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HER2 levels post-treatment.

HER2 levels post-treatment.

ABT-737 enhances the effectiveness of T-DM1 in vivo.

p63 MCL-1 HER3 post-treatment.

Assessment of ERBB2 amplification.

Comparison of continuous versus pulsatile combination treatments.

Macroscopic comparison of tumors.

Supplementary Table 1. Tumor IHC marker specifics; Supplementary Table 2. p-values for Figure 4 comparisons; Supplementary Table 3. p-values for Figure 5 comparisons

To describe a new international dataset for pathology reporting of ductal carcinoma in situ (DCIS), variants of lobular carcinoma in situ (LCIS) and low-grade lesions (encapsulated papillary carcinoma, solid papillary carcinoma in situ, Paget's disease) produced by the International Collaboration on Cancer Reporting (ICCR).The ICCR, a global alliance of pathology bodies, uses a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Their aim is to support quality pathology reporting and engender understanding between the breast surgeon, pathologist, and oncologist for optimal and uniform patient management globally. Here we describe the dataset for DCIS, some variants of LCIS (namely the pleomorphic and the florid variants), and low-grade lesions by a multidisciplinary panel of internationally recognized experts. The agreed dataset comprises 12 core (required) and five noncore (recommended) elements suitable for both developed and low-income jurisdictions, derived from a review of current evidence. Areas of contention were addressed using a pragmatic approach in the absence of evidence. Use of all core elements is the minimum reporting standard for any individual case. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or noncore.This first internationally agreed dataset for DCIS, variants of LCIS, and low-grade lesions reporting will enable their standardization of pathology reporting and enhance clinicopathological communication leading to improved patient outcomes. Widespread adoption will also facilitate international comparisons, multinational clinical trials, and help to improve the management of breast disease globally.

Introduction: It could be theorised that liver fibrosis and acute ischemic stroke (AIS) are related by inflammatory changes, but few studied this link, let alone in patients receiving intravenous thrombolysis (IVT). The Fibrosis (FIB)-4 index is an established rapid score to detect liver fibrosis. We aimed to understand the role of FIB-4 in predicting AIS subtype, severity and outcomes after IVT. Methods: AIS patients receiving IVT without severe liver derangement from 2006 to 2018 at a stroke centre were studied. Stroke subtype was defined using Trial of Org 10172 in Acute Stroke Treatment. Moderate and severe stroke was defined as National Institutes of Health Stroke Scale (NIHSS) ≥10. FIB-4 index was stratified into no advanced fibrosis (FIB-4 3.25). The primary outcome - functional outcome at 90-days using the modified Rankin Scale (mRS) - was analysed by ordinal shift analysis. Multivariable adjusted logistic regression evaluated associations of FIB-4 with stroke severity, functional independence (90-day mRS 0-2 vs 3-6), 90-day mortality, and symptomatic intracranial hemorrhage (SICH). Results: Among 900 patients, higher median FIB-4 was seen in cardioembolic stroke (CES) than non-CES (1.93 [IQR: 1.39-2.81] vs 1.27 [IQR: 0.92-1.90], p Conclusion: Liver fibrosis was associated with higher rates of CES, more severe AIS, and poorer outcomes after IVT. This is a novel marker that could prognosticate IVT use in AIS.

Introduction: Whilst surgical decompression in malignant middle cerebral artery infarction is well established, its role in malignant posterior circulation infarction (MPCI) is unclear. Recent small cohort studies suggest that neurosurgery in this group may be beneficial. This systematic review and meta-analysis aims to compare outcomes of MPCI patients undergoing surgical intervention versus medical therapy. Methods: Medline, Embase and Cochrane were searched from inception until 2 April 2021. Studies were included if they evaluated patients with posterior circulation stroke treated with neurosurgical intervention. Observational cohort studies and case series with death and functional outcome data were included. Death was defined as Glasgow Outcome Scale (GOS) 1 and modified Rankin scale (mRS) 6, or extracted from the text. Favourable functional outcome was defined as mRS 0-2, GOS 4-5, Barthel Index 91-100 or extracted from text at the latest follow-up period. 6673 studies were filtered, with 31 studies included for data extraction, of which 8 studies included both a surgical and medical therapy group. Random effects meta-analysis, analysis of proportions and meta-regression were performed. Results: The medical therapy cohort (n=235) had significantly better odds of good functional outcome (GFO) than the surgical cohort. There was no significant difference in odds of death between the two groups (Figure 1). Amongst surgical patients (n=184), 18% died and 55% had GFO. On meta-regression, the proportion of patients with atrial fibrillation and hydrocephalus was negatively associated with odds of death and GFO respectively (both p Conclusion: In patients with MPCI, neurosurgery did not improve functional outcome or mortality in comparison with medical therapy. Larger cohort studies are warranted to resolve this clinical equipoise.

Background: Contradicting evidence exists regarding the role of lipids in intravenous (IV) thrombolysis with tissue plasminogen activator (tPA), with some studies suggesting low lipid levels are paradoxically associated with poorer post-thrombolysis outcomes. Methods: Restricted cubic spline regression, multivariable-adjusted logistic regression and risk score models evaluated associations of five lipid parameters with poor functional outcome (90-day modified Rankin Scale >2), symptomatic intracranial hemorrhage (SICH), and mortality among 1004 acute ischemic stroke (AIS) patients who received IV tPA in a comprehensive stroke center. Results: There was a U-shaped relationship of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) with all three outcomes using spline regression. Quartile (Q) 2 and Q4 of non-HDL-C were associated with increased odds of SICH (OR 4.2, 95% CI 1.2-15.0, p=0.026 and OR 5.1, 95% CI 1.4-18.2, p=0.011) compared to Q3. Similar quartile associations were found for total cholesterol (TC), and for LDL-C/HDL-C ratio with poor functional outcome. Q1 and Q2 of HDL-C were associated with increased odds of poor functional outcome (OR 1.6, 95% CI 1.0-2.5, p=0.043 and OR 1.6, 95% CI 1.0-2.4, p=0.042) compared to Q4. Only Q3 of LDL-C/HDL-C ratio was associated with increased odds of large-artery atherosclerotic stroke (OR 1.9, 95% CI 1.0-3.7, p=0.039) compared to Q1. Conclusion: In AIS patients who received IV tPA, a U-shaped relationship was found between non-HDL-C and SICH. Low LDL-C was associated with increased odds of mortality, while HDL-C may be protective against poor functional outcome.

One of the most recent advances in the treatment of HER2+ breast cancer is the development of the antibody–drug conjugate, T-DM1. T-DM1 has proven clinical benefits for patients with advanced and/or metastatic breast cancer who have progressed on prior HER2-targeted therapies. However, T-DM1 resistance ultimately occurs and represents a major obstacle in the effective treatment of this disease. Because anti-apoptotic BCL-2 family proteins can affect the threshold for induction of apoptosis and thus limit the effectiveness of the chemotherapeutic payload, we examined whether inhibition of BCL-2/XL would enhance the efficacy of T-DM1 in five HER2-expressing patient-derived breast cancer xenograft models. Inhibition of BCL-2/XL via navitoclax/ABT-263 significantly enhanced the cytotoxicity of T-DM1 in two of three models derived from advanced and treatment-exposed metastatic breast tumors. No additive effects of combined treatment were observed in the third metastatic tumor model, which was highly sensitive to T-DM1, as well as a primary treatment-exposed tumor, which was refractory to T-DM1. A fifth model, derived from a treatment naïve primary breast tumor, was sensitive to T-DM1 but markedly benefited from combination treatment. Notably, both PDXs that were highly responsive to the combination therapy expressed low HER2 protein levels and lacked ERBB2 amplification, suggesting that BCL-2/XL inhibition can enhance sensitivity of tumors with low HER2 expression. Toxicities associated with combined treatments were significantly ameliorated with intermittent ABT-263 dosing. Taken together, these studies provide evidence that T-DM1 cytotoxicity could be significantly enhanced via BCL-2/XL blockade and support clinical investigation of this combination beyond ERBB2-amplified and/or HER2-overexpressed tumors.

Background Targeted therapies for triple-negative breast cancer (TNBC) are limited; however, the epidermal growth factor receptor (EGFR) represents a potential target, as the majority of TNBC express EGFR. The purpose of these studies was to evaluate the effectiveness of two EGFR-targeted antibody-drug conjugates (ADC: ABT-414; ABBV-321) in combination with navitoclax, an antagonist of the anti-apoptotic BCL-2 and BCL-XL proteins, in order to assess the translational relevance of these combinations for TNBC. Methods The pre-clinical efficacy of combined treatments was evaluated in multiple patient-derived xenograft (PDX) models of TNBC. Microscopy-based dynamic BH3 profiling (DBP) was used to assess mitochondrial apoptotic signaling induced by navitoclax and/or ADC treatments, and the expression of EGFR and BCL-2/XL was analyzed in 46 triple-negative patient tumors. Results Treatment with navitoclax plus ABT-414 caused a significant reduction in tumor growth in five of seven PDXs and significant tumor regression in the highest EGFR-expressing PDX. Navitoclax plus ABBV-321, an EGFR-targeted ADC that displays more effective wild-type EGFR-targeting, elicited more significant tumor growth inhibition and regressions in the two highest EGFR-expressing models evaluated. The level of mitochondrial apoptotic signaling induced by single or combined drug treatments, as measured by DBP, correlated with the treatment responses observed in vivo. Lastly, the majority of triple-negative patient tumors were found to express EGFR and co-express BCL-XL and/or BCL-2. Conclusions The dramatic tumor regressions achieved using combined agents in pre-clinical TNBC models underscore the abilities of BCL-2/XL antagonists to enhance the effectiveness of EGFR-targeted ADCs and highlight the clinical potential for usage of such targeted ADCs to alleviate toxicities associated with combinations of BCL-2/XL inhibitors and systemic chemotherapies.

One of the most recent advances in the treatment of HER2+ breast cancer is the development of the antibody-drug conjugate, T-DM1. T-DM1 has proven clinical benefits for patients with advanced and/or metastatic breast cancer who have progressed on prior HER2-targeted therapies. However, T-DM1 resistance ultimately occurs and represents a major obstacle in the effective treatment of this disease. Since anti-apoptotic BCL-2 family proteins can affect the threshold for induction of apoptosis and thus limit the effectiveness of the chemotherapeutic payload, we examined whether inhibition of BCL-2/X(L) would enhance the efficacy of T-DM1 in five HER2-expressing patient-derived breast cancer xenograft models. Inhibition of BCL-2/X(L) via navitoclax/ABT-263 significantly enhanced the cytotoxicity of T-DM1 in two of three models derived from advanced and treatment-exposed metastatic breast tumors. No additive effects of combined treatment were observed in the third metastatic tumor model which was highly sensitive to T-DM1, as well as a primary treatment-exposed tumor, which was refractory to T-DM1. A fifth model, derived from a treatment naïve primary breast tumor, was sensitive to T-DM1 but markedly benefited from combination treatment. Notably, both PDXs that were highly responsive to the combination therapy expressed low HER2 protein levels and lacked ERBB2 amplification, suggesting that BCL-2/X(L) inhibition can enhance sensitivity of tumors with low HER2 expression. Toxicities associated with combined treatments were significantly ameliorated with intermittent ABT-263 dosing. Taken together, these studies provide evidence that T-DM1 cytotoxicity could be significantly enhanced via BCL-2/X(L) blockade and support clinical investigation of this combination beyond ERBB2-amplified and/or HER2-overexpressed tumors.

Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours.

Introduction: Low-flow significant aortic stenosis (AS) with preserved left ventricular ejection fraction (LVEF>50%) is associated with worse clinical outcomes. In classical severe AS, guidelines have indicated that deterioration of LVEF to Methods: Consecutive subjects (n=162) with low-flow (stroke volume index 180 days apart) were studied. Significant predictors of LVEF deterioration on univariate analyses were fit into a multivariable logistic regression. A risk score was then developed by converting the B-coefficients into weights, and its performance in predicting the LVEF deterioration to Results: There were 50 patients (30.9%) with significant deterioration of LVEF to 70g/cm2 (p=0.001) – 2 points, and left ventricular mass index >100g/m2 (p=0.010) – 1 point). The risk score performed well under receiver operating characteristic curve (AUC=0.78, 95%CI 0.72-0.85, p Conclusions: Despite preserved LVEF, subclinical myocardial dysfunction may represent an important comorbidity in patients with low-flow AS, which may accelerate inappropriate left ventricular remodelling. The risk score may be used to identify patients at risk of significant LVEF deterioration, thereby allowing for closer monitoring and earlier surgical intervention.