Institution
Peter MacCallum Cancer Centre
Healthcare•Melbourne, Victoria, Australia•
About: Peter MacCallum Cancer Centre is a healthcare organization based out in Melbourne, Victoria, Australia. It is known for research contribution in the topics: Cancer & Breast cancer. The organization has 4077 authors who have published 9806 publications receiving 458873 citations. The organization is also known as: Peter Mac & Peter MacCallum Cancer Institute.
Topics: Cancer, Breast cancer, Population, Prostate cancer, Radiation therapy
Papers published on a yearly basis
Papers
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TL;DR: Compared with chemotherapy, crizotinib demonstrated a significantly higher intracranial disease control rate (IC-DCR) in patients with tBM, although sensitivity to detect treatment differences in or between the two subgroups was low.
Abstract: PurposeIntracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non–small-cell lung cancer.Patients and MethodsPatients were randomly assigned to receive crizotinib (250 mg twice daily; n = 172) or chemotherapy (pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin at area under the curve 5 to 6, every 3 weeks for ≤ six cycles; n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively; intracranial time to tumor progression (IC-TTP; per protocol) and intracranial disease control rate (IC-DCR; post hoc) were measured. The intent-to-treat population was also assessed.ResultsOf 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard rat...
198 citations
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TL;DR: A detailed study of human Scribble function in the polarized mammary cell line, MCF10A is undertaken and identifies an essential role for mammalian Scribble in the regulation of the polarity specifically involved in directed epithelial migration.
Abstract: Altered expression of human Scribble is associated with invasive epithelial cancers, however, its role in tumour development remains unclear. Mutations in Drosophila Scribble result in loss of polarity, overproliferation and 3D-tumourous overgrowth of epithelial cells. Using complementation studies in Drosophila we recently demonstrated that expression of human Scribble can also regulate polarity and restrict tissue overgrowth. Here, we have undertaken a detailed study of human Scribble function in the polarized mammary cell line, MCF10A. We show that although Scribble does not seem to be required for apical-basal polarity or proliferation control in MCF10A cells, Scribble is essential for the control of polarity associated with directed epithelial cell migration. Scribble-depleted MCF10A cells show defective in vitro wound closure and chemotactic movement. The cells at the wound edge fail to polarize, show reduced lamellipodia formation and impaired recruitment of Cdc42 and Rac1 to the leading edge. Furthermore, we show that this function is relevant in vivo as Scribble mutant mice show defective epidermal wound healing. This data identifies an essential role for mammalian Scribble in the regulation of the polarity specifically involved in directed epithelial migration.
198 citations
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Francis Crick Institute1, University College London2, Max Delbrück Center for Molecular Medicine3, Dartmouth College4, Aarhus University5, Aarhus University Hospital6, Rockefeller University7, Katholieke Universiteit Leuven8, University of Oxford9, Wellcome Trust Sanger Institute10, The Royal Marsden NHS Foundation Trust11, Stanford University12, Lund University13, University Hospital of Basel14, Swiss Institute of Bioinformatics15, Guy's and St Thomas' NHS Foundation Trust16, Peter MacCallum Cancer Centre17, Institut Gustave Roussy18, Aix-Marseille University19, Edinburgh Cancer Research Centre20, Harvard University21, Massachusetts Institute of Technology22, University of California, San Francisco23, University of Melbourne24, Université Paris-Saclay25, Okinawa Institute of Science and Technology26, Netherlands Cancer Institute27, Maastricht University28, Semmelweis University29, Boston Children's Hospital30, Memorial Sloan Kettering Cancer Center31, German Cancer Research Center32
TL;DR: Multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types are used to show that continuous chromosomal instability results in pervasive SCNA heterogeneity.
Abstract: Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2+ breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.
198 citations
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TL;DR: The combination of limited surgery, anthracycline-containing chemotherapy, and involved-field RT produced the best outcome in the pre-rituximab era, and a prospective trial is pursued to confirm these results.
198 citations
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National and Kapodistrian University of Athens1, University of Sydney2, Dalhousie University3, Peter MacCallum Cancer Centre4, University of Auvergne5, Northwestern University6, Emory University7, McGill University Health Centre8, Vanderbilt University9, Harvard University10, University of Paris11, University of Patras12, University of Ulm13
TL;DR: The proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L) were studied.
Abstract: Summary Background In the era of widespread rituximab use for Waldenstrom's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenstrom's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. Methods This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenstrom's macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. Findings Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58–74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenstrom Macroglobulinaemia, median number of previous therapies was four (IQR 2–6), and all were rituximab-refractory. At a median follow-up of 18·1 months (IQR 17·5–18·9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66–94), and the estimated 18 month overall survival rate was 97% (95% CI 79–100). Baseline median haemoglobin of 10·3 g/dL (IQR 9·3–11·7) increased to 11·4 g/dL (10·9–12·4) after 4 weeks of ibrutinib treatment and reached 12·7 g/dL (11·8–13·4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. Interpretation The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenstrom's macroglobulinaemia. Funding Pharmacyclics LLC, an AbbVie Company.
198 citations
Authors
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Name | H-index | Papers | Citations |
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Dorret I. Boomsma | 176 | 1507 | 136353 |
Douglas F. Easton | 165 | 844 | 113809 |
Caroline S. Fox | 155 | 599 | 138951 |
Mark J. Smyth | 153 | 713 | 88783 |
Hideo Yagita | 137 | 946 | 70623 |
Ko Okumura | 134 | 1057 | 67530 |
Neville Owen | 127 | 700 | 74166 |
Patricia A. Ganz | 120 | 701 | 57204 |
Paul Flicek | 104 | 310 | 82599 |
Melissa C. Southey | 103 | 652 | 46736 |
Georgia Chenevix-Trench | 101 | 546 | 53048 |
Alison M. Dunning | 99 | 437 | 39481 |
Gregory J. Riely | 99 | 306 | 53019 |
Giovanni Martinelli | 99 | 1233 | 45436 |
Heli Nevanlinna | 97 | 390 | 40509 |