The prognostic value of lymph node to primary tumor standardized uptake value ratio in cancer patients: a meta-analysis.

OBJECTIVE: The lymph node to primary tumor standardized uptake value ratio (NTR) is an innovative parameter derived from positron emission tomography/computed tomography (PET/CT) scans that captures the intricate relationship between primary tumors and associated lymph nodes. This meta-analysis aimed to investigate the prognostic value of NTR in cancer patients. METHODS: A systematic search of PubMed, Cochrane, and Embase databases was conducted to identify studies investigating the association between NTR and survival outcomes in cancer patients. The pooled adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Twelve studies comprising a total of 2037 patients were included in the meta-analysis. Elevated NTR was significantly associated with worse overall survival aHR (2.21, 95% CI 1.63 to 2.99), disease-free survival aHR (3.27, 95% CI 2.12 to 5.05), and distant metastasis-free survival aHR (2.07, 95% CI 1.55 to 2.78) in cancer patients. Subgroup analyses by cancer type showed consistent results across various malignancies, including head and neck squamous cell carcinoma, endometrial carcinoma, lung cancer, breast cancer, and nasopharyngeal carcinoma. CONCLUSIONS: This meta-analysis provides evidence for a significant association between elevated NTR and worse survival outcomes in cancer patients. Elevated NTR may serve as a useful prognostic biomarker for cancer patients and could potentially be used to guide treatment decisions and monitor disease progression. Future studies should aim to validate these findings in larger and more diverse patient populations and investigate the underlying mechanisms for the observed association between NTR and survival outcomes.

Postoperative radiotherapy versus surgery alone in pN1 oral cavity cancer patients: A meta-analysis.

Objectives: The aim of this meta-analysis is to evaluate the potential benefits of postoperative radiotherapy (PORT) in patients with pN1 oral cavity squamous cell carcinoma. Methods: A literature search through major databases was conducted until January 2023. The adjusted hazard ratio (aHR) or risk ratio (RR) with 95% confidence intervals (CIs) of different survival outcomes were extracted and pooled. Results: Ten studies published between 2005 and 2022, with a pooled patient population of 2888, were included in this meta-analysis. Due to differences in study design and reported outcomes, the studies were categorized into distinct groups. In pN1 patients without extranodal extension (ENE), PORT was associated with a significant improvement in overall survival (OS) (aHR 0.76, 95% CI: 0.61-0.94). In pN1 patients without ENE and positive margins, PORT improved OS (aHR 0.71, 95% CI: 0.56-0.89) and was associated with a lower regional recurrence rate (RR 0.35, 95% CI: 0.15-0.83). However, in pN1 patients without ENE, positive margins, perineural invasion, and lymphovascular invasion, there were no significant differences observed between the PORT and observation groups in either 5-year OS (RR 0.48, 95% CI: 0.07-3.41) or 5-year disease-free survival (RR 0.37, 95% CI: 0.07-2.06). Conclusions: The current study demonstrated that PORT has the potential to improve OS in pN1 disease. However, the decision of whether to administer PORT still hinges on diverse clinical scenarios, and additional research is necessary to furnish a more conclusive resolution. Level of Evidence: 2.

Dose-Escalated Radiation Therapy as Primary Treatment for Residual Bladder Cancer After Transurethral Resection.

Purpose: The aim of this study was to determine whether escalating the local radiation dose can improve the outcome of residual bladder cancer after transurethral resection of bladder tumor without increasing treatment-related toxicity. Methods and Materials: The treatment plans and medical records of patients with bladder cancer treated with curative-intent radiation therapy between 2008 and 2020 were reviewed. Those who had residual tumors in the computed tomography simulation images were included. A cumulative radiation dose higher than 6600 cGy was defined as dose escalation. The effect of dose escalation on 3-year locoregional control, progression-free survival, and overall survival was evaluated. Results: A total of 149 patients with residual tumors were identified. The median follow-up period was 27.5 months. Among them, 51 patients received an escalated radiation dose, and 98 received a standard dose in the residual tumor area. Patients in the dose-escalation group had higher 3-year locoregional control (65.6% vs 27.8%; P < .001) and progression-free survival (42.6% vs 18.2%; P < .001) than the standard-dose group. Overall survival also showed a trend favoring the dose-escalation group (54.9% vs 36.2%; P = .059). In the multivariate analyses, the differences between the dose-escalation and standard-dose groups were significant in terms of locoregional control (hazard ratio, 0.32; CI, 0.18-0.59; P = <.001) and progression-free survival (hazard ratio, 0.51; CI, 0.32-0.82; P = .005). There was no statistical difference in acute and chronic treatment-related toxicities between the 2 groups. Conclusions: The outcome of residual bladder cancer after transurethral resection of bladder tumor could be improved by dose-escalated radiation therapy.

A Radiotherapy Dose Map-Guided Deep Learning Method for Predicting Pathological Complete Response in Esophageal Cancer Patients after Neoadjuvant Chemoradiotherapy Followed by Surgery.

Esophageal cancer is a deadly disease, and neoadjuvant chemoradiotherapy can improve patient survival, particularly for patients achieving a pathological complete response (ypCR). However, existing imaging methods struggle to accurately predict ypCR. This study explores computer-aided detection methods, considering both imaging data and radiotherapy dose variations to enhance prediction accuracy. It involved patients with node-positive esophageal squamous cell carcinoma undergoing neoadjuvant chemoradiotherapy and surgery, with data collected from 2014 to 2017, randomly split into five subsets for 5-fold cross-validation. The algorithm DCRNet, an advanced version of OCRNet, integrates RT dose distribution into dose contextual representations (DCR), combining dose and pixel representation with ten soft regions. Among the 80 enrolled patients (mean age 55.68 years, primarily male, with stage III disease and middle-part lesions), the ypCR rate was 28.75%, showing no significant demographic or disease differences between the ypCR and non-ypCR groups. Among the three summarization methods, the maximum value across the CTV method produced the best results with an AUC of 0.928. The HRNetV2p model with DCR performed the best among the four backbone models tested, with an AUC of 0.928 (95% CI, 0.884-0.972) based on 5-fold cross-validation, showing significant improvement compared to other models. This underscores DCR-equipped models' superior AUC outcomes. The study highlights the potential of dose-guided deep learning in ypCR prediction, necessitating larger, multicenter studies to validate the results.

Prognostic value of interim CT-based peritumoral and intratumoral radiomics in laryngeal and hypopharyngeal cancer patients undergoing definitive radiotherapy.

BACKGROUND AND PURPOSE: We aimed to investigate the prognostic value of peritumoral and intratumoral computed tomography (CT)-based radiomics during the course of radiotherapy (RT) in patients with laryngeal and hypopharyngeal cancer (LHC). MATERIALS AND METHODS: A total of 92 eligible patients were 1:1 randomly assigned into training and validation cohorts. Pre-RT and mid-RT radiomic features were extracted from pre-treatment and interim CT. LASSO-Cox regression was used for feature selection and model construction. Time-dependent area under the receiver operating curve (AUC) analysis was applied to evaluate the models' prognostic performances. Risk stratification ability on overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method and Cox regression. The associations between radiomics and clinical parameters as well as circulating lymphocyte counts were also evaluated. RESULTS: The mid-RT peritumoral (AUC: 0.77) and intratumoral (AUC: 0.79) radiomic models yielded better performance for predicting OS than the pre-RT intratumoral model (AUC: 0.62) in validation cohort. This was confirmed by Kaplan-Meier analysis, in which risk stratification depended on the mid-RT peritumoral (p = 0.009) and intratumoral (p = 0.003) radiomics could be improved for OS, in comparison to the pre-RT intratumoral radiomics (p = 0.199). Multivariate analysis identified mid-RT peritumoral and intratumoral radiomic models as independent prognostic factors for both OS and PFS. Mid-RT peritumoral and intratumoral radiomics were correlated with treatment-related lymphopenia. CONCLUSION: Mid-RT peritumoral and intratumoral radiomic models are promising image biomarkers that could have clinical utility for predicting OS and PFS in patients with LHC treated with RT.

Utility of High-Sensitivity Modified Glasgow Prognostic Score in Cancer Prognosis: A Systemic Review and Meta-Analysis.

The suitability of the high-sensitivity modified Glasgow Prognostic Score (HS-mGPS) in cancer patients remains unknown. We performed a systematic database search from 1 January 2010 to 30 September 2022, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Selected studies reported the HS-mGPS and survival outcomes in cancer patients. The association between the HS-mGPS and survival outcomes was evaluated using a random-effects model and expressed as pooled hazard ratios (HRs) with 95% CIs. This meta-analysis evaluated 17 studies with a total of 5828 cancer patients. A higher HS-mGPS was found to be associated with an adverse OS (HR = 2.17; 95% CI: 1.80-2.60), DSS (HR = 3.81; 95% CI: 2.03-7.17), and DFS (HR = 1.96; 95% CI: 1.48-2.58; all p ≤ 0.001). The prognostic value of the HS-mGPS for the OS trended in a consistent direction after subgrouping and sensitivity analysis. In conclusion, the HS-mGPS serves as a valid prognostic biomarker for cancer patients, with a high HS-mGPS associated with adverse survival outcomes.

Adjuvant Chemoradiotherapy Associated with Improved Overall Survival in Resected Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy in Intensity-Modulated Radiotherapy Era.

BACKGROUND: The prognosis of patients with resected esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy is particularly poor in those who were staged as ypT3/T4 and/or ypN+. This study investigated whether adjuvant chemoradiotherapy was associated with improved clinical outcomes in these patients. METHODS: we identified patients with esophageal squamous cell carcinoma who were staged as ypT3/T4 and/or ypN+ after being treated with neoadjuvant chemoradiotherapy followed by esophagectomy between the years 2013 and 2019. Patients were divided into two groups based on whether they received adjuvant chemoradiotherapy. The Kaplan-Meier method and Cox regression modeling were performed for survival analyses and multivariable analysis, respectively. RESULTS: 76 eligible patients were included in the analyses. The median follow-up for the study cohort was 43.4 months. On Kaplan-Meier analyses of the overall population, adjuvant chemoradiotherapy was associated with significantly improved median overall survival (31.7 months vs. 16.3 months, p = 0.036). On Kaplan-Meier analyses of the 35 matched pairs generated by propensity score matching, adjuvant chemoradiotherapy was associated with significantly longer median overall survival (31.7 months vs. 14.3 months; p = 0.004) and median recurrence-free survival (18.9 months vs. 11.7 months; p = 0.020). In multivariable analysis, adjuvant chemoradiotherapy was independently associated with a 60% reduction in mortality (p = 0.003) and a 48% reduction in risk of recurrence (p = 0.035) after adjusting for putative confounders. In addition, microscopic positive resection margin and Mandard tumor regression grade 3-4 were independently associated with increased mortality and risk of recurrence. While a greater number of lymph nodes dissected was independently associated with significantly improved overall survival, the number of positive lymph nodes was independently associated with significantly worse overall survival and a trend (p = 0.058) towards worse recurrence-free survival. CONCLUSIONS: This study demonstrated that adjuvant CRT was independently associated with a significantly improved survival and lower risk of recurrence than observation in esophageal squamous cell carcinoma patients staged as ypT3 and/or ypN+ after receiving neoadjuvant chemoradiotherapy and radical surgery. The results of this study have implications for the design of future clinical trials and may improve treatment outcomes of patients in this setting who cannot afford or are without access to adjuvant nivolumab.

Missed radiation therapy sessions in first three weeks predict distant metastasis and less favorable outcomes in surgically treated patients with oral cavity squamous cell carcinoma.

BACKGROUND: We sought to investigate the prognostic impact of missed RT sessions in patients who had undergone surgery for oral cavity squamous cell carcinoma (OCSCC). METHODS: The study sample consisted of 905 patients with surgically treated OCSCC who fulfilled criteria of RT course ≤8 weeks. The study participants were divided into three groups based on the characteristics of missed RT, as follows: 1) early missed RT, 2) late missed RT, and 3) RT as scheduled. RESULTS: The 5-year overall survival (OS) rates in the early missed RT, late missed RT, and RT as scheduled groups were 53.0, 58.1, and 64.5%, respectively (p = 0.046). In multivariate analysis, early missed RT was independently associated with both OS (hazard ratio (HR) = 1.486; 95% confidence interval (CI): 1.122-1.966; p = 0.006) and the occurrence of distant metastasis (HR = 1.644; 95% CI: 1.047-2.583; p = 0.031). CONCLUSION: Early missed RT was independently associated with a higher occurrence of distant metastasis and less favorable OS in patients who had undergone surgery for OCSCC.

Outcomes in patients with lacrimal gland carcinoma treated with definitive radiotherapy or eye-sparing surgery followed by adjuvant radiotherapy.

BACKGROUND: The optimal treatment for lacrimal gland cancer remains unclear. Eye-preserving surgery, as opposed to exenteration, followed by adjuvant radiotherapy (RT), has recently been reported to deliver satisfactory outcomes, but evidence is sparse. The aim of the present study was to evaluate outcomes in patients with lacrimal gland cancer treated at two tertiary medical centers. METHODS: We retrospectively examined data from patients with lacrimal gland cancer who had received eye-preserving surgical treatment followed by adjuvant RT with or without chemotherapy, or (if the tumor was inoperable) needle biopsy with definitive RT with or without chemotherapy. Baseline clinical and pathological characteristics were considered. Outcomes of interest included post-treatment complications, overall survival (OS), locoregional progression-free survival (LPFS), and distant metastasis-free survival (DMFS). RESULTS: Eighteen patients were included. Two-year OS, LPFS, and DMFS rates were 69.0, 76.7, and 71.4%, respectively. Patients with early-stage (T1-T2) lacrimal gland cancer had significantly better outcomes than those with advanced-stage disease (T3-T4). Two-year OS, LPFS, and DMFS rates were each 100% in patients with disease stages T1-T2, and 37.5, 50, and 37.5%, respectively, in those with disease stages T3-T4 (P < 0.05). Orbital complications were well tolerated. CONCLUSIONS: Eye-sparing surgery with adjuvant RT can achieve satisfactory results in patients with T1-T2 lacrimal gland carcinoma. Disease stage T3 and above was associated with poor outcomes even with post-operative RT, likely due to distant metastasis. Adding neoadjuvant chemotherapy or adjuvant chemotherapy to current treatment strategies might be a suitable choice for this group of patients.

Prognostic value of lymph node to primary tumor standardized uptake value ratio in unresectable esophageal cancer.

BACKGROUND: Unresectable esophageal cancer harbors high mortality despite chemoradiotherapy. Better patient selection for more personalized management may result in better treatment outcomes. We presume the ratio of maximum standardized uptake value (SUV) of metastatic lymph nodes to primary tumor (NTR) in 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT) may provide prognostic information and further stratification of these patients. METHODS: The patients with non-metastatic and unresectable esophageal squamous cell carcinoma (SCC) receiving FDG PET/CT staging and treated by chemoradiotherapy were retrospectively reviewed. Receiver operating characteristic (ROC) analysis was performed to determine the optimal cut-off value for NTR. Kaplan-Meier method and Cox regression model were used for survival analyses and multivariable analyses, respectively. RESULTS: From 2010 to 2016, 96 eligible patients were analyzed. The median follow-up time was 10.2 months (range 1.6 to 83.6 months). Using ROC analysis, the best NTR cut-off value was 0.46 for prediction of distant metastasis. The median distant metastasis-free survival (DMFS) was significantly lower in the high-NTR group (9.5 vs. 22.2 months, p = 0.002) and median overall survival (OS) (9.5 vs. 11.6 months, p = 0.013) was also significantly worse. Multivariable analysis revealed that NTR was an independent prognostic factor for DMFS (hazard ratio [HR] 1.81, p = 0.023) and OS (HR 1.77, p = 0.014). CONCLUSIONS: High pretreatment NTR predicts worse treatment outcomes and could be an easy-to-use and helpful prognostic factor to provide more personalized treatment for patients with non-metastatic and unresectable esophageal SCC.

Prognostic Value of Lymph Node-To-Primary Tumor Standardized Uptake Value Ratio in Esophageal Squamous Cell Carcinoma Treated with Definitive Chemoradiotherapy.

We aimed to investigate the prognostic value of the relative maximum standardized uptake value (SUV) of metastatic lymph node (LN) compared with that of primary tumor (SUVLN / SUVTumor) based on a pretreatment [18F]-FDG PET/CT scan in patients with clinically node-positive esophageal squamous cell carcinoma (cN+ ESCC) treated with definitive chemoradiotherapy (dCRT). We retrospectively evaluated cN+ ESCC patients who underwent a PET/CT scan before dCRT. Time-dependent receiver operating characteristics analysis was performed to identify the optimal cutoff value for SUVLN / SUVTumor. Prognostic influences of SUVLN / SUVTumor on distant metastasis-free survival (DMFS) and overall survival (OS) were evaluated using the Kaplan-Meier method and log-rank test for univariate analysis and Cox's proportional hazards regression model for multivariate analysis. We identified 112 patients with newly diagnosed cN+ ESCC. After a median follow-up of 32.0 months, 50 (44.6%) patients had distant failure and 84 (75.0%) patients died. Patients with high SUVLN / SUVTumor (≥ 0.39) experienced worse outcomes than low SUVLN / SUVTumor (< 0.39) (two-year DMFS: 26% vs. 70%, p < 0.001; two-year OS: 21% vs. 48%, p = 0.001). Multivariate analysis showed that SUVLN / SUVTumor was an independent prognostic factor for both DMFS (adjusted HR 2.24, 95% CI 1.34-3.75, p = 0.002) and OS (adjusted HR 1.61, 95% CI 1.03-2.53, p = 0.037). Pretreatment of SUVLN / SUVTumor is a simple and useful marker for prognosticating DMFS and OS in cN+ ESCC patients treated with dCRT, which may help in tailoring treatment and designing future clinical trials.

Optimal Timing for Postsurgical Adjuvant Therapy in Patients with Gastric Cancer: A Propensity Score Matching Study.

Background: In clinical trials, adjuvant therapy (AT) has been shown to improve the prognosis in patients with gastric adenocarcinoma who undergo curative gastrectomy and adequate lymph node dissection. However, the optimal timing for initiating AT is still unclear. Method: We collected data from 538 patients with stage II-III gastric cancer who underwent curative gastrectomy and AT in two tertiary hospitals from 2006 to 2013. Patients were divided into the early group (≤8 weeks, n=393) and the late group (>8 weeks, n=145), based on the interval between gastrectomy and initiation of AT. Propensity score matching was applied according to baseline characteristics. Results: After 1:1 propensity score matching, an even distribution of characteristics in both groups (143:143) was achieved. The 5-year overall survival (OS) rates were 56.6% and 40.2% in the matched early and late groups, respectively (p=0.062), while the corresponding 5-year recurrence-free survival (RFS) rates were 57.6% and 46.4%, respectively (p=0.028). The time to AT initiation was correlated with RFS and had a positive association with OS. The 5-year distant metastasis-free survival was also significantly better (HR 0.682, 95% CI 0.472-0.985, p=0.040), suggesting an early AT results in a better outcome in patients. Conclusion: We observed that initiation of AT within 8 weeks of curative gastrectomy produces better disease control and may contribute to better overall survival.

Development and Validation of a Nomogram for Assessing Survival in Patients With Metastatic Lung Cancer Referred for Radiotherapy for Bone Metastases.

Importance: A survival prediction model for patients with bone metastases arising from lung cancer would be highly valuable. Objective: To develop and validate a nomogram for assessing the survival probability of patients with metastatic lung cancer receiving radiotherapy for osseous metastases. Design, Setting, Participants: In this prognostic study, the putative prognostic indicators for constructing the nomogram were identified using multivariable Cox regression analysis with backward elimination and model selection based on the Akaike information criterion. The nomogram was subjected to internal (bootstrap) and external validation; its calibration and discriminative ability were evaluated with calibration plots and the Uno C statistic, respectively. The training and validation set cohorts were from a tertiary medical center in northern Taiwan and a tertiary institution in southern Taiwan, respectively. The training set comprised 477 patients with metastatic lung cancer who received radiotherapy for osseous metastases between January 2000 and December 2013. The validation set comprised 235 similar patients treated between January 2011 and December 2017. Data analysis was conducted May 2018 to July 2018. Main Outcomes and Measures: The nomogram end points were death within 3, 6, and 12 months. Results: Of 477 patients in the training set, 292 patients (61.2%) were male, and the mean (SD) age was 62.86 (11.66) years. Of 235 patients in the validating set, 113 patients (48.1%) were male, and the mean (SD) age was 62.65 (11.49) years. In the training set, 186 (39%), 291 (61%), and 359 (75%) patients died within 3, 6, and 12 months, respectively, and the median overall survival was 4.21 (95% CI, 3.68-4.90) months. In the validating set, 84 (36%), 120 (51%), and 144 (61%) patients died within 3, 6, and 12 months, respectively, and the median overall survival was 5.20 (95% CI, 4.07-7.17) months. Body mass index (18.5 to <25 vs ≥25: hazard ratio [HR], 1.42; 95% CI, 1.14-1.78 and <18.5 vs ≥25: HR, 2.31; 95% CI, 1.56-3.44), histology (non-small cell vs small cell lung cancer: HR, 0.59; 95% CI, 0.41-0.86), epidermal growth factor receptor mutation (positive vs unknown: HR, 0.66; 95% CI, 0.46-0.93 and negative vs unknown: HR, 0.98; 95% CI, 0.66-1.45), smoking status (ever smoker vs never smoker: HR, 1.50; 95% CI, 1.24-1.83), age, and neutrophil to lymphocyte ratio were incorporated. The HRs of age and neutrophil to lymphocyte ratio were modeled nonlinearly with restricted cubic splines (both P < .001). The nomogram's discriminative ability was good in the training set (C statistic, ≥0.77; P < .001) and was validated using both an internal bootstrap method (C statistic, ≥0.76; P < .001) and an external validating set (C statistic, ≥0.75; P < .001). The calibration plots for the end points showed optimal agreement between the nomogram's assessment and actual observations. Conclusions and Relevance: The nomogram (with web-based tool) can be useful for assessing the probability of survival at 3, 6, and 12 months in patients with metastatic lung cancer referred for radiotherapy to treat bone metastases, and it may guide radiation oncologists in treatment decision making and engaging patients in end-of-life discussions and/or hospice referrals at appropriate times.

Favorable versus unfavorable prognostic groups by post-chemoradiation FDG-PET imaging in node-positive esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy.

PURPOSE: Our purpose was to examine the prognostic value of post-CRT PET based on the presence or absence of FDG-avid metastatic lymph node(s) and metabolic response of the primary tumor in patients with clinically node-positive ESCC treated with definitive chemoradiotherapy (dCRT). METHODS: We identified 108 eligible patients treated by chemoradiotherapy (CRT) with or without resection from our prospectively collected database. Absence of FDG-avid metastatic lymph node with at least partial response of the primary tumor on PET scan after initial CRT was defined as the Post-CRT PET favorable group (yPET-F), and otherwise as unfavorable group (yPET-U). The Kaplan-Meier method and Cox regression were performed for survival analyses and multivariable analysis, respectively. RESULTS: The study cohort was comprised of 59 patients receiving dCRT. Forty-five patients receiving trimodality therapy (TMT) comprised the comparative group and four patients were excluded from further analyses for developing interval distant metastasis detected on post-CRT PET scan. The median follow-up for the study cohort was 41 months. On K-M analysis of the study cohort, yPET-F was found to have significantly better OS (2-year: 72.5% vs 13.7%, p < 0.01) and DMFS (2-year: 71.6% vs 36.6%, p = 0.01) than yPET-U. In multivariable analysis, yPET-F remained as a strong independent favorable prognosticator on both OS (HR 0.08, p < 0.01) and DMFS (HR 0.14, p = 0.02) for the dCRT cohort. Compared with TMT cohort, for yPET-U patients, TMT had better OS (p = 0.03) than dCRT-Operable and dCRT-Operable had superior OS (p = 0.04) than dCRT-Unresectable. For yPET-F patients, there was no difference in both OS (p > 0.99) and DMFS (p = 0.92) between these three groups. CONCLUSIONS: Absence of FDG-avid metastatic lymph node with at least partial response of the primary tumor on PET scan after CRT (i.e., yPET-F status) prognosticate for excellent OS and DMFS in cN+ ESCC patients treated with dCRT, and might be comparable to TMT.