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Search Results: 1 - 10 of 12245 matches for " Matthew Ellis "
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Genome-forward oncology: how do we get there?
Matthew Ellis
Genome Biology , 2011, DOI: 10.1186/gb-2011-12-s1-i5
Current and future choices in endocrine therapy
Matthew Ellis
Breast Cancer Research , 2007, DOI: 10.1186/bcr1813
Abstract: So why is it that endocrine therapy does not cure all cases of ER-positive breast cancer, and what are the research choices that we should be making in order to design definitive clinical trials that address this critical problem? The conventional answer to this question is that ER-positive breast cancer is a spectrum of tumour types with different patterns of somatic mutations that influence ER function and reduce the efficacy of endocrine agents [4]. The best support for this hypothesis is the now definitive conclusion that HER2 gene amplification reduces efficacy of endocrine approaches to ER-positive breast cancer. In a variety of contexts, including endocrine therapy for advanced disease, the adjuvant endocrine setting and the neoadjuvant endocrine setting, the consistent pattern of evidence demonstrates that ER-positive, HER2-positive breast cancer does poorly in comparison with ER-positive, HER2-negative disease [5]. Furthermore, treatment with trastuzumab dramatically reduces the relapse rate for these patients when combined with chemotherapy. So where will we find the next example of a somatic mutation that can be targeted in the remaining cases of poor prognosis ER-positive, HER2-negative disease? The answer to this question must evolve from a study of the breast cancer genome using techniques such as array comparative genomic hybridization and high-throughput sequencing [4].Examples of other receptor tyrosine kinase amplification events that might be relevant to the problem of endocrine therapy resistance include fibroblast growth factor receptor (FGFR)1 amplification, which appears to be relatively common in ER-positive disease (frequency about 10%) and insulin-like growth factor 1 receptor (IGF1R) amplification, which is less common (frequency <5%), but it is of considerable interest because of the new generation of therapeutic IGF1R monoclonal antibodies. Downstream of the receptor tyrosine kinases include gain-of-function mutations in the α catalytic
Microarray data analysis in neoadjuvant biomarker studies in estrogen receptor-positive breast cancer
Jingqin Luo, Matthew J Ellis
Breast Cancer Research , 2010, DOI: 10.1186/bcr2616
Abstract: Taylor and colleagues [1] examined the time course of gene expression profile changes in estrogen (E2)-treated and E2 and tamoxifen-treated mouse xenografts. The authors presented three distinct categories of gene expression temporal profiles, each characterized by two sets of genes. Differentially expressed genes at some early time points following treatment were found to be prognostic of survival in clinical data sets, but not those identified at other time points. This implies that the timing of the post-treatment sample for gene expression analysis will be critical for the development of prognostic and predictive biomarkers.Adjuvant endocrine treatment in estrogen receptor-positive (ER+) breast cancer patients reduces the risk of relapse and death from breast cancer [2], but large numbers of patients still die of endocrine therapy-resistant disease [3]. Researchers have therefore devoted intensive efforts to identify molecular biomarkers to predict response to endocrine treatment and, in spite of the inherent heterogeneity among ER+ breast tumors, gene expression signatures have been successfully developed [4-6]. However, the existing signatures are based on gene expression information in a single baseline tumor sample that may not capture all the biological information necessary for predictive accuracy. Clinically, patients fall into three broad categories, continuously responding, continuously resistant, and a substantial group of patients with an initial response followed by a transition at varying rates to an acquired resistance phenotype. Late recurrence in resistant patients might be avoided if these tumors could be identified early, before the onset of clinical resistance, and subjected to an effective salvage intervention. Therefore, the discovery of gene signatures differentiating the three response groups logically requires the identification of temporal changes in gene expression along the treatment course. The paper by Taylor and colleagues [1] illus
"I'm pregnant and I have breast cancer"
Michael J Naughton, Matthew Ellis
BMC Cancer , 2007, DOI: 10.1186/1471-2407-7-93
Abstract: "I'm pregnant" is a phrase most women share with their partners and family with great joy, anticipation, and exuberance. "I have breast cancer" is a phrase all women dread. A small number of women experience both sets of emotions in quick succession after being diagnosed with breast cancer in early pregnancy. It is currently estimated that 1 in 3000 pregnancies is complicated by breast cancer [1] and this number is expected to rise with the tendency of women to delay child bearing in developed countries [2,3].In an article published in BMC Cancer, Dr. Epstein addresses many of the uncertainties that confront a patient and care team faced with this situation [4]. Here, we attempt to provide some guidance regarding currently accepted approaches to this complex situation.The diagnosis of breast cancer during pregnancy presents a unique clinical challenge. The management of breast cancer involves a number of important decisions of high complexity, often requiring the collaboration of patient, family, and interdisciplinary care team. Add an early pregnancy into the equation and the complexity increases dramatically. This is in no small part due to the probabilistic nature of many of the decisions made in the treatment of breast cancer. The data we use to make decisions in the treatment of breast cancer is incomplete and evolving. In the setting of pregnancy, this is even more difficult, as the existing data is even less complete, and the additional issues concerning the safety of the unborn child need to be considered.The goals of treating breast cancer in pregnancy are the same as in any other setting, preserving the life and health of the woman affected with breast cancer. In woman with local or regional disease, this means local and systemic control of her disease. If the pregnancy is to be continued, the treatment of the breast cancer may need to be modified minimize potential fetal toxicity. There is some consensus that both surgery and chemotherapy can be utilized
Treating breast cancer through novel inhibitors of the phosphatidylinositol 3'-kinase pathway
Robert J Crowder, Matthew J Ellis
Breast Cancer Research , 2005, DOI: 10.1186/bcr1307
Abstract: The phosphatidylinositol 3'-kinase (PI3K) signaling cascade is involved in regulating many cellular processes that are required for tumorigenesis, including protein synthesis and glucose metabolism, cell survival, proliferation, cell migration, and angiogenesis. Recent investigations indicate that constitutive activation of the PI3K pathway promotes resistance to estrogen receptor and human epidermal growth factor receptor (HER)2 directed therapy for breast cancer patients [1,2]. The major mechanism for abnormal PI3K activation in cancer is thought to be somatic mutation in the genes that encode positive and negative effectors of this pathway. These insights suggest that many breast cancers exhibit a 'genetic dependency' on PI3K pathway mutations that can be exploited for therapeutic gain. For example, abnormal PI3K activation in breast cancer can occur though amplification of the HER2 gene, the gene product of which is effectively targeted with the monoclonal antibody trastuzumab [3]. In addition, loss of expression of PTEN, a powerful negative regulator of PI3K signaling, or functional loss of PTEN due to PTEN gene mutations occurs in up to 50% of breast tumors and results in constitutive PI3K pathway signaling [4,5]. Loss of PTEN expression produces resistance to breast cancer endocrine therapy and trastuzumab treatment, and is a predictor of poor prognosis [1,2,5]. More recently, activating mutations in the PIK3CA gene, which encodes the PI3K p110α catalytic subunit, were found to occur in about 20–40% of breast tumors [6-9]. Interestingly, one study involving a large cohort of breast tumor samples [9] reported that PIK3CA gene mutations are mutually exclusive with PTEN gene loss, and that PIK3CA mutations correlate with HER2 expression and estrogen receptor positive status in breast tumors, although these correlations were not seen in other studies involving smaller samples sizes [7,8]. The RPS6KB1 gene, which encodes the mammalian target of rapamycin (mTOR) ef
Joubert Syndrome Presenting with Motor Delay and Oculomotor Apraxia
Harjinder Gill,Brinda Muthusamy,Denize Atan,Cathy Williams,Matthew Ellis
Case Reports in Pediatrics , 2011, DOI: 10.1155/2011/262641
Abstract: We describe two sisters who presented in early childhood with motor delay and unusual eye movements. Both demonstrated hypotonia and poor visual attention. The older girl at 14 weeks of age showed fine pendular horizontal nystagmus more pronounced on lateral gaze, but despite investigation with cranial MRI no diagnosis was reached. The birth of her younger sister four years later with a similar presentation triggered review of the sisters’ visual behaviour. Each had developed an unusual but similar form of oculomotor apraxia (OMA) with head thrusts to maintain fixation rather than to change fixation. MRI of the older sibling demonstrated the characteristic “molar tooth sign” (MTS) of Joubert syndrome which was subsequently confirmed on MRI in the younger sibling. We discuss the genetically heterogeneous ciliopathies now grouped as Joubert syndrome and Related Disorders. Clinicians need to consider this group of disorders when faced with unusual eye movements in the developmentally delayed child.
Abdominal Compartment Syndrome: Risk Factors, Diagnosis, and Current Therapy
Gina M. Luckianow,Matthew Ellis,Deborah Governale,Lewis J. Kaplan
Critical Care Research and Practice , 2012, DOI: 10.1155/2012/908169
Abstract: Abdominal compartment syndrome’s manifestations are difficult to definitively detect on physical examination alone. Therefore, objective criteria have been articulated that aid the bedside clinician in detecting intra-abdominal hypertension as well as the abdominal compartment syndrome to initiate prompt and potentially life-saving intervention. At-risk patient populations should be routinely monitored and tiered interventions should be undertaken as a team approach to management. 1. Introduction The concepts of intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are pervasive, but the objective criteria by which to diagnose each of these entities are often misunderstood [1]. IAH and ACS occur in both medical and surgical Intensive Care Units (ICU), the general ward, and may even occur the Emergency Department. Successful outcomes rely on early and accurate diagnosis combined with timely therapy [2–4]. Herein we describe these conditions, identify the at-risk patient populations, review diagnostic techniques as well as tiered medical management strategies, acute surgical therapy and long-term interventions to improve patient safety, optimize survival, and decrease morbidity. 2. Epidemiology Changes in fluid resuscitation paradigms, such as Early Goal Directed Therapy (EGDT) in the medical realm, and “damage control resuscitation” in the trauma realm, have increased patient survival [5, 6]. As a result of vigorous fluid resuscitation, however, each has also been associated with an unanticipated and undesired consequence—intra-abdominal hypertension and abdominal compartment syndrome (ACS). Given the detrimental effects of ACS (organ failure and death), heightened awareness surrounding the recognition of IAH and its progression to ACS, as well as the reporting of ACS, is paramount for optimal patient care. IAH is estimated to occur in 32.1% of ICU patients, and ACS has been reported in up to 4.2% of patients requiring critical care [7]. In order to identify each of these, one must be familiar with their definitions. 3. Definitions According to the World Society of the Abdominal Compartment Syndrome (WSACS), ACS may be defined as sustained intra-abdominal pressure (IAP) of >20?mm?Hg with the presence of an attributable organ failure [8]. While the WSACS has defined the parameters of ACS, it is important to delineate ACS from its predecessor, intra-abdominal hypertension. Absent from any disease processes, the average intra-abdominal pressure ranges from 5 to 7?mm?Hg with a normal upper limit of 12?mm?Hg [8]. Thus, a sustained IAP
The Role of Surgery, Radiosurgery and Whole Brain Radiation Therapy in the Management of Patients with Metastatic Brain Tumors
Thomas L. Ellis,Matthew T. Neal,Michael D. Chan
International Journal of Surgical Oncology , 2012, DOI: 10.1155/2012/952345
Abstract: Brain tumors constitute the most common intracranial tumor. Management of brain metastases has become increasingly complex as patients with brain metastases are living longer and more treatment options develop. The goal of this paper is to review the role of stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), and surgery, in isolation and in combination, in the contemporary treatment of brain metastases. Surgery and SRS both offer management options that may help to optimize therapy in selected patients. WBRT is another option but can lead to late toxicity and suboptimal local control in longer term survivors. Improved prognostic indices will be critical for selecting the best therapies. Further prospective trials are necessary to continue to elucidate factors that will help triage patients to the proper brain-directed therapy for their cancer. 1. Introduction Brain metastases are the most common intracranial tumor, arising in 10%–40% of all cancer patients [1, 2] and accounting for up to 170,000 new cases per year in the United States [3]. The observation of rising incidence is most likely related to the aging population, improved systemic treatment for the primary disease, and improved imaging techniques [4]. As a result, brain metastases are an increasing source of morbidity and mortality as well as cognitive impairment at the time of cancer diagnosis [5, 6]. Cancers with a high incidence in the general population (e.g., lung and breast) are the most frequently encountered source of brain metastases, accounting for up to two thirds of new cases [7]. Solid tumors constitute 95% of brain metastases, while leptomeningeal involvement makes up the remaining 5% [8–10]. Approximately 50%–60% of patients with solid tumors present with multiple metastases, while the remaining patients harbor a single mass [1, 11, 12]. The prognosis for patients with brain metastases from any histology is poor overall, with a median survival of only 4–7 months following treatment with WBRT alone [12–22]. For patients harboring a single, surgically amenable lesion, resection followed by WBRT has been found to be favorable to WBRT alone in two of three randomized controlled trials [17, 19, 22]. The local control rates and overall survival for patients with a single metastasis treated either with surgical resection followed by WBRT or with stereotactic radiosurgery (SRS) alone have been found to be similar [18, 19, 22–28]. On the other hand, SRS may yield superior local control rates for radioresistant brain metastases (e.g., from melanoma and renal cell) and
Molecular Basis of Triple Negative Breast Cancer and Implications for Therapy
Parvin F. Peddi,Matthew J. Ellis,Cynthia Ma
International Journal of Breast Cancer , 2012, DOI: 10.1155/2012/217185
Abstract: Triple negative breast cancer is an aggressive form of breast cancer with limited treatment options and is without proven targeted therapy. Understanding the molecular basis of triple negative breast cancer is crucial for effective new drug development. Recent genomewide gene expression and DNA sequencing studies indicate that this cancer type is composed of a molecularly heterogeneous group of diseases that carry multiple somatic mutations and genomic structural changes. These findings have implications for therapeutic target identification and the design of future clinical trials for this aggressive group of breast cancer. 1. Introduction Triple negative breast cancer (TNBC) is defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER-2 Overexpression. It accounts for 15–20% of all breast cancer cases [1, 2], but occurs at a higher frequency in young premenopausal women with African Ancestry (AA) [3]. High body mass index (BMI) and high parity, instead of low parity in other types of breast cancer, have been associated with increased risk for TNBC [4–6]. TNBC is associated with an overall poor prognosis as exemplified by a higher rate of early recurrence and distant metastasis to brain and lungs compared to other breast cancer subtypes [7, 8]. The unfavorable clinical outcome is partly explained by its aggressive pathologic features including a higher histology grade and mitotic index [9]. Chemotherapy is the only systemic therapy currently available for TNBC and is curative in a subset of patients with chemotherapy-sensitive disease. A higher rate of pathologic complete response (pCR) to standard chemotherapy has been observed in patients with TNBC compared to ER+ disease. A pCR rate of 22% in TNBC versus 11% in ER+ disease was reported in a study of over 1?000 patients treated with neoadjuvant anthracycline and taxane-based chemotherapy regimens [10]. The excellent outcome associated with the pCR, however, is in contrast to the high risk of recurrence and cancer-related deaths in those with residue disease. Although alternative agents such as platinum compounds have demonstrated promising activity, up to 70–80% of patients have residual cancer following neoadjuvant cisplatin [11]. In the metastatic setting, TNBC is typically associated with an initially higher response rate, but in a shorter time to progression following treatment with existing chemotherapy agents, resulting a shorter overall survival compared to ER+ breast cancer in multiple studies [12]. The underlying molecular mechanism for this paradox is yet to be
Treatment-Induced Bone Loss and Fractures in Cancer Patients Undergoing Hormone Ablation Therapy: Efficacy and Safety of Denosumab
Allan Lipton, Matthew R. Smith, Georgiana K. Ellis and Carsten Goessl
Clinical Medicine Insights: Oncology , 2012, DOI: 10.4137/CMO.S8511
Abstract: Hormone ablation therapy (HALT) for breast or prostate cancer accelerates the development of osteoporosis in both men and women by causing estrogen deficiency, which increases the risk for fracture by promoting bone resorption mediated by osteoclasts. Denosumab, a fully human monoclonal antibody that inhibits osteoclast formation and function, increases bone mass in patients undergoing hormone ablation therapy. In the HALT study of 1,468 men with prostate cancer on androgen-deprivation therapy, denosumab significantly reduced the risk of new vertebral fractures, increased bone mineral density (BMD), and reduced markers of bone turnover. In a study of 252 women with breast cancer undergoing adjuvant aromatase inhibitor (AI) therapy, denosumab increased BMD at 12 and 24 months, overall and in all patient subgroups. The overall rates of adverse events were similar to placebo. Clinicians should consider fracture risk assessment and therapies such as denosumab to increase bone mass in patients on hormone ablation therapy who are at high risk for fracture.
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