Helping ourselves, helping others: the Young Women's Breast Cancer Study (YWS) - a multisite prospective cohort study to advance the understanding of breast cancer diagnosed in women aged 40 years and younger.

PURPOSE: Compared with older women diagnosed with breast cancer, younger women are more likely to die of breast cancer and more likely to suffer psychosocially in both the short-term and long term. The Young Women's Breast Cancer Study (YWS) is a multisite prospective cohort study established to address gaps in our knowledge about this vulnerable and understudied population. PARTICIPANTS: The YWS enrolled 1302 women newly diagnosed with stages 0-IV breast cancer at age 40 years or younger at 13 academic and community sites in North America between 2006 and 2016. Longitudinal patient-reported outcome data are complemented by clinical data abstraction and biospecimen collection at multiple timepoints. FINDINGS TO DATE: Key findings related to fertility include that nearly 40% of participants were interested in pregnancy following diagnosis; of those who reported interest, 10% pursued fertility preservation. Overall, approximately 10% of YWS participants became pregnant in the first 5 years after diagnosis; follow-up is ongoing for pregnancies after 5 years. Studies focused on psychosocial outcomes have characterised quality of life, post-traumatic stress and fear of recurrence, with findings detailing the factors associated with the substantial psychosocial burden many young women face during and following active treatment. Multiple studies have leveraged YWS biospecimens, including whole-exome sequencing of tumour analyses that revealed that select somatic alterations occur at different frequencies in young (age≤35) versus older women with luminal A breast cancer, and a study that explored clonal hematopoiesis of indeterminate potential found it to be rare in young survivors. FUTURE PLANS: With a median follow-up of approximately 10 years, the cohort is just maturing for many relevant long-term outcomes and provides outstanding opportunities to further study and build collaborations to address gaps in our knowledge, with the ultimate objective to improve care and outcomes for young women with breast cancer. TRIAL REGISTRATION NUMBER: NCT01468246.

Cancer and Fertility: Exploring Uncertainty Management Strategies of Young Adult Female Survivors.

This study describes young adult female (YA-F) cancer survivors' uncertainty management strategies related to fertility/family building. Cross-sectional data were analyzed (n = 98). Participants reported higher rates of seeking information to reduce fertility-related uncertainty (M = 5.48, ±1.03), than avoiding information (M = 4.77, ±1.29). Controlling for relevant covariates (i.e., reproductive distress, household income, and health literacy), greater avoidance was related to higher reproductive distress (ß = 0.293, p = 0.011) and lower household income (ß = -0.281, p = 0.047). Evidence suggests that some survivors may avoid fertility-related information to manage uncertainty and distress, which may impact family-building success. Fertility avoidance may be an important target of intervention.

Second primary non-breast cancers in young breast cancer survivors.

PURPOSE: We evaluated the incidence, timing, and risk factors for second primary non-breast cancers (SPNBC) among young breast cancer (BC) survivors. METHODS: This study included participants of the Young Women's BC Study (YWS) who were diagnosed with stage 0-III BC between 2006 and 2016 and age 40 or younger at diagnosis (N = 1,230). Patient characteristics, treatment information, and clinical events were collected via serial surveys. Tumor and treatment data were obtained from medical record review. Five- and 10-year risks of SPNBCs were estimated via the cumulative incidence function, considering death, metastasis, or second primary BC as competing events. Fine and Gray subdistribution hazard models estimated subdistribution hazard ratios (sHRs) and 95% confidence intervals (CI) for SPNBC risk based on risk factors including demographics, germline genetics, primary BC characteristics, and treatments. RESULTS: Among 1,230 women, over a median follow-up of 10.1 years, 47 patients (4%) developed an SPNBC. Types of malignancy included melanoma (n = 10), thyroid (n = 10), ovarian (n = 4), sarcoma (n = 4), uterine (n = 3), rectal (n = 3), bladder (n = 2), cervical (n = 2), head/neck (n = 2), lung (n = 2), lymphoma (n = 2), pancreatic (n = 2), and renal (n = 1). Five and 10-year cumulative incidence were 1.4% and 3.2%, respectively. Median time between primary BC and SPNBC was 7.3 years. No patient factors, primary tumor characteristics, or treatments were statistically significantly associated with SPNBC in univariable or multivariable models. CONCLUSION: In this population, five-year cumulative incidence was higher than that reported among healthy women under 50 years of age, highlighting the importance of long-term surveillance for new non-breast cancers in young adult BC survivors.

Second Primary Breast Cancer in Young Breast Cancer Survivors.

Importance: Among women diagnosed with primary breast cancer (BC) at or younger than age 40 years, prior data suggest that their risk of a second primary BC (SPBC) is higher than that of women who are older when they develop a first primary BC. Objective: To estimate cumulative incidence and characterize risk factors of SPBC among young patients with BC. Design, Setting, and Participants: Participants were enrolled in the Young Women's Breast Cancer Study, a prospective study of 1297 women aged 40 years or younger who were diagnosed with stage 0 to III BC from August 2006 to June 2015. Demographic, genetic testing, treatment, and outcome data were collected by patient surveys and medical record review. A time-to-event analysis was used to account for competing risks when determining cumulative incidence of SPBC, and Fine-Gray subdistribution hazard models were used to evaluate associations between clinical factors and SPBC risk. Data were analyzed from January to May 2023. Main Outcomes and Measures: The 5- and 10- year cumulative incidence of SPBC. Results: In all, 685 women with stage 0 to III BC (mean [SD] age at primary BC diagnosis, 36 [4] years) who underwent unilateral mastectomy or lumpectomy as the primary surgery for BC were included in the analysis. Over a median (IQR) follow-up of 10.0 (7.4-12.1) years, 17 patients (2.5%) developed an SPBC; 2 of these patients had cancer in the ipsilateral breast after lumpectomy. The median (IQR) time from primary BC diagnosis to SPBC was 4.2 (3.3-5.6) years. Among 577 women who underwent genetic testing, the 10-year risk of SPBC was 2.2% for women who did not carry a pathogenic variant (12 of 544) and 8.9% for carriers of a pathogenic variant (3 of 33). In multivariate analyses, the risk of SPBC was higher among PV carriers vs noncarriers (subdistribution hazard ratio [sHR], 5.27; 95% CI, 1.43-19.43) and women with primary in situ BC vs invasive BC (sHR, 5.61; 95% CI, 1.52-20.70). Conclusions: Findings of this cohort study suggest that young BC survivors without a germline pathogenic variant have a low risk of developing a SPBC in the first 10 years after diagnosis. Findings from germline genetic testing may inform treatment decision-making and follow-up care considerations in this population.

Preliminary testing of "roadmap to parenthood" decision aid and planning tool for family building after cancer: Results of a single-arm pilot study.

OBJECTIVE: Many young adult female cancer survivors need to use reproductive medicine, surrogacy, or adoption to have a child. This study pilot tested Roadmap to Parenthood, a web-based, self-guided decision aid and planning tool for family building after cancer (disease agnostic). METHODS: A single-arm pilot study tested feasibility, acceptability, and obtained effect size estimates of the Roadmap tool. Participants, recruited via hospital-based and social media strategies, completed a baseline survey (T1), accessed the Roadmap tool (website), then completed surveys at one- and 3-months (T2 and T3, respectively). Feasibility and acceptability were evaluated with rates of eligibility, enrollment, and survey completion, and feedback. Pairwise t-tests and repeated measures ANOVA evaluated usage effects. Effect size estimates were calculated. RESULTS: Participants (N = 98) averaged 31 years old (SD = 5.61); 71% were nulliparous. Enrollment rate was 73%, T1-T2 completion rate was 80%, and 93% accessed the website. From T1-T2, participants reported improvements in decisional conflict (p < 0.001; Cohen's d = 0.85), unmet information needs (p < 0.001; Cohen's d = 0.70), self-efficacy (p = 0.003; Cohen's d = 0.40), and self-efficacy for managing negative emotions (p = 0.03; Cohen's d = 0.29); effects were sustained at T3. There was no change in reproductive distress (p = 0.22). By T3, 94% reported increased consideration of preparatory actions and 20%-61% completed such actions. CONCLUSIONS: The Roadmap intervention was feasible to conduct, acceptable to users, and led to improvements in key psychosocial outcomes. Future directions will test intervention efficacy in a randomized controlled trial with a larger sample and over a longer period. A web-based tool may help women make decisions about family building after cancer and prepare for potential challenges.

"Like not having an arm": a qualitative study of the impact of visitor restrictions on cancer care during the COVID-19 pandemic.

PURPOSE: Visitor restriction policies to prevent the spread of COVID-19 among patients and clinicians were widespread during the pandemic, resulting in the exclusion of caregivers at key points of cancer care and treatment decision-making. The aim of this study was to explore how visitor restrictions impacted cancer treatment decision-making and care from patient and physician perspectives. METHODS: Sixty-seven interviews, including 48 cancer patients and 19 cancer and palliative care physicians from four academic cancer centers in the USA between August 2020 and July 2021. RESULTS: Visitor restrictions that prevented caregivers from participating in clinic appointments and perioperative hospital care created challenges in cancer care that spanned three domains: practical, social, and informational. We identified eight themes that characterized challenges within the three domains across all three groups, and that these challenges had negative emotional and psychological consequences for both groups. Physicians perceived that patients' negative experiences due to lack of support through the physical presence of caregivers may have worsened patient outcomes. CONCLUSIONS: Our data demonstrate the tripartite structure of the therapeutic relationship in cancer care with caregivers providing critical support in the decision-making and care process to both patients and physicians. Caregiver absences led to practical, psychosocial, and informational burdens on both groups, and likely increased the risk of burnout among physicians. Our findings suggest that the quality of cancer care can be enhanced by engaging caregivers and promoting their physical presence during clinical encounters.

Developing "The Health After Cancer Podcast" to amplify cancer survivors' voices through digital storytelling.

BACKGROUND: Cancer survivors experience complex medical and psychosocial challenges after a cancer diagnosis, leading to unmet informational and emotional needs. There is a paucity of cancer survivorship educational resources co-created by survivors and medical professionals. OBJECTIVE: Our aim was to create an educational resource for cancer survivors, caregivers, and medical professionals that would leverage digital storytelling to address survivorship topics. PATIENT INVOLVEMENT: Our content and production team included cancer survivors, clinicians, educators, and design experts. All content was co-created by cancer survivors and medical experts. METHODS: We conducted an environmental scan of existing cancer survivorship educational resources in academic and public domains. Applying human-centered design principles, we incorporated patient perspectives through advisory board meetings and focus groups and identified a podcast as the preferred medium. We selected content and speakers, produced the podcast, and developed a corresponding website. RESULTS: Based on patient recommendations, podcast episodes address mental health, fear of cancer recurrence, relationships, parenting, relating to a new body, care transitions for adult survivors of childhood cancer, disclosing health information, and financial burden of cancer. Podcast guests were invited based on lived or learned experience in these domains. Thirteen guests (survivors, experts) and four hosts (two cancer survivors, two oncologists) co-created 15 podcast episodes. Podcast guests found the storytelling experience to be powerful and therapeutic. DISCUSSION: Digital storytelling is a scalable and accessible educational tool for communicating complex survivorship concepts that can amplify survivors' voices and increase awareness among survivors and clinicians. Co-creation of educational resources for cancer survivorship by survivors and professionals is a feasible and innovative educational strategy. PRACTICAL VALUE: A podcast created by and for cancer survivors in partnership with medical experts highlights opportunities for peer-to-peer digital storytelling to foster community among survivors and caregivers. FUNDING: Podcast production was supported by the Stanford Comprehensive Cancer Center.

Cancer Survivorship at Stanford Cancer Institute.

The Stanford Cancer Survivorship Program is a key initiative of Stanford Cancer Institute. The program's mission is to improve the experience and outcomes of patients and family caregivers throughout all phases of the cancer trajectory by advancing survivorship research, clinical care, and education. The four pillars of the program include clinical care delivery with a focus on primary care-survivorship collaboration and expanding specialty services, education and training of healthcare professionals, transdisciplinary patient-oriented research, and community engagement. Cross-cutting areas of expertise include the following: (a) adolescents and young adults (AYAs), (b) mental health and patient self-management, (c) integration of primary care, and (d) postgraduate medical education. The clinical care model includes embedded survivorship clinics within disease groups in outpatient clinics, novel clinics designed to address unmet needs such as sexual health for women, and primary care-based faculty-led survivorship clinics for patients undergoing active cancer care requiring co-management, those who have completed active therapy and those at high risk for cancer due to genetic risk. Educational initiatives developed to date include an online course and medical textbook for primary care clinicians, a lecture series, monthly research team meetings, and rotations for medical trainees. Patient-facing activities include webinars and a podcast series designed to promote awareness, thus expanding the provision of expert-vetted information. Ongoing research focuses on oncofertility and family building after cancer, improving communication for AYAs, changing mindsets to improve quality of life through targeted digital interventions, increasing capacity to care for cancer survivors, and strengthening collaboration with community partners. IMPLICATIONS FOR CANCER SURVIVORS: Stanford's Cancer Survivorship Program includes a robust transdisciplinary and interdisciplinary research, training and clinical platform that is committed to advancing access and improving care for people living with and beyond cancer, through innovation in design and care delivery.

A qualitative study of childhood cancer families' post-treatment needs and the impact of a community-based organization in a rural, socioeconomically disadvantaged, majority Hispanic/Latino region.

BACKGROUND: Individual- and population-level socioeconomic disadvantages contribute to unequal outcomes among childhood cancer survivors. Reducing health disparities requires understanding experiences of survivors from historically marginalized communities, including those with non-English language preference. PROCEDURE: We partnered with a community-based organization (CBO) serving families of children with cancer in a rural region in California with low socioeconomic status and majority Hispanic/Latino (H/L) residents. We interviewed English- and Spanish-speaking adolescent/young adult (AYA) childhood cancer survivors (≥15 years old, ≥5 years from diagnosis), parents, and CBO staff to evaluate post-treatment needs and impact of CBO support. Data were analyzed qualitatively using applied thematic analysis. Themes were refined through team discussions with our community partners. RESULTS: Twelve AYAs (11 H/L, 11 bilingual), 11 parents (eight H/L, seven non-English preferred), and seven CBO staff (five H/L, five bilingual) participated. AYAs (five female, seven male) were of median (min-max) age 20 (16-32) and 9 (5-19) years post diagnosis; parents (nine female, two male) were age 48 (40-60) and 14 (6-23) years post child's diagnosis. Themes included challenges navigating healthcare, communication barriers among the parent-AYA-clinician triad, and lasting effects of childhood cancer on family dynamics and mental health. Subthemes illustrated that language and rurality may contribute to health disparities. CBO support impacted families by serving as a safety-net, fostering community, and facilitating H/L families' communication. CONCLUSIONS: Childhood cancer has long-lasting effects on families, and those with non-English language preference face additional burdens. Community-based support buffers some of the negative effects of childhood cancer and may reduce disparities.

Conception and pregnancy among women with a live birth after breast cancer treatment: A survey study of young breast cancer survivors.

BACKGROUND: Breast cancer (BC) is the most common malignancy in women of reproductive age. This study sought to explore the postcancer conception and pregnancy experience of young BC survivors to inform counseling. METHODS: In the Young Women's Breast Cancer Study (NCT01468246), a multicenter, prospective cohort, participants diagnosed at age ≤40 years with stage 0-III BC who reported ≥1 postdiagnosis live birth were sent an investigator-developed survey. RESULTS: Of 119 eligible women, 94 (79%) completed the survey. Median age at diagnosis was 32 years (range, 17-40) and at first postdiagnosis delivery was 38 years (range, 29-47). Most had stage I or II (77%) and HR+ (78%) BC; 51% were nulligravida at diagnosis. After BC treatment, most (62%) conceived naturally, though 38% used assisted reproductive technology, 74% of whom first attempted natural conception for a median of 9 months (range, 2-48). Among women with a known inherited pathogenic variant (n = 20), two underwent preimplantation genetic testing. Of 59 women on endocrine therapy before pregnancy, 26% did not resume treatment. Hypertensive disorders of pregnancy (20%) was the most common obstetrical condition. Nine percent of newborns required neonatal intensive care unit admission and 9% had low birth weight. CONCLUSION: Among women with live births after BC treatment, most conceived naturally and having a history of BC did not appear to negatively impact pregnancy complications, though the high rate of hypertensive disorders of pregnancy warrants further investigation. The prolonged period of attempting natural conception for some survivors suggests the potential need for improved understanding and counseling surrounding family planning goals after BC.

Cancer center-based follow-up among pediatric and adolescent/young adult cancer survivors: the role of a community-based organization and the social determinants of health.

PURPOSE: Adherence to survivorship care is suboptimal among pediatric and adolescent/young adult (AYA) cancer survivors. We evaluated predictors of cancer center-based follow-up among pediatric/AYA cancer survivors, with an emphasis on social determinants of health (SDOH). METHODS: This retrospective cohort study used electronic health record data at an academic medical center to identify patients aged 0-29 years at last cancer treatment who completed treatment 2010-2019. Cancer center-based follow-up was defined by oncology or survivorship clinic visits through 12/31/2022. Multivariate logistic regression models (overall, ages 0-19 [pediatric], 20-29 [YA]) evaluated the association of demographics, clinical/treatment characteristics, and SDOH (insurance type, distance to cancer center, area deprivation index) with clinic attendance. Further modeling accounted for the service area of a community-based organization (CBO) that supports families of children with cancer. RESULTS: A total of 2210 survivors were included (56% pediatric, 44% YA; 66% non-White). Cancer center-based follow-up decreased from 94% 1-year post-treatment to 35% at > 5-7 years. In adjusted analysis, AYAs had the lowest follow-up (5-7 years post-treatment: OR 0.25 [0.15-0.41] for age 25-29; OR 0.25 [0.16-0.41] for age 20-24; OR 0.32 [0.20-0.52] for age 15-19). Survivors residing within the CBO service area were twice as likely to follow-up (OR 2.10 [1.34-3.29]). CONCLUSIONS: Among a diverse population, AYA survivors were vulnerable to loss to follow-up. Other SDOH were not consistently associated with follow-up. Support from a CBO may partly explain these findings. IMPLICATIONS FOR CANCER SURVIVORS: CBOs may strengthen survivorship follow-up within medically underserved communities. More research is needed to understand community support in survivorship.

Greater fertility distress and avoidance relate to poorer decision making about family building after cancer among adolescent and young adult female survivors.

BACKGROUND: Many adolescent and young adult female (AYA-F) cancer survivors face decisions about family building using reproductive medicine or adoption to achieve parenthood. This study evaluated associations among reproductive distress, avoidance, and family-building decision making and identified sociodemographic and clinical characteristics related to high distress and avoidance. METHODS: A cross-sectional survey assessed AYA-F survivors' oncofertility experiences. Measures included an investigator-designed Unmet Information Needs scale, Reproductive Concerns After Cancer Scale, Impact of Events Scale-Avoidance subscale, Decision Self-Efficacy scale, and Decision Conflict Scale. Two linear regression models evaluated correlates of decision self-efficacy and decisional conflict about family building after cancer. Bivariate analyses evaluated correlates of avoidance using Pearson's correlation, t-test, and ANOVA. RESULTS: AYA-Fs (N = 111) averaged 31-years-old (SD = 5.49) and 3 years post-treatment (range: 1-23 years); 90% were nulliparous. Most common diagnoses were leukemia (24%) and breast cancer (22%). Average decisional conflict was 52.12 (SD = 23.87, range: 0-100); 74% of the sample reported DCS scores within the clinically significant range. Higher levels of reproductive distress (B = -0.23, p = 0.04) and avoidance (B = -0.24, p = 0.02) related to lower decision self-efficacy. Younger age (B = -0.18, p = 0.03), greater unmet information needs (B = 0.33, p < 0.001), and higher levels of reproductive distress (B = 0.34, p = 0.001) related to worse decisional conflict. Predictors of distress and avoidance were identified. CONCLUSIONS: After cancer treatment, high fertility distress and avoidant coping were associated with poorer quality decision making about family building after cancer. Fertility counseling post-treatment should support self-efficacy and constructive coping skills to counteract high distress, maladaptive coping, and facilitate values-based decision making.

Implementation of a Pilot Clinic for Pediatric to Adult Cancer Survivorship Transitions.

Childhood cancer survivors are recommended to have lifelong survivorship care, yet many become disengaged during pediatric to adult care transitions. We implemented a pilot clinic for adult survivors of pediatric or adolescent and young adult (AYA) leukemia transitioning to adult-focused survivorship care. The clinic featured AYA-specific care, bidirectional communication with primary care, and a quality improvement (QI) cycle. During the 1-year QI period, 27 patients were seen and 21 completed postvisit interviews. The clinic was positively received by patients and primary care providers, showed promise for improving self-management and care coordination, and highlighted the need for novel approaches to connect survivors with primary care.

Changing cancer mindsets: A randomized controlled feasibility and efficacy trial.

OBJECTIVE: A cancer diagnosis and subsequent treatment can disrupt the full spectrum of physical, social, emotional, and functional quality of life. But existing psychological treatments are focused primarily on specific psychological symptoms as opposed to improving the overall patient experience. We studied the feasibility and efficacy of a novel digital intervention targeting patient mindsets-core assumptions about the nature and meaning of illness-designed to improve overall health-related quality of life (HRQoL) in newly diagnosed cancer patients undergoing treatment with curative intent. METHODS: Recently diagnosed (≤150 days) adult patients with non-metastatic cancers undergoing systemic treatment (N = 361) were recruited from across the United States to participate in this decentralized clinical trial. Patients were randomized 1:1 to receive the Cancer Mindset Intervention (CMI) or Treatment as Usual (TAU). Participants in the CMI group completed seven online modules over 10 weeks (2.5 h total) targeting mindsets about cancer and the body. The primary outcome was overall HRQoL, and secondary outcomes were coping behaviors and symptom distress. RESULTS: Patients in the CMI group reported significant (p < 0.001) improvements in adaptive mindsets about cancer and the body over time. Compared with the TAU condition, the CMI group reported significant improvements in overall HRQoL (B = 0.60; 95% CI 0.34-0.85; p < 0.001), increased engagement in adaptive coping behaviors (B = 0.03; 95% CI 0.02-0.04; p < 0.001), and reduced distress from physical symptoms (B = -0.29; 95% CI -0.44 to -0.14; p < 0.01). Effect sizes of these changes ranged from d = 0.42-d = 0.54. CONCLUSION: A brief mindset-focused digital intervention was effective at improving physical, social, emotional, and functional HRQoL, increasing adaptive coping behaviors, and reducing physical symptom distress in newly diagnosed cancer patients.

NCCN Guidelines® Insights: Survivorship, Version 1.2023.

The NCCN Guidelines for Survivorship are intended to help healthcare professionals address the complex and varied needs of cancer survivors. The NCCN Guidelines provide screening, evaluation, and treatment recommendations for psychosocial and physical problems resulting from adult-onset cancer and its treatment; recommendations to help promote healthy behaviors and immunizations in survivors; and a framework for care coordination. These NCCN Guidelines Insights summarize recent guideline updates and panel discussions pertaining to sleep disorders, fatigue, and cognitive function in cancer survivors.

Genomics of ERBB2-Positive Breast Cancer in Young Women Before and After Exposure to Chemotherapy Plus Trastuzumab.

PURPOSE: Erb-B2 receptor tyrosine kinase 2 (ERBB2)-positive breast cancer (BC) is particularly common in young women. Genomic features of ERBB2-positive tumors before and after chemotherapy and trastuzumab (chemo + H) have not been described in young women and are important for guiding study of therapeutic resistance in this population. METHODS: From a large prospective cohort of women age 40 years or younger with BC, we identified patients with ERBB2-positive BC and tumor tissue available before and after chemo + H. Whole-exome sequencing (WES) was performed on each tumor and on germline DNA from blood. Tumor-normal pairs were analyzed for mutations and copy number (CN) changes. RESULTS: Twenty-two women had successful WES on samples from at least one time point; 12 of these had paired sequencing results from before and after chemo + H and 10 had successful sequencing from either time point. TP53 was the only significantly recurrently mutated gene in both pre- and post-treatment samples. MYC gene amplification was observed in four post-treatment tumors. Seven of 12 patients with paired samples showed acquired and/or clonally enriched alterations in cancer-related genes. One patient had an increased clonality putative activating mutation in ERBB2. Another patient acquired a clonal hotspot mutation in TP53. Other genomic changes acquired in post-treatment specimens included alterations in NOTCH2, STIL, PIK3CA, and GATA3. There was no significant change in median ERBB2 CN (20.3 v 22.6; Wilcoxon P = .79) between paired samples. CONCLUSION: ERBB2-positive BCs in young women displayed substantial genomic evolution after treatment with chemo + H. Approximately half of patients with paired samples demonstrated acquired and/or clonally enriched genomic changes in cancer genes. ERBB2 CN changes were uncommon. We identified several genes warranting exploration as potential mechanisms of resistance to therapy in this population.