Highly efficient reprogrammable mouse lines with integrated reporters to track the route to pluripotency.

Revealing the molecular events associated with reprogramming different somatic cell types to pluripotency is critical for understanding the characteristics of induced pluripotent stem cell (iPSC) therapeutic derivatives. Inducible reprogramming factor transgenic cells or animals-designated as secondary (2°) reprogramming systems-not only provide excellent experimental tools for such studies but also offer a strategy to study the variances in cellular reprogramming outcomes due to different in vitro and in vivo environments. To make such studies less cumbersome, it is desirable to have a variety of efficient reprogrammable mouse systems to induce successful mass reprogramming in somatic cell types. Here, we report the development of two transgenic mouse lines from which 2° cells reprogram with unprecedented efficiency. These systems were derived by exposing primary reprogramming cells containing doxycycline-inducible Yamanaka factor expression to a transient interruption in transgene expression, resulting in selection for a subset of clones with robust transgene response. These systems also include reporter genes enabling easy readout of endogenous Oct4 activation (GFP), indicative of pluripotency, and reprogramming transgene expression (mCherry). Notably, somatic cells derived from various fetal and adult tissues from these 2° mouse lines gave rise to highly efficient and rapid reprogramming, with transgene-independent iPSC colonies emerging as early as 1 wk after induction. These mouse lines serve as a powerful tool to explore sources of variability in reprogramming and the mechanistic underpinnings of efficient reprogramming systems.

Effectiveness of mRNA COVID-19 Monovalent and Bivalent Vaccine Booster Doses Against Omicron Severe Outcomes Among Adults Aged ≥50 Years in Ontario, Canada: A Canadian Immunization Research Network Study.

We estimated the effectiveness of booster doses of monovalent and bivalent mRNA COVID-19 vaccines against Omicron-associated severe outcomes among adults aged ≥50 years in Ontario, Canada. Monovalent and bivalent mRNA COVID-19 booster doses provided similar strong initial protection against severe outcomes. Uncertainty remains around waning of protection from these vaccines.

Comparing Time to Diagnosis and Treatment Between Younger and Older Adults With Colorectal Cancer: A Population-Based Study.

BACKGROUND & AIMS: Younger adults (aged <50 years) with colorectal cancer (CRC) may have prolonged delays to diagnosis and treatment that are associated with adverse outcomes. We compared delay intervals by age for patients with CRC in a large population. METHODS: This was a population-based study of adults diagnosed with CRC in Ontario, Canada, from 2003 to 2018. We measured the time between presentation and diagnosis (diagnostic interval), diagnosis and treatment start (treatment interval), and the time from presentation to treatment (overall interval). We compared interval lengths between adults aged <50 years, 50 to 74 years, and 75 to 89 years using multivariable quantile regression. RESULTS: Included were 90,225 patients with CRC. Of these, 6853 patients (7.6%) were aged <50 years. Younger patients were more likely to be women, present emergently, have stage IV disease, and have rectal cancer compared with middle-aged patients. Factors associated with significantly longer overall intervals included female sex (8.7 days; 95% confidence interval [CI], 6.6-10.9 days) and rectal cancer compared with proximal colon cancer (9.8 days; 95% CI, 7.4-2.2 days). After adjustment, adults aged <50 years had significantly longer diagnostic intervals (4.3 days; 95% CI. 1.3-7.3 days) and significantly shorter treatment intervals (-4.5 days; 95% CI, -5.3 to -3.7 days) compared with middle-aged patients. However, there was no significant difference in the overall interval (-0.6 days; 95% CI, -4.3 to 3.2 days). In stratified models, younger adults with stage IV disease who presented emergently and patients aged >75 years had longer overall intervals. CONCLUSIONS: Younger adults present more often with stage IV CRC but have overall similar times from presentation to treatment as screening-eligible older adults.

Neoadjuvant chemotherapy for triple-negative and Her2 +ve breast cancer: striving for the standard of care.

PURPOSE: Neoadjuvant chemotherapy (NAC) for triple-negative (TN) and Her2-positive (HER2) breast cancers is supported by international guidelines as it can decrease extent of surgery, provide prognostic information, and allow response-driven adjuvant therapies. Our goal was to describe practice patterns for patients with TN and HER2-positive breast cancer and identify the factors associated with the receipt of NAC versus surgery as initial treatment. METHODS: A retrospective population-based cohort study of adult women diagnosed with stage I-III TN or HER2-positive breast cancer (2012-2020) in Ontario was completed using linked administrative datasets. The primary outcome was NAC as first treatment. The association between NAC and patient, tumor, and practice-related factors was examined using multivariable logistic regression models. RESULTS: Of 14,653 patients included, 23.9% (n = 3500) underwent NAC as first treatment. Patients who underwent NAC were more likely to be younger and have larger tumors, node-positive disease, and stage 3 disease. Of patients who underwent surgery first, 8.8% were seen by a medical oncologist prior to surgery. On multivariable analysis, increasing tumor size (T2 vs T1/T0: 2.75 (2.31-3.28)) and node-positive (N1 vs N0: OR 3.54 (2.92-4.30)) disease were both associated increased odds of receiving NAC. CONCLUSION: A considerable proportion of patients with TN and HER2-positive breast cancer do not receive NAC as first treatment. Of those, most were not assessed by both a surgeon and medical oncologist prior to initiating therapy. This points toward potential gaps in multidisciplinary assessment and disparities in receipt of guideline-concordant care.

Cost-effectiveness analysis of bevacizumab biosimilars versus originator bevacizumab for metastatic colorectal cancer: a comparative study using real-world data.

OBJECTIVE: MVASI (Amgen) and Zirabev (Pfizer) are two of the earliest bevacizumab biosimilars approved for the first-line treatment of metastatic colorectal cancer (mCRC). We aimed to confirm and quantify the real-world cost-savings and cost-effectiveness of MVASI and Zirabev relative to originator bevacizumab for patients with mCRC. METHODS: We conducted a population-based, retrospective cohort study in Ontario, Canada, where originator and biosimilar bevacizumab are universally publicly funded. All mCRC patients who received originator bevacizumab between January 2008 and August 2019 or biosimilar bevacizumab between August 2019 and March 2021 were propensity score-matched (1:4) to adjust for baseline differences. Total 1-year patient-level costs (CAD) and effects (life years (LY) and quality-adjusted life years (QALY)) were calculated from the public health payer's perspective. Primary outcomes included incremental net monetary benefit (INMB) and incremental net health benefit (INHB). Sensitivity analyses included a subgroup analysis by biosimilar type (MVASI/Zirabev) and a 2-year analysis. RESULTS: The matched cohort included 747 biosimilar cases and 2,945 comparators. Bevacizumab biosimilars were associated with an incremental cost of -$6,379 (95%CI: -9,417, -3,537) (i.e., cost-saving) and incremental effect of 0.0 (95% CI: -0.02, 0.02) LY and -0.01 (95%CI: -0.03, 0) QALY gained. INMB and INHB estimates were $6,331 (95% CI: 6,245, 6,417) and 0.127 LY (95% CI: 0.125, 0.128), respectively, at a willingness-to-pay threshold of $50,000/LYG, with all estimates indicating the cost-effectiveness of biosimilar bevacizumab. Cost-effectiveness remained consistent across biosimilar brand subgroups and 2-year sensitivity analyses. CONCLUSION: Bevacizumab biosimilars demonstrated real-world cost-savings while providing similar survival benefit as originator bevacizumab, confirming the initial expectations of their implementation and supporting health system sustainability.

Effectiveness and Duration of Protection of a Fourth Dose of Coronavirus Disease 2019 Messenger RNA Vaccine Among Long-term Care Residents in Ontario, Canada.

We estimated the effectiveness of a fourth dose of messenger RNA coronavirus disease 2019 vaccine against Omicron infections and severe outcomes over time among long-term care residents in Ontario, Canada. Fourth doses provide additional protection against Omicron-related outcomes, but the protection wanes over time, with more waning seen against infection than severe outcomes.

Protection conferred by COVID-19 vaccination, prior SARS-CoV-2 infection, or hybrid immunity against Omicron-associated severe outcomes among community-dwelling adults.

INTRODUCTION: We assessed protection from COVID-19 vaccines and/or prior SARS-CoV-2 infection against Omicron-associated severe outcomes during successive sublineage-predominant periods. METHODS: We used a test-negative design to estimate protection by vaccines and/or prior infection against hospitalization/death among community-dwelling, PCR-tested adults aged ≥50 years in Ontario, Canada between January 2, 2022 and June 30, 2023. Multivariable logistic regression was used to estimate the relative change in the odds of hospitalization/death with each vaccine dose (2-5) and/or prior PCR-confirmed SARS-CoV-2 infection (compared with unvaccinated, uninfected subjects) up to 15 months since the last vaccination or infection. RESULTS: We included 18,526 cases with Omicron-associated severe outcomes and 90,778 test-negative controls. Vaccine protection was high during BA.1/BA.2 predominance, but was generally <50% during periods of BA.4/BA.5 and BQ/XBB predominance without boosters. A third/fourth dose transiently increased protection during BA.4/BA.5 predominance (third-dose, 6-month: 68%, 95%CI 63%-72%; fourth-dose, 6-month: 80%, 95%CI 77%-83%), but was lower and waned quickly during BQ/XBB predominance (third-dose, 6-month: 59%, 95%CI 48%-67%; 12-month: 49%, 95%CI 41%-56%; fourth-dose, 6-month: 62%, 95%CI 56%-68%, 12-months: 51%, 95%CI 41%-56%). Hybrid immunity conferred nearly 90% protection throughout BA.1/BA.2 and BA.4/BA.5 predominance, but was reduced during BQ/XBB predominance (third-dose, 6-month: 60%, 95%CI 36%-75%; fourth-dose, 6-month: 63%, 95%CI 42%-76%). Protection was restored with a fifth dose (bivalent; 6-month: 91%, 95%CI 79%-96%). Prior infection alone did not confer lasting protection. CONCLUSION: Protection from COVID-19 vaccines and/or prior SARS-CoV-2 infections against severe outcomes is reduced when immune-evasive variants/subvariants emerge and may also wane over time. Our findings support a variant-adapted booster vaccination strategy with periodic review.

Impact of non-adherence to endocrine therapy on recurrence risk in older women with stage I breast cancer after breast-conserving surgery.

PURPOSE: We examined the impact of non-adherence to adjuvant endocrine therapy (ET) on the risk and site of recurrence among older women with early stage, hormone receptor positive (HR+) breast cancer (EBC). METHODS: A population-based cohort of women age ≥ 65 years with T1N0 HR + EBC who were diagnosed between 2010 and 2016 and treated with breast-conserving surgery (BCS) + ET was identified. Treatment and outcomes were ascertained through linkage with administrative databases. ET non-adherence was examined as a time-dependent covariate in multivariable cause-specific Cox regression models to evaluate its effect on the risks of ipsilateral local recurrence (LR), contralateral breast cancer, and distant metastases. RESULTS: The population cohort includes 2637 women; 73% (N = 1934) received radiation (RT) + ET and 27% (N = 703) received ET alone. At a median follow-up of 8.14 years, the first event was LR in 3.6% of women treated with ET alone and 1.4% for those treated with RT + ET (p < 0.001); the risk of distant metastases was < 1% in both groups. The proportion of time adherent to ET was 69.0% among those treated with RT + ET and 62.8% for those treated with ET alone. On multivariable analysis, increasing proportion of time non-adherent to ET was associated with increased risk of LR ((HR = 1.52 per 20% increase in time; 95%CI 1.25, 1.85; p < 0.001), contralateral BC (HR = 1.55; 95%CI 1.30, 1.84; p < 0.001), and distant metastases (HR = 1.44; 95%CI 1.08, 1.94; p = 0.01) but absolute risks were low. CONCLUSION: Non-adherence to adjuvant ET was associated with an increased risk of recurrence, but absolute recurrence rates were low.

The Association Between Surgical Axillary Staging, Adjuvant Treatment Use and Survival in Older Women with Early Stage Breast Cancer: A Population-Based Study.

BACKGROUND: Choosing Wisely guidelines recommend against surgical axillary staging (AS) in women ≥70 years with ER+/HER2- early stage breast cancer (BC). This study examined the impact of AS omission on survival in older patients with BC. METHODS: This was a population-based cohort study using health administrative data in Ontario, Canada. We identified women aged 65-95 years who underwent surgery for Stage I/II BC between 2010 and 2016. Patients were weighted by propensity scores for receipt of AS that included patient and disease characteristics using overlap weights. Association with overall survival (OS) was calculated using weighted Cox models, and breast cancer-specific survival (BCSS) was calculated using weighted Fine and Gray models, adjusting for biomarkers and adjuvant treatments. Adjuvant treatment receipt was modelled with weighted log-binomial models. RESULTS: Among 17,370 older women, the 1771 (10.2%) who did not undergo AS were older, more comorbid, and less likely to undergo mastectomy. Women who did not undergo AS were less likely to receive adjuvant chemotherapy (RR 0.68, 95% CI 0.57-0.82), endocrine therapy (RR 0.85, 95% CI 0.81-0.89) or radiotherapy (RR 0.69, 95% CI 0.65-0.74). After weighting and adjustment, there was no significant difference in BCSS (sdHR 0.98, 95% CI 0.77-1.25), but women who did not undergo AS had worse OS (HR 1.14, 95% CI 1.04-1.25). The results among 6215 ER+/HER2- women ≥70 years undergoing SLNB vs no AS were similar. CONCLUSIONS: The omission of AS in older women with early stage BC was not associated with adverse BCSS, although OS was worse.

Expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy.

Hyperactivation of the mTOR pathway during foetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR signalling in the formation of focal malformation of cortical development and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics because these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient focal malformation of cortical development tissue and in a mouse model of focal malformation of cortical development. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by focal malformation of cortical development in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern and aberrant expression of HCN4 ion channels. Further, 4E-BP1 expression in juvenile focal malformation of cortical development mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat focal malformation of cortical development-related epilepsy during childhood with potentially long-lasting effects in adults.

mTOR Hyperactivity Levels Influence the Severity of Epilepsy and Associated Neuropathology in an Experimental Model of Tuberous Sclerosis Complex and Focal Cortical Dysplasia.

Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) are focal malformations of cortical development (FMCDs) that are highly associated with intractable epilepsy. TSC and FCD are mTORopathies caused by a spectrum of pathogenic variants in the mechanistic target of rapamycin (mTOR) pathway genes leading to differential activation of mTOR signaling. However, whether the degree of mTOR hyperactivity influences disease severity remains unclear. Here, we examined the effects of differential mTOR hyperactivity levels on epilepsy and associated neuropathology in a mouse model of TSC and FCD. Constitutively active Rheb (RhebCA), the canonical activator of mTOR complex 1 (mTORC1), was expressed in mouse embryos of either sex via in utero electroporation at low, intermediate, and high concentrations to induce different mTORC1 activity levels in developing cortical neurons. We found that RhebCA expression induced mTORC1 hyperactivation and increased neuronal soma size and misplacement in a dose-dependent manner. No seizures were detected in the low RhebCA mice, whereas the intermediate and high RhebCA mice displayed spontaneous, recurrent seizures that significantly increased with higher RhebCA concentrations. Seizures were associated with a global increase in microglial activation that was notably higher in the regions containing RhebCA-expressing neurons. These data demonstrate that neuronal mTOR hyperactivity levels influence the severity of epilepsy and associated neuropathology in experimental TSC and FCD. Overall, these findings highlight the importance of evaluating the outcome of individual variants on mTOR activity levels and support personalized medicine strategies based on patient variants and mTOR activity level for TSC, FCD, and potentially other mTORopathies.SIGNIFICANCE STATEMENT Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) are epileptogenic cortical malformations caused by pathogenic variants in mechanistic target of rapamycin (mTOR) pathway genes leading to differential mTOR hyperactivation. Here, we present novel findings that neuronal mTOR hyperactivity levels correlate with the severity of epilepsy and associated neuropathology in a mouse model of TSC and FCD. Our findings suggest the need to evaluate the outcome of individual variants on mTOR activity levels in clinical assessments and support personalized medicine strategies based on patient variants and mTOR activity level. Additionally, we present useful modifications to a previously described mouse model of TSC and FCD that allows for titration of seizure frequency and generation of a mild to severe epilepsy phenotype as applicable for preclinical drug testing and mechanistic studies.

Association of Cervical Microglandular Hyperplasia With Exogenous Progestin Exposure.

OBJECTIVES: Although microglandular hyperplasia is a benign endocervical lesion, it may raise concern of malignancy in an inexperienced pathologist, because clinicians may not be familiar with it on a report. It has been reported to occur in association with progestational stimulation, but this has not been well studied. The aim of the study was to evaluate this potential association. MATERIALS AND METHODS: This was an observational case control study of patients seen from January 01, 1991 to November 01, 2014 at the University Hospital, Newark, New Jersey. Cases of microglandular hyperplasia and controls were identified from the files of the Department of Pathology. Controls were cases of endocervical curettages for whom no microglandular hyperplasia was detected. Medical records were reviewed for evidence of exogenous progestin exposure within the previous 6 months. RESULTS: Eighty-nine cases of microglandular hyperplasia and 97 controls were identified. Of the cases of microglandular hyperplasia, 26 (29.2%) of 89 cases had exposure to progestational medication, significantly greater than that of controls (10/97, 10.3%; p = .0014). CONCLUSIONS: Our data show that a significantly higher percentage of women with microglandular hyperplasia had progestin exposure than women who do not exhibit this benign lesion. Clinicians and pathologists should be aware of this association, as well as the benign nature of the lesion.

mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia.

OBJECTIVE: Hyperactivation of the mechanistic target of rapamycin (mTOR; also known as mammalian target of rapamycin) pathway has been demonstrated in human cortical dysplasia (CD) as well as in animal models of epilepsy. Although inhibition of mTOR signaling early in epileptogenesis suppressed epileptiform activity in the neuron subset-specific Pten knockout (NS-Pten KO) mouse model of CD, the effects of mTOR inhibition after epilepsy is fully established were not previously examined in this model. Here, we investigated whether mTOR inhibition suppresses epileptiform activity and other neuropathological correlates in adult NS-Pten KO mice with severe and well-established epilepsy. METHODS: The progression of epileptiform activity, mTOR pathway dysregulation, and associated neuropathology with age in NS-Pten KO mice were evaluated using video-electroencephalography (EEG) recordings, Western blotting, and immunohistochemistry. A cohort of NS-Pten KO mice was treated with the mTOR inhibitor rapamycin (10 mg/kg i.p., 5 days/week) starting at postnatal week 9 and video-EEG monitored for epileptiform activity. Western blotting and immunohistochemistry were performed to evaluate the effects of rapamycin on the associated pathology. RESULTS: Epileptiform activity worsened with age in NS-Pten KO mice, with parallel increases in the extent of hippocampal mTOR complex 1 and 2 (mTORC1 and mTORC2, respectively) dysregulation and progressive astrogliosis and microgliosis. Rapamycin treatment suppressed epileptiform activity, improved baseline EEG activity, and increased survival in severely epileptic NS-Pten KO mice. At the molecular level, rapamycin treatment was associated with a reduction in both mTORC1 and mTORC2 signaling and decreased astrogliosis and microgliosis. SIGNIFICANCE: These findings reveal a wide temporal window for successful therapeutic intervention with rapamycin in the NS-Pten KO mouse model, and they support mTOR inhibition as a candidate therapy for established, late-stage epilepsy associated with CD and genetic dysregulation of the mTOR pathway.

The mTOR pathway genes mTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function.

Brain somatic mutations in various components of the mTOR complex 1 (mTORC1) pathway have emerged as major causes of focal malformations of cortical development and intractable epilepsy. While these distinct gene mutations converge on excessive mTORC1 signaling and lead to common clinical manifestations, it remains unclear whether they cause similar cellular and synaptic disruptions underlying cortical network hyperexcitability. Here, we show that in utero activation of the mTORC1 activators, Rheb or mTOR, or biallelic inactivation of the mTORC1 repressors, Depdc5, Tsc1, or Pten in mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability but different changes in excitatory synaptic transmission. Our findings suggest that, despite converging on mTORC1 signaling, mutations in different mTORC1 pathway genes differentially impact cortical excitatory synaptic activity, which may confer gene-specific mechanisms of hyperexcitability and responses to therapeutic intervention.

The mTOR pathway genes MTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function.

Brain somatic mutations in various components of the mTOR complex 1 (mTORC1) pathway have emerged as major causes of focal malformations of cortical development and intractable epilepsy. While these distinct gene mutations converge on excessive mTORC1 signaling and lead to common clinical manifestations, it remains unclear whether they cause similar cellular and synaptic disruptions underlying cortical network hyperexcitability. Here, we show that in utero activation of the mTORC1 activator genes, Rheb or MTOR, or biallelic inactivation of the mTORC1 repressor genes, Depdc5, Tsc1, or Pten in the mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability but different changes in excitatory synaptic transmission. Our findings suggest that, despite converging on mTORC1 signaling, mutations in different mTORC1 pathway genes differentially impact cortical excitatory synaptic activity, which may confer gene-specific mechanisms of hyperexcitability and responses to therapeutic intervention.

Impact of Location of Residence and Distance to Cancer Centre on Medical Oncology Consultation and Neoadjuvant Chemotherapy for Triple-Negative and HER2-Positive Breast Cancer.

Despite consensus guidelines, most patients with early-stage triple-negative (TN) and HER2-positive (HER2+) breast cancer do not see a medical oncologist prior to surgery and do not receive neoadjuvant chemotherapy (NAC). To understand barriers to care, we aimed to characterize the relationship between geography (region of residence and cancer centre proximity) and receipt of a pre-treatment medical oncology consultation and NAC for patients with TN and HER2+ breast cancer. Using linked administrative datasets in Ontario, Canada, we performed a retrospective population-based analysis of women diagnosed with stage I-III TN or HER2+ breast cancer from 2012 to 2020. The outcomes were a pre-treatment medical oncology consultation and the initiation of NAC. We created choropleth maps to assess the distribution of the outcomes and cancer centres across census divisions. To assess the relationship between distance to the nearest cancer centre and outcomes, we performed multivariable regression analyses adjusted for relevant factors, including tumour extent and nodal status. Of 14,647 patients, 29.9% received a pre-treatment medical oncology consultation and 77.7% received NAC. Mapping demonstrated high interregional variability, ranging across census divisions from 12.5% to 64.3% for medical oncology consultation and from 8.8% to 64.3% for NAC. In the full cohort, compared to a distance of ≤5 km from the nearest cancer centre, only 10-25 km was significantly associated with lower odds of NAC (OR 0.83, 95% CI 0.70-0.99). Greater distances were not associated with pre-treatment medical oncology consultation. The interregional variability in medical oncology consultation and NAC for patients with TN and HER2+ breast cancer suggests that regional and/or provider practice patterns underlie discrepancies in the referral for and receipt of NAC. These findings can inform interventions to improve equitable access to NAC for eligible patients.

Molecular Expression Assays Improve the Prediction of Local and Invasive Local Recurrence After Breast-Conserving Surgery for Ductal Carcinoma In Situ.

PURPOSE: Ductal carcinoma in situ (DCIS) is routinely treated with adjuvant radiotherapy (RT) after breast-conserving surgery (BCS). The inability to accurately estimate an individual's risk of local recurrence (LR) and invasive LR using clinicopathologic factors (CPF) contributes to the overtreatment of DCIS. We examined the impact of the 12-gene DCIS Score (DS) and the 21-gene Recurrence Score (RS) on the accuracy of predicting LR and invasive LR. METHODS: A population-based cohort diagnosed with pure DCIS treated with BCS ± RT from 1994 to 2003 was used. All patients had expert pathology review and assessment of the DS and RS. Predictive models (CPF alone, DS + CPF, and RS + CPF) were developed using multivariable Cox regression analyses to predict 10-year LR and invasive LR risks. Models were evaluated on the basis of c-statistic, -2log likelihood estimate (-2LLE), and Akaike information criterion. Calibration was performed using bootstrap resamples, with replacement. RESULTS: The cohort includes 1,226 women treated with BCS; 712 received RT. 194 women (15.8%) experienced ipsilateral LR as a first event; 112 were invasive. Models including the DS or RS performed better in predicting the 10-year risk of LR compared with models on the basis of CPF alone with excellent calibration. The two molecular-based models also performed better in predicting invasive LR compared with the CPF model but the model incorporating the RS did not perform better in the prediction of invasive LR compared with the DS-based model. CONCLUSION: Models incorporating the DS or RS more accurately predicted the 10-year risk of LR and invasive LR after BCS compared with models on the basis of CPF alone. Inclusion of the RS, compared with DS, did not improve the prediction of the 10-year risk of invasive LR.

4E-BP1 expression in embryonic postmitotic neurons mitigates mTORC1-induced cortical malformations and behavioral seizure severity but does not prevent epilepsy in mice.

Hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway during neurodevelopment leads to focal cortical malformations associated with intractable seizures. Recent evidence suggests that dysregulated cap-dependent translation downstream of mTORC1 contributes to cytoarchitectural abnormalities and seizure activity. Here, we examined whether reducing cap-dependent translation by expressing a constitutively active form of the translational repressor, 4E-BP1, downstream of mTORC1 would prevent the development of cortical malformations and seizures. 4E-BP1CA was expressed embryonically either in radial glia (neural progenitor cells) that generate cortical layer 2/3 pyramidal neurons or in migrating neurons destined to layer 2/3 using a conditional expression system. In both conditions, 4E-BP1CA expression reduced mTORC1-induced neuronal hypertrophy and alleviated cortical mislamination, but a subset of ectopic neurons persisted in the deep layers and the white matter. Despite the above improvements, 4E-BP1CA expression in radial glia had no effects on seizure frequency and further exacerbated behavioral seizure severity associated with mTORC1 hyperactivation. In contrast, conditional 4E-BP1CA expression in migratory neurons mitigated the severity of behavioral seizures but the seizure frequency remained unchanged. These findings advise against targeting 4E-BPs by 4E-BP1CA expression during embryonic development for seizure prevention and suggest the presence of a development-dependent role for 4E-BPs in mTORC1-induced epilepsy.

The impact of a cancer diagnosis on nonfatal self-injury: a matched cohort study in Ontario.

BACKGROUND: Psychological distress following a cancer diagnosis potentially increases the risk of intentional, nonfatal self-injury. The purpose of this work is to evaluate and compare rates of nonfatal self-injury among individuals in Ontario diagnosed with cancer against matched controls with no history of cancer. METHODS: Adults in Ontario diagnosed with cancer from 2007 to 2019 were matched to 2 controls with no history of cancer, based on age and sex. We calculated the absolute and relative difference in rates of nonfatal self-injury in the 5 years before and after the index date (date of cancer diagnosis and dummy date for controls). We used crude difference-in-differences methods and adjusted Poisson regression-based analyses to examine whether the change in rates of nonfatal self-injury before and after index differed between cancer patients and controls. RESULTS: The cohort included 803 740 people with cancer and 1 607 480 matched controls. In the first year after diagnosis, individuals with cancer had a 1.17-fold increase in rates of nonfatal self-injury (95% confidence interval [CI] 1.03-1.33) compared with matched controls, after accounting for pre-existing differences in rates of nonfatal self-injury and other clinical characteristics between the groups. Rates of nonfatal self-injury remained elevated in the cancer group by 1.07-fold for up to 5 years after diagnosis (95% CI 0.95-1.21). INTERPRETATION: In this study, incidence of nonfatal self-injury was higher among individuals diagnosed with cancer, with the greatest impact observed in the first year after diagnosis. This work highlights the need for robust and accessible psychosocial oncology programs to support mental health along the cancer journey.