Publications by authors named "Xianming Tan"

83 Publications

Inferring latent heterogeneity using many feature variables supervised by survival outcome.

Stat Med 2021 Apr 5. Epub 2021 Apr 5.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

In cancer studies, it is important to understand disease heterogeneity among patients so that precision medicine can particularly target high-risk patients at the right time. Many feature variables such as demographic variables and biomarkers, combined with a patient's survival outcome, can be used to infer such latent heterogeneity. In this work, we propose a mixture model to model each patient's latent survival pattern, where the mixing probabilities for latent groups are modeled through a multinomial distribution. The Bayesian information criterion is used for selecting the number of latent groups. Furthermore, we incorporate variable selection with the adaptive lasso into inference so that only a few feature variables will be selected to characterize the latent heterogeneity. We show that our adaptive lasso estimator has oracle properties when the number of parameters diverges with the sample size. The finite sample performance is evaluated by the simulation study, and the proposed method is illustrated by two datasets.
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http://dx.doi.org/10.1002/sim.8972DOI Listing
April 2021

Estimation of the binomial probabilities in a two-stage phase II clinical trial with two co-primary endpoints.

Contemp Clin Trials 2021 Apr 2;105:106390. Epub 2021 Apr 2.

Canadian Cancer Trials Group, Queen's University, Kingston, ON K7L 3N6, Canada. Electronic address:

In cancer research, two-stage designs are usually used to assess the effect of a new agent in phase II clinical trials. Optimal two-stage designs with two co-primary endpoints have been proposed to assess the effects of new cancer treatments, such as cytostatic or molecularly targeted agents (MTAs), based on both response rate and early progression rate. Accurate estimation of response and early progression rates based on the data from the phase II trials conducted according to the optimal two-stage designs would be very useful for further testing of the agents in phase II trials. In this paper, we derive some estimation procedures, which include both standard and bias-corrected maximum likelihood estimates (MLE) and uniformly minimum variance unbiased estimate (UMVUE), for two binomial probabilities which are used to define the hypotheses for two co-primary endpoints tested in a two-stage phase II clinical trial. Simulation studies were performed to evaluate the performance of these procedures. These procedures are also applied to analyze the data from a phase II trial conducted by the Canadian Cancer Trials Group.
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http://dx.doi.org/10.1016/j.cct.2021.106390DOI Listing
April 2021

Clinical Outcomes of Patients With pT1-T2N0 Oral Tongue Squamous Cell Carcinoma.

Am J Clin Oncol 2021 May;44(5):200-205

Department of Radiation Oncology, University of North Carolina Hospitals.

Objective: The objective of this study was to evaluate the clinical outcomes in a cohort of patients with early-stage oral tongue squamous cell carcinoma (OTSCC).

Materials And Methods: We conducted a retrospective analysis of patients with pT1-T2N0 (American Joint Committee on Cancer [AJCC] seventh edition) OTSCC treated from 2000 to 2018. Two-year actuarial rates of local regional control, cancer-specific survival, and overall survival were calculated for the entire cohort and patients with/without adjuvant radiation.

Results: Ninety-six patients met the criteria with a median follow-up of 4 years; 14 had adjuvant radiation, while 82 had surgery alone. Two-year local regional control was 82.7% (75.4% to 90.8%) for the entire cohort, 84.9% (77.8% to 93.2%) for surgery only, and 70.7% (50.2% to 99.6%) for patients with adjuvant radiation. Two-year progression-free survival was 82.7% (75.3% to 90.8%). Of the 20 patients with recurrence, 11 (55%) were successfully salvaged.

Conclusion: Local regional recurrence remains modest in early-stage OTSCC, but salvage is possible with high survival rates.

Level Of Evidence: Level III-retrospective cohort study.
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http://dx.doi.org/10.1097/COC.0000000000000806DOI Listing
May 2021

Underascertainment of Clinically Meaningful Symptoms During Prostate Cancer Radiation Therapy-Does This Vary by Patient Characteristics?

Int J Radiat Oncol Biol Phys 2021 Feb 2. Epub 2021 Feb 2.

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Radiation Oncology, University of Kansas Cancer Center, Kansas City, Kansas. Electronic address:

Purpose: It is well known that physicians underascertain chemotherapy-related toxicity compared with patient self-report. However, symptom underascertainment in radiation therapy and characterization of patient groups at increased risk for underascertainment have not been examined.

Methods And Materials: As part of routine clinical care, 7 urinary and gastrointestinal symptoms were prospectively collected with both patient-report outcomes (PROs) using the validated Prostate Cancer Symptom Indices and physician-graded symptoms using Common Terminology Criteria for Adverse Events (CTCAE) for 544 consecutive patients from 2010 to 2018 who received intensity modulated radiation therapy to the prostate or prostate bed. Data from weekly treatment visits and the first posttreatment follow-up were analyzed. Underascertainment was defined as an occurrence when a clinically meaningful symptom was indicated on PROs but not physician CTCAE assessment. Univariate and multivariable logistic regression examined characteristics associated with underascertainment.

Results: Overall, 85.3% of patients had underascertainment of at least 1 symptom. Per PRO, 16.9% of assessments reported clinically meaningful symptoms, in contrast to only 3.4% per CTCAE, representing an approximate 5-fold difference. Multivariable analysis showed underascertainment was more common in patients who were unmarried (odds ratio [OR] 1.28; 95% confidence interval [CI], 1.18-1.38), lived in rural regions (OR 1.10; 95% CI, 1.01-1.21), incarcerated (OR 1.58; 95% CI, 1.36-1.84), retired/unemployed (OR 1.29; 95% CI, 1.18-1.40), received prostate gland (vs prostate bed) treatment (OR 1.43; 95% CI, 1.31-1.58), and received concurrent hormone therapy (OR 1.16; 95% CI, 1.04-1.29). Patients age >70 years were less likely to have underascertainment compared with those age <60 years (OR 0.82; 95% CI, 0.73-0.92).

Conclusions: This is the first study to show underascertainment of clinically meaningful symptoms in radiation therapy patients in routine clinical care and further to demonstrate that certain patient groups are especially vulnerable to underascertainment. These results highlight the importance of incorporating PROs in the clinical care of radiation therapy patients. If PROs are not routinely used, vulnerable patient groups may need additional attention during cancer treatment to ensure accurate toxicity assessment and management.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.034DOI Listing
February 2021

Light-Controlled Release of Therapeutic Proteins from Red Blood Cells.

ACS Cent Sci 2021 Jan 9;7(1):93-103. Epub 2020 Dec 9.

Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, United States.

Protein therapeutics are a powerful class of drugs known for their selectivity and potency. However, the potential efficacy of these therapeutics is commonly offset by short circulatory half-lives and undesired action at otherwise healthy tissue. We describe herein a targeted protein delivery system that employs engineered red blood cells (RBCs) as carriers and light as the external trigger that promotes hemolysis and drug release. RBCs internally loaded with therapeutic proteins are readily surface modified with a dormant hemolytic peptide. The latter is activated via easily assigned wavelengths that extend into the optical window of tissue. We have demonstrated that photorelease transpires with spatiotemporal control and that the liberated proteins display the anticipated biological effects . Furthermore, we have confirmed targeted delivery of a clot-inducing enzyme in a mouse model. Finally, we anticipate that this strategy is not limited to RBC carriers but also should be applicable to nano- and microtransporters comprised of bilayer lipid membranes.
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http://dx.doi.org/10.1021/acscentsci.0c01151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844852PMC
January 2021

AIM2 in regulatory T cells restrains autoimmune diseases.

Nature 2021 03 27;591(7849):300-305. Epub 2021 Jan 27.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

The inflammasome initiates innate defence and inflammatory responses by activating caspase-1 and pyroptotic cell death in myeloid cells. It consists of an innate immune receptor/sensor, pro-caspase-1, and a common adaptor molecule, ASC. Consistent with their pro-inflammatory function, caspase-1, ASC and the inflammasome component NLRP3 exacerbate autoimmunity during experimental autoimmune encephalomyelitis by enhancing the secretion of IL-1β and IL-18 in myeloid cells. Here we show that the DNA-binding inflammasome receptor AIM2 has a T cell-intrinsic and inflammasome-independent role in the function of T regulatory (T) cells. AIM2 is highly expressed by both human and mouse T cells, is induced by TGFβ, and its promoter is occupied by transcription factors that are associated with T cells such as RUNX1, ETS1, BCL11B and CREB. RNA sequencing, biochemical and metabolic analyses demonstrated that AIM2 attenuates AKT phosphorylation, mTOR and MYC signalling, and glycolysis, but promotes oxidative phosphorylation of lipids in T cells. Mechanistically, AIM2 interacts with the RACK1-PP2A phosphatase complex to restrain AKT phosphorylation. Lineage-tracing analysis demonstrates that AIM2 promotes the stability of T cells during inflammation. Although AIM2 is generally accepted as an inflammasome effector in myeloid cells, our results demonstrate a T cell-intrinsic role of AIM2 in restraining autoimmunity by reducing AKT-mTOR signalling and altering immune metabolism to enhance the stability of T cells.
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http://dx.doi.org/10.1038/s41586-021-03231-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080937PMC
March 2021

Comparing Laparotomy with Robot-assisted Interval Debulking Surgery for Patients with Advanced Epithelial Ovarian Cancer Receiving Neoadjuvant Chemotherapy.

J Minim Invasive Gynecol 2020 Nov 26. Epub 2020 Nov 26.

Gynecologic Oncology Division, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine (Drs. Zhang, Paraghamian, Clark, and Ms. Grant).

Study Objective: Compare survival of patients with advanced epithelial ovarian cancer (EOC) undergoing interval debulking surgery (IDS) with either robot-assisted (R-IDS) or open (O-IDS) approach. Second, we assessed the impact of adjuvant and neoadjuvant chemotherapy (NACT) cycles as independent variables associated with survival in this patient population.

Design: Retrospective cohort study.

Setting: Single tertiary care center.

Patients: Total of 93 patients diagnosed with advanced EOC who underwent NACT before primary debulking surgery after consultation with a gynecologic oncologist.

Interventions: All patients underwent IDS after completion of NACT with either R-IDS or O-IDS between 2011 and 2018 at a single tertiary care center. Exclusion criteria included receiving fewer than 3 or more than 6 cycles of NACT or having concurrent diagnoses of other malignancies during the treatment period.

Measurements And Main Results: A total of 93 patients were identified (n = 43 R-IDS; n = 50 O-IDS). Median age (63.0 vs 66.2 years) did not differ between the 2 groups (p = .1). Of the total patients, 91% were optimally cytoreduced (57% R0 and 34% R1), and R0 rate was not influenced by surgical modality (52% O-IDS vs 63% R-IDS, p = .4). Progression-free survival (PFS) and overall survival (OS) did not differ between patients undergoing O-IDS and those undergoing R-IDS (PFS 15.4 vs 16.7 months, p = .7; OS 38.2 vs 35.6 months, p = .7). Cytoreduction to R0 improved both PFS and OS independent of surgical approach. Subgroup analysis showed that, specifically in patients undergoing R-IDS, receiving >6 total cycles of chemotherapy was independently associated with both decreased PFS (hazard ratio 3.85; 95% confidence interval, 1.52-9.73) and OS (hazard ratio 3.97; 95% confidence interval, 1.08-14.59). When analyzed separately, neither NACT nor adjuvant cycle numbers had any effect on survival.

Conclusion: In this retrospective study of patients with advanced EOC undergoing IDS after NACT, the use of robot-assisted surgery did not affect debulking success or oncologic survival indices. Receiving >6 total cycles of chemotherapy before IDS was associated with a decrease in both PFS and OS in patients undergoing R-IDS in this cohort and warrants further investigation.
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http://dx.doi.org/10.1016/j.jmig.2020.11.015DOI Listing
November 2020

Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites.

Science 2020 10;370(6516)

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Ionizing radiation causes acute radiation syndrome, which leads to hematopoietic, gastrointestinal, and cerebrovascular injuries. We investigated a population of mice that recovered from high-dose radiation to live normal life spans. These "elite-survivors" harbored distinct gut microbiota that developed after radiation and protected against radiation-induced damage and death in both germ-free and conventionally housed recipients. Elevated abundances of members of the bacterial taxa and were associated with postradiation restoration of hematopoiesis and gastrointestinal repair. These bacteria were also found to be more abundant in leukemia patients undergoing radiotherapy, who also displayed milder gastrointestinal dysfunction. In our study in mice, metabolomics revealed increased fecal concentrations of microbially derived propionate and tryptophan metabolites in elite-survivors. The administration of these metabolites caused long-term radioprotection, mitigation of hematopoietic and gastrointestinal syndromes, and a reduction in proinflammatory responses.
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http://dx.doi.org/10.1126/science.aay9097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898465PMC
October 2020

Associations of Leisure-Time Physical Activity and Television Viewing with Life Expectancy Cancer-Free at Age 50: The ARIC Study.

Cancer Epidemiol Biomarkers Prev 2020 Dec 25;29(12):2617-2625. Epub 2020 Sep 25.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background: Physical activity has been associated with longer chronic disease-free life expectancy, but specific cancer types have not been investigated. We examined whether leisure-time moderate-to-vigorous physical activity (LTPA) and television (TV) viewing were associated with life expectancy cancer-free.

Methods: We included 14,508 participants without a cancer history from the Atherosclerosis Risk in Communities (ARIC) study. We used multistate survival models to separately examine associations of LTPA (no LTPA,
Results: Compared with no LTPA, participants who engaged in LTPA ≥median had a greater life expectancy cancer-free from colorectal [men-2.2 years (95% confidence interval (CI), 1.7-2.7), women-2.3 years (95% CI, 1.7-2.8)], lung [men-2.1 years (95% CI, 1.5-2.6), women-2.1 years (95% CI, 1.6-2.7)], prostate [1.5 years (95% CI, 0.8-2.2)], and postmenopausal breast cancer [2.4 years (95% CI, 1.4-3.3)]. Compared with watching TV often/very often, participants who seldom/never watched TV had a greater colorectal, lung, and postmenopausal breast cancer-free life expectancy of ∼1 year.

Conclusions: Participating in LTPA was associated with longer life expectancy cancer-free from colorectal, lung, prostate, and postmenopausal breast cancer. Viewing less TV was associated with more years lived cancer-free from colorectal, lung, and postmenopausal breast cancer.

Impact: Increasing physical activity and reducing TV viewing may extend the number of years lived cancer-free.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710595PMC
December 2020

Breast cancer treatment delays by socioeconomic and health care access latent classes in Black and White women.

Cancer 2020 Nov 21;126(22):4957-4966. Epub 2020 Sep 21.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background: Breast cancer mortality is higher for Black and younger women. This study evaluated 2 possible contributors to disparities-time to treatment and treatment duration-by race and age.

Methods: Among 2841 participants with stage I-III disease in the Carolina Breast Cancer Study, we identified groups of women with similar patterns of socioeconomic status (SES), access to care, and tumor characteristics using latent class analysis. We then evaluated latent classes in association with treatment delay (initiation >60 days after diagnosis) and treatment duration (in quartiles by treatment modality).

Results: Thirty-two percent of younger Black women were in the highest quartile of treatment duration (versus 22% of younger White women). Black women experienced a higher frequency of delayed treatment (adjusted relative frequency difference [RFD], 5.5% [95% CI, 3.2%-7.8%]) and prolonged treatment duration (RFD, 8.8% [95% CI, 5.7%-12.0%]). Low SES was significantly associated with treatment delay among White women (RFD, 3.5% [95% CI, 1.1%-5.9%]), but treatment delay was high at all levels of SES in Black women (eg, 11.7% in high SES Black women compared with 10.6% and 6.7% among low and high SES White women, respectively). Neither SES nor access to care classes were significantly associated with delayed initiation among Black women, but both low SES and more barriers were associated with treatment duration across both groups.

Conclusions: Factors that influence treatment timeliness persist throughout the care continuum, with prolonged treatment duration being a sensitive indicator of differences by race, SES, and care barriers.
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http://dx.doi.org/10.1002/cncr.33121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789230PMC
November 2020

Cardiovascular disease, risk factors, and health behaviors among cancer survivors and spouses: A MEPS Study.

Cancer Med 2020 09 4;9(18):6864-6874. Epub 2020 Aug 4.

School of Medicine, UNC-CH, Chapel Hill, NC, USA.

Purpose: The purpose of this study was to examine the prevalences of CVD, CVD risk factors. and health behaviors among cancer survivor-spouse dyads, assess how these prevalences differ by role (survivor vs spouse) and gender, and report congruences in health behaviors between survivors and their spouses.

Methods: We identified 1026 survivor-spouse dyads from the 2010-2015 Medical Expenditure Panel Survey. We used weighted multivariable logistic and linear regressions to analyze the data related to CVD, CVD risk factors, and health behaviors.

Results: Survivors and spouses reported high prevalences of CVD and CVD risk factors but low engagement in healthy behaviors, including non-smoking, physical activity, and maintaining a healthy weight (proxy for healthy diet). Gender and role differences were significantly related to the prevalence of CVD, CVD risk factors, and health behaviors among survivors and spouses. From 39% to 88% of survivors and spouses were congruent in their current smoking status, physical activity engagement/disengagement, and BMI.

Conclusion: Cancer survivors and spouses have high rates of CVD and CVD risk factors and poor engagement in healthful lifestyle behaviors. A high proportion of survivors and spouses were congruent in their current smoking status, physical activity engagement/disengagement, and BMI. Effective lifestyle interventions are needed for this high-risk population. Couple-focused interventions may be well-suited for these dyads and warrant further study.

Implications For Cancer Survivors: Both cancer survivors and their spouses need to be non-moking, more physically active, and maintain normal BMI in order to reduce their high risk of CVD and CVD risk factors.
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http://dx.doi.org/10.1002/cam4.3336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520310PMC
September 2020

Enhancing survivorship care planning for patients with localized prostate cancer using a couple-focused web-based, mHealth program: the results of a pilot feasibility study.

J Cancer Surviv 2021 Feb 17;15(1):99-108. Epub 2020 Jul 17.

School of Nursing, University of North Carolina (UNC), Carrington Hall, Chapel Hill, NC, 27599-7460, USA.

Purpose: To examine the feasibility of an enhanced survivorship care plan (ESCP) that integrated the web-based program Patient Education Resources for Couples (PERC) into a standardized survivorship care plan (SCP) and estimated the outcomes of ESCPs versus SCPs.

Methods: In this randomized pilot trial, localized prostate cancer (PC) patients and partners (i.e., couple) were randomly assigned to ESCP that contained a link to PERC or to SCP that contained a link to general PC information on the National Cancer Institute website. Couples completed assessments measuring quality of life (QOL), appraisal of symptoms, and coping resources at baseline (T1) and 4-6 months later (T2). We examined feasibility (e.g., recruitment and retention) using descriptive statistics. Linear mixed models examined changes in couples' outcomes over time and Poisson regression examined differences in patient healthcare utilization.

Results: Sixty-two couples completed T1 surveys (recruitment rate 41.6%) and were randomly assigned to receive ESCP (n = 31) or SCP (n = 31). Twenty-eight (ESCP) and 25 (SCP) couples completed T2 surveys (retention rates = 90.3% vs. 80.7%). ESCP participants (70%) reviewed webpages consistent with patients' symptoms. ESCP patients reported greater program satisfaction (p = 0.02) and better urinary symptom scores (p < 0.01) than SCP patients.

Conclusions: Delivering ESCPs that embed a web-link to a couple-focused, tailored program is feasible and can potentially improve patient outcomes. The promising results need to be validated in a larger definitive trial using a diverse sample.

Implications For Cancer Survivors: SCPs, enhanced using a web-based intervention (e.g., PERC), may help PC cancer survivors better manage their urinary symptoms.

Trial Registration: ClinicalTrials.gov identifier: NCT04350788.
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http://dx.doi.org/10.1007/s11764-020-00914-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855003PMC
February 2021

Psychometric properties of the FACT-G quality of life scale for family caregivers of cancer patients.

Qual Life Res 2020 Aug 3;29(8):2241-2252. Epub 2020 Apr 3.

School of Nursing, University of Michigan-Ann Arbor, Ann Arbor, MI, USA.

Purpose: This study aimed to examine psychometric properties of a caregiver version of the well-established Functional Assessment of Cancer Therapy-General Scale (FACT-G) after conducting focus groups and obtaining expert input.

Methods: We made minor wording modifications to the Patient FACT-G to enable caregivers to report how the illness affected their overall quality of life (QOL) and well-being on four subscales (physical, social, emotional, functional). We tested the acceptability, precision, factor structure, reliability and validity of the Caregiver FACT-G among partners of prostate cancer patients (N = 263) and caregivers (spouses, siblings, adult children) of patients with advanced cancer (breast, lung, colorectal, prostate) (N = 484) using data from two Randomized Clinical Trials (RCTs).

Results: With a factor structure similar to the Patient FACT-G, Caregiver FACT-G was acceptable and precise in measuring caregiver QOL, with high inter-factor correlations and internal consistency reliability (Cronbach's alphas 0.81-0.91). The Caregiver FACT-G had strong convergent validity demonstrated by significant positive correlations with caregiver self-efficacy (0.25-0.63), dyadic communication (0.18-0.51), and social support (0.18-0.54) in both samples. It also had strong discriminant validity evidenced by significant inverse correlations with negative appraisal of caregiving (- 0.37 to - 0.69), uncertainty (- 0.28 to - 0.53), hopelessness (- 0.25 to - 0.60), and avoidant coping (- 0.26 to - 0.58) in both samples. Caregivers' baseline FACT-G scores were significantly associated with their physical (0.23) and mental well-being (0.54; 4-month follow-up) and their depression (- 0.69; 3-month follow-up), indicating strong predictive validity.

Conclusion: This is the first study evaluating the psychometric properties of the Caregiver FACT-G. More psychometric testing is warranted, especially among caregivers of diverse sociocultural backgrounds.
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http://dx.doi.org/10.1007/s11136-020-02477-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363734PMC
August 2020

Development of an Art of Oncology Curriculum to Mitigate Burnout and Foster Solidarity Among Hematology/Oncology Fellows.

JCO Oncol Pract 2020 04 26;16(4):e384-e394. Epub 2020 Feb 26.

UNC Lineberger Comprehensive Cancer Center, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Purpose: Oncologists and fellows in hematology/oncology (HO) training programs report high levels of burnout. The Accreditation Council for Graduate Medical Education requires accredited programs to have a mechanism to foster well-being among fellows.

Methods: Through an iterative process involving a multidisciplinary committee, we created a 3-year longitudinal Art of Oncology (AOO) curriculum intended to address burnout and foster solidary among HO fellows. Sessions used narratives to promote the formation of a shared mental model through discussion of the mutual experience of caring for patients with cancer. We tested the feasibility, acceptability, and initial effectiveness of implementing the curriculum into traditional didactic lectures as a pilot intervention from 2018 to 2019. Eight sessions were completed.

Results: Sixteen fellows participated. Most were married (63%) and planned on pursuing careers in academic medicine (75%). The sample was racially and ethnically diverse (31% minority representation). Thirty-eight percent of fellows reported burnout symptoms. AOO sessions had higher attendance than didactic lectures ( = .04). Of 14 fellows who completed all follow-up assessments (87.5% response rate), 93% (13 of 14 fellows) felt the sessions were very or somewhat helpful and that sessions improved solidarity. Preparedness in managing work-life balance significantly improved (paired test, mean difference, 0.53; = .04). Measured levels of burnout did not significantly improve from baseline (mean difference, -0.133; = .67). Work-life balance was associated with burnout on multivariable analysis (coefficient, 0.40; = .03).

Conclusion: The implementation of a dedicated AOO curriculum is feasible and viewed as helpful by HO fellows. Larger studies are needed to assess the efficacy of this curricular intervention.
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http://dx.doi.org/10.1200/JOP.19.00529DOI Listing
April 2020

Evaluation of a commercial DIR platform for contour propagation in prostate cancer patients treated with IMRT/VMAT.

J Appl Clin Med Phys 2020 Feb;21(2):14-25

Department of Radiation Oncology, University of North Carolina at Chapel Hill, NC.

Purpose: To assess the performance and limitations of contour propagation with three commercial deformable image registration (DIR) algorithms using fractional scans of CT-on-rails (CTOR) and Cone Beam CT (CBCT) in image guided prostate therapy patients treated with IMRT/VMAT.

Methods: Twenty prostate cancer patients treated with IMRT/VMAT were selected for analysis. A total of 453 fractions across those patients were analyzed. Image data were imported into MIM (MIM Software, Inc., Cleveland, OH) and three DIR algorithms (DIR Profile, normalized intensity-based (NIB) and shadowed NIB DIR algorithms) were applied to deformably register each fraction with the planning CT. Manually drawn contours of bladder and rectum were utilized for comparison against the DIR propagated contours in each fraction. Four metrics were utilized in the evaluation of contour similarity, the Hausdorff Distance (HD), Mean Distance to Agreement (MDA), Dice Similarity Coefficient (DSC), and Jaccard indices. A subfactor analysis was performed per modality (CTOR vs. CBCT) and time (fraction). Point estimates and 95% confidence intervals were assessed via a Linear Mixed Effect model for the contour similarity metrics.

Results: No statistically significant differences were observed between the DIR Profile and NIB algorithms. However, statistically significant differences were observed between the shadowed NIB and NIB algorithms for some of the DIR evaluation metrics. The Hausdorff Distance calculation showed the NIB propagated contours vs. shadowed NIB propagated contours against the manual contours were 14.82 mm vs. 8.34 mm for bladder and 15.87 mm vs. 11 mm for rectum, respectively. Similarly, the Mean Distance to Agreement calculation comparing the NIB propagated contours vs. shadowed NIB propagated contours against the manual contours were 2.43 mm vs. 0.98 mm for bladder and 2.57 mm vs. 1.00 mm for rectum, respectively. The Dice Similarity Coefficients comparing the NIB propagated contours and shadowed NIB propagated contours against the manual contours were 0.844 against 0.936 for bladder and 0.772 against 0.907 for rectum, respectively. The Jaccard indices comparing the NIB propagated contours and shadowed NIB propagated contours against the manual contours were 0.749 against 0.884 for bladder and 0.637 against 0.831 for rectum, respectively. The shadowed NIB DIR, which showed the closest agreement with the manual contours performed significantly better than the DIR Profile in all the comparisons. The OAR with the greatest agreement varied substantially across patients and image guided radiation therapy (IGRT) modality. Intra-patient variability of contour metric evaluation was insignificant across all the DIR algorithms. Statistical significance at α = 0.05 was observed for manual vs. deformably propagated contours for bladder for all the metrics except Hausdorff Distance (P = 0.01 for MDA, P = 0.02 for DSC, P = 0.01 for Jaccard), whereas the corresponding values for rectum were: P = 0.03 for HD, P = 0.01 for MDA, P < 0.01 for DSC, P < 0.01 for Jaccard. The performance of the different metrics varied slightly across the fractions of each patient, which indicates that weekly contour propagation models provide a reasonable approximation of the daily contour propagation models.

Conclusion: The high variance of Hausdorff Distance across all automated methods for bladder indicates widely variable agreement across fractions for all patients. Lower variance across all modalities, methods, and metrics were observed for rectum. The shadowed NIB propagated contours were substantially more similar to the manual contours than the DIR Profile or NIB contours for both the CTOR and CBCT imaging modalities. The relationship of each algorithm to similarity with manual contours is consistent across all observed metrics and organs. Screening of image guidance for substantial differences in bladder and rectal filling compared with the planning CT reference could aid in identifying fractions for which automated DIR would prove insufficient.
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http://dx.doi.org/10.1002/acm2.12787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020979PMC
February 2020

A hierarchical testing approach for detecting safety signals in clinical trials.

Stat Med 2020 05 12;39(10):1541-1557. Epub 2020 Feb 12.

Department of Biostatistics, UNC at Chapel Hill, Chapel Hill, North Carolina.

Detecting safety signals in clinical trial safety data is known to be challenging due to high dimensionality, rare occurrence, weak signal, and complex dependence. We propose a new hierarchical testing approach for analyzing safety data from a typical randomized clinical trial. This approach accounts for the hierarchical structure of adverse events (AEs), that is, AEs are categorized by system organ class (SOC). Our approach contains two steps: the first step tests, for each SOC, whether any AEs within this SOC are differently distributed between treatment arms; and the second step identifies signal AEs from SOCs passing the first step tests. We show the superiority, in terms of power of detecting safety signals given controlled false discovery rate, of the new approach comparing with currently available approaches through simulation studies. We also demonstrate this approach with two real data examples.
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http://dx.doi.org/10.1002/sim.8495DOI Listing
May 2020

Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss.

Mol Cell 2020 03 4;77(6):1294-1306.e5. Epub 2020 Feb 4.

Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

von Hippel-Lindau (VHL) is a critical tumor suppressor in clear cell renal cell carcinomas (ccRCCs). It is important to identify additional therapeutic targets in ccRCC downstream of VHL loss besides hypoxia-inducible factor 2α (HIF2α). By performing a genome-wide screen, we identified Scm-like with four malignant brain tumor domains 1 (SFMBT1) as a candidate pVHL target. SFMBT1 was considered to be a transcriptional repressor but its role in cancer remains unclear. ccRCC patients with VHL loss-of-function mutations displayed elevated SFMBT1 protein levels. SFMBT1 hydroxylation on Proline residue 651 by EglN1 mediated its ubiquitination and degradation governed by pVHL. Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and inhibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq, RNA-seq, and patient prognosis identified sphingosine kinase 1 (SPHK1) as a key SFMBT1 target gene contributing to its oncogenic phenotype. Therefore, the pVHL-SFMBT1-SPHK1 axis serves as a potential therapeutic avenue for ccRCC.
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http://dx.doi.org/10.1016/j.molcel.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093231PMC
March 2020

Plasma Circulating Tumor HPV DNA for the Surveillance of Cancer Recurrence in HPV-Associated Oropharyngeal Cancer.

J Clin Oncol 2020 04 4;38(10):1050-1058. Epub 2020 Feb 4.

Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, NC.

Purpose: Plasma circulating tumor human papillomavirus DNA (ctHPVDNA) is a sensitive and specific biomarker of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). We investigated whether longitudinal monitoring of ctHPVDNA during post-treatment surveillance could accurately detect clinical disease recurrence.

Methods And Materials: A prospective biomarker clinical trial was conducted among patients with nonmetastatic HPV-associated (p16-positive) OPSCC. All patients were treated with curative-intent chemoradiotherapy (CRT). Patients underwent a 3-month post-CRT positron emission tomography/computed tomography scan and were thereafter clinically evaluated every 2-4 months (years 1-2), then every 6 months (years 3-5). Chest imaging was performed every 6 months. Blood specimens were collected every 6-9 months for analysis of plasma ctHPVDNA using a multianalyte digital polymerase chain reaction assay. The primary endpoint was to estimate the negative predictive value (NPV) and positive predictive value (PPV) of ctHPVDNA surveillance.

Results: One hundred fifteen patients were enrolled, and 1,006 blood samples were analyzed. After a median follow-up time of 23 months (range, 6.1-54.7 months), 15 patients (13%) developed disease recurrence. Eighty-seven patients had undetectable ctHPVDNA at all post-treatment time points, and none developed recurrence (NPV, 100%; 95% CI, 96% to 100%). Twenty-eight patients developed a positive ctHPVDNA during post-treatment surveillance, 15 of whom were diagnosed with biopsy-proven recurrence. Sixteen patients had 2 consecutively positive ctHPVDNA blood tests, 15 of whom developed biopsy-proven recurrence. Two consecutively positive ctHPVDNA blood tests had a PPV of 94% (95% CI, 70% to 99%). Median lead time between ctHPVDNA positivity and biopsy-proven recurrence was 3.9 months (range, 0.37-12.9 months).

Conclusion: Detection of ctHPVDNA in two consecutive plasma samples during post-treatment surveillance has high PPV and NPV for identifying disease recurrence in patients with HPV-associated oropharyngeal cancer and may facilitate earlier initiation of salvage therapy.
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http://dx.doi.org/10.1200/JCO.19.02444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106982PMC
April 2020

Integrating access to care and tumor patterns by race and age in the Carolina Breast Cancer Study, 2008-2013.

Cancer Causes Control 2020 Mar 16;31(3):221-230. Epub 2020 Jan 16.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Purpose: Understanding breast cancer mortality disparities by race and age is complex due to disease heterogeneity, comorbid disease, and the range of factors influencing access to care. It is important to understand how these factors group together within patients.

Methods: We compared socioeconomic status (SES) and comorbidity factors in the Carolina Breast Cancer Study Phase 3 (CBCS3, 2008-2013) to those for North Carolina using the 2010 Behavioral Risk Factor Surveillance Study. In addition, we used latent class analysis of CBCS3 data to identify covariate patterns by SES/comorbidities, barriers to care, and tumor characteristics and examined their associations with race and age using multinomial logistic regression.

Results: Major SES and comorbidity patterns in CBCS3 participants were generally similar to patterns in the state. Latent classes were identified for SES/comorbidities, barriers to care, and tumor characteristics that varied by race and age. Compared to white women, black women had lower SES (odds ratio (OR)  6.3, 95% confidence interval (CI) 5.2, 7.8), more barriers to care (OR 5.6, 95% CI 3.9, 8.1) and several aggregated tumor aggressiveness features. Compared to older women, younger women had higher SES (OR 0.5, 95% CI 0.4, 0.6), more barriers to care (OR 2.1, 95% CI 1.6, 2.9) and aggregated tumor aggressiveness features.

Conclusions: CBCS3 is representative of North Carolina on comparable factors. Patterns of access to care and tumor characteristics are intertwined with race and age, suggesting that interventions to address disparities will need to target both access and biology.
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http://dx.doi.org/10.1007/s10552-019-01265-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188189PMC
March 2020

TBK1 Is a Synthetic Lethal Target in Cancer with Loss.

Cancer Discov 2020 03 6;10(3):460-475. Epub 2019 Dec 6.

Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.

TANK binding kinase 1 (TBK1) is an important kinase involved in the innate immune response. Here we discover that TBK1 is hyperactivated by von Hippel-Lindau () loss or hypoxia in cancer cells. Tumors from patients with kidney cancer with loss display elevated TBK1 phosphorylation. Loss of TBK1 via genetic ablation, pharmacologic inhibition, or a new cereblon-based proteolysis targeting chimera specifically inhibits VHL-deficient kidney cancer cell growth, while leaving VHL wild-type cells intact. TBK1 depletion also significantly blunts kidney tumorigenesis in an orthotopic xenograft model . Mechanistically, TBK1 hydroxylation on Proline 48 triggers VHL as well as the phosphatase PPM1B binding that leads to decreased TBK1 phosphorylation. We identify that TBK1 phosphorylates p62/SQSTM1 on Ser366, which is essential for p62 stability and kidney cancer cell proliferation. Our results establish that TBK1, distinct from its role in innate immune signaling, is a synthetic lethal target in cancer with VHL loss. SIGNIFICANCE: The mechanisms that lead to TBK1 activation in cancer and whether this activation is connected to its role in innate immunity remain unclear. Here, we discover that TBK1, distinct from its role in innate immunity, is activated by VHL loss or hypoxia in cancer...
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http://dx.doi.org/10.1158/2159-8290.CD-19-0837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058506PMC
March 2020

PIK3CA Mutation in HPV-Associated OPSCC Patients Receiving Deintensified Chemoradiation.

J Natl Cancer Inst 2020 08;112(8):855-858

Department of Radiation Oncology, University of North Carolina Hospitals, Chapel Hill, NC.

PIK3CA is the most frequently mutated gene in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Prognostic implications of such mutations remain unknown. We sought to elucidate the clinical significance of PIK3CA mutations in HPV-associated OPSCC patients treated with definitive chemoradiation (CRT). Seventy-seven patients with HPV-associated OPSCC were enrolled on two phase II clinical trials of deintensified CRT (60 Gy intensity-modulated radiotherapy with concurrent weekly cisplatin). Targeted next-generation sequencing was performed. Of the 77 patients, nine had disease recurrence (two regional, four distant, three regional and distant). Thirty-four patients had mutation(s) identified; 16 had PIK3CA mutations. Patients with wild-type-PIK3CA had statistically significantly higher 3-year disease-free survival than PIK3CA-mutant patients (93.4%, 95% confidence interval [CI] = 85.0% to 99.9% vs 68.8%, 95% CI = 26.7% to 89.8%; P = .004). On multivariate analysis, PIK3CA mutation was the only variable statistically significantly associated with disease recurrence (hazard ratio = 5.71, 95% CI = 1.53 to 21.3; P = .01). PIK3CA mutation is associated with worse disease-free survival in a prospective cohort of newly diagnosed HPV-associated OPSCC patients treated with deintensified CRT.
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http://dx.doi.org/10.1093/jnci/djz224DOI Listing
August 2020

Exercise restores impaired endothelium-derived hyperpolarizing factor-mediated vasodilation in aged rat aortic arteries via the TRPV4-K2.3 signaling complex.

Clin Interv Aging 2019 2;14:1579-1587. Epub 2019 Sep 2.

Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, People's Republic of China.

Background: Aging leads to structural and functional changes in the vasculature characterized by arterial endothelial dysfunction and stiffening of large elastic arteries and is a predominant risk factor for cardiovascular disease, the leading cause of morbidity and mortality in modern societies. Although exercise reduces the risk of many age-related diseases, including cardiovascular disease, the mechanisms underlying the beneficial effects of exercise on age-related endothelial function fully elucidated.

Purpose: The present study explored the effects of exercise on the impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilation in aged arteries and on the involvement of the transient receptor potential vanilloid 4 (TRPV4) channel and the small-conductance calcium-activated potassium (K2.3) channel signaling in this process.

Methods: Male Sprague-Dawley rats aged 19-21 months were randomly assigned to a sedentary group or to an exercise group. Two-month-old rats were used as young controls.

Results: We found that TRPV4 and K2.3 isolated from primary cultured rat aortic endothelial cells pulled each other down in co-immunoprecipitation assays, indicating that the two channels could physically interact. Using ex vivo functional arterial tension assays, we found that EDHF-mediated relaxation induced by acetylcholine or by the TRPV4 activator GSK1016790A was markedly decreased in aged rats compared with that in young rats and was significantly inhibited by TRPV4 or K2.3 blockers in both young and aged rats. However, exercise restored both the age-related and the TRPV4-mediated and K2.3-mediated EDHF responses.

Conclusion: These results suggest an important role for the TRPV4-K2.3 signaling undergirding the beneficial effect of exercise to ameliorate age-related arterial dysfunction.
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http://dx.doi.org/10.2147/CIA.S220283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731547PMC
December 2019

Quantitative expression of MMPs 2, 9, 14, and collagen IV in LCIS and paired normal breast tissue.

Sci Rep 2019 09 17;9(1):13432. Epub 2019 Sep 17.

Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Certain matrix metalloproteinases (MMPs) have the ability to degrade collagen IV, a main component of the breast lobular basement membrane. In this cross-sectional study, we evaluated expression of MMPs 2, 9, and 14 and collagen IV in LCIS and adjacent normal breast tissue among LCIS patients without invasive breast cancer to determine whether expression differed between benign and preinvasive breast epithelial tissue. A total of 64 LCIS patients, diagnosed 2004-2014, were included; 44 had sufficient paired normal tissue for analysis. Marker epithelial expression was measured using immunofluorescence and quantified using the H score (MMPs) or pixel intensity (collagen IV). Associations were evaluated using the Spearman correlation or the Wilcoxon signed-rank test. In LCIS and normal tissue, there was a strong correlation between MMP2 and MMP14 expression (LCIS r = 0.69, normal r = 0.81, both P < 0.01). Other pairwise correlations were moderate to weak (range: LCIS r = 0.32-0.47, normal r = 0.19-0.32). For all markers, expression was lower in LCIS vs. normal tissue (all P ≤ 0.05). In sum, collagenase MMPs were expressed in normal breast and LCIS lesions of LCIS patients. However, expression was not higher in LCIS compared with normal tissue, suggesting collagenase MMP expression does not increase as breast tissue gains a more proliferative phenotype.
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http://dx.doi.org/10.1038/s41598-019-48602-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748975PMC
September 2019

Associations of Leisure-Time Physical Activity and Television Viewing With Life Expectancy Free of Nonfatal Cardiovascular Disease: The ARIC Study.

J Am Heart Assoc 2019 09 9;8(18):e012657. Epub 2019 Sep 9.

Department of Epidemiology University of North Carolina at Chapel Hill NC.

Background High levels of physical activity have been associated with longer life expectancy free of cardiovascular disease (CVD), but specific types of CVD and sedentary behavior have not been examined. We examined associations of leisure-time moderate-to-vigorous physical activity (LTPA) and television viewing with life expectancy free of 3 types of CVD. Methods and Results We included 13 534 participants from the ARIC (Atherosclerosis Risk in Communities) cohort. We used multistate survival models to estimate associations of LTPA in the past year (no LTPA, less than the median, equal to or greater than the median) and television viewing (often or very often, sometimes, seldom or rarely) with life expectancy at age 50 free of nonfatal coronary heart disease (CHD), stroke, and heart failure (HF). Over 27 years of follow-up, 4519 participants developed one of the 3 nonfatal CVDs and 5475 deaths occurred. Compared with participants who engaged in no LTPA, participants who engaged in LTPA equal to or greater than the median had longer life expectancy free of nonfatal CHD (men: 1.5 years [95% CI, 1.0-2.0]; women: 1.6 years [95% CI, 1.1-2.2]), stroke (men: 1.8 years [95% CI, 1.2-2.3]; women: 1.8 years [95% CI, 1.3-2.3]), and HF (men: 1.6 years [95% CI, 1.1-2.1]; women: 1.7 years [95% CI, 1.2-2.2]). Compared with viewing more television, watching less television was associated with longer life expectancy free of CHD, stroke, and HF (≈0.8 year). Conclusions Higher levels of LTPA and less television viewing were associated with longer life expectancy free of CHD, stroke, and HF. Engaging in LTPA and watching less television may increase the number of years lived free of CHD, stroke, and HF.
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http://dx.doi.org/10.1161/JAHA.119.012657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818021PMC
September 2019

Prevalence of cardiovascular disease and risk factors, quality of life, and health behaviors of cancer survivors and their spouses: findings from MEPS.

J Cancer Surviv 2019 Oct 22;13(5):739-748. Epub 2019 Aug 22.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive N.C, Chapel Hill, NC, 27599, USA.

Purpose: Few population-based studies have examined the prevalence of cardiovascular disease (CVD) and risk factors, quality of life (QOL), and health behaviors of cancer survivors and their spouses. This case-control study aimed to fill this gap using the data from a set of large-scale surveys of individuals and families across the USA.

Methods: Data were obtained from the 2010-2015 Medical Expenditure Panel Survey (MEPS). Using one-to-many (1:5) propensity score matching, we identified cancer survivors (N = 1037) and noncancer-matched controls (N = 5185), as well as survivor spouses (N = 1038) and matched controls (N = 5190). We used weighted multivariable logistic and linear regressions to examine the categorical and numerical outcomes.

Results: Compared with noncancer controls, survivors have higher rates of stroke (p < .05), hypertension (p < .05), high cholesterol (p < .01), fair or poor health (p < .0001), and report self-reported worse physical QOL scores (PCS) (p < .0001). A higher percentage of survivors report receiving BP checks (p < .01), serum cholesterol assessments (p < .001), routine physical checkups (p < .01), blood stool tests (p < .05), colonoscopies (p < .0001), and flu vaccinations (p < .05). Survivor spouses, compared to their respective matched controls, reported higher rates of serum cholesterol testing (p < .001), routine physical checkups (p < .01), and flu vaccinations (p < .01).

Conclusions: Compared to the general population, cancer survivors are at higher risk for CVD, report worse physical QOL, and, along with their spouses, more frequently receive certain preventive health care services.

Implications For Cancer Survivors: There is a need for intervention to more fully engage cancer survivors and spouses in lifestyle behavior change associated with decreased CVD and related risk factors and improved QOL.
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http://dx.doi.org/10.1007/s11764-019-00792-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439220PMC
October 2019

Phase II Trial of De-Intensified Chemoradiotherapy for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

J Clin Oncol 2019 10 14;37(29):2661-2669. Epub 2019 Aug 14.

University of Florida Hospitals, Gainesville, FL.

Purpose: To report the results of a phase II clinical trial of de-intensified chemoradiotherapy for patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma.

Materials And Methods: Major inclusion criteria were (1) having American Joint Committee on Cancer (AJCC) 7th edition T0-T3, N0-N2c, M0 (AJCC 8th edition T0-T3, N0-N2, M0), (2) being p16 positive, and (3) reporting minimal or remote smoking history. Treatment was limited to 60 Gy intensity-modulated radiotherapy with concurrent intravenous cisplatin 30 mg/m once per week. Patients with T0-T2 N0-1 (AJCC 7th edition) did not receive chemotherapy. All patients had a 10- to 12-week post-treatment positron emission tomography/computed tomography to assess for neck dissection. The primary end point was 2-year progression-free survival. Secondary end points included 2-year local-regional control, distant metastasis-free survival and overall survival, and patient-reported outcomes (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire and the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events).

Results: One hundred fourteen patients were enrolled (median follow-up of 31.8 months), with 81% having a minimum follow-up of 2 years. Eighty percent of patients had 10 or fewer tobacco pack-years. Two-year local-regional control, distant metastasis-free survival, progression-free survival, and overall survival were as follows: 95%, 91%, 86%, and 95%, respectively. Mean pre- and 2-year post-treatment European Organisation for Research and Treatment of Cancer quality of life scores were as follows: global, 79/84 (lower worse); swallowing, 8/9 (higher worse); and dry mouth, 14/45 (higher worse). Mean pre- and 2-year post-treatment patient-reported outcomes version of the Common Terminology Criteria for Adverse Events scores (0 to 4 scale, higher worse) were as follows: swallowing, 0.5/0.7, and dry mouth, 0.4/1.3. Thirty-four percent of patients required a feeding tube (median, 10.5 weeks; none permanent). There were no grade 3 or higher late adverse events.

Conclusion: Clinical outcomes with a de-intensified chemoradiotherapy regimen of 60 Gy intensity-modulated radiotherapy with concurrent low-dose cisplatin are favorable in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma. Neither neoadjuvant chemotherapy nor routine surgery is needed to obtain favorable results with de-escalation.
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http://dx.doi.org/10.1200/JCO.19.01007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010421PMC
October 2019

Controlling false discovery proportion in identification of drug-related adverse events from multiple system organ classes.

Stat Med 2019 09 17;38(22):4378-4389. Epub 2019 Jul 17.

Department of Biostatistics, UNC at Chapel Hill, Chapel Hill, North Carolina.

Analyzing safety data from clinical trials to detect safety signals worth further examination involves testing multiple hypotheses, one for each observed adverse event (AE) type. There exists certain hierarchical structure for these hypotheses due to the classification of the AEs into system organ classes, and these AEs are also likely correlated. Many approaches have been proposed to identify safety signals under the multiple testing framework and tried to achieve control of false discovery rate (FDR). The FDR control concerns the expectation of the false discovery proportion (FDP). In practice, the control of the actual random variable FDP could be more relevant and has recently drawn much attention. In this paper, we proposed a two-stage procedure for safety signal detection with direct control of FDP, through a permutation-based approach for screening groups of AEs and a permutation-based approach of constructing simultaneous upper bounds for false discovery proportion. Our simulation studies showed that this new approach has controlled FDP. We demonstrate our approach using data sets derived from a drug clinical trial.
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http://dx.doi.org/10.1002/sim.8304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731544PMC
September 2019