Publications by authors named "Sin-Ho Jung"

213 Publications

Group sequential testing for cluster randomized trials with time-to-event endpoint.

Biometrics 2021 Jun 2. Epub 2021 Jun 2.

Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina.

We propose group sequential methods for cluster randomized trials (CRTs) with time-to-event endpoint. The alpha spending function approach is used for sequential data monitoring. The key to this approach is determining the joint distribution of test statistics and the information fraction at the time of interim analysis. We prove that the sequentially computed log-rank statistics in CRTs do not have independent increment property. We also propose an information fraction for group sequential trials with clustered survival data and a corresponding sample size determination approach. Extensive simulation studies are conducted to evaluate the performance of our proposed testing procedure using some existing alpha spending functions in terms of expected sample size and maximal sample size. Real study examples are taken to demonstrate our method.
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http://dx.doi.org/10.1111/biom.13498DOI Listing
June 2021

Design and Analysis of Cancer Clinical Trials for Personalized Medicine.

Authors:
Sin-Ho Jung

J Pers Med 2021 May 4;11(5). Epub 2021 May 4.

Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710, USA.

Biomarkers play a key role in the development of personalized medicine. Cancer clinical trials with biomarker should be appropriately designed and analyzed reflecting the various factors, such as the phase of trials, the type of biomarker, the study objectives, and whether the used biomarker is already validated or not. In this paper, we demonstrate design and analysis of two phase II cancer clinical trials, one with a predictive biomarker and the other with a prognostic biomarker. A statistical testing method and its sample size calculation method are presented for each of the trials. We assume that the primary endpoint of these trials is a time to event variable, but this concept can be used for any type of endpoint with associated testing methods. The test statistics and their sample size formulas are derived using the large sample approximation based on the martingale central limit theorem. Using simulations, we find that the test statistics control the type I error rate accurately and the sample sizes calculated using the formulas maintain the statistical power specified at the design stage.
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http://dx.doi.org/10.3390/jpm11050376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147797PMC
May 2021

Decreased Mortality in 1-Year Survivors of Umbilical Cord Blood Transplant vs. Matched Related or Matched Unrelated Donor Transplant in Patients with Hematologic Malignancies.

Transplant Cell Ther 2021 08 12;27(8):669.e1-669.e8. Epub 2021 May 12.

Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina. Electronic address:

Allogeneic hematopoietic stem cell transplantation (HCT) has the potential to cure hematologic malignancies but is associated with significant morbidity and mortality. Although deaths during the first year after transplantation are often attributable to treatment toxicities and complications, death after the first year may be due to sequelae of accelerated aging caused by cellular senescence. Cytotoxic therapies and radiation used in cancer treatments and conditioning regimens for HCT can induce aging at the molecular level; HCT patients experience time-dependent effects, such as frailty and aging-associated diseases, more rapidly than people who have not been exposed to these treatments. Consistent with this, recipients of younger cells tend to have decreased markers of aging and improved survival, decreased graft-versus-host disease, and lower relapse rates. Given that umbilical cord blood (UCB) is the youngest donor source available, we studied the outcomes after the first year of UCB transplantation versus matched related donor (MRD) and matched unrelated donor (MUD) transplantation in patients with hematologic malignancies over a 20-year period. In this single-center, retrospective study, we examined the outcomes of all adult patients who underwent their first allogeneic HCT through the Duke Adult Bone Marrow Transplant program from January 1, 1996, to December 31, 2015, to allow for at least 3 years of follow-up. Patients were excluded if they died or were lost to follow-up before day 365 after HCT, received an allogeneic HCT for a disease other than a hematologic malignancy, or received cells from a haploidentical or mismatched adult donor. UCB recipients experienced a better unadjusted overall survival than MRD/MUD recipients (log rank P = .03, median overall survival: UCB not reached, MRD/MUD 7.4 years). After adjusting for selected covariates, UCB recipients who survived at least 1 year after HCT had a hazard of death that was 31% lower than that of MRD/MUD recipients (hazard ratio, 0.69; 95% confidence interval, 0.47-0.99; P = .049). This trend held true in a subset analysis of subjects with acute leukemia. UCB recipients also experienced lower rates of moderate or severe chronic graft-versus-host disease (GVHD) and nonrelapse mortality, and slower time to relapse. UCB and MRD/MUD recipients experienced similar rates of grade 2-4 acute GVHD, chronic GHVD, secondary malignancy, and subsequent allogeneic HCT. UCB is already widely used as a donor source in pediatric HCT; however, adult outcomes and adoption have historically lagged behind in comparison. Recent advancements in UCB transplantation such as the implementation of lower-intensity conditioning regimens, double unit transplants, and ex vivo expansion have improved early mortality, making UCB an increasingly attractive donor source for adults; furthermore, our findings suggest that UCB may actually be a preferred donor source for mitigating late effects of HCT.
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http://dx.doi.org/10.1016/j.jtct.2021.05.002DOI Listing
August 2021

Randomised, double-blind, placebo-controlled trial of Probiotics To Eliminate COVID-19 Transmission in Exposed Household Contacts (PROTECT-EHC): a clinical trial protocol.

BMJ Open 2021 05 5;11(5):e047069. Epub 2021 May 5.

Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA

Introduction: The COVID-19 pandemic has proven to be an unprecedented challenge to worldwide health, and strategies to mitigate the spread and severity of COVID-19 infection are urgently needed. Emerging evidence suggests that the composition of the gut microbiome and modification of microbial ecology via probiotics can affect susceptibility to a wide range of infections, including respiratory tract infections. In this study, we aim to evaluate the effects of the probiotic (LGG) versus placebo on COVID-19 infection status and the gut microbiome in subjects with a household contact who has tested positive for COVID-19.

Methods And Analysis: In this double-blinded, randomised, placebo-controlled trial, we will randomise 1132 subjects having a household contact who has recently (≤7 days) tested positive for COVID-19 to daily oral LGG or placebo for 28 days. We hypothesise that taking LGG as a probiotic will protect against COVID-19 infection and reduce the severity of disease in those who become infected (primary endpoint: decreased symptoms), and will be associated with beneficial changes in the composition of the gut microbiome. Stool samples and nasal swabs will be collected to evaluate the microbiome by 16S rRNA sequencing and the presence of SARS-CoV-2 by PCR, respectively. We will also conduct multivariate analysis of demographic, behavioural, temporal, and other variables that may predict development of symptoms and other outcomes.

Ethics And Dissemination: This trial is conducted under a Food and Drug Administration Investigational New Drug for LGG, has received ethics approval by the institutional review board of Duke University and enrolment has begun. We plan to disseminate the results in peer-reviewed journals and at national and international conferences.

Trial Registration Number: NCT04399252.
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http://dx.doi.org/10.1136/bmjopen-2020-047069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102858PMC
May 2021

Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma.

J Immunother Cancer 2021 Apr;9(4)

Duke Cancer Institute, Duke University, Durham, NC, USA.

Background: While programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antagonists have improved the prognosis for many patients with melanoma, around 60% fail therapy. PVSRIPO is a non-neurovirulent rhinovirus:poliovirus chimera that facilitates an antitumor immune response following cell entry via the poliovirus receptor CD155, which is expressed on tumor and antigen-presenting cells. Preclinical studies show that oncolytic virus plus anti-PD-1 therapy leads to a greater antitumor response than either agent alone, warranting clinical investigation.

Methods: An open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (American Joint Committee on Cancer V.7 stage IIIB, IIIC, or IV) was performed. Eligible patients had disease progression on anti-PD-1 and V-raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen activated protein kinase kinase (MEK) inhibitors (if BRAF mutant). The primary objective was to characterize the safety and tolerability of PVSRIPO. Twelve patients in four cohorts received a total of 1, 2 or 3 injections of PVSRIPO monotherapy, with 21 days between injections.

Results: PVSRIPO injections were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) reported. All adverse events (AEs) were grade (G) 1 or G2 (G1 pruritus most common at 58%); all but two PVSRIPO-treatment related AEs were localized to the injected or adjacent lesions (n=1 G1 hot flash, n=1 G1 fatigue). Four out of 12 patients (33%) achieved an objective response per immune-related response criteria (two observations, 4 weeks apart), including 4/6 (67%) who received three injections. In the four patients with in-transit disease, a pathological complete response (pCR) was observed in two (50%) patients. Following study completion, 11/12 patients (92%) reinitiated immune checkpoint inhibitor-based therapy, and 6/12 patients (50%) remained without progression at a median follow-up time of 18 months.

Conclusion: Intratumoral PVSRIPO was well tolerated. Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients>5 lesions), intratumoral PVSRIPO showed promising antitumor activity, with pCR in injected as well as non-injected lesions in select patients.

Trial Registration Number: NCT03712358.
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http://dx.doi.org/10.1136/jitc-2020-002203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057552PMC
April 2021

The Influence of Vitamin D on Mammographic Density: Results from CALGB 70806 (Alliance) a Randomized Clinical Trial.

Cancer Prev Res (Phila) 2021 Jul 13;14(7):753-762. Epub 2021 Apr 13.

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

Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and toxicity limits use of these agents. Vitamin D is a potential prevention therapy for both ER+ and ER- disease and is safe with few side effects. This study evaluates the effect of 1-year of vitamin D supplementation on mammographic density (MD), a biomarker of breast cancer risk in a multicenter randomized controlled trial. Premenopausal women with ≥25% MD and no history of cancer were randomly assigned to 2,000 international units (IU) of vitamin D or placebo orally daily for 1 year. Change in percent MD was evaluated using Cumulus software after all participants completed treatment. Three hundred women enrolled between January 2011 and December 2013 with a mean age of 43 and diverse ethnicity [14% Hispanic, 12% African American (AA)]. Supplementation significantly increased vitamin D levels compared with placebo (14.5 ng/mL vs. -1.6 ng/mL; < 0.0001) with all participants on the vitamin D arm achieving vitamin D sufficiency at 12 months. Vitamin D was safe and well tolerated. After adjustment for baseline MD, the mean between-arm difference (vitamin D vs. placebo) at 1 year was -0.75 (-0.26, 1.76; = 0.56). A greater effect was seen for women with ≥50% MD and AA women, although neither reached significance. This randomized controlled trial demonstrated significant improvement in vitamin D levels with 2,000 IU for 1 year, with 100% of supplemented women achieving sufficiency. However, a null effect was seen regarding change in MD for premenopausal women (the primary outcome of the study). PREVENTION RELEVANCE: Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and are underutilized due to toxicity and side effects. Vitamin D is a potential prevention therapy for both ER+ and ER- disease and is safe with few side effects.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0581DOI Listing
July 2021

Long-term outcomes of aortic root operations in the United States among Medicare beneficiaries.

J Thorac Cardiovasc Surg 2021 Feb 25. Epub 2021 Feb 25.

Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, NC. Electronic address:

Objective: The best method of aortic root repair in older patients remains unknown given a lack of comparative effectiveness of long-term outcomes data. The objective of this study was to compare long-term outcomes of different surgical approaches for aortic root repair in Medicare patients using The Society of Thoracic Surgeons Adult Cardiac Surgery Database-Centers for Medicare & Medicaid Services-linked data.

Methods: A retrospective cohort study was performed by querying the Society of Thoracic Surgeons Adult Cardiac Surgery Database for patients aged 65 years or more who underwent elective aortic root repair with or without aortic valve replacement. Primary long-term end points were mortality, any stroke, and aortic valve reintervention. Short-term outcomes and long-term survival were compared among each root repair strategy. Additional risk factors for mortality after aortic root repair were assessed with a multivariable Cox proportional hazards model.

Results: A total of 4173 patients aged 65 years or more underwent elective aortic root repair. Patients were stratified by operative strategy: mechanical Bentall, stented bioprosthetic Bentall, stentless bioprosthetic Bentall, or valve-sparing root replacement. Mean follow-up was 5.0 (±4.6) years. Relative to mechanical Bentall, stented bioprosthetic Bentall (adjusted hazard ratio, 0.80; confidence interval, 0.66-0.97) and stentless bioprosthetic Bentall (adjusted hazard ratio, 0.70; confidence interval, 0.59-0.84) were associated with better long-term survival. In addition, stentless bioprosthetic Bentall (adjusted hazard ratio, 0.64; confidence interval, 0.47-0.80) and valve-sparing root replacement (adjusted hazard ratio, 0.51; confidence interval, 0.29-0.90) were associated with lower long-term risk of stroke. Aortic valve reintervention risk was 2-fold higher after valve-sparing root replacement compared with other operative strategies.

Conclusions: In the Medicare population, there was poorer late survival and greater late stroke risk for patients undergoing mechanical Bentall and a higher rate of reintervention for valve-sparing root replacement. Bioprosthetic Bentall may be the procedure of choice in older patients undergoing aortic root repair, particularly in the era of transcatheter aortic valve replacement.
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http://dx.doi.org/10.1016/j.jtcvs.2021.02.068DOI Listing
February 2021

Chlorhexidine Gluconate Bathing Reduces the Incidence of Bloodstream Infections in Adults Undergoing Inpatient Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 03 7;27(3):262.e1-262.e11. Epub 2021 Jan 7.

Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina. Electronic address:

Bloodstream infections (BSIs) occur in 20% to 45% of inpatient autologous and allogeneic hematopoietic cell transplant (HCT) patients. Daily bathing with the antiseptic chlorhexidine gluconate (CHG) has been shown to reduce the incidence of BSIs in critically ill patients, although very few studies include HCT patients or have evaluated the impact of compliance on effectiveness. We conducted a prospective cohort study with historical controls to assess the impact of CHG bathing on the rate of BSIs and gut microbiota composition among adults undergoing inpatient HCT at the Duke University Medical Center. We present 1 year of data without CHG bathing (2016) and 2 years of data when CHG was used on the HCT unit (2017 and 2018). Because not all patients adhered to CHG, patients were grouped into four categories by rate of daily CHG usage: high (>75%), medium (50% to 75%), low (1% to 49%), and none (0%). Among 192 patients, univariate trend analysis demonstrated that increased CHG usage was associated with decreased incidence of clinically significant BSI, defined as any BSI requiring treatment by the medical team (high, 8% BSI; medium, 15.2%; low, 15.6%; no CHG, 30.3%; P = .003), laboratory-confirmed BSI (LCBI; P = .03), central line-associated BSI (P = .04), and mucosal barrier injury LCBI (MBI-LCBI; P = .002). Multivariate analysis confirmed a significant effect of CHG bathing on clinically significant BSI (P = .023) and MBI-LCBI (P = .007), without consistently impacting gut microbial diversity. Benefits of CHG bathing were most pronounced with >75% daily usage, and there were no adverse effects attributable to CHG. Adherence to daily CHG bathing significantly decreases the rate of bloodstream infection following HCT.
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http://dx.doi.org/10.1016/j.jtct.2021.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010223PMC
March 2021

Diagnostic Performance of An Artificial Intelligence System in Breast Ultrasound.

J Ultrasound Med 2021 Mar 5. Epub 2021 Mar 5.

Department of Electrical and Computer Engineering, University of Rochester, Rochester, New York, USA.

Objectives: We study the performance of an artificial intelligence (AI) program designed to assist radiologists in the diagnosis of breast cancer, relative to measures obtained from conventional readings by radiologists.

Methods: A total of 10 radiologists read a curated, anonymized group of 299 breast ultrasound images that contained at least one suspicious lesion and for which a final diagnosis was independently determined. Separately, the AI program was initialized by a lead radiologist and the computed results compared against those of the radiologists.

Results: The AI program's diagnoses of breast lesions had concordance with the 10 radiologists' readings across a number of BI-RADS descriptors. The sensitivity, specificity, and accuracy of the AI program's diagnosis of benign versus malignant was above 0.8, in agreement with the highest performing radiologists and commensurate with recent studies.

Conclusion: The trained AI program can contribute to accuracy of breast cancer diagnoses with ultrasound.
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http://dx.doi.org/10.1002/jum.15684DOI Listing
March 2021

Sample size calculation for cluster randomization trials with a time-to-event endpoint.

Stat Med 2020 11 30;39(25):3608-3623. Epub 2020 Jul 30.

Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, USA.

Cluster randomization trials randomize groups (called clusters) of subjects (called subunits) between intervention arms, and observations are collected from each subject. In this case, subunits within each cluster share common frailties, so that the observations from subunits of each cluster tend to be correlated. Oftentimes, the outcome of a cluster randomization trial is a time-to-event endpoint with censoring. In this article, we propose a closed form sample size formula for weighted rank tests to compare the marginal survival distributions between intervention arms under cluster randomization with possibly variable cluster sizes. Extensive simulation studies are conducted to evaluate the performance of our sample size formula under various design settings. Real study examples are taken to demonstrate our method.
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http://dx.doi.org/10.1002/sim.8683DOI Listing
November 2020

Survival outcomes in sinonasal carcinoma with neuroendocrine differentiation: A NCDB analysis.

Am J Otolaryngol 2021 Mar-Apr;42(2):102851. Epub 2020 Dec 17.

Division of Rhinology & Endoscopic Skull Base Surgery, Department of Head and Neck Surgery & Communication Sciences, Duke University Health System, Durham, NC, USA. Electronic address:

Background: Sinonasal carcinoma with neuroendocrine differentiation (SCND) is a rare group of tumors with poor prognosis. Treatment and sequence of therapies are still unclear. The goal of this study is to analyze treatment outcomes in SCND using a national database.

Methods: The National Cancer Database was queried for SCND from 2004 to 2014. Patient demographics, tumor characteristics and treatment paradigms were tabulated. Multivariable Cox proportional hazards regression was performed for statistical analysis of treatment regimen on overall survival (OS).

Results: A total of 415 patients were identified. Most patients were male (61.2%), with a median age of 58 years and the most common primary site was the nasal cavity (52.5%). T4 tumors were observed in 67.7% of cases. Unimodality (41.9%) and bimodality (43.9%) therapies were the most common treatment modalities. Radiation therapy was the only treatment administered in 30% of the patients, while 27.2% received definitive chemoradiation (CRT) and 11.6% had surgery with adjuvant CRT. In our Cox-PH model, age (HR = 1.04, p < 0.001), T4 (HR = 2.6, p = 0.004) and N2/N3 (HR = 2.18, p = 0.001) were associated with worse survival. Trimodality (HR = 0.49, p = 0.005) and bimodality (HR = 0.65, p = 0.009) therapies had a better OS compared to unimodality. Patients treated with definitive CRT or surgery with adjuvant CRT had a significant increase in OS (p = 0.01 and 0.002 respectively).

Conclusion: SCND appears to be best treated using a multimodality approach with definitive CRT or surgery followed by CRT. Neoadjuvant chemotherapy could be helpful in selecting the best treatment strategy.
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http://dx.doi.org/10.1016/j.amjoto.2020.102851DOI Listing
September 2021

Characterization of Sentinel Lymph Node Immune Signatures and Implications for Risk Stratification for Adjuvant Therapy in Melanoma.

Ann Surg Oncol 2021 Jul 17;28(7):3501-3510. Epub 2020 Nov 17.

Department of Surgery, Duke University Medical Center, Durham, NC, USA.

Background: Although sentinel lymph node (SLN) biopsy is a standard procedure used to identify patients at risk for melanoma recurrence, it fails to risk-stratify certain patients accurately. Because processes in SLNs regulate anti-tumor immune responses, the authors hypothesized that SLN gene expression may be used for risk stratification.

Methods: The Nanostring nCounter PanCancer Immune Profiling Panel was used to quantify expression of 730 immune-related genes in 60 SLN specimens (31 positive [pSLNs], 29 negative [nSLNs]) from a retrospective melanoma cohort. A multivariate prediction model for recurrence-free survival (RFS) was created by applying stepwise variable selection to Cox regression models. Risk scores calculated on the basis of the model were used to stratify patients into low- and high-risk groups. The predictive power of the model was assessed using the Kaplan-Meier and log-rank tests.

Results: During a median follow-up period of 6.3 years, 20 patients (33.3%) experienced recurrence (pSLN, 45.2% [14/31] vs nSLN, 20.7% [6/29]; p = 0.0445). A fitted Cox regression model incorporating 12 genes accurately predicted RFS (C-index, 0.9919). Improved RFS was associated with increased expression of TIGIT (p = 0.0326), an immune checkpoint, and decreased expression of CXCL16 (p = 0.0273), a cytokine important in promoting dendritic and T cell interactions. Independent of SLN status, the model in this study was able to stratify patients into cohorts at high and low risk for recurrence (p < 0.001, log-rank).

Conclusions: Expression profiles of the SLN gene are associated with melanoma recurrence and may be able to identify patients as high or low risk regardless of SLN status, potentially enhancing patient selection for adjuvant therapy.
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http://dx.doi.org/10.1245/s10434-020-09277-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126577PMC
July 2021

Biomarkers for Risk Stratification in Patients With Previously Untreated Follicular Lymphoma Receiving Anti-CD20-based Biological Therapy.

Am J Surg Pathol 2021 03;45(3):384-393

Cleveland Clinic, Cleveland, OH.

Follicular lymphoma (FL) is an indolent B-cell neoplasm of germinal center origin. Standard treatment regimens consist of anti-CD20 therapy with or without chemotherapy. While high response rates to initial therapy are common, patients ultimately relapse or have progressive disease. Clinical risk factors such as the Follicular Lymphoma International Prognostic Index (FLIPI) have been identified, but there is a need for prognostic and predictive biomarkers. We studied markers of lymphoma cells and tumor microenvironment by immunohistochemistry in tissue samples from patients enrolled in 1 of 4 phase 2 trials of anti-CD20-based biological therapy for previously untreated grades 1 to 2 or 3A FL. Results were correlated with progression-free survival (PFS) and PFS status at 24 months. The 4 trials included 238 patients (51.1% male, median age: 55 y) with stage III, IV, or bulky stage II disease. By FLIPI, 24.6% had low-risk, 56.8% had intermediate-risk, and 18.6% had high-risk disease. The outcome differed significantly for patients treated with lenalidomide and rituximab (CALGB 50803) compared with the other 3 trials (median: PFS not reached vs. 3.0 y, hazard ratio=3.47, 95% confidence interval: 2.11-5.72); therefore, data were stratified by clinical trial (CALGB 50803 vs. all others) and adjusted for FLIPI risk group. Among 154 patients with available tissue, interfollicular BCL6 positivity, interfollicular CD10 positivity, and elevated Ki67 proliferation index ≥30% within neoplastic follicles were each associated with inferior PFS and a high risk of the early event by PFS status at 24 months. We identify promising biomarkers for FL risk stratification that warrant further validation in phase 3 trials.
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http://dx.doi.org/10.1097/PAS.0000000000001609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878306PMC
March 2021

A 10-year trend in income disparity of cardiovascular health among older adults in South Korea.

SSM Popul Health 2020 Dec 20;12:100682. Epub 2020 Oct 20.

Duke University School of Nursing, Durham, NC, USA.

Objectives: Although cardiovascular disease (CVD) risk has lessened in Korea, it is unclear whether older adults in all socioeconomic strata have benefited equally. This study explored trends in income disparities in CVD risk among older adults in Korea.

Methods: This was a secondary analysis of Korean National Health and Nutrition Examination Survey data (2008-2017), targeting 14,836 older adults (≥65 years). Socioeconomic position, defined as income and use of welfare benefits, was the primary indicator. The outcome was binary for predicted CVD risk (<90th vs. ≥ 90th). The Slope Index of Inequality (SII) and Relative Index of Inequality (RII) were used to assess trends in disparities.

Results: The percentage of older adults with a predicted CVD risk of 90% or more declined over time, but this was due to a decrease among the more affluent. Disparities have persisted since 2012, with a worsening trend seen for Medicaid recipients. We found significant absolute and relative disparities among men over 75 years of age in recent years (SII > 0.19, RII > 7).

Conclusions: These results may inform and improve policies regarding income disparity reduction and cardiovascular health.
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http://dx.doi.org/10.1016/j.ssmph.2020.100682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589532PMC
December 2020

Bacteremia in solid organ transplant recipients as compared to immunocompetent patients: Acute phase cytokines and outcomes in a prospective, matched cohort study.

Am J Transplant 2021 06 20;21(6):2113-2122. Epub 2020 Nov 20.

Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina, USA.

We undertook a prospective, matched cohort study of patients with Staphylococcus aureus bacteremia (SAB) and gram-negative bacteremia (GNB) to compare the characteristics, outcomes, and chemokine and cytokine response in transplant recipients to immunocompetent, nontransplant recipients. Fifty-five transplant recipients (GNB n = 29; SAB n = 26) and 225 nontransplant recipients (GNB n = 114; SAB n = 111) were included for clinical analysis. Transplant GNB had a significantly lower incidence of septic shock than nontransplant GNB (10.3% vs 30.7%, p = .03). Thirty-day mortality did not differ significantly between transplant and nontransplant recipients with GNB (10.3% vs 15.8%, p = .57) or SAB (0.0% vs 11.7%, p = .13). Next, transplant patients were matched 1:1 with nontransplant patients for the chemokine and cytokine analysis. Five cytokines and chemokines were significantly lower in transplant GNB vs nontransplant GNB: IL-2 (median [IQR]: 7.1 pg/ml [7.1, 7.1] vs 32.6 pg/ml [7.1, 88.0]; p = .001), MIP-1β (30.7 pg/ml [30.7, 30.7] vs 243.3 pg/ml [30.7, 344.4]; p = .001), IL-8 (32.0 pg/ml [5.6, 53.1] vs 59.1 pg/ml [39.2, 119.4]; p = .003), IL-15 (12.0 pg/ml [12.0, 12.0] vs 12.0 pg/ml [12.0, 126.7]; p = .03), and IFN-α (5.1 pg/mL [5.1, 5.1] vs 5.1 pg/ml [5.1, 26.3]; p = .04). Regulated upon Activation, Normal T Cell Expressed and Secreted (RANTES) was higher in transplant SAB vs nontransplant SAB (mean [SD]: 750.2 pg/ml [194.6] vs 656.5 pg/ml [147.6]; p = .046).
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http://dx.doi.org/10.1111/ajt.16388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085168PMC
June 2021

Pre-transplant hepatic steatosis (fatty liver) is associated with chronic graft-vs-host disease but not mortality.

PLoS One 2020 11;15(9):e0238824. Epub 2020 Sep 11.

Division of Hematologic Malignancies and Cell Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America.

Allogeneic-HCT (allo-HCT), while potentially curative, can result in significant complications including graft versus host disease (GVHD). Prior studies suggest that metabolic syndrome may be one risk factor for GVHD. We hypothesized that hepatic steatosis on pre-HCT computed tomography (CT) scans may be a marker for development of GVHD and poor outcomes in allo-HCT. In this retrospective study, we reviewed the pre-HCT CT scans and transplant outcome data of patients who underwent allo-HCT at Duke University Medical Center from 2009 to 2017. The presence of steatosis was confirmed using CT attenuation measurements. We then assessed the association between pre-HCT hepatic steatosis and HCT-related outcomes including GVHD. 80 patients who had pre-HCT CT scans were included in the study. Pre-transplant hepatic steatosis was associated with the development of chronic GVHD (OR 4.2, p = 0.02), but was not associated with acute GVHD (OR 1.3, p = 0.7), non-relapse mortality (p = 0.81) or overall survival (p = 0.74). Based on this single center retrospective study, pre-transplant hepatic steatosis is associated with development of chronic GVHD. Further, prospective study with other imaging modalities including non-contrasted CT scans is needed to determine if this association is reproducible.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238824PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485815PMC
November 2020

Higher BMI, But Not Sarcopenia, Is Associated With Pembrolizumab-related Toxicity in Patients With Advanced Melanoma.

Anticancer Res 2020 Sep;40(9):5245-5254

Department of Surgery, Duke University Medical Center, Durham, NC, U.S.A.

Background/aim: To determine whether BMI and sarcopenia were related to treatment-limiting toxicity or efficacy of pembrolizumab treatment in melanoma patients.

Patients And Methods: Medical records for melanoma patients undergoing pembrolizumab treatment at Duke University from January 2014 to September 2018 were reviewed. Pre-treatment measurements such as BMI were collected. Pre-treatment CT imaging was used to determine psoas muscle index (PMI). Patients in the lowest sex-specific tertile of PMI were sarcopenic. Logistic regression measured associations with treatment toxicity and response. Kaplan-Meier analysis assessed progression-free survival (PFS) and overall survival (OS).

Results: Among 156 patients, the overall objective response rate was 46.2% and 29 patients (18.6%) experienced treatment-limiting toxicity. Sarcopenia was not significantly associated with toxicity, response, or survival. However, obese patients (BMI >30) experienced higher rates of toxicity (p=0.0007).

Conclusion: Sarcopenia did not appear to predict clinically relevant outcomes. Obesity, however, represents a readily available predictor of pembrolizumab toxicity.
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http://dx.doi.org/10.21873/anticanres.14528DOI Listing
September 2020

Sinonasal Squamous Cell Carcinoma Outcomes: Does Treatment at a High-Volume Center Confer Survival Benefit?

Otolaryngol Head Neck Surg 2020 11 30;163(5):986-991. Epub 2020 Jun 30.

Division of Rhinology and Skull Base Surgery, Department of Head and Neck Surgery and Communication Sciences, Duke University Health System, Durham, North Carolina, USA.

Objective: To determine whether treatment of sinonasal squamous cell carcinoma (SCC) at a high-volume facility affects survival.

Study Design: Retrospective database analysis.

Setting: National Cancer Database (2004-2014).

Subjects And Methods: The National Cancer Database was queried for sinonasal SCC from 2004 to 2014. Patient demographics, tumor characteristics and classification, resection margins, treatment regimen, and facility case-specific volume-averaged per year and grouped in tertiles as low (0%-33%), medium (34%-66%), and high (67%-100%)-were compared. Overall survival was compared with Cox proportional hazards regression analysis.

Results: A total of 3835 patients treated for sinonasal SCC between 2004 and 2014 were identified. Therapeutic options included surgery alone (18.6%), radiotherapy (RT) alone (29.1%), definitive chemoradiation (15.4%), surgery with adjuvant RT (22.8%), and combinations (14.1%) of the aforementioned treatments. Patients who underwent surgery with adjuvant RT had better overall survival (hazard ratio [HR], 0.74; < .001; 95% CI, 0.63-0.86). As for treatment volume per facility, 7.4% of patients were treated at a low-volume center, 17.5% at a medium-volume center, and 75.1% at a high-volume center. Univariate analysis showed that treatment at a high-volume facility conferred a significantly better overall survival (HR, 0.77; = .002). Multivariable Cox proportional hazards regression analysis, adjusting for age, sex, tumor classification, and treatment regimen, demonstrated that patients who underwent treatment at a high-volume facility (HR, 0.81; < .001) had significantly improved survival.

Conclusion: This study shows a better overall survival for sinonasal SCC treated at high-volume centers. Further study may be needed to understand the effect of case volume on the paradigms of sinonasal SCC management.
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http://dx.doi.org/10.1177/0194599820935395DOI Listing
November 2020

Longitudinal Toxicity over Time (ToxT) analysis to evaluate tolerability: a case study of lenalidomide in the CALGB 50401 (Alliance) trial.

Lancet Haematol 2020 Jun;7(6):e490-e497

Alliance Statistics and Data Center, Mayo Clinic, Scottsdale, AZ, USA.

Evaluation of tolerability is increasingly relevant for patients with haematological malignancies treated with chronically administered therapies. Adverse events from these agents might affect the ability of patients to tolerate treatment over time. Conventional toxicity tables that include the incidence of high-grade adverse events, defined by the Common Terminology Criteria for Adverse Events, do not provide information on the time profile of these adverse events or reflect the continuous, lower grade symptomatic toxicities that are particularly relevant to treatment tolerability for patients living with indolent disease. Modern approaches to the evaluation and reporting of toxicity that capture the tolerability of treatment to the patient are imperative. In this Viewpoint, we present a focused, pilot, and longitudinal Toxicity over Time analysis of adverse events from lenalidomide and lenalidomide with rituximab in patients with follicular lymphoma treated in the CALGB 50401 (Alliance; NCT00238238) trial to define the trajectory of adverse events and quantify the burden of continuous, low-grade events. Toxicity over Time analyses provided clinically relevant descriptions of neutropenia and fatigue trajectories caused by lenalidomide that were not identified by standard analysis of the maximum grade events defined by the Common Terminology Criteria for Adverse Events. Systematic, rigorous incorporation of patient-reported outcomes in clinical trials will be crucial to our understanding of the tolerability of chronically administered therapies in patients with haematological malignancies.
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http://dx.doi.org/10.1016/S2352-3026(20)30067-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457391PMC
June 2020

Nomogram to predict lymph node metastasis in patients with early gastric cancer: a useful clinical tool to reduce gastrectomy after endoscopic resection.

Endoscopy 2020 06 11;52(6):435-443. Epub 2020 Mar 11.

Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Background: The indications for endoscopic dissection have been expanded to improve the quality of life of patients with early gastric cancer (EGC). This study aimed to develop a nomogram to predict the status of lymph node metastasis with the aim of avoiding unnecessary gastrectomies.

Methods: We reviewed the clinicopathological data of 10 579 patients who underwent curative resection for EGC. The nomogram was developed by multivariate analysis and was evaluated by external validation. Overall, disease-free and recurrence-free survival were compared between the gastrectomy group of 6641 patients and the endoscopic dissection group of 999 patients to show the efficacy of the nomogram.

Results: Multivariate analyses revealed that age, tumor size, lymphatic invasion, depth of invasion, and histologic differentiation were all significant prognostic factors for lymph node metastasis. The nomogram had good discriminatory performance, with a concordance index of 0.846. This was supported by the external validation point of 0.813. For patients with low risk of lymph node metastasis on the nomogram (≤ 3 % of the provisional value in this study), the endoscopic dissection and gastrectomy groups had comparable rates of overall ( = 0.32), disease-free ( = 0.47), and recurrence-free ( = 0.09) survival.

Conclusions: We developed and validated a nomogram that predicts the risk of lymph node metastasis in EGC based on a large database. This precision nomogram is useful to avoid unnecessary gastrectomy after endoscopic dissection, which may ultimately improve the quality of life of patients with EGC.
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http://dx.doi.org/10.1055/a-1117-3059DOI Listing
June 2020

Clinical Factors Affecting Survival in Pediatric Vascular Tumors of the Head and Neck.

J Craniofac Surg 2020 May/Jun;31(3):628-629

Department of Biostatistics and Bioinformatics, Duke University, Durham, NC.

Clinical factors associated with the behavior and outcomes of nonbenign, head, and neck vascular tumors in children are not well described. Our aim is to provide descriptive information and identify prognostic factors associated with lower overall survival for children with these types of tumors. A retrospective cohort study was performed using the SEER database (years 1973-2015). Children aged 18 years and under with the diagnosis of a vascular tumor with locally aggressive or borderline and malignant behavior, classified by ICD-O-3, within the head and neck were included. Vascular tumors with benign behavior as classified by ISSVA were excluded. One hundred forty-eight children were identified. Mean age was 9.9 years (SD = 6.4). A gender predilection was noted with more males affected, female (37.8%) and male (62.2%), P = 0.0031. Majority of the children were white (79.4%) and angiosarcoma was the most common histologic subtype (68.2%). Children had a significantly better overall survival than adults with head and neck vascular tumors, P < 0.0001. Univariate and multivariate analysis did not reveal any factors with significant association to overall survival. Vascular tumors in the head and neck in children most commonly affect males and white children, with angiosarcoma as the most common histologic subtype. Children seem to have a more favorable overall survival compared to adults.
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http://dx.doi.org/10.1097/SCS.0000000000006040DOI Listing
August 2020

Tracing Tumor Evolution in Sarcoma Reveals Clonal Origin of Advanced Metastasis.

Cell Rep 2019 09;28(11):2837-2850.e5

Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA; Duke Cancer Institute, Duke University, Durham, NC, USA; Regeneration Next Initiative, Duke University, Durham, NC, USA; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Electronic address:

Cellular heterogeneity is frequently observed in cancer, but the biological significance of heterogeneous tumor clones is not well defined. Using multicolor reporters and CRISPR-Cas9 barcoding, we trace clonal dynamics in a mouse model of sarcoma. We show that primary tumor growth is associated with a reduction in clonal heterogeneity. Local recurrence of tumors following surgery or radiation therapy is driven by multiple clones. In contrast, advanced metastasis to the lungs is driven by clonal selection of a single metastatic clone (MC). Using RNA sequencing (RNA-seq) and in vivo assays, we identify candidate suppressors of metastasis, namely, Rasd1, Reck, and Aldh1a2. These genes are downregulated in MCs of the primary tumors prior to the formation of metastases. Overexpression of these suppressors of metastasis impair the ability of sarcoma cells to colonize the lungs. Overall, this study reveals clonal dynamics during each step of tumor progression, from initiation to growth, recurrence, and distant metastasis.
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http://dx.doi.org/10.1016/j.celrep.2019.08.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750751PMC
September 2019

Immunogenicity and Optimal Timing of 13-Valent Pneumococcal Conjugate Vaccination during Adjuvant Chemotherapy in Gastric and Colorectal Cancer: A Randomized Controlled Trial.

Cancer Res Treat 2020 Jan 9;52(1):246-253. Epub 2019 Jul 9.

Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University College of Medicine, Hwasun, Korea.

Purpose: Pneumococcal vaccination (13-valent pneumococcal conjugate vaccine [PCV13]) is recommended to cancer patients undergoing systemic chemotherapy. However, the optimal time interval between vaccine administration and initiation of chemotherapy has been little studied in adult patients with solid malignancies.

Materials And Methods: We conducted a prospective randomized controlled trial to evaluate whether administering PCV13 on the first day of chemotherapy is non-inferior to vaccinating 2 weeks prior to chemotherapy initiation. Patients were randomly assigned to two study arms, and serum samples were collected at baseline and 4 weeks after vaccination to analyze the serologic response against Streptococcus pneumoniae using a multiplexed opsonophagocytic killing assay.

Results: Of the 92 patients who underwent randomization, 43 patients in arm A (vaccination 2 weeks before chemotherapy) and 44 patients in arm B (vaccination on the first day of chemotherapy) were analyzed. Immunogenicity was assessed by geometric mean and fold-increase of post-vaccination titers, seroprotection rates (percentage of patients with post-vaccination titers > 1:64), and seroconversion rates (percentage of patients with > 4-fold increase in post-vaccination titers). Serologic responses to PCV13 did not differ significantly between the two study arms according to all three types of assessments.

Conclusion: The overall antibody response to PCV13 is adequate in patients with gastric and colorectal cancer during adjuvant chemotherapy, and no significant difference was found when patients were vaccinated two weeks before or on the day of chemotherapy initiation.
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http://dx.doi.org/10.4143/crt.2019.189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962463PMC
January 2020

Randomized trial of ofatumumab and bendamustine versus ofatumumab, bendamustine, and bortezomib in previously untreated patients with high-risk follicular lymphoma: CALGB 50904 (Alliance).

Cancer 2019 10 7;125(19):3378-3389. Epub 2019 Jun 7.

Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.

Background: This multicenter, randomized phase 2 trial evaluated complete responses (CRs), efficacy, and safety with ofatumumab and bendamustine and with ofatumumab, bendamustine, and bortezomib in patients with untreated, high-risk follicular lymphoma (FL).

Methods: Patients with grade 1 to 3a FL and either a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 with 1 lymph node >6 cm or an FLIPI score of 3 to 5 were randomized to arm A (ofatumumab, bendamustine, and maintenance ofatumumab) or to arm B (ofatumumab, bendamustine, bortezomib, and maintenance ofatumumab and bortezomib).

Results: One hundred twenty-eight patients (66 in arm A and 62 in arm B) received treatment. The median age was 61 years, and 61% had disease >6 cm; 29% had an FLIPI score of 2, and 71% had an FLIPI score of 3 to 5. In arm A, 86% completed induction, and 64% completed maintenance. In arm B, 66% and 52% completed induction and maintenance, respectively. Dose modifications were required in 65% and 89% in arms A and B, respectively. Clinically significant grade 3 to 4 toxicities included neutropenia (A, 36%; B, 31%), nausea/vomiting (A, 0%; B, 8%), diarrhea (A, 5%; B, 11%), and sensory neuropathy (A, 0%; B, 5%). The estimated CR rates were 62% (95% confidence interval [CI], 50%-74%) and 60% (95% CI, 47%-72%) in arms A and B, respectively (P = .68). With a median follow-up of 3.3 years, the estimated 2-year progression-free survival (PFS) and overall survival (OS) rates were 80% and 97%, respectively, for arm A and 76% and 91%, respectively, for arm B.

Conclusions: The CR rates, PFS, and OS were not improved with the addition of bortezomib to ofatumumab and bendamustine in patients with high-risk FL. Although grade 3 to 4 toxicities were similar, more patients treated with bortezomib required dose modifications and early discontinuation.
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http://dx.doi.org/10.1002/cncr.32289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744328PMC
October 2019

Impact of Microbiological Organism Type on Surgically Managed Endocarditis.

Ann Thorac Surg 2019 11 16;108(5):1325-1329. Epub 2019 May 16.

Department of Surgery, Duke University Medical Center, Durham, North Carolina. Electronic address:

Background: This study describes the impact of organism and valve type on surgically managed infective endocarditis (IE) from The Society of Thoracic Surgeons (STS) database. We developed a risk model for surgically managed endocarditis that includes the microbiological organism.

Methods: The STS database was queried for adult patients with surgically managed endocarditis from July 1, 2011, to June 30, 2016. Outcomes were compared based on (1) causative microbiological organism, (2) valve type (native vs prosthetic), and (3) endocarditis on the right (tricuspid) vs left (mitral, aortic) sides. Univariate and risk adjusted models were developed with odds ratios for mortality for each organism type referenced against Streptococcus.

Results: The study population included 21,388 operations (93%) for left-sided IE and 1698 (7%) for right-sided IE. Streptococcus (28%) and Staphylococcus (27%) were the most common infecting organisms, followed by Enterococcus (11%). After multivariate adjustment, microbiological organism type was significantly associated with operative mortality for patients with left-sided endocarditis, with an adjusted odds ratio of 2.9 for fungal, 1.4 for Staphylococcus, and 1.3 for culture-negative vs Streptococcus. For right-sided endocarditis, there were no differences in outcomes by organism type. Left-sided prosthetic valve endocarditis had a higher operative mortality than left-sided native valve endocarditis (12% vs 8%, P < .001). In contrast, surgery for right-sided endocarditis carried lower operative mortality, with no mortality difference between prosthetic valve endocarditis and native valve endocarditis (5% vs 4%, P = .6).

Conclusions: Organism type influences the operative mortality for left-sided endocarditis. Surgery for left-sided and prosthetic valve endocarditis is associated with higher operative mortality. Risk adjustment for operative outcomes in endocarditis may need to account for microbiological organism type.
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http://dx.doi.org/10.1016/j.athoracsur.2019.04.025DOI Listing
November 2019

Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303.

J Clin Oncol 2019 07 2;37(21):1790-1799. Epub 2019 Apr 2.

14 Cornell University Medical College, New York, NY.

Purpose: Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large B-cell lymphoma.

Patients And Methods: Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary objective was progression-free survival (PFS); secondary clinical objectives included response rate, overall survival (OS), and safety.

Results: Between 2005 and 2013, 524 patients were registered; 491 eligible patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different between the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common ( < .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% 10.7%, respectively), febrile neutropenia (35.0% 17.7%, respectively), mucositis (8.4% 2.1%, respectively), and neuropathy (18.6% 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm.

Conclusion: In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.
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http://dx.doi.org/10.1200/JCO.18.01994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774813PMC
July 2019

Phase 2 multicentre study of single-agent ofatumumab in previously untreated follicular lymphoma: CALGB 50901 (Alliance).

Br J Haematol 2019 04 5;185(1):53-64. Epub 2019 Feb 5.

Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC, USA.

Rituximab monotherapy has proven efficacy in treatment-naïve, asymptomatic advanced-stage follicular lymphoma (FL). Ofatumumab is a fully humanized anti-CD20 monoclonal antibody with increased CD20 affinity and complement-dependent cytotoxicity. This phase 2 trial (NCT01190449) evaluated ofatumumab in patients with untreated, low/intermediate-risk FL International Prognostic Index (FLIPI), advanced-stage FL to determine single-agent efficacy. Patients with measurable disease in stages III/IV or bulky stage II, regardless of Groupe d'Etude des Lymphomes Folliculaires criteria, received 4 weekly 1000 mg doses followed by four extended induction doses once every 8 weeks. Primary endpoint was overall response rate (ORR) to 1000 mg; secondary endpoints were progression-free survival (PFS) and safety. Fifty-one patients were enrolled. Fifteen patients were randomized to 500 mg prior to discontinuing that arm for slow accrual. Among 36 patients on the 1000 mg arm, ORR was 84%, median PFS was 1·9 years and median response duration was 23·7 months. All patients remain alive. No grade 4 infusion reactions or grade 3/4 infections occurred. Grade 3 infusion reactions occurred in 25% in the 1000 mg arm only (all first infusion); all but two patients continued on study. Discontinuation was 6% for the total study population. Ofatumumab monotherapy administered by extended induction in untreated, low/intermediate-risk FLIPI, advanced-stage FL is well tolerated and active. Activity appears similar to that reported with single-agent rituximab.
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http://dx.doi.org/10.1111/bjh.15768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462222PMC
April 2019

K-Sample comparisons using propensity analysis.

Biom J 2019 05 7;61(3):698-713. Epub 2019 Jan 7.

Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

In this paper, we investigate K-group comparisons on survival endpoints for observational studies. In clinical databases for observational studies, treatment for patients are chosen with probabilities varying depending on their baseline characteristics. This often results in noncomparable treatment groups because of imbalance in baseline characteristics of patients among treatment groups. In order to overcome this issue, we conduct propensity analysis and match the subjects with similar propensity scores across treatment groups or compare weighted group means (or weighted survival curves for censored outcome variables) using the inverse probability weighting (IPW). To this end, multinomial logistic regression has been a popular propensity analysis method to estimate the weights. We propose to use decision tree method as an alternative propensity analysis due to its simplicity and robustness. We also propose IPW rank statistics, called Dunnett-type test and ANOVA-type test, to compare 3 or more treatment groups on survival endpoints. Using simulations, we evaluate the finite sample performance of the weighted rank statistics combined with these propensity analysis methods. We demonstrate these methods with a real data example. The IPW method also allows us for unbiased estimation of population parameters of each treatment group. In this paper, we limit our discussions to survival outcomes, but all the methods can be easily modified for any type of outcomes, such as binary or continuous variables.
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http://dx.doi.org/10.1002/bimj.201800049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461520PMC
May 2019

The prognostic significance of PFS24 in follicular lymphoma following firstline immunotherapy: A combined analysis of 3 CALGB trials.

Cancer Med 2019 01 21;8(1):165-173. Epub 2018 Dec 21.

Emory University School of Medicine, Atlanta, Georgia.

Follicular lymphoma (FL) patients treated with firstline R-CHOP who experience progression of disease (POD) within 2 years have a shorter survival than those who do not have POD within 2 years. Whether this observation holds for patients treated initially with biologic immunotherapy alone is unknown. We performed a retrospective analysis of 174 patients pooled from three frontline rituximab (R)-based nonchemotherapy doublet trials: R-galiximab (Anti-CD80, CALGB 50402), R-epratuzumab (Anti-CD22, CALGB 50701), and R-lenalidomide (CALGB 50803) to determine outcomes of early progressors and risk factors for early POD, defined as progression within 24 months from study entry. Twenty-eight percent (48/174) of patients had early POD. After adjusting for the Follicular Lymphoma International Prognostic Index (FLIPI), patients with early POD from study entry had a worse OS compared with patients who did not progress within 2 years (HR = 4.33 (95% CI 1.50-12.5), P = 0.007). For early POD, the 2-year survival was 80% vs 99% for nonearly POD, and the 5-year survival was 74% vs 90%, respectively. These findings suggest that the adverse survival of patients with early POD may be independent of initial treatment modality.
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http://dx.doi.org/10.1002/cam4.1918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346218PMC
January 2019

A Randomized, Open-Label, Phase II Study Comparing Pemetrexed Plus Cisplatin Followed by Maintenance Pemetrexed versus Pemetrexed Alone in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Non-small Cell Lung Cancer after Failure of First-Line EGFR Tyrosine Kinase Inhibitor: KCSG-LU12-13.

Cancer Res Treat 2019 Apr 3;51(2):718-726. Epub 2018 Sep 3.

Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: The optimal cytotoxic regimens have not been established for patients with non-small cell lung cancer (NSCLC) who develop disease progression on first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI).

Materials And Methods: We conducted a multi-center randomized phase II trial to compare the clinical outcomes between pemetrexed plus cisplatin combination therapy followed by maintenance pemetrexed (PC) and pemetrexed monotherapy (P) after failure of first-line EGFR-TKI. The primary objective was progression-free survival (PFS), and secondary objectives included overall response rate (ORR), overall survival (OS), health-related quality of life (HRQOL), and safety and toxicity profiles.

Results: A total of 96 patientswere randomized, and 91 patientswere treated at 14 centers in Korea. The ORR was 34.8% (16/46) for the PC arm and 17.8% (8/45) for the P arm (p=0.066). With 23.4 months of follow-up, the median PFS was 5.4 months in the PC arm and 6.4 months in the P arm (p=0.114). The median OS was 17.9 months and 15.7 months in PC and P arms, respectively (p=0.787). Adverse events ≥ grade 3 were reported in 12 patients (26.1%) in the PC arm and nine patients (20.0%) in the P arm (p=0.491). The overall time trends of HRQOL were not significantly different between the two arms.

Conclusion: The outcomes of pemetrexed therapy in NSCLC patients with disease progression after firstline EGFR-TKI might not be improved by adding cisplatin.
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http://dx.doi.org/10.4143/crt.2018.324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473296PMC
April 2019
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