC). Cardiac radiation dose was characterized, including mean and those exceeding historical or recently proposed Radiation Therapy Oncology Group and NRG Oncology constraints. Sites were surveyed to determine dose constraints used in practice. Patient-, anatomic-, and treatment-related associations with cardiac dose were analyzed using multivariable regression analysis and inverse probability weighting.

Results: Thirty-eight percent of patients had a left-sided primary, and 80% had N2 or N3 disease. Median prescription was 60 Gy (interquartile range, 60-66 Gy). Twenty-two percent of patients were prescribed 60 Gy in 2012, which increased to 62% by 2017 (P < .001). Median mean heart dose was 12 Gy (interquartile range, 5-19 Gy). The volume receiving 30 Gy (V30 Gy) exceeded 50% in 5% of patients, and V40 Gy was >35% in 3% of cases. No heart dose constraint was uniformly applied. Intensity modulated radiation therapy (IMRT) usage increased from 33% in 2012 to 86% in 2017 (P < .001) and was significantly associated with more complex cases (larger planning target volume, higher stage, and preexisting cardiac disease). In multivariable regression analysis, IMRT was associated with a lower percent of the heart receiving V30 Gy (absolute reduction = 3.0%; 95% confidence interval, 0.5%-5.4%) and V50 Gy (absolute reduction = 3.6%; 95% confidence interval, 2.4%-4.8%) but not mean dose. In inverse probability weighting analysis, IMRT was associated with 29% to 48% relative reduction in percent of the heart receiving V40-V60 Gy without increasing lung or esophageal dose or compromising planning target volume coverage.

Conclusions: Within MROQC, historical cardiac constraints were met in most cases, yet 1 in 4 patients received a mean heart dose exceeding 20 Gy. Future work is required to standardize heart dose constraints and to develop treatment approaches that allow for constraints to be met without compromising other planning goals.
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http://dx.doi.org/10.1016/j.prro.2019.07.013DOI Listing
June 2020

Recommendations for Single-Fraction Radiation Therapy and Stereotactic Body Radiation Therapy in Palliative Treatment of Bone Metastases: A Statewide Practice Patterns Survey.

Pract Radiat Oncol 2019 Nov 19;9(6):e541-e548. Epub 2019 Jul 19.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. Electronic address:

Purpose: Single-fraction (SF) radiation therapy is effective and convenient for patients with painful noncomplex bone metastases. Prior survey results reported a low recommendation of SF radiation therapy in the US. We sought to assess contemporary treatment recommendations for the management of bone metastases among diverse physicians participating in a statewide quality consortium.

Methods And Materials: Members of the Michigan Radiation Oncology Quality Consortium were surveyed between April and May 2017. Physicians rated the importance of 31 variables on their choice of dose fractionation. The survey also covered 7 patient scenarios.

Results: Fifty-six physicians responded who were practicing at 18 of 20 centers surveyed. Respondents recommended 23 dose-fractionation schedules across the 7 scenarios. Highest-rated factors considered when choosing a dose fractionation regimen were performance status, prognosis, spinal cord compression, and prior radiation therapy. Recommendations for SF overall were uncommon (16.1%). On multivariable analysis, factors associated with SF use included academic employment (odds ratio [OR] 2.04; 95% CI, 1.02-4.08; P = .044) and higher palliative case volume (OR 2.59; 95% CI, 1.45-4.63; P = .001). Stereotactic body radiation therapy (SBRT) was recommended in 16.4% of scenarios overall, and on multivariable analysis, significant predictors for SBRT use were academic employment (OR 2.99; 95% CI, 1.39-6.44; P = .005), more recent residency completion (OR 4.37; 95% CI, 1.26-15.17; P = .02), spine location (OR 12.54; 95% CI, 3.96-39.68; P < .001), and prior radiation therapy (OR 26.67; 95% CI, 7.86-90.57; P < .001). SF rates were higher than in a survey reported in 2009 (16.1% vs 9.4%, P = .0004).

Conclusions: SF radiation therapy remains uncommonly recommended, although it may be recommended more now than it was 10 years ago despite the increased utilization of SBRT. We identify multiple key drivers in physician decision making affecting SF recommendations that have not been addressed by prior level one evidence. Further research with evidence-based recommendations to clarify the role of SF and SBRT in management of patients with bony metastases are needed.
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http://dx.doi.org/10.1016/j.prro.2019.07.005DOI Listing
November 2019
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