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    ABSTRACT: Although there have been recent advances with targeted therapies in chronic lymphocytic leukemia (CLL), chemoimmunotherapy remains the treatment of choice; however, this approach is not curative. A key feature of CLL is that it induces a state of immunosuppression, causing increased susceptibility to infections and failure of an antitumor immune response, often worsened by the immunosuppressive effect of treatment. Because of its improved specificity, immunotherapy potentially offers a way out of this dilemma. Allogeneic stem cell transplantation remains the only curative option, but is hampered by the toxicity of GVHD. After many years of promise but little reward, many other immunotherapeutic approaches are now in transition to the clinical setting. Clinical trials including CLL vaccines, CXCR4 antagonists, and adoptive cellular immunotherapies such as chimeric antigen receptor-modified T cells, CD40 ligand gene therapy, and the immunomodulatory drug lenalidomide are ongoing. Results to date suggest that immunotherapeutic approaches for the treatment of CLL might finally be fulfilling their promise.
    Hematology 12/2013; 2013:151-7. DOI:10.1182/asheducation-2013.1.151
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    ABSTRACT: Pancreatic cancer is characterised by desmoplasia, driven by activated pancreatic stellate cells (PSCs). Over-expression of FGFs and their receptors is a feature of pancreatic cancer and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localise to the nucleus in activated PSCs but not cancer cells. In vitro, inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. In physiomimetic organotypic co-cultures, FGFR inhibition prevented PSC as well as cancer cell invasion. FGFR inhibition resulted in cytoplasmic localisation of FGFR1 and FGF2, in contrast to vehicle-treated conditions where PSCs with nuclear FGFR1 and FGF2 led cancer cells to invade the underlying extra-cellular matrix. Strikingly, abrogation of nuclear FGFR1 and FGF2 in PSCs abolished cancer cell invasion. These findings suggest a novel therapeutic approach, where preventing nuclear FGF/FGFR mediated proliferation and invasion in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion.
    Pancreatology 11/2013; 13(1):e10–e11. DOI:10.1016/j.pan.2012.12.032
  • Blood 11/2013; 122(19):3241-2. DOI:10.1182/blood-2013-09-526376
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    ABSTRACT: There is increasing interest in stereotactic body radiotherapy (SBRT) for the management of prostate adenocarcinoma, with encouraging initial biological progression-free survival results. However, the limited literature is dominated by the use of the Cyberknife platform. This led to an international phase III study comparing outcomes for Cyberknife SBRT with both surgery and conventionally fractionated intensity-modulated radiotherapy (the PACE study). We aim to compare Cyberknife delivery with Rapidarc, a more widely available treatment platform. The scans of six previous prostate radiotherapy patients with a range of prostate sizes were chosen. The clinical target volume was defined as the prostate gland, with 3 mm added for the Cyberknife planning target volume (PTV) and 5 mm for the Rapidarc PTV. Accuray multiplan v. 4.5 was used for planning with delivery on a Cyberknife VSI system v9.5; Varian Eclipse v10 was used for Rapidarc planning with delivery using a Varian 21EX linear accelerator. Both systems attempted to deliver at least 35 Gy to the PTV in five fractions with PTV heterogeneity <12%. All organ at risk (OAR) constraints were achieved by both platforms, whereas the Cyberknife failed to achieve the desired PTV homogeneity constraint in two cases. In other OARs without constraints, Cyberknife delivered higher doses. The volume of the 35 Gy isodose was slightly larger with Rapidarc, but conversely at doses <35 Gy normal tissues received higher doses with Cyberknife. The mean planning and delivery time was in favour of Rapidarc. We have shown that there is no discernible dosimetric advantage to choosing Cyberknife over Rapidarc for SBRT delivery in prostate cancer. Given the significant benefits of Rapidarc in terms of availability, planning and delivery time, the authors suggest that phase III trials of SBRT should include Rapidarc or equivalent rotational delivery platforms.
    Clinical Oncology 09/2013; 26(1). DOI:10.1016/j.clon.2013.08.008
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    ABSTRACT: The Gleason scoring (GS) system underwent revision at the International Society of Urological Pathology (ISUP) conference in 2005. It is not known how uropathologists have interpreted its recommendations. A web-based survey to European Network of Uropathology members received replies from 266 pathologists in 22 countries. 89% claimed to follow ISUP recommendations. Key areas of disagreement included the following. Smoothly rounded cribriform glands were assigned Gleason pattern (GP) 3 by 51% and 4 by 49%. Necrosis was diagnosed as GP 5 by 62%. Any amount of secondary pattern of higher grade of needle biopsies was included in the GS by 58%. Tertiary GP of higher grade on needle biopsies was included in the GS by only 58%. If biopsy cores were embedded separately, only 56% would give a GS for each core/slide examined. 68% would give a concluding GS and the most common method was a global GS (77%). Among those who blocked multiple biopsy cores together, 46% would only give an overall GS for the case. Misinterpretation of ISUP 2005 is widespread and may explain the variation in Gleason scoring seen. Clarity and uniformity in teaching ISUP 2005 recommendations is necessary. This article is protected by copyright. All rights reserved.
    Histopathology 09/2013; 64(3). DOI:10.1111/his.12284
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Although significant advances have been made in the treatment of CLL in the last decade, it remains incurable. Treatments may be too toxic for some elderly patients, who constitute most of the individuals with this disease, and there remain subgroups of patients for which this therapy has minimal activity. This article summarizes the current understanding of the immune defects in CLL. It also examines the potential clinical implications of these findings.
    Hematology/oncology clinics of North America 04/2013; 27(2):207-35. DOI:10.1016/j.hoc.2013.01.003
  • Pancreatology 02/2013; 13(1):e4. DOI:10.1016/j.pan.2012.12.013
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    ABSTRACT: Aims:  The 2005 International Society of Urological Pathology (ISUP) modification of Gleason grading recommended that the highest grade should always be included in the Gleason score (GS) in prostate biopsies. We analysed the impact of this recommendation on reporting of GS 6 versus 7. Methods and results:  Fifteen expert uropathologists reached two-thirds consensus on 15 prostate biopsies with GS 6-7 cancer. Eighty-five microphotographs were graded by 337 of 617 members of the European Network of Uropathology (ENUP), representing 19 countries. There was agreement between expert and majority member GS in 12 of 15 cases, while members upgraded in three cases. Among members and the expert consensus, a GS >6 was assigned by 64.5% and 60%, respectively. Mean member GS was higher than consensus GS in nine of 15 cases. A Gleason pattern (GP) 5 was reported by 0.3-5.6% in 10 cases. Agreement between consensus and member GS was 58.2-89.3% (mean 71.4%) in GS 6 cases and 46.3-63.8% (mean 56.4%) in GS 7 cases (P = 0.009). Conclusions:  While undergrading of prostate cancer used to be prevalent, some now tend to overgrade. Minimum diagnostic criteria for GP 4 and 5 in biopsies need to be better defined. Image libraries reviewed by experts may be useful for standardization.
    Histopathology 01/2013; 62(2):247-256. DOI:10.1111/his.12008
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    ABSTRACT: A key feature of the clinical course of chronic lymphocytic leukemia (CLL) is that it induces a state of immunosuppression, causing increased susceptibility to infections and failure of anti-tumor immune responses. Cytotoxic chemotherapy still forms the mainstay of most current treatment regimens, but is not curative, and its lack of specificity means that it also targets normal immune cells, exacerbating this immunosuppression. This can result in effective treatments being limited by infectious complications, particularly in the elderly who comprise the majority of patients with this disease. Immunotherapy potentially offers a way out of this dilemma, due to its improved specificity and ability to enhance immune responses to both the tumor and infectious agents. There has been a dramatic increase in the range of available immunotherapeutic options over the past decade, and many are now in the process of making the transition to the clinic. This review will discuss both the immune defect in CLL, and emerging immunotherapies, including CD40 ligand gene therapy, lenalidomide, CLL vaccines, CXCR4 antagonists, and adoptive cellular immunotherapies such as chimeric antigen receptor modified T-cells.
    Current pharmaceutical design 05/2012; 18(23):3389-98. DOI:10.2174/138161212801227023
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    ABSTRACT: Combination chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has emerged as the current standard of care in the treatment of chronic lymphocytic leukemia (CLL). Despite very high response rates, this treatment is too toxic for many patients, and it remains unclear as how to manage patients who do not respond to these agents or who relapse early after treatment. An increase in our understanding of the biology of CLL has led to the development of a wide range of therapies aimed at specific defects in this disease. B-cell receptor signaling is aberrantly increased in CLL, and so many of these drugs target key steps in these pathways. Antitumor immunity is also impaired, and a number of strategies are being developed to repair this acquired immune dysfunction. This review highlights some of the emerging agents and describes the biological rationale for their use in CLL.
    Current Oncology Reports 07/2011; 13(5):379-85. DOI:10.1007/s11912-011-0188-6
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