• A parallel proteomic and metabolomic analysis of the hydrogen peroxide- and Sty1p-dependent stress response in Schizosaccharomyces pombe.

      Weeks, Mark E; Sinclair, John; Butt, Amna; Chung, Yuen-Li; Worthington, Jessica L; Wilkinson, Caroline R M; Griffiths, John R; Jones, Nic; Waterfield, Michael D; Timms, John F; et al. (2006-05)
      Using an integrated approach incorporating proteomics, metabolomics and published mRNA data, we have investigated the effects of hydrogen peroxide on wild type and a Sty1p-deletion mutant of the fission yeast Schizosaccharomyces pombe. Differential protein expression analysis based on the modification of proteins with matched fluorescent labelling reagents (2-D-DIGE) is the foundation of the quantitative proteomics approach. This study identifies 260 differentially expressed protein isoforms from 2-D-DIGE gels using MALDI MS and reveals the complexity of the cellular response to oxidative stress and the dependency on the Sty1p stress-activated protein kinase. We show the relationship between these protein changes and mRNA expression levels identified in a parallel whole genome study, and discuss the regulatory mechanisms involved in protecting cells against hydrogen peroxide and the involvement of Sty1p-dependent stress-activated protein kinase signalling. Metabolomic profiling of 29 intermediates using 1H NMR was also conducted alongside the protein analysis using the same sample sets, allowing examination of how the protein changes might affect the metabolic pathways and biological processes involved in the oxidative stress response. This combined analysis identifies a number of interlinked metabolic pathways that exhibit stress- and Sty1-dependent patterns of regulation.
    • The paralogous hematopoietic regulators Lyl1 and Scl are coregulated by Ets and GATA factors, but Lyl1 cannot rescue the early Scl-/- phenotype.

      Chan, Wan Y I; Follows, George A; Lacaud, Georges; Pimanda, John E; Landry, Josette-Renee; Kinston, Sarah; Knezevic, Kathy; Piltz, Sandie; Donaldson, Ian J; Gambardella, Laure; et al. (2007-03-01)
      Transcription factors are key regulators of hematopoietic stem cells (HSCs), yet the molecular mechanisms that control their expression are largely unknown. Previously, we demonstrated that expression of Scl/Tal1, a transcription factor required for the specification of HSCs, is controlled by Ets and GATA factors. Here we characterize the molecular mechanisms controlling expression of Lyl1, a paralog of Scl also required for HSC function. Two closely spaced promoters directed expression to hematopoietic progenitor, megakaryocytic, and endothelial cells in transgenic mice. Conserved binding sites required for promoter activity were bound in vivo by GATA-2 and the Ets factors Fli1, Elf1, Erg, and PU.1. However, despite coregulation of Scl and Lyl1 by the same Ets and GATA factors, Scl expression was initiated prior to Lyl1 in embryonic stem (ES) cell differentiation assays. Moreover, ectopic expression of Scl but not Lyl1 rescued hematopoietic differentiation in Scl-/- ES cells, thus providing a molecular explanation for the vastly different phenotypes of Scl-/- and Lyl1-/- mouse embryos. Furthermore, coregulation of Scl and Lyl1 later during development may explain the mild phenotype of Scl-/- adult HSCs.
    • PARG inhibition: development of novel compounds and a biomarker strategy to determine cell line sensitivity in breast cancer

      Waddell, Ian D; James, Dominic I; Smith, Kate M; Holt, Sarah V; Acton, Ben; Fairweather, Emma E; Hamilton, Niall M; Hamilton, Nicola S; Hitchin, James R; Huttom, Colin; et al. (2015)
    • PARG inhibitors exhibit synthetic lethality with XRCC1 deficiency and a cellular mechanism of action that is distinct from PARP inhibition

      Martin, Leenus; Cheng, Tzuling; James, Dominic I; Begum, Habiba; Smith, Kate M; Jordan, Allan M; Waddell, Ian D; Vaidya, Kedar; Fischer, Marcus; Yao, Bing; et al. (2018)
    • Partial trisomy 14q-- and pseudoxanthoma elasticum.

      Muldal, S; Enoch, B A; Ahmed, A; Harris, R; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1973-06)
    • Pathbase: a database of mutant mouse pathology.

      Schofield, Paul N; Bard, Jonathan B L; Booth, Catherine; Boniver, Jacques; Covelli, Vincenzo; Delvenne, Philippe; Ellender, Michele; Engstrom, Wilhelm; Goessner, Wolfgang; Gruenberger, Michael; et al. (2004-01-01)
      Pathbase is a database that stores images of the abnormal histology associated with spontaneous and induced mutations of both embryonic and adult mice including those produced by transgenesis, targeted mutagenesis and chemical mutagenesis. Images of normal mouse histology and strain-dependent background lesions are also available. The database and the images are publicly accessible (http://www.pathbase.net) and linked by anatomical site, gene and other identifiers to relevant databases; there are also facilities for public comment and record annotation. The database is structured around a novel ontology of mouse disorders (MPATH) and provides high-resolution downloadable images of normal and diseased tissues that are searchable through orthogonal ontologies for pathology, developmental stage, anatomy and gene attributes (GO terms), together with controlled vocabularies for type of genetic manipulation or mutation, genotype and free text annotation for mouse strain and additional attributes. The database is actively curated and data records assessed by pathologists in the Pathbase Consortium before publication. The database interface is designed to have optimal browser and platform compatibility and to interact directly with other web-based mouse genetic resources.
    • Patient age and risk of recurrence of primary melanoma at high risk of spread

      Ghiasvand, R.; Khosrotehrani, K.; Hughes, M. C. B.; von Schuckmann, L. A.; Beesley, V. L.; Malt, M.; Smithers, B. M.; Green, Adèle C; Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway. (2020)
      Melanoma is more aggressive with poorer outcomes in older than younger patients. Older age has been associated with greater tumour thickness, higher rates of ulceration, and high mitotic rates,1,2 but it is not clear whether poorer outcomes in the elderly are solely due to these tumour-specific features or to additional effects of age-related decline in in immune surveillance, greater comorbidity, and age-related behaviours such as delayed diagnosis.
    • Patient-derived xenograft (PDX) models in basic and translational breast cancer research.

      Dobrolecki, L; Airhart, S; Alférez, Denis G; Aparicio, S; Behbod, F; Bentires-Alj, M; Brisken, C; Bult, C; Cai, S; Clarke, R; et al. (2016-12)
      Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward "credentialing" of PDX models as surrogates to represent individual patients for use in preclinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research.
    • The pattern of expression of the 5T4 oncofoetal antigen on normal, dysplastic and malignant oral mucosa.

      Ali, A; Langdon, J; Stern, Peter L; Partridge, M; Maxillofacial Unit/Molecular Oncology, King's College Hospital, Denmark Hill, SE5 8RX, London, UK. (2001-01)
      The human 5T4 oncofoetal antigen is expressed by all types of trophoblast in pregnancy but is not detected on most adult tissues, although low levels are found on some epithelia. However, this antigen is strongly expressed by many cancers and tumour-associated labelling correlates with metastatic spread and poor clinical outcome for patients with gastric and colon cancer. Over-expression of the gene influences cell adhesion, shape and motility, which may be related to changes in the cellular localisation of the 5T4 oncofoetal antigen as malignancy develops. To establish whether the 5T4 oncofoetal antigen can serve as a tumour-specific marker for oral cancer and precancer, we have evaluated the pattern of expression on biopsies of normal, inflamed and dysplastic oral mucosa using immunohistochemistry. Oral mucosa, taken from different sites in the mouth, expressed the 5T4 oncofoetal antigen with varying intensity and pattern. The majority of the immunoreactivity was detected in the basal and suprabasal layers, with expression extending into the spinous cells at fully keratinised sites and when inflammation was present. This antigen was also detected in the underlying connective tissue. Oral squamous cell carcinoma showed a variety of patterns and intensity of staining corresponding to those found for normal mucosa. However, 21 of 41 cases showed no stromal labelling, a finding also observed for dysplastic lesions. The alterations in the pattern and intensity of 5T4 oncofoetal antigen expression were not related to clinicopathological features of the tumours examined. These data show that the 5T4 oncofoetal antigen is expressed on normal oral mucosa, such that this target cannot be used for detection of neoplastic or preneoplastic cells, although altered expression may contribute to the pathogenesis of these lesions.
    • Patterns of mortality after prolonged follow-up of a randomised controlled trial using granulocyte colony-stimulating factor to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma.

      Clamp, Andrew R; Ryder, W David J; Bhattacharya, Soumo; Pettengell, Ruth; Radford, John A; Department of Medical Oncology, Cancer Research UK, University of Manchester, Christie Hospital, Wilmslow Rd., Manchester M20 4BX, UK. Andrew.clamp@christie.nhs.uk (2008-07-22)
      The effect of utilising granulocyte colony-stimulating factor (G-CSF) to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma (NHL) on long-term mortality patterns has not been formally evaluated. We analysed prolonged follow-up data from the first randomised controlled trial investigating this approach. Data on 10-year overall survival (OS), progression-free survival (PFS), freedom from progression (FFP) and incidence of second malignancies were collected for 80 patients with aggressive subtypes of NHL, who had been randomised to receive either VAPEC-B chemotherapy or VAPEC-B+G-CSF. Median follow-up was 15.7 years for surviving patients. No significant differences were found in PFS or OS. However, 10-year FFP was better in the G-CSF arm (68 vs 47%, P=0.037). Eleven deaths from causes unrelated to NHL or its treatment occurred in the G-CSF arm compared to five in controls. More deaths occurred from second malignancies (4 vs 2) and cardiovascular causes (5 vs 0) in the G-CSF arm. Although this pharmacovigilance study has insufficient statistical power to draw conclusions and is limited by the lack of data on smoking history and other cardiovascular risk factors, these unique long-term outcome data generate hypotheses that warrant further investigation.
    • Patterns of omega-3 and omega-6 fatty acid dietary intake and melanoma thickness at diagnosis

      Mahamat-Saleh, Y.; Hughes, M. C. B.; Miura, K.; Malt, M. K.; von Schuckmann, L.; Khosrotehrani, K.; Smithers, B. M.; Green, Adèle C; Centre for Research in Epidemiology and Population Health (CESP) School of Medicine, Universite Paris Sud School of Medicine, Universite Versailles Saint-Quentin-en-Yvelines (UVSQ); INSERM French National Institute for Health and Medical Research, Universite Paris Saclay, Villejuif, France. (2020)
      Background: Experimental evidence suggests that dietary intakes of omega-3 and omega-6 polyunsaturated fatty acids have divergent effects on melanoma growth, but epidemiologic evidence on their combined effect is lacking. Methods: In 634 Australian patients with primary melanoma, we assessed prediagnosis consumption of 39 food groups by food frequency questionnaires completed within 2 months of diagnosis. We derived, by reduced rank regression, dietary patterns that explained variability in selected omega-3 and omega-6 fatty acid intakes. Prevalence ratios (PR) and 95% confidence intervals (CI) for the association between tertiles of dietary patterns and melanoma thickness >2 mm versus ≤2 mm were estimated using Poisson regression. Results: Overall omega-3 fatty acid intakes were low. Two major fatty acid dietary patterns were identified: "meat, fish, and fat," positively correlated with intakes of all fatty acids; and "fish, low-meat, and low-fat," positively correlated with long-chain omega-3 fatty acid intake, and inversely with medium-chain omega-3 and omega-6 fatty acid intakes. Prevalence of thick melanomas was significantly higher in those in the highest compared with lowest tertile of the "meat, fish, and fat" pattern (PR, 1.40; 95% CI, 1.01-1.94), especially those with serious comorbidity (PR, 1.83; 95% CI, 1.15-2.92) or a family history (PR, 2.32; 95% CI, 1.00-5.35). The "fish, low-meat, and low-fat" pattern was not associated with melanoma thickness. Conclusions: People with high meat, fish, and fat intakes, who thus consumed relatively high levels of omega-3 and high omega-6 fatty acid intakes, are more likely to be diagnosed with thick than thin melanomas.
    • Patterns of practice for adaptive and real-time radiation therapy: part I intra-fraction motion

      Distefano, G.; Bertholet, J.; Poulsen, P.; Roggen, T.; Garibaldi, C.; Tilly, N.; Booth, J.; Oelfke, U.; Heijmen, B; Aznar, Marianne Camille; et al. (2020)
      Purpose or Objective The patterns of practice for adaptive and real-time radiation therapy (POP-ART RT) study aims to determine to which extent and how these methods are used in clinical practice and to understand the barriers to implementation. Here we report on part I: real-time respiratory motion management (RRMM). Material and Methods An institution-specific questionnaire developed during the 2nd ESTRO physics workshop was distributed worldwide. The focus was both on current practice and wishes for implementation. Therefore, centres not (yet) doing RRMM were encouraged to participate. RRMM was defined as the use of gating in free-breathing (FB) or breath-hold (BH), or tracking if the beam is continuously realigned with the target in real-time (via robotic or gimbal guidance, MLC or couch tracking). Respondents were asked if they used RRMM for selected tumor sites, the percentage of patients treated with RRMM, eligibility criteria and the monitoring signal used to guide gating or tracking. Respondents were also asked if they wished 1) to change or expand their use of RRMM for a tumor site already treated with RRMM and 2) to implement RRMM for a new tumor site and to rank the barriers to implementation in order of importance. Results The questionnaire was filled out by 200 centres from 41 countries. 68% of respondents used RRMM in at least one tumor site (“users”). Inspiration BH was the dominant technique for breast and lymphoma, whereas the spread in technique was greater for other sites (Table 1). Within any given tumor site, users only applied RRMM in a subset of patients. The most frequently selected percentage range of patients treated using RRMM was <25% for lung, pancreas and lymphoma, 25-50% for breast and >75% for liver. However, for liver and pancreas, >50% of users applied RRMM in >50% of patients. The main selection criteria was “left breast” (76%) for breast and SBRT (~50%) for lung, liver and pancreas. Across all tumor sites, external marker was the main RRMM signal used by >60% of respondents. For breast and lymphoma this was followed by surface imaging and breathing volume. KV/MV imaging was frequently used for liver and pancreas (with markers) and for lung (with or without markers) (Fig 1a). Tracking was mainly done on robotic linacs with hybrid monitoring. For breast and lung, 36% and 49% of the centres respectively wish to expand or implement RRMM (Fig 1b). In contrast, for liver and pancreas >55% of centres do not use RRMM and do not wish to implement it. Overall 71% of centres wish to implement RRMM for any new treatment site (Fig 1c) but human/financial resources and capacity on machine were the main barriers Conclusion Thirty-two percent of respondents do not use any form of RRMM. Although RRMM was common in the thorax, it was generally applied for less than half of the patients. There is an unmet need for RRMM solutions, particularly in lung cancer. The main barriers to implement RRMM are human/financial resources and capacity on the machine.
    • Patterns of recurrence and survival in the randomized Portec-3 trial of chemoradiotherapy for high-risk endometrial cancer

      de Boer, S; Powell, ME; Mileshkin, L; Katsaros, D; Bessette, P; Haie-Meder, C; Ottevanger, PB; Ledermann, JA; Khaw, P; Colombo, A; et al. (2019)
    • Patterns of recurrence in the randomised PORTEC-3 trial of chemoradiotherapy for endometrial cancer.

      De Boer, S; Powell, M; Mileshkin, L; Katsaros, D; Bessette, P; Haie-Meder, C; Ottevanger, P; Ledermann, J; Khaw, P; Colombo, A; et al. (2018)
    • Patterns of sulphation in heparan sulphate: polymorphism based on a common structural theme.

      Gallagher, John T; Turnbull, Jeremy E; Lyon, Malcolm; CRC Department of Medical Oncology, Christie Hospital and Holt Radium Institute, Manchester, U.K. (1992-04)
      HS appears to be a well-organised molecule with a domain structure that is apparently unique amongst the GAG family (Gallagher, 1989). Further refinements in sequence analysis are needed to corroborate the simplified model proposed in Fig. 4. It is still not clear why evolution has favoured a structural motif of widely spaced sulphated domains. Presumably, some advantages must accrue to the organism from this design, and one idea, that we have discussed previously, is that the polysaccharide functions as a "template" for the organisation of structural proteins in the ECM and for the binding and presentation of growth factors within the matrix polymer network. The sulphated regions are likely to display considerable conformational versatility as a result of the presence of the iduronate residues, and this property may be very important for the protein-binding properties of the polysaccharides (Casu et al., 1988). Sulphation patterns within these regions could favour oligosaccharide conformations necessary for specific protein interactions. An important question in this context is why different cells express on their surfaces HS with subtle differences in sulphation pattern. Perhaps the polymorphic features of HS are involved in higher-order tissue- and organ-specific mechanisms controlling cellular recognition and morphogenesis. The consistency with which aberrant sulphation of HS is detected in malignant disease (Gallagher and Lyon, 1989) in which cellular recognition and differentiation are impaired, adds some substance to this view.
    • Patterns of use of chemotherapy with radiotherapy in the treatment of muscle-invasive bladder cancer: Data from the RAIDER randomized trial of adaptive radiotherapy

      Huddart, R. A.; Lewis, R.; Griffin, C.; Alonzi, R.; Birtle, A. J.; Choudhury, Ananya; Cresswell, J.; Foroudi, F.; Hafeez, S.; Henry, A.; et al. (2020)
      Background: Level 1 evidence exists for the use of both neoadjuvant chemotherapy (NAC) and concomitant radiosensitization (CRS) to improve outcomes in patients receiving radical radiotherapy (RT) for muscle invasive bladder cancer, but uptake has been patchy. We report here the current patterns of usage in an ongoing trial of adaptive radiotherapy. Methods: RAIDER is an international randomized phase II trial recruiting patients with unifocal T2-T4a urothelial carcinoma of the bladder suitable for RT (ISCRTN:26779187). Patients are randomized in a 1:1:2 ratio to one of 3 arms: Standard whole bladder RT (control); Standard dose adaptive tumour focused RT; Dose escalated (DE) adaptive tumour boost RT. Standard dose patients are treated to either 64Gy/32f or 55Gy/20f and DE patients to 70Gy in 32f or 60Gy in 20f. Patients are encouraged to receive NAC and CRS. The primary endpoint is the rate of late toxicity 6-18 months post treatment in arm 3, with secondary endpoints of patient reported and disease related outcomes. Results: To August 2019, 285 patients had been recruited. Median age is 72 years (IQR 67-79). Stage of disease is T2 79%, T3 19%, T4 2%; 19% have hydronephrosis. Patients receiving NAC were more likely to be PS 0 at trial entry (70% v 45%). Variation in frequency of CRS use is seen across sites, with some offering to >90% of participants and some <50%. Data on NAC and CRS use is available for 249 patients recruited to date is shown in table. Conclusions: In this ongoing clinical trial the majority of patients are receiving NAC and/or CRS. However, uptake is not universal with ~30% of patients not receiving low dose CRS, including some who have received NAC. Clinical trial information: 26779187.
    • PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum

      Alhalabi, K. T.; Stichel, D.; Sievers, P.; Peterziel, H.; Sommerkamp, A. C.; Sturm, D.; Wittmann, A.; Sill, M.; Jäger, N.; Beck, P.; et al. (2021)
      Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.
    • A PAX3/BRN2 rheostat controls the dynamics of BRAF mediated MITF regulation in MITFhigh /AXLlow melanoma.

      Smith, M; Rana, S; Ferguson, J; Rowling, E; Flaherty, K; Wargo, J; Marais, Richard; Wellbrock, C; Manchester Cancer Research Centre, Faculty of Biology, Medicine& Health, Division of Cancer Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT (2018-10-01)
      The BRAF-kinase and the MAPK-pathway are targets of current melanoma therapies. However, MAPK-pathway inhibition results in dynamic changes of down-stream targets that can counteract inhibitor-action not only during treatment, but also in acquired resistant tumours. One such dynamic change involves the expression of the transcription factor MITF, a crucial regulator of cell survival and proliferation in untreated as well as drug-addicted acquired resistant melanoma. Tight control over MITF expression levels is required for optimal melanoma growth, and while it is well established that the MAPK-pathway regulates MITF expression, the actual mechanism is insufficiently understood. We reveal here, how BRAF through action on the transcription factors BRN2 and PAX3 executes control over the regulation of MITF expression in a manner that allows for considerable plasticity. This plasticity provides robustness to the BRAF mediated MITF regulation and explains the dynamics in MITF expression that are observed in patients in response to MAPK-inhibitor therapy. This article is protected by copyright. All rights reserved.
    • Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial.

      Sternberg, Cora N; Davis, Ian D; Mardiak, Jozef; Szczylik, Cezary; Lee, Eunsik; Wagstaff, John; Barrios, Carlos H; Salman, Pamela; Gladkov, Oleg A; Kavina, Alexander; et al. (2010-02-20)
      PURPOSE Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.
    • Pazopanib versus sunitinib in metastatic renal-cell carcinoma.

      Motzer, R; Hutson, T; Cella, D; Reeves, J; Hawkins, Robert E; Guo, J; Nathan, P; Staehler, M; de Souza, P; Merchan, J; et al. (2013-08-22)
      Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy.