The effect of the COVID-19 pandemic on the mental health of obstetrics and gynaecology trainees: a world-wide literature review.

BACKGROUND: Coronavirus (COVID-19) pandemic has affected the training and wellbeing of obstetrics and gynaecology (O&G) trainees. The aim of this review is to offer a worldwide overview on its' impact on the mental health of O&G trainees, so that measures can be put into place to better support trainees during the transition back to the 'new normal'. METHODS: Key search terms used on PubMed and Google Scholar databases include: mental health, COVID-19, O&G, trainees, residents. RESULTS: Fifteen articles (cumulative number of respondents = 3230) were identified, of which eight employed validated questionnaires (n = 1807 respondents), while non-validated questionnaires were used in seven (n = 1423 respondents). Studies showed that COVID-19 appeared to exert more of a negative impact on females and on senior trainees' mental health, while protective factors included marriage/partner and having had children. Validated and non-validated questionnaires suggested that trainees were exposed to high levels of anxiety and depression. Their mental health was also affected by insomnia, stress, burnout and fear of passing on the virus. DISCUSSION: This review analyses the global impact of COVID-19 on O&G trainees' mental health, showing a pervasive negative effect linked to fear of the virus. Limited psychological support has led to prolonged issues, hindering patient safety and increasing sick leave. The study underscores the urgency of comprehensive support, particularly in female-dominated fields. Addressing these challenges is crucial for future pandemics, highlighting the need to learn from past mistakes and prioritise mental health resources for trainee well-being during and beyond pandemics.

This review provides a worldwide overview of the impact Coronavirus (COVID-19) pandemic on the mental health of obstetrics and gynaecology (O&G) trainees. Fifteen articles were identified, of which eight employed validated questionnaires (n = 1807 respondents), while non-validated questionnaires were used in seven (n = 1423 respondents). The pandemic appeared to exert more of a negative impact on females and on senior trainees' mental health, while protective factors included marriage/partner and having had children. Studies suggested that trainees were exposed to high levels of anxiety and depression. Their mental health was also affected by insomnia, stress, burnout and fear of passing on the virus.Limited psychological support has led to prolonged recovery issues and increasing sick leave. The study underscores the urgency of comprehensive support, particularly in female-dominated fields. Addressing these challenges is crucial for future pandemics, highlighting the need to learn from past mistakes and prioritise mental health resources for trainee well-being.

Low language capacity in childhood: A systematic review of prevalence estimates.

BACKGROUND AND AIMS: Epidemiological studies have provided invaluable insight into the origin and impact of low language skills in childhood and adolescence. However, changing terminology and diagnostic guidelines have contributed to variable estimations of the prevalence of developmental language difficulties. The aim of this review was to profile the extent and variability of low language prevalence estimates through a systematic review of epidemiological literature. METHODS: A systematic review of the empirical research (August 2022) was undertaken to identify studies that aimed to estimate the prevalence of low language skills in children (<18 years). A total of 19 studies published between 1980-2022 met inclusion criteria for review. RESULTS: Studies reported prevalence estimates of low language skills in children between 1 and 16 years. Estimated rates varied from 0.4% to 25.2%. More stable estimations were observed in studies of children aged 5 years and older and those that applied updated diagnostic criteria to performance on standardised assessments of receptive and expressive language. CONCLUSIONS AND IMPLICATIONS: The estimated prevalence of low language skills in childhood varies considerably in the literature. Application of updated diagnostic criteria, including the assessment of functional impact, is critical to inform advocacy efforts and govern social, health and educational policies. WHAT THIS PAPER ADDS: What is already known on the subject Epidemiological research has informed our understanding of the origin and impact of low language capacity in childhood. Childhood language disorder is met with a rich history of evolving terminology and diagnostic guidelines to identify children with low language skills. Inconsistent definitions of and methods to identify low language in children have resulted in variable prevalence estimates in population-based studies. Variability in prevalence estimates impacts advocacy efforts to inform social, health and educational policy for child language disorder. What this study adds A total of 19 studies published at the time of this review aimed to provide estimates of the proportion of children who experience low language skills. Prevalence estimates varied between 0.4% and 25.2%, with more stable estimates reported in studies of older school-age children and those which utilised standardised assessments of both expressive and receptive language. Few studies utilised assessments of functional impact of language difficulties, which is misaligned with updated diagnostic criteria for child language disorder. What are the clinical implications of this work? This review reports substantial variability in estimates of the proportion of children and adolescents who live with low language skills. This variability underscores the importance of applying updated diagnostic criteria to identify the prevalence low language in childhood. Efforts to estimate the prevalence of low language must include measures of functional impact of low language skills. This aligns with clinical recommendations, which call for routine assessment of functional outcomes. To this end, we require a unified understanding of the term 'functional impact' in the context of low language, including the development and evaluation of measures that assess impact across emotional, social and academic domains.

Common origin of sterol biosynthesis points to a feeding strategy shift in Neoproterozoic animals.

Steranes preserved in sedimentary rocks serve as molecular fossils, which are thought to record the expansion of eukaryote life through the Neoproterozoic Era ( ~ 1000-541 Ma). Scientists hypothesize that ancient C27 steranes originated from cholesterol, the major sterol produced by living red algae and animals. Similarly, C28 and C29 steranes are thought to be derived from the sterols of prehistoric fungi, green algae, and other microbial eukaryotes. However, recent work on annelid worms-an advanced group of eumetazoan animals-shows that they are also capable of producing C28 and C29 sterols. In this paper, we explore the evolutionary history of the 24-C sterol methyltransferase (smt) gene in animals, which is required to make C28+ sterols. We find evidence that the smt gene was vertically inherited through animals, suggesting early eumetazoans were capable of C28+ sterol synthesis. Our molecular clock of the animal smt gene demonstrates that its diversification coincides with the rise of C28 and C29 steranes in the Neoproterozoic. This study supports the hypothesis that early eumetazoans were capable of making C28+ sterols and that many animal lineages independently abandoned its biosynthesis around the end-Neoproterozoic, coinciding with the rise of abundant eukaryotic prey.

Comparative assessment of radiation therapy-induced vasculitis using [18F]FDG-PET/CT in patients with non-small cell lung cancer treated with proton versus photon radiotherapy.

PURPOSE: To assess radiation therapy (RT)-induced vasculitis in patients with non-small cell lung cancer (NSCLC) by examining changes in the uptake of 18F-fluoro-D-deoxyglucose ([18F]FDG) by positron emission tomography/computed tomography (PET/CT) images of the ascending aorta (AA), descending aorta (DA), and aortic arch (AoA) before and after proton and photon RT. METHOD: Thirty-five consecutive locally advanced NSCLC patients were definitively treated with proton (n = 27) or photon (n = 8) RT and concurrent chemotherapy. The patients were prospectively enrolled to undergo [18F]FDG-PET/CT imaging before and 3 months after RT. An adaptive contrast-oriented thresholding algorithm was applied to generate mean standardized uptake values (SUVmean) for regions of interest (ROIs) 3 mm outside and 3 mm inside the outer perimeter of the AA, DA, and AoA. These ROIs were employed to exclusively select the aortic wall and remove the influence of blood pool activity. SUVmeans before and after RT were compared using two-tailed paired t-tests. RESULTS: RT treatments were associated with increased SUVmeans in the AA, DA, and AoA-1.9%, 0.3%, and 1.3% for proton and 15.8%, 9.5%, and 15.5% for photon, respectively. There was a statistically significant difference in the ∆SUVmean (post-RT SUVmean - pre-RT SUVmean) in patients treated with photon RT when compared to ∆SUVmean in patients treated with proton RT in the AA (p = 0.043) and AoA (p = 0.015). There was an average increase in SUVmean that was related to dose for photon patients (across structures), but that was not seen for proton patients, although the increase was not statistically significant. CONCLUSION: Our results suggest that patients treated with photon RT for NSCLC may exhibit significantly more RT-induced inflammation (measured as ∆SUVmean) in the AA and AoA when compared to patients who received proton RT. Knowledge gained from further analyses in larger cohorts could aid in treatment planning and help prevent the significant morbidity and mortality associated with RT-induced vascular complications. TRIAL REGISTRATION: NCT02135679.

Carboplatin dosage: prospective evaluation of a simple formula based on renal function.

A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the dosage formula dose (mg) = target area under the free carboplatin plasma concentration versus time curve (AUC) x (1.2 x GFR + 20). In a prospective clinical and pharmacokinetic study the formula was used to determine the dose required to treat 31 patients (GFR range, 33 to 135 mL/min) with 40 courses of carboplatin. The target AUC was escalated from 3 to 8 mg carboplatin/mL/min. Over this AUC range the formula accurately predicted the observed AUC (observed/predicted ratio 1.24 +/- 0.11, r = 0.886) and using these additional data, the formula was refined. Dose (mg) = target AUC x (GFR + 25) is now the recommended formula. AUC values of 4 to 6 and 6 to 8 mg/mL. min gave rise to manageable hematological toxicity in previously treated and untreated patients, respectively, and hence target AUC values of 5 and 7 mg/mL min are recommended for single-agent carboplatin in these patient groups. Pharmacokinetic modeling demonstrated that the formula was reasonably accurate regardless of whether a one- or two-compartment model most accurately described carboplatin pharmacokinetics, assuming that body size did not influence nonrenal clearance. The validity of this assumption was demonstrated in 13 patients where no correlation between surface area and nonrenal clearance was found (r = .31, P = .30). Therefore, the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.

Machine-guided design of synthetic cell type-specific cis-regulatory elements.

Cis-regulatory elements (CREs) control gene expression, orchestrating tissue identity, developmental timing, and stimulus responses, which collectively define the thousands of unique cell types in the body. While there is great potential for strategically incorporating CREs in therapeutic or biotechnology applications that require tissue specificity, there is no guarantee that an optimal CRE for an intended purpose has arisen naturally through evolution. Here, we present a platform to engineer and validate synthetic CREs capable of driving gene expression with programmed cell type specificity. We leverage innovations in deep neural network modeling of CRE activity across three cell types, efficient in silico optimization, and massively parallel reporter assays (MPRAs) to design and empirically test thousands of CREs. Through in vitro and in vivo validation, we show that synthetic sequences outperform natural sequences from the human genome in driving cell type-specific expression. Synthetic sequences leverage unique sequence syntax to promote activity in the on-target cell type and simultaneously reduce activity in off-target cells. Together, we provide a generalizable framework to prospectively engineer CREs and demonstrate the required literacy to write regulatory code that is fit-for-purpose in vivo across vertebrates.

Challenging gestational trophoblastic disease cases and mimics: An exemplar for the management of rare tumours.

OBJECTIVE: Rare tumour management is challenging for clinicians as evidence bases are limited and clinical trials are difficult to conduct. It is even more difficult for patients where self-reliance alone is insufficient to overcome the challenges of navigating care which is often poorly evidence based. In Ireland, a national Gestational Trophoblastic Disease (GTD) service was established as one of 3 initiatives for rare tumours by the National Cancer Control Programme. The service has a national clinical lead, a dedicated supportive nursing service and a clinical biochemistry liaison team. This study sought to assess the impact of a GTD centre using national clinical guidelines and integrating and networking with European and International GTD groups on the clinical management of challenging GTD cases and to consider the application of this model of care to other rare tumour management. STUDY DESIGN: In this article, we analyse the impact of a national GTD service on five challenging cases, and review how the service affects patient management in this rare tumour type. These cases were selected from a cohort of patients who were voluntarily registered in the service based on the diagnostic management dilemma they posed. RESULTS: Case management was impacted by the identification of GTD mimics, the provision of lifesaving treatment of metastatic choriocarcinoma with brain metastasis, networking with international colleagues, the identification of early relapse, the use of genetics to differentiate treatment pathways and prognosis, and supportive supervision of treatment courses of up to 2 years of therapy in a cohort of patients starting or completing families. CONCLUSION: The National GTD service could be an exemplar for the management of rare tumours (such as cholangiocarcinoma) in our jurisdiction which could benefit from a similar constellation of supports. Our study demonstrates the importance of a nominated national clinical lead, dedicated nurse navigator support, registration of cases and networking. The impact of our service would be greater if registration was mandatory rather than voluntary. Such a measure would also ensure equity of access for patients to the service, assist in quantifying the need for resourcing and facilitate research to improve outcomes.

Pulmonary fibrosis in COVID-19: mechanisms, consequences and targets.

Pulmonary fibrosis is characterized by extracellular deposition in the lung primarily collagen but also other ECM molecules. The primary cell type responsible for this is the myofibroblast, and this can be induced by various stressors and signals. Infections be they bacterial or viral can cause pulmonary fibrosis (PF). In 2019, severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2) originated in Wuhan, China, has led to a worldwide pandemic and can lead to acute respiratory distress and lung fibrosis. The virus itself can be cleared, but patients may develop long-term PF, which can be debilitating and life-limiting. There is a significantly perturbed immune response that shapes the fibrotic response leading to fibrosis. Given the importance of PF irrespective of cause, understanding the similarities and differences in pathogenesis caused by SARS-CoV-2-induced PF may yield new therapeutic targets. This review examines the pathology associated with the disease and discusses possible targets.

EPIC: an evaluation of the psychological impact of early-phase clinical trials in cancer patients.

BACKGROUND: Anxiety and depression in patients with cancer is associated with decreased quality of life and increased morbidity and mortality. However, these are often overlooked and untreated. Early-phase clinical trials (EPCTs) recruit patients with advanced cancers who frequently lack future treatment options, which may lead to increased anxiety and depression. Despite this, EPCTs do not routinely consider psychological screening for patients. PATIENTS AND METHODS: This prospective observational study explored levels of anxiety and depression alongside impact of trial participation in the context of EPCTs. The Hospital Anxiety and Depression Scale and the Brief Illness Perceptions Questionnaire were completed at the point of EPCT consent, the end of screening and at pre-specified time points thereafter. RESULTS: Sixty-four patients (median age 56 years; median Eastern Cooperative Oncology Group performance status 1) were recruited. At consent, 57 patients returned questionnaires; 39% reported clinically relevant levels of anxiety whilst 18% reported clinically relevant levels of depression. Sixty-three percent of patients experiencing psychological distress had never previously reported this. Males were more likely to be depressed (P = 0.037) and females were more likely to be anxious (P = 0.011). Changes in anxiety or depression were observed after trial enrolment on an individual level, but not significant on a population level. CONCLUSIONS: Patients on EPCTs are at an increased risk of anxiety and depression but may not seek relevant support. Sites offering EPCTs should consider including psychological screening to encourage a more holistic approach to cancer care and consider the sex of individuals when tailoring psychological support to meet specific needs.

Management of newly diagnosed glioblastoma multiforme: current state of the art and emerging therapeutic approaches.

Glioblastoma multiforme represent > 50% of primary gliomas and have five year survival rates of ~ 5%. Maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide remains the standard treatment since published by Stupp et al. (in N Engl J Med 352:987-996, 2005), with additional benefit for patients with MGMT-methylated tumors. We review the current treatment landscape and ongoing efforts to improve these outcomes. An extensive literature search of Pubmed and Google Scholar involving the search terms "glioblastoma," "glioblastoma multiforme," or "GBM" for papers published to July 2021 was conducted and papers evaluated for relevance. As well as current data that informs clinical practice, we review ongoing clinical research in both newly diagnosed and recurrent settings that provides hope for a breakthrough. The Stupp protocol remains standard of care in 2021. Addition of tumor treating fields improved mOS modestly, with benefit seen in MGMT-methylated and unmethylated cohorts and also improved time to cognitive decline but has not been widely adopted. The addition of lomustine to temozolomide, in MGMT-methylated patients, also showed a mOS benefit but further investigation is required. Other promising therapeutic strategies including anti-angiogenic therapy, targeted therapy, and immunotherapy have yet to show a survival advantage. Improvements in the multidisciplinary management, surgical techniques and equipment, early palliative care, carrier support, and psychological support may be responsible for improving survival over time. Despite promising preclinical rationale, immunotherapy and targeted therapy are struggling to impact survival. A number of ongoing clinical trials provide hope for a breakthrough.

Secondary Risk Reduction Strategies in Breast Cancer Care.

Over the past three decades breast cancer survival rates have increased in Ireland. This is due to advances in cancer diagnostics and therapeutics. Cure is now anticipated for most newly diagnosed patients. Cancer survivorship however is associated with an increased risk of additional cancers and the development of other non-communicable diseases such as cardiovascular disease. At present, secondary risk reduction strategies are an integral part of cardiovascular disease management. Given the improvements in breast cancer survival, similar strategies should be implemented as part of routine early-stage breast cancer care treatment plan. Herein, we present compelling evidence to support the integration of secondary risk reduction strategies for patients as a standard of care.

Heat Therapy Can Improve Hepatic Mitochondrial Function and Glucose Control.

This review proposes the novel hypothesis that heat can be used as an alternative therapy to exercise to improve hepatic mitochondrial function and glucose regulation in patients with nonalcoholic fatty liver disease. Although exercise has proven benefits in treating nonalcoholic fatty liver disease, barriers to exercise in the majority of patients necessitate an alternative method of treatment.

Immune Checkpoint Inhibitors and Palliative Care at the End of Life: An Irish Multicentre Retrospective Study.

Background and Objectives: Immune checkpoint inhibitors (ICIs) have less toxicity than standard chemotherapy and are now standard of care for many patients with advanced cancer. A manageable side effect profile and potential for durable responses may lead to aggressive care of the palliative patient. We sought to evaluate palliative care input and ICI use at the end of life at two Irish cancer centres. Methods: We identified deceased patients who received at least one dose of an ICI between first of January 2013 to 31st of December 2018. A retrospective electronic chart review was performed. Results: The electronic records of 102 patients were analysed. Fifty eight percent were male and the median age of diagnosis of advanced disease was 60 years (range 17-78). Median time from last dose of ICI to death was 57 days (range 8-574) and 20% of patients died within 30 days of last dose of ICI. Most patients, 92%, were referred to palliative care. The median time from palliative care referral to death was 64 days (range 1- 1010). In the last 30 days of life, 39% of patients attended the emergency department (ED) and 46% had at least one hospital admission. Late palliative care referrals, ≤3 months before death, were associated with hospitalisations in the last month of life (64% vs. 36%, P = .02). Timing of palliative care referral did not affect ICI prescribing at the end of life (P = 0.38). ICI use in the last 30 days of life was not associated with increased ED presentations or hospitalisations at the end of life. Patients who received ICI in the last month had a higher likelihood of in-hospital death (43% vs. 16%, P = 0.02). Conclusions: ICI within 30 days of death was associated with dying in hospital but did not lead to more hospitalisations and emergency department presentations. Early palliative care did not affect ICI use but reduced hospitalisations at the end of life.

Are we meeting the needs of vulnerable children? Distribution of speech-language pathology services on the Gold Coast, Australia.

BACKGROUND: Compared to national averages, the Gold Coast, Australia, has a proportionately higher number of children entering their first year of primary school with 'at risk' or 'vulnerable' language skills. This paper investigates the distribution of paediatric speech-language pathology (SLP) services on the Gold Coast, relative to children's language and cognitive skills, and socioeconomic status (SES). METHODS: SLP service locations were identified through national association data and a manual search and mapped against SES and Australian Early Development Census data, for language and cognitive skills. RESULTS: Data for 7595 children was included, with 943 (12.4%) at risk and 780 (12.6%) vulnerable for language and cognitive skills. A total of 75 SLPs were identified (85.3% private, 14.6% public), which is 1 SLP to every 23 children who might have current or impending speech, language and communication needs. Fewer services were available in areas where vulnerable children were located and most were private providers, leading to further potential barriers to service access. CONCLUSIONS: The number of SLP services located on the Gold Coast is inadequate to meet the needs of children with language and cognitive skill vulnerabilities. Consideration of how services might be distributed is explored and warrants further consideration.

The Silk Vista Baby - The UK experience.

BACKGROUND: The Silk Vista Baby (SVB) flow diverter (FDS) is the only FDS deliverable via a 0.017 inch microcatheter and is specifically designed for the distal vasculature. We sought to evaluate the safety and efficacy of the SVB. MATERIALS AND METHODS: We performed a retrospective review to identify SVB cases at 4 tertiary neurosurgical centres within the U.K. Clinical, procedural, angiographic and follow-up data were collected. RESULTS: We identified 60 patients (35 female, 58%) of average age 54 ± 10.5 (range 30-72) with 61 aneurysms, 50 (81.9%) located in the anterior circulation. The majority of the aneurysms treated were unruptured (46, 75.4%) and saccular (46, 75.4%). Dome size was 6.2 ± 6.2 mm (range 1-36mm) and parent vessel diameter was 2.3 ± 0.4 mm (range 1.2-3.3 mm).An average number of 1.07 devices were implanted. Coils or other devices were implanted in 14 aneurysms (23.3%). At last angiographic follow-up (n = 55), 7.5 ± 4.2 months post-procedure, 32 aneurysms (57.1%) were graded as RRC I, 7 (12.5%) RRC II, and 17 RRC III (30.4%).Clinical complications, excluding death, were seen in 4 patients (6.8%) including 1 delayed aneurysm rupture and 3 symptomatic ischaemic events. Only one patient had permanent morbidity (mRS 1). 3 patients died during follow-up (5.1%); 2 deaths were related to the aneurysms (3.4%) - one ruptured dissecting MCA aneurysm, and one giant partially thrombosed posterior circulation aneurysm. 93% of patients were mRS ≤ 2 at last follow-up. CONCLUSION: The SVB has high rates of technical success and an acceptable safety profile. Distal aneurysms may occlude slower due to relative oversizing of the devices.

Treatment of acute aneurysmal subarachnoid haemorrhage with primary flow diversion: 5-year single-centre experience.

AIM: To evaluate the safety and efficacy of treatment of patients presenting with acute aneurysmal subarachnoid haemorrhage (SAH) with primary flow-diverting stents (FDS; with or without adjuncts), with comparison to the published literature. MATERIALS AND METHODS: A retrospective single-centre review was undertaken of prospectively obtained data on patients treated for SAH over a 60-month period. Of 354 patients treated for SAH during that time period, 24 patients with a total of 25 aneurysms were identified. Baseline patient demographics were recorded and clinical and imaging outcomes assessed. RESULTS: Eighty-eight per cent (22/25) of the aneurysms were completely occluded (Raymond-Roy 1) at mean 12-month follow-up. The minor complication rate was 12.5% (3/24) without permanent morbidity. Mortality rate was 4% (1/25) after one patient died following aneurysmal rebleed on day 7 post-procedure. Forty-two per cent (10/24) of patients had a high-pressure shunt placed prior to endovascular treatment, no haemorrhagic complications of neurosurgical intervention were observed. CONCLUSION: The necessity of dual antiplatelet therapy (DAPT) therapy when deploying FDS will rightly continue to limit their use in the acutely ruptured setting to a case-by-case basis whereby other treatment options are deemed unsafe. Methods employed to minimise subsequent haemorrhagic risks from DAPT in these patients may be worthy of further investigation.

Continuous versus intermittent extended adjuvant letrozole for breast cancer: final results of randomized phase III SOLE (Study of Letrozole Extension) and SOLE Estrogen Substudy.

BACKGROUND: Late recurrences in postmenopausal women with hormone receptor-positive breast cancers remain an important challenge. Avoidance or delayed development of resistance represents the main objective in extended endocrine therapy (ET). In animal models, resistance was reversed with restoration of circulating estrogen levels during interruption of letrozole treatment. This phase III, randomized, open-label Study of Letrozole Extension (SOLE) studied the effect of extended intermittent letrozole treatment in comparison with continuous letrozole. In parallel, the SOLE estrogen substudy (SOLE-EST) analyzed the levels of estrogen during the interruption of treatment. PATIENTS AND METHODS: SOLE enrolled 4884 postmenopausal women with hormone receptor-positive, lymph node-positive, operable breast cancer between December 2007 and October 2012 and among them, 104 patients were enrolled in SOLE-EST. They must have undergone local treatment and have completed 4-6 years of adjuvant ET. Patients were randomized between continuous letrozole (2.5 mg/day orally for 5 years) and intermittent letrozole treatment (2.5 mg/day for 9 months followed by a 3-month interruption in years 1-4 and then 2.5 mg/day during all of year 5). RESULTS: Intention-to-treat population included 4851 women in SOLE (n = 2425 in the intermittent and n = 2426 in the continuous letrozole groups) and 103 women in SOLE-EST (n = 78 in the intermittent and n = 25 in the continuous letrozole groups). After a median follow-up of 84 months, 7-year disease-free survival (DFS) was 81.4% in the intermittent group and 81.5% in the continuous group (hazard ratio: 1.03, 95% confidence interval: 0.91-1.17). Reported adverse events were similar in both groups. Circulating estrogen recovery was demonstrated within 6 weeks after the stop of letrozole treatment. CONCLUSIONS: Extended adjuvant ET by intermittent administration of letrozole did not improve DFS compared with continuous use, despite the recovery of circulating estrogen levels. The similar DFS coupled with previously reported quality-of-life advantages suggest intermittent extended treatment is a valid option for patients who require or prefer a treatment interruption.