Marital Status, Living Arrangement, and Cancer Recurrence and Survival in Patients with Stage III Colon Cancer: Findings from CALGB 89803 (Alliance).

BACKGROUND: Limited and conflicting findings have been reported regarding the association between social support and colorectal cancer (CRC) outcomes. We sought to assess the influences of marital status and living arrangement on survival outcomes among patients with stage III colon cancer. PATIENTS AND METHODS: We conducted a secondary analysis of 1082 patients with stage III colon cancer prospectively followed in the CALGB 89803 randomized adjuvant chemotherapy trial. Marital status and living arrangement were both self-reported at the time of enrollment as, respectively, married, divorced, separated, widowed, or never-married, and living alone, with a spouse or partner, with other family, in a nursing home, or other. RESULTS: Over a median follow-up of 7.6 years, divorced/separated/widowed patients experienced worse outcomes relative to those married regarding disease free-survival (DFS) (hazards ratio (HR), 1.44 (95% CI, 1.14-1.81); P =.002), recurrence-free survival (RFS) (HR, 1.35 (95% CI, 1.05-1.73); P = .02), and overall survival (OS) (HR, 1.40 (95% CI, 1.08-1.82); P =.01); outcomes were not significantly different for never-married patients. Compared to patients living with a spouse/partner, those living with other family experienced a DFS of 1.47 (95% CI, 1.02-2.11; P = .04), RFS of 1.34 (95% CI, 0.91-1.98; P = .14), and OS of 1.50 (95% CI, 1.00-2.25; P =.05); patients living alone did not experience significantly different outcomes. CONCLUSION: Among patients with stage III colon cancer who received uniform treatment and follow-up within a nationwide randomized clinical trial, being divorced/separated/widowed and living with other family were significantly associated with greater colon cancer mortality. Interventions enhancing social support services may be clinically relevant for this patient population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00003835.

Associations Between Unprocessed Red Meat and Processed Meat With Risk of Recurrence and Mortality in Patients With Stage III Colon Cancer.

Importance: The American Cancer Society and American Institute for Cancer Research recommend that cancer survivors limit intake of red and processed meats. This recommendation is based on consistent associations between red and processed meat intake and cancer risk, particularly risk of colorectal cancer, but fewer data are available on red and processed meat intake after cancer diagnosis. Objectives: To examine whether intake of unprocessed red meat or processed meat is associated with risk of cancer recurrence or mortality in patients with colon cancer. Design, Setting, and Participants: This prospective cohort study used data from participants with stage III colon cancer enrolled in the Cancer and Leukemia Group B (CALGB 89803/Alliance) trial between 1999 and 2001. The clinical database for this analysis was frozen on November 9, 2009; the current data analyses were finalized in December 2021. Exposures: Quartiles of unprocessed red meat and processed meat intake assessed using a validated food frequency questionnaire during and 6 months after chemotherapy. Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs for risk of cancer recurrence or death and all-cause mortality. Results: This study was conducted among 1011 patients with stage III colon cancer. The median (IQR) age at enrollment was 60 (51-69) years, 442 patients (44%) were women, and 899 patients (89%) were White. Over a median (IQR) follow-up period of 6.6 (1.9-7.5) years, we observed 305 deaths and 81 recurrences without death during follow-up (386 events combined). Intake of unprocessed red meat or processed meat after colon cancer diagnosis was not associated with risk of recurrence or mortality. The multivariable HRs comparing the highest vs lowest quartiles for cancer recurrence or death were 0.84 (95% CI, 0.58-1.23) for unprocessed red meat and 1.05 (95% CI, 0.75-1.47) for processed meat. For all-cause mortality, the corresponding HRs were 0.71 (95% CI, 0.47-1.07) for unprocessed red meat and 1.04 (95% CI, 0.72-1.51) for processed meat. Conclusions and Relevance: In this cohort study, postdiagnosis intake of unprocessed red meat or processed meat was not associated with risk of recurrence or death among patients with stage III colon cancer.

Diet- and Lifestyle-Based Prediction Models to Estimate Cancer Recurrence and Death in Patients With Stage III Colon Cancer (CALGB 89803/Alliance).

PURPOSE: Current tools in predicting survival outcomes for patients with colon cancer predominantly rely on clinical and pathologic characteristics, but increasing evidence suggests that diet and lifestyle habits are associated with patient outcomes and should be considered to enhance model accuracy. METHODS: Using an adjuvant chemotherapy trial for stage III colon cancer (CALGB 89803), we developed prediction models of disease-free survival (DFS) and overall survival by additionally incorporating self-reported nine diet and lifestyle factors. Both models were assessed by multivariable Cox proportional hazards regression and externally validated using another trial for stage III colon cancer (CALGB/SWOG 80702), and visual nomograms of prediction models were constructed accordingly. We also proposed three hypothetical scenarios for patients with (1) good-risk, (2) average-risk, and (3) poor-risk clinical and pathologic features, and estimated their predictive survival by considering clinical and pathologic features with or without adding self-reported diet and lifestyle factors. RESULTS: Among 1,024 patients (median age 60.0 years, 43.8% female), we observed 394 DFS events and 311 deaths after median follow-up of 7.3 years. Adding self-reported diet and lifestyle factors to clinical and pathologic characteristics meaningfully improved performance of prediction models (c-index from 0.64 [95% CI, 0.62 to 0.67] to 0.69 [95% CI, 0.67 to 0.72] for DFS, and from 0.67 [95% CI, 0.64 to 0.70] to 0.71 [95% CI, 0.69 to 0.75] for overall survival). External validation also indicated good performance of discrimination and calibration. Adding most self-reported favorable diet and lifestyle exposures to multivariate modeling improved 5-year DFS of all patients and by 6.3% for good-risk, 21.4% for average-risk, and 42.6% for poor-risk clinical and pathologic features. CONCLUSION: Diet and lifestyle factors further inform current recurrence and survival prediction models for patients with stage III colon cancer.

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

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, P = .75) for disease-free survival, 0.91 (95% CI = 0.62 to 1.35, P = .65) for recurrence-free survival, and 1.07 (95% CI = 0.73 to 1.57, P = .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, P trend = .18) for disease-free survival, 0.89 (95% CI = 0.66 to 1.22, P trend = .14) for recurrence-free survival, and 0.87 (95% CI = 0.63 to 1.19, P trend = .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.

The Diet of Higher Insulinemic Potential Is Not Associated with Worse Survival in Patients with Stage III Colon Cancer (Alliance).

BACKGROUND: Hyperinsulinemia is considered to be important in the development of colon cancer, but few studies have investigated the associations of hyperinsulinemia with colon cancer survival via dietary scores. METHODS: Empirical dietary index for hyperinsulinemia (EDIH) was derived to assess the insulinemic potential of daily diets reflecting the long-term insulin exposure, with higher (more positive) scores indicating higher insulinemic diets. We prospectively estimated the HRs and 95% confidence intervals (CI) to investigate the association of EDIH with disease-free, recurrence-free, and overall survival among patients with stage III colon cancer (1999-2009) enrolled in a randomized adjuvant chemotherapy trial (CALGB 89803). RESULTS: Of 1,024 patients (median follow-up: 7.3 years), 311 died, 350 had recurrences, and 394 had events for disease-free survival. Compared with patients in the lowest quintile of EDIH, the corresponding HRs of patients in the highest quintile for disease-free survival events, cancer recurrence, and overall mortality were 0.80 (95% CI, 0.56-1.15), 0.76 (95% CI, 0.51-1.11), and 0.77 (95% CI, 0.52-1.14). CONCLUSIONS: Higher EDIH was not associated with the risk of colon cancer recurrence or mortality in this population of patients with stage III colon cancer. IMPACT: EDIH, as a measure of dietary insulinemic potential, may be associated with colon cancer risk but not survival in patients with late-stage colon cancer.

Dietary Insulin Load and Cancer Recurrence and Survival in Patients With Stage III Colon Cancer: Findings From CALGB 89803 (Alliance).

BACKGROUND: Evidence suggests that diets inducing postprandial hyperinsulinemia may be associated with increased cancer-related mortality. The goal of this study was to assess the influence of postdiagnosis dietary insulin load and dietary insulin index on outcomes of stage III colon cancer patients. METHODS: We conducted a prospective observational study of 1023 patients with resected stage III colon cancer enrolled in an adjuvant chemotherapy trial who reported dietary intake halfway through and six months after chemotherapy. We evaluated the association of dietary insulin load and dietary insulin index with cancer recurrence and survival using Cox proportional hazards regression adjusted for potential confounders; statistical tests were two-sided. RESULTS: High dietary insulin load had a statistically significant association with worse disease-free survival (DFS), comparing the highest vs lowest quintile (adjusted hazard ratio [HR] = 2.77, 95% confidence interval [CI] = 1.90 to 4.02, Ptrend < .001). High dietary insulin index was also associated with worse DFS (highest vs lowest quintile, HR = 1.75, 95% CI = 1.22 to 2.51, Ptrend= .01). The association between higher dietary insulin load and worse DFS differed by body mass index and was strongest among patients with obesity (HR = 3.66, 95% CI = 1.88 to 7.12, Pinteraction = .04). The influence of dietary insulin load on cancer outcomes did not differ by mutation status of KRAS, BRAF, PIK3CA, TP53, or microsatellite instability. CONCLUSIONS: Patients with resected stage III colon cancer who consumed a high-insulinogenic diet were at increased risk of recurrence and mortality. These findings support the importance of dietary management following resection of colon cancer, and future research into underlying mechanisms of action is warranted.

Associations of artificially sweetened beverage intake with disease recurrence and mortality in stage III colon cancer: Results from CALGB 89803 (Alliance).

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Grain Intake and Clinical Outcome in Stage III Colon Cancer: Results From CALGB 89803 (Alliance).

BACKGROUND: Energy balance-related risk factors for colon cancer recurrence and mortality-type II diabetes, hyperinsulinemia, inflammation, and visceral obesity-are positively correlated with consumption of refined grains and negatively correlated with consumption of whole grains. We examined the relationship between the consumption of refined and whole grains with cancer recurrence and mortality in a cohort of patients with colon cancer. METHODS: We conducted a prospective observational study of 1024 patients with stage III colon cancer who participated in a randomized trial of postoperative chemotherapy. Patients reported consumption of refined and whole grains using a food frequency questionnaire during and six months after chemotherapy. The primary outcome was disease-free survival (DFS). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. All P values are two-sided. RESULTS: During a median follow-up of 7.3 years, 394 patients experienced a DFS event. The hazard ratio for DFS was 1.56 (95% CI = 1.09 to 2.24) for patients consuming three or more servings per day of refined grains compared with patients consuming less than one serving per day (Ptrend = .005). The hazard ratio for DFS was 0.89 (95% CI = 0.66 to 1.20) for patients consuming three or more servings per day of whole grains compared with patients consuming less than one serving per day (Ptrend = .54). The hazard ratio for DFS of substituting one serving per day of refined grain with one serving per day of whole grain was 0.87 (95% CI = 0.79 to 0.96, P = .007). CONCLUSIONS: The choice of grain consumed may be associated with cancer recurrence and mortality. Future studies are necessary to confirm our findings and to inform the design of randomized trials.

Association of Survival With Adherence to the American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors After Colon Cancer Diagnosis: The CALGB 89803/Alliance Trial.

Importance: The American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors (ACS guidelines) include maintaining (1) a healthy body weight; (2) physical activity; and (3) a diet that includes vegetables, fruits, and whole grains. It is not known whether patients with colon cancer who follow these guidelines have improved survival. Objective: To examine whether a lifestyle consistent with the ACS guidelines is associated with improved survival rates after colon cancer. Design, Setting, and Participants: This prospective cohort study included 992 patients with stage III colon cancer who were enrolled in the CALGB 89803 randomized adjuvant chemotherapy trial from 1999 through 2001. Data for the present study were analyzed between November 2016 and December 2017. Exposures: We assigned an ACS guidelines score for each included patient based on body mass index; physical activity; and intake of vegetables, fruits, whole grains, and red/processed meats (score range, 0-6, with higher score indicating healthier behaviors). Secondarily, we examined a score that also included alcohol intake in addition to the other factors (range, 0-8). Lifestyle was assessed during and 6 months after chemotherapy. Main Outcomes and Measures: Hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free, recurrence-free, and overall survival. Results: Of the 992 patients enrolled in the study, 430 (43%) were women, and the mean (SD) age was 59.6 (11.2) years (range, 21-85 years). Over a 7-year median follow-up, we observed 335 recurrences and 299 deaths (43 deaths without recurrence). Compared with patients with a 0 to 1 ACS guidelines score (n = 262; 26%), patients with a 5 to 6 score (n = 91; 9%) had a 42% lower risk of death during the study period (HR, 0.58; 95% CI, 0.34-0.99; P = .01 for trend) and improved disease-free survival (HR, 0.69; 95% CI, 0.45-1.06; P = .03 for trend). When alcohol consumption was included in the score, the adjusted HRs comparing patients with scores of 6 to 8 (n = 162; 16%) vs those with scores of 0 to 2 (187; 91%) were 0.49 for overall survival (95% CI, 0.32-0.76; P = .002 for trend), 0.58 for disease-free survival (95% CI, 0.40, 0.84; P = .01 for trend), and 0.64 for recurrence-free survival (95% CI, 0.44-0.94; P = .05 for trend). Conclusions and Relevance: Having a healthy body weight, being physically active, and eating a diet rich in vegetables, fruits, and whole grains after diagnosis of stage III colon cancer was associated with a longer survival. Trial Registration: clinicaltrials.gov Identifier: NCT00003835.

Nut Consumption and Survival in Patients With Stage III Colon Cancer: Results From CALGB 89803 (Alliance).

Purpose Observational studies have reported increased colon cancer recurrence and mortality in patients with states of hyperinsulinemia, including type 2 diabetes, obesity, sedentary lifestyle, and high glycemic load diet. Nut intake has been associated with a lower risk of type 2 diabetes, metabolic syndrome, and insulin resistance. However, the effect of nut intake on colon cancer recurrence and survival is not known. Patients and Methods We conducted a prospective, observational study of 826 eligible patients with stage III colon cancer who reported dietary intake on food frequency questionnaires while enrolled onto a randomized adjuvant chemotherapy trial. Using Cox proportional hazards regression, we assessed associations of nut intake with cancer recurrence and mortality. Results After a median follow-up of 6.5 years, compared with patients who abstained from nuts, individuals who consumed two or more servings of nuts per week experienced an adjusted hazard ratio (HR) for disease-free survival of 0.58 (95% CI, 0.37 to 0.92; Ptrend = .03) and an HR for overall survival of 0.43 (95% CI, 0.25 to 0.74; Ptrend = .01). In subgroup analysis, the apparent benefit was confined to tree nut intake (HR for disease-free survival, 0.54; 95% CI, 0.34 to 0.85; Ptrend = .04; and HR for overall survival, 0.47; 95% CI, 0.27 to 0.82; Ptrend = .04). The association of total nut intake with improved outcomes was maintained across other known or suspected risk factors for cancer recurrence and mortality. Conclusion Diets with a higher consumption of nuts may be associated with a significantly reduced incidence of cancer recurrence and death in patients with stage III colon cancer.

Marine ω-3 Polyunsaturated Fatty Acid and Fish Intake after Colon Cancer Diagnosis and Survival: CALGB 89803 (Alliance).

Background: Marine ω-3 polyunsaturated fatty acids (PUFAs), primarily found in dark fish, may prevent colorectal cancer progression, in part through inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2). However, data in humans are limited.Methods: We examined marine ω-3 PUFAs and fish intake and survival among 1,011 colon cancer patients enrolled in Cancer and Leukemia Group B 89803 between 1999 and 2001 and followed through 2009. Diet was assessed during and 6 months after chemotherapy. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free (DFS), recurrence-free (RFS), and overall survival (OS).Results: We observed 343 recurrences and 305 deaths (median follow-up: 7 years). Patients in the highest vs. lowest quartile of marine ω-3 PUFA intake had an HR for DFS of 0.72 (95% CI, 0.54-0.97; Ptrend = 0.03). Individuals who consumed dark fish ≥1/week versus never had longer DFS (HR 0.65; 95% CI, 0.48-0.87; P-value = 0.007), RFS (HR 0.61; 95% CI, 0.46-0.86; Ptrend = 0.007), and OS (HR 0.68; 95% CI, 0.48-0.96; Ptrend = 0.04). In a subset of 510 patients, the association between marine ω-3 PUFA intake and DFS appeared stronger in patients with high PTGS2 expression (HR 0.32; 95% CI, 0.11-0.95; Ptrend = 0.01) compared with patients with absent/low PTGS2 expression (HR 0.78; 95% CI, 0.48-1.27; Ptrend = 0.35; Pinteraction = 0.19).Conclusions: Patients with high intake of marine ω-3 PUFAs and dark fish after colon cancer diagnosis may have longer DFS.Impact: Randomized controlled trials examining dark fish and/or marine ω-3 PUFA supplements and colon cancer recurrence/survival are needed. Cancer Epidemiol Biomarkers Prev; 27(4); 438-45. ©2018 AACR.

Coffee Intake, Recurrence, and Mortality in Stage III Colon Cancer: Results From CALGB 89803 (Alliance).

PURPOSE: Observational studies have demonstrated increased colon cancer recurrence in states of relative hyperinsulinemia, including sedentary lifestyle, obesity, and increased dietary glycemic load. Greater coffee consumption has been associated with decreased risk of type 2 diabetes and increased insulin sensitivity. The effect of coffee on colon cancer recurrence and survival is unknown. PATIENTS AND METHODS: During and 6 months after adjuvant chemotherapy, 953 patients with stage III colon cancer prospectively reported dietary intake of caffeinated coffee, decaffeinated coffee, and nonherbal tea, as well as 128 other items. We examined the influence of coffee, nonherbal tea, and caffeine on cancer recurrence and mortality using Cox proportional hazards regression. RESULTS: Patients consuming 4 cups/d or more of total coffee experienced an adjusted hazard ratio (HR) for colon cancer recurrence or mortality of 0.58 (95% CI, 0.34 to 0.99), compared with never drinkers (Ptrend = .002). Patients consuming 4 cups/d or more of caffeinated coffee experienced significantly reduced cancer recurrence or mortality risk compared with abstainers (HR, 0.48; 95% CI, 0.25 to 0.91; Ptrend = .002), and increasing caffeine intake also conferred a significant reduction in cancer recurrence or mortality (HR, 0.66 across extreme quintiles; 95% CI, 0.47 to 0.93; Ptrend = .006). Nonherbal tea and decaffeinated coffee were not associated with patient outcome. The association of total coffee intake with improved outcomes seemed consistent across other predictors of cancer recurrence and mortality. CONCLUSION: Higher coffee intake may be associated with significantly reduced cancer recurrence and death in patients with stage III colon cancer.

Sugar-sweetened beverage intake and cancer recurrence and survival in CALGB 89803 (Alliance).

BACKGROUND: In colon cancer patients, obesity, sedentary lifestyle, and high dietary glycemic load have been associated with increased risk of cancer recurrence. High sugar-sweetened beverage intake has been associated with obesity, diabetes, and cardio-metabolic diseases, but the influence on colon cancer survival is unknown. METHODS: We assessed the association between sugar-sweetened beverage consumption on cancer recurrence and mortality in 1,011 stage III colon cancer patients who completed food frequency questionnaires as part of a U.S. National Cancer Institute-sponsored adjuvant chemotherapy trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazard models. RESULTS: Patients consuming ≥ 2 servings of sugar-sweetened beverages per day experienced an adjusted HR for disease recurrence or mortality of 1.67 (95% CI, 1.04-2.68), compared with those consuming <2 servings per month (P(trend) = 0.02). The association of sugar-sweetened beverages on cancer recurrence or mortality appeared greater among patients who were both overweight (body mass index ≥ 2 5 kg/m(2)) and less physically active (metabolic equivalent task-hours per week <18) (HR = 2.22; 95% CI, 1.29-3.81, P(trend) = 0.0025). CONCLUSION: Higher sugar-sweetened beverage intake was associated with a significantly increased risk of cancer recurrence and mortality in stage III colon cancer patients.

Impact of physical activity after cancer diagnosis on survival in patients with recurrent colon cancer: Findings from CALGB 89803/Alliance.

BACKGROUND: The impact of physical activity on survival outcomes in patients with recurrent colon cancer has not been studied. We tested the association between the level of postdiagnosis physical activity and survival outcomes of patients with recurrent colon cancer. PATIENTS AND METHODS: We conducted a prospective observational study of 237 patients with stage III colon cancer who had recurrence of disease. Physical activity was measured approximately 6 months after the completion of therapy (14 months after surgical resection) but before detection of recurrent disease. The primary end point of the study was survival time after recurrence. RESULTS: The hazard ratio comparing patients who reported at least 18 metabolic equivalent task (MET) hours per week of physical activity with those engaging in < 3 MET hours per week was 0.71 (95% confidence interval, 0.46-1.11). Increasing total MET hours of physical activity per week was associated with a borderline statistical significance trend for improved survival after recurrence (P = .052). The benefit of physical activity on survival was not significantly modified by sex, body mass index (BMI), number of positive lymph nodes, age, baseline performance status, adjuvant chemotherapy regimen, or recurrence-free survival period. CONCLUSION: To our knowledge, this is the first study investigating the association of physical activity with survival outcome of patients with recurrent colon cancer. Although the association exceeded our predefined P trend < .05 for statistical significance, these findings warrant further studies of physical activity in patients with recurrent colorectal cancer.

Human amnion epithelial cell transplantation abrogates lung fibrosis and augments repair.

RATIONALE: Chronic lung disease characterized by loss of lung tissue, inflammation, and fibrosis represents a major global health burden. Cellular therapies that could restore pneumocytes and reduce inflammation and fibrosis would be a major advance in management. OBJECTIVES: To determine whether human amnion epithelial cells (hAECs), isolated from term placenta and having stem cell-like and antiinflammatory properties, could adopt an alveolar epithelial phenotype and repair a murine model of bleomycin-induced lung injury. METHODS: Primary hAECs were cultured in small airway growth medium to determine whether the cells could adopt an alveolar epithelial phenotype. Undifferentiated primary hAECs were also injected parenterally into SCID mice after bleomycin-induced lung injury and analyzed for production of surfactant protein (SP)-A, SP-B, SP-C, and SP-D. Mouse lungs were also analyzed for inflammation and collagen deposition. MEASUREMENTS AND MAIN RESULTS: hAECs grown in small airway growth medium developed an alveolar epithelial phenotype with lamellar body formation, production of SPs A-D, and SP-D secretion. Although hAECs injected into mice lacked SPs, hAECs recovered from mouse lungs 2 weeks post-transplantation produced SPs. hAECs remained engrafted over the 4-week test period. hAEC administration reduced inflammation in association with decreased monocyte chemoattractant protein-1, tumor necrosis factor-alpha, IL-1 and -6, and profibrotic transforming growth factor-beta in mouse lungs. In addition, lung collagen content was significantly reduced by hAEC treatment as a possible consequence of increased degradation by matrix metalloproteinase-2 and down-regulation of the tissue inhibitors of matrix metalloproteinase-1 and 2. CONCLUSIONS: hAECs offer promise as a cellular therapy for alveolar restitution and to reduce lung inflammation and fibrosis.

Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury.

Acute respiratory distress syndrome is characterized by loss of lung tissue as a result of inflammation and fibrosis. Augmenting tissue repair by the use of mesenchymal stem cells may be an important advance in treating this condition. We evaluated the role of term human umbilical cord cells derived from Wharton's jelly with a phenotype consistent with mesenchymal stem cells (uMSCs) in the treatment of a bleomycin-induced mouse model of lung injury. uMSCs were administered systemically, and lungs were harvested at 7, 14, and 28 days post-bleomycin. Injected uMSCs were located in the lung 2 weeks later only in areas of inflammation and fibrosis but not in healthy lung tissue. The administration of uMSCs reduced inflammation and inhibited the expression of transforming growth factor-beta, interferon-gamma, and the proinflammatory cytokines macrophage migratory inhibitory factor and tumor necrosis factor-alpha. Collagen concentration in the lung was significantly reduced by uMSC treatment, which may have been a consequence of the simultaneous reduction in Smad2 phosphorylation (transforming growth factor-beta activity). uMSCs also increased matrix metalloproteinase-2 levels and reduced their endogenous inhibitors, tissue inhibitors of matrix metalloproteinases, favoring a pro-degradative milieu following collagen deposition. Notably, injected human lung fibroblasts did not influence either collagen or matrix metalloproteinase levels in the lung. The results of this study suggest that uMSCs have antifibrotic properties and may augment lung repair if used to treat acute respiratory distress syndrome.

Phase I study of a 3-drug regimen of gemcitabine/cisplatin/pemetrexed in patients with metastatic transitional cell carcinoma of the urothelium.

OBJECTIVES: Gemcitabine (G) plus cisplatin (C) is standard care for metastatic transitional cell carcinoma (TCC) of the urothelium. Pemetrexed (P), alone or in combination with G, is active in metastatic TCC. However, the safety and efficacy of P combined with GC therapy is unknown. This phase I trial was designed to determine the maximum tolerated dose (MTD) of GC followed by P+G in patients with metastatic TCC. METHODS: Cohorts of 3 to 6 patients received escalating doses 28-day cycles (maximum 6 cycles): G 800-1,000 mg/m2 on days 1 and 15; P 400-500 mg/m2 on day 15; and C 50-70 mg/m2 on day 1. All patients received folic acid, vitamin B12, and full supportive care. The 3+3 standard phase I escalation rule was used to determine MTD. RESULTS: Fifteen patients registered: 13/15 white males; median age 70 years (range, 53-82); 11/15 had KPS>or=90. At dose level 0, 2/4 patients experienced unrelated DLTs, and 1 patient was replaced (completed<1 cycle). Dose escalation proceeded to dose level 1. At level 1, 4/6 patients experienced DLTs; dosing decreased to level 0 and 4/5 patients experienced DLTs. The MTD was not determined. The 2 patients that completed 6 cycles both had partial responses. Grades 3-4 hematologic toxicities included neutropenia (60%), leukopenia (20%), and febrile neutropenia (13%). CONCLUSION: Adding P to the standard GC regimen as first-line therapy for metastatic TCC produced no benefit. The MTD exceeded therapeutic gemcitabine and cisplatin doses for urothelial cancer and thus the study was aborted.