Publications by authors named "Donna Niedzwiecki"

174 Publications

Survival in Young-Onset Metastatic Colorectal Cancer: Findings from Cancer and Leukemia Group B (Alliance)/SWOG 80405.

J Natl Cancer Inst 2021 Oct 12. Epub 2021 Oct 12.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Background: The incidence of young-onset colorectal cancer (yoCRC) is increasing. It is unknown if there are survival differences between young and older patients with metastatic colorectal cancer (mCRC).

Methods: We studied the association of age with survival in 2326 mCRC patients enrolled in the CALGB/SWOG 80405 trial, a multi-center, randomized trial of first-line chemotherapy plus biologics. The primary and secondary outcomes of this study were overall survival (OS) and progression-free survival (PFS), respectively, which were assessed by Kaplan Meier method and compared among younger versus older patients with the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated based on Cox proportional hazards modeling, adjusting for known prognostic variables. All statistical tests were 2-sided.

Results: Of 2326 eligible subjects, 514 (22.1%) were younger than age 50 years at study entry (yoCRC cohort). The median age of yoCRC patients was 44.3 vs. 62.5 years in patients age 50 and over. There was no statistically significant difference in OS between yoCRC vs. older-onset patients (median = 27.07 vs. 26.12 months; adjusted HR = 0.98, 95% CI = 0.88-1.10, P = .78). The median PFS was also similar in yoCRC vs. older patients (10.87 vs. 10.55 months) with an adjusted HR of 1.02 (95% CI = 0.92-1.13, P = .67). Patients younger than age 35 years had the shortest OS with median OS of 21.95 vs. 26.12 months in older-onset patients with an adjusted HR of 1.08 (95% CI = 0.81-1.44, Ptrend =0.93).

Conclusion: In this large study of mCRC patients, there were no statistically significant differences in survival between patients with yoCRC and CRC patients age 50 and older.
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http://dx.doi.org/10.1093/jnci/djab200DOI Listing
October 2021

Classification of older adults who underwent lumbar-related surgery using pre-operative biopsychosocial predictors and relationships with surgical recovery: An observational study conducted in the United States.

Health Soc Care Community 2021 Sep 29. Epub 2021 Sep 29.

Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA.

Lumbar surgery is a commonly prescribed intervention for low back pain but poses higher risks and worse outcomes for older adults. Identifying clinical phenotypes based on biopsychosocial factors may help identify older adults who are at greatest risk for poor postoperative recovery. This study aimed to (a) classify older adults who underwent lumbar surgery based on preoperative biopsychosocial factors, and (b) quantify the association between preoperative biopsychosocial classifications and 3 and 12 months postoperative improvement outcomes. Latent class analysis was used to identify biopsychosocial classifications in 10,283 individuals aged ≥60 from the Quality Outcomes Database (the United States, 2021-2018). Logistic regression models measured the association between biopsychosocial classifications and 3 and 12 months postoperative outcomes (back/leg pain intensity, disability and quality of life), adjusting for covariates. Three classes were identified based on 19 a priori biopsychosocial factors and were characterised as 'high-risk' (15%), 'physical-/social health-risk' (44%) and 'low-risk' (41%). The high-risk class demonstrated increased odds of failing to recover post-operatively compared to the other classes. Similarly, the physical-/social-risk class demonstrated increased odds of failing to recover in all outcomes and time points compared to the low-risk class. Biopsychosocial factors with higher prevalence in the high versus low-risk class were depression (92.5% vs. 10.6%), multiple morbidities (55.3% vs. 25.7%) and obesity (59.5% vs. 37.2%). This study introduces novel non-recovery phenotypes for older adults undergoing lumbar surgery and may lead to the development of tailored interventions to improve clinical care and outcomes for this population.
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http://dx.doi.org/10.1111/hsc.13584DOI Listing
September 2021

Establishing ADC-Based Histogram and Texture Features for Early Treatment-Induced Changes in Head and Neck Squamous Cell Carcinoma.

Front Oncol 2021 2;11:708398. Epub 2021 Sep 2.

Department of Radiation Oncology, Duke University Medical Center, Durham, NC, United States.

The purpose of this study was to assess baseline variability in histogram and texture features derived from apparent diffusion coefficient (ADC) maps from diffusion-weighted MRI (DW-MRI) examinations and to identify early treatment-induced changes to these features in patients with head and neck squamous cell carcinoma (HNSCC) undergoing definitive chemoradiation. Patients with American Joint Committee on Cancer Stage III-IV (7 edition) HNSCC were prospectively enrolled on an IRB-approved study to undergo two pre-treatment baseline DW-MRI examinations, performed 1 week apart, and a third early intra-treatment DW-MRI examination during the second week of chemoradiation. Forty texture and six histogram features were derived from ADC maps. Repeatability of the features from the baseline ADC maps was assessed with the intra-class correlation coefficient (ICC). A Wilcoxon signed-rank test compared average baseline and early treatment feature changes. Data from nine patients were used for this study. Comparison of the two baseline ADC maps yielded 11 features with an ICC ≥ 0.80, indicating that these features had excellent repeatability: Run Gray-Level Non-Uniformity, Coarseness, Long Zone High Gray-Level, Variance (Histogram Feature), Cluster Shade, Long Zone, Variance (Texture Feature), Run Length Non-Uniformity, Correlation, Cluster Tendency, and ADC Median. The Wilcoxon signed-rank test resulted in four features with significantly different early treatment-induced changes compared to the baseline values: Run Gray-Level Non-Uniformity (p = 0.005), Run Length Non-Uniformity (p = 0.005), Coarseness (p = 0.006), and Variance (Histogram) (p = 0.006). The feasibility of histogram and texture analysis as a potential biomarker is dependent on the baseline variability of each metric, which disqualifies many features.
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http://dx.doi.org/10.3389/fonc.2021.708398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444263PMC
September 2021

Recumbent Total Skin Electron Beam Therapy.

Adv Radiat Oncol 2021 Jul-Aug;6(4):100698. Epub 2021 Apr 22.

Departments of Radiation Oncology.

Purpose: Our purpose was to describe preliminary dosimetric and clinical results of a recumbent total skin electron beam therapy (TSEBT) technique and compare this to a conventional standing TSEBT technique.

Methods And Materials: A customized treatment platform with recessed side wheels was constructed and commissioned for patients to be treated in a recumbent position. Dosimetric and clinical information was collected for patients treated with this new recumbent technique in addition to that of a cohort of patients treated contemporaneously using the conventional standing method. Dose delivery and clinical outcomes were compared for patients treated with the recumbent and standing techniques.

Results: Between 2017 and 2019, 27 patients were treated with TSEBT with the recumbent (n = 13) or conventional standing technique (n = 14) at our institution. Measured dose at 15 body sites could be directly compared. Of these, 10 showed no significant difference between the two techniques while five sites showed significant differences in median measured dose, including the top of left shoulder, right biceps, bend of left elbow, upper back, and medial right thigh ( < .003). Measured dose was significantly higher with the standing technique at these sites with the exception of the upper back. Rates of complete response (25% vs 23%), partial response (50% vs 69%), and stable disease (17% vs 8%) were similar between the standing and recumbent cohorts, respectively ( = .78).

Conclusions: We have developed, commissioned, and implemented a floor-based, recumbent technique that allows for treatment of patients who would otherwise not be eligible for TSEBT. Dosimetric and clinical measurements suggest that this technique is a viable alternative to the standing method.
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http://dx.doi.org/10.1016/j.adro.2021.100698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361039PMC
April 2021

Congenital human cytomegalovirus infection is associated with decreased transplacental IgG transfer efficiency due to maternal hypergammaglobulinemia.

Clin Infect Dis 2021 Jul 14. Epub 2021 Jul 14.

Duke Human Vaccine Institute, Duke University, Durham, NC, USA.

Background: Placentally-transferred maternal IgG protects against pathogens in early life, yet vertically-transmitted infections can interfere with transplacental IgG transfer. Although human cytomegalovirus (HCMV) is the most common placentally-transmitted viral infection worldwide, the impact of congenital HCMV (cCMV) infection on transplacental IgG transfer has been underexplored.

Methods: We evaluated total and antigen-specific maternal and cord blood IgG levels and transplacental IgG transfer efficiency in a U.S-based cohort of 93 mother-infant pairs including 27 cCMV-infected and 66 cCMV-uninfected pairs, of which 29 infants were born to HCMV-seropositive non-transmitting mothers and 37 to HCMV-seronegative mothers. Controls were matched on sex, race/ethnicity, maternal age, and delivery year.

Results: Transplacental IgG transfer efficiency was decreased by 23% (95% CI 10-36%, p=0.0079) in cCMV-infected pairs and 75% of this effect (95% CI 28-174%, p=0.0085) was mediated by elevated maternal IgG levels (i.e., hypergammaglobulinemia) in HCMV-transmitting women. Despite reduced transfer efficiency, IgG levels were similar in cord blood from infants with and without cCMV infection.

Conclusions: Our results indicate that cCMV infection moderately reduces transplacental IgG transfer efficiency due to maternal hypergammaglobulinemia; however, infants with and without cCMV infection had similar antigen-specific IgG levels, suggesting comparable protection from maternal IgG acquired via transplacental transfer.
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http://dx.doi.org/10.1093/cid/ciab627DOI Listing
July 2021

Effective Pain Control With Very Low Dose Palliative Radiation Therapy for Patients With Multiple Myeloma With Uncomplicated Osseous Lesions.

Adv Radiat Oncol 2021 Jul-Aug;6(4):100729. Epub 2021 May 28.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Background: Osteolytic lesions are present in 75% of patients with multiple myeloma (MM) and frequently require palliation with radiation therapy (RT). Prior case series of patients with MM with bone pain undergoing palliative RT suggests doses ≥12 Gy (equivalent dose in 2Gy fractions, EQD2) provide excellent bone pain relief. However, recent advances in care and novel biologic agents have significantly improved overall survival and quality of life for patients with MM. We hypothesized that lower-dose RT (LDRT, EQD2 <12 Gy) offers an effective alternative to higher-dose RT (HDRT, EQD2 ≥12 Gy) for palliation of painful, uncomplicated MM bone lesions.

Methods: We retrospectively identified patients with MM treated with RT for uncomplicated, painful bone lesions and stratified by EQD2 ≥/< 12 Gy. Clinical pain response (CPR) rates, acute and late toxicity, pain response duration, and retreatment rates between LDRT and HDRT groups were analyzed.

Results: Thirty-five patients with 70 treated lesions were included: 24 patients (48 lesions) treated with HDRT and 11 patients (22 lesions) with LDRT. Median follow-up was 14 and 16.89 months for HDRT and LDRT, respectively. The median dose of HDRT treatment was 20 Gy versus 4 Gy in the LDRT group. The CPR rate was 98% for HDRT and 95% for LDRT. There was no significant difference in any-grade acute toxicity between the HDRT and LDRT cohorts (24.5% vs 9.1%, Χ  = .20). Pain recurred in 10% of lesions (12% HDRT vs 9.5% LDRT). Median duration of pain response did not significantly differ between cohorts ( = .91). Five lesions were retreated, 2 (9.5%) in the LDRT cohort, and 3 (6.3%) in the HDRT cohort.

Conclusion: In this study, LDRT effectively palliated painful, uncomplicated MM bony lesions with acceptable CPR and duration of palliation. These data support prospective comparisons of LDRT versus HDRT for palliation of painful, uncomplicated MM bony lesions.
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http://dx.doi.org/10.1016/j.adro.2021.100729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256178PMC
May 2021

Pharmacogenetic study in gastric cancer patients treated with adjuvant fluorouracil/leucovorin or epirubicin/cisplatin/fluorouracil before and after chemoradiation on CALGB 80101 (Alliance).

Pharmacogenet Genomics 2021 Dec;31(9):215-220

Department of Precision Medicine, USF Taneja College of Pharmacy and the Geriatric Oncology Consortium, Tampa, Florida, USA.

There is a lack of pharmacogenetic predictors of outcome in gastric cancer patients. The aim of this study was to assess previously identified candidate genes associated with 5-fluorouracil (5-FU), cisplatin, or epirubicin toxicity or response in a cohort of resected gastric cancer patients treated on CALGB (Alliance) 80101. Gastric or gastroesophageal cancer patients randomized to adjuvant 5-FU/leucovorin or epirubicin/cisplatin/5-FU before and after 5-FU chemoradiation were genotyped for single nucleotide polymorphisms (SNPs) in GSTP1 (rs1695), ERCC1 (rs11615 and rs3212986), XRCC1 (rs25487), UGT2B7 (rs7439366) and the 28 base-pair tandem repeats in TYMS (rs34743033). Logistic regression and log rank tests were used to assess the association between each SNP and incidence of grade 3/4 neutropenia and leukopenia, overall (OS) and progression-free survival (PFS), respectively. Toxicity endpoint analyses were adjusted for the treatment arm, while OS and PFS were also adjusted for performance status, sex, age, lymph node involvement, and primary tumor site and size. Of 281 subjects with successful genotyping results and available clinical (toxicity and efficacy) data, 166 self-reported non-Hispanic White patients were included in the final analysis. There was a lack of evidence of an association among any SNPs tested with grade 3/4 neutropenia and leukopenia or OS and PFS. Age, lymph node involvement, and primary tumor size were significantly associated with OS and PFS. This study failed to confirm results of previous gastric cancer pharmacogenetic studies.
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http://dx.doi.org/10.1097/FPC.0000000000000442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490297PMC
December 2021

Race, Income, and Survival in Stage III Colon Cancer: CALGB 89803 (Alliance).

JNCI Cancer Spectr 2021 Jun 12;5(3):pkab034. Epub 2021 Apr 12.

Yale School of Medicine, New Haven, CT, USA.

Background: Disparities in colon cancer outcomes have been reported across race and socioeconomic status, which may reflect, in part, access to care. We sought to assess the influences of race and median household income (MHI) on outcomes among colon cancer patients with similar access to care.

Methods: We conducted a prospective, observational study of 1206 stage III colon cancer patients enrolled in the CALGB 89803 randomized adjuvant chemotherapy trial. Race was self-reported by 1116 White and 90 Black patients at study enrollment; MHI was determined by matching 973 patients' home zip codes with publicly available US Census 2000 data. Multivariate analyses were adjusted for baseline sociodemographic, clinical, dietary, and lifestyle factors. All statistical tests were 2-sided.

Results: Over a median follow-up of 7.7 years, the adjusted hazard ratios for Blacks (compared with Whites) were 0.94 (95% confidence interval [CI] = 0.66 to 1.35, =.75) for disease-free survival, 0.91 (95% CI = 0.62 to 1.35, =.65) for recurrence-free survival, and 1.07 (95% CI = 0.73 to 1.57, =.73) for overall survival. Relative to patients in the highest MHI quartile, the adjusted hazard ratios for patients in the lowest quartile were 0.90 (95% CI = 0.67 to 1.19, = .18) for disease-free survival, 0.89 (95% CI = 0.66 to 1.22, =.14) for recurrence-free survival, and 0.87 (95% CI = 0.63 to 1.19, = .23) for overall survival.

Conclusions: In this study of patients with similar health-care access, no statistically significant differences in outcomes were found by race or MHI. The substantial gaps in outcomes previously observed by race and MHI may not be rooted in differences in tumor biology but rather in access to quality care.
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http://dx.doi.org/10.1093/jncics/pkab034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178799PMC
June 2021

Randomized Phase II Study of PET Response-Adapted Combined Modality Therapy for Esophageal Cancer: Mature Results of the CALGB 80803 (Alliance) Trial.

J Clin Oncol 2021 Sep 2;39(25):2803-2815. Epub 2021 Jun 2.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: To evaluate the use of early assessment of chemotherapy responsiveness by positron emission tomography (PET) imaging to tailor therapy in patients with esophageal and esophagogastric junction adenocarcinoma.

Methods: After baseline PET, patients were randomly assigned to an induction chemotherapy regimen: modified oxaliplatin, leucovorin, and fluorouracil (FOLFOX) or carboplatin-paclitaxel (CP). Repeat PET was performed after induction; change in maximum standardized uptake value (SUV) from baseline was assessed. PET nonresponders (< 35% decrease in SUV) crossed over to the alternative chemotherapy during chemoradiation (50.4 Gy/28 fractions). PET responders (≥ 35% decrease in SUV) continued on the same chemotherapy during chemoradiation. Patients underwent surgery at 6 weeks postchemoradiation. Primary end point was pathologic complete response (pCR) rate in nonresponders after switching chemotherapy.

Results: Two hundred forty-one eligible patients received Protocol treatment, of whom 225 had an evaluable repeat PET. The pCR rates for PET nonresponders after induction FOLFOX who crossed over to CP (n = 39) or after induction CP who changed to FOLFOX (n = 50) was 18.0% (95% CI, 7.5 to 33.5) and 20% (95% CI, 10 to 33.7), respectively. The pCR rate in responders who received induction FOLFOX was 40.3% (95% CI, 28.9 to 52.5) and 14.1% (95% CI, 6.6 to 25.0) in responders to CP. With a median follow-up of 5.2 years, median overall survival was 48.8 months (95% CI, 33.2 months to not estimable) for PET responders and 27.4 months (95% CI, 19.4 months to not estimable) for nonresponders. For induction FOLFOX patients who were PET responders, median survival was not reached.

Conclusion: Early response assessment using PET imaging as a biomarker to individualize therapy for patients with esophageal and esophagogastric junction adenocarcinoma was effective, improving pCR rates in PET nonresponders. PET responders to induction FOLFOX who continued on FOLFOX during chemoradiation achieved a promising 5-year overall survival of 53%.
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http://dx.doi.org/10.1200/JCO.20.03611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407649PMC
September 2021

Increasing physical activity in Cancer Survivors through a Text-messaging Exercise motivation Program (ICanSTEP).

Support Care Cancer 2021 May 28. Epub 2021 May 28.

Department of Population Health Sciences, Duke School of Medicine, Durham, NC, 27710, USA.

Purpose: Cancer survivors are often sedentary. Self-monitoring may promote physical activity through self-activation. We conducted a pilot trial to evaluate whether wearable activity tracker with personalized text message feedback would increase physical activity.

Methods: We enrolled 30 patients with solid tumor cancers into a non-randomized prospective intervention trial (NCT02627079): 15 had completed treatment in the past year and 15 under active treatment. Each participant received an activity tracker and daily text messages personalized to their activity level. We assessed patient-reported outcomes and 6-min walk (6 MW) at baseline and 3 months.

Results: Twenty-six participants completed the study. There was substantial variation in baseline activity. Overall, 39% of participants increased their steps taken by at least 20%, and 23% increased their 6 MW distance by 20% or more. More participants who had completed treatment strongly agreed (73%) that the intervention increased their exercise levels than those receiving active treatment (47%). At 3 months, there was a significant improvement in median Beck Depression Inventory-II and Godin Leisure Index composite scores. At 6 months, 72% still wore their activity tracker at least 4 days per week.

Conclusion: We found that the intervention was well-accepted with a high completion rate at 3 months and continued self-use at 6 months. In this pilot study of combined activity tracker and motivational messaging, we found a signal for increased physical activity over a 3-month period. Future research is needed to study this technique for its impact on activity and other physical and psychological measures of well-being.

Implication For Cancer Survivors: Activity tracker with personalized motivational messaging may be useful in promoting physical activity in cancer survivors.
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http://dx.doi.org/10.1007/s00520-021-06281-yDOI Listing
May 2021

Intrinsic radiomic expression patterns after 20 Gy demonstrate early metabolic response of oropharyngeal cancers.

Med Phys 2021 Jul 2;48(7):3767-3777. Epub 2021 Jun 2.

Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA.

Purpose: This study investigated the prognostic potential of intra-treatment PET radiomics data in patients undergoing definitive (chemo) radiation therapy for oropharyngeal cancer (OPC) on a prospective clinical trial. We hypothesized that the radiomic expression of OPC tumors after 20 Gy is associated with recurrence-free survival (RFS).

Materials And Methods: Sixty-four patients undergoing definitive (chemo)radiation for OPC were prospectively enrolled on an IRB-approved study. Investigational F-FDG-PET/CT images were acquired prior to treatment and 2 weeks (20 Gy) into a seven-week course of therapy. Fifty-five quantitative radiomic features were extracted from the primary tumor as potential biomarkers of early metabolic response. An unsupervised data clustering algorithm was used to partition patients into clusters based only on their radiomic expression. Clustering results were naïvely compared to residual disease and/or subsequent recurrence and used to derive Kaplan-Meier estimators of RFS. To test whether radiomic expression provides prognostic value beyond conventional clinical features associated with head and neck cancer, multivariable Cox proportional hazards modeling was used to adjust radiomic clusters for T and N stage, HPV status, and change in tumor volume.

Results: While pre-treatment radiomics were not prognostic, intra-treatment radiomic expression was intrinsically associated with both residual/recurrent disease (P = 0.0256, test) and RFS (HR = 7.53, 95% CI = 2.54-22.3; P = 0.0201). On univariate Cox analysis, radiomic cluster was associated with RFS (unadjusted HR = 2.70; 95% CI = 1.26-5.76; P = 0.0104) and maintained significance after adjustment for T, N staging, HPV status, and change in tumor volume after 20 Gy (adjusted HR = 2.69; 95% CI = 1.03-7.04; P = 0.0442). The particular radiomic characteristics associated with outcomes suggest that metabolic spatial heterogeneity after 20 Gy portends complete and durable therapeutic response. This finding is independent of baseline metabolic imaging characteristics and clinical features of head and neck cancer, thus providing prognostic advantages over existing approaches.

Conclusions: Our data illustrate the prognostic value of intra-treatment metabolic image interrogation, which may potentially guide adaptive therapy strategies for OPC patients and serve as a blueprint for other disease sites. The quality of our study was strengthened by its prospective image acquisition protocol, homogenous patient cohort, relatively long patient follow-up times, and unsupervised clustering formalism that is less prone to hyper-parameter tuning and over-fitting compared to supervised learning.
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http://dx.doi.org/10.1002/mp.14926DOI Listing
July 2021

Hospital-level compliance with the commission on cancer's quality of care measures and the association with patient survival.

Cancer Med 2021 06 4;10(11):3533-3544. Epub 2021 May 4.

Department of Surgery, Duke University, Duke Cancer Institute, Durham, NC, USA.

Background: Quality measurement has become a priority for national healthcare reform, and valid measures are necessary to discriminate hospital performance and support value-based healthcare delivery. The Commission on Cancer (CoC) is the largest cancer-specific accreditor of hospital quality in the United States and has implemented Quality of Care Measures to evaluate cancer care delivery. However, none has been formally tested as a valid metric for assessing hospital performance based on actual patient outcomes.

Methods: Eligibility and compliance with the Quality of Care Measures are reported within the National Cancer Database, which also captures data for robust patient-level risk adjustment. Hospital-level compliance was calculated for the core measures, and the association with patient survival was tested using Cox regression.

Results: Seven hundred sixty-eight thousand nine hundred sixty-nine unique cancer cases were included from 1323 facilities. Increasing hospital-level compliance was associated with improved survival for only two measures, including a 35% reduced risk of mortality for the gastric cancer measure G15RLN (HR 0.65, 95% CI 0.58-0.72) and a 19% reduced risk of mortality for the colon cancer measure 12RLN (HR 0.81, 95% CI 0.77-0.85). For the lung cancer measure LNoSurg, increasing compliance was paradoxically associated with an increased risk of mortality (HR 1.14, 95% CI 1.08-1.20). For the remaining measures, hospital-level compliance demonstrated no consistent association with patient survival.

Conclusion: Hospital-level compliance with the CoC's Quality of Care Measures is not uniformly aligned with patient survival. In their current form, these measures do not reliably discriminate hospital performance and are limited as a tool for value-based healthcare delivery.
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http://dx.doi.org/10.1002/cam4.3875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178497PMC
June 2021

Effect of Celecoxib vs Placebo Added to Standard Adjuvant Therapy on Disease-Free Survival Among Patients With Stage III Colon Cancer: The CALGB/SWOG 80702 (Alliance) Randomized Clinical Trial.

JAMA 2021 04;325(13):1277-1286

Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.

Importance: Aspirin and cyclooxygenase 2 (COX-2) inhibitors have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies. The effect of celecoxib, a COX-2 inhibitor, as treatment for nonmetastatic colon cancer is unknown.

Objective: To determine if the addition of celecoxib to adjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) improves disease-free survival in patients with stage III colon cancer.

Design, Setting, And Participants: Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group 80702 was a 2 × 2 factorial design, phase 3 trial conducted at 654 community and academic centers throughout the United States and Canada. A total of 2526 patients with stage III colon cancer were enrolled between June 2010 and November 2015 and were followed up through August 10, 2020.

Interventions: Patients were randomized to receive adjuvant FOLFOX (every 2 weeks) for 3 vs 6 months with or without 3 years of celecoxib (400 mg orally daily; n = 1263) vs placebo (n = 1261). This report focuses on the results of the celecoxib randomization.

Main Outcomes And Measures: The primary end point was disease-free survival, measured from the time of randomization until documented recurrence or death from any cause. Secondary end points included overall survival, adverse events, and cardiovascular-specific events.

Results: Of the 2526 patients who were randomized (mean [SD] age, 61.0 years [11 years]; 1134 women [44.9%]), 2524 were included in the primary analysis. Adherence with protocol treatment, defined as receiving celecoxib or placebo for more than 2.75 years or continuing treatment until recurrence, death, or unacceptable adverse events, was 70.8% for patients treated with celecoxib and 69.9% for patients treated with placebo. A total of 337 patients randomized to celecoxib and 363 to placebo experienced disease recurrence or died, and with 6 years' median follow-up, the 3-year disease-free survival was 76.3% for celecoxib-treated patients vs 73.4% for placebo-treated patients (hazard ratio [HR] for disease recurrence or death, 0.89; 95% CI, 0.76-1.03; P = .12). The effect of celecoxib treatment on disease-free survival did not vary significantly according to assigned duration of adjuvant chemotherapy (P for interaction = .61). Five-year overall survival was 84.3% for celecoxib vs 81.6% for placebo (HR for death, 0.86; 95% CI, 0.72-1.04; P = .13). Hypertension (any grade) occurred while treated with FOLFOX in 14.6% of patients in the celecoxib group vs 10.9% of patients in the placebo group, and a grade 2 or higher increase in creatinine levels occurred after completion of FOLFOX in 1.7% vs 0.5% of patients, respectively.

Conclusions And Relevance: Among patients with stage III colon cancer, the addition of celecoxib for 3 years, compared with placebo, to standard adjuvant chemotherapy did not significantly improve disease-free survival.

Trial Registration: ClinicalTrials.gov Identifier: NCT01150045.
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http://dx.doi.org/10.1001/jama.2021.2454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025124PMC
April 2021

Racial and Socioeconomic Disparities in Utilization of Telehealth in Patients with Liver Disease During COVID-19.

Dig Dis Sci 2021 Jan 28. Epub 2021 Jan 28.

Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Box 3913, Durham, NC, 27710, USA.

Background And Aims: The coronavirus disease 2019 (COVID-19) pandemic resulted in a rapid expansion of telehealth services in hepatology. However, known racial and socioeconomic disparities in internet access potentially translate into barriers for the use of telehealth, particularly video technology. The specific aim of this study was to determine if disparities in race or socioeconomic status exist among patients utilizing telehealth visits during COVID-19.

Methods: We performed a retrospective cohort study of all adult patients evaluated in hepatology clinics at Duke University Health System. Visit attempts from a pre-COVID baseline period (January 1, 2020 through February 29, 2020; n = 3328) were compared to COVID period (April 1, 2020 through May 30, 2020; n = 3771).

Results: On multinomial regression modeling, increasing age was associated with higher odds of a phone or incomplete visit (canceled, no-show, or rescheduled after May 30,2020), and non-Hispanic Black race was associated with nearly twice the odds of completing a phone visit instead of video visit, compared to non-Hispanic White patients. Compared to private insurance, Medicaid and Medicare were associated with increased odds of completing a telephone visit, and Medicaid was associated with increased odds of incomplete visits. Being single or previously married (separated, divorced, widowed) was associated with increased odds of completing a phone compared to video visit compared to being married.

Conclusions: Though liver telehealth has expanded during the COVID-19 pandemic, disparities in overall use and suboptimal use (phone versus video) remain for vulnerable populations including those that are older, non-Hispanic Black, or have Medicare/Medicaid health insurance.
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http://dx.doi.org/10.1007/s10620-021-06842-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842167PMC
January 2021

Primary Mediastinal (Thymic) Large B-Cell Lymphoma: Fidelity of Diagnosis Using WHO Criteria.

Clin Lymphoma Myeloma Leuk 2021 05 30;21(5):e464-e469. Epub 2020 Dec 30.

Department of Radiation Oncology Duke University Medical Center, Durham, NC.

Purpose: Diagnosing primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is challenging because it is a clinicopathologic entity that shares characteristics with other lymphomas and lacks pathognomonic features. We sought to investigate the fidelity between a working diagnosis of PMBCL at our institution and the clinicopathologic criteria established within the 2017 World Health Organization (WHO) classification.

Patients And Methods: Medical records and archived tissue of patients treated for stage I-II PMBCL from 1998 to 2018 were retrospectively reviewed for clinical and pathologic conformity with current WHO criteria. Disease was characterized as definitely PMBCL if all of the following were present: anterior mediastinal mass with or without lymph node involvement, no extranodal disease, B-cell antigen expression, Epstein-Barr virus negativity, and at least one supportive feature: female gender under age 40, bulky primary tumor, CD30 weakly positive, compartmentalizing alveolar fibrosis, lack of surface immunoglobulin expression, and MUM1 or CD23 positivity. Disease without supportive features or other pathologic findings more suggestive of other entities was characterized as equivocal for PMBCL. Lack of an anterior mediastinal mass, presence of distant lymph node involvement or extranodal disease, lack of B-cell antigen expression, or Epstein-Barr virus positivity were characterized as definitely not PMBCL. Clinical management and outcomes were also assessed.

Results: Of 63 patients treated for presumed stage I-II PMBCL, 58 (92%) met the criteria for PMBCL. The most common reason for a discordant diagnosis was lack of an anterior mediastinal mass (n = 3). Two additional patients were characterized as having disease equivocal for PMBCL. In retrospect, one patient most likely had a mediastinal gray zone lymphoma due to CD15 positivity and another diffuse large B cell, not otherwise specified, at pathologic review. Five-year progression-free and overall survival were 67% (95% confidence interval, 54-77) and 81% (95% confidence interval, 68-89), respectively, for all patients.

Conclusion: Despite the complexity of the clinicopathologic criteria of PMBCL, most patients (92%) who were treated for stage I-II PMBCL at our institution appear to have been accurately diagnosed.
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http://dx.doi.org/10.1016/j.clml.2020.12.015DOI Listing
May 2021

Why do patients with chronic hepatitis C drink alcohol? An examination of pain, depression and drinking motives.

J Viral Hepat 2021 05 13;28(5):699-709. Epub 2021 Feb 13.

Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.

Alcohol consumption in the setting of chronic HCV is associated with accelerated progression towards cirrhosis, increased risk of hepatocellular carcinoma and higher mortality. This analysis contextualizes how sociodemographic factors, chronic pain and depression relate to the motivations of individuals with chronic HCV to consume alcohol. We conducted a secondary analysis of baseline data from the Hep ART trial of behavioural interventions on alcohol use among patients with HCV. Alcohol consumption was measured using the Drinking Motives Questionnaire and a novel 6-item measure of pain-related drinking motives. Statistical analyses performed included ANOVA for bivariate analyses and multivariable ordinary least-squares linear regression. At study baseline, 181 participants had an average age of 55 years; the majority (66.7%) reported beyond-minor pain; and a third (37%) met criteria for depression; drinking motives were higher for individuals with beyond-minor pain (means 9.9 vs. 4.6, p < .001) and who met criteria for depression (means 10.9 vs. 6.4, p < .001) when using the pain-related drinking motives items. Average pain(coef = 1.0410067141 < .001) was significantly associated with increased motives to drink to relieve pain in the full baseline model specification controlling for all covariates using ordinary at least squares; depression (coef = 7.06; 95% CI 1.32, 12.81; p = .016) was significantly associated with increased non-pain-related motives to drink. From baseline to 3-month follow-up, compared to participants who had mean average pain scores among the sample, motives to drink to relieve pain decreased in participants who had higher average pain scores (coef = -0.30; 95% CI -0.59, -0.01; p = .40). Physical pain and depression are associated with increased motives to consume alcohol. Patients with chronic liver disease should be screened for chronic pain and depression and, if present, referred to pain specialists or co-managed in partnership with pain specialists in hepatology clinics.
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http://dx.doi.org/10.1111/jvh.13474DOI Listing
May 2021

Cabozantinib and Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer.

Oncologist 2021 06 9;26(6):465-e917. Epub 2021 Feb 9.

Duke University Medical Center, Durham, North Carolina, USA.

Lessons Learned: Antitumor activity was observed in the study population. Dose modifications of cabozantinib improve long-term tolerability. Biomarkers are needed to identify patient populations most likely to benefit. Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted.

Background: The epidermal growth factor receptor (EGFR) antibody panitumumab is active in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), but nearly all patients experience resistance. MET amplification is a driver of panitumumab resistance. Cabozantinib is an inhibitor of multiple kinases, including vascular endothelial growth factor receptor 2 (VEGFR2) and c-MET, and may delay or reverse anti-EGFR resistance.

Methods: In this phase Ib clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of cabozantinib and panitumumab. We then treated an expansion cohort to further describe the tolerability and clinical activity of the RP2D. Eligibility included patients with KRAS WT mCRC (later amended to include only RAS WT mCRC) who had received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab.

Results: Twenty-five patients were enrolled and treated. The MTD/RP2D was cabozantinib 60 mg p.o. daily and panitumumab 6 mg/kg I.V. every 2 weeks. The objective response rate (ORR) was 16%. Median progression free survival (PFS) was 3.7 months (90% confidence interval [CI], 2.3-7.1). Median overall survival (OS) was 12.1 months (90% CI, 7.5-14.3). Five patients (20%) discontinued treatment due to toxicity, and 18 patients (72%) required a dose reduction of cabozantinib.

Conclusion: The combination of cabozantinib and panitumumab has activity. Dose reductions of cabozantinib improve tolerability.
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http://dx.doi.org/10.1002/onco.13678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176979PMC
June 2021

IGF-Binding Proteins, Adiponectin, and Survival in Metastatic Colorectal Cancer: Results From CALGB (Alliance)/SWOG 80405.

JNCI Cancer Spectr 2021 Feb 27;5(1):pkaa074. Epub 2020 Aug 27.

Department of Medical Oncology, Dana-Farber/Partners CancerCare, Boston, MA, USA.

Background: Energy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study.

Methods: Baseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute-sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). values are 2-sided.

Results: Median follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; < .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS ( = .03).

Conclusions: Among patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.
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http://dx.doi.org/10.1093/jncics/pkaa074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785047PMC
February 2021

Image quality of EOS low-dose radiography in comparison with conventional radiography for assessment of ventriculoperitoneal shunt integrity.

J Neurosurg Pediatr 2021 Jan 8:1-7. Epub 2021 Jan 8.

4Neurosurgery, and.

Objective: Patients with shunted hydrocephalus often accumulate high levels of radiation over their lifetimes during evaluation of hardware integrity. Current practice involves the use of a series of conventional radiographs for this purpose. Newer low-dose EOS radiography is currently used to evaluate scoliosis but has not been explored to evaluate shunt integrity on a large scale. The goal of this study was to compare the quality of imaging using EOS low-dose radiography to conventional radiography to evaluate shunt tubing.

Methods: A retrospective chart review was performed on 57 patients who previously had both conventional radiographs and low-dose EOS images of their cerebral shunt tubing from 2000 to 2018. Patient demographics (age, sex, type of shunt tubing, primary diagnosis) were collected. Conventional radiographic images and low-dose EOS images were independently analyzed by a neurosurgeon and neuroradiologist in three categories: image quality, delineation of shunt, and distinction of shunt compared to adjacent anatomy.

Results: All patients had shunted hydrocephalus due to spina bifida and Chiari type II malformation. Ratings of EOS and conventional radiographic images by both raters did not differ significantly in terms of image quality (rater 1, p = 0.499; rater 2, p = 0.578) or delineation of shunt (p = 0.107 and p = 0.256). Conventional radiographic images received significantly higher ratings than EOS on the ability to distinguish the shunt versus adjacent anatomy by rater 1 (p = 0.039), but not by rater 2 (p = 0.149). The overall score of the three categories combined was not significantly different between EOS and conventional radiography (rater 1, p = 0.818; rater 2, p = 0.186). In terms of cost, an EOS image was less costly than a conventional radiography shunt series ($236-$366 and $1300-$1547, respectively). The radiation dose was also lower for EOS images, with an effective dose of 0.086-0.140 mSv compared to approximately 1.6 mSv for a similar field of view with conventional radiography.

Conclusions: The image quality of low-dose EOS radiography does not significantly differ from conventional radiography for the evaluation of cerebral shunts. In addition, EOS affords a much lower radiation dose and a lower cost.
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http://dx.doi.org/10.3171/2020.8.PEDS20428DOI Listing
January 2021

Need for Pretransplant Midodrine Does Not Negatively Impact Simultaneous Liver-kidney Transplant Outcomes.

Transplant Direct 2021 Jan 15;7(1):e640. Epub 2020 Dec 15.

Division of Gastroenterology, Duke University, Durham, NC.

Background: Midodrine is often needed pretransplant to improve hemodynamics in simultaneous liver-kidney transplant candidates. Previous research has shown that patients requiring midodrine before kidney transplant alone have increased posttransplant risk for delayed allograft function, graft failure, and death. However, the impact of pretransplant midodrine use on outcomes after simultaneous liver-kidney transplant is unknown.

Methods: We performed a retrospective study of all adult (age ≥18 y) simultaneous liver-kidney transplant recipients from a single academic transplant center from February 1, 2002, to June 30, 2019.

Results: Sixty-four simultaneous liver-kidney transplants were performed in our institution during this time period, of which, 43 were not on midodrine before transplant, 17 were on midodrine alone, and 4 were on intravenous (IV) vasopressor therapy. Despite the midodrine group having a higher MELD-Na at listing, higher MELD-Na at transplant, and being older, there were no significant differences in key outcomes including delayed renal allograft function, estimated glomerular filtration rate at transplant discharge, and estimated glomerular filtration rate at 1 y after transplant compared with the nonmidodrine group. There was no significant difference in graft failure or survival at last follow-up.

Conclusions: Our study suggests that need for pretransplant midodrine should not be a barrier to simultaneous liver-kidney transplant.
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http://dx.doi.org/10.1097/TXD.0000000000001071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738159PMC
January 2021

Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials.

Lancet Oncol 2020 12;21(12):1620-1629

Department of Health Science Research, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: A prospective, pooled analysis of six randomised phase 3 trials was done to investigate disease-free survival regarding non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer; non-inferiority was not shown. Here, we report the final overall survival results.

Methods: In this prospective, pooled analysis of six randomised phase 3 trials, we included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-1 recruited between June 20, 2007, and Dec 31, 2015, across 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials, who started any treatment (modified intention-to-treat). Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) every 2 weeks or capecitabine and oxaliplatin (CAPOX) in different doses and methods every 3 weeks, at the treating physician's discretion. The primary endpoint was disease-free survival (time to relapse, secondary colorectal primary tumour, or death due to all causes), and overall survival (time to death due to all causes) was the prespecified secondary endpoint. The non-inferiority margin for overall survival was set as a hazard ratio (HR) of 1·11. Pre-planned subgroup analyses included regimen and risk group. Non-inferiority was declared if the one-sided false discovery rate adjusted (FDRadj) p value was less than 0·025.

Findings: With median follow-up of 72·3 months (IQR 72·2-72·5), 2584 deaths among 12 835 patients were observed. 5064 (39·5%) patients received CAPOX and 7771 (60·5%) received FOLFOX. 5-year overall survival was 82·4% (95% CI 81·4-83·3) with 3 months of therapy and 82·8% (81·8-83·8) with 6 months of therapy (HR 1·02 [95% CI 0·95-1·11]; non-inferiority FDRadj p=0·058). For patients treated with CAPOX, 5-year overall survival was 82·1% (80·5-83·6) versus 81·2% (79·2-82·9; HR 0·96 [0·85-1·08]); non-inferiority FDRadj p=0·033), and for patients treated with FOLFOX 5-year overall survival was 82·6% (81·3-83·8) and 83·8% (82·6-85·0; HR 1·07 [0·97-1·18]; non-inferiority FDRadj p=0·34). Updated disease-free survival results confirmed previous findings (HR 1·08 [95% CI 1·02-1·15]; non-inferiority FDRadj p=0·25). Data on adverse events were not further recorded.

Interpretation: Non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0·4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration.

Funding: US National Cancer Institute.
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http://dx.doi.org/10.1016/S1470-2045(20)30527-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786835PMC
December 2020

Predictors of Abnormal Functional Luminal Impedance Planimetry Findings in Non-mechanical Esophagogastric Junction Outflow Obstruction.

Dig Dis Sci 2021 Nov 28;66(11):3968-3975. Epub 2020 Nov 28.

Division of Gastroenterology, Duke University School of Medicine, 200 Morris Street, Suite 6524, Durham, NC, 27705, USA.

Background: Esophagogastric junction outflow obstruction (EGJOO) is a common but nonspecific motility pattern identified by esophageal high-resolution manometry (HRM). Functional luminal impedance planimetry (FLIP) provides information regarding lower esophageal sphincter (LES) mechanics, which can identify achalasia spectrum disorders and is useful in evaluating EGJOO. However, the relationship between HRM and FLIP parameters in EGJOO is not clearly defined.

Aims: To identify predictors of abnormal FLIP findings in patients with non-mechanical EGJOO.

Methods: This is a retrospective cohort study of patients with non-mechanical EGJOO who underwent FLIP between 10/1/16 and 7/1/19. Demographic data including age and gender, examination indication, concomitant medications, HRM parameters, symptom burden, and FLIP metrics of diameter and distensibility index (DI) were collected. DI was categorized as not low (DI > 2.8), borderline low (DI 1.1-2.8), and definitely low (DI ≤ 1). Kruskal-Wallis and Fisher's exact tests were used to assess the relationship between HRM and FLIP parameters and to identify predictors of abnormal FLIP.

Results: Among the 44 patients studied, most were female (n = 33, 75%) and the median age was 63. The median IRP was 18.2, and 10 (23%) patients used chronic narcotics. Lower total heartburn and regurgitation scores, and LES diameter by FLIP are associated with definitely low DI.

Conclusions: In patients with non-mechanical EGJOO, reflux burden scores and FLIP diameters can aid in predicting DI. These results may provide useful adjunctive data to help in differentiating which patients have meaningful outflow obstruction.
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http://dx.doi.org/10.1007/s10620-020-06726-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248766PMC
November 2021

Long-term survival of patients with stage III colon cancer treated with VRP-CEA(6D), an alphavirus vector that increases the CD8+ effector memory T cell to Treg ratio.

J Immunother Cancer 2020 11;8(2)

Surgery, Duke University School of Medicine, Durham, North Carolina, USA

Background: There remains a significant need to eliminate the risk of recurrence of resected cancers. Cancer vaccines are well tolerated and activate tumor-specific immune effectors and lead to long-term survival in some patients. We hypothesized that vaccination with alphaviral replicon particles encoding tumor associated antigens would generate clinically significant antitumor immunity to enable prolonged overall survival (OS) in patients with both metastatic and resected cancer.

Methods: OS was monitored for patients with stage IV cancer treated in a phase I study of virus-like replicon particle (VRP)-carcinoembryonic antigen (CEA), an alphaviral replicon particle encoding a modified CEA. An expansion cohort of patients (n=12) with resected stage III colorectal cancer who had completed their standard postoperative adjuvant chemotherapy was administered VRP-CEA every 3 weeks for a total of 4 immunizations. OS and relapse-free survival (RFS) were determined, as well as preimmunization and postimmunization cellular and humoral immunity.

Results: Among the patients with stage IV cancer, median follow-up was 10.9 years and 5-year survival was 17%, (95% CI 6% to 33%). Among the patients with stage III cancer, the 5-year RFS was 75%, (95%CI 40% to 91%); no deaths were observed. At a median follow-up of 5.8 years (range: 3.9-7.0 years) all patients were still alive. All patients demonstrated CEA-specific humoral immunity. Patients with stage III cancer had an increase in CD8 +T (in 10/12) and decrease in FOXP3 +Tregs (in 10/12) following vaccination. Further, CEA-specific, IFNγ-producing CD8+granzyme B+T cells were increased.

Conclusions: VRP-CEA induces antigen-specific effector T cells while decreasing Tregs, suggesting favorable immune modulation. Long-term survivors were identified in both cohorts, suggesting the OS may be prolonged.
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http://dx.doi.org/10.1136/jitc-2020-001662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661359PMC
November 2020

Body Mass Index and Weight Loss in Metastatic Colorectal Cancer in CALGB (Alliance)/SWOG 80405.

JNCI Cancer Spectr 2020 Jun 31;4(3):pkaa024. Epub 2020 Mar 31.

Department of Medical Oncology, Dana-Farber/Partners CancerCare, Boston, MA, USA.

Background: In nonmetastatic colorectal cancer, overweight and mild-to-moderately obese patients experience improved outcomes compared with other patients. Obesity's influence on advanced or metastatic colorectal cancer (mCRC) is relatively unexplored.

Methods: We conducted a prospective body mass index (BMI) companion study in Cancer and Leukemia Group B (now Alliance)/SWOG 80405, a phase III metastatic colorectal cancer (mCRC) treatment trial. BMI was measured at trial registration. Primary and secondary endpoints were overall and progression-free survival, respectively. To minimize confounding by poor and rapidly declining health, we used Cox proportional hazards regression to adjust for known prognostic factors, comorbidities, physical activity, and weight loss during the 6 months prior to study entry. We also examined weight loss prior to enrollment as an independent predictor of patient outcome. All statistical tests were two-sided.

Results: Among 2323 patients with mCRC, there were no statistically significant associations between BMI and overall or progression-free survival (adjusted = .12 and .40, respectively). Weight loss during the 6 months prior to study entry was associated with shorter overall and progression-free survival; compared with individuals with stable weight ±4.9%, individuals with weight loss greater than 15% experienced an adjusted hazard ratio of 1.52 for all-cause mortality (95% confidence interval [CI] = 1.26 to 1.84; < .001) and of 1.23 for disease progression or death (95% CI = 1.02 to 1.47; = .006).

Conclusions: In this prospective study of patients with mCRC, BMI at time of first-line chemotherapy initiation was not associated with patient outcome. Weight loss prior to study entry was associated with increased risk of patient mortality and disease progression.
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http://dx.doi.org/10.1093/jncics/pkaa024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590517PMC
June 2020

Association of Diet Quality With Survival Among People With Metastatic Colorectal Cancer in the Cancer and Leukemia B and Southwest Oncology Group 80405 Trial.

JAMA Netw Open 2020 10 1;3(10):e2023500. Epub 2020 Oct 1.

Dana-Farber/Partners CancerCare, Boston, Massachusetts.

Importance: Diet has been associated with survival in patients with stage I to III colorectal cancer, but data on patients with metastatic colorectal cancer are limited.

Objective: To examine the association between diet quality and overall survival among individuals with metastatic colorectal cancer.

Design, Setting, And Participants: This was a prospective cohort study of patients with metastatic colorectal cancer who were enrolled in the Cancer and Leukemia Group B (Alliance) and Southwest Oncology Group 80405 trial between October 27, 2005, and February 29, 2012, and followed up through January 2018.

Exposures: Participants completed a validated food frequency questionnaire within 4 weeks after initiation of first-line treatment for metastatic colorectal cancer. Diets were categorized according to the Alternative Healthy Eating Index (AHEI), Alternate Mediterranean Diet (AMED) score, Dietary Approaches to Stop Hypertension (DASH) score, and Western and prudent dietary patterns derived using principal component analysis. Participants were categorized into sex-specific quintiles.

Main Outcomes And Measures: Multivariable hazard ratios (HRs) and 95% CIs for overall survival.

Results: In this cohort study of 1284 individuals with metastatic colorectal cancer, the median age was 59 (interquartile range [IQR]: 51-68) years, median body mass index was 27.2 (IQR, 24.1-31.4), 521 (41%) were female, and 1102 (86%) were White. There were 1100 deaths during a median follow-up of 73 months (IQR, 64-87 months). We observed an inverse association between the AMED score and risk of death (HR quintile 5 vs quintile 1, 0.83; 95% CI, 0.67-1.04; P = .04 for trend), but the point estimates were not statistically significant. None of the other diet scores or patterns were associated with overall survival.

Conclusions And Relevance: In this prospective analysis of patients with metastatic colorectal cancer, diet quality assessed at initiation of first-line treatment for metastatic disease was not associated with overall survival.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.23500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599454PMC
October 2020

Reduced Alcohol Use Is Sustained in Patients Provided Alcohol-Related Counseling During Direct-Acting Antiviral Therapy for Hepatitis C.

Dig Dis Sci 2021 09 23;66(9):2956-2963. Epub 2020 Sep 23.

Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.

Background: Patients with chronic hepatitis C and risky/harmful alcohol use experience poor outcomes. Granular data evaluating whether alcohol counseling during hepatitis C treatment impacts longitudinal alcohol consumption are lacking.

Aims: To evaluate whether provider-delivered counseling in the context of direct-acting antiviral hepatitis C treatment associates with decreased longitudinal alcohol consumption.

Methods: We performed secondary data analysis from the Hep ART study including adults with hepatitis C who underwent provider-delivered counseling during direct-acting antiviral treatment between October 2014 and September 2017. Demographics and disease characteristics were summarized. Alcohol consumption, abstinence, and heavy drinking were evaluated in periods before, during, and after direct-acting antiviral treatment. Multivariate regression analyses were performed to evaluate the association of alcohol consumption with each 12-week time period for all patients and a subsample with cirrhosis.

Results: One hundred twenty-three patients were included; 41 had cirrhosis. Most patients were male (74.0%) and Black (58.5%). Alcohol consumption improved during direct-acting antiviral treatment and was notably sustained (< 12 weeks before treatment 32.5 g/day; during treatment 20.0 g/day; and 12-24 weeks after treatment 23.7 g/day). Multivariable analyses showed significantly improved alcohol consumption metrics during and after antiviral treatment compared to < 12 weeks before treatment (during treatment 13.04 g/day less, p = 0.0001; > 24 weeks after treatment 15.29 g/day less, p = 0.0001). The subsample with cirrhosis showed similar results (during treatment 13.21 g/day less, p = 0.0001; > 24 weeks after treatment 7.69 g/day less, p = 0.0001).

Conclusions: Patients with chronic HCV and risky/harmful alcohol use given provider-delivered alcohol-related counseling during HCV treatment sustain decreased alcohol consumption patterns during and after treatment.
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http://dx.doi.org/10.1007/s10620-020-06616-5DOI Listing
September 2021

Use, Yield, and Risk of Device-assisted Enteroscopy in the United States: Results From a Large Retrospective Multicenter Cohort.

J Clin Gastroenterol 2021 10;55(9):792-797

Division of Gastroenterology, Duke University Medical Center.

Introduction: Since 2001, device-assisted enteroscopy (DAE) has revolutionized the diagnostic and therapeutic capabilities for managing small bowel pathology. Though commonly performed, there have been no recent large studies to assess the use, yield, and risks of DAE and none that include all 3 DAE modalities. We hypothesized that DAE is safe with high diagnostic and therapeutic yields achieved within reasonable procedure duration and here we present a large retrospective multicenter US study evaluating the use, yield, and complications of DAE.

Methods: After obtaining institutional review board approval, electronic records were used to identify all DAE's performed for luminal small bowel evaluation in adult patients at 4 US referral centers (Duke University Medical Center, New York University Langone Medical Center, Louisiana State University Health Sciences Center, and University of Massachusetts Medical Center) from January 1, 2014 to January 1, 2019. Electronic medical records were reviewed to collect and analyze a variety of procedure-related outcomes. Using the data pooled across centers, descriptive statistics were generated for the patient and procedure-related characteristics and outcomes; relationships between characteristics and outcomes were explored.

Results: A total of 1787 DAE's were performed over this 5-year period (392 at Duke University Medical Center, 887 at Louisiana State University Health Sciences Center, 312 at New York University Langone Medical Center, and 195 at University of Massachusetts Medical Center). Of these, there were 1017 (57%) double-balloon, 391 (29%) single-balloon, and 378 (21%) spiral enteroscopies. The mean age of patients undergoing DAE was 66 years and 53% of examinations were performed on women; 18% of patients in the cohort underwent >1 DAE over this time span. A total of 53% of examinations were performed for suspected small bowel bleeding, 31% were directly guided by video capsule endoscopy findings and 8% were performed for abnormal imaging. A total of 85% of examinations used an antegrade approach and DAE took a mean of 45 minutes to complete; 76% of examinations revealed abnormal findings, with vascular, inflammatory, and neoplastic findings seen in 49%, 17%, and 15% of the cohort, respectively. Older age was significantly associated with any abnormal finding, including arteriovenous malformations (P<0.0001); 50% of examinations included a therapeutic maneuver, most commonly argon plasma coagulation/cautery (43%). There were complications in 16 examinations (0.9%) including 2 perforations (0.1%), 6 cases with bleeding (0.3%) and 1 episode of pancreatitis (0.1%).

Conclusions: DAE is most commonly performed to evaluate suspected small bowel bleeding and is commonly directed by video capsule findings. DAE is safe, has a high diagnostic yield, with 76% of examinations showing abnormal findings, and frequently features therapeutic maneuvers. Advancing age is associated with abnormal findings on DAE.
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http://dx.doi.org/10.1097/MCG.0000000000001426DOI Listing
October 2021

Association of Coffee Intake With Survival in Patients With Advanced or Metastatic Colorectal Cancer.

JAMA Oncol 2020 Nov;6(11):1713-1721

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

Importance: Several compounds found in coffee possess antioxidant, anti-inflammatory, and insulin-sensitizing effects, which may contribute to anticancer activity. Epidemiological studies have identified associations between increased coffee consumption and decreased recurrence and mortality of colorectal cancer. The association between coffee consumption and survival in patients with advanced or metastatic colorectal cancer is unknown.

Objective: To evaluate the association of coffee consumption with disease progression and death in patients with advanced or metastatic colorectal cancer.

Design, Setting, And Participants: This prospective observational cohort study included 1171 patients with previously untreated locally advanced or metastatic colorectal cancer who were enrolled in Cancer and Leukemia Group B (Alliance)/SWOG 80405, a completed phase 3 clinical trial comparing the addition of cetuximab and/or bevacizumab to standard chemotherapy. Patients reported dietary intake using a semiquantitative food frequency questionnaire at the time of enrollment. Data were collected from October 27, 2005, to January 18, 2018, and analyzed from May 1 to August 31, 2018.

Exposures: Consumption of total, decaffeinated, and caffeinated coffee measured in cups per day.

Main Outcomes And Measures: Overall survival (OS) and progression-free survival (PFS).

Results: Among the 1171 patients included in the analysis (694 men [59%]; median age, 59 [interquartile range, 51-67] years). The median follow-up time among living patients was 5.4 years (10th percentile, 1.3 years; IQR, 3.2-6.3 years). A total of 1092 patients (93%) had died or had disease progression. Increased consumption of coffee was associated with decreased risk of cancer progression (hazard ratio [HR] for 1-cup/d increment, 0.95; 95% CI, 0.91-1.00; P = .04 for trend) and death (HR for 1-cup/d increment, 0.93; 95% CI, 0.89-0.98; P = .004 for trend). Participants who consumed 2 to 3 cups of coffee per day had a multivariable HR for OS of 0.82 (95% CI, 0.67-1.00) and for PFS of 0.82 (95% CI, 0.68-0.99), compared with those who did not drink coffee. Participants who consumed at least 4 cups of coffee per day had a multivariable HR for OS of 0.64 (95% CI, 0.46-0.87) and for PFS of 0.78 (95% CI, 0.59-1.05). Significant associations were noted for both caffeinated and decaffeinated coffee.

Conclusions And Relevance: Coffee consumption may be associated with reduced risk of disease progression and death in patients with advanced or metastatic colorectal cancer. Further research is warranted to elucidate underlying biological mechanisms.
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http://dx.doi.org/10.1001/jamaoncol.2020.3938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499248PMC
November 2020

System for High-Intensity Evaluation During Radiation Therapy (SHIELD-RT): A Prospective Randomized Study of Machine Learning-Directed Clinical Evaluations During Radiation and Chemoradiation.

J Clin Oncol 2020 11 4;38(31):3652-3661. Epub 2020 Sep 4.

Department of Radiation Oncology, Duke University, Durham, NC.

Purpose: Patients undergoing outpatient radiotherapy (RT) or chemoradiation (CRT) frequently require acute care (emergency department evaluation or hospitalization). Machine learning (ML) may guide interventions to reduce this risk. There are limited prospective studies investigating the clinical impact of ML in health care. The objective of this study was to determine whether ML can identify high-risk patients and direct mandatory twice-weekly clinical evaluation to reduce acute care visits during treatment.

Patients And Methods: During this single-institution randomized quality improvement study (ClinicalTrials.gov identifier: NCT04277650), 963 outpatient adult courses of RT and CRT started from January 7 to June 30, 2019, were evaluated by an ML algorithm. Among these, 311 courses identified by ML as high risk (> 10% risk of acute care during treatment) were randomized to standard once-weekly clinical evaluation (n = 157) or mandatory twice-weekly evaluation (n = 154). Both arms allowed additional evaluations on the basis of clinician discretion. The primary end point was the rate of acute care visits during RT. Model performance was evaluated using receiver operating characteristic area under the curve (AUC) and decile calibration plots.

Results: Twice-weekly evaluation reduced rates of acute care during treatment from 22.3% to 12.3% (difference, -10.0%; 95% CI, -18.3 to -1.6; relative risk, 0.556; 95% CI, 0.332 to 0.924; = .02). Low-risk patients had a 2.7% acute care rate. Model discrimination was good in high- and low-risk patients undergoing standard once-weekly evaluation (AUC, 0.851).

Conclusion: In this prospective randomized study, ML accurately triaged patients undergoing RT and CRT, directing clinical management with reduced acute care rates versus standard of care. This prospective study demonstrates the potential benefit of ML in health care and offers opportunities to enhance care quality and reduce health care costs.
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http://dx.doi.org/10.1200/JCO.20.01688DOI Listing
November 2020

Early F-FDG-PET Response During Radiation Therapy for HPV-Related Oropharyngeal Cancer May Predict Disease Recurrence.

Int J Radiat Oncol Biol Phys 2020 11 13;108(4):969-976. Epub 2020 Aug 13.

Department of Radiation Oncology, Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina; Department of Head and Neck Surgery & Communication Sciences, Duke University School of Medicine, Durham, North Carolina.

Purpose: Early indication of treatment outcome may guide therapeutic de-escalation strategies in patients with human papillomavirus (HPV)-related oropharyngeal cancer (OPC). This study investigated the relationships between tumor volume and F-fluorodeoxyglucose positron emission tomography (PET) parameters before and during definitive radiation therapy with treatment outcomes.

Methods And Materials: Patients undergoing definitive (chemo)radiation for HPV-related/p16-positive OPC were prospectively enrolled on an institutional review board-approved study. F-fluorodeoxyglucose PET/computed tomography scans were performed at simulation and after 2 weeks at a dose of ∼20 Gy. Tumor volume and standardized uptake value (SUV) characteristics were measured. SUV was normalized to blood pool uptake. Tumor volume and PET parameters associated with recurrence were identified through recursive partitioning (RPART). Recurrence-free survival (RFS) and overall survival (OS) curves between RPART-identified cohorts were estimated using the Kaplan-Meier method, and Cox models were used to estimate the hazard ratios (HRs).

Results: From 2012 to 2016, 62 patients with HPV-related OPC were enrolled. Median follow-up was 4.4 years. RPART identified patients with intratreatment SUV (normalized to blood pool SUV) <6.7 or SUV (normalized to blood pool SUV) ≥6.7 with intratreatment SUV ≥2.75 as less likely to recur. For identified subgroups, results of Cox models showed unadjusted HRs for RFS and OS (more likely to recur vs less likely) of 7.33 (90% confidence interval [CI], 2.97-18.12) and 6.09 (90% CI, 2.22-16.71), respectively, and adjusted HRs of 6.57 (90% CI, 2.53-17.05) and 5.61 (90% CI, 1.90-16.54) for RFS and OS, respectively.

Conclusions: PET parameters after 2 weeks of definitive radiation therapy for HPV-related OPC are associated with RFS and OS, thus potentially informing an adaptive treatment approach.
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http://dx.doi.org/10.1016/j.ijrobp.2020.08.029DOI Listing
November 2020
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