Rates of Pathologic Complete Response and Overall Survival in Patients with Inflammatory Breast Cancer: A National Cancer Database Study.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have worse survival compared with stage III non-IBC matched cohorts; however, the prognostic significance of achieving pathologic complete response (pCR) in the setting of IBC is not well described. We evaluated overall survival (OS) between IBC patients and non-IBC patients who achieved pCR. METHODS: Adult females diagnosed in 2010-2018 with clinical prognostic stage III unilateral invasive breast cancer treated with neoadjuvant chemotherapy (NAC) followed by surgery were selected from the National Cancer Database. Unadjusted OS from surgery was estimated using the Kaplan-Meier method, and log-rank tests were used to compare groups. Cox proportional hazard models were used to estimate the association of study groups with OS after adjustment for available covariates. RESULTS: The study included 38,390 patients; n = 4600 (12.0%) IBC and n = 33,790 (88.0%) non-IBC. Overall pCR rates were lower for IBC compared with non-IBC (20.7% vs. 23.3%; p < 0.001). Among those achieving pCR, 5-year mortality was higher for IBC patients (16.4%, 95% confidence interval [CI] 13.9-19.1%) versus non-IBC patients (9.1%, 95% CI 8.4-9.8%; log-rank p < 0.001). Among all patients achieving pCR, IBC remained associated with worse OS compared with non-IBC (hazard ratio 1.48, 95% CI 1.19-1.85; p < 0.001). CONCLUSION: We found a lower pCR rate and worse OS in IBC patients compared with non-IBC stage III patients. Despite effective systemic therapies, achieving a pCR for IBC patients may not carry the same prognostic impact compared with non-IBC stage III patients.

Assessment of Treatment Sequence in Patients With Stage III Breast Cancer.

INTRODUCTION: Stage III breast cancer is defined as locally advanced breast cancer and is treated with curative intent. Historically, overall survival (OS) did not differ based on treatment sequence (neoadjuvant chemotherapy [NAC] followed by surgery versus surgery followed by chemotherapy). Given recent advancements, we examined if treatment sequence may be associated with improved OS in a contemporary cohort of patients with stage III breast cancer. METHODS: Patients aged 18-80 years with prognostic stage III breast cancer who received chemotherapy and surgery were selected from the Surveillance, Epidemiology, and End Results database. Patients were stratified by treatment sequence (NAC versus surgery first). Unadjusted OS and breast cancer-specific survival (BCSS) were estimated using the Kaplan-Meier method and compared with log-rank tests. Cox proportional hazards models were used to estimate the association of treatment sequence with OS and BCSS after adjustment for selected covariates. RESULTS: The study included 26,573 patients; median follow-up was 62.0 months (95% confidence interval [CI] 61.0-63.0). Patients receiving NAC had a worse OS and BCSS compared to those who underwent surgery first (5-year OS rates 0.66 versus 0.73; 5-year BCSS rates 0.70 versus 0.77; both log-rank P < 0.001). After adjustment for tumor subtype, receipt of NAC (versus surgery first) remained associated with a worse OS (hazard ratio 1.27, 95% CI 1.2-1.34, P < 0.001) and BCSS (hazard ratio 1.35, 95% CI 1.27-1.43, P < 0.001). CONCLUSIONS: Based on data from patients treated largely before 2020, undergoing surgery first may be associated with improved survival, even after adjustment for known covariates including tumor subtype. These findings may inform treatment when caring for patients with operable, locally advanced breast cancer.

Comparison of incident breast cancer cases in the largest national US tumor registries.

BACKGROUND: This study compared incident breast cancer cases in the National Cancer Database (NCDB) and Surveillance, Epidemiology, End Results Program (SEER) to a national population cancer registry. METHODS: Patients with malignant or in situ breast cancer (BC) 2010-2019 in the NCDB and SEER were compared to the US Cancer Statistics (USCS). Case coverage was estimated as the number of patients in the NCDB/SEER as a proportion of USCS cases. RESULTS: The USCS reported 3,047,509 patients; 77.5% patients were included in the NCDB and 46.0% in SEER. Case ascertainment varied significantly by patient sex (both registries, p < .001). For males, 84.1% were captured in the NCDB, whereas only 77.5% of females were included. Case coverage in SEER was better for females than males (46.1% vs. 43.5%). Registries varied significantly by race/ethnicity (both p < .001). Case coverage in the NCDB was highest for non-Hispanic White (78.2%), non-Hispanic Black (77.7%), and non-Hispanic Asian or Pacific Islander (72.5%) BC patients, and lowest for Hispanic (56.4%) and non-Hispanic American Indian/Alaska Native (41.1%) patients. In SEER, case coverage was highest for non-Hispanic Asian or Pacific Islander (78.1%) and Hispanic (69.6%) patients and it was significantly lower for all other subgroups (non-Hispanic Black, 44.8%; non-Hispanic White, 42.4%; and non-Hispanic American Indian/Alaska Native, 36.6%). CONCLUSIONS: National US tumor registries provide data for a large sampling of breast cancer patients, yet significant differences in case coverage were observed based on age, sex, and race/ethnicity. These findings suggest that analyses using these data sets and interpretation of findings should account for these meaningful variances.

Demographics and Clinical Decision Making in Patients with Germline Moderate Penetrance Non-BRCA Mutations in Breast Cancer Related Genes.

BACKGROUND: Management of pathogenic variants in high penetrance genes related to breast cancer (BC), such as BRCA1 and BRCA2, are well established. However, moderate penetrance mutations are understudied. We aim to compare risk reduction decision-making patterns in patients with a moderate penetrance BC-related genetic mutations, without a prior BC diagnosis. PATIENTS AND METHODS: Female patients aged ≥ 18 years who tested positive for a BRCA1/2, high penetrance, or moderate penetrance mutation related to BC between 1996 and 2023 without a concurrent or prior BC diagnosis were retrospectively identified from a single academic center's database. Groups were stratified by mutation type: BRCA1/2 mutations (BRCA1, BRCA2), high penetrance mutations (HPM; CDH1, PALB2, PTEN, STK11, TP53), or moderate penetrance mutations (MPM; ATM, BARD1, CHEK2, NF1, RAD51C, RAD51D). Demographics and clinical outcomes were compared. RESULTS: A total of 528 patients met the inclusion criteria, with 66% (n = 350) having a BRCA1/2 mutation, 8% (n = 44) having HPM, and 25% (n = 134) having MPM; the median follow-up was 56.0 months. In our cohort, 20.9% of patients with BRCA mutations, 9.1% with HPM, and 7.5% with MPM chose to undergo risk-reducing mastectomies (RRM). Within the moderate penetrance cohort, patients who chose to undergo RRM were younger at the time of genetic testing (39.4 vs. 47.5 years, p = 0.03) and had a higher number of family members with BC (2 vs. 1, p = 0.05). CONCLUSIONS: Our findings provide insights into the demographic characteristics and family history of patients with moderate penetrance mutations and those who pursue risk-reducing surgery.

Trajectory of Subsequent Breast Cancer Diagnoses in a Diverse Patient Cohort with Breast Atypia.

BACKGROUND: Proliferative breast atypical lesions, including atypical ductal hyperplasia (ADH) and lobular intraepithelial neoplasms (LIN), represent benign entities that confer an elevated risk of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC). However, the timing of disease progression is variable and risk factors associated with the trajectory of disease are unknown. METHODS: Patients diagnosed with ADH or LIN from 1992 to 2017 at an academic center were identified. Early progression was defined as DCIS or IBC diagnosed within 5 years following the initial atypia diagnosis. Unadjusted cancer-free survival was estimated using the Kaplan-Meier method. Demographics, clinicopathologic features, and use of chemoprevention were compared between the early and late development groups. RESULTS: Overall, 418 patients were included-73.7% with ADH and 26.3% with LIN. Over a median follow up of 92.1 months, 71/418 (17.0%) patients developed IBC (57.7%) or DCIS (42.3%). Almost half (47.9%, 34/71) were diagnosed within 5 years of their initial atypia diagnosis, and 52.1% (37/71) were diagnosed after 5 years. Patient and atypia characteristics were not associated with rate of events or time to events. There was a trend of early events being more often ipsilateral (76.5% early vs. 54.1% late; p = 0.13) versus contralateral. CONCLUSIONS: In a large cohort of patients with breast atypia and long-term follow up, 17% experienced subsequent breast events, with approximately half of the events occurring within the first 5 years following the initial atypia diagnosis. Clinical features were not associated with the trajectory to subsequent events, supporting that atypia signals both local and overall malignancy risk.

Utility of Axillary Staging in Older Patients with HER2-Positive Breast Cancer.

BACKGROUND: The utility of sentinel lymph node biopsy (SLNB) in older patients remains controversial. Advancements in human epidermal growth factor receptor 2 (HER2)-directed therapy have revolutionized disease response rates and prognosis, supporting efforts to re-evaluate the utility of SLNB. We aimed to assess the differences in treatment and overall survival (OS) in older patients with HER2-positive breast cancer based on SLNB. METHODS: Using the National Cancer Database (2010-2020), patients ≥ 70 years of age diagnosed with cT1-2/cN0/M0, HER2-positive breast cancer were identified. Logistic regression assessed associations with SLNB, systemic therapy, and radiation. Cox proportional hazard models were used to identify factors associated with OS. Analyses were stratified by treatment sequence, i.e. upfront surgery or neoadjuvant therapy (NAT) followed by surgery. RESULTS: Of the 17,609 patients included, 94% underwent upfront surgery (n = 16,492) and the remaining underwent NAT (n = 1117). Those who underwent SLNB were more likely to receive adjuvant therapy, irrespective of nodal status {upfront surgery/systemic therapy (odds ratio [OR] 2.82, 95% confidence interval [CI] 2.17-3.67); upfront surgery/radiation (OR 3.97, 95% CI 3.03-5.21); NAT/radiation (OR 5.69, 95% CI 1.83-17.69)}. The breast pathologic complete response (pCR) rate was highest among the hormone receptor (HR)-negative/HER2-positive subtype (50.0%), of which none were found to be ypN+. Comorbidity burden was associated with significantly lower rates of adjuvant systemic therapy and worse OS. CONCLUSIONS: Patients who underwent SLNB, regardless of pN status, were more likely to receive adjuvant therapy. Nodal positivity is exceedingly rare for patients with a breast pCR following NAT, especially among the HR-negative/HER2-positive subtype. It is reasonable to consider omission of SLNB in select subgroups of older patients with HER2-positive breast cancer.

Clinical efficacy of CDK4/6 inhibitor plus endocrine therapy in HR-positive/HER2-0 and HER2-low-positive metastatic breast cancer: a secondary analysis of PALOMA-2 and PALOMA-3 trials.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC. METHODS: This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan-Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135. FINDINGS: Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48-1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41-0.66, p < 0.0001). The PALOMA-3 study analysed 520 patients with MBC. Within the 153 HER2-0 patients, the palbociclib-fulvestrant group showed a significantly longer PFS than the placebo-fulvestrant group (hazard ratio = 0.54, 95% CI 0.30-0.95, p = 0.034). Among the 367 HER2-low-positive patients, palbociclib-fulvestrant improved PFS (hazard ratio = 0.39, 95% CI 0.28-0.54, p < 0.0001). INTERPRETATION: The combination of a CDK4/6 inhibitor with ET significantly improved PFS in HER2-low-positive patients, while for HER2-0 patients, benefits were primarily observed in patients who had progressed on previous ET. Furthermore, HER2-0 patients may derive limited benefits from first-line CDK4/6 inhibitor treatment. Further work is needed to validate these findings and to delineate patient subsets that are most likely to benefit from the combination of CDK4/6 inhibitors and ET as first-line treatments. FUNDING: None.

Cancer Surveillance in Solid Organ Transplant Recipients With a Pretransplant History of Malignancy: Multidisciplinary Collaborative Expert Opinion.

With improved medical treatments, the prognosis for many malignancies has improved, and more patients are presenting for transplant evaluation with a history of treated cancer. Solid organ transplant (SOT) recipients with a prior malignancy are at higher risk of posttransplant recurrence or de novo malignancy, and they may require a cancer surveillance program that is individualized to their specific needs. There is a dearth of literature on optimal surveillance strategies specific to SOT recipients. A working group of transplant physicians and cancer-specific specialists met to provide expert opinion recommendations on optimal cancer surveillance after transplantation for patients with a history of malignancy. Surveillance strategies provided are mainly based on general population recurrence risk data, immunosuppression effects, and limited transplant-specific data and should be considered expert opinion based on current knowledge. Prospective studies of cancer-specific surveillance models in SOT recipients should be supported to inform posttransplant management of this high-risk population.

Digital Health Platforms for Breast Cancer Care: A Scoping Review.

Breast cancer is a significant global health concern affecting millions of women each year. Digital health platforms are an easily accessible intervention that can improve patient care, though their efficacy in breast cancer care is unknown. This scoping review aims to provide an overview of existing research on the utilization of digital health platforms for breast cancer care and identify key trends and gaps in the literature. A comprehensive literature search was conducted across electronic databases, including Ovid MEDLINE, Elsevier EMBASE, and Elsevier Scopus databases. The search strategy incorporated keywords related to "digital health platforms", "breast cancer care", and associated terminologies. After screening for eligibility, a total of 25 articles were included in this scoping review. The identified studies comprised mobile applications and web-based interventions. These platforms demonstrated various functionalities, including patient education, symptom monitoring, treatment adherence, and psychosocial support. The findings indicate the potential of digital health platforms in improving breast cancer care and patients' overall experiences. The positive impact on patient outcomes, including improved quality of life and reduced psychological distress, underscores the importance of incorporating digital health solutions into breast cancer management. Additional research is necessary to validate the effectiveness of these platforms in diverse patient populations and assess their impact on healthcare-resource utilization.

Clinical genetics in breast cancer.

As genetic testing becomes increasingly more accessible and more applicable with a broader range of clinical implications, it may also become more challenging for breast cancer providers to remain up-to-date. This review outlines some of the current clinical guidelines and recent literature surrounding germline genetic testing, as well as genomic testing, in the screening, prevention, diagnosis, and treatment of breast cancer, while identifying potential areas of further research.

Survival among patients with untreated metastatic breast cancer: "What if I do nothing?"

PURPOSE: We sought to assess survival outcomes of patients with de novo metastatic breast cancer (dnMBC) who did not receive treatment irrespective of the reason. METHODS: Adults with dnMBC were selected from the NCDB (2010-2016) and stratified based on receipt of treatment (treated = received at least one treatment and untreated = received no treatments). Overall survival (OS) was estimated using the Kaplan-Meier method, and groups were compared. Cox proportional hazards models were used to identify factors associated with OS. RESULTS: Of the 53,240 patients with dnMBC, 92.1% received at least one treatment (treated), and 7.9% had no documented treatments, irrespective of the reason (untreated). Untreated patients were more likely to be older (median 68 y vs 61 y, p < 0.001), have higher comorbidity scores (p < 0.001), have triple-negative disease (17.8% vs 12.6%), and a higher disease burden (≥ 2 metastatic sites: 38.2% untreated vs 29.2% treated, p < 0.001). The median unadjusted OS in the untreated subgroup was 2.5 mo versus 36.4 mo in the treated subgroup (p < 0.001). After adjustment, variables associated with a worse OS in the untreated cohort included older age, higher comorbidity scores, higher tumor grade, and triple-negative (vs HR + /HER2-) subtype (all p < 0.05), while the number of metastatic sites was not associated with survival. CONCLUSIONS: Patients with dnMBC who do not receive treatment are more likely to be older, present with comorbid conditions, and have clinically aggressive disease. Similar to those who do receive treatment, survival in an untreated population is associated with select patient and disease characteristics. However, the prognosis for untreated dnMBC is dismal.

Anatomy Versus Biology: What Guides Chemotherapy Decisions in Older Patients With Breast Cancer?

INTRODUCTION: With the increasing utilization of genomic assays, such as the Oncotype DX recurrence score (RS), the relevance of anatomic staging has been questioned for select older patients with breast cancer. We sought to evaluate differences in chemotherapy receipt and/or survival among older patients based on RS and sentinel lymph node biopsy (SLNB) receipt/result. METHODS: Patients aged ≥ 65 diagnosed with pT1-2/cN0/M0 hormone-receptor-positive (HR+)/HER2-breast cancer (2010-2019) were selected from the National Cancer Database. Logistic regression was used to identify factors associated with chemotherapy receipt. Cox proportional hazards models were used to estimate the association of RS/SLNB group with overall survival. A cost-benefit study was also performed. RESULTS: Of the 75,428 patients included, the majority had an intermediate RS (58.2% versus 27.9% low, 13.8% high) and were SLNB- (85.1% versus 11.6% SLNB+, 3.3% none). Chemotherapy was recommended for 13,442 patients (17.8%). After adjustment, chemotherapy receipt was more likely with higher RS and SLNB+. After adjustment, SLNB receipt/result was only associated with overall survival among those with an intermediate RS. However, returning to the OR for SLNB is not cost-effective. CONCLUSIONS: SLNB receipt/result was associated with survival for those with an intermediate RS, but not a low or high RS, suggesting that an SLNB may indeed be unnecessary for select older patients with breast cancer.

Racial/Ethnic Disparities in Pathologic Complete Response and Overall Survival in Patients With Triple-Negative Breast Cancer Treated With Neoadjuvant Chemotherapy.

PURPOSE: Black women have higher rates of death from triple-negative breast cancer (TNBC) than White women. We hypothesized that pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and overall survival (OS) may vary by race/ethnicity in patients with TNBC. METHODS: We identified women 18 years and older with stage I-III TNBC who received NAC followed by surgery from the National Cancer Database (2010-2019). We excluded patients without race/ethnicity or pathology data. Primary outcomes were pCR rates and OS on the basis of race/ethnicity. RESULTS: Forty thousand eight hundred ninety women with TNBC met inclusion criteria (median age [IQR], 53 [44-61] years): 26,150 Non-Hispanic White (64%, NHW), 9,672 Non-Hispanic Black (23.7%, NHB), 3,267 Hispanic (8%), 1,368 Non-Hispanic Asian (3.3%, NHA), and 433 Non-Hispanic Other (1.1%, NHO) patients. Overall, 29.8% demonstrated pCR (NHW: 30.5%, NHB: 27%, Hispanic: 32.6%, NHA: 28.8%, NHO: 29.8%). Unadjusted OS was significantly higher for those with pCR compared with those with residual disease (5-year OS, 0.917 [95% CI, 0.911 to 0.923] v 0.667 [95% CI, 0.661 to 0.673], log-rank P < .001), and this association persisted after adjustment for demographic and tumor factors. The effect of achieving pCR on OS did not differ by race/ethnicity (interaction P = .10). However, NHB patients were less likely (odds ratio [OR], 0.89 [95% CI, 0.83 to 0.95], P = .001) and Hispanic patients were more likely (OR, 1.19 [95% CI, 1.08 to 1.31], P = .001) to achieve pCR than NHW patients. After adjustment for patient and disease factors, including achievement of pCR, Hispanic (hazard ratio [HR], 0.76 [95% CI, 0.69 to 0.85], P < .001) and NHA (HR, 0.64 [95% CI, 0.55 to 0.75], P < .001) race/ethnicity remained associated with OS. CONCLUSION: Odds of achieving pCR and OS in patients with TNBC appear to be associated with race/ethnicity. Additional research is necessary to understand how race/ethnicity is associated with rates of pCR and OS, whether related to socioeconomic factors or biologic variables, or both.

Axillary nodal disease burden is not associated with an elevated 21-gene recurrence score in post-menopausal women presenting with a clinically negative axilla.

BACKGROUND: The predictive and prognostic value of the recurrence score (RS) has emphasized the importance of tumor biology and has reduced the prognostic implications of limited nodal burden in post-menopausal women with HR+/HER2-invasive breast cancer (IBC). It is unclear whether routine axillary staging has a continued role in the management of small, clinically node negative (cN0) HR+/HER2- IBC. We sought to estimate the association of RS with pN stage. METHODS: Patients >50yo diagnosed with cN0, HR+/HER2- IBC (2015-2019) with an available RS were identified from the National Cancer Database. The clinicopathologic characteristics and rates of pN-stage (pN0, pN1, pN2/3) were compared for RS of ≤25 vs. >25. RESULTS: The median patient age was 64.1 (IQR 58-69) and the majority (75%) of tumors displayed ductal histology. Most (81.6%) were cT1 on presentation and pT1 (74.7%) on final pathology. There were 130,568 (86.2%) with a RS â€‹≤ â€‹25 and 20,879 (13.8%) with a RS â€‹> â€‹25. On final pathology, 128,995 (85.2%) were pN0 and 21,991 (14.5%) pN1. Of the pN1, 2699 (12.3%) yielded a RS â€‹> â€‹25. There were 461 (0.3%) patients with pN2-pN3 disease. Of those, 57 (12.4%) had RS â€‹> â€‹25. CONCLUSION: In our analysis, pN0 and pN1 tumors are biologically similar by gene expression assay in postmenopausal patients with similar proportions of high RS. These data support the notion that tumor biology examined via RS may have more prognostic and predictive value than metastatic dissemination to limited lymph nodes. These findings support the ongoing evaluation of routine axillary staging in postmenopausal patients with HR+/HER2- IBC.

Society of Surgical Oncology Breast Disease Site Working Group Statement on Contralateral Mastectomy: Indications, Outcomes, and Risks.

Rates of contralateral mastectomy (CM) among patients with unilateral breast cancer have been increasing in the United States. In this Society of Surgical Oncology position statement, we review the literature addressing the indications, risks, and benefits of CM since the society's 2017 statement. We held a virtual meeting to outline key topics and then conducted a literature search using PubMed to identify relevant articles. We reviewed the articles and made recommendations based on group consensus. Patients consider CM for many reasons, including concerns regarding the risk of contralateral breast cancer (CBC), desire for improved cosmesis and symmetry, and preferences to avoid ongoing screening, whereas surgeons primarily consider CBC risk when making a recommendation for CM. For patients with a high risk of CBC, CM reduces the risk of new breast cancer, however it is not known to convey an overall survival benefit. Studies evaluating patient satisfaction with CM and reconstruction have yielded mixed results. Imaging with mammography within 12 months before CM is recommended, but routine preoperative breast magnetic resonance imaging is not; there is also no evidence to support routine postmastectomy imaging surveillance. Because the likelihood of identifying an occult malignancy during CM is low, routine sentinel lymph node surgery is not recommended. Data on the rates of postoperative complications are conflicting, and such complications may not be directly related to CM. Adjuvant therapy delays due to complications have not been reported. Surgeons can reduce CM rates by encouraging shared decision making and informed discussions incorporating patient preferences.