Brennan A.J.,Peter MacCallum Cancer Center
Nature Nanotechnology | Year: 2017
Perforin is a key protein of the vertebrate immune system. Secreted by cytotoxic lymphocytes as soluble monomers, perforin can self-assemble into oligomeric pores of 10–20 nm inner diameter in the membranes of virus-infected and cancerous cells. These large pores facilitate the entry of pro-apoptopic granzymes, thereby rapidly killing the target cell. To elucidate the pathways of perforin pore assembly, we carried out real-time atomic force microscopy and electron microscopy studies. Our experiments reveal that the pore assembly proceeds via a membrane-bound prepore intermediate state, typically consisting of up to approximately eight loosely but irreversibly assembled monomeric subunits. These short oligomers convert to more closely packed membrane nanopore assemblies, which can subsequently recruit additional prepore oligomers to grow the pore size. © 2017 Nature Publishing Group
iCAD Announces First Early Stage Breast Cancer Patient Treated with Intraoperative Radiation Therapy Using the Xoft System at Monash Cancer Centre, a partnership between Peter MacCallum Cancer Centre and Monash Health in Australia
News Article | May 1, 2017
NASHUA, N.H. and MELBOURNE, Australia, May 01, 2017 (GLOBE NEWSWIRE) -- iCAD, Inc. (Nasdaq:ICAD), an industry-leading provider of advanced image analysis, workflow solutions and radiation therapy for the early identification and treatment of cancer, today announced the first early-stage breast cancer patient was treated in Australia with intraoperative radiation therapy (IORT) using the Xoft® Axxent® Electronic Brachytherapy (eBx®) System®. The patient was treated at Monash Cancer Centre, a partnership between Peter MacCallum Cancer Centre and Monash Health, in Melbourne, Australia. “In recent years, healthcare facilities around the world have increasingly adopted the Xoft System, recognizing the unique benefits this revolutionary technology offers to both patients and clinicians in treating a range of different cancers,” said Ken Ferry, CEO of iCAD. “We are pleased to join with Monash Cancer Centre to provide unprecedented access to this advanced treatment option to patients in Australia.” In March 2017, Monash Cancer Centre became the first medical center in Australia to adopt the Xoft System through iCAD’s local distribution partner, Regional Health Care Group Pty Ltd. The system is FDA cleared, CE marked, entered in the Australian Register of Therapeutic Goods (ARTG), and licensed in a growing number of countries for the treatment of cancer anywhere in the body, including early-stage breast cancer, non-melanoma skin cancer, and gynecological cancer. For the treatment of early-stage breast cancer, IORT with the Xoft System allows radiation oncologists and breast surgeons to work together to administer one precise, concentrated dose of radiation to a tumor site at the time of lumpectomy. IORT with the Xoft System can be completed in as little as eight minutes, making it possible to replace six to eight weeks of traditional radiation therapy with a single treatment. The Xoft System’s miniaturized x-ray source can be inserted into a variety of applicators that are specifically designed for certain clinical indications. Monash Cancer Centre will offer the complete suite of Xoft System applicators used to deliver IORT, skin eBx, endometrial and cervical cancer radiation treatment. “Our adoption of the Xoft System underscores our commitment to providing optimal quality of care to our patients and we are proud to be the first to offer this technology to patients in Australia in the context of an international clinical trial,” said Dr. Steven David, MBBS, FRANZCR, Radiation Oncologist, Moorabbin Campus Director, Peter MacCallum Cancer Centre. “In our detailed review of the range of available radiation therapy solutions, the Xoft System’s distinguished versatility across a variety of clinical applications, mobility, and unique patient benefits made it the preeminent solution for our practice.” Monash Cancer Centre is the second international site to participate in iCAD’s clinical trial evaluating the Xoft System for the treatment of early-stage breast cancer, called the ExBRT trial (“A Safety and Efficacy Study of Intra-Operative Radiation Therapy [IORT] Using the Xoft® Axxent® Electronic Brachytherapy [eBx®] System at the Time of Breast Conservation Surgery for Early-Stage Breast Cancer”). “Intraoperative radiotherapy will offer women with early-stage breast cancer another therapeutic option, and, we believe, a better patient experience with less treatment morbidity, and a more rapid return to normal activity. As well as our current commitment to the study, we hope the breast service and other Monash Cancer Centre tumor services, will be able to contribute to understanding the use of this technology in other disease types and stages,” said Dr. Jane Fox, Director, Breast Services, Monash Health. “We are encouraged by the research to date as the global community of treatment centers continues to provide appropriate patients with the unique option to complete a full dose of radiation therapy in a single treatment.” “Monash Cancer Centre’s participation in the ExBRT trial offers important growth of the body of international clinical data demonstrating the safety and efficacy of the Xoft System for appropriate patients,” added Mr. Ferry. “We remain committed to continuing to expand research to identify additional treatment areas like IORT that have the potential to transform the treatment of cancer for patients worldwide.” Monash Cancer Centre at Moorabbin Hospital is a key service of Monash Health – Victoria’s largest health service. The Monash Cancer Centre provides the more than 1.5 million residents of southern Melbourne with access to world leading cancer treatment integrated in one convenient location through this key collaboration between Monash Health and the Peter MacCallum Cancer Centre. Cancer patients receive all care, from diagnosis to treatment and follow-up support, at the one place. Peter MacCallum Cancer Centre is one of the world’s leading cancer research, education and treatment centres and is Australia’s only public hospital solely dedicated to caring for people affected by cancer. Peter MacCallum Cancer Centre has over 2,500 staff, including more than 580 laboratory and clinical researchers, all focused on providing better treatments, better care and potential cures for cancer. For more information on Peter MacCallum Cancer Centre, please visit the website at www.petermac.org. Regional Health Care Group (RHCG) is 100% Australian-owned and one of Australia’s most successful privately-owned groups of companies in the Healthcare / Research & Development sector. RHCG is highly regarded in all clinical settings as a provider of premium quality capital equipment & medical consumables, with business extending across the Australian continent & New Zealand. RHCG are specialists in successfully introducing innovative technology & devices to the Australian & NZ healthcare market. For more information on RHCG, please visit the company’s website at www.rhcg.com.au. The Xoft System is an isotope-free radiation treatment that is FDA cleared, CE marked, and licensed in a growing number of countries for the treatment of cancer anywhere in the body, including treatment of early-stage breast cancer, gynecological cancers and non-melanoma skin cancer. It utilizes a proprietary miniaturized x-ray as the radiation source that delivers precise treatment directly to cancerous areas while sparing healthy tissue and organs. The Xoft System requires only minimal shielding and therefore does not require room redesign or construction investment. Minimal shielding also allows medical personnel to remain in the room with the patient during treatment. The mobility of the Xoft System makes it easy to treat patients at multiple locations and to easily store the system when not in use. The Axxent Hub is a cloud-based oncology collaboration software solution that enables centers to monitor treatment workflow and enhance communication between clinical specialists. Xoft is a wholly owned subsidiary of iCAD, Inc. For more information about Xoft visit www.xoftinc.com, like us on Facebook or follow us on Twitter at @xofticad. iCAD delivers innovative cancer detection and radiation therapy solutions and services that enable clinicians to find and treat cancers earlier and faster while improving patient outcomes. iCAD offers a comprehensive range of upgradeable computer aided detection (CAD) and workflow solutions to support rapid and accurate detection of breast, prostate and colorectal cancers. iCAD’s Xoft® Axxent® Electronic Brachytherapy (eBx®) System® delivers high dose rate, low energy radiation, which targets cancer while minimizing exposure to surrounding healthy tissue. The Xoft System is FDA cleared and CE marked for use anywhere in the body, including treatment of non-melanoma skin cancer, early-stage breast cancer and gynecological cancers. The comprehensive iCAD technology platforms include advanced hardware and software as well as management services designed to support cancer detection and radiation therapy treatments. For more information, visit or www.icadmed.com or www.xoftinc.com. "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995 Certain statements contained in this News Release constitute “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve a number of known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements of the Company to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Such factors include, but are not limited to the Company’s ability to defend itself in litigation matters, to achieve business and strategic objectives, the risks of uncertainty of patent protection, the impact of supply and manufacturing constraints or difficulties, uncertainty of future sales levels, protection of patents and other proprietary rights, the impact of supply and manufacturing constraints or difficulties, product market acceptance, possible technological obsolescence of products, increased competition, litigation and/or government regulation, changes in Medicare or other reimbursement policies, risks relating to our existing and future debt obligations, competitive factors, the effects of a decline in the economy or markets served by the Company; and other risks detailed in the Company’s filings with the Securities and Exchange Commission. The words “believe”, “demonstrate”, “intend”, “expect”, “would”, “could”, “consider”, “project”, “estimate”, “will”, “continue”, “anticipate”, “likely”, “seek”, and similar expressions identify forward-looking statements. Readers are cautioned not to place undue reliance on those forward-looking statements, which speak only as of the date the statement was made. The Company is under no obligation to provide any updates to any information contained in this release. For additional disclosure regarding these and other risks faced by iCAD, please see the disclosure contained in our public filings with the Securities and Exchange Commission, including the 10-K for the year ended December 31, 2016, available on the Investors section of our website at http://www.icadmed.com and on the SEC’s website at http://www.sec.gov.
Vesely M.D.,University of Washington |
Kershaw M.H.,Peter MacCallum Cancer Center |
Kershaw M.H.,University of Melbourne |
Kershaw M.H.,Monash University |
And 3 more authors.
Annual Review of Immunology | Year: 2011
The immune system can identify and destroy nascent tumor cells in a process termed cancer immunosurveillance, which functions as an important defense against cancer. Recently, data obtained from numerous investigations in mouse models of cancer and in humans with cancer offer compelling evidence that particular innate and adaptive immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor-suppressor mechanisms. However, the immune system can also promote tumor progression. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. In this review, we discuss the current experimental and human clinical data supporting a cancer immunoediting process that provide the fundamental basis for further study of immunity to cancer and for the rational design of immunotherapies against cancer. © 2011 by Annual Reviews. All rights reserved.
Kelleher F.C.,St Vincents University Hospital |
Kelleher F.C.,Peter MacCallum Cancer Center
Carcinogenesis | Year: 2011
Objective: To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis. Method. PubMed search (2000-2010) and literature based references. Results: Firstly, in 2009 a genetic analysis of pancreatic cancers found that a core set of 12 cellular signaling pathways including hedgehog were genetically altered in 67-100% of cases. Secondly, in vitro and in vivo studies of treatment with cyclopamine (a naturally occurring antagonist of the hedgehog signaling pathway component; Smoothened) has shown that inhibition of hedgehog can abrogate pancreatic cancer metastasis. Thirdly, experimental evidence has demonstrated that sonic hedgehog (Shh) is correlated with desmoplasia in pancreatic cancer. This is important because targeting the Shh pathway potentially may facilitate chemotherapeutic drug delivery as pancreatic cancers tend to have a dense fibrotic stroma that extrinsically compresses the tumor vasculature leading to a hypoperfusing intratumoral circulation. It is probable that patients with locally advanced pancreatic cancer will derive the greatest benefit from treatment with Smoothened antagonists. Fourthly, it has been found that ligand dependent activation by hedgehog occurs in the tumor stromal microenvironment in pancreatic cancer, a paracrine effect on tumorigenesis. Finally, in pancreatic cancer, cells with the CD44+CD24+ESA+ immunophenotype select a population enriched for cancer initiating stem cells. Shh is increased 46-fold in CD44+CD24+ESA+ cells compared with normal pancreatic epithelial cells. Medications that destruct pancreatic cancer initiating stem cells are a potentially novel strategy in cancer treatment. Conclusions: Aberrant hedgehog signaling occurs in pancreatic cancer tumorigenesis and therapeutics that target the transmembrane receptor Smoothened abrogate hedgehog signaling and may improve the outcomes of patients with pancreatic cancer. © The Author 2010. Published by Oxford University Press. All rights reserved.
Prince H.M.,Peter MacCallum Cancer Center
Future oncology (London, England) | Year: 2013
Cutaneous T-cell lymphomas are relatively rare lymphomas and the most common form is mycosis fungoides. Its rare leukemic variant is Sezary syndrome. Advanced-stage disease is typically treated with bexarotene (a retinoid), IFN-α or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors that modify the epigenome are an attractive addition to the armamentarium. Based on two large Phase II studies, the US FDA approved intravenous romidepsin for patients with relapsed/refractory cutaneous T-cell lymphomas. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side-effect profile.
Kinnane N.A.,Peter MacCallum Cancer Center
Supportive Care in Cancer | Year: 2012
Background: Although information seeking is encouraged by health care professionals as a positive coping strategy evidence suggests information needs of those affected by cancer are not always fully met. In response to the need for novel models of information provision and educational support for people affected by cancer, a hospital-based cancer information and support centre (CISC) was introduced into a tertiary cancer hospital. Professional support is provided by a cancer support nurse (CSN) with the clinical experience of working with cancer patients, whilst peer support is provided by volunteers. Materials and methods: A survey was developed to ascertain the perceptions and experiences of consumers (users) of a hospital-based CISC. The aim was to understand what information and support patients and families consider important and helpful in order to develop the service to reflect the needs of its users. During a 12-month period 111 surveys were distributed to users of the centre. Results: Sixty-nine surveys were returned (62.1%). Nearly all visits were motivated by the need to access (58/84.0%) information, indicating an unmet or changing need. The CSN initiated referrals to support services, both internal and community based, for 21 (53.9%) participants with whom there was contact. Contact with the CISC volunteers also resulted in internal or community-based referrals for 15 (32.6%) of participants. Of note, half of the participants (35/50.7%) reported seeking additional information from the internet as a consequence of having visited the CISC and/or having contact with the CSN or volunteer, in contrast to the six (8.7%) who had reported internet use for information prior to their first visit. Participants indicated a desire for the service to provide additional support to enhance self-care capacity and to do so alongside other people affected by cancer. Conclusions: Our study results support the capacity of a hospital-based CISC to provide a highly valued service that can broaden information options and meet changing information and support needs of people affected by cancer in an ongoing capacity. An experienced, qualified CSN in this setting is ideally positioned to screen for unmet information and support needs and deliver tailored education to support both inpatient and ambulatory care services. Information prescriptions have the potential to provide a 'directed information seeking approach' to those who visit a CISC. Through the use of information technology there is scope to develop information and support that expands beyond pamphlets and booklets. © 2011 Springer-Verlag.
Stagg J.,Peter MacCallum Cancer Center |
Smyth M.J.,Peter MacCallum Cancer Center
Oncogene | Year: 2010
Adenosine triphosphate (ATP) is actively released in the extracellular environment in response to tissue damage and cellular stress. Through the activation of P2X and P2Y receptors, extracellular ATP enhances tissue repair, promotes the recruitment of immune phagocytes and dendritic cells, and acts as a co-activator of NLR family, pyrin domain-containing 3 (NLRP3) inflammasomes. The conversion of extracellular ATP to adenosine, in contrast, essentially through the enzymatic activity of the ecto-nucleotidases CD39 and CD73, acts as a negative-feedback mechanism to prevent excessive immune responses. Here we review the effects of extracellular ATP and adenosine on tumorigenesis. First, we summarize the functions of extracellular ATP and adenosine in the context of tumor immunity. Second, we present an overview of the immunosuppressive and pro-angiogenic effects of extracellular adenosine. Third, we present experimental evidence that extracellular ATP and adenosine receptors are expressed by tumor cells and enhance tumor growth. Finally, we discuss recent studies, including our own work, which suggest that therapeutic approaches that promote ATP-mediated activation of inflammasomes, or inhibit the accumulation of tumor-derived extracellular adenosine, may constitute effective new means to induce anticancer activity. © 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10.
Harvey K.F.,Peter MacCallum Cancer Center |
Harvey K.F.,University of Melbourne |
Zhang X.,Peter MacCallum Cancer Center |
Zhang X.,University of Melbourne |
And 2 more authors.
Nature Reviews Cancer | Year: 2013
The Hippo pathway controls organ size in diverse species, whereas pathway deregulation can induce tumours in model organisms and occurs in a broad range of human carcinomas, including lung, colorectal, ovarian and liver cancer. Despite this, somatic or germline mutations in Hippo pathway genes are uncommon, with only the upstream pathway gene neurofibromin 2 (NF2) recognized as a bona fide tumour suppressor gene. In this Review, we appraise the evidence for the Hippo pathway as a cancer signalling network, and discuss cancer-relevant biological functions, potential mechanisms by which Hippo pathway activity is altered in cancer and emerging therapeutic strategies. © 2013 Macmillan Publishers Limited. All rights reserved.
Lopez J.A.,Peter MacCallum Cancer Center
Blood | Year: 2013
Cytotoxic lymphocytes serve a key role in immune homeostasis by eliminating virus-infected and transformed target cells through the perforin-dependent delivery of proapoptotic granzymes. However, the mechanism of granzyme entry into cells remains unresolved. Using biochemical approaches combined with time-lapse microscopy of human primary cytotoxic lymphocytes engaging their respective targets, we defined the time course of perforin pore formation in the context of the physiological immune synapse. We show that, on recognition of targets, calcium influx into the lymphocyte led to perforin exocytosis and target cell permeabilization in as little as 30 seconds. Within the synaptic cleft, target cell permeabilization by perforin resulted in the rapid diffusion of extracellular milieu-derived granzymes. Repair of these pores was initiated within 20 seconds and was completed within 80 seconds, thus limiting granzyme diffusion. Remarkably, even such a short time frame was sufficient for the delivery of lethal amounts of granzymes into the target cell. Rapid initiation of apoptosis was evident from caspase-dependent target cell rounding within 2 minutes of perforin permeabilization. This study defines the final sequence of events controlling cytotoxic lymphocyte immune defense, in which perforin pores assemble on the target cell plasma membrane, ensuring efficient delivery of lethal granzymes.
Thomas D.M.,Peter MacCallum Cancer Center
Journal of Pathology | Year: 2011
Next-generation sequencing technologies are having an enormous impact on mapping mutations in cancer. However, it is unclear to what extent mutations in genes are shared between cancer types, and to what extent these are unique to different cancers. While the mapping of mutations is almost saturated in common cancer types, the study of rare tumours offers surprising insights into pathways that are deranged in cancer. The paper by Amary et al. in this issue of the Journal of Pathology illustrates the value of studying uncommon cancer types. The authors report on a startlingly high incidence of IDH1/2 mutations in cartilaginous tumours. This finding not only represent a major step forward in mapping the molecular pathogenesis of these tumours, but provides further evidence of the intriguing roles of metabolic pathways in carcinogenesis. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.