ORCID Profile
0000-0002-2527-5428
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Publisher: Springer Science and Business Media LLC
Date: 25-02-2021
DOI: 10.1186/S13073-021-00841-X
Abstract: Whole genome sequencing (WGS) has the potential to outperform clinical microarrays for the detection of structural variants (SV) including copy number variants (CNVs), but has been challenged by high false positive rates. Here we present ClinSV , a WGS based SV integration, annotation, prioritization, and visualization framework, which identified 99.8% of simulated pathogenic ClinVar CNVs 10 kb and 11/11 pathogenic variants from matched microarrays. The false positive rate was low (1.5–4.5%) and reproducibility high (95–99%). In clinical practice, ClinSV identified reportable variants in 22 of 485 patients (4.7%) of which 35–63% were not detectable by current clinical microarray designs. ClinSV is available at github.com/KCCG/ClinSV .
Publisher: Cold Spring Harbor Laboratory
Date: 04-04-2018
Abstract: Genomic rearrangements are common in cancer, with demonstrated links to disease progression and treatment response. These rearrangements can be complex, resulting in fusions of multiple chromosomal fragments and generation of derivative chromosomes. Although methods exist for detecting in idual fusions, they are generally unable to reconstruct complex chained events. To overcome these limitations, we adopted a new optical mapping approach, allowing megabase-length genome maps to be reconstructed and rearranged genomes to be visualized without loss of integrity. Whole-genome mapping (Bionano Genomics) of a well-studied highly rearranged liposarcoma cell line resulted in 3338 assembled consensus genome maps, including 72 fusion maps. These fusion maps represent 112.3 Mb of highly rearranged genomic regions, illuminating the complex architecture of chained fusions, including content, order, orientation, and size. Spanning the junction of 147 chromosomal translocations, we found a total of 28 Mb of interspersed sequences that could not be aligned to the reference genome. Traversing these interspersed sequences using short-read sequencing breakpoint calls, we were able to identify and place 399 sequencing fragments within the optical mapping gaps, thus illustrating the complementary nature of optical mapping and short-read sequencing. We demonstrate that optical mapping provides a powerful new approach for capturing a higher level of complex genomic architecture, creating a scaffold for renewed interpretation of sequencing data of particular relevance to human cancer.
Publisher: American Psychological Association (APA)
Date: 06-2022
DOI: 10.1037/HEA0001181
Abstract: Comprehensive tumor genomic profiling (CGP) offers hope for personalized treatment for cancer patients when other treatment options have been exhausted. However, receipt of nonactionable or ambiguous results could be an ongoing source of distress. We investigated patterns of hope, anxiety, depression, and CGP-specific anxiety in advanced cancer patients after receiving CGP results and 2-3 months later. Participants were enrolled in a longitudinal psychosocial substudy, embedded in the Molecular Screening and Therapeutics Program, and had advanced solid cancers of any histological type with sufficient and accessible tissue for CGP. At T0 (before receiving CGP results), 1,431 participants completed sociodemographic, disease and psychosocial measures. At T1 (1-4 weeks after receiving CGP results) and T2 (2-3 months post-T1), 374 participants completed psychological outcome measures. Predictors of outcomes at T2 were identified using multinomial logistic regression. Approximately 75% of participants did not experience significant hopelessness or distress at T1 and T2. Hope decreased by T2, yet general anxiety and CGP-specific anxiety also decreased. Receiving actionable results did not impact psychological outcomes at T2. At T2, lower hope, and higher anxiety, depression and CGP-specific anxiety were associated with lower self-efficacy. Psychological and demographic factors (age, socioeconomic status, language, medical occupation, urban living, family history of cancer) independently predicted one or more psychological trajectories. Worse health status and perceived susceptibility to cancer progression predicted hope and anxiety trajectories. Further research on interventions to best support patients undergoing CGP with high anxiety, hopelessness, fear of cancer progression, and poorer health is urgently needed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
Publisher: Mary Ann Liebert Inc
Date: 2007
Abstract: Osteosarcoma is a devastating but rare disease, whose study has illuminated both the basic biology and clinical management of cancer over the past 30 years. These contributions have included insight into the roles of key cancer genes such as the retinoblastoma tumor suppressor gene and TP53, the identification of familial cancer syndromes implicating DNA helicases, and dramatic improvements in survival by the use of adjuvant chemotherapy. This review provides a synoptic overview of our current understanding of the molecular causes of osteosarcoma, and suggests future directions for study.
Publisher: Wiley
Date: 29-11-2019
DOI: 10.1002/GCC.22697
Abstract: Sarcomas have a strong genetic etiology, and the study of families affected by sarcomas has informed much of what we now understand of modern cancer biology. The recent emergence of powerful genetic technologies has led to astonishing reductions in costs and increased throughput. In the clinic, these technologies are revealing a previously unappreciated and rich landscape of genetic cancer risk. In addition to both known and new cancer risk mutations, genomic tools are cataloguing complex and polygenic risk patterns, collectively explaining between 15-25% of apparently sporadic sarcoma cases. The impact on clinical management is exemplified by Li-Fraumeni Syndrome, the most penetrant sarcoma syndrome. Whole body magnetic resonance imaging can identify surgically resectable cancers in up to one in ten in iduals with Li-Fraumeni Syndrome. Taken together, parallel developments in genomics, therapeutics and imaging technologies will drive closer engagement between genetics and multidisciplinary care of the sarcoma patient in the 21st century.
Publisher: Wiley
Date: 2010
DOI: 10.1002/PATH.2635
Abstract: The Wnt pathway plays vital roles in bone and in cancer. In this issue of The Journal of Pathology, Cai and colleagues report results that suggest that the Wnt pathway is inactivated in bone cancers, a finding that could have significant implications for the development of Wnt agonists as bone anabolic agents. While these findings are at odds with the prevailing view that the Wnt pathway is oncogenic in all systems studied to date, they remind us how complex and still poorly understood this important signalling pathway remains. At the very least, these findings should provoke debate and stimulate further research into the role of Wnt signalling in osteosarcoma.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2015
DOI: 10.1158/2159-8290.CD-15-0125
Abstract: Metastasis is the leading cause of death in patients with osteosarcoma, the most common pediatric bone malignancy. We conducted a multistage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified an SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P = 1.2 × 10−9 OR, 2.43 95% confidence interval, 1.83–3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. In addition, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib and with lowered NFIB expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis and that NFIB is an osteosarcoma metastasis susceptibility gene. Significance: Metastasis at diagnosis in osteosarcoma is the leading cause of death in these patients. Here we show data that are supportive for the NFIB locus as associated with metastatic potential in osteosarcoma. Cancer Discov 5(9) 920–31. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 893
Publisher: Wiley
Date: 12-11-2013
DOI: 10.1002/PATH.4251
Abstract: The clinical management of patients with cancer of unknown primary ( CUP ) is h ered by the absence of a definitive site of origin. We explored the utility of massively‐parallel (next‐generation) sequencing for the diagnosis of a primary site of origin and for the identification of novel treatment options. DNA enrichment by hybridization capture of 701 genes of clinical and/or biological importance, followed by massively‐parallel sequencing, was performed on 16 CUP patients who had defied attempts to identify a likely site of origin. We obtained high quality data from both fresh‐frozen and formalin‐fixed, paraffin‐embedded s les, demonstrating accessibility to routine diagnostic material. DNA copy‐number obtained by massively‐parallel sequencing was comparable to that obtained using oligonucleotide microarrays or quantitatively hybridized fluorescently tagged oligonucleotides. Sequencing to an average depth of 458‐fold enabled detection of somatically acquired single nucleotide mutations, insertions, deletions and copy‐number changes, and measurement of allelic frequency. Common cancer‐causing mutations were found in all cancers. Mutation profiling revealed therapeutic gene targets and pathways in 12/16 cases, providing novel treatment options. The presence of driver mutations that are enriched in certain known tumour types, together with mutational signatures indicative of exposure to sunlight or smoking, added to clinical, pathological, and molecular indicators of likely tissue of origin. Massively‐parallel DNA sequencing can therefore provide comprehensive mutation, DNA copy‐number, and mutational signature data that are of significant clinical value for a majority of CUP patients, providing both cumulative evidence for the diagnosis of primary site and options for future treatment. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publisher: American Association for Cancer Research (AACR)
Date: 11-2019
DOI: 10.1158/2159-8290.CD-19-0154
Abstract: Few novel systemic therapies targeting osteosarcoma have emerged in the last four decades. Using insights gained from a genome-wide association study and mouse modeling, we show that GRM4 plays a role in driving osteosarcoma via a non–cell-autonomous mechanism regulating IL23, opening new avenues for therapeutic intervention. See related commentary by Jones, p. 1484. This article is highlighted in the In This Issue feature, p. 1469
Publisher: Elsevier BV
Date: 09-1998
DOI: 10.1016/S8756-3282(98)00095-7
Abstract: Skeletal growth is the net product of coordinated bone formation and resorption. Insulin is known to stimulate bone formation by actions on osteoblasts. It is not known whether insulin receptors are present on osteoclasts, or whether insulin regulates osteoclastic function. We present here immunocytochemical evidence of insulin receptor expression by mature mono- and multinucleated murine osteoclast-like cells generated in vitro, and in primary neonatal rat and mouse osteoclasts. Radiolabeled studies indicated that progressive enrichment of osteoclast-like cells in coculture was associated with increased insulin binding. When osteoclast-like cells generated in vitro were plated onto dentine slices, insulin dose-dependently inhibited pit formation by up to 80%, suggesting a role for insulin in osteoclast function. These data are consistent with an effect of insulin on bone resorption in addition to those previously recognized on bone formation, actions that together result in net bone growth.
Publisher: Frontiers Media SA
Date: 27-01-2016
Publisher: Informa UK Limited
Date: 11-2012
DOI: 10.4161/ONCI.21680
Publisher: Springer Science and Business Media LLC
Date: 02-06-2013
DOI: 10.1038/NG.2645
Publisher: Wiley
Date: 19-01-2021
DOI: 10.1002/JGC4.1384
Abstract: Polygenic risk scores (PRS) are personalized assessments of disease risk based on the cumulative effect of common low‐risk genetic variants. PRS have been shown to accurately predict women's breast cancer risk and are likely to be incorporated into personalized breast cancer risk management programs. However, there are few studies investigating the in idual impact of receiving a breast cancer PRS. Existing studies have not demonstrated significant changes in perceived risk or risk management behaviors after receipt of polygenic risk information. The aim of this qualitative study was to explore how women with a family history of breast cancer construct breast cancer risk perceptions after receipt of a breast cancer PRS. Unaffected women with a family history of breast cancer who had not previously received genetic counseling regarding their breast cancer risk were invited to participate in this study. In‐depth, semi‐structured interviews were conducted with 20 women who attended a familial cancer clinic in the Australian states of Victoria and Tasmania. Data were analyzed using an inductive thematic approach. Women's lived experience played a significant role in the construction and maintenance of their breast cancer risk perception. Women's pre‐existing risk perceptions were informed by their family history and their knowledge that breast cancer is a multifactorial disease. Knowing that breast cancer is a multifactorial disease enabled most women to integrate genetic information with their pre‐existing notions of risk. Women reported that the information they received was consistent with their existing notions of personal risk and screening advice. Therefore, the PRS did not lead to a change in perceived risk or risk management behaviors for most women. The results of this study provide insight into how polygenic risk information is integrated with pre‐existing notions of risk, which will inform its implementation into clinical practice.
Publisher: Cold Spring Harbor Laboratory
Date: 22-12-2020
DOI: 10.1101/2020.12.18.20248521
Abstract: While several key resources exist that interpret therapeutic significance of genomic alterations in cancer, many regional real-world issues limit access to drugs. There is a need for a pragmatic, evidence-based, context-adapted tool to guide clinical management based on molecular biomarkers. A compendium of approved and experimental therapies with associated biomarkers was built following a survey of drug regulatory databases, existing knowledge bases, and published literature. Each biomarker-disease-therapy triplet was then categorized using a tiering system reflective of key therapeutic considerations: approved and reimbursed standard-of-care therapies with respect to a jurisdiction (Tier 1), evidence of efficacy or approval in another jurisdiction (Tier 2), evidence of antitumour activity (Tier 3), and plausible biological rationale (Tier 4). Two resistance categories were defined: lack of efficacy (Tier R1), and lack of antitumor activity (Tier R2). Following comprehensive literature review and appraisal, we developed a curated knowledge base focused on drugs relevant and accessible in the Australian healthcare system (TOPOGRAPH: Therapy Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals). As of November 2020, TOPOGRAPH comprised 2810 biomarker-disease-therapy triplets in 989 expert-appraised entries, including 373 therapies, 199 predictive biomarkers, and 106 cancer types. In the 345 biomarker-linked therapies catalogued, 84 (24%) and 65 (19%) therapies in contexts of different cancer types have Tier 1 and 2 designations respectively, while 271 (79%) therapies were supported by preclinical studies, early clinical trials, retrospective studies, or case series (Tiers 3 and 4). A total of 119 of 373 (33%) therapies associated with biomarkers of resistance were also catalogued. A clinical algorithm was also developed to support therapeutic decision-making using predictive biomarkers. This resource is accessible online at topograph.info/ . TOPOGRAPH is intended to support oncologists with context-appropriate clinical decision-making– optimising selection and accessibility of the most appropriate targeted therapy for any given genomic biomarker. Our approach can be readily adapted to build jurisdiction-specific resources to standardise decision-making in precision oncology.
Publisher: Cambridge University Press (CUP)
Date: 22-05-2007
DOI: 10.1017/S1478951507070253
Abstract: Adolescence and young adulthood is a time of enormous change. For many young people, the profound shift from dependence to autonomy that is the hallmark of this period is physically, emotionally, and spiritually demanding. On the other hand, this phase of life is generally marked by an exuberant optimism that is the envy of jaded adulthood. This optimism, when coupled with intelligence, lack of respect for established forms, and iconoclastic energy, may be the source of a lifetime's achievement.
Publisher: ACM
Date: 08-12-2008
Publisher: Elsevier BV
Date: 11-2013
Publisher: Wiley
Date: 21-09-2016
DOI: 10.1111/HIS.13031
Abstract: Recurrent Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangements characterize a select group of bone and soft tissue tumours. In our routine diagnostic practice with fluorescence in-situ hybridization (FISH), we have occasionally observed EWSR1 gene rearrangements in tumours not associated classically with EWSR1 translocations. This study aimed to review our institutional experience of this phenomenon and also to highlight the occurrence of unusual EWSR1 FISH signals (i.e. 5' centromeric region or 3' telomeric region signals) that do not fulfil the published diagnostic criteria for rearrangements. Using an EWSR1 break-apart probe, we performed FISH assays on formalin-fixed paraffin-embedded tissue sections from 135 bone and soft tissue specimens as part of their routine diagnostic work-up. EWSR1 gene rearrangements were identified in 51% of cases, 56% of which also showed an abnormal FISH signal pattern (in addition to classically rearranged signals). However, atypical FISH signals were present in 45% of the non-rearranged cases. In addition, we observed tumours unrelated to those described classically as EWSR1-associated that were technically EWSR1-rearranged in 6% of cases. Borderline levels of rearrangement (affecting 10-30% of lesional cells) were present in an additional 17% of these cases. While our study confirmed that FISH is a sensitive and specific tool in the diagnosis of EWSR1-associated tumours, atypical FISH signals and classical rearrangement in entities other than EWSR1-associated tumours can occur. Therefore, it is essential that the FISH result not be used as an isolated test, but must be evaluated in the context of clinical features, imaging, pathological and immunohistochemical findings.
Publisher: Wiley
Date: 20-04-2012
DOI: 10.1111/J.1445-5994.2006.01062.X
Abstract: The optimal management of adolescent and young adult cancer has been the subject of vigorous debate in paediatric and adult cancer community for many years. This debate is rapidly coming to the boil. There is international recognition that not only is cancer in young people on the rise but also that improvements in outcomes of cancer in young people lag well behind the advances that have been achieved for both children and older adults in the past 30 years. The underlying problems appear to relate to a complex set of interactions between the health-care system and the prevalence of cancer in this age group and the unique psychosocial and educational needs of this population. This article explores why we should be concerned about Australian health outcomes in this group and considers how best we might respond to these concerns.
Publisher: Springer Science and Business Media LLC
Date: 24-02-2017
DOI: 10.1038/NCOMMS14607
Abstract: Genetic evolution that occurs during cancer progression enables tumour heterogeneity, thereby fostering tumour adaptation, therapeutic resistance and metastatic potential. Immune responses are known to select (immunoedit) tumour cells displaying immunoevasive properties. Here we address the role of IFN-γ in mediating the immunoediting process. We observe that, in several mouse tumour models such as HA-expressing 4T1 mammary carcinoma cells, OVA-expressing EG7 lymphoma cells and CMS5 MCA-induced fibrosarcoma cells naturally expressing mutated extracellular signal-regulated kinase (ERK) antigen, the action of antigen-specific cytotoxic T cell (CTL) in vivo results in the emergence of resistant cancer cell clones only in the presence of IFN-γ within the tumour microenvironment. Moreover, we show that exposure of tumours to IFN-γ-producing antigen-specific CTLs in vivo results in copy-number alterations (CNAs) associated with DNA damage response and modulation of DNA editing/repair gene expression. These results suggest that enhanced genetic instability might be one of the mechanisms by which CTLs and IFN-γ immunoedits tumours, altering their immune resistance as a result of genetic evolution.
Publisher: Wiley
Date: 26-11-2019
DOI: 10.1111/CGE.13664
Abstract: Implementation of any new medical test, including germline genome sequencing (GS) to inform cancer risk, should take place only when a test is effective, ethically justifiable and acceptable to a population. Little empirical evidence exists on patient views regarding GS for cancer risk. The aim of this study was to elicit opinions on who should be offered GS and who should pay for it. Participants with a probable genetic basis for their cancer (n = 335) and blood relatives (n = 199) were recruited to undergo GS and invited to complete questionnaires at baseline. A subset (n = 40) also participated in qualitative interviews about their views regarding access to GS to detect cancer risk. Our response rate was 92% for questionnaires and 100% for interviews. Participants expressed high enthusiasm overall for access to GS for those with a family history of cancer and anyone who requested testing, but enthusiasm was lower for universal access, if opting out was possible and finances not an issue. Rationales for these views reflected maximising the sound use of resources. Challenges to introducing community screening via GS to limit cancer burden were raised, including the current limits of science and in idual ability to cope with uncertain results. Participants undergoing GS supported cancer risk testing for those with a family history of cancer but were concerned about the challenges of designing and implementing a population-based GS cancer-screening program.
Publisher: Springer Science and Business Media LLC
Date: 05-04-2018
Publisher: Informa UK Limited
Date: 23-01-2015
Publisher: Cold Spring Harbor Laboratory
Date: 04-2019
DOI: 10.1101/MCS.A003764
Abstract: Adrenocortical carcinoma is a rare malignancy with a poor prognosis and few treatment options. Molecular characterization of this cancer remains limited. We present a case of an adrenocortical carcinoma (ACC) in a 37-yr-old female, with dual lung metastases identified 1 yr following commencement of adjuvant mitotane therapy. As standard therapeutic regimens are often unsuccessful in ACC, we undertook a comprehensive genomic study into this case to identify treatment options and monitor disease progress. We performed targeted and whole-genome sequencing of germline, primary tumor, and both metastatic tumors from this patient and monitored recurrence over 2 years using liquid biopsy for ctDNA and steroid hormone measurements. Sequencing revealed the primary and metastatic tumors were hyperhaploid, with extensive loss of heterozygosity but few structural rearrangements. Loss-of-function mutations were identified in MSH2 , TP53 , RB1 , and PTEN , resulting in tumors with mismatch repair signatures and microsatellite instability. At the cellular level, tumors were populated by mitochondria-rich oncocytes. Longitudinal ctDNA mutation and hormone profiles were unable to detect micrometastatic disease, consistent with clinical indicators of disease remission. The molecular signatures in our ACC case suggested immunotherapy in the event of disease progression however, the patient remains free of cancer. The extensive molecular analysis presented here could be applied to other rare and/or poorly stratified cancers to identify novel or repurpose existing therapeutic options, thereby broadly improving diagnoses, treatments, and prognoses.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.PEC.2021.05.018
Abstract: To understand advanced cancer patients' experience of uncertainty when receiving comprehensive tumor genomic profiling (CTGP) results, and their perceptions of how healthcare provider (HCP) communication impacts uncertainty. Thirty-seven semi-structured interviews with advanced cancer patients were conducted within two weeks of patients receiving CTGP results. Transcripts were thematically analyzed, using an inductive approach. We identified three themes that illustrate patient experience of uncertainties when receiving CTGP results: 1. Type and degree of uncertainty fluctuates along with changing illness circumstances and the nature of the CTGP results 2. HCPs' co-ordination of care and communication shapes uncertainty, with immediate, clearer and simpler information promoting certainty and 3. Patients felt that communicating results to reduce relatives' uncertainty is important, with patients choosing the time and process for achieving this and desiring HCPs support. Oncology patients are confronted with an array of uncertainties. Clear, simple communication from HCPs about results and their implications, and support to manage uncertainty, will be of benefit. If CTGP is to become routine clinical practice, clear communication will be crucial in reducing uncertainty. Awareness of potential uncertainties experienced by patients when receiving results, will assist HCPs to address uncertainties, reduce uncertainty where possible, and offer targeted support to patients struggling with uncertainty.
Publisher: Informa UK Limited
Date: 03-01-2014
DOI: 10.4161/ONCI.27569
Publisher: Informa UK Limited
Date: 2008
Abstract: Positron emission tomography (PET) is a noninvasive functional imaging technique that allows assessment of key biological processes important in cancer development and progression. It provides information complementary to conventional anatomic imaging, demonstrating utility in a range of cancer settings from diagnosis, biopsy guidance, tumor stratification and prognostication, and staging and surveillance of disease recurrence. Its ability to evaluate vital processes in tumor biology also makes it a potentially valuable and sensitive tool for assessing therapeutic response. The development of novel PET tracers and improvements in technology will only continue to augment the potential of PET and enhance its attractiveness as an instrument to facilitate drug development. This article will discuss the above issues, using the setting of sarcomas as an ex le.
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1053/J.SEMINONCOL.2009.03.006
Abstract: The outcomes in young adults aged 20-39 with sarcoma tend to be inferior compared to those in children and adolescents. There are differences in sarcoma histotype distribution with age, such that pediatric-type tumors predominate in the 20- to 25-year-old group while more adult-type sarcomas occur in those aged 35-39 years. Certain occupational exposures, co-infection with human herpes virus 8 (HHV-8) and human immunodeficiency virus (HIV), prior radiation exposure, and genetic syndromes are relevant risk factors. In many of the types of sarcoma encountered in 20 to 39 year olds, there are important biological differences compared to the tumors in younger patients that play a role in the outcomes for these patients. Increased research into these differences and incorporating our knowledge about them into treatments tailored towards this age group is necessary to overcome the relatively poor outcomes in young adult sarcoma patients.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-11-2010
Abstract: Adolescent and young adult (AYA) patients seem to be in a sort of no-man's land, halfway between the two different worlds of pediatric and adult medical oncology and bearing the brunt, in terms of inclusion in clinical trials and quality of professional care, of the lack of integration between these two worlds. This article discusses the different organization models of care used in pediatric oncology (mainly family-focused) and in adult medical oncology (disease-focused). There is a growing awareness that these models are not ideally suited to the complex needs of AYA patients, which require a different, new, patient-focused multidisciplinary approach. A comprehensive, multipronged effort is required to bridge the gap in the care of AYA patients, with the ultimate challenge of creating a new discipline, AYA oncology. In this article, we review the experiences of AYA oncology programs in Europe, North America, and Australia, focusing on similarities and differences in strategy, as well as the major challenges and opportunities faced by these programs. Among the most important factors for the successful establishment of an AYA oncology service are the degree of engagement of both pediatric and adult medical oncologists, the philanthropic support of powerful charities, and the role of dedicated professionals across a range of disciplines in driving the development of services for AYA patients.
Publisher: Wiley
Date: 18-04-2011
Publisher: PUBLISHED BY IMPERIAL COLLEGE PRESS AND DISTRIBUTED BY WORLD SCIENTIFIC PUBLISHING CO.
Date: 11-2009
Publisher: Hindawi Limited
Date: 18-03-2019
DOI: 10.1002/HUMU.23739
Abstract: Germline pathogenic variants in the TP53 gene cause Li-Fraumeni syndrome, a condition that predisposes in iduals to a wide range of cancer types. Identification of in iduals carrying a TP53 pathogenic variant is linked to clinical management decisions, such as the avoidance of radiotherapy and use of high-intensity screening programs. The aim of this study was to develop an evidence-based quantitative model that integrates independent in silico data (Align-GVGD and BayesDel) and somatic to germline ratio (SGR), to assign pathogenicity to every possible missense variant in the TP53 gene. To do this, a likelihood ratio for pathogenicity (LR) was derived from each component calibrated using reference sets of assumed pathogenic and benign missense variants. A posterior probability of pathogenicity was generated by combining LRs, and algorithm outputs were validated using different approaches. A total of 730 TP53 missense variants could be assigned to a clinically interpretable class. The outputs of the model correlated well with existing clinical information, functional data, and ClinVar classifications. In conclusion, these quantitative outputs provide the basis for in idualized assessment of cancer risk useful for clinical interpretation. In addition, we propose the value of the novel SGR approach for use within the ACMG/AMP guidelines for variant classification.
Publisher: American Medical Association (AMA)
Date: 14-05-2020
Publisher: Wiley
Date: 23-04-2009
DOI: 10.1002/IJC.24376
Abstract: Good evidence indicates that adolescents and young adults (AYAs) with cancer do badly compared with children with similar cancers. The reasons are poorly understood. Australian registry data on 14,824 cancers of adolescence and young adulthood seen between 1982 and 2002 were reviewed. A detailed substudy of clinical characteristics was analyzed from 179 AYAs with Hodgkin lymphoma (HL), Ewing sarcoma (ES) or osteosarcomas (OS) treated at a single institution. Despite significant improvements in survival for both groups over the period in question, for acute lymphoblastic leukaemia, rhabdomyosarcoma, ES, OS and HL, survival for AYAs was worse than for children. For ES, OS and HL, the survival gap occurred almost entirely in males (Hazard ratios compared with female AYAs of 1.8 [p < 0.01], 1.4 [p = 0.03] and 1.5 [p < 0.01] respectively). Survival outcomes from ES, OS and HL for female AYAs were not significantly different from children of either sex. For brain tumors and thyroid cancers, which are primarily treated surgically, there were no gender-related differences in outcomes. Although no differences in tumor stage or compliance were identified, male AYAs experienced less toxicity and lower response rates to chemotherapy (p = 0.008). Young males account almost entirely for excess mortality from chemosensitive cancers of adolescence and young adulthood compared to children, which may be due to relative underdosing with current chemotherapy dosing algorithms.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Wiley
Date: 09-2004
Publisher: Wiley
Date: 24-09-2007
Publisher: American Association for Cancer Research (AACR)
Date: 02-2013
DOI: 10.1158/0008-5472.CAN-13-2424
Abstract: Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic lification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n = 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity. RNA sequencing revealed that the global transcriptomic profiles of these sarcomas provided a more robust prediction of apoptotic responses to Nutlin-3a. Expression profiling revealed a subset of TP53 target genes that were transactivated specifically in sarcomas that were highly sensitive to Nutlin-3a. Of these target genes, the GADD45A promoter region was shown to be hypermethylated in 82% of wild-type TP53 sarcomas that did not respond to Nutlin-3a, thereby providing mechanistic insight into the innate ability of sarcomas to resist apoptotic death following Nutlin-3a treatment. Collectively, our findings argue that the existing benchmark biomarker for MDM2 antagonist efficacy (MDM2 lification) should not be used to predict outcome but rather global gene expression profiles and epigenetic status of sarcomas dictate their sensitivity to p53/MDM2 antagonists. Cancer Res 74(3) 921–31. ©2013 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 02-2011
DOI: 10.1158/1078-0432.CCR-10-2050
Abstract: Purpose: Reactivation of p53 tumor suppressor activity in diseases such as soft-tissue sarcoma is considered an attractive means of targeted therapy. By systematically assessing alterations affecting the p53 pathway, we aimed to (a) classify sarcoma subtypes, (b) define a potential role in malignancy, and (c) identify potential patient biomarkers in this heterogeneous disease. Experimental Design: We have mapped mutational events in a panel of 192 benign or malignant bone and soft-tissue sarcomas. Analyses included TP53 and CDKN2A mutational and SNP status, MDM2 and MDM4 lification and MDM2 SNP309 status. Results: We found an inverse relationship between MDM2 lification and TP53 mutations, with a predominantly wild-type CDKN2A background. A high rate of point mutations in TP53 was observed uniquely in leiomyosarcoma, osteosarcoma, and MFH. Both MDM2 and MDM4 were also lified in a subtype-specific manner, which was frequently seen as a co lification event. We have also analyzed the risk allele frequencies for MDM2 SNP309, and show that the G allele was strongly associated with both liposarcomas and MDM2 lification. Conclusions: Our data emphasize the critical role of p53 inactivation in sarcomagenesis, whereby different pathway alterations may be related to the heterogeneity of the disease. Moreover, we observed a strong association of malignancy with TP53 mutation, or MDM2 lification and the presence of a G allele in SNP309, especially in lipoma versus liposarcoma. We propose, therefore, that MDM2 markers along with TP53 sequencing should be considered as patient biomarkers in clinical trials of sarcomas using MDM2 antagonists. Clin Cancer Res 17(3) 416–26. ©2010 AACR.
Publisher: Springer Science and Business Media LLC
Date: 18-11-2005
DOI: 10.1007/S00256-005-0044-6
Abstract: Mesenchymal chondrosarcoma is a rare but aggressive, high-grade malignancy of primitive cartilage-forming mesenchyme that arises most commonly from skeletal sites. Although there are radiological findings suggestive of the diagnosis, imaging features often overlap with those of other skeletal sarcomas. The definitive diagnosis relies on the histological finding of a typical bimorphic appearance, consisting of nests of small, round, poorly differentiated cells and more mature cartilaginous tissue. To highlight this, we present the case of a 21-year-old man who was referred to our institution with a history of right knee pain. Initial imaging and histological evaluation of a core biopsy of the lesion suggested osteosarcoma of the distal right femur after review, however, the correct diagnosis of mesenchymal chondrosarcoma was made. Adequate tissue s ling and thorough histological evaluation of biopsy specimens is vital for the accurate diagnosis of primary bone malignancies, especially those of chondroid origin.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2023
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-01-2018
Abstract: In this review, we highlight the complexities of the natural history, biology, and clinical management of three intermediate connective tissue tumors: desmoid tumor (DT) or aggressive fibromatosis, tenosynovial giant cell tumor (TGCT) or diffuse-type pigmented villonodular synovitis (dtPVNS), and giant cell tumor of bone (GCTB). Intermediate histologies include tumors of both soft tissue and bone origin and are locally aggressive and rarely metastatic. Some common aspects to these tumors are that they can be locally infiltrative and/or impinge on critical organs, which leads to disfigurement, pain, loss of function and mobility, neurovascular compromise, and occasionally life-threatening consequences, such as mesenteric, bowel, ureteral, and/or bladder obstruction. DT, PVNS, and GCTB have few and recurrent molecular aberrations but, paradoxically, can have variable natural histories. A multidisciplinary approach is recommended for optimal management. In DT and PVNS, a course of observation may be appropriate, and any intervention should be guided by symptoms and/or disease progression. A surgical approach should take into consideration the infiltrative nature, difficulty in obtaining wide margins, high recurrence rates, acute and chronic surgical morbidities, and impact on quality of life. There are similar concerns with radiation, which especially relate to optimal field and transformation to high-grade radiation-associated sarcomas. Systemic therapies must be considered carefully in light of acute and chronic toxicities. Although standard and novel therapies are promising, many unanswered questions, such as duration of therapy and optimal end points to evaluate efficacy of drugs in clinical practice and trials, exist. Predictive biomarkers and novel clinical trial end points, such as volumetric measurement, magnetic resonance imaging T2 weighted mapping, nuclear imaging, and patient-reported outcomes, are in development and will require validation in prospective trials.
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2017
DOI: 10.1158/0008-5472.CAN-16-2550
Abstract: Despite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have demonstrated limited clinical success, urging an unbiased and comprehensive analysis of oncogenic signaling networks to reveal therapeutic targets and personalized treatment strategies. Here we applied mass spectrometry–based phosphoproteomic profiling to the largest and most heterogeneous set of sarcoma cell lines characterized to date and identified novel tyrosine phosphorylation patterns, enhanced tyrosine kinases in specific subtypes, and potential driver kinases. ALK was identified as a novel driver in the Aska-SS synovial sarcoma (SS) cell line via expression of an ALK variant with a large extracellular domain deletion (ALKΔ2–17). Functional ALK dependency was confirmed in vitro and in vivo with selective inhibitors. Importantly, ALK immunopositivity was detected in 6 of 43 (14%) of SS patient specimens, one of which exhibited an ALK rearrangement. High PDGFRα phosphorylation also characterized SS cell lines, which was accompanied by enhanced MET activation in Yamato-SS cells. Although Yamato-SS cells were sensitive to crizotinib (ALK/MET-inhibitor) but not pazopanib (VEGFR/PDGFR-inhibitor) monotherapy in vitro, synergistic effects were observed upon drug combination. In vivo, both drugs were in idually effective, with pazopanib efficacy likely attributable to reduced angiogenesis. MET or PDGFRα expression was detected in 58% and 84% of SS patients, respectively, with coexpression in 56%. Consequently, our integrated approach has led to the identification of ALK and MET as promising therapeutic targets in SS. Cancer Res 77(16) 4279–92. ©2017 AACR.
Publisher: Wiley
Date: 05-04-2006
DOI: 10.1002/JCB.20850
Abstract: Almost all tumors are characterized by both architectural and cellular abnormalities in differentiation. Osteoblast development is relatively well understood, making osteosarcoma a good model for understanding how tumorigenesis perturbs normal differentiation. We argue that there are two key transition points in normal cellular differentiation that are the focus of oncogenic events, in both of which epigenetic processes are critical. The first is the transition from an uncommitted pluripotent precursor (mesenchymal stem cell) to the 'transit- lifying compartment' of the osteoblast lineage. This transition, normally exquisitely regulated in space and time, is abnormal in cancer. The second involves termination of lineage expansion, equally tightly regulated under normal circumstances. In cancer, the mechanisms that mandate eventual cessation of cell ision are almost universally disrupted. This model predicts that key differentiation genes in bone, such as RUNX2, act in an oncogenic fashion to initiate entry into a proliferative phase of cell differentiation, and anti-oncogenically into the post-mitotic state, resulting in ambivalent roles in tumorigenesis. Polycomb genes exemplify epigenetic processes in the stem cell compartment and tumorigenesis, and are implicated in skeletal development in vivo. The epigenetic functions of the retinoblastoma protein, which plays a key role in tumorigenesis in bone, is discussed in the context of terminal cell cycle exit.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2015
Publisher: Elsevier BV
Date: 09-2020
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2012
DOI: 10.1158/1078-0432.CCR-12-0578
Abstract: Purpose: Giant-cell tumor of bone (GCTB) is a locally aggressive, benign osteolytic tumor in which bone destruction is mediated by RANK ligand (RANKL). The RANKL inhibitor denosumab is being investigated for treatment of GCTB. We describe histologic analyses of GCTB tumor s les from a phase II study of denosumab in GCTB. Experimental Design: Adult patients with recurrent or unresectable GCTB received subcutaneous denosumab 120 mg every 4 weeks (with additional doses on days 8 and 15). The primary histologic efficacy endpoint was the proportion of patients who had a 90% or more elimination of giant cells from their tumor. Baseline and on-study specimens were also evaluated for overall tumor morphology and expression of RANK and RANKL. Results: Baseline tumor s les were typically composed of densely cellular proliferative RANKL-positive tumor stromal cells, RANK-positive rounded mononuclear cells, abundant RANK-positive tumor giant cells, and areas of scant de novo osteoid matrix and woven bone. In on-study s les from 20 of 20 patients (100%), a decrease of 90% or more in tumor giant cells and a reduction in tumor stromal cells were observed. In these analyses, thirteen patients (65%) had an increased proportion of dense fibro-osseous tissue and/or new woven bone, replacing areas of proliferative RANKL-positive stromal cells. Conclusions: Denosumab treatment of patients with GCTB significantly reduced or eliminated RANK-positive tumor giant cells. Denosumab also reduced the relative content of proliferative, densely cellular tumor stromal cells, replacing them with nonproliferative, differentiated, densely woven new bone. Denosumab continues to be studied as a potential treatment for GCTB. Clin Cancer Res 18(16) 4415–24. ©2012 AACR.
Publisher: Wiley
Date: 13-09-2010
Publisher: Wiley
Date: 28-05-2019
DOI: 10.1111/AJCO.12980
Abstract: Fluorescence in situ hybridization (FISH) is an important ancillary tool for the classification of bone/soft tissue (BST) tumors. The aim of this study was to evaluate the contribution of FISH to the final classification of common BST entities in the molecular pathology department of the Royal Prince Alfred Hospital (RPAH), which is one of the most important referral centers for the management of sarcomas in Australia. All routine diagnostic FISH tests performed on BST formalin-fixed paraffin embedded (FFPE) tissue specimens at the RPAH in a 5-year period (February, 2010-November, 2015) were reviewed. FISH analyses presented in this study include commercial break-apart probes (SS18, FUS, DDIT3, FUS, USP6, PDGFB, TFE3 and ALK) and a single enumeration (MDM2) probe. There were 434 interpretable FISH assays on BST s les including MDM2 (n=180), SS18 (n=97), FUS (n=64), DDIT3 (n=37), USP6 (n=30), PDGFB (n=13), TFE3 (n=8) and ALK (n=5). Discrepancies between the histopathological diagnosis and the FISH results were seen in 12% of the cases. In this subset of discordant cases, FISH contributed to the re-classification of 7% of cases originally diagnosed as synovial sarcoma (SS18) and 6% of adipocytic neoplasms (MDM2) based on the presence or absence of the expected gene alteration. Our study confirms that paraffin FISH is a sensitive and specific ancillary tool in the diagnosis of BST neoplasms when used in the appropriate clinicopathological context. These findings highlight the need for further ancillary molecular tools in the diagnosis and characterization of challenging cases.
Publisher: Springer Science and Business Media LLC
Date: 15-06-2022
DOI: 10.1038/S41467-022-30496-0
Abstract: There are more than 70 distinct sarcomas, and this ersity complicates the development of precision-based therapeutics for these cancers. Prospective comprehensive genomic profiling could overcome this challenge by providing insight into sarcomas’ molecular drivers. Through targeted panel sequencing of 7494 sarcomas representing 44 histologies, we identify highly recurrent and type-specific alterations that aid in diagnosis and treatment decisions. Sequencing could lead to refinement or reassignment of 10.5% of diagnoses. Nearly one-third of patients (31.7%) harbor potentially actionable alterations, including a significant proportion (2.6%) with kinase gene rearrangements 3.9% have a tumor mutational burden ≥10 mut/Mb. We describe low frequencies of microsatellite instability ( .3%) and a high degree of genome-wide loss of heterozygosity (15%) across sarcomas, which are not readily explained by homologous recombination deficiency (observed in 2.5% of cases). In a clinically annotated subset of 118 patients, we validate actionable genetic events as therapeutic targets. Collectively, our findings reveal the genetic landscape of human sarcomas, which may inform future development of therapeutics and improve clinical outcomes for patients with these rare cancers.
Publisher: Springer Science and Business Media LLC
Date: 13-05-2014
Publisher: Elsevier BV
Date: 06-2015
Publisher: Wiley
Date: 2001
Publisher: Springer Science and Business Media LLC
Date: 12-2006
Abstract: The development of targeted therapies has created a pressing clinical need for the rapid and robust molecular characterisation of cancers. We describe here the application of high-resolution melting analysis (HRM) to screen for KRAS mutations in clinical cancer s les. In non-small cell lung cancer, KRAS mutations have been shown to identify a group of patients that do not respond to EGFR targeted therapies and the identification of these mutations is thus clinically important. We developed a high-resolution melting (HRM) assay to detect somatic mutations in exon 2, notably codons 12 and 13 of the KRAS gene using the intercalating dye SYTO 9. We tested 3 different cell lines with known KRAS mutations and then examined the sensitivity of mutation detection with the cell lines using 189 bp and 92 bp licons spanning codons 12 and 13. We then screened for KRAS mutations in 30 non-small cell lung cancer biopsies that had been previously sequenced for mutations in EGFR exons 18–21. Known KRAS mutations in cell lines (A549, HCT116 and RPMI8226) were readily detectable using HRM. The shorter 92 bp licon was more sensitive in detecting mutations than the 189 bp licon and was able to reliably detect as little as 5–6% of each cell line DNA diluted in normal DNA. Nine of the 30 non-small cell lung cancer biopsies had KRAS mutations detected by HRM analysis. The results were confirmed by standard sequencing. Mutations in KRAS and EGFR were mutually exclusive. HRM is a sensitive in-tube methodology to screen for mutations in clinical s les. HRM will enable high-throughput screening of gene mutations to allow appropriate therapeutic choices for patients and accelerate research aimed at identifying novel mutations in human cancer.
Publisher: Wiley
Date: 12-1997
DOI: 10.1111/J.1445-5994.1997.TB01009.X
Abstract: There is little information about neuropsychiatric comorbidities in Charcot-Marie-Tooth disease (CMT). We assessed frequency of anxiety, depression, and general distress in CMT. We administered online the Hospital Anxiety-Depression Scale (HADS) to CMT patients of the Italian registry and controls. HADS-A and HADS-D scores ≥ 11 defined the presence of anxiety/depression and HADS total score (HADS-T) ≥ 22 of general distress. We analysed correlation with disease severity and clinical characteristics, use of anxiolytics/antidepressants and analgesic/anti-inflammatory drugs. We collected data from 252 CMT patients (137 females) and 56 controls. CMT patient scores for anxiety (mean ± standard deviation, 6.7 ± 4.8), depression (4.5 ± 4.0), and general distress (11.5 ± 8.1) did not differ from controls and the Italian population. However, compared to controls, the percentages of subjects with depression (10% vs 2%) and general distress (14% vs 4%) were significantly higher in CMT patients. We found no association between HADS scores and disease duration or CMT type. Patients with general distress showed more severe disease and higher rate of positive sensory symptoms. Depressed patients also had more severe disease. Nineteen percent of CMT patients took antidepressants/anxiolytics (12% daily) and 70% analgesic/anti-inflammatory drugs. Patients with anxiety, depression, and distress reported higher consumption of anxiolytics/antidepressants. About 50% of patients with depression and/or general distress did not receive any specific pharmacological treatment. An appreciable proportion of CMT patients shows general distress and depression. Both correlated with disease severity and consumption of antidepressants/anxiolytics, suggesting that the disease itself is contributing to general distress and depression.
Publisher: Springer Science and Business Media LLC
Date: 23-01-2020
DOI: 10.1038/S41467-019-14079-0
Abstract: Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly in iduals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB in iduals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing.
Publisher: Informa UK Limited
Date: 2020
Publisher: Elsevier BV
Date: 05-2021
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1053/J.SEMINONCOL.2009.06.008
Abstract: Despite complex genetics, aneuploid tumors like dedifferentiated liposarcoma have specific and reproducible chromosomal changes such as lification of HDM2 and CDK4 that represent potential targets for systemic therapy. In addition, there are cancer cell survival pathways that may not be the target of chromosomal translocations or mutations that are still estimable targets for new systemic therapeutics, be it pathways involved in angiogenesis or apoptosis. In this review, we examine target selection for specific sarcoma subtypes, and demonstrate with a few ex les new techniques being used to delineate novel therapeutic inroads for patients with sarcoma.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2011
DOI: 10.1007/S11912-011-0173-0
Abstract: Soft tissue sarcomas are rare tumors and include subtypes with variable clinical, pathological, and genetic characteristics, including leiomyosarcoma. Current chemotherapy options include the use of doxorubicin, ifosfamide, gemcitabine and docetaxel, and trabectedin, but these have poor response rates in the metastatic setting. While some targeted therapies with tyrosine kinase inhibitors have shown promise, there is a clear need for novel, targeted strategies for this enigmatic form of soft-tissue sarcoma. The genomic instability and multiple, complex karyotypic abnormalities of leiomyosarcomas is a potential for therapy with agents with proven activity in other cancers with genomic instability, such as BRCA-related breast or ovarian cancer. There are few pathways affected in leiomyosarcoma that suggest obvious opportunities, but poly ADP-ribose polymerase (PARP) inhibitors hold promise. This article outlines current therapeutic options available and undergoing study, as well as explores the rationale for the study of PARP inhibitors in leiomyosarcomas, with or without chemotherapy.
Publisher: Springer Science and Business Media LLC
Date: 27-03-2019
DOI: 10.1038/S41467-019-09374-9
Abstract: Fusion genes are a major cause of cancer. Their rapid and accurate diagnosis can inform clinical action, but current molecular diagnostic assays are restricted in resolution and throughput. Here, we show that targeted RNA sequencing (RNAseq) can overcome these limitations. First, we establish that fusion gene detection with targeted RNAseq is both sensitive and quantitative by optimising laboratory and bioinformatic variables using spike-in standards and cell lines. Next, we analyse a clinical patient cohort and improve the overall fusion gene diagnostic rate from 63% with conventional approaches to 76% with targeted RNAseq while demonstrating high concordance for patient s les with previous diagnoses. Finally, we show that targeted RNAseq offers additional advantages by simultaneously measuring gene expression levels and profiling the immune-receptor repertoire. We anticipate that targeted RNAseq will improve clinical fusion gene detection, and its increasing use will provide a deeper understanding of fusion gene biology.
Publisher: Springer Science and Business Media LLC
Date: 07-03-2013
DOI: 10.1038/NRC3458
Abstract: The Hippo pathway controls organ size in erse 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.
Publisher: Portland Press Ltd.
Date: 23-08-2005
DOI: 10.1042/BJ20050351
Abstract: Perturbation of oxygen flow occurs in disease states such as diabetic retinopathy and cancer. To maintain oxygen homoeostasis, the mammalian microvascular endothelium undergoes a dramatic reorganization to assist in bringing oxygen and nutrients to oxygen-starved tissues. This process is termed angiogenesis and is common in certain cancers with hypoxic foci and in areas of focal ischaemia in the diabetic retina. In the present study, we report on the activation of the JAK2/STAT5 pathway (where JAK stands for Janus kinase and STAT stands for signal transduction and activator of transcription) by low oxygen in microvascular endothelial cells. This activation appears to occur downstream of VEGF (vascular endothelial growth factor), a well-known proangiogenic factor, and is related to repression of proapoptotic FAS(CD95)/FASL(CD95L). These results indicate that the JAK/STAT pathway may play a pivotal role during tumour-associated or retinal angiogenesis in which endothelial cell survival during tissue hypoxia is critical for maintaining either the growth of neoplasms or the inappropriate retinal neovascularization common in diabetic retinopathy.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-07-2011
Abstract: Colorectal cancer predominantly occurs in the elderly, but approximately 5% of patients are 50 years old or younger. We sought to determine whether young age is prognostic, or whether it influences efficacy/toxicity of chemotherapy, in patients with advanced disease. We analyzed in idual data on 6,284 patients from nine phase III trials of advanced colorectal cancer (aCRC) that used fluorouracil-based single-agent and combination chemotherapy. End points included progression-free survival (PFS), overall survival (OS), response rate (RR), and grade 3 or worse adverse events. Stratified Cox and adjusted logistic-regression models were used to test for age effects and age-treatment interactions. A total of 793 patients (13%) were younger than 50 years old 188 of these patients (3% of total patients) were younger than 40 years old. Grade 3 or worse nausea (10% v 7% P = .01) was more common, and severe diarrhea (11% v 14% P = .001) and neutropenia (23% v 26% P .001) were less common in young (younger than 50 years) than in older (older than 50 years) patients. Age was prognostic for PFS, with poorer outcomes occurring in those younger than 50 years (median, 6.0 v 7.5 months hazard ratio, 1.10 P = .02), but it did not affect RR or OS. In the subset of monotherapy versus combination chemotherapy trials, the relative benefits of multiagent chemotherapy were similar for young and older patients. Results were comparable when utilizing an age cut point of 40 years. Young age is modestly associated with poorer PFS but not OS or RR in treated patients with aCRC, and young patients have more nausea but less diarrhea and neutropenia with chemotherapy in general. Young versus older patients derive the same benefits from combination chemotherapy. Absent results of a clinical trial, standard combination chemotherapy approaches are appropriate for young patients with aCRC.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2018
DOI: 10.1007/S00280-018-3683-8
Abstract: For many cancers, adolescents and young adults (AYA) have worse outcomes than for children and adults. Many factors may contribute to the AYA survival gap, including differences in biology, therapeutic intent, and adherence to therapy. It has been observed that male AYAs have poorer outcomes than females. The purpose of this work was to test the proposition that gender-related pharmacologic factors may account for a component of the AYA survival gap. A prospective, multi-institutional pharmacologic study of 79 patients in total with chemosensitive cancers (Ewing sarcoma, osteosarcoma and Hodgkin lymphoma) was conducted, with conventional doxorubicin treatment. Pharmacokinetic data of 13 children, 40 AYAs and 13 adults were valid for analysis. Population pharmacokinetics models were developed for doxorubicin and its metabolite doxorubicinol based on the data created in this study. Consequently, model-based analysis was conducted to investigate the relevant topics. The clearance of doxorubicinol (normalized to body surface area), the main active metabolite of doxorubicin, appears faster in male AYAs than female (p = 0.04, 95% CI 0.1-3.9 L/h). The exposure of doxorubicinol (normalized to dose) is lower in male AYA than female (p = 0.03, 95% CI - 0.005 to - 0.0002 h/L). These might be correlated to the observed difference on nadir neutrophil count between male AYA and female (p = 0.027, 95% CI 0.09-1.4). Gender-related differences in doxorubicin pharmacology may account for worse outcomes for male AYAs with chemosensitive cancers compared to females. These findings may reduce the AYA survival gap compared to other age groups.
Publisher: Wiley
Date: 05-08-2011
DOI: 10.1002/CNCR.26409
Abstract: Pigmented villonodular synovitis (PVNS) (also known as diffuse-type giant cell tumor) and tenosynovial giant cell tumors (TGCT) are rare, usually benign neoplasms that affect the synovium and tendon sheaths in young adults. These tumors are driven by the overexpression of colony stimulating factor-1 (CSF1). CSF1 is expressed by a minority of tumor cells, which, in turn attract non-neoplastic inflammatory cells that express CSF1 receptor (CSF1R) through a paracrine effect. Imatinib mesylate (IM) blocks CSF1R, and previous case reports indicated that it also exerts antitumor activity in PVNS. The authors conducted a multi-institutional retrospective study to assess the activity of IM in patients with locally advanced/metastatic PVNS/TGCT. Twenty-nine patients from 12 institutions in Europe, Australia, and the United States were included. There were 13 men, the median age was 41 years, and the most common site of disease was the knee (n = 17 59%). Two patients had metastatic disease to the lung and/or bone. Five of 27 evaluable patients had Response Evaluation in Solid Tumor (RECIST) responses (overall response rate, 19% 1 complete response and 4 partial responses), and 20 of 27 patients (74%) had stable disease. Symptomatic improvement was noted in 16 of 22 patients (73%) who were assessable for symptoms. Despite a high rate of symptomatic improvement and a favorable safety profile, 6 patients discontinued because of toxicity, and 4 patients decided to discontinue IM for no clear medical reason. IM displayed interesting activity in patients with PVNS/TGCT, providing proof of concept for targeting CSF1R in this disease. The authors concluded that the benefits of alleviating morbidity in patients with localized PVNS/TGCT must be balanced against the potential toxicity of chronic drug therapy.
Publisher: Springer Science and Business Media LLC
Date: 02-02-2015
DOI: 10.1038/BMT.2014.313
Abstract: Thymoglobulin (TG) given with conditioning for allogeneic haematopoietic SCT (alloHSCT) is effective in reducing the risk of acute and chronic GVHD (cGVHD). Whether conventional risk factors for GVHD apply to TG-conditioned alloHSCT is unknown. We retrospectively studied 356 adults from three centres who received TG 4.5 mg/kg prior to alloHSCT for haematologic malignancy. Donors were unrelated in 64%. At 3 years, OS was 61% (95% confidence interval (CI) 55-67%), cumulative incidence of relapse was 28% (95% CI 23-33%) and non-relapse mortality was 19% (14-24%). The cumulative incidences of grade 2-4, and grade 3-4 acute GVHD were 23% (95% CI 19-28%) and 10% (95% CI 6-13%), respectively. The cumulative incidence of cGVHD requiring systemic immunosuppression (cGVHD-IS) at 3 years was 32% (95% CI 27-37%). On multivariate analysis, counterintuitively, recipient age over 40 was associated with a significantly decreased risk of cGVHD-IS (P=0.001). We report for the first time a paradoxical association of older age with reduced cGVHD in TG recipients, and conclude that traditional risk factors for GVHD may behave differently in the context of pre-transplant TG.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-11-2010
Publisher: Cold Spring Harbor Laboratory
Date: 22-11-2019
DOI: 10.1101/852210
Abstract: Mitochondrial diseases (MDs) are the most common group of inherited metabolic disorders and are often challenging to diagnose due to extensive genotype-phenotype heterogeneity. MDs are caused by mutations in the nuclear or mitochondrial genome, where pathogenic mitochondrial variants are usually heteroplasmic and typically at much lower allelic fraction in the blood than affected tissues. Both genomes can now be readily analysed using unbiased whole genome sequencing (WGS), but most nuclear variant detection methods fail to detect low heteroplasmy variants in the mitochondrial genome. We present mity , a bioinformatics pipeline for detecting and interpreting heteroplasmic SNVs and INDELs in the mitochondrial genome using WGS data. In 2,980 healthy controls, we observed on average 3,166× coverage in the mitochondrial genome using WGS from blood. mity utilises this high depth to detect pathogenic mitochondrial variants, even at low heteroplasmy. mity enables easy interpretation of mitochondrial variants and can be incorporated into existing diagnostic WGS pipelines. This could simplify the diagnostic pathway, avoid invasive tissue biopsies and increase the diagnostic rate for MDs and other conditions caused by impaired mitochondrial function. mity is available from github.com/KCCG/mity under an MIT license. clare.puttick@crick.ac.uk , carolyn.sue@sydney.edu.au , MCowley@ccia.org.au
Publisher: Springer Science and Business Media LLC
Date: 19-02-2019
DOI: 10.1038/S41571-019-0179-3
Abstract: Cancer is a genetic disease. To date, translational cancer genomics has focused largely on somatic alterations, driven by the desire to identify targets for personalized therapy. However, therapeutically relevant information is also latent within the germline genome. In addition to cancer susceptibility, alterations present in the germ line can determine responses to both targeted and more traditional anticancer therapies, as well as their toxicities. Despite the importance of these alterations, many algorithms designed to analyse somatic mutations conversely continue to subtract information on germline genetics during analysis. In the light of low actionable yields from somatic tumour testing, a need exists for ersification of the sources of potential therapeutic biomarkers. In this Review, we summarize the literature on the therapeutic potential of alterations in the germline genome. The therapeutic value of germline information will not only be manifest as improvements in treatment but will also drive greater levels of engagement and cooperation between traditional oncology services and familial risk management clinics.
Publisher: American Medical Association (AMA)
Date: 05-2020
Publisher: Public Library of Science (PLoS)
Date: 26-09-2013
Publisher: Wiley
Date: 23-12-2017
DOI: 10.1002/IJC.31195
Publisher: American Association for Cancer Research (AACR)
Date: 11-11-2009
Publisher: Wiley
Date: 23-10-2017
DOI: 10.1111/CGE.12868
Abstract: Evidence suggests that a significant proportion of in iduals referred to cancer genetic counselling (GC) do not attend, and thus may not be engaged in adequate cancer risk management. We aimed to review the literature to better understand barriers to accessing GC and how they may be overcome. We conducted a systematic literature search for articles examining factors influencing cancer GC uptake as well as motivators and barriers to GC attendance. Factors were categorised as sociodemographic, psychosocial or clinical. The literature search identified 1413 citations, 35 of which met the inclusion criteria. GC uptake ranged from 19% to 88%. With the exceptions of education level, socioeconomic status, cancer-specific distress, personal cancer diagnosis and actual and perceived risk of cancer, support was lacking for most sociodemographic, clinical and psychosocial factors as predictors of GC uptake. Cost and logistical barriers, emotional concerns, family concerns and low perceived personal relevance were reported as important considerations for those declining GC. We conclude that there is poor understanding of GC and a lack of decision support among those referred to GC. Research into ways of providing education and support to referred in iduals will be important as the scope and availability of GC and genetic testing broaden.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Wiley
Date: 06-03-2006
DOI: 10.1359/JBMR.060303
Abstract: The retinoblastoma protein, pRb, can activate the transcription factor RUNX2, an essential regulator of osteogenic differentiation, but the mechanism of this activation is unknown. Here we studied the interaction of pRb and RUNX2 with HES1, previously reported to augment RUNX2 activity. PRb can act to promote RUNX2/HES1 association with concomitant promoter occupancy and transcriptional activation in bone cells. RUNX2 (also known as OSF2/CBFA1) is a transcription factor required for osteoblast differentiation and bone formation. We have reported that RUNX2 can associate with the retinoblastoma protein pRb, a common tumor suppressor in bone, and the resultant complex can bind and activate transcription from bone-specific promoters. This activity of the pRb/RUNX2 complex may thus link differentiation control with tumor suppressor activity. However, the mechanism through which pRb can activate RUNX2 is unknown. HES1 is a reported co-activator of RUNX2 that shares a binding site on RUNX2 with pRb. Thus, we have tested the cooperativity among these factors in activating transcription from bone specific promoters. Coimmunoprecipitation, chromatin immunoprecipitation, and EMSA experiments were used to study the interaction of RUNX2, HES1, and pRb in cell lysates and on DNA. Transcriptional reporter assays were used to analyze the activity of RUNX2 in the presence and absence of HES1 and pRb. We showed that pRb can associate with HES1, a previously described RUNX2 interactor that can itself augment RUNX2-dependent transcription. The association of HES1 with RUNX2 is augmented by pRb. Furthermore, both pRb and HES1 increase the amount of RUNX2 bound to promoter sites in vivo, pRb and HES1 synergistically activate a RUNX2-dependent reporter gene, and depletion of HES1 reduces RUNX2 Rb activity. These data indicate that pRb acts as a RUNX2 co-activator at least in part by recruiting HES1 into the pRb/RUNX2 complex and further elucidate a novel role for pRb as a transcriptional co-activator in osteogenesis.
Publisher: American Society of Hematology
Date: 05-08-2022
DOI: 10.1182/BLOODADVANCES.2022007505
Abstract: There have been no comprehensive studies of a full range of blood group polymorphisms within the Australian population. This problem is compounded by the absence of any databases carrying genomic information on chronically transfused patients and low frequency blood group antigens in Australia. Here, we use RBCeq, a web server–based blood group genotyping software, to identify unique blood group variants among Australians and compare the variation detected vs global data. Whole-genome sequencing data were analyzed for 2796 healthy older Australians from the Medical Genome Reference Bank and compared with data from 1000 Genomes phase 3 (1KGP3) databases comprising 661 African, 347 American, 503 European, 504 East Asian, and 489 South Asian participants. There were 661 rare variants detected in this Australian s le population, including 9 variants that had clinical associations. Notably, we identified 80 variants that were computationally predicted to be novel and deleterious. No clinically significant rare or novel variants were found associated with the genetically complex ABO blood group system. For the Rh blood group system, 2 novel and 15 rare variants were found. Our detailed blood group profiling results provide a starting point for the creation of an Australian blood group variant database.
Publisher: Oxford University Press (OUP)
Date: 15-05-2020
DOI: 10.1093/JNCI/DJAA070
Abstract: BRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal and ovarian cancer (OC) do not consistently support improved survival following platinum chemotherapy. We examine the characteristics of BRCA1-methylated OC in a meta-analysis of in idual participant data. Data of 2636 participants across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinicopathological characteristics were evaluated. The effects of methylation on overall survival (OS) and progression-free survival (PFS) were examined using mixed-effects models. All statistical tests were 2-sided. 430 (16.3%) tumors were BRCA1-methylated. BRCA1 methylation was associated with younger age and advanced-stage, high-grade serous OC. There were no survival differences between BRCA1-methylated and non–BRCA1-methylated OC (median PFS = 20.0 vs 18.5 months, hazard ratio [HR] = 1.01, 95% CI = 0.87 to 1.16 P = .98 median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87 to 1.18 P = .96). Where BRCA1/2 mutations were evaluated (n = 1248), BRCA1 methylation displayed no survival advantage over BRCA1/2-intact (BRCA1/2 wild-type non–BRCA1-methylated) OC. Studies used different methods to define BRCA1 methylation. Where BRCA1 methylation was determined using methylation-specific polymerase chain reaction and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66 to 0.97 P = .02 OS: HR = 0.80, 95% CI = 0.63 to 1.00 P = .05) on mixed-effects modeling. BRCA1-methylated OC displays similar clinicopathological features to BRCA1-mutated OC but is not associated with survival. Heterogeneity within BRCA1 methylation assays influences associations. Refining these assays may better identify cases with silenced BRCA1 function and improved patient outcomes.
Publisher: Elsevier BV
Date: 08-2001
DOI: 10.1016/S1097-2765(01)00327-6
Abstract: The incidence of osteosarcoma is increased 500-fold in patients who inherit mutations in the RB gene. To understand why the retinoblastoma protein (pRb) is specifically targeted in osteosarcoma, we studied its function in osteogenesis. Loss of pRb but not p107 or p130 blocks late osteoblast differentiation. pRb physically interacts with the osteoblast transcription factor, CBFA1, and associates with osteoblast-specific promoters in vivo in a CBFA1-dependent fashion. Association of pRb with CBFA1 and promoter sequences results in synergistic transactivation of an osteoblast-specific reporter. This transactivation function is lost in tumor-derived pRb mutants, underscoring a potential role in tumor suppression. Thus, pRb functions as a direct transcriptional coactivator promoting osteoblast differentiation, which may contribute to the targeting of pRb in osteosarcoma.
Publisher: American Medical Association (AMA)
Date: 12-2017
Publisher: American Association for Cancer Research (AACR)
Date: 11-2005
DOI: 10.1158/0008-5472.CAN-05-2285
Abstract: In vivo models that recapitulate oncogene-dependent tumorigenesis will greatly facilitate development of molecularly targeted anticancer therapies. We have developed a model based on activating mutations in c-KIT in gastrointestinal stromal tumors (GISTs). This model comprises murine tumors of FDC-P1 cell lines expressing c-KIT mutations that render the tumors either responsive (V560G) or resistant (D816V) to the small-molecule c-KIT inhibitor, imatinib. Clinically, GIST response to imatinib is associated with rapid reduction in fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), preceding changes in conventional response criteria by several weeks. Using the FDC-P1 model in small animal PET, FDG uptake into tumors expressing the c-KIT V560G mutation was significantly reduced as early as 4 hours after imatinib treatment. In contrast, no change in FDG uptake was observed in resistant c-KIT D816V-expressing tumors after 48 hours of imatinib treatment. Consistent with the PET results, expression of the glucose transporter, GLUT1, was significantly reduced in V560G tumors at 4 hours, preceding changes in markers of proliferation by several hours. In vitro, imatinib treatment of V560G cells resulted in a reduction of glucose transporter numbers at the cell surface and decreased glucose uptake well before changes in cell viability. Notably, decreased ambient glucose concentrations enhanced the cytotoxic effect of imatinib. Taken together, these data account for the rapidity and significance of the PET response to imatinib and suggest that metabolic effects may contribute to imatinib cytotoxicity. Further, the FDC-P1 model represents a very useful paradigm for molecularly targeted drug development.
Publisher: Springer Science and Business Media LLC
Date: 26-05-2015
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1038/S41379-019-0312-Y
Abstract: Despite advances in our understanding of the underlying molecular drivers of sarcomas, few treatments are available with proven benefit for advanced metastatic sarcomas. Immunotherapy has value in this setting for some types of cancers, but sarcomas, with their multiplicity of rare types, have not been characterized in detail for their expression of targetable immune biomarkers. This study provides the most systematic evaluation to date of tumor-infiltrating lymphocytes and immune checkpoint biomarker expression in sarcomas. We examined by morphology and immunohistochemistry 1072 sarcoma specimens representing 22 types, in addition to 236 benign bone and soft-tissue tumors. Genomically-complex sarcoma types-those driven by mutations and/or copy-number alterations-had much higher numbers of tumor-infiltrating lymphocytes than translocation-associated sarcomas. Prior exposure to radiotherapy was associated with increased immune infiltrates. Higher lymphocytic infiltration was associated with better overall survival among the non-translocation-associated sarcomas. Expression of PD-1 and CD56 were associated with worse overall survival. LAG-3 and TIM-3, two emerging immune checkpoints, were frequently expressed in most sarcoma types. Indeed, most cases positive for PD-(L)1 coexpressed one or both of these novel biomarkers, providing a potential rationale in support for trials targeting LAG-3 and/or TIM-3 in conjunction with PD-1 inhibition.
Publisher: Springer Science and Business Media LLC
Date: 04-2008
DOI: 10.1038/NRC2349
Abstract: One explanation for the relative lack of progress in treating cancer in adolescents and young adults is that the biology of malignant diseases in this age group is different than in younger and older persons, not only in the spectrum of cancers but also within in idual cancer types and within the patient (host). Molecular, epidemiological and therapeutic outcome comparisons offer clues to this distinctiveness in most of the common cancers of adolescents and young adults. Translational and clinical research should not assume that the biology of cancers and patients is the same as in other age groups, and treatment strategies should be tailored to the differences.
Publisher: Proceedings of the National Academy of Sciences
Date: 25-11-2008
Abstract: We have previously shown that the retinoblastoma protein (pRb) can activate expression of Runx2-dependent, bone-specific genes in cultured cells. We now show that pRb also plays a role early in osteogenesis, and that in primary RB1 −/− calvarial cells there is an increased osteoprogenitor pool. To understand pRb's function in vivo, we generated a conditional RB1 -KO mouse in which pRb expression is efficiently extinguished in osteoblasts. These animals display an apparent developmental defect in bones, most strikingly in the calvaria. Cultured RB1 −/− calvarial osteoblasts fail to cease proliferation upon reaching confluence or following differentiation. Re-plating assays of primary RB1 −/− calvarial cells after differentiation showed a clear adipogenic ability with increased multipotency. RB1 −/− osteoblasts display a severe reduction in levels of mRNAs expressed late in differentiation. In this study, we present strong evidence that pRb has multiple regulatory roles in osteogenesis. Furthermore, in the absence of RB1 −/− there is a larger pool of multipotent cells compared with the WT counterpart. This increased pool of osteoprogenitor cells may be susceptible to additional transforming events leading to osteosarcoma, and is therefore key to understanding RB1 as a target in malignancy.
Publisher: American Association for Cancer Research (AACR)
Date: 31-05-2017
DOI: 10.1158/1055-9965.EPI-16-0695
Abstract: Background: Li–Fraumeni syndrome (LFS) is associated with germline TP53 mutations and a very high lifetime cancer risk. Algorithms that assess a patient's risk of inherited cancer predisposition are often used in clinical counseling. The existing LFS criteria have limitations, suggesting the need for an advanced prediction tool to support clinical decision making for TP53 mutation testing and LFS management. Methods: Based on a Mendelian model, LFSPRO estimates TP53 mutation probability through the Elston–Stewart algorithm and consequently estimates future risk of cancer. With independent datasets of 1,353 tested in iduals from 867 families, we evaluated the prediction performance of LFSPRO. Results: LFSPRO accurately predicted TP53 mutation carriers in a pediatric sarcoma cohort from MD Anderson Cancer Center in the United States, the observed to expected ratio (OE) = 1.35 (95% confidence interval, 0.99–1.80) area under the receiver operating characteristic curve (AUC) = 0.85 (0.75–0.93) a population-based sarcoma cohort from the International Sarcoma Kindred Study in Australia, OE = 1.62 (1.03–2.55) AUC = 0.67 (0.54–0.79) and the NCI LFS study cohort, OE = 1.28 (1.17–1.39) AUC = 0.82 (0.78–0.86). LFSPRO also showed higher sensitivity and specificity than the classic LFS and Chompret criteria. LFSPRO is freely available through the R packages LFSPRO and BayesMendel. Conclusions: LFSPRO shows good performance in predicting TP53 mutations in in iduals and families in varied situations. Impact: LFSPRO is more broadly applicable than the current clinical criteria and may improve clinical management for in iduals and families with LFS. Cancer Epidemiol Biomarkers Prev 26(6) 837–44. ©2017 AACR.
Publisher: Wiley
Date: 21-10-2015
DOI: 10.1002/JSO.23809
Abstract: Sarcomas are a rare group of mesenchymal tumors affecting a younger population. The etiology remains unknown in most cases. Environmental factors that increase sarcoma risk include radiation exposure and chemical carcinogens. Several familial cancer syndromes confer sarcoma predisposition, such as the Li-Fraumeni Syndrome (LFS). In this increasingly genomic focussed era of medicine, it will be clinically important to understand the genetic basis of sarcoma risk.
Publisher: American Association for Cancer Research (AACR)
Date: 12-2012
DOI: 10.1158/2159-8290.CD-12-0210
Abstract: Patient stratification biomarkers that enable the translation of cancer genetic knowledge into clinical use are essential for the successful and rapid development of emerging targeted anticancer therapeutics. Here, we describe the identification of patient stratification biomarkers for NVP-BGJ398, a novel and selective fibroblast growth factor receptor (FGFR) inhibitor. By intersecting genome-wide gene expression and genomic alteration data with cell line–sensitivity data across an annotated collection of cancer cell lines called the Cancer Cell Line Encyclopedia, we show that genetic alterations for FGFR family members predict for sensitivity to NVP-BGJ398. For the first time, we report oncogenic FGFR1 lification in osteosarcoma as a potential patient selection biomarker. Furthermore, we show that cancer cell lines harboring FGF19 copy number gain at the 11q13 licon are sensitive to NVP-BGJ398 only when concomitant expression of β-klotho occurs. Thus, our findings provide the rationale for the clinical development of FGFR inhibitors in selected patients with cancer harboring tumors with the identified predictors of sensitivity. Significance: The success of a personalized medicine approach using targeted therapies ultimately depends on being able to identify the patients who will benefit the most from any given drug. To this end, we have integrated the molecular profiles for more than 500 cancer cell lines with sensitivity data for the novel anticancer drug NVP-BGJ398 and showed that FGFR genetic alterations are the most significant predictors for sensitivity. This work has ultimately endorsed the incorporation of specific patient selection biomakers in the clinical trials for NVP-BGJ398. Cancer Discov 2(12) 1118–33. ©2012 AACR. Read the Commentary on this article by Loch and Pollock, p. 1081 This article is highlighted in the In This Issue feature, p. 1065
Publisher: Springer Science and Business Media LLC
Date: 08-06-2012
DOI: 10.1007/S00428-012-1256-5
Abstract: While surgery is the usual treatment for localized well-differentiated and dedifferentiated liposarcomas (WDLPS/DDLPS), the therapeutic options for patients with advanced disease are limited. The classical antimitotic treatments are most often inefficient. The establishment of genetically characterized cell lines is therefore crucial for providing in vitro models for novel targeted therapies. We have used spectral karyotyping, fluorescence in situ hybridization with whole chromosome painting and locus-specific probes, and array-comparative genomic hybridization to identify the chromosomal and molecular alterations of a novel cell line established from a recurring sclerosing WDLPS. The karyotype was hypertriploid and showed multiple structural anomalies. All cells retained the presence of a giant marker chromosome that had been previously identified in the primary cell cultures. This giant chromosome contained high-level lification of chromosomal regions 12q13-21 and lacked the alpha-satellite centromeric sequences associated with WDLPS/DDLPS. The 12q licon was large, containing 370 lified genes. The DNA copy number ranged from 3 to 57. The highest levels of lification were observed at 12q14.3 for GNS, WIF1, and HMGA2. We analyzed the mRNA expression status by real-time reverse transcription polymerase chain reaction for six genes from this licon: MDM2, HMGA2, CDK4, TSPAN31, WIF1, and YEATS4. mRNA overexpression was correlated with genomic lification. A second licon originating from 10p11-14 was also present in the giant marker chromosome. The 10p licon contained 62 genes, including oncogenes such as MLLT10, previously described in chimeric fusion with MLL in leukemias, NEBL, and BMI1.
Publisher: Springer Science and Business Media LLC
Date: 06-03-2006
Abstract: Although PPARγ antagonists have shown considerable pre-clinical efficacy, recent studies suggest PPARγ ligands induce PPARγ-independent effects. There is a need to better define such effects to permit rational utilization of these agents. We have studied the effects of a range of endogenous and synthetic PPARγ ligands on proliferation, growth arrest (FACS analysis) and apoptosis (caspase-3/7 activation and DNA fragmentation) in multiple prostate carcinoma cell lines (DU145, PC-3 and LNCaP) and in a series of cell lines modelling metastatic transitional cell carcinoma of the bladder (TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1-B2). 15-deoxy-prostaglandin J 2 (15dPGJ2), troglitazone (TGZ) and to a lesser extent ciglitazone exhibited inhibitory effects on cell number the selective PPARγ antagonist GW9662 did not reverse these effects. Rosiglitazone and pioglitazone had no effect on proliferation. In addition, TGZ induced G0/G1 growth arrest whilst 15dPGJ2 induced apoptosis. Troglitazone and 15dPGJ2 inhibit growth of prostate and bladder carcinoma cell lines through different mechanisms and the effects of both agents are PPARγ-independent.
Publisher: Wiley
Date: 13-12-2023
Abstract: There is an urgent need to identify biomarkers of early response that can accurately predict the benefit of immune checkpoint inhibitors (ICI). Patients receiving durvalumab/tremelimumab had tumor s les sequenced before treatment (baseline) to identify variants for the design of a personalized circulating tumor (ctDNA) assay. ctDNA was assessed at baseline and at 4 and/or 8 weeks into treatment. Correlations between ctDNA changes to radiographic response and overall survival (OS) were made to assess potential clinical benefit. 35/40 patients (87.5%) had personalized ctDNA assays designed, and 29/35 (82.9%) had plasma available for baseline analysis, representing 16 unique solid tumor histologies. As early as 4 weeks after treatment, decline in ctDNA from baseline predicted improved OS ( P = 0.0144 HR = 9.98) and ctDNA changes on treatment‐supported and refined radiographic response calls. ctDNA clearance at any time through week 8 identified complete responders by a median lead time of 11.5 months ahead of radiographic imaging. ctDNA response monitoring is emerging as a dynamic, personalized biomarker method that may predict survival outcomes in patients with erse solid tumor histologies, complementing and sometimes preceding standard‐of‐care imaging assessments.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2012
Publisher: Portico
Date: 2013
DOI: 10.1358/DOT.2013.49.11.2064725
Abstract: Giant cell tumor of bone (GCTB) is an osteolytic, usually benign neoplasm characterized by infiltration with osteoclast-like giant cells, and the osteoclast differentiation factor receptor activator of nuclear factor kappa-B ligand (RANKL) is heavily involved in its pathogenesis. Denosumab belongs to a new class of drugs that inhibit RANKL. Prior to denosumab, multimodality treatment in refractory, recurrent and metastatic GCTB has shown variable results. Recent phase II data have demonstrated denosumab's activity with regard to disease and symptom control, without significant adverse effects. On the basis of this data, the FDA approved denosumab for the treatment of patients whose GCTB is unresectable, or when surgery is likely to result in severe morbidity. Ongoing questions remain, including the optimal scheduling, patient selection, use in the adjuvant setting and long-term toxicity concerns.
Publisher: Future Medicine Ltd
Date: 2018
Abstract: Aim: To compare Australian and French perceptions of genetics and preferences regarding the return of incidental findings. Methods: Participants from the International Sarcoma Kindred Study received a survey at intake to cancer referral units. A total of 1442 Australian and 479 French in iduals affected by sarcoma and their unaffected family members responded to four hypothetical scenarios depicting hereditary conditions of varying treatability and severity. Results: Australians’ preference for the return of incidental findings was consistently higher than French for all scenarios. Country group differences were significant for two scenarios when in idual characteristics were controlled through multivariable analyses. Conclusion: Findings support the need for guidelines that are sensitive to sociocultural context and promote autonomous decision-making.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-06-2013
Abstract: The LIVESTRONG Young Adult Alliance has conducted a meta-analysis of in idual patient data from prospective neoadjuvant chemotherapy osteosarcoma studies and registries to examine the relationships of sex, age, and toxicity on survival. Suitable data sets were identified by a survey of published data reported in PubMed. The final pooled data set comprised 4,838 patients from five international cooperative groups. After accounting for important variables known at study entry such as tumor location and histology, females experienced higher overall survival rates than males (P = .005) and children fared better than adolescents and adults (P = .002). Multivariate landmark analysis following surgery indicated that a higher rate of chemotherapy-induced tumor necrosis was associated with longer survival (P .001), as was female sex (P = .004) and the incidence of grade 3 or 4 mucositis (P = .03). Age group was not statistically significant in this landmark analysis (P = .12). Females reported higher rates of grade 3 or 4 thrombocytopenia relative to males (P .001). Children reported the highest rates of grade 3 or 4 neutropenia (P .001) and thrombocytopenia (P .001). The achievement of good tumor necrosis was higher for females than for males (P = .002) and for children than for adults (P .001). These results suggest fundamental differences in the way chemotherapy is handled by females compared with males and by children compared with older populations. These differences may influence survival in a disease in which chemotherapy is critical to overall outcomes.
Publisher: Elsevier BV
Date: 10-2003
DOI: 10.1016/J.BBRC.2003.08.129
Abstract: Compounds that block angiogenesis are effective in the treatment of certain cancers and other angiogenesis-related diseases. Many of these compounds specifically target the rapidly proliferating and migrating endothelial cell. However, angiogenesis is a multi-faceted process involving heterotypic interactions between various cell types. For ex le, PDGFBB is an important cytokine secreted by endothelial cells that attracts smooth muscle cells to surround and stabilize a nascent vessel. Therefore, we hypothesized that STI-571, a tyrosine kinase inhibitor with PDGFbeta receptor activity, would inhibit angiogenesis through an anti-migratory effect on smooth muscle cells. We demonstrate that STI-571 completely inhibits in vitro angiogenesis in fibrinogen-embedded mouse aorta. Furthermore, this angiostatic property was due mainly to an anti-migratory and anti-proliferative effect upon smooth muscle cells. These data suggest that STI-571, in addition to its efficacy in the treatment of certain cancers, may also prove to be clinically useful in diseases characterized by unregulated angiogenesis.
Publisher: Wiley
Date: 11-1998
DOI: 10.1111/J.1440-1681.1998.TB02339.X
Abstract: 1. Painstaking progress in drug development is well illustrated by 5-fluorouracil (5FU), originally designed 40 years ago as a fluorinated analogue of the naturally occurring base uracil. Innovative pharmacokinetic and pharmacodynamic strategies have seen significant clinical improvements for cancer patients over the past decade. 2. 5-Fluorouracil acts by three main mechanisms. Principally, the intermediate metabolite fluorodeoxyuridine monophosphate inhibits a key enzyme in pyrimidine biosynthesis, namely thymidylate synthase (TS). Additionally, 5FU is metabolized to ribo- and deoxy-ribonucleotides, which act as false bases for incorporation into RNA and DNA. 3. Biomodulation of 5FU has been attempted with methotrexate (MTX), folinic acid, interferons, cisplatin and radiotherapy. Methotrexate augments the actions of 5FU by inhibiting dihydrofolate reductase and decreasing the folate pool required for pyrimidine biosynthesis, inhibiting TS via MTX-polyglutamate and directly inhibiting purine biosynthesis. Interferons increase steady state concentrations of 5FU. 5-Fluorouracil enhances the cytotoxicity of cisplatin and radiotherapy by inhibiting DNA repair. Folinic acid enhances TS inhibition by increasing the intracellular pool of folates that stabilize the 5FU-TS complex. 4. 5-Fluorouracil has a short plasma half-life. Thymidylate synthase inhibition is limited to the S-phase of the cell cycle and only a small fraction of most cancer cells are in S-phase at any one time. Increased response rates seen with infusional protocols may reflect the effective recruitment of additional mechanisms of cytotoxicity, not dependent on cell cycle, including effects on RNA synthesis. 5. Patients with localized metastatic disease may benefit from locoregional treatments. These include hepatic intra-arterial therapy with related compounds, such as floxuridine, which reach high concentrations at sites of tumour, while systemic toxicities are minimized by efficient hepatic clearance. 6. Recent developments include orally bioavailable formulations, such as ftorafur, capecitabine and the combination of 5FU with the dihydropyrimidine phosphate dehydrogenase inhibitor ethynyluracil. Recognition of diurnal variation in the activity of such key enzymes as DPD has led to the administration of 5FU at regulated, variable infusion rates (chronomodulation). These promising pharmacological approaches may further improve clinical outcomes in common cancers.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.DRUDIS.2015.10.009
Abstract: Genomic cancer medicine promises revolutionary change in oncology. The impacts of 'personalized medicine', based upon a molecular classification of cancer and linked to targeted therapies, will extend from in idual patient outcomes to the health economy at large. To address the 'whole-of-system' impact of genomic cancer medicine, we have established a prospective cohort of patients with newly diagnosed cancer in the state of Victoria, Australia, about whom we have collected a broad range of clinical, demographic, molecular, and patient-reported data, as well as data on health resource utilization. Our goal is to create a model for investigating public investment in genomic medicine that maximizes the cost:benefit ratio for the Australian community at large.
Publisher: Informa UK Limited
Date: 08-2009
DOI: 10.1586/ERA.09.77
Abstract: Retroperitoneal soft-tissue sarcomas are complex, heterogeneous cancers requiring expert multidisciplinary care. They can occur anywhere in the retroperitoneal abdominal or pelvic space. Usually large at presentation they present particular challenges for both local treatment and systemic control. The most common adult subtypes are liposarcomas and leiomyosarcomas, followed by pleomorphic sarcoma/malignant fibros histiocytoma (an entity not always easily distinguishable from dedifferentiated liposarcoma). A variety of additional histotypes may also be observed, but are uncommon in the retroperitoneum, either because of intrinsic rarity or because they are usually found in other anatomic sites. The underlying biology varies according to the different histotypes. Pediatric subtypes mainly comprise extraskeletal Ewing sarcoma PNET and alveolar rhabdomyosarcoma. Surgery is critical for controlling these tumors and requires an aggressive approach. It may also provide useful palliation for patients with advanced slow-growing disease. Radiotherapy has acquired a definite position in attempting to reduce relapse, although prospective trials of adjuvant or neoadjuvant radiotherapy are needed. Chemotherapy has a limited role in the adjuvant setting for most forms of retroperitoneal sarcoma (excluding pediatric subtypes), but has an increasing role in advanced disease. Novel targeted therapeutic agents that target specific lification or translocation products offer promise for subsets of these diseases.
Publisher: Springer Science and Business Media LLC
Date: 07-11-2016
DOI: 10.1007/S40273-015-0343-2
Abstract: There is a growing appetite for large complex databases that integrate a range of personal, socio-demographic, health, genetic and financial information on in iduals. It has been argued that 'Big Data' will provide the necessary catalyst to advance both biomedical research and health economics and outcomes research. However, it is important that we do not succumb to being data rich but information poor. This paper discusses the benefits and challenges of building Big Data, analysing Big Data and making appropriate inferences in order to advance cancer care, using Cancer 2015 (a prospective, longitudinal, genomic cohort study in Victoria, Australia) as a case study. Cancer 2015 has been linked to State and Commonwealth reimbursement databases that have known limitations. This partly reflects the funding arrangements in Australia, a country with both public and private provision, including public funding of private healthcare, and partly the legislative frameworks that govern data linkage. Additionally, linkage is not without time delays and, as such, achieving a contemporaneous database is challenging. Despite these limitations, there is clear value in using linked data and creating Big Data. This paper describes the linked Cancer 2015 dataset, discusses estimation issues given the nature of the data and presents panel regression results that allow us to make possible inferences regarding which patient, disease, genomic and treatment characteristics explain variation in health expenditure.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Springer Science and Business Media LLC
Date: 31-07-2019
Publisher: BMJ
Date: 24-01-2020
DOI: 10.1136/JMEDGENET-2019-106410
Abstract: Little is known about knowledge of, and attitudes towards, genome sequencing (GS) among in iduals with a personal history of cancer who decide to undergo GS. This qualitative study aimed to investigate baseline knowledge and attitudes among in iduals previously diagnosed with a cancer of likely genetic origin who have consented to GS. Semistructured interviews were conducted with purposively selected participants (n=20) from the longitudinal Psychosocial Issues in Genomic Oncology study, within a month of consenting to GS and prior to receiving any results. Participants were adults with a cancer of likely genetic aetiology who are undertaking GS as part of a larger genetic study. Analysis identified three main themes: limited understanding of genomics multifactorial motivation and complex decision making. While motivations such as obtaining health information about self and family appear to be the main drivers for undertaking GS, these motivations are sometimes based on limited knowledge of the accuracy and utility of GS, creating unrealistic expectations. This in turn can prolong the deliberation process and lead to ongoing decisional conflict. Understanding the degree and nature of patient understanding of GS, as well as their attitudes and decision-making processes, will enable healthcare professionals to better manage patient expectations and appropriately engage and support patients to make an informed decision when pursuing GS.
Publisher: Elsevier BV
Date: 04-2015
Publisher: Springer Science and Business Media LLC
Date: 04-01-2023
DOI: 10.1038/S41698-022-00343-Y
Abstract: Science has made remarkable advances in understanding the molecular basis of disease, generating new and effective rationally-designed treatments at an accelerating rate. Ironically, the successes of science is creating a crisis in the affordability of equitable health care. The COVID-19 pandemic underscores both the value of science in health care, and the apparently inevitable tension between health and the economy. Drug development in ever-smaller target populations is a critical component of the rising costs of care. For structural and historical reasons, drug development is inefficient and poorly integrated across the public and private sectors. We postulate an alternative, integrated model in which governments and industry share the risks and benefits of drug development. The Australian government recently announced support for a AU$185 million innovative multi-stakeholder public-private partnership model for sustainable precision oncology, accelerating biomarker-dependent drug development through integrating clinical trials into the standard of care.
Publisher: Wiley
Date: 03-1999
DOI: 10.1359/JBMR.1999.14.3.342
Abstract: A significant proportion of patients will be long-term survivors of bone marrow transplantation (BMT) and little is known about their risk of late bony complications. We therefore evaluated bone mineral density (BMD) prior to BMT, post-transplantation changes in BMD, and mechanisms of bone loss in long-term survivors. We performed two analyses. The first was a cross-sectional study of 83 consecutive BMT patients (38 F, 45 M), examining the relationship between BMD and bone turnover, measured immediately prior to transplantation, and a number of disease and patient variables. The second was a prospective study of 39 patients (19F, 20 M) followed for a median of 30 months (range 5-64 months) following either allogeneic (allo, n = 29) or autologous (auto, n = 10) BMT to determine if bone loss was related to treatment of graft versus host disease (GVHD) with glucocorticoids and cyclosporine A, high bone turnover rates, or hypogonadism. Auto BMT recipients acted as a control group for effects of GVHD therapy on BMD. Prior to BMT, spinal and femoral neck (FN) BMDs were 8.6% and 14% lower in female auto BMT recipients than in female allo BMT recipients, respectively (p = 0.12 and p = 0. 003). Urinary bone resorption markers were higher than in normal gender- and age-matched control subjects. Patients treated previously with glucocorticoids also had 8% lower FN BMD. Glucocorticoid-pretreated women with amenorrhoea had lower lumbar spine (LS) and FN BMDs than eumenorrheic women and women receiving HRT. Post-allo BMT, patients lost 11.7% of FN BMD compared with a nonsignificant decrease of 1.1% post-auto BMT (p < 0.001). Spinal BMD and total body bone mineral content (TBBMC) decreased by 3.9% and 3.5%, respectively, post-allo, compared with an increase (1.5%, p = 0.03) or nonsignificant decrease (-3.7%, p = NS), respectively, post-auto BMT. Post-allo BMT bone loss correlated best with the cumulative prednisolone dose at the LS and FN, and with average daily prednisolone dose for TBBMC. At the spine, the rate of bone loss was 4%/10 g of prednisolone, while the rate of bone loss at the FN was greater (9%/10 g of prednisolone). Bone loss was also negatively related to the duration of cyclosporine therapy for GVHD and baseline deoxypyridinoline concentrations. Avascular necrosis of the femoral head occurred in four, and vertebral and rib fractures occurred in one of the allo BMT patients, but in no auto BMT patients. In conclusion, BMT recipients are at risk of osteoporosis secondary to bone loss associated with their underlying illness and/or chemotherapy, particularly in female autograft recipients, and in allograft recipients secondary to GVHD and its treatment.
Publisher: Wiley
Date: 11-08-2020
DOI: 10.1002/PON.5446
Publisher: Elsevier BV
Date: 03-2010
Publisher: Wiley
Date: 02-2011
DOI: 10.1002/CNCR.25757
Abstract: Targeted therapy in osteosarcoma (OS) is needed to improve patient outcomes. Human RECK may have a role because it inhibits cancer invasion and regulates angiogenesis. This study aimed to characterize RECK expression in human OS, to examine in vitro effects of RECK on vascular endothelium and OS cell behavior, and to analyze the effect of RECK on OS grown orthotopically in nude mice. RECK was examined in human OS s les. Interactions between RECK and VEGF were studied in tissue and cells. RECK transfection was used to study its effects on vascular endothelial (HMEC-1) and OS (SaOS-2) cell behavior in vitro and in vivo. SaOS-2 co-culture with RAW 246.7-derived osteoclasts on osteoslides was used to assess effects on osteoclast activity. RECK was absent from OS cells but was expressed in tumor vessel endothelium. Via microarray analysis, RECK mRNA was elevated in s les with low proliferative activity, a trend most evident in poorly differentiated s les. VEGF induced RECK expression in HMEC-1. RECK transfection inhibited HMEC-1 invasion and induced thicker, although more numerous, tube formation. RECK inhibited SaOS-2 invasion, proliferation, colony formation, and osteoclast activity but supported SaOS-2 adhesion to collagen I. In vivo, RECK inhibited SaOS-2 tumor growth, bone destruction, and consequent metastasis. RECK expression is downregulated in highly proliferative OS but is present in tumor vessels and upregulated in endothelium by VEGF. RECK inhibits invasion and tumorigenic properties in SaOS-2, as confirmed in vivo. Further testing of RECK delivery in OS is warranted.
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/614179
Abstract: In 2013 Australia introduced Wiki-based Clinical Practice Guidelines for the Management of Adult Onset Sarcoma. These guidelines utilized a customized MediaWiki software application for guideline development and are the first evidence-based guidelines for clinical management of sarcoma. This paper presents our experience with developing and implementing web-based interactive guidelines and reviews some of the challenges and lessons from adopting an evidence-based (rather than consensus-based) approach to clinical sarcoma guidelines. Digital guidelines can be easily updated with new evidence, continuously reviewed and widely disseminated. They provide an accessible method of enabling clinicians and consumers to access evidence-based clinical practice recommendations and, as evidenced by over 2000 views in the first four months after release, with 49% of those visits being from countries outside of Australia. The lessons learned have relevance to other rare cancers in addition to the international sarcoma community.
Publisher: Elsevier BV
Date: 04-2006
Publisher: Wiley
Date: 06-06-2011
DOI: 10.1002/PATH.2928
Abstract: 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.
Publisher: Wiley
Date: 12-2016
DOI: 10.1111/IMJ.13232
Abstract: Immunotherapy agents show anti-cancer activity in several solid cancers. Efficacy in non-melanoma solid tumours for non-approved indications is unknown. To evaluate patient and disease characteristics, rate and duration of response, and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers. Retrospective review describing outcomes and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers treated at Chris O'Brien Lifehouse. From April 2015 to December 2015, 21 patients received or were planned to receive self-funded pembrolizumab. The median age was 50 years (16-76), 28 and 10% had an Eastern Cooperative Oncology Group performance status of 2, and 3-4 respectively. Sixty-two percent received at least two to four lines of prior drug treatment. Median follow-up was 3.0 months (range, 0.4-9.6). Fourteen (67%) patients requested pembrolizumab. Pembrolizumab was clinician offered for 7 (33%) patients. Patients who requested pembrolizumab had worse outcomes. Three patients died before receiving pembrolizumab. Of the 18 patients that received at least one dose, a partial response was observed in 3 (17%). Progressive disease occurred in 83%. Four patients received only one cycle of pembrolizumab and died after a median of 27 days (range 13-43). Immune-related adverse events of any grade occurred in 33%. No grade 3-4 events were observed. Pembrolizumab was well tolerated. Meaningful responses were observed in 17% of treated patients. Response continues after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other responding patient. Financial impact to the patient can be substantial. Outcomes for 33% were poor with three patients dying prior to receiving therapy and four dying within weeks of receiving one dose. This highlights issues regarding the careful selection of patients, futility of anti-cancer therapy at the end-of-life and patients' perceived benefit of receiving this therapy.
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.CTRV.2022.102455
Abstract: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS. Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel results were summarized by descriptive statistics and discussed during a second meeting (November 2021). Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice. These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors.
Publisher: Future Medicine Ltd
Date: 09-2013
DOI: 10.2217/PGS.13.142
Abstract: The development of genomic technologies has ushered in the era of pharmacogenomics. However, discoveries and clinical use of targeted therapies are still in their infancy. A focus on monogenic pharmacogenetic traits may contribute to this lack of progress. Variation in drug response is likely a complex paradigm involving not only genomic factors but proteomic, metabolomic and epigenomic influences. The incorporation of these omics elements into pharmaceutical development and clinical decision-making will ultimately require the use of methods to determine clinical and economic value. Current methodologies and guidelines for determining clinical effectiveness and cost–effectiveness may have limited applicability to the increasingly personalized nature of omics treatment strategies. Using ex les from oncology, this article argues for the adaptation and tailoring of three existing methods for ensuring development and clinical use of multiomics-guided therapies that are effective, safe and offer value for money.
Publisher: Springer Science and Business Media LLC
Date: 04-2022
DOI: 10.1038/S41591-022-01717-2
Abstract: With the increasing use of genomic profiling for diagnosis and therapy guidance in many tumor types, precision oncology is rapidly reshaping cancer care. However, the current trajectory of drug development in oncology results in a paradox: if patients cannot access advanced diagnostics, we may be developing drugs that will reach few patients. In this Perspective, we outline the major challenges to the implementation of precision oncology and discuss critical steps toward resolving these, including facilitation of equal access to genomics tests, ensuring that clinical studies provide robust evidence for new drugs and technologies, enabling physicians to interpret genomics data, and empowering patients toward shared decision-making. A multi-stakeholder approach to evidence generation, value assessment, and healthcare delivery is necessary to translate advances in precision oncology into benefits for patients with cancer globally.
Publisher: Informa UK Limited
Date: 03-2003
DOI: 10.4161/CBT.2.2.235
Publisher: Hindawi Limited
Date: 11-2017
DOI: 10.1002/HUMU.23342
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.CCELL.2014.09.010
Abstract: We isolated and analyzed, at single-nucleotide resolution, cancer-associated neochromosomes from well- and/or dedifferentiated liposarcomas. Neochromosomes, which can exceed 600 Mb in size, initially arise as circular structures following chromothripsis involving chromosome 12. The core of the neochromosome is lified, rearranged, and corroded through hundreds of breakage-fusion-bridge cycles. Under selective pressure, lified oncogenes are overexpressed, while co lified passenger genes may be silenced epigenetically. New material may be captured during punctuated chromothriptic events. Centromeric corrosion leads to crisis, which is resolved through neocentromere formation or native centromere capture. Finally, lification terminates, and the neochromosome core is stabilized in linear form by telomere capture. This study investigates the dynamic mutational processes underlying the life history of a special form of cancer mutation.
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.LUNGCAN.2016.05.024
Abstract: To identify parameters that drive the cost-effectiveness of precision medicine by comparing the use of multiplex targeted sequencing (MTS) to select targeted therapy based on tumour genomic profiles to either no further testing with chemotherapy or no further testing with best supportive care in the fourth-line treatment of metastatic lung adenocarcinoma. A combined decision tree and Markov model to compare costs, life-years, and quality-adjusted life-years over a ten-year time horizon from an Australian healthcare payer perspective. Data sources included the published literature and a population-based molecular cohort study (Cancer 2015). Uncertainty was assessed using deterministic sensitivity analyses and quantified by estimating expected value of perfect artial perfect information. Uncertainty due to technological/scientific advancement was assessed through a number of plausible future scenario analyses. Point estimate incremental cost-effective ratios indicate that MTS is not cost-effective for selecting fourth-line treatment of metastatic lung adenocarcinoma. Lower mortality rates during testing and for true positive patients, lower health state utility values for progressive disease, and targeted therapy resulting in reductions in inpatient visits, however, all resulted in more favourable cost-effectiveness estimates for MTS. The expected value to decision makers of removing all current decision uncertainty was estimated to be between AUD 5,962,843 and AUD 13,196,451, indicating that additional research to reduce uncertainty may be a worthwhile investment. Plausible future scenarios analyses revealed limited improvements in cost-effectiveness under scenarios of improved test performance, decreased costs of testing/interpretation, and no biopsy costs/adverse events. Reductions in off-label targeted therapy costs, when considered together with the other scenarios did, however, indicate more favourable cost-effectiveness of MTS. As more clinical evidence is generated for MTS, the model developed should be revisited and cost-effectiveness re-estimated under different testing scenarios to further understand the value of precision medicine and its potential impact on the overall health budget.
Publisher: Wiley
Date: 30-10-2022
DOI: 10.1002/GCC.23006
Abstract: Identification of cancer‐predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs). An enrichment burden analysis compared rare deleterious germline CPG variants in the patient cohort with those in a healthy aged control population. A subset of predicted deleterious variants in novel candidate CPGs was investigated further by examining matched tumor s les, and the functional impact of AXIN1 variants was analyzed in cultured cells. Twenty‐two pathogenic/likely pathogenic (P/LP) germline variants detected in 13 CPGs were identified in 19 of 76 patients (25.0%). Unclear association with the diagnosed cancer types was observed in 11 of 19 patients carrying P/LP CPG variants. The burden of rare deleterious germline variants in autosomal dominant CPGs was significantly higher in study patients versus healthy aged controls. A novel AXIN1 frameshift variant (Ser321fs) may impact the regulation of β‐catenin levels. Selection of childhood cancer patients for germline testing based on features suggestive of an underlying genetic predisposition could help to identify carriers of clinically relevant germline CPG variants, and streamline the integration of germline genomic testing in the pediatric oncology clinic.
Publisher: Elsevier
Date: 2016
DOI: 10.1016/BS.AI.2015.12.004
Abstract: Immunotherapy is now evolving into a major therapeutic option for cancer patients. Such clinical advances also promote massive interest in the search for novel immunotherapy targets, and to understand the mechanism of action of current drugs. It is projected that a series of novel immunotherapy agents will be developed and assessed for their therapeutic activity. In light of this, in vivo experimental mouse models that recapitulate human malignancies serve as valuable tools to validate the efficacy and safety profile of immunotherapy agents, before their transition into clinical trials. In this review, we will discuss the major classes of experimental mouse models of cancer commonly used for immunotherapy assessment and provide ex les to guide the selection of appropriate models. We present some new data concerning the utility of a carcinogen-induced tumor model for comparing immunotherapies and combining immunotherapy with chemotherapy. We will also highlight some recent advances in experimental modeling of human malignancies in mice that are leading towards personalized therapy in patients.
Publisher: Wiley
Date: 04-1998
DOI: 10.1111/J.1445-5994.1998.TB02968.X
Abstract: Much research has been conducted into the pathobiology, diagnosis, and management of acute myeloid leukaemia (AML) since 1980, with major contributions from Australian studies in this period. To determine whether advances in basic and clinical research into AML have translated into improved survival for patients in the community. A retrospective survey of records of all patients with AML presenting to the Royal Melbourne Hospital (RMH) over a 16 year period, analysed according to induction therapy and established prognostic factors. Between 1980 and December 1996 223 (98%) of 227 patients were evaluable. The probability of survival at five years for patients treated since 1990 has improved significantly compared to the cohort treated between 1980-89 (34 +/- 5% vs 4 +/- 2% mean +/- standard error). This benefit is most evident in patients less than 60 years of age (50 +/- 7% vs 11 +/- 4%). Successive induction protocols in the context of clinical trials conducted since 1985 contributed to improved outcomes. The selective application of bone marrow transplantation, and use of retinoic acid as induction therapy for acute promyelocytic leukaemia has also improved survival. Despite increases in dose-intensity, early death rates for patients undergoing induction therapy fell during the study period. Participation in clinical and basic research with the development of more intense and specific treatments for patients with AML has contributed to better outcomes, underpinned by improvements in supportive care.
Publisher: Wiley
Date: 13-12-2020
DOI: 10.1002/CNR2.1327
Publisher: Springer International Publishing
Date: 18-11-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2009
Publisher: Elsevier BV
Date: 05-2011
Publisher: Springer Science and Business Media LLC
Date: 03-11-2006
Publisher: Elsevier BV
Date: 08-2015
Publisher: Rockefeller University Press
Date: 06-12-2004
Abstract: The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2, a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27KIP1, thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2012
DOI: 10.1007/S00520-010-1059-7
Abstract: Most psychosocial research in cancer has been restricted to paediatric or older adult populations. This study aimed to explore psychological distress and unmet needs in adolescents and young adults (AYA) with cancer and identify predictors of distress among demographic and illness characteristics and supportive care needs. Fifty-three patients between 16 and 30 years completed a cross-sectional survey, administered shortly after presentation to an AYA oncology service and within 4 months of diagnosis. Measures included the Beck Depression Inventory-Fast Screen (BDI-FS), State-Trait Anxiety Inventory-State Form (STAI-S) and the Supportive Care Needs Survey. Level of distress-related sypmtomatology in this population was based on previous work, whereby a cut-off score of 4 or greater was used for the BDI-FS, and one standard deviation above the s le population mean was used for the STAI-S. Prevalence of distress (25%) was lower than that found previously in AYA with cancer. Physical and daily living needs were the most frequently unmet needs overall, followed by psychological needs, health system and information needs and care and support needs. Lastly, being pre-treatment predicted increased depression and state anxiety, while having treatment post-surgery predicted reduced state anxiety. After controlling for treatment status, however, the main predictors of depression and state anxiety were physical and daily living needs and health system and information needs, respectively. Lower levels of distress and unmet psychological needs were related to the few participants (17%) in this study who were pre-treatment, when distress was most likely. However, physical needs and information needs, which are almost inevitable throughout treatment and beyond, were more important predictors of distress. Further exploration must consider the psychosocial difficulties underlying this association and the needs of AYA at transitions between critical periods in their cancer journey (i.e., upon diagnosis, during treatment, etc.).
Publisher: Springer Science and Business Media LLC
Date: 09-11-2016
Publisher: Bioscientifica
Date: 04-1995
Abstract: This study characterizes the actions of insulin and parathyroid hormone (PTH) on the glucose transport system in the rat osteogenic sarcoma cell line UMR 106–01, which expresses a number of features of the osteoblast phenotype. Using [1,2- 3 H]2-deoxyglucose (2-DOG) as a label, UMR 106–01 cells were shown to possess a glucose transport system which was enhanced by insulin. In contrast, PTH influenced glucose transport in a biphasic manner with a stimulatory effect at 1 h and a more potent inhibitory effect at 16 h on basal and insulin-stimulated 2-DOG transport. To explore the mechanism of PTH action, a direct agonist of cAMP-dependent protein kinase (PKA) was tested. 8-Bromo-cAMP had no acute stimulatory effect but inhibited basal and insulin-stimulated 2-DOG transport at 16 h. This result suggested that the prolonged, but not the acute, effect of PTH was mediated by the generation of cAMP. Further studies with the cell line UMR 4–7, a UMR 106–01 clone stably transfected with an inducible mutant inactive regulatory subunit of PKA, confirmed that the inhibitory but not the stimulatory effect of PTH was mediated by the PKA pathway. Northern blot data indicated that the prolonged inhibitory effects of PTH and 8-bromo-cAMP on glucose transport were likely to be mediated in part by reduction in the levels of GLUT1 (HepG2/brain glucose transporter) mRNA.
Publisher: American Medical Association (AMA)
Date: 12-2017
Publisher: Springer International Publishing
Date: 2016
DOI: 10.1007/978-3-319-29998-3_10
Abstract: Sarcomas are rare and heterogeneous diseases that affect a younger population than most epithelial cancers. Epidemiologic studies suggest a strong genetic component to sarcomas, and many familial cancer syndromes have been described, in which sarcomas are a feature. The best known of these are the Li-Fraumeni and retinoblastoma syndromes, study of which has been pivotal to elucidating the molecular basis for the cell response to DNA damage and the cell ision. Although much has been learnt about cancer biology from the study of sarcoma families, in general clinical management of increased sarcoma risk has lagged behind other cancer predisposition syndromes. With the advent of genomic tools for genetic testing, it is likely that a substantial fraction of sarcoma patients will be identified as carriers of known risk alleles. The translation of this knowledge into effective risk management programs and cancer treatments will be essential to changes in routine clinical practice.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2021
DOI: 10.1038/S41698-021-00194-Z
Abstract: While several resources exist that interpret therapeutic significance of genomic alterations in cancer, many regional real-world issues limit access to drugs. There is a need for a pragmatic, evidence-based, context-adapted tool to guide clinical management based on molecular biomarkers. To this end, we have structured a compendium of approved and experimental therapies with associated biomarkers following a survey of drug regulatory databases, existing knowledge bases, and published literature. Each biomarker-disease-therapy triplet was categorised using a tiering system reflective of key therapeutic considerations: approved and reimbursed therapies with respect to a jurisdiction (Tier 1), evidence of efficacy or approval in another jurisdiction (Tier 2), evidence of antitumour activity (Tier 3), and plausible biological rationale (Tier 4). Two resistance categories were defined: lack of efficacy (Tier R1) or antitumor activity (Tier R2). Based on this framework, we curated a digital resource focused on drugs relevant in the Australian healthcare system (TOPOGRAPH: Therapy Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals). As of November 2020, TOPOGRAPH comprised 2810 biomarker-disease-therapy triplets in 989 expert-appraised entries, including 373 therapies, 199 biomarkers, and 106 cancer types. In the 345 therapies catalogued, 84 (24%) and 65 (19%) were designated Tiers 1 and 2, respectively, while 271 (79%) therapies were supported by preclinical studies, early clinical trials, retrospective studies, or case series (Tiers 3 and 4). A companion algorithm was also developed to support rational, context-appropriate treatment selection informed by molecular biomarkers. This framework can be readily adapted to build similar resources in other jurisdictions to support therapeutic decision-making.
Publisher: Springer Science and Business Media LLC
Date: 05-03-2015
DOI: 10.1038/BJC.2015.80
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.PEC.2021.07.004
Abstract: Germline genome sequencing (GS) is becoming mainstream in cancer diagnosis and risk management. Identifying knowledge gaps and determinants of health behavior change intentions will enable effective targeting of educational and management strategies to translate genomic findings into improved cancer outcomes. Probands diagnosed with cancer of likely genetic origin that consented to but not yet undergone GS, and their biological relatives, completed a cross-sectional questionnaire assessing GS knowledge and hypothetical intention to change behaviors. Probands (n = 348 57% university educated) and relatives (n = 213 38% university educated) had moderate GS knowledge levels, with greater knowledge associated with higher education. Both populations reported high behavioral change intentions, significantly associated with being female (p = 0.01) and greater perceived importance of GS (p < 0.001), and for probands: being from English-speaking households (p = 0.003), higher socio-economic status (p = 0.01) and greater self-efficacy (p = 0.02). Increasing GS knowledge will enable realistic participant expectations surrounding germline GS. Actual behavior change should be monitored to determine whether increased cancer risk knowledge results in altered cancer-related behavior and ultimately, cancer outcomes. Educational resources should target specific populations to ensure informed decision-making and expectation management. Support tools facilitating and maintaining behavioral change may be needed to achieve improved cancer patient outcomes.
Publisher: Elsevier BV
Date: 09-2010
Publisher: BMJ
Date: 16-03-2020
DOI: 10.1136/JMEDGENET-2019-106734
Abstract: Although considerable effort has been put into decoding of the osteosarcoma genome, very little is known about germline mutations that underlie this primary malignant tumour of bone. We followed here a coincidental finding in a multiple endocrine neoplasia family in which a 32-year-old patient carrying a germline pathogenic RET mutation developed an osteosarcoma 2 years after the resection of a medullary thyroid carcinoma. Sequencing analysis of additional 336 patients with osteosarcoma led to the identification of germline activating mutations in the RET proto-oncogene in three cases and somatic lifications of the gene locus in five matched tumours (4%, n=5/124 tumours). Functional analysis of the pathogenic variants together with an integrative analysis of osteosarcoma genomes confirmed that the mutant RET proteins couple functional kinase activity to dysfunctional ligand binding. RET mutations further co-operated with alterations in TP53 and RB1 , suggesting that osteosarcoma pathogenesis bears reminiscence to the stepwise model of medullary thyroid carcinoma. After Li-Fraumeni-predisposing mutations in TP53 , RET becomes the second most mutated cancer-predisposing gene in the germline of patients with osteosarcoma. Hence, early identification of RET mutation carriers can help to identify at-risk family members and carry out preventive measures.
Publisher: Springer Science and Business Media LLC
Date: 09-07-2022
DOI: 10.1007/S00520-022-07272-3
Abstract: The introduction of comprehensive tumour genomic profiling (CGP) into clinical oncology allows the identification of molecular therapeutic targets. However, the potential complexity of genomic results and their implications may cause confusion and distress for patients undergoing CGP. We investigated the experience of advanced cancer patients receiving CGP results in a research setting. Semi-structured interviews with 37 advanced cancer patients were conducted within two weeks of patients receiving CGP results. Interviewees were purposively s led based on CGP result, cancer type, age and gender to ensure ersity. Themes were derived from interview transcripts using a framework analysis approach. We identified six themes: (1) hoping against the odds (2) managing expectations (3) understanding is cursory (4) communication of results is cursory (5) genomics and incurable cancer and (6) decisions about treatment. Despite enthusiasm regarding CGP about the hope it provides for new treatments, participants experienced challenges in understanding results, and acceptance of identified treatments was not automatic. Support is needed for patients undergoing CGP to understand the implications of testing and cope with non-actionable results.
Publisher: Hindawi Limited
Date: 2011
DOI: 10.1155/2011/483154
Abstract: Sarcomas are a group of heterogeneous tumours with varying genetic basis. Cytogenetic abnormalities range from distinct genomic rearrangements such as pathognomonic translocation events and common chromosomal lification or loss, to more complex rearrangements involving multiple chromosomes. The different subtypes of liposarcoma are spread across this spectrum and constitute an interesting tumour type for molecular review. This paper will outline molecular pathogenesis of the three main subtypes of liposarcoma: well-differentiated/dedifferentiated, myxoid/round cell, and pleomorphic liposarcoma. Both the molecular basis and future avenues for therapeutic intervention will be discussed.
Publisher: MDPI AG
Date: 19-10-2022
DOI: 10.3390/HEALTHCARE10102086
Abstract: Health systems internationally must prepare for a future of genetic/genomic testing to inform healthcare decision-making while creating research opportunities. High functioning testing services will require additional considerations and health system conditions beyond traditional diagnostic testing. Based on a literature review of good practices, key informant interviews, and expert discussion, this article attempts to synthesize what conditions are necessary, and what good practice may look like. It is intended to aid policymakers and others designing future systems of genome-based care and care prevention. These conditions include creating communities of practice and healthcare system networks resource planning across-region informatics having a clear entry/exit point for innovation evaluative function(s) concentrated or coordinated service models mechanisms for awareness and care navigation integrating innovation and healthcare delivery functions and revisiting approaches to financing, education and training, regulation, and data privacy and security. The list of conditions we propose was developed with an emphasis on describing conditions that would be applicable to any healthcare system, regardless of capacity, organizational structure, financing, population characteristics, standardization of care processes, or underlying culture.
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.HLC.2007.11.144
Abstract: Future improvements in lung cancer survival are likely to come from delineating its putative oncogenic pathways. The development of microarray technology to perform thousands of simultaneous genetic experiments and the linking of this to clinical information is an imperative for refining our current treatments and developing new ones. This paper reviews the state of this research, describes a typical microarray experiment and the implications for diagnosis and treatment of non-small cell lung cancer.
Publisher: Wiley
Date: 21-10-2009
Abstract: Malignant tumours are often characterised by significant rearrangement of the genome. This may be visible in the form of a deranged karyotype with both loss and gain of DNA sequences extending from chromosomal regions to whole chromosomes. In several tumour types, however, gross genomic derangements are minimal, and tumour cells contain one or more additional (supernumerary) chromosomes that may be unrecognisable in terms of a single origin. In this review we term such chromosomes cancer-associated neochromosomes (CaNCs). In the absence of other identified genomic abnormalities, and because the CaNC is a common feature of the cancer type, it is hypothesised that the genetic alterations required for cell transformation are contained within its structure. In this review, we discuss the potential impact of modern genomic technologies on our understanding of the nature and causes of CaNC formation, which is central to several cancer types, exemplified here by well-differentiated liposarcoma.
Publisher: Public Library of Science (PLoS)
Date: 22-07-2013
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-01-2023
Abstract: Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 07-2012
Abstract: Limited data exist regarding the outcomes of adjuvant therapy in younger patients with stage II and III colon cancer. We examined disease-free survival (DFS), overall survival (OS), recurrence-free interval (RFI), and grade 3+ adverse events (AEs) in younger patients in the 33,574 patient Adjuvant Colon Cancer Endpoints Group data set. In idual patient data from 24 randomized phase III clinical trials were obtained for survival outcomes, which included 10 clinical trials for AE outcomes. Two age-based cutoff points were used to define younger patients: age younger than 40 years and younger than 50 years. Adjuvant therapy benefit analyses were limited to the nine clinical trials in which the investigational chemotherapeutic arm demonstrated benefit. One thousand seven hundred fifty-eight patients (5.2%) were younger than 40 years, 5,817 patients (17.3%) were younger than 50 years, and only 299 patients (0.9%) were younger than 30 years. No meaningful differences in sex or stage were noted in younger versus older patients. Younger and older patients did not differ in RFI (age, 40 years: hazard ratio [HR], 1.0 P = .62 and age 50 years: HR, 1.02 P = .35). Younger patients (both cutoff points), had longer OS and DFS than older patients. In trials demonstrating adjuvant therapy benefit, similar DFS benefit was observed by age. Younger patients experienced less leukopenia and stomatitis, but more frequent nausea/vomiting. Among patients on clinical trials, younger and older patients with stage II and III colon cancer had similar RFI and adjuvant therapy benefit. Younger patients have longer OS and DFS, which is likely primarily because of fewer competing causes of death. Adjuvant therapy is beneficial for colon cancer in patients younger than 50 years who meet typical clinical trial eligibility criteria.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Springer Science and Business Media LLC
Date: 2004
Publisher: Springer Science and Business Media LLC
Date: 03-05-2019
Publisher: Springer Science and Business Media LLC
Date: 08-04-2020
DOI: 10.1038/S41467-020-15697-9
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Wiley
Date: 24-11-2015
Abstract: Despite efforts to restructure mental health (MH) services across Victoria, the social and economic burden of MH illness continues to grow. This study compares MH presentations to EDs with a study undertaken 10 years earlier. The article is a retrospective observational study of MH presentations to four Victorian EDs between May and October 2013. Subjects were included if the presentation was MH related as determined by an International Classification of Diseases (version 10) discharge diagnosis, they were referred to an emergency crisis assessment team or had a documented presenting psychiatric complaint. Variables were extracted from electronic medical records and compared with 2004 data from a previous published study. There were 5659 MH presentations over the 5 months compared with 2788 in 2004. The median ED length of stay decreased from 4:18 h in 2004 to 3:20 h in 2013 (P 4 h from 52.5% to 35.4% (P < 0.001). There was a 22-fold increase in short stay units as discharge destination from 0.9% to 20.2% (P < 0.001). Patients presenting with concurrent meth hetamine exposure doubled from 2.2% of presentations to 4.3% (P < 0.001). Despite increasing MH-related presentations, changes in ED practice have allowed improvements in delivery of care through a shortened ED length of stay and the virtual elimination of very long stays over 24 h. However, there continues to be significant variability in management and performance across hospital sites. Identifying which interventions lead to standout site performance, and subsequent application more broadly, may improve future ED delivery of care.
Publisher: Springer International Publishing
Date: 2017
Publisher: Springer Science and Business Media LLC
Date: 05-10-2020
Publisher: Springer Science and Business Media LLC
Date: 25-05-2021
Publisher: Wiley
Date: 17-02-2018
DOI: 10.1007/S10897-018-0223-Y
Abstract: Germline genomic testing is increasingly used in research to identify genetic causes of disease, including cancer. However, there is evidence that in iduals who are notified of clinically actionable research findings have difficulty making informed decisions regarding uptake of genetic counseling for these findings. This study aimed to produce and pilot test a decision aid to assist participants in genomic research studies who are notified of clinically actionable research findings to make informed choices regarding uptake of genetic counseling. Development was guided by published literature, the International Patient Decision Aid Standards, and the expertise of a steering committee of clinicians, researchers, and consumers. Decision aid acceptability was assessed by self-report questionnaire. All 19 participants stated that the decision aid was easy to read, clearly presented, increased their understanding of the implications of taking up research findings, and would be helpful in decision-making. While low to moderate levels of distress/worry were reported after reading the booklet, a majority of participants also reported feeling reassured. All participants would recommend the booklet to others considering uptake of clinically actionable research findings. Results indicate the decision aid is acceptable to the target audience, with potential as a useful decision support tool for genomic research participants.
Publisher: Springer Science and Business Media LLC
Date: 17-04-2019
DOI: 10.1038/S41571-019-0212-6
Abstract: The originally published article contained errors in the main text and in figure 1 in the reported number of patients with pathogenic or likely pathogenic germline variants. The originally reported numbers did not take into account the presence of more than one variant in an in idual patient. This has been corrected in the HTML and PDF versions of the manuscript.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2021
DOI: 10.1038/S41375-021-01246-W
Abstract: The majority of studies assessing the contribution of pathogenic germline variants (PGVs) to cancer predisposition have focused on patients with single cancers. We analyzed 45 known cancer predisposition genes (CPGs) in germline s les of 202 patients with hematological malignancies (HMs) plus one or more other independent cancer managed at major tertiary medical centers on two different continents. This included 120 patients with therapy-related myeloid neoplasms (t-MNs), where the HM occurred after cytotoxic treatment for a first malignancy, and 82 patients with multiple cancers in which the HM was not preceded by cytotoxic therapy (MC-HM). Using American College of Medical Genetics/Association for Molecular Pathology variant classification guidelines, 13% of patients had PGVs, most frequently identified in CHEK2 (17% of PGVs), BRCA1 (13%), DDX41 (13%), and TP53 (7%). The frequency of PGVs in MC-HM was higher than in t-MN, although not statistically significant (18 vs. 9% p = 0.085). The frequency of PGVs in lymphoid and myeloid HM patients was similar (19 vs. 17.5% p > 0.9). Critically, patients with PGVs in BRCA1, BRCA2 or TP53 did not satisfy current clinical phenotypic criteria for germline testing. Our data suggest that a personal history of multiple cancers, one being a HM, should trigger screening for PGVs.
Publisher: Wiley
Date: 29-02-2016
DOI: 10.1111/AJCO.12457
Abstract: Integration of clinical genetics into oncology is variable. Sarcomas have a strong genetic component, with up to 1/30 patients carrying germline TP53 mutations. This study aimed to define genetic risk awareness among sarcoma physicians. Outcomes were attitudes toward genetic testing, level of cancer risk and awareness of risk reduction measures. An online survey was administered to members of the Connective Tissue Oncology Society and the Australasian Sarcoma Study Group. Sarcoma physicians (N = 124) from 21 countries participated, 40% of whom favored TP53 mutation testing in children regardless of family history, increasing to ∼83% for all age groups if a family history was present and ∼85% if multiple primary cancers were present. However, 33% were not aware that risk reduction strategies might identify some cancers at a more curable stage in carriers. Clinical genetics is not yet standard of care for multidisciplinary management of sarcoma. Awareness of genetic risk is important among sarcoma physicians. Attitudes among the sarcoma community were generally positive, but education on genetic risk in sarcoma patients and collaboration with clinical genetics services might improve quality of care. Sarcoma physicians need routine access to clinical genetics services so that potential germline TP53 mutation carriers are recognized.
Publisher: Wiley
Date: 06-04-2014
Abstract: Despite the remarkable achievements of novel targeted anti-cancer drugs, most therapies only produce remission for a limited time, resistance to treatment, and relapse, often being the ultimate outcome. Drug resistance is due to highly efficient adaptive strategies utilized by cancer cells. Exogenous and endogenous stress stimuli are known to induce first-line responses, capable of re-establishing cellular homeostasis and determining cell fate decisions. Cancer cells may also mount second-line adaptive strategies, such as the mutator response. Hypermutable subpopulations of cells may expand under severe selective stress, thereby accelerating the emergence of adapted clones. As with first-line protective responses, these strategies appear highly conserved, and are found in yeasts and bacteria. We hypothesize that evolutionarily conserved programs rheostatically regulate mutability in fluctuating environments, and contribute to drug resistance in cancer cells. Elucidating the conserved genetic and molecular mechanisms may present novel opportunities to increase the effectiveness of cancer therapies.
Publisher: Springer Science and Business Media LLC
Date: 23-04-2018
Publisher: Springer Science and Business Media LLC
Date: 03-07-2012
Publisher: Elsevier BV
Date: 1996
Abstract: Expression of the glucose transporter GLUT 3 is mainly restricted to neuronal tissues, with lower levels in testis and placenta. In addition, GLUT 3 has recently been reported in neonatal rat calvaria by in situ hybridisation. We report the co-expression of GLUT 1 and GLUT 3 mRNA and protein in UMR 106-01, a clonal osteosarcoma cell line. By semi-quantitative analysis we show that GLUT 3 protein is expressed at levels comparable to GLUT 1. Insulin stimulates glucose uptake in UMR 106-01 cells. GLUT 3 mRNA and protein are increased by chronic (16 h) treatment with insulin, and the increase in GLUT 3 mRNA is not inhibited by cycloheximide. Regulation of GLUT 3 mRNA by insulin has not been previously shown. UMR 106-01 represents a useful model for investigating regulation of GLUT 3 expression.
Publisher: Springer Science and Business Media LLC
Date: 16-04-2021
DOI: 10.1186/S13059-021-02315-0
Abstract: Targeted sequencing using oncopanels requires comprehensive assessments of accuracy and detection sensitivity to ensure analytical validity. By employing reference materials characterized by the U.S. Food and Drug Administration-led SEquence Quality Control project phase2 (SEQC2) effort, we perform a cross-platform multi-lab evaluation of eight Pan-Cancer panels to assess best practices for oncopanel sequencing. All panels demonstrate high sensitivity across targeted high-confidence coding regions and variant types for the variants previously verified to have variant allele frequency (VAF) in the 5–20% range. Sensitivity is reduced by utilizing VAF thresholds due to inherent variability in VAF measurements. Enforcing a VAF threshold for reporting has a positive impact on reducing false positive calls. Importantly, the false positive rate is found to be significantly higher outside the high-confidence coding regions, resulting in lower reproducibility. Thus, region restriction and VAF thresholds lead to low relative technical variability in estimating promising biomarkers and tumor mutational burden. This comprehensive study provides actionable guidelines for oncopanel sequencing and clear evidence that supports a simplified approach to assess the analytical performance of oncopanels. It will facilitate the rapid implementation, validation, and quality control of oncopanels in clinical use.
Publisher: Wiley
Date: 09-2002
DOI: 10.1046/J.1445-5994.2002.00249.X
Abstract: Cancer patients are at risk of venous thromboembolism (VTE). Currently, management of these patients is based on studies performed in the general population. To determine whether the natural history of VTE in cancer patients differs sufficiently from patients in general such that a specific management approach is required. A retrospective survey was conducted using case records from three tertiary referral hospitals (1993-2001). One hundred and forty-seven VTE patients with cancer and 82 control patients matched for age and gender were followed for a median of 24 months (0-104 months). The overall prevalence of cancer among patients with VTE was 19.3% (vs 4% in patients with arterial thromboembolic events). In the follow-up groups, cancer conferred a significantly worse functional status, although other risk factors for VTE were similar. Proximal sites of VTE were twice as common in cancer as in non-cancer patients. The majority of patients in both groups were treated with oral anticoagulants. Complications were more common in cancer patients (40% vs 23%) and occurred more frequently despite apparently adequate anticoagulation. Following VTE, cancer patient survival (median 4.1 months, 127 deaths) was markedly worse than non-cancer patients (median not reached, eight deaths). Thirty-five cancer deaths occurred within 5 weeks of VTE. Eleven deaths in cancer patients were directly related to VTE compared to three in patients without cancer. Cancer patients with VTE fare extremely poorly compared to the general hospital population. Prospective treatment studies, specifically in cancer patients with VTE, are needed.
Publisher: Elsevier BV
Date: 12-2015
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/S0002-9440(10)62959-8
Abstract: Giant cell tumor of bone (GCT) is a generally benign, osteolytic neoplasm comprising stromal cells and osteoclast-like giant cells. The osteoclastic cells, which cause bony destruction, are thought to be recruited from normal monocytic pre-osteoclasts by stromal cell expression of the ligand for receptor activator of nuclear factor kappaB (RANKL). This model forms the foundation for clinical trials in GCTs of novel cancer therapeutics targeting RANKL. Using expression profiling, we identified both osteoblast and osteoclast signatures within GCTs, including key regulators of osteoclast differentiation and function such as RANKL, a C-type lectin, osteoprotegerin, and the wnt inhibitor SFRP4. After ex vivo generation of stromal- and osteoclast-enriched cultures, we unexpectedly found that RANKL mRNA and protein were more highly expressed in osteoclasts than in stromal cells, as determined by expression profiling, flow cytometry, immunohistochemistry, and reverse transcriptase-polymerase chain reaction. The expression patterns of molecules implicated in signaling between stromal cells and monocytic osteoclast precursors were analyzed in both primary and fractionated GCTs. Finally, using array-based comparative genomic hybridization, neither GCTs nor the derived stromal cells demonstrated significant genomic gains or losses. These data raise questions regarding the role of RANKL in GCTs that may be relevant to the development of molecularly targeted therapeutics for this disease.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2014
DOI: 10.1038/BJC.2014.537
Publisher: American Association for Cancer Research (AACR)
Date: 15-01-2020
DOI: 10.1158/0008-5472.CAN-19-0728
Abstract: These findings provide specific penetrance estimates for LFS-associated cancers, which will likely impact the management of families at high risk of LFS. See related article by Shin et al., p. 347
Publisher: Springer Science and Business Media LLC
Date: 24-10-2019
Publisher: American Association for Cancer Research (AACR)
Date: 30-04-2015
DOI: 10.1158/1078-0432.CCR-15-0426
Abstract: Purpose: Personalized medicine strategies using genomic profiling are particularly pertinent for pancreas cancer. The In idualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial was initially designed to exploit results from genome sequencing of pancreatic cancer under the auspices of the International Cancer Genome Consortium (ICGC) in Australia. Sequencing revealed small subsets of patients with aberrations in their tumor genome that could be targeted with currently available therapies. Experimental Design: The pilot stage of the IMPaCT trial assessed the feasibility of acquiring suitable tumor specimens for molecular analysis and returning high-quality actionable genomic data within a clinically acceptable timeframe. We screened for three molecular targets: HER2 lification KRAS wild-type and mutations in DNA damage repair pathways (BRCA1, BRCA2, PALB2, ATM). Results: Tumor biopsy and archived tumor s les were collected from 93 patients and 76 were screened. To date 22 candidate cases have been identified: 14 KRAS wild-type, 5 cases of HER2 lification, 2 mutations in BRCA2, and 1 ATM mutation. Median time from consent to the return of validated results was 21.5 days. An inability to obtain a biopsy or insufficient tumor content in the available specimen were common reasons for patient exclusion from molecular analysis while deteriorating performance status prohibited a number of patients from proceeding in the study. Conclusions: Documenting the feasibility of acquiring and screening biospecimens for actionable molecular targets in real time will aid other groups embarking on similar trials. Key elements include the need to better prescreen patients, screen more patients, and offer more attractive clinical trial options. Clin Cancer Res 21(9) 2029–37. ©2015 AACR.
Publisher: American Medical Association (AMA)
Date: 12-2022
DOI: 10.1001/JAMAONCOL.2022.4457
Abstract: Personalized medicine based on tumor profiling and identification of actionable genomic alterations is pivotal in cancer management. Although tissue biopsy is still preferred for diagnosis, liquid biopsy of blood-based tumor analytes, such as circulating tumor DNA, is a rapidly emerging technology for tumor profiling. This review presents a practical overview for clinicians and allied health care professionals for selection of the most appropriate liquid biopsy assay, specifically focusing on circulating tumor DNA and how it may affect patient treatment and case management across multiple tumor types. Multiple factors influence the analytical validity, clinical validity, and clinical utility of testing. This review provides recommendations and practical guidance for best practice. Current methodologies include polymerase chain reaction-based approaches and those that use next-generation sequencing (eg, capture-based profiling, whole exome, or genome sequencing). Factors that may influence utility include sensitivity and specificity, quantity of circulating tumor DNA, detection of a small vs a large panel of genes, and clonal hematopoiesis of indeterminate potential. Currently, liquid biopsy appears useful in patients unable to undergo biopsy or where mutations detected may be more representative of the predominant tumor burden than for tissue-based assays. Other potential applications may include screening, primary diagnosis, residual disease, local recurrence, therapy selection, or early therapy response and resistance monitoring. This review found that liquid biopsy is increasingly being used clinically in advanced lung cancer, and ongoing research is identifying applications of circulating tumor DNA-based testing that complement tissue analysis across a broad range of clinical settings. Circulating tumor DNA technologies are advancing quickly and are demonstrating potential benefits for patients, health care practitioners, health care systems, and researchers, at many stages of the patient oncologic journey.
Publisher: Elsevier BV
Date: 06-2011
Publisher: Elsevier BV
Date: 09-2016
Publisher: Springer Science and Business Media LLC
Date: 16-10-2014
DOI: 10.1038/NRC3838
Abstract: For the past 30 years, improvements in the survival of patients with osteosarcoma have been mostly incremental. Despite evidence of genomic instability and a high frequency of chromothripsis and kataegis, osteosarcomas carry few recurrent targetable mutations, and trials of targeted agents have been generally disappointing. Bone has a highly specialized immune environment and many immune signalling pathways are important in bone homeostasis. The success of the innate immune stimulant mifamurtide in the adjuvant treatment of non-metastatic osteosarcoma suggests that newer immune-based treatments, such as immune checkpoint inhibitors, may substantially improve disease outcome.
Publisher: Springer Science and Business Media LLC
Date: 07-03-2011
Publisher: American Society for Clinical Investigation
Date: 15-11-2013
DOI: 10.1172/JCI70559
Publisher: Elsevier BV
Date: 08-2003
DOI: 10.1016/S0006-291X(03)01294-4
Abstract: TGF-beta increases bone resorption in vivo and greatly increases osteoclast formation stimulated by receptor activator of NF-kappaB ligand (RANKL) in vitro. TGF-beta does not independently affect the differentiation state of RAW264.7 preosteoclasts, but increases cell attachment to vitronectin. This effect is mediated by increased expression of alphaV integrin subunit mRNA and protein. Concomitant with induction of osteoclast differentiation, RANKL causes relocation of alphaV to focal sites in the cell. This effect is potentiated by TGF-beta. Integrin blockade disrupts both attachment to vitronectin and RANKL-induced osteoclast formation, but culture on vitronectin has little effect. Ectopic expression of alphaV stimulates multinucleation of RAW264.7 cells and increases the number of osteoclasts formed in the presence of RANKL. These data suggest that TGF-beta potentiates RANKL-induced osteoclast formation, in part by increased expression of the alphaV integrin subunit, which may contribute to cell fusion.
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.PHARMTHERA.2012.08.004
Abstract: The hedgehog signaling pathway is important in embryogenesis and post natal development. Constitutive activation of the pathway due to mutation of pathway components occurs in ~25% of medulloblastomas and also in basal cell carcinomas. In many other malignancies the therapeutic role for hedgehog inhibition though intriguing, based on preclinical data, is far from assured. Hedgehog inhibition is not an established part of the treatment paradigm of sarcoma but the scientific rationale for a possible benefit is compelling. In chondrosarcoma there is evidence of hedgehog pathway activation and an ontologic comparison between growth plate chondrocyte differentiation and different chondrosarcoma subtypes. Immunostaining epiphyseal growth plate for Indian hedgehog is particularly positive in the zone of pre-hypertrophic chondrocytes which correlates ontologically with conventional chondrosarcoma. In Ewing sarcoma/PNET tumors the Gli1 transcription factor is a direct target of the EWS-FLI1 oncoprotein present in 85% of cases. In many cases of rhabdomyosarcomas there is increased expression of Gli1 (Ragazzini et al., 2004). Additionally, a third of embryonal rhabdomyosarcomas have loss of Chr.9q22 that encompasses the patched locus (Bridge et al., 2000). The potential to treat osteosarcoma by inhibition of Gli2 and the role of the pathway in ovarian fibromas and other connective tissue tumors is also discussed (Nagao et al., 2011 Hirotsu et al., 2010). Emergence of acquired secondary resistance to targeted therapeutics is an important issue that is also relevant to hedgehog inhibition. In this context secondary resistance of medulloblastomas to treatment with a smoothened antagonist in two tumor mouse models is examined.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2017
DOI: 10.1007/S10689-016-9964-7
Abstract: Germline TP53 mutation carriers are at high risk of developing a range of cancers. Effective cancer risk management is an important issue for these in iduals. We assessed the psychosocial impact in TP53 mutation carriers of WB-MRI screening as part of the Surveillance in Multi-Organ Cancer (SMOC+) protocol, measuring their unmet needs, anxiety and depression levels as well as cancer worry using psychological questionnaires and in-depth interviews about their experiences of screening. We present preliminary psychosocial findings from 17 participants during their first 12 months on the trial. We found a significant reduction in participants' mean anxiety from baseline to two weeks post WB-MRI (1.2, 95% CI 0.17 to 2.23 p = 0.025), indicative of some benefit. Emerging qualitative themes show most participants are emotionally supported and contained by the screening program and are motivated by their immediate concern about staying alive, despite being informed about the current lack of evidence around efficacy of screening for people with TP53 mutations in terms of cancer morbidity or mortality. For those that do gain emotional reassurance from participating in the screening study, feelings of abandonment by the research team are a risk when the study ends. For others, screening was seen as a burden, consistent with the relentless nature of cancer risk associated with Li-Fraumeni syndrome, though these patients still declared they wished to participate due to their concern with staying alive. Families with TP53 mutations need ongoing support due to the impact on the whole family system. These findings suggest a comprehensive multi-organ screening program for people with TP53 mutations provides psychological benefit independent of an impact on cancer morbidity and mortality associated with the syndrome. The benefits of a multi-organ screening program will be greater still if the screening tests additionally reduce the cancer morbidity and mortality associated with the syndrome. These findings may also inform the care of in iduals and families with other multi-organ cancer predisposition syndromes.
Publisher: Springer Science and Business Media LLC
Date: 18-03-2014
DOI: 10.1038/NRCLINONC.2014.41
Abstract: Carriers of germline mutations in the TP53 gene, encoding the cell-cycle regulator and tumour suppressor p53, have a markedly increased risk of cancer-related morbidity and mortality during both childhood and adulthood, and thus require appropriate and effective cancer risk management. However, the predisposition of such patients to multiorgan tumorigenesis presents a specific challenge for cancer risk management programmes. Herein, we review the clinical implications of germline mutations in TP53 and the evidence for cancer screening and prevention strategies in in iduals carrying such mutations, as well as examining the potential psychosocial implications of lifelong management for a ubiquitous cancer risk. In addition, we propose an evidence-based framework for the clinical management of TP53 mutation carriers and provide a platform for addressing the management of other cancer predisposition syndromes that can affect multiple organs.
Publisher: American Association for Cancer Research (AACR)
Date: 14-09-2009
DOI: 10.1158/0008-5472.CAN-09-0194
Abstract: Parathyroid hormone–related protein (PTHrP) is required for mammary gland development and promotes the growth of breast cancer metastases within bone. However, there are conflicting reports of the prognostic significance of its expression in primary breast cancers. To study the role of PTHrP in early breast cancer, the effect of conditional deletion of PTHrP was examined in the context of neu-induced mammary tumorigenesis. Loss of PTHrP resulted in a higher tumor incidence. Transcriptional profiling of the tumors revealed that PTHrP influenced genes relevant to heterotypic cell signaling, including regulators of monocyte recruitment. Immunohistochemical analysis of human breast cancers revealed that PTHrP expression was associated with both HER-2/neu expression and macrophage infiltration in preinvasive ductal carcinoma in situ. The gene expression signature associated with loss of PTHrP expression in vivo correlated with poorer outcome in human breast cancer. Together, these data indicate that loss of PTHrP accelerates mammary tumorigenesis possibly by a non–cell-autonomous tumor suppressor pathway. [Cancer Res 2009 (18):7473–9]
Publisher: Springer Science and Business Media LLC
Date: 11-03-2022
DOI: 10.1038/S41431-022-01069-Y
Abstract: Germline genome sequencing (GS) holds great promise for cancer prevention by identifying cancer risk and guiding prevention strategies, however research evidence is mixed regarding patient preferences for receiving GS results. The aim of this study was to discern preferences for return of results by cancer patients who have actually undergone GS. We conducted a mixed methods study with a cohort of cancer probands ( n = 335) and their genetic relatives ( n = 199) undergoing GS in a research setting. Both groups completed surveys when giving consent. A subset of participants ( n = 40) completed semi-structured interviews. A significantly higher percentage of probands thought people would like to be informed about genetic conditions for which there is prevention or treatment that can change cancer risk compared to conditions for which there is no prevention or treatment (93% [311] versus 65% [216] p 0.001). Similar results were obtained for relatives (91% [180] versus 61% [121] p 0.001). Themes identified in the analysis of interviews were: (1) Recognised benefits of GS, (2) Balancing benefits with risks, (3) Uncertain results are perceived as unhelpful and (4) Competing obligations. While utility was an important discriminator in what was seen as valuable for this cohort, there was a variety of responses. In view of varied participant preferences regarding return of results, it is important to ensure patient understanding of test validity and identify in idual choices at the time of consent to GS. The nature and value of the information, and a contextual understanding of researcher obligations should guide result return.
Publisher: Elsevier BV
Date: 11-2020
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-06-2020
Abstract: Bacteria adapt to harsh conditions such as antibiotic exposure by acquiring new mutations, a process called stress-induced mutagenesis. Cipponi et al. investigated whether similar programs of mutagenesis play a role in the response of cancer cells to targeted therapies. Using in vitro models of intense drug selection and genome-wide functional screens, the authors found evidence for an analogous process in cancer and showed that it is regulated by the mammalian target of rapamycin (mTOR) signaling pathway. This pathway appears to mediate a stress-related switch to error-prone DNA repair, resulting in the generation of mutations that facilitate the emergence of drug resistance. Science , this issue p. 1127
Publisher: Springer Science and Business Media LLC
Date: 09-09-2007
DOI: 10.1007/S10555-007-9093-8
Abstract: The RECK (reversion-inducing cysteine rich protein with Kazal motifs) protein was initially discovered by its ability to induce reversion in ras-activated fibroblasts. The key action of RECK is to inhibit matrix metalloproteinases (MMPs) involved in breakdown of the extracellular matrix (ECM), and angiogenesis-namely MMP-2, MMP-9 and MTP-1. To this effect, it plays important physiological roles in embryogenesis and vasculogenesis. Additionally, it has a significant effect on tumorigenesis by limiting angiogenesis and invasion of tumours through the ECM. RECK has been studied in the context of a number of human tumours including colorectal, breast, pancreas, gastric, hepatocellular, prostate, and non-small cell lung carcinoma. In many of these tumours, RECK is down-regulated most likely as a result of inhibition at the Sp1 promoter site. MMP-2 and MMP-9 generally show an inverse association with RECK expression, but there are exceptions to this rule. Likewise, a reduction in tumour microvascular density (MVD) and VEGF have also been correlated with increased RECK levels, although more studies are required to define this effect. The predominant finding across all human tumour studies is a significantly improved prognosis (due to decreased invasion and metastasis) in tumours with preserved RECK expression. Although further research is required, RECK is a promising prognostic marker and potential therapeutic agent in multiple cancers.
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/608964
Abstract: Histone deacetylase inhibitors (HDACi) were identified nearly four decades ago based on their ability to induce cellular differentiation. However, the clinical development of these compounds as cancer therapies has focused on their capacity to induce apoptosis in hematologic and lymphoid malignancies, often in combination with conventional cytotoxic agents. In many cases, HDACi doses necessary to induce these effects result in significant toxicity. Since osteosarcoma cells express markers of terminal osteoblast differentiation in response to DNA methyltransferase inhibitors, we reasoned that the epigenetic reprogramming capacity of HDACi might be exploited for therapeutic benefit. Here, we show that continuous exposure of osteosarcoma cells to low concentrations of HDACi LBH589 (Panobinostat) over a three-week period induces terminal osteoblast differentiation and irreversible senescence without inducing cell death. Remarkably, transcriptional profiling revealed that HDACi therapy initiated gene signatures characteristic of chondrocyte and adipocyte lineages in addition to marked upregulation of mature osteoblast markers. In a mouse xenograft model, continuous low dose treatment with LBH589 induced a sustained cytostatic response accompanied by induction of mature osteoblast gene expression. These data suggest that the remarkable capacity of osteosarcoma cells to differentiate in response to HDACi therapy could be exploited for therapeutic benefit without inducing systemic toxicity.
Publisher: Bioscientifica
Date: 08-1996
Abstract: Corticosteroids have profound effects on bone metabolism, though the underlying mechanisms remain unclear. They are also known to alter glucose metabolism, in part by induction of insulin resistance. To determine whether corticosteroids impair glucose metabolism in bone cells, we have examined the actions of dexamethasone (DEX) on glucose transport and insulin receptor expression using osteoblast-like UMR 106-01 cells. DEX was shown to inhibit basal 2-deoxyglucose uptake by up to 30% in a time- and dose-dependent manner. It inhibited insulin-stimulated glucose transport by 13%. By Northern and Western blot analysis, DEX was shown to stimulate insulin receptor mRNA and protein by up to 5·6-fold, but it had no effect on expression of the glucose transporter GLUT 1 mRNA or protein under basal conditions. However, DEX augmented insulin-stimulated GLUT 1 mRNA and protein levels. By Scatchard analysis of labelled insulin binding, DEX increased insulin receptor number per cell by 54%. Subcellular fractionation and Western blot analysis demonstrated that DEX caused a redistribution of immunoreactive GLUT 1 from plasma membrane to intracellular microsomes, resulting in a 21% decrease in GLUT 1 at the plasma membrane. These data suggest that (i) DEX impairs basal glucose transport by post-translational mechanisms in UMR 106-01 cells, (ii) DEX increases insulin receptor mRNA, protein and insulin binding and (iii) the inhibition of glucose transport by DEX dominates its effects on the insulin receptor. It is possible that DEX inhibition of glucose transport in osteoblasts may contribute to steroid-induced osteoporosis.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Hindawi Limited
Date: 2010
DOI: 10.1155/2011/746939
Abstract: The p53 tumour suppressor plays a pivotal role in the prevention of oncogenic transformation. Cancers frequently evade the potent antitumour surveillance mechanisms of p53 through mutation of the TP53 gene, with approximately 50% of all human malignancies expressing dysfunctional, mutated p53 proteins. Interestingly, genetic lesions in the TP53 gene are only observed in 10% of Ewing Sarcomas, with the majority of these sarcomas expressing a functional wild-type p53. In addition, the p53 downstream signaling pathways and DNA-damage cell cycle checkpoints remain functionally intact in these sarcomas. This paper summarizes recent insights into the functional capabilities and regulation of p53 in Ewing Sarcoma, with a particular focus on the cross-talk between p53 and the EWS-FLI1 gene rearrangement frequently associated with this disease. The development of several activators of p53 is discussed, with recent evidence demonstrating the potential of small molecule p53 activators as a promising systemic therapeutic approach for the treatment of Ewing Sarcomas with wild-type p53.
No related grants have been discovered for David Thomas.