The presence of
(
) in colorectal carcinoma tissue has been associated with microsatellite instability (MSI), lower-level T-cell infiltrates, and poor clinical outcomes. Considering differences in ...the tumor-immune microenvironment between MSI-high and non-MSI-high carcinomas, we hypothesized that the association of
with immune response might differ by tumor MSI status. Using samples from 1,041 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study, we measured
DNA in tumor tissue by a quantitative polymerase chain reaction assay. Multivariable logistic regression models were used to examine the association between
status and histopathologic lymphocytic reactions or density of CD3
cells, CD8
cells, CD45RO (PTPRC)
cells, or FOXP3
cells in strata of tumor MSI status. We adjusted for potential confounders, including CpG island methylator phenotype; LINE-1 methylation; and
, and
mutations. The association of
with tumor-infiltrating lymphocytes (TIL) and intratumoral periglandular reaction differed by tumor MSI status (
= 0.002). The presence of
was negatively associated with TIL in MSI-high tumors multivariable odds ratio (OR), 0.45; 95% confidence interval (CI), 0.22-0.92, but positively associated with TIL in non-MSI-high tumors (multivariable OR 1.91; 95% CI, 1.12-3.25). No significant differential association was observed for peritumoral lymphocytic reaction, Crohn-like lymphoid reaction, or T-cell densities. In conclusion, the association of
with immune response to colorectal carcinoma differs by tumor MSI status, suggesting that
and MSI status interact to affect antitumor immune reactions.
.
Over 1.3 million people live with colorectal cancer in the United States. Physical activity is associated with lower risk of colorectal cancer recurrence and mortality. Interventions are needed to ...increase physical activity in colorectal cancer survivors.
We conducted a 2-arm non-blinded pilot randomized controlled trial at the University of California, San Francisco among 42 individuals who had completed curative-intent treatment for colorectal cancer to determine the feasibility and acceptability of a 12-week (84 days) physical activity intervention using a Fitbit Flex™ and daily text messages. Participants were randomized 1:1 to receive the intervention with print educational materials or print educational materials alone. We explored the impact of the intervention versus usual care on physical activity using ActiGraph GT3X+ accelerometers pre-/post-intervention.
We screened 406 individuals and randomized 42 to intervention (n = 21) or control (n = 21) groups. During the 12-week study, the intervention arm wore their Fitbits a median of 74 days 88% of days in study period, interquartile range: 23-83 days and responded to a median of 34 (out of 46) text messages that asked for a reply (interquartile range: 13-38 text messages). Among the 16 intervention participants who completed the feedback survey, the majority (88%) reported that the intervention motivated them to exercise and that they were satisfied with their experience. No statistically significant difference in change in moderate-to-vigorous physical activity was found from baseline to 12 weeks between arms.
A 12-week physical activity intervention with a Fitbit and text messages was feasible and acceptable among colorectal cancer patients after curative treatment. Larger studies are needed to determine whether the intervention increases physical activity.
Clinicaltrials.gov Identifier NCT02966054 . Registered 17 November 2016, retrospectively registered.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background & Aims: Long-term data on the risk of colorectal cancer according to dose, duration, and consistency of aspirin therapy are limited. Methods: We conducted a prospective study of 47,363 ...male health professionals who were ages 40–75 years at enrollment in 1986. Biennially, we collected data on aspirin use, other risk factors, and diagnoses of colorectal cancer. We confirmed all reports of colorectal cancer through 2004 by review of medical records. Results: During 18 years of follow-up, we documented 975 cases of colorectal cancer over 761,757 person-years. After adjustment for risk factors, men who regularly used aspirin (≥2 times per week) had a multivariate relative risk (RR) for colorectal cancer of 0.79 (95% confidence interval, CI, 0.69–0.90) compared with nonregular users. However, significant risk reduction required at least 6–10 years of use ( P for trend = .008) and was no longer evident within 4 years of discontinuing use (multivariate RR, 1.00; CI, 0.72–1.39). The benefit appeared related to increasing cumulative average dose: compared with men who denied any aspirin use, the multivariate RRs for cancer were 0.94 (CI, 0.75–1.18) for men who used 0.5–1.5 standard aspirin tablets per week, 0.80 (CI, 0.63–1.01) for 2–5 aspirin tablets per week, 0.72 (CI, 0.56–0.92) for 6–14 aspirin tablets per week, and 0.30 (CI, 0.11–0.81) for >14 aspirin tablets per week ( P for trend = .004). Conclusions: Regular, long-term aspirin use reduces risk of colorectal cancer among men. However, the benefit of aspirin necessitates at least 6 years of consistent use, with maximal risk reduction at doses greater than 14 tablets per week. The potential hazards associated with long-term use of such doses should be carefully considered.
Quantifying the association of chemotherapy relative dose intensity (RDI) with overall survival may enable supportive care interventions that improve chemotherapy RDI to estimate their magnitude of ...potential clinical benefit.
This cohort study included 533 patients with stage II-III colon cancer who initiated a planned regimen of 12 cycles of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. The primary exposure was chemotherapy RDI. The primary outcome was overall survival. Restricted cubic splines estimated hazard ratios (HR).
Chemotherapy regimen RDI was associated with overall survival in an L-shaped pattern (linear P = 0.006; nonlinear P = 0.057); the risk of death was flat above 85% but increased linearly below 85%. For example, a decrease in RDI from 85 to 75% was associated with an increased risk of death HR: 1.20 (95% CI: 1.08, 1.52), whereas an increase in RDI from 85 to 95% was not associated with the risk of death HR: 1.06 (95% CI: 0.82, 1.38).
If chemotherapy RDI is considered a potential surrogate of overall survival, supportive care interventions that improve chemotherapy RDI might confer a potential clinical benefit in this population.
Although high T-cell density is a well-established favorable prognostic factor in colorectal cancer, the prognostic significance of tumor-associated plasma cells, neutrophils, and eosinophils is less ...well-defined.
We computationally processed digital images of hematoxylin and eosin (H&E)-stained sections to identify lymphocytes, plasma cells, neutrophils, and eosinophils in tumor intraepithelial and stromal areas of 934 colorectal cancers in two prospective cohort studies. Multivariable Cox proportional hazards regression was used to compute mortality HR according to cell density quartiles. The spatial patterns of immune cell infiltration were studied using the G
function, which estimates the likelihood of any tumor cell in a sample having at least one neighboring immune cell of the specified type within a certain radius. Validation studies were performed on an independent cohort of 570 colorectal cancers.
Immune cell densities measured by the automated classifier demonstrated high correlation with densities both from manual counts and those obtained from an independently trained automated classifier (Spearman's ρ 0.71-0.96). High densities of stromal lymphocytes and eosinophils were associated with better cancer-specific survival
< 0.001; multivariable HR (4th vs 1st quartile of eosinophils), 0.49; 95% confidence interval, 0.34-0.71. High G
area under the curve (AUC
;
= 0.002) and high G
AUC
(
< 0.001) also showed associations with better cancer-specific survival. High stromal eosinophil density was also associated with better cancer-specific survival in the validation cohort (
< 0.001).
These findings highlight the potential for machine learning assessment of H&E-stained sections to provide robust, quantitative tumor-immune biomarkers for precision medicine.
Observational studies have demonstrated increased colon cancer recurrence and mortality in states of excess energy balance, as denoted by factors including sedentary lifestyle, diabetes, increased ...dietary glycemic load, and increased intake of sugar-sweetened beverages. Nonetheless, the relation between artificially sweetened beverages, a popular alternative for sugar-sweetened beverages, and colon cancer recurrence and survival is unknown.
We analyzed data from 1,018 patients with stage III colon cancer who prospectively reported dietary intake during and after chemotherapy while enrolled in a National Cancer Institute-sponsored trial of adjuvant chemotherapy. Using Cox proportional hazards regressions, we assessed associations of artificially sweetened beverage intake with cancer recurrence and mortality.
Patients consuming one or more 12-ounce servings of artificially sweetened beverages per day experienced an adjusted hazard ratio for cancer recurrence or mortality of 0.54 (95% confidence interval, 0.36 to 0.80) when compared to those who largely abstained (Ptrend = .004). Similarly, increasing artificially sweetened beverage intake was also associated with a significant improvement in both recurrence-free survival (Ptrend = .005) and overall survival (Ptrend = .02). Substitution models demonstrated that replacing a 12-ounce serving of a sugar-sweetened beverage with an isovolumetric serving of an artificially sweetened beverage per day was associated with a 23% lower risk of cancer recurrence and mortality (relative risk, 0.77; 95% confidence interval, 0.63 to 0.95; P = .02).
Higher artificially sweetened beverage consumption may be associated with significantly reduced cancer recurrence and death in patients with stage III colon cancer. This association may be mediated by substitution for sugar-sweetened alternatives. Further studies are needed to confirm these findings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Evidence suggests a possible role of Fusobacterium nucleatum in colorectal carcinogenesis, especially in right-sided proximal colorectum. Considering a change in bowel contents and microbiome from ...proximal to distal colorectal segments, we hypothesized that the proportion of colorectal carcinoma enriched with F. nucleatum might gradually increase along the bowel subsites from rectum to cecum.
A retrospective, cross-sectional analysis was conducted on 1,102 colon and rectal carcinomas in molecular pathological epidemiology databases of the Nurses' Health Study and the Health Professionals Follow-up Study. We measured the amount of F. nucleatum DNA in colorectal tumor tissue using a quantitative PCR assay and equally dichotomized F. nucleatum-positive cases (high vs. low). We used multivariable logistic regression analysis to examine the relationship of a bowel subsite variable (rectum, rectosigmoid junction, sigmoid colon, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon, and cecum) with the amount of F. nucleatum.
The proportion of F. nucleatum-high colorectal cancers gradually increased from rectal cancers (2.5%; 4/157) to cecal cancers (11%; 19/178), with a statistically significant linear trend along all subsites (P<0.0001) and little evidence of non-linearity. The proportion of F. nucleatum-low cancers was higher in rectal, ascending colon, and cecal cancers than in cancers of middle segments.
The proportion of F. nucleatum-high colorectal cancers gradually increases from rectum to cecum. Our data support the colorectal continuum model that reflects pathogenic influences of the gut microbiota on neoplastic and immune cells and challenges the prevailing two-colon (proximal vs. distal) dichotomy paradigm.
Recent increasing trends in early-onset colorectal cancer (CRC) strongly supports that early-life diet is involved in CRC development. However, data are lacking on the relationship with high sugar ...intake during early life.
We prospectively investigated the association of adolescent simple sugar (fructose, glucose, added sugar, total sugar) and sugar-sweetened beverage (SSB) intake with CRC precursor risk in 33,106 participants of the Nurses’ Health Study II who provided adolescent dietary information in 1998 and subsequently underwent lower gastrointestinal endoscopy between 1999 and 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression for clustered data.
During follow-up, 2909 conventional adenomas (758 high-risk) and 2355 serrated lesions were identified (mean age at diagnoses, 52.2 ± 4.3 years). High sugar and SSB intake during adolescence was positively associated with risk of adenoma, but not serrated lesions. Per each increment of 5% of calories from total fructose intake, multivariable ORs were 1.17 (95% CI, 1.05–1.31) for total and 1.30 (95% CI, 1.06–1.60) for high-risk adenoma. By subsite, ORs were 1.12 (95% CI, 0.96–1.30) for proximal, 1.24 (95% CI, 1.05–1.47) for distal, and 1.43 (95% CI, 1.10–1.86) for rectal adenoma. Per 1 serving/day increment in SSB intake, ORs were 1.11 (95% CI, 1.02–1.20) for total and 1.30 (95% CI, 1.08–1.55) for rectal adenoma. Contrary to adolescent intake, sugar and SSB intake during adulthood was not associated with adenoma risk.
High intake of simple sugars and SSBs during adolescence was associated with increased risk of conventional adenoma, especially rectal adenoma.
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Branched‐chain amino acids (BCAAs), including leucine, isoleucine and valine, may potentially influence cancer progression by various mechanisms including its role in insulin resistance. However, the ...association of BCAAs with survival among patients with established colorectal cancer (CRC) remains unclear. We evaluated the associations between postdiagnostic BCAA intake with CRC‐specific mortality and overall mortality among 1674 patients with nonmetastatic CRC in the Nurses' Health Study and the Health Professionals Follow‐up Study. Patients completed a validated food frequency questionnaire. Multivariable hazard ratios (HRs) were calculated using Cox proportional‐hazards regression model after adjustment for tumor characteristics and potential confounding factors. Comparing the highest with the lowest quartile intake of postdiagnostic total BCAA, the multivariable HRs were 1.18 (95% confidence interval CI, 0.75‐1.85, P for trend = .46 across quartiles) for CRC‐specific mortality and 1.30 (95% CI, 1.01‐1.69, P for trend = .04) for all‐cause mortality. The multivariable HRs (the highest vs the lowest quartile) for all‐cause mortality were 1.33 (95% CI, 1.03‐1.73, Ptrend = .02) for valine, 1.28 (95% CI, 0.99‐1.66, P for trend = .05) for leucine and 1.25 (95% CI, 0.96‐1.61, P for trend = .06) for isoleucine. No statistically significant associations with each of the BCAA intake were observed for CRC‐specific mortality (all P for trend > .30). Our findings suggest positive associations between higher intake of dietary BCAAs and risk of all‐cause mortality in CRC patients. These findings need to be confirmed and potential mechanisms underlying this association need to be elucidated.
What's new?
Animal protein sources such as meat and milk are high in branched‐chain amino acids (BCAAs). BCAAs may potentially influence cancer progression by various mechanisms, including providing an energy source for tumor growth, and activation of the mTOR/p70S6K pathway. However, the impact of BCAAs on survival among patients with colorectal cancer (CRC) has been unclear. The results of this study suggest that higher intake of dietary BCAAs is associated with overall mortality risk in CRC patients.
While increased adherence to colorectal cancer (CRC) screening guidelines in the US has been associated with significant reductions in cancer incidence in US individuals aged 50 years and older, the ...incidence of CRC among those aged younger than 50 years has been steadily increasing. Understanding the survival among individuals with early-onset CRC compared with those aged 50 years and older is fundamental to informing treatment approaches and understanding the unique biological distinctiveness within early-onset CRC.
To characterize the overall survival for individuals with early-onset CRC.
This cohort study used data from the National Cancer Database. Included individuals were ages 0 to 90 years and diagnosed with primary CRC from January 1, 2004, through December 31, 2015. Individuals diagnosed at ages 51 through 55 years were selected as the reference group and defined as later-onset CRC for this study. Individuals diagnosed at age 50 years were excluded to minimize an apparent screening detection bias at that age in our population, given that these individuals disproportionately presented with earlier stage. All statistical analyses were conducted from January 4, 2020, through December 26, 2020.
Early-onset CRC was defined as age younger than 50 years at diagnosis.
Overall survival was assessed by Kaplan-Meier analysis and Cox proportional hazards regression.
Among 769 871 individuals with CRC (377 890 49.1% women; 636 791 White individuals 82.7%), 353 989 individuals (46.0%) died (median range follow-up: 2.9 0-14.0 years), 102 168 individuals (13.3%) had early-onset CRC, and 78 812 individuals (10.2%) had later-onset CRC. Individuals with early-onset CRC, compared with those diagnosed with CRC at ages 51 through 55 years, had a lower 10-year survival rate (53.6% 95% CI, 53.2%-54.0% vs 54.3% 95% CI, 53.8%-54.8%; P < .001) in unadjusted analysis. However, after adjustment for other factors associated with mortality, most notably stage, individuals with early-onset CRC had a lower risk of death compared with individuals diagnosed from ages 51 through 55 years (adjusted hazard ratio HR, 0.95 95% CI, 0.93-0.96; P < .001). In the model adjusted for stage, the HR for individuals with early-onset CRC was 0.89 (95% CI, 0.88-0.90; P < .001). The survival advantage was greatest for individuals diagnosed at ages 35 through 39 years (adjusted HR, 0.88 95% CI, 0.84-0.92; P < .001) and stages I (adjusted HR, 0.87 95% CI, 0.81-0.93; P < .001) and II (adjusted HR, 0.86 95% CI, 0.82-0.90; P < .001) and was absent among those diagnosed at ages 25 years or younger and stages III through IV.
These findings suggest that there is a survival benefit for individuals with early-onset CRC compared with those diagnosed with CRC at later ages. Further study is needed to understand the underlying heterogeneity of survival among individuals with early-onset CRC by age and stage.
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