Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial.

BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.

Automatic Prostate Cancer Segmentation Using Kinetic Analysis in Dynamic Contrast-Enhanced MRI.

BACKGROUND: Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) provides functional information on the microcirculation in tissues by analyzing the enhancement kinetics which can be used as biomarkers for prostate lesions detection and characterization. OBJECTIVE: The purpose of this study is to investigate spatiotemporal patterns of tumors by extracting semi-quantitative as well as wavelet-based features, both extracted from pixel-based time-signal intensity curves to segment prostate lesions on prostate DCE-MRI. METHODS: Quantitative dynamic contrast-enhanced MRI data were acquired on 22 patients. Optimal features selected by forward selection are used for the segmentation of prostate lesions by applying fuzzy c-means (FCM) clustering. The images were reviewed by an expert radiologist and manual segmentation performed as the ground truth. RESULTS: Empirical results indicate that fuzzy c-mean classifier can achieve better results in terms of sensitivity, specificity when semi-quantitative features were considered versus wavelet kinetic features for lesion segmentation (Sensitivity of 87.58% and 75.62%, respectively) and (Specificity of 89.85% and 68.89 %, respectively). CONCLUSION: The proposed segmentation algorithm in this work can potentially be implemented for automatic prostate lesion detection in a computer aided diagnosis scheme and combined with morphologic features to increase diagnostic credibility.

Heart Rate Variability Classification using Support Vector Machine and Genetic Algorithm.

BACKGROUND: Electrocardiogram (ECG) is defined as an electrical signal, which represents cardiac activity. Heart rate variability (HRV) as the variation of interval between two consecutive heartbeats represents the balance between the sympathetic and parasympathetic branches of the autonomic nervous system. OBJECTIVE: In this study, we aimed to evaluate the efficiency of discrete wavelet transform (DWT) based features extracted from HRV which were further selected by genetic algorithm (GA), and were deployed by support vector machine to HRV classification. MATERIALS AND METHODS: In this paper, 53 ECGs including 3 different beat types (ventricular fibrillation (VF), atrial fibrillation (AF) and also normal sinus rhythm (NSR)), were selected from the MIT/BIH arrhythmia database. The approach contains 4 stages including HRV signal extraction from each ECG signal, feature extraction using DWT (entropy, mean, variance, kurtosis and spectral component ß), best features selection by GA and classification of normal and abnormal ECGs using the selected features by support vector machine (SVM). RESULTS: The performance of the classification procedure employing the combination of selected features were evaluated using several measures including accuracy, sensitivity, specificity and precision which resulted in 97.14%, 97.54%, 96.9% and 97.64%, respectively. CONCLUSION: A comparative analysis with the related existing methods illustrates the proposed method has a higher potential in the classification of AF and VF. The attempt to classify the ECG signal has been successfully achieved. The proposed method has shown a promising sensitivity of 97.54% which indicates that this technique is an excellent model for computer-aided diagnosis of cardiac arrhythmias.

Leber's hereditary optic neuropathy: the spectrum of mitochondrial DNA mutations in Iranian patients.

We studied 14 patients with Leber's hereditary optic neuropathy (LHON) to investigate the mtDNA haplotypes associated with the primary mutation(s). Eleven patients carried the mitochondrial DNA (mtDNA) G11778A mutation, while one had the T14484C mutation; one patient had the G3460A mutation and one the G14459A mutation. The Iranian G11778A LHON mutation was not associated with two mtDNA haplogroups-M (0.0% compared with 3.2% in healthy controls) and J (7.7% compared with 10% in healthy controls). Our results showed a similarity in the pattern of LHON primary point mutations between Iranian families with LHON and those of Russian, European, and North American origin. Our results also do not support an association between mtDNA haplogroups J and M with LHON primary point mutations.

Optimizing the management of HER2-positive early breast cancer: the clinical reality.

Breast cancer positive for HER2 (human epidermal growth factor receptor 2) is associated with a poor prognosis for patients with both early-stage and metastatic breast cancer. Trastuzumab has been shown to be effective and is now considered the standard of care for early-stage patients with HER2-positive breast cancer. In that population, trastuzumab has been studied in six randomized clinical trials. Overall, use of this agent leads to a significant reduction in risk of disease recurrence and improvement in overall survival. Despite the strong evidence for the use of trastuzumab in managing HER2-positive early breast cancer (EBC), a number of clinical controversies remain. The authors of this paper undertook a review of the available scientific literature on adjuvant trastuzumab to produce practical considerations from Canadian oncologists. The panel focused their discussion on five key areas: Management of node-negative disease with tumours 1 cm or smaller in size. Management of HER2-positive EBC across the spectrum of the disease (that is, nodal and steroid hormone receptor status, tumour size) Timing of trastuzumab therapy with chemotherapy for early-stage disease: concurrent or sequential. Treatment duration of trastuzumab for EBC. The role of non-anthracycline trastuzumab-based regimens.

Simvastatin protects against cholestasis-induced liver injury.

BACKGROUND: Bile duct obstruction is associated with hepatic accumulation of leukocytes and liver injury. The aim of this study was to evaluate the effect of simvastatin on cholestasis-induced liver inflammation and tissue damage. EXPERIMENTAL APPROACH: C57BL/6 mice were treated with simvastatin (0.02 and 0.2 mg.kg(-1)) and vehicle before and after undergoing bile duct ligation (BDL) for 12 h. Leukocyte recruitment and microvascular perfusion in the liver were analysed using intravital fluorescence microscopy. CXC chemokines in the liver were determined by enzyme-linked immunosorbent assay. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of myeloperoxidase (MPO) were also determined. KEY RESULTS: Administration of 0.2 mg.kg(-1) simvastatin decreased ALT and AST by 87% and 83%, respectively, in BDL mice. This dose of simvastatin reduced hepatic formation of CXC chemokines by 37-82% and restored sinusoidal perfusion in cholestatic animals. Moreover, BDL-induced leukocyte adhesion in sinusoids and postsinusoidal venules, as well as MPO levels in the liver, was significantly reduced by simvastatin. Notably, administration of 0.2 mg.kg(-1) simvastatin 2 h after BDL induction also decreased cholestatic liver injury and inflammation. CONCLUSIONS AND IMPLICATIONS: These findings show that simvastatin protects against BDL-induced liver injury. The hepatoprotective effect of simvastatin is mediated, at least in part, by reduced formation of CXC chemokines and leukocyte recruitment. Thus, our novel data suggest that the use of statins may be an effective strategy to protect against the hepatic injury associated with obstructive jaundice.

Monoclonal antibody against T-cell receptor alphabeta induces self-tolerance in chronic experimental autoimmune encephalomyelitis.

The therapeutic effect of monoclonal antibody (H57-597 MoAb) against T-cell receptor (TCR) alphabeta has been investigated on MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE), as a model system for T-cell-mediated chronic inflammation in the central nervous system (CNS). Short-term administration of the anti-TCR alphabeta immediately after immunization protected the mice from EAE. Furthermore, anti-TCR alphabeta treatment on an established disease restored the self-tolerance which led to a complete remission of EAE and a dramatic reduction of inflammatory cells in the CNS, while treatment with control antibody (hamster IgG) was ineffective. The remission was durable and not associated with disappearance of autoreactive T cells as measured by persistence of MOG-reactive T-cell proliferation in vitro. However, MOG-reactive T cells from anti-TCR-treated animals produced significantly lower amounts of inflammatory TNF-alpha and IFN-gamma. In addition, while a transient deletion of CD4(+) and CD8(+) T cells was observed, a population of T cells expressing CD3, NK1.1 and CD69 (NKT cells) were expanding. By transfer of spleen cells from anti-TCR MoAb-treated animals, we could show that the tolerogenic capacity can be transferred to untreated recipients with EAE. The data indicate therapeutic effect of anti-TCR alphabeta MoAb (H57-597), which represents a promising approach in treatment of T-cell-mediated autoimmune diseases.

A3--a novel colon and pancreatic cancer reactive antibody from a primate phage library selected using intact tumour cells.

The identification of novel tumour-associated antigens (TAAs) is pivotal for progression in the fields of tumour immunotherapy and diagnosis. In the present study, we have developed, based on flow cytometric evaluation and use of a mini-library composed of specific antibody clones linked to different antibiotic resistance markers, methods for positive and subtractive selection of phage antibodies employing intact cells as the antigen source. An scFv phage library (2.7 x 10(7)) was constructed from a primate (Macaca fascicularis) immunised with pooled human colon carcinomas. This library was selected for 3 rounds by binding to Colo 205 colon adenocarcinoma cells and proteolytic elution followed by phage amplification. Several antibodies reactive with colon carcinomas and with restricted reactivity to a few epithelial normal tissues were identified by immunohistochemistry. One clone, A3 scFv, recognised an epitope that was homogeneously expressed in 11/11 of colon and 4/4 pancreatic carcinomas studied and in normal tissue restricted to subtypes of epithelia in the gastrointestinal tract. The A3 scFv had an apparent overall affinity approximately 100-fold higher than an A3 Fab, suggesting binding of scFv homodimers. The cell surface density of the A3 epitope, calculated on the basis of Fab binding, was exceptionally high, approaching 3 million per cell. We also demonstrate efficient T-cell-mediated killing of colon cancer cells coated with A3 scFv fused to the low MHC class II binding superantigen mutant SEA(D227A). The identified A3 molecule thus represents a TAA with properties that suggest its use for immunotherapy of colon and pancreatic cancer.

Abnormal DNA damage-inducible protein in cells from Sjögren's syndrome patients.

Antinuclear antibodies are commonly found in patients with Sjögren's syndrome. It has been suggested that the development of antinuclear antibodies depends on the activation of the spliceosome and other transcription-related subcellular particles, some of which have recently been shown also to function in DNA-modifying processes, such as DNA repair and V(D)J recombination. These observations add weight to a previously proposed model for the aetiology of Sjögren's syndrome. This includes the abnormal processing of the T-cell receptor and immunoglobulin genes. To test this hypothesis further, the present study on DNA-modifying proteins in Sjögren's syndrome was initiated. Gel-shift experiments using protein extracted from UV-treated Sjögren cells provided evidence of high molecular weight DNA-binding protein in six out of 12 Sjögren patients studied (but not among seven healthy controls). Some Sjögren sera displayed antibodies to protein extracts from cells treated with psoralen plus UVA radiation. These results indicate an abnormal DNA damage-inducible response in Sjögren's syndrome. It may therefore be concluded that alterations in nuclear protein may play a role in the aetiology of Sjögren's syndrome.