Background Cyclin-dependent kinase 12 (CDK12) regulates general gene transcription elongation and plays multiple roles in RNA splicing, DNA damage-response, cell cycle, and genomic stability. However, transcriptional partners that guide CDK12-specific gene programs have not been identified. Genomic alterations in CDK12 have been observed in multiple cancers, exhibiting both pro-tumorigenic and tumor-suppressive functions, suggesting a context-dependent mechanism of action.Methods CDK12 copy number alterations and gene expression levels were analyzed in matched primary and brain metastatic patient tumors. Clinical significance was assessed by immunohistochemistry in a large cohort of primary breast cancer patient tumors. RNA sequencing, ChIP sequencing, and molecular studies were conducted to explore CDK12's mechanism of action, and pharmacological studies were performed both in vitro and in vivo using models of advanced (endocrine-resistant and metastatic) estrogen receptor positive (ER+) disease.Results CDK12 amplifications and gene overexpression were observed in brain metastatic tumors. In ER+ primary patient tumors, high CDK12 protein expression was significantly associated with poor overall survival, particularly within the ER+/HER2-negative group. In ER+ endocrine resistant models, CDK12 regulated estrogen signaling pathways, with ER/MED1 identified as the master transcriptional complex directing CDK12-specific pro-tumorigenic gene programs. Pharmacological inhibition of CDK12 significantly reduced viability in endocrine resistant and metastatic cell and organoid models in vitro, and decreased metastatic spread in vivo.Conclusion This work describes a novel mechanism for CDK12, suggesting a potential vulnerability in ER+ breast cancer. These findings provide a basis for further investigation into the role of CDK12 inhibition as a therapeutic approach, particularly in advanced disease settings.

Abstract Introduction LigaSure is an electrothermal bipolar vessel-sealing system shown to decrease blood loss and drainage volume compared to electrocautery in axillary node dissection. This prospective randomised controlled trial aimed to assess whether using LigaSure improved perioperative outcomes when compared with monopolar diathermy alone in performing mastectomy without axillary dissection. Methods Mastectomy was performed with the LigaSure device and compared with mastectomy using conventional monopolar diathermy in a prospective randomised trial. Patients were recruited over 39 months and were aged from 33 to 86 years of age. Block randomisation (44 in the Ligasure group and 42 in the diathermy group) was performed. The primary outcome measures include total volume in drain output (ml), time to drain volume less than 30mls in 24 hours and operating time. Results Drain output volume was measured to the day the drain yielded less than 30mls in a 24 hour period in both groups (484 mls in the monopolar group v 494 mls in Ligasure group). This time point was also used to calculate time to drain removal in both groups (Monopolar 7.2 days and Ligasure 7.3 days). Drain output volume and number or days to drain removal did not show any significant difference in both groups (p=0.05). The operative time in both groups was similar (106mins in monopolar group and 112.5 mins in LigaSure group). Conclusion Use of the LigaSure device is feasible in performing mastectomy. It is not associated with reduced drain volume or shorter operative time compared with monopolar diathermy.

BACKGROUND AND PURPOSE: Randomized trials in the late window have demonstrated the efficacy and safety of endovascular thrombectomy in large-vessel occlusions. Patients with M2-segment MCA occlusions were excluded from these trials. We com-pared outcomes with endovascular thrombectomy in patients with M2-versus-M1 occlusions presenting 6-24 hours after symptom onset.MATERIALS AND METHODS: Analyses were on pooled data from studies enrolling patients with stroke treated with endovascular thrombectomy 6-24 hours after symptom onset. We compared 90-day functional independence (mRS =2), mortality, symptomatic intracranial hemorrhage, and successful reperfusion (expanded TICI = 2b-3) between patients with M2 and M1 occlusions. The benefit of successful reperfusion was then assessed among patients with M2 occlusion.RESULTS: Of 461 patients, 367 (79.6%) had M1 occlusions and 94 (20.4%) had M2 occlusions. Patients with M2 occlusions were older and had lower median baseline NIHSS scores. Patients with M2 occlusion were more likely to achieve 90-day functional independ-ence than those with M1 occlusion (adjusted OR = 2.13; 95% CI, 1.25-3.65). There were no significant differences in the proportion of successful reperfusion (82.9% versus 81.1%) or mortality (11.2% versus 17.2%). Symptomatic intracranial hemorrhage risk was lower in patients with M2-versus-M1 occlusions (4.3% versus 12.2%, P = .03). Successful reperfusion was independently associated with functional independence among patients with M2 occlusions (adjusted OR = 2.84; 95% CI, 1.11-7.29).CONCLUSIONS: In the late time window, patients with M2 occlusions treated with endovascular thrombectomy achieved better clinical outcomes, similar reperfusion, and lower symptomatic intracranial hemorrhage rates compared with patients with M1 occlusion. These results support the safety and benefit of endovascular thrombectomy in patients with M2 occlusions in the late window.

Introduction Delays have a negative impact on successful reperfusion with endovascular thrombectomy (EVT) in early-window strokes. Late window patients may be further disadvantaged due to their late presentation. We assessed the impact of delays on reperfusion success in late window stroke patients. Materials and Methods We pooled data from seven trials and registries in North America, Europe, and Korea, for anterior circulation stroke patients treated with EVT between 6 and 24 hours from onset. We explored the impact of delays across multiple time metrics, including onset (or last known well) to hospital arrival; hospital arrival to arterial puncture; and CT to arterial puncture. Our primary outcome was successful reperfusion, defined as a final thrombolysis in cerebral infarction (TICI) score of 2b-3. Univariable and multivariable logistic regression analyses were performed to assess the association between each of the time metrics and successful reperfusion; adjusting for age, sex, occlusion site, NIHSS score, and wake-up stroke status. Results We included 608 patients. The median age was 70 years (IQR: 21), 307 [50.2%] were females, and 311 (53.2%) had wake-up strokes. All patients had CT and CT angiography imaging, and 379 patients (62.3%) also underwent perfusion imaging. Successful reperfusion was achieved in 494 (81.2%) patients. Patients with successful reperfusion were more likely to have had wake-up strokes (55.7% versus 42.7%, p=0.02) and lower NIHSS scores (median 15 [IQR 8] versus 17 [10], p=0.02) compared to unsuccessful reperfusion patients. Successfully reperfused patients had a significantly shorter hospital arrival to arterial puncture time (90 minutes [60–150] versus 110 minutes [84.5–150], p=0.01) compared to unsuccessfully reperfused patients. The odds of successful reperfusion decreased by 6% for every one-hour delay in arrival to puncture (adjusted OR 0.94, 95% CI 0.89–0.99). The CT to puncture time was not different between the successful versus unsuccessful reperfusion patients in univariable and multivariable analyses (65 minutes [39–111] versus 66 minutes [46–105], p=0.33). The onset (last known well) to hospital arrival was longer in the successful reperfusion patients (555 minutes [412–692] versus 436 minutes [362–639.5], p=0.01). This difference, however, did not persist in the multivariable analysis (adjusted OR 1.07 for every one-hour delay, 95% CI 0.93–1.23). Conclusion Faster hospital arrival to arterial puncture time is associated with a higher rate of successful reperfusion in late window stroke patients. Pre-hospital delays were not associated with subsequent reperfusion. Disclosures I. Alhabli: None. F. Benali: None. S. Murphy: None. D. Toni: None. P. Michel: None. M. Hill: None. D. Herlihy: None. I. Casetta: None. S. Power: None. V. Saia: None. A. Hegarty: None. G. Pracucci: None. A. Demchuk: None. S. Mangiafico: None. K. Boyle: None. M. Goyal: None. S. Nannoni: None. E. Fainardi: None. J. Thornton: None. B. Kim: None. B. Menon: None. M. Almekhlafi: None. F. Bala: None.

Abstract BACKGROUND Finding effective treatment options for patients with brain metastasis remains an unmet need. Given the limitations imposed by the blood-brain-barrier for systemic approaches, radiotherapy offers a superior ability to access the brain. While clinical practice recently adapted the use of stereotactic radiosurgery (SRS), Whole-Brain-Radiotherapy (WBRT) continuous to be an important treatment option, since many patients present with multifocal lesions or bad performance scores, rendering them ineligible for SRS. Unfortunately, overall survival of patients remains unaffected by radiotherapy. Despite this clinical data, the molecular mechanisms that allow metastatic cells to resist radiotherapy in the brain is unknown. MATERIAL AND METHODS We have applied WBRT to experimental brain metastasis from lung and breast adenocarcinoma and validated their resistance in vivo. RESULTS An unbiased search to identify potential mediators of resistance identified the S100A9-RAGE-NFκB-JunB pathway. Targeting this pathway genetically reverts the resistance to radiotherapy and increases therapeutic benefits in vivo. In two independent cohorts of brain metastasis from lung and breast adenocarcinoma patients, levels of S100A9 correlate with the response to radiotherapy, offering a novel approach to stratify patients according to their expected benefit. In order to make this biomarker also available for brain metastasis patients receiving palliative WBRT without preceding surgery, we complemented our tumor-specimen based approach with the less invasive detection of S100A9 from liquid biopsies. Here, serum S100A9 also correlated with a worse response to WBRT in brain metastasis patients. Furthermore, we have validated the use of a blood-brain-barrier permeable RAGE inhibitor to restore radio-sensitivity in experimental brain metastasis models in vivo and in patient-derived organotypic cultures of radio-resistant brain metastasis ex vivo. CONCLUSION We identified S100A9 as a major mediator of radio-resistance in brain metastasis and offer the molecular framework to personalize radiotherapy by exploiting it as a biomarker and as a therapeutic target, thus maximizing the benefits for the patient.

Abstract Introduction Sentinel lymph node biopsy (SLNB) is the gold standard for determining axillary nodal status. There is growing interest in using preoperative axillary ultrasound (AUS) as a non-invasive means of assessing the axilla. However, AUS has limited sensitivity and is subject to operator dependency. This study aimed to quantify axillary nodal burden in preoperative AUS. Method This retrospective study used an institutional database of all primary invasive breast carcinomas from 2006–2019. Those with pathologically proven axillary metastatic disease were included. Patients were considered in two groups, low nodal burden/LNB(1-2LN) and high nodal burden/HNB(≥3LN) based on total positive lymph node count(SLNB+ALND). Preoperative AUS reports were assessed to determine those suspicious for axillary metastasis. Result Of the 347 patients (n=349 axillae), 77.9% had LNB and 22.1% had HNB. In patients with LNB, 228(83.8%) had a normal AUS versus 44(16.2%) suspicious AUS. In those with HNB 60(77.9%) had normal AUS findings versus 17(22.1%) suspicious findings. On multivariate analysis Nottingham Grade-3 was associated with suspicious AUS findings (p=0.02). However, receptor status, SLN macro-metastasis and extra-nodal extension were not associated with abnormal AUS. Conclusion As the surgical approach to the axilla becomes increasingly conservative, detection of axillary involvement by non-invasive means is an area of increasing research. In this cohort, AUS did not reliably identify patients with axillary metastasis. These results highlight the challenges in accurately assessing the axilla using preoperative AUS, which may result in axillary undertreatment if used as an alternative to surgical staging. Take-home message As the surgical approach to the axilla becomes increasingly conservative, detection of axillary involvement by non-invasive means is an area of increasing research. This study highlights the challenges in accurately assessing the axilla using preoperative AUS, which may result in axillary undertreatment if used as an alternative to surgical staging.

Background Collateral assessment using CT angiography (CTA) is promising to increase the eligibility for endovascular thrombectomy (EVT) in the late window (6–24 hours). The outcome of these patients compared to those selected using perfusion imaging is not clear. We aimed to describe the outcomes of EVT in patients selected using collateral vs perfusion imaging in the late time window. Methods We pooled individual patient-level data from seven trials and registries of EVT-treated patients in the late-time window. These studies were conducted in North America, Europe, and Korea. We collected clinical, imaging, and outcome data. We classified patients according to whether selection for EVT was done using collateral imaging alone (collateral cohort) vs perfusion plus collateral imaging (perfusion cohort). The primary outcome was the proportion of patients achieving independent 90-day functional outcome (modified Rankin scale 'mRS' 0–2). We also collected data on successful reperfusion (thrombolysis in cerebral infarction 2b-3), and symptomatic intracranial hemorrhage. We used the propensity score-weighting method to balance important predictors between the perfusion vs collateral cohorts. Results In 608 patients from seven studies, the mean (SD) age was 67.4 (14.6) years, and 50.5% were females. The median onset/last known well to emergency arrival time was 8.8 hours and 53.2% had wake-up strokes. Both cohorts had collateral imaging and 379 patients (62.3%) also had perfusion imaging. Independent functional outcome was achieved in 43.1% overall. In the perfusion cohort, 168/379 patients (45.5%) achieved functional independence vs 94/214 (43.9%) in the collateral cohort (P=0.71). A logistic regression model adjusting for inverse-probability-weighting showed no difference in 90-day mRS score of 0–2 (adjusted OR 1.05, 95%CI 0.69 to 1.59, P= 0.83) or in a favorable shift in 90-day mRS (common adjusted OR 1.01, 95%CI 0.69 to 1.47, P= 0.97) among patients in the perfusion vs collateral cohorts. Conclusion In this pooled individual patient-level analysis from multi-national studies and registries, late window patients who were selected for EVT using collateral imaging achieved comparable functional outcomes to patients who had perfusion imaging. Disclosures M. Almekhlafi: None. J. Thornton: None. I. Casetta: None. M. Goyal: None. N. Stefania: None. D. Herlihy: None. E. Fainardi: None. S. Power: None. V. Saia: None. A. Hegarty: None. G. Pracucci: None. A. Demchuk: None. S. Mangiafico: None. K. Boyle: None. P. Michel: None. F. Bala: None. R. Gill: None. A. Kuczynski: None. A. Ademola: None. M. Hill: None. D. Toni: None. S. Murphy: None. B. Kim: None. B. Menon: None.

Introduction Intensive care units (ICU) in Irish academic centres are known to fare as well as their international counterparts. Our aim in this study was to characterise the role and outcomes of an ICU in a smaller Irish hospital and to compare these to international best practice. Methods We reviewed admissions of patients to the ICU of St. Luke’s Hospital, Kilkenny. Patient demographics, indications for admission, and outcomes were all recorded and analysed. Sequential organ failure assessment (SOFA) scores were calculated. Results Forty-three patients were included in our study, 33 (76.7 %) of which were emergency admissions. Median length of stay was 2 days. The observed mortality rate in our cohort was 20.9 %. The median SOFA score in patients admitted was 7. Higher median SOFA scores on admission were predictive of mortality. The ICU occupancy rate during the duration of our study was 98 %, with only 15 (35.7 %) of admissions to ICU occurring within core working hours. Conclusion Critical care can be provided safely and in line with current best practice in smaller Irish hospitals. There is a cohort of patients for whom care may be best provided in a tertiary centre, how best to provide for these patients will likely be achieved by early identification (e.g. with SOFA score). Bed capacity issues remain problematic.