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Item A Modified Tumor-Node-Metastasis Classification for Primary Operable Colorectal Cancer(Oxford University Press, 2020-10-16) Zhang, Chundong; Mei, Zubing; Pei, Junpeng; Abe, Masanobu; Zeng, Xiantao; Huang, Qiao; Nishiyama, Kazuhiro; Akimoto, Naohiko; Haruki, Koichiro; Nan, Hongmei; Meyerhardt, Jeffrey A.; Zhang, Rui; Li, Xinxiang; Ogino, Shuji; Ugai, Tomotaka; Community and Global Health, School of Public HealthBackground: The American Joint Committee on Cancer (AJCC) 8th tumor-node-metastasis (TNM) classification for colorectal cancer (CRC) has limited ability to predict prognosis. Methods: We included 45 379 eligible stage I-III CRC patients from the Surveillance, Epidemiology, and End Results Program. Patients were randomly assigned individually to a training (n = 31 772) or an internal validation cohort (n = 13 607). External validation was performed in 10 902 additional patients. Patients were divided according to T and N stage permutations. Survival analyses were conducted by a Cox proportional hazard model and Kaplan-Meier analysis, with T1N0 as the reference. Area under receiver operating characteristic curve and Akaike information criteria were applied for prognostic discrimination and model fitting, respectively. Clinical benefits were further assessed by decision curve analyses. Results: We created a modified TNM (mTNM) classification: stages I (T1-2N0-1a); IIA (T1N1b, T2N1b, T3N0); IIB (T1-2N2a-2b, T3N1a-1b, T4aN0); IIC (T3N2a, T4aN1a-2a, T4bN0); IIIA (T3N2b, T4bN1a); IIIB (T4aN2b, T4bN1b); and IIIC (T4bN2a-2b). In the internal validation cohort, compared with the AJCC 8th TNM classification, the mTNM classification showed superior prognostic discrimination (area under receiver operating characteristic curve = 0.675 vs 0.667, respectively; 2-sided P < .001) and better model fitting (Akaike information criteria = 70 937 vs 71 238, respectively). Similar findings were obtained in the external validation cohort. Decision curve analyses revealed that the mTNM had superior net benefits over the AJCC 8th TNM classification in the internal and external validation cohorts. Conclusions: The mTNM classification provides better prognostic discrimination than AJCC 8th TNM classification, with good applicability in various populations and settings, to help better stratify stage I-III CRC patients into prognostic groups.Item Age and comorbidity association with survival outcomes in metastatic colorectal cancer: CALGB 80405 analysis(Elsevier, 2022) McCleary, Nadine J.; Zhang, Sui; Ma, Chao; Ou, Fang-Shu; Bainter, Tiffany M.; Venook, Alan P.; Niedzwiecki, Donna; Lenz, Heinz-Josef; Innocenti, Federico; O'Neil, Bert H.; Polite, Blase N.; Hochster, Howard S.; Atkins, James N.; Goldberg, Richard M.; Ng, Kimmie; Mayer, Robert J.; Blanke, Charles D.; O'Reilly, Eileen M.; Fuchs, Charles S.; Meyerhardt, Jeffrey A.; Medicine, School of MedicineBackground: Little is known about the interaction of comorbidities and age on survival outcomes in colorectal cancer (mCRC), nor how comorbidities impact treatment tolerance. Methods: We utilized a cohort of 1345 mCRC patients enrolled in CALGB/SWOG 80405, a multicenter phase III trial of fluorouracil/leucovorin + oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) plus bevacizumab, cetuximab or both. Endpoints were overall survival (OS), progression-free survival (PFS), and grade ≥ 3 toxicities assessed using NCI CTCAE v.3.0. Participants completed a questionnaire, including a modified Charlson Comorbidity Index. Adjusted Cox and logistic regression models tested associations of comorbidities and age on the endpoints. Results: In CALGB/SWOG 80405, 1095 (81%) subjects were < 70 years and >70 250 (19%). Presence of ≥1 comorbidity was not significantly associated with either OS (HR 1.10, 95% CI 0.96-1.25) or PFS (HR 1.03, 95% CI 0.91-1.16). Compared to subjects <70 with no comorbidities, OS was non-significantly inferior for ≥70 with no comorbidities (HR 1.21, 95% CI 0.98-1.49) and significantly inferior for ≥70 with at least one comorbidity (HR 1.51, 95% CI 1.22-1.86). There were no significant associations or interactions between age or comorbidity with PFS. Comorbidities were not associated with treatment-related toxicities. Age ≥ 70 was associated with greater risk of grade ≥ 3 toxicities (OR 2.15, 95% CI 1.50-3.09, p < 0.001). Conclusions: Among participants in a clinical trial of combination chemotherapy for mCRC, presence of older age with comorbidities was associated with worse OS but not PFS. The association of age with toxicity suggests additional factors of care should be measured in clinical trials.Item Association of Coffee Intake With Survival in Patients With Advanced or Metastatic Colorectal Cancer(American Medical Association, 2020-11-01) Mackintosh, Christopher; Yuan, Chen; Ou, Fang-Shu; Zhang, Sui; Niedzwiecki, Donna; Chang, I-Wen; O’Neil, Bert H.; Mullen, Brian C.; Lenz, Heinz-Josef; Blanke, Charles D.; Venook, Alan P.; Mayer, Robert J.; Fuchs, Charles S.; Innocenti, Federico; Nixon, Andrew B.; Goldberg, Richard M.; O’Reilly, Eileen M.; Meyerhardt, Jeffrey A.; Ng, Kimmie; Medicine, School of MedicineImportance: 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.Item Association of Diet Quality With Survival Among People With Metastatic Colorectal Cancer in the Cancer and Leukemia B and Southwest Oncology Group 80405 Trial(AMA, 2020-10-30) Van Blarigan, Erin L.; Zhang, Sui; Ou, Fang-Shu; Venlo, Alan; Ng, Kimmie; Atreya, Chloe; Van Loon, Katherine; Niedzwiecki, Donna; Giovannucci, Edward; Wolfe, Eric G.; Lenz, Heinz-Josef; Innocenti, Federico; O'Neil, Bert H.; Shaw, James E.; Polite, Blase N.; Hochster, Howard S.; Atkins, James N.; Goldberg, Richard M.; Mayer, Robert J.; Blanke, Charles D.; O'Reilly, Eileen M.; Fuchs, Charles S.; Meyerhardt, Jeffrey A.; Medicine, School of MedicineImportance: 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.Item Body Mass Index and Weight Loss in Metastatic Colorectal Cancer in CALGB (Alliance)/SWOG 80405(Oxford University Press, 2020-03-31) Guercio, Brendan J.; Zhang, Sui; Venook, Alan P.; Ou, Fang-Shu; Niedzwiecki, Donna; Lenz, Heinz-Josef; Innocenti, Federico; Mullen, Brian C.; O’Neil, Bert H.; Shaw, James E.; Polite, Blase N.; Hochster, Howard S.; Atkins, James N.; Goldberg, Richard M.; Brown, Justin C.; O’Reilly, Eileen M.; Mayer, Robert J.; Blanke, Charles D.; Fuchs, Charles S.; Meyerhardt, Jeffrey A.; Medicine, School of MedicineBackground: 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 P trend = .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; P trend < .001) and of 1.23 for disease progression or death (95% CI = 1.02 to 1.47; P trend = .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.Item Calcium Intake and Risk of Colorectal Cancer According to Tumor-infiltrating T Cells(AACR, 2019-05) Yang, Wanshui; Liu, Li; Keum, NaNa; Qian, Zhi Rong; Nowak, Jonathan A.; Hamada, Tsuyoshi; Song, Mingyang; Cao, Yin; Nosho, Katsuhiko; Smith-Warner, Stephanie A.; Zhang, Sui; Masugi, Yohei; Ng, Kimmie; Kosumi, Keisuke; Ma, Yanan; Garrett, Wendy S.; Wang, Molin; Nan, Hongmei; Giannakis, Marios; Meyerhardt, Jeffrey A.; Chan, Andrew T.; Fuchs, Charles S.; Nishihara, Reiko; Wu, Kana; Giovannucci, Edward L.; Ogino, Shuji; Zhang, Xuehong; Epidemiology, School of Public HealthCalcium intake has been associated with a lower risk of colorectal cancer. Calcium signaling may enhance T-cell proliferation and differentiation, and contribute to T-cell–mediated antitumor immunity. In this prospective cohort study, we investigated the association between calcium intake and colorectal cancer risk according to tumor immunity status to provide additional insights into the role of calcium in colorectal carcinogenesis. The densities of tumor-infiltrating T-cell subsets [CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ cell] were assessed using IHC and computer-assisted image analysis in 736 cancer cases that developed among 136,249 individuals in two cohorts. HRs and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. Total calcium intake was associated with a multivariable HR of 0.55 (comparing ≥1,200 vs. <600 mg/day; 95% CI, 0.36–0.84; Ptrend = 0.002) for CD8+ T-cell–low but not for CD8+ T-cell–high tumors (HR = 1.02; 95% CI, 0.67–1.55; Ptrend = 0.47). Similarly, the corresponding HRs (95% CIs) for calcium for low versus high T-cell–infiltrated tumors were 0.63 (0.42–0.94; Ptrend = 0.01) and 0.89 (0.58–1.35; Ptrend = 0.20) for CD3+; 0.58 (0.39–0.87; Ptrend = 0.006) and 1.04 (0.69–1.58; Ptrend = 0.54) for CD45RO+; and 0.56 (0.36–0.85; Ptrend = 0.006) and 1.10 (0.72–1.67; Ptrend = 0.47) for FOXP3+, although the differences by subtypes defined by T-cell density were not statistically significant. These potential differential associations generally appeared consistent regardless of sex, source of calcium intake, tumor location, and tumor microsatellite instability status. Our findings suggest a possible role of calcium in cancer immunoprevention via modulation of T-cell function.Item Coffee Intake of Colorectal Cancer Patients and Prognosis According to Histopathologic Lymphocytic Reaction and T-Cell Infiltrates(Elsevier, 2022) Ugai, Tomotaka; Haruki, Koichiro; Väyrynen, Juha P.; Borowsky, Jennifer; Fujiyoshi, Kenji; Lau, Mai Chan; Akimoto, Naohiko; Zhong, Rong; Kishikawa, Junko; Arima, Kota; Shi, Shan-shan; Zhao, Melissa; Fuchs, Charles S.; Zhang, Xuehong; Giannakis, Marios; Song, Mingyang; Nan, Hongmei; Meyerhardt, Jeffrey A.; Wang, Molin; Nowak, Jonathan A.; Ogino, Shuji; Community and Global Health, Richard M. Fairbanks School of Public HealthGiven previous biological evidence of immunomodulatory effects of coffee, we hypothesized that the association between coffee intake of colorectal cancer patients and survival differs by immune responses. Using a molecular pathological epidemiology database of 4,465 incident colorectal cancer cases, including 1,262 cases with molecular data, in the Nurses’ Health Study and the Health Professionals Follow-up Study, we examined the association between coffee intake of colorectal cancer patients and survival in strata of levels of histopathologic lymphocytic reaction and T-cell infiltrates in tumor tissue. We did not observe a significant association of coffee intake with colorectal cancer-specific mortality [multivariable-adjusted hazard ratio (HR) for one cup increase of coffee intake per day, 0.93; 95% confidence interval (CI), 0.84-1.03]. Although statistical significance was not reached at the stringent level (α=0.005), the association of coffee intake with colorectal cancer-specific mortality differed by Crohn's-like lymphoid reaction (Pinteraction=.007). Coffee intake was associated with lower colorectal cancer-specific mortality in patients with high Crohn's-like reaction (multivariable HR for one cup increase of coffee intake per day, 0.55; 95% CI, 0.37–0.81; Ptrend=.002), but not in patients with intermediate Crohn's-like reaction (the corresponding HR, 1.02; 95% CI, 0.72–1.44) or negative/low Crohn's-like reaction (the corresponding HR, 0.95; 95% CI, 0.83–1.07). The associations of coffee intake with colorectal cancer-specific mortality did not significantly differ by levels of other lymphocytic reaction or any T-cell subset (Pinteraction>.18). There is suggestive evidence for differential prognostic effects of coffee intake by Crohn’s-like lymphoid reaction in colorectal cancer.Item Diabetes and Clinical Outcome in Patients With Metastatic Colorectal Cancer: CALGB 80405 (Alliance)(Oxford University Press, 2020-02) Brown, Justin C.; Zhang, Sui; Ou, Fang-Shu; Venook, Alan P.; Niedzwiecki, Donna; Heinz-Josef Lenz, Heinz-Josef; Innocenti, Federico; O’Neil, Bert H.; Shaw, James E.; Polite, Blase N.; Denlinger, Crystal S.; Atkins, James N.; Goldberg, Richard M.; Ng, Kimmie; Mayer, Robert J.; Blanke, Charles D.; O’Reilly, Eileen M.; Fuchs, Charles S.; Meyerhardt, Jeffrey A.; Medicine, School of MedicineBackground Diabetes is a prognostic factor for some malignancies, but its association with outcome in patients with advanced or metastatic colorectal cancer (CRC) is less clear. Methods This cohort study was nested within a randomized trial of first-line chemotherapy and bevacizumab and/or cetuximab for advanced or metastatic CRC. Patients were enrolled at 508 community and academic centers throughout the National Clinical Trials Network. The primary exposure was physician-documented diabetes at the time of enrollment. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS) and adverse events. Tests of statistical significance were two-sided. Results Among 2326 patients, 378 (16.3%) had diabetes. The median follow-up time was 6.0 years. We observed 1973 OS events and 2173 PFS events. The median time to an OS event was 22.7 months among those with diabetes and 27.1 months among those without diabetes (HR = 1.27, 95% CI = 1.13 to 1.44; P < .001). The median time to a PFS event was 9.7 months among those with diabetes and 10.8 months among those without diabetes (HR = 1.16, 95% CI = 1.03 to 1.30; P = .02). Patients with diabetes were more likely to experience no less than grade 3 hypertension (8.1% vs 4.4%; P = .054) but were not more likely to experience other adverse events, including neuropathy. Conclusions Diabetes is associated with an increased risk of mortality and tumor progression in patients with advanced or metastatic CRC. Patients with diabetes tolerate first-line treatment with chemotherapy and monoclonal antibodies similarly to patients without diabetes.Item Effect of resistance training on physical function during chemotherapy in colon cancer(Oxford University Press, 2024) Brown, Justin C.; Yang, Shengping; Compton, Stephanie L. E.; Campbell, Kristin L.; Cespedes Feliciano, Elizabeth M.; Quinney, Sara; Sternfeld, Barbara; Caan, Bette J.; Meyerhardt, Jeffrey A.; Schmitz, Kathryn H.; Obstetrics and Gynecology, School of MedicineBackground: The decline of physical function during chemotherapy predicts poor quality of life and premature death. It is unknown if resistance training prevents physical function decline during chemotherapy in colon cancer survivors. Methods: This multicenter trial randomly assigned 181 colon cancer survivors receiving postoperative chemotherapy to home-based resistance training or usual care control. Physical function outcomes included the short physical performance battery, isometric handgrip strength, and the physical function subscale of the Medical Outcomes Short-Form 36-item questionnaire. Mixed models for repeated measures quantified estimated treatment differences. Results: At baseline, participants had a mean (SD) age of 55.2 (12.8) years; 67 (37%) were 60 years or older, and 29 (16%) had a composite short physical performance battery score of no more than 9. Compared with usual care control, resistance training did not improve the composite short physical performance battery score (estimated treatment difference = -0.01, 95% confidence interval [CI] = -0.32 to 0.31; P = .98) or the short physical performance battery scores for balance (estimated treatment difference = 0.01, 95% CI = -0.10 to 0.11; P = .93), gait speed (estimated treatment difference = 0.08, 95% CI = -0.06 to 0.22; P = .28), and sit-to-stand (estimated treatment difference = -0.08, 95% CI = -0.29 to 0.13; P = .46). Compared with usual care control, resistance training did not improve isometric handgrip strength (estimated treatment difference = 1.50 kg, 95% CI = -1.06 to 4.05; P = .25) or self-reported physical function (estimated treatment difference = -3.55, 95% CI = -10.03 to 2.94); P = .28). The baseline short physical performance battery balance score (r = 0.21, 95% CI = 0.07 to 0.35) and handgrip strength (r = 0.23, 95% CI = 0.09 to 0.36) correlated with chemotherapy relative dose intensity. Conclusion: Among colon cancer survivors with relatively high physical functioning, random assignment to home-based resistance training did not prevent physical function decline during chemotherapy.Item IGF-Binding Proteins, Adiponectin, and Survival in Metastatic Colorectal Cancer: Results From CALGB (Alliance)/SWOG 80405(Oxford University Press, 2020-08-27) Guercio, Brendan J.; Zhang, Sui; Ou, Fang-Shu; Venook, Alan P.; Niedzwiecki, Donna; Lenz, Heinz-Josef; Innocenti, Federico; Pollak, Michael N.; Nixon, Andrew B.; Mullen, Brian C.; O'Neil, Bert H.; Shaw, James E.; Polite, Blase N.; Benson, Al Bowen, III.; Atkins, James N.; Goldberg, Richard M.; Brown, Justin C.; O'Reilly, Eileen M.; Mayer, Robert J.; Blanke, Charles D.; Fuchs, Charles S.; Meyerhardt, Jeffrey A.; Medicine, School of MedicineBackground: 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). P 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; P nonlinearity < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; P trend = .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; P trend < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; P trend < .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 (P nonlinearity = .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.