Publications by authors named "J A Meyerhardt"

353 Publications

Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer.

Cancer Immunol Immunother 2021 Sep 16. Epub 2021 Sep 16.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave., EBRC Room 404A, Boston, MA, 02115, USA.

Background: Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (< 50 "early onset," 50-54 "intermediate onset,"  ≥ 55 "later onset").

Methods: We examined 1,518 incident CRC cases with available tissue data, including 35 early-onset and 73 intermediate-onset cases. To identify immune cells in tumor intraepithelial and stromal areas, we developed three multiplexed immunofluorescence assays combined with digital image analyses and machine learning algorithms, with the following markers: (1) CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 for T cells; (2) CD68, CD86, IRF5, MAF, and MRC1 (CD206) for macrophages; and (3) ARG1, CD14, CD15, CD33, and HLA-DR for myeloid cells.

Results: Although no comparisons between age groups showed statistically significant differences at the stringent two-sided α level of 0.005, compared to later-onset CRC, early-onset CRC tended to show lower levels of tumor-infiltrating lymphocytes (P = 0.013), intratumoral periglandular reaction (P = 0.025), and peritumoral lymphocytic reaction (P = 0.044). Compared to later-onset CRC, intermediate-onset CRC tended to show lower densities of overall macrophages (P = 0.050), M1-like macrophages (P = 0.062), CD14HLA-DR cells (P = 0.015), and CD3CD4FOXP3 cells (P = 0.039).

Conclusions: This hypothesis-generating study suggests possible differences in histopathologic lymphocytic reaction patterns, macrophages, and regulatory T cells in the tumor microenvironment by age at diagnosis.
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http://dx.doi.org/10.1007/s00262-021-03056-6DOI Listing
September 2021

Yoga for chronic chemotherapy-induced peripheral neuropathy pain: a pilot, randomized controlled trial.

J Cancer Surviv 2021 Sep 15. Epub 2021 Sep 15.

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

Purpose: To determine the feasibility of implementing a yoga intervention for cancer survivors with chronic CIPN pain, as well as the impact of the intervention on patient-reported outcomes.

Methods: Cancer survivors with chronic CIPN pain were recruited from the breast, gastrointestinal, and gynecological oncology centers at Dana-Farber Cancer Institute. Participants were randomized (2:1) to receive an 8-week yoga intervention or usual care. After 21/50 of participants were enrolled, the COVID-19 pandemic required the yoga intervention to be delivered virtually (i.e., Zoom). Pre- and post-intervention, participants self-reported CIPN and co-occurring symptom severity. Adherence to the intervention was defined as practicing ≥ 12 yoga sessions over the 8-week intervention period. Changes in patient-reported outcomes between groups were compared using Wilcoxon's rank-sum tests.

Results: Participants (n = 28 yoga, n = 16 control) were mainly female (96%) and diagnosed with stage III/IV disease (66%). Overall, 19/28 (67.8%) of yoga group participants were adherent to the yoga protocol. Yoga group participants experienced significant within-group improvements in all patient-reported outcomes, including worst CIPN pain (median change =  - 1.7, p < 0.0001) and sensory CIPN (median change =  - 14.8, p < 0.0001), but only improvements in fatigue (p = 0.05) and depression (p = 0.04) were significant compared to the control. There were no differences (p > 0.05) in changes in patient-reported outcomes between in-person (n = 6) or virtual (n = 15) yoga group participants.

Conclusions: Yoga is a feasible non-pharmacological modality for cancer survivors with CIPN, but more information is needed regarding its impact on CIPN and other symptoms.

Trial Registration: ClinicalTrials.gov Identifier: NCT03824860 IMPLICATIONS FOR CANCER SURVIVORS: Oncology clinicians may consider referring cancer survivors to yoga for chronic CIPN pain, but yoga cannot be currently recommended as an efficacious treatment.
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http://dx.doi.org/10.1007/s11764-021-01081-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442518PMC
September 2021

Abdominal adipose tissue radiodensity is associated with survival after colorectal cancer.

Am J Clin Nutr 2021 Sep 12. Epub 2021 Sep 12.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

Background: Adipose tissue radiodensity may have prognostic importance for colorectal cancer (CRC) survival. Lower radiodensity is indicative of larger adipocytes, while higher radiodensity may represent adipocyte atrophy, inflammation, or edema.

Objectives: We investigated associations of adipose tissue radiodensity and longitudinal changes in adipose tissue radiodensity with mortality among patients with nonmetastatic CRC.

Methods: In 3023 patients with stage I-III CRC, radiodensities of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were quantified from diagnostic computed tomography (CT) images. There were 1775 patients with follow-up images available. Cox proportional hazards models and restricted cubic splines were used to examine associations of at-diagnosis values and of longitudinal changes in VAT and SAT radiodensities with risks of death after adjusting for potential confounders, including body size and comorbidities.

Results: VAT and SAT radiodensities were linearly associated with all-cause mortality: the HRs for death per SD increase were 1.21 (95% CI, 1.11-1.32) for VAT radiodensity and 1.18 (95% CI, 1.11-1.26) for SAT radiodensity. Changes in adipose tissue radiodensity had curvilinear associations with risks of death. The HR for an increase in VAT radiodensity of at least 1 SD was 1.53 (95% CI, 1.23-1.90), while the HR for a decrease of at least 1 SD was nonsignificant at 1.11 (95% CI, 0.84-1.47) compared with maintaining radiodensity within 1 SD of baseline. Similarly, increases (HR, 1.88; 95% CI, 1.48-2.40) but not decreases (HR, 1.20; 95% CI, 0.94-1.54) in SAT radiodensity significantly increased the risk of death compared with no change in radiodensity.

Conclusions: In patients with nonmetastatic CRC, adipose tissue radiodensity is a novel risk factor for total mortality that is independent of BMI and changes in body weight.
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http://dx.doi.org/10.1093/ajcn/nqab285DOI Listing
September 2021

Association of mutation and PTEN loss with expression of CD274 (PD-L1) in colorectal carcinoma.

Oncoimmunology 2021 2;10(1):1956173. Epub 2021 Aug 2.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Immunotherapy targeting the CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint axis has emerged as a promising treatment strategy for various cancers. Experimental evidence suggests that phosphatidylinositol-4,5-bisphosphonate 3-kinase (PI3K) signaling may upregulate CD274 expression. Thus, we hypothesized that mutation, PTEN loss, or their combined status might be associated with CD274 overexpression in colorectal carcinoma. We assessed tumor CD274 and PTEN expression by immunohistochemistry and assessed mutation by pyrosequencing in 753 patients among 4,465 incident rectal and colon cancer cases that had occurred in two U.S.-wide prospective cohort studies. To adjust for potential confounders and selection bias due to tissue availability, inverse probability weighted multivariable ordinal logistic regression analyses used the 4,465 cases and tumoral data including microsatellite instability, CpG island methylator phenotype, and mutations. mutation and loss of PTEN expression were detected in 111 of 753 cases (15%) and 342 of 585 cases (58%), respectively. Tumor CD274 expression was negative in 306 (41%), low in 195 (26%), and high in 252 (33%) of 753 cases. PTEN loss was associated with CD274 overexpression [multivariable odds ratio (OR) 1.83; 95% confidence interval (CI), 1.22-2.75; = .004]. mutation was statistically-insignificantly ( = .036 with the stringent alpha level of 0.005) associated with CD274 overexpression (multivariable OR, 1.54; 95% CI, 1.03-2.31). -mutated PTEN-lost tumors (n = 33) showed higher prevalence of CD274-positivity (82%) than -wild-type PTEN-lost tumors (n = 204; 70% CD274-positivity) and PTEN-expressed tumors (n = 147; 50% CD274-positivity) ( = .003). Our findings support the role of PI3K signaling in the CD274/PDCD1 pathway.
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http://dx.doi.org/10.1080/2162402X.2021.1956173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331006PMC
August 2021

The Early Impact of the IDEA Collaboration Results: How the Results Changed Prescribing Practice.

JNCI Cancer Spectr 2021 Aug 15;5(4):pkab043. Epub 2021 Jun 15.

Dana-Farber Cancer Institute, Boston, MA, USA.

Background: Traditionally, adjuvant treatment for colon cancer has been 6 months of combination chemotherapy. Six phase III trials tested the hypothesis that 3 months is noninferior in efficacy to 6 months and reduces long-term side effects for patients. The results were pooled in the International Duration Evaluation of Adjuvant therapy (IDEA) collaboration. Although this did not meet the noninferiority endpoint, a preplanned subgroup analysis by chemotherapy regimen did demonstrate noninferiority for capecitabine and oxaliplatin. Additionally, risk stratification by T and N stage was defined.

Methods: In an effort to understand the real-life impact of these results, 4 months after the IDEA results, an online survey was distributed to clinicians to ask their approach to the adjuvant treatment of patients with stage III colon cancer.

Results: The survey was completed by 458 clinicians from 12 countries. Assuming that 6 months of treatment was the pretrial standard of care, 89.5% of clinicians reported they had changed practice to prescribe 3 months of treatment for some patients. For patients with low-risk stage III disease, there was a preference for 3 months, and for patients with high-risk stage III disease, most clinicians still prescribed 6 months at that time. Overall, capecitabine and oxaliplatin regimen was the most popular. There were important differences in responses depending on the location of respondent and T and N stage of disease.

Conclusion: This survey shows that the IDEA collaboration has been practice changing but reveals important differences in the way results are interpreted by individual clinicians.
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http://dx.doi.org/10.1093/jncics/pkab043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328095PMC
August 2021
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