124 results on '"Millward MJ"'
Search Results
2. The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study
- Author
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Millward, MJ, House, C, Bowtell, D, Webster, L, Olver, IN, Gore, M, Copeman, M, Lynch, K, Yap, A, Wang, Y, Cohen, PS, Zalcberg, J, Millward, MJ, House, C, Bowtell, D, Webster, L, Olver, IN, Gore, M, Copeman, M, Lynch, K, Yap, A, Wang, Y, Cohen, PS, and Zalcberg, J
- Abstract
Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had >50% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies.
- Published
- 2006
3. Effect of the paclitaxel vehicle, Cremophor EL, on the pharmacokinetics of doxorubicin and doxorubicinol in mice
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Webster, LK, primary, Cosson, EJ, additional, Stokes, KH, additional, and Millward, MJ, additional
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- 1996
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4. The use of granuloctye colony-stimulating factor to deliver four cycles of ifosfamide and epirubicin every 14 days in women with advanced or metastatic breast cancer
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Lind, MJ, primary, Gumbrell, L, additional, Cantwell, BMJ, additional, Millward, MJ, additional, Simmonds, D, additional, Proctor, M, additional, Chapman, F, additional, McCann, E, additional, Middleton, I, additional, and Calvert, AH, additional
- Published
- 1995
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5. Oral verapamil with chemotherapy for advanced non-small cell lung cancer: a randomised study
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Millward, MJ, primary, Cantwell, BMJ, additional, Munro, NC, additional, Robinson, A, additional, Corris, PA, additional, and Harris, AL, additional
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- 1993
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6. Etoposide phosphate (EP): A comparative intrapatient bio-equivalence study with etoposide(E)
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Bailey, N, primary, Millward, MJ, additional, Newell, DR, additional, Charlton, CJ, additional, Gumbrell, LA, additional, Lind, MJ, additional, Dore-Green, F, additional, Proctor, M, additional, Simmonds, D, additional, McDaniel, C, additional, Winograd, B, additional, Igwemezie, LN, additional, and Calvert, AH, additional
- Published
- 1993
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7. A phase II trial of goserelin (Zoladex) in relapsed epithelial ovarian cancer
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Lind, MJ, primary, Cantwell, BMJ, additional, Millward, MJ, additional, Robinson, A, additional, Proctor, M, additional, Simmons, D, additional, Carmichael, J, additional, and Harris, AL, additional
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- 1992
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8. A phase II study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma.
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Nowak AK, Millward MJ, Creaney J, Francis RJ, Dick IM, Hasani A, van der Schaaf A, Segal A, Musk AW, Byrne MJ, Nowak, Anna K, Millward, Michael J, Creaney, Jenette, Francis, Roslyn J, Dick, Ian M, Hasani, Arman, van der Schaaf, Agatha, Segal, Amanda, Musk, Arthur W, and Byrne, Michael J
- Published
- 2012
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9. A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer.
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Baggstrom MQ, Qi Y, Koczywas M, Argiris A, Johnson EA, Millward MJ, Murphy SC, Erlichman C, Rudin CM, Govindan R, Mayo Phase 2 Consortium, Baggstrom, Maria Q, Qi, Yingwei, Koczywas, Marianna, Argiris, Athanassios, Johnson, Elizabeth A, Millward, Michael J, Murphy, Sara C, Erlichman, Charles, and Rudin, Charles M
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- 2011
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10. Phase II clinical and endocrine study of Anandron (RU-23908) in advanced post-menopausal breast cancer
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Millward, MJ, primary, Cantwell, BMJ, additional, Dowsett, M, additional, Carmichael, J, additional, and Harris, AL, additional
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- 1991
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11. Early [18F]fluorodeoxyglucose-positron emission tomography responses in metastatic melanoma: what do they mean?
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Millward MJ and Millward, Michael J
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- 2012
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12. Time-course RNAseq data of murine AB1 mesothelioma and Renca renal cancer following immune checkpoint therapy.
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Chin WL, Zemek RM, Tilsed CM, Forrest ARR, Fear VS, Forbes C, Boon L, Bosco A, Guo BB, Millward MJ, Nowak AK, Lake RA, Lesterhuis WJ, and Lassmann T
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- Animals, Mice, RNA-Seq, Sequence Analysis, RNA, Single-Cell Analysis, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell genetics, Immune Checkpoint Inhibitors therapeutic use, Kidney Neoplasms drug therapy, Kidney Neoplasms genetics, Mesothelioma drug therapy, Mesothelioma genetics, Tumor Microenvironment
- Abstract
Time-critical transcriptional events in the immune microenvironment are important for response to immune checkpoint blockade (ICB), yet these events are difficult to characterise and remain incompletely understood. Here, we present whole tumor RNA sequencing data in the context of treatment with ICB in murine models of AB1 mesothelioma and Renca renal cell cancer. We sequenced 144 bulk RNAseq samples from these two cancer types across 4 time points prior and after treatment with ICB. We also performed single-cell sequencing on 12 samples of AB1 and Renca tumors an hour before ICB administration. Our samples were equally distributed between responders and non-responders to treatment. Additionally, we sequenced AB1-HA mesothelioma tumors treated with two sample dissociation protocols to assess the impact of these protocols on the quality transcriptional information in our samples. These datasets provide time-course information to transcriptionally characterize the ICB response and provide detailed information at the single-cell level of the early tumor microenvironment prior to ICB therapy., (© 2024. The Author(s).)
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- 2024
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13. Immune checkpoint therapy responders display early clonal expansion of tumor infiltrating lymphocytes.
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Kidman J, Zemek RM, Sidhom JW, Correa D, Principe N, Sheikh F, Fear VS, Forbes CA, Chopra A, Boon L, Zaitouny A, de Jong E, Holt RA, Jones M, Millward MJ, Lassmann T, Forrest ARR, Nowak AK, Watson M, Lake RA, Lesterhuis WJ, and Chee J
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- Animals, Mice, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes metabolism, Humans, Mice, Inbred C57BL, Female, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta metabolism, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating metabolism
- Abstract
Immune checkpoint therapy (ICT) causes durable tumour responses in a subgroup of patients, but it is not well known how T cell receptor beta (TCRβ) repertoire dynamics contribute to the therapeutic response. Using murine models that exclude variation in host genetics, environmental factors and tumour mutation burden, limiting variation between animals to naturally diverse TCRβ repertoires, we applied TCRseq, single cell RNAseq and flow cytometry to study TCRβ repertoire dynamics in ICT responders and non-responders. Increased oligoclonal expansion of TCRβ clonotypes was observed in responding tumours. Machine learning identified TCRβ CDR3 signatures unique to each tumour model, and signatures associated with ICT response at various timepoints before or during ICT. Clonally expanded CD8+ T cells in responding tumours post ICT displayed effector T cell gene signatures and phenotype. An early burst of clonal expansion during ICT is associated with response, and we report unique dynamics in TCRβ signatures associated with ICT response., Competing Interests: LB is employed by the company JJP Biologics. WJL received research funding from Douglas Pharmaceuticals, AstraZeneca, ENA therapeutics, consultancy for Douglas Pharmaceuticals and MSD. AN is on the advisory board of Boehringer Ingelheim, Bayer, Roche, BMS; and received research funding from AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)
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- 2024
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14. Temporally restricted activation of IFNβ signaling underlies response to immune checkpoint therapy in mice.
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Zemek RM, Chin WL, Fear VS, Wylie B, Casey TH, Forbes C, Tilsed CM, Boon L, Guo BB, Bosco A, Forrest ARR, Millward MJ, Nowak AK, Lake RA, Lassmann T, and Lesterhuis WJ
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- Animals, Interferon-alpha, Interferon-beta genetics, Interferon-beta therapeutic use, Mice, Signal Transduction, Interferon Type I, Neoplasms drug therapy, Neoplasms genetics
- Abstract
The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin therapeutic efficacy due to the inability to frequently sample tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tumours within two mouse models at four time points during ICB. We find that responding tumours display on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies markedly improves ICB efficacy, but only when IFNβ is targeted, not IFNα. We identify Ly6C
+ /CD11b+ inflammatory monocytes as the primary source of IFNβ and find that active type-I-IFN signaling in tumour-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response., (© 2022. The Author(s).)- Published
- 2022
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15. Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy.
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Tilsed CM, Casey TH, de Jong E, Bosco A, Zemek RM, Salmons J, Wan G, Millward MJ, Nowak AK, Lake RA, and Lesterhuis WJ
- Abstract
With immune checkpoint therapy (ICT) having reshaped the treatment of many cancers, the next frontier is to identify and develop novel combination therapies to improve efficacy. Previously, we and others identified beneficial immunological effects of the vitamin A derivative tretinoin on anti-tumour immunity. Although it is known that tretinoin preferentially depletes myeloid derived suppressor cells in blood, little is known about the effects of tretinoin on the tumour microenvironment, hampering the rational design of clinical trials using tretinoin in combination with ICT. Here, we aimed to identify how tretinoin changed the tumour microenvironment in mouse tumour models, using flow cytometry and RNAseq, and we sought to use that information to establish optimal dosing and scheduling of tretinoin in combination with several ICT antibodies in multiple cancer models. We found that tretinoin rapidly induced an interferon dominated inflammatory tumour microenvironment, characterised by increased CD8+ T cell infiltration. This phenotype completely overlapped with the phenotype that was induced by ICT itself, and we confirmed that the combination further amplified this inflammatory milieu. The addition of tretinoin significantly improved the efficacy of anti-CTLA4/anti-PD-L1 combination therapy, and staggered scheduling was more efficacious than concomitant scheduling, in a dose-dependent manner. The positive effects of tretinoin could be extended to ICT antibodies targeting OX40, GITR and CTLA4 monotherapy in multiple cancer models. These data show that tretinoin induces an interferon driven, CD8+ T cell tumour microenvironment that is responsive to ICT., Competing Interests: EJ, AB, RZ, RL and WL are co-inventors on patents relating to aspects of this manuscript (WO2016015095A1 and WO2019178650A1). AB, MM, AN, RL and WL have received consultancy fees from Douglas Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tilsed, Casey, de Jong, Bosco, Zemek, Salmons, Wan, Millward, Nowak, Lake and Lesterhuis.)
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- 2022
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16. Changes in expression of PD-L1 on peripheral T cells in patients with melanoma and lung cancer treated with PD-1 inhibitors.
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Dart SJ, Cook AM, Millward MJ, McDonnell AM, Chin WL, Hakeem MU, Meniawy TM, and Bowyer SE
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- Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized pharmacology, Antibodies, Monoclonal, Humanized therapeutic use, B7-H1 Antigen antagonists & inhibitors, B7-H1 Antigen genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Female, Humans, Immune Checkpoint Inhibitors adverse effects, Immune Checkpoint Inhibitors therapeutic use, Ipilimumab administration & dosage, Ipilimumab adverse effects, Ipilimumab pharmacology, Kaplan-Meier Estimate, Lung Neoplasms drug therapy, Male, Melanoma drug therapy, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Nivolumab administration & dosage, Nivolumab adverse effects, Nivolumab pharmacology, Nivolumab therapeutic use, Pilot Projects, Progression-Free Survival, Prospective Studies, T-Lymphocytes, Regulatory drug effects, B7-H1 Antigen biosynthesis, Carcinoma, Non-Small-Cell Lung metabolism, Gene Expression Regulation, Neoplastic drug effects, Immune Checkpoint Inhibitors pharmacology, Lung Neoplasms metabolism, Melanoma metabolism, Molecular Targeted Therapy, Neoplasm Proteins biosynthesis, T-Lymphocytes drug effects
- Abstract
Advances in cancer immunology have increased the use of immune checkpoint inhibitors in clinical practice, however not all patients respond, and treatment can have severe side-effects. Blood-based immunological biomarkers are an attractive method for predicting which patients will respond to therapy, however, reliable biomarkers for immune checkpoint blockade are lacking. This study aimed to identify patients before or early in treatment who would best respond to PD-1 inhibitors. We hypothesised that higher baseline PD-L1 and/or PD-1 on peripheral blood T cells could predict radiological response to PD-1 inhibitors. This pilot prospective cohort study assessed 26 patients with melanoma or non-small cell lung cancer, treated with pembrolizumab, nivolumab, or nivolumab/ipilimumab combined. Response was assessed by RECIST 1.1. Peripheral blood lymphocytes collected at baseline, after one cycle, 10 weeks and at discontinuation of therapy were analysed by flow cytometry. Patients with a higher proportion of PD-L1
+ T cells at baseline had improved objective response to PD-1 inhibitor therapy, and patients with a lower proportion of regulatory T cells at baseline experienced more immune-related adverse events. These findings may prove useful to assist in clinical decision making. Further studies with larger cohorts are required to validate these findings., (© 2021. The Author(s).)- Published
- 2021
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17. A phase 1b clinical trial optimizing regulatory T cell depletion in combination with platinum-based chemotherapy in thoracic cancers.
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Cook AM, McDonnell A, Millward MJ, Creaney J, Hasani A, McMullen M, Meniawy T, Robinson BWS, Lake RA, and Nowak AK
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- Antineoplastic Combined Chemotherapy Protocols, Cisplatin, Cyclophosphamide administration & dosage, Cyclophosphamide toxicity, Humans, Pemetrexed, Platinum therapeutic use, T-Lymphocytes, Regulatory, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Background : Single-agent cyclophosphamide can deplete regulatory T-cells (Treg). We aimed to determine optimal dosing and scheduling of oral cyclophosphamide, alongside pemetrexed-based chemotherapy, to deplete Treg in mesothelioma or non-small-cell lung cancer patients. Methods : 31 Patients received pemetrexed ± cisplatin or carboplatin on day 1 of a 21-day cycle (maximum 6 cycles). From cycle two, patients received cyclophosphamide, 50 mg/day, with intrapatient escalation to maximum 100/150 mg/day alternately. Immunological changes were examined by flow cytometry. Primary endpoint was Treg proportion of CD4
+ T-cells, with doses tailored to target Treg nadir <4%. Results : Reduction in Treg proportion was observed on day 8 of all cycles, and was not augmented by cyclophosphamide. Few patients achieved the <4% Treg target. Treg proliferation reached nadir one week after chemotherapy, and peaked on day 1 of the subsequent cycle. Efficacy parameters were similar to chemotherapy alone. Seventeen percent of patients ceased cyclophosphamide due to toxicity. Conclusions : Specific Treg depletion to the degree seen with single-agent cyclophosphamide was not observed during pemetrexed-based chemotherapy. This study highlights the poor evidence basis for use of cyclophosphamide as an immunotherapeutic in combination with chemotherapy, and the importance of detailed flow cytometry studies. Trial registration : Clinical trial registration: www.anzctr.org.au identifier is ACTRN12609000260224.- Published
- 2021
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18. Hydantoin-bridged medium ring scaffolds by migratory insertion of urea-tethered nitrile anions into aromatic C-N bonds.
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Millward MJ, Ellis E, Ward JW, and Clayden J
- Abstract
Bicyclic or tricyclic nitrogen-containing heterocyclic scaffolds were constructed rapidly by intramolecular nucleophilic aromatic substitution of metallated nitriles tethered by a urea linkage to a series of electronically unactivated heterocyclic precursors. The substitution reaction constitutes a ring expansion, enabled by the conformationally constrained tether between the nitrile and the heterocycle. Attack of the metallated urea leaving group on the nitrile generates a hydantoin that bridges the polycyclic products. X-ray crystallography reveals ring-dependant strain within the hydantoin., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)
- Published
- 2020
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19. Association of Known Melanoma Risk Factors with Primary Melanoma of the Scalp and Neck.
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Wood RP, Heyworth JS, McCarthy NS, Mauguen A, Berwick M, Thomas NE, Millward MJ, Anton-Culver H, Cust AE, Dwyer T, Gallagher RP, Gruber SB, Kanetsky PA, Orlow I, Rosso S, Moses EK, Begg CB, and Ward SV
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- Aged, Female, Humans, Male, Melanoma physiopathology, Middle Aged, Risk Factors, Skin Neoplasms physiopathology, Melanoma complications, Neck pathology, Scalp pathology, Skin Neoplasms complications
- Abstract
Background: Scalp and neck (SN) melanoma confers a worse prognosis than melanoma of other sites but little is known about its determinants. We aimed to identify associations between SN melanoma and known risk genes, phenotypic traits, and sun exposure patterns., Methods: Participants were cases from the Western Australian Melanoma Health Study ( n = 1,200) and the Genes, Environment, and Melanoma Study ( n = 3,280). Associations between risk factors and SN melanoma, compared with truncal and arm/leg melanoma, were investigated using binomial logistic regression. Facial melanoma was also compared with the trunk and extremities, to evaluate whether associations were subregion specific, or reflective of the whole head/neck region., Results: Compared with other sites, increased odds of SN and facial melanoma were observed in older individuals [SN: OR = 1.28, 95% confidence interval (CI) = 0.92-1.80, P
trend = 0.016; Face: OR = 4.57, 95% CI = 3.34-6.35, Ptrend < 0.001] and those carrying IRF4 -rs12203592*T (SN: OR = 1.35, 95% CI = 1.12-1.63, Ptrend = 0.002; Face: OR = 1.29, 95% CI = 1.10-1.50, Ptrend = 0.001). Decreased odds were observed for females (SN: OR = 0.49, 95% CI = 0.37-0.64, P < 0.001; Face: OR = 0.66, 95% CI = 0.53-0.82, P < 0.001) and the presence of nevi (SN: OR = 0.66, 95% CI = 0.49-0.89, P = 0.006; Face: OR = 0.65, 95% CI = 0.52-0.83, P < 0.001)., Conclusions: Differences observed between SN melanoma and other sites were also observed for facial melanoma. Factors previously associated with the broader head and neck region, notably older age, may be driven by the facial subregion. A novel finding was the association of IRF4 -rs12203592 with both SN and facial melanoma., Impact: Understanding the epidemiology of site-specific melanoma will enable tailored strategies for risk factor reduction and site-specific screening campaigns., (©2020 American Association for Cancer Research.)- Published
- 2020
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20. An International Phase 2 Study of Pazopanib in Progressive and Metastatic Thyroglobulin Antibody Negative Radioactive Iodine Refractory Differentiated Thyroid Cancer.
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Bible KC, Menefee ME, Lin CJ, Millward MJ, Maples WJ, Goh BC, Karlin NJ, Kane MA, Adkins DR, Molina JR, Donehower RC, Lim WT, Flynn PJ, Richardson RL, Traynor AM, Rubin J, LoRusso PM, Smallridge RC, Burton JK, Suman VJ, Kumar A, Voss JS, Rumilla KM, Kipp BR, Chintakuntlawar AV, Harris P, and Erlichman C
- Subjects
- Aged, Antibodies chemistry, Biomarkers, Tumor, Cell Differentiation, DNA Mutational Analysis, Disease Progression, Disease-Free Survival, Female, Humans, Iodine Radioisotopes pharmacology, Male, Middle Aged, Progression-Free Survival, Prospective Studies, Protein Kinase Inhibitors therapeutic use, Salvage Therapy, Thyroid Neoplasms therapy, Treatment Outcome, Indazoles therapeutic use, Pyrimidines therapeutic use, Sulfonamides therapeutic use, Thyroglobulin immunology, Thyroid Neoplasms immunology
- Abstract
Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6-50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: -86.8%; interquartile range [IQR]: -90.7% to -70.9%) compared with the 28 who did not (median: -69.0%; IQR: -78.1% to -27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (-23.5% [CI: -55.3 to 8.3]; Fisher's exact test p -value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.
- Published
- 2020
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21. Longitudinal Monitoring of ctDNA in Patients with Melanoma and Brain Metastases Treated with Immune Checkpoint Inhibitors.
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Lee JH, Menzies AM, Carlino MS, McEvoy AC, Sandhu S, Weppler AM, Diefenbach RJ, Dawson SJ, Kefford RF, Millward MJ, Al-Ogaili Z, Tra T, Gray ES, Wong SQ, Scolyer RA, Long GV, and Rizos H
- Subjects
- Aged, Biomarkers, Tumor genetics, Brain Neoplasms blood, Brain Neoplasms mortality, Brain Neoplasms secondary, Circulating Tumor DNA genetics, Female, Follow-Up Studies, GTP Phosphohydrolases blood, GTP Phosphohydrolases genetics, Humans, Kaplan-Meier Estimate, Longitudinal Studies, Male, Melanoma blood, Melanoma mortality, Melanoma secondary, Membrane Proteins blood, Membrane Proteins genetics, Middle Aged, Mutation, Prognosis, Proto-Oncogene Proteins B-raf blood, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins c-kit genetics, Risk Assessment methods, Risk Assessment statistics & numerical data, Skin Neoplasms blood, Skin Neoplasms mortality, Skin Neoplasms pathology, Treatment Outcome, Biomarkers, Tumor blood, Brain Neoplasms drug therapy, Circulating Tumor DNA blood, Immune Checkpoint Inhibitors therapeutic use, Melanoma drug therapy, Skin Neoplasms drug therapy
- Abstract
Purpose: Brain involvement occurs in the majority of patients with metastatic melanoma. The potential of circulating tumor DNA (ctDNA) for surveillance and monitoring systemic therapy response in patients with melanoma brain metastases merits investigation., Experimental Design: This study examined circulating BRAF, NRAS , and c-KIT mutations in patients with melanoma with active brain metastases receiving PD-1 inhibitor-based therapy. Intracranial and extracranial disease volumes were measured using the sum of product of diameters, and response assessment performed using RECIST. Longitudinal plasma samples were analyzed for ctDNA over the first 12 weeks of treatment (threshold 2.5 copies/mL plasma)., Results: Of a total of 72 patients, 13 patients had intracranial metastases only and 59 patients had concurrent intracranial and extracranial metastases. ctDNA detectability was 0% and 64%, respectively, and detectability was associated with extracranial disease volume ( P < 0.01). Undetectable ctDNA on-therapy was associated with extracranial response ( P < 0.01) but not intracranial response. The median overall survival in patients with undetectable ( n = 34) versus detectable ( n = 38) ctDNA at baseline was 39.2 versus 10.6 months [HR, 0.51; 95% confidence interval (CI), 0.28-0.94; P = 0.03] and on-therapy was 39.2 versus 9.2 months (HR, 0.32; 95% CI, 0.16-0.63; P < 0.01)., Conclusions: ctDNA remains a strong prognostic biomarker in patients with melanoma with brain metastases, especially in patients with concurrent extracranial disease. However, ctDNA was not able to detect or monitor intracranial disease activity, and we recommend against using ctDNA as a sole test during surveillance and therapeutic monitoring in patients with melanoma., (©2020 American Association for Cancer Research.)
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- 2020
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22. Bilateral murine tumor models for characterizing the response to immune checkpoint blockade.
- Author
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Zemek RM, Fear VS, Forbes C, de Jong E, Casey TH, Boon L, Lassmann T, Bosco A, Millward MJ, Nowak AK, Lake RA, and Lesterhuis WJ
- Subjects
- Animals, Cell Line, Tumor, Female, Mice, Mice, Inbred BALB C, Antineoplastic Agents, Immunological, Drug Screening Assays, Antitumor, Neoplasms, Experimental
- Abstract
The therapeutic response to immune checkpoint blockade (ICB) is highly variable, not only between different cancers but also between patients with the same cancer type. The biological mechanisms underlying these differences in response are incompletely understood. Identifying correlates in patient tumor samples is challenging because of genetic and environmental variability. Murine studies usually compare different tumor models or treatments, introducing potential confounding variables. This protocol describes bilateral murine tumor models, derived from syngeneic cancer cell lines, that display a symmetrical yet dichotomous response to ICB. These models enable detailed analysis of whole tumors in a highly homogeneous background, combined with knowledge of the therapeutic outcome within a few weeks, and could potentially be used for mechanistic studies using other (immuno-)therapies. We discuss key considerations and describe how to use two cell lines as fully optimized models. We discuss experimental details, including proper inoculation technique to achieve symmetry and one-sided surgical tumor removal, which takes only 5 min per mouse. Furthermore, we outline the preparation of bulk tissue or single-cell suspensions for downstream analyses such as bulk RNA-seq, immunohistochemistry, single-cell RNA-seq and flow cytometry.
- Published
- 2020
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23. Sensitizing the Tumor Microenvironment to Immune Checkpoint Therapy.
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Zemek RM, Chin WL, Nowak AK, Millward MJ, Lake RA, and Lesterhuis WJ
- Subjects
- Animals, Biomarkers, Tumor, Humans, Interferon-gamma physiology, Mice, Microbiota, Neoplasms blood supply, Neoplasms immunology, Oncolytic Virotherapy, Precision Medicine, T-Lymphocytes immunology, Immune Checkpoint Inhibitors therapeutic use, Neoplasms drug therapy, Tumor Microenvironment
- Abstract
Immune checkpoint blockade (ICB) has revolutionized cancer treatment, providing remarkable clinical responses in some patients. However, the majority of patients do not respond. It is therefore crucial both to identify predictive biomarkers of response and to increase the response rates to immune checkpoint therapy. In this review we explore the current literature about the predictive characteristics of the tumor microenvironment and discuss therapeutic approaches that aim to change this toward a milieu that is conducive to response. We propose a personalized biomarker-based adaptive approach to immunotherapy, whereby a sensitizing therapy is tailored to the patient's specific tumor microenvironment, followed by on-treatment verification of a change in the targeted biomarker, followed by immune checkpoint therapy. By incorporating detailed knowledge of the immunological tumor microenvironment, we may be able to sensitize currently non-responsive tumors to respond to immune checkpoint therapy., (Copyright © 2020 Zemek, Chin, Nowak, Millward, Lake and Lesterhuis.)
- Published
- 2020
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24. A Phase I Study of LY3009120, a Pan-RAF Inhibitor, in Patients with Advanced or Metastatic Cancer.
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Sullivan RJ, Hollebecque A, Flaherty KT, Shapiro GI, Rodon Ahnert J, Millward MJ, Zhang W, Gao L, Sykes A, Willard MD, Yu D, Schade AE, Crowe K, Flynn DL, Kaufman MD, Henry JR, Peng SB, Benhadji KA, Conti I, Gordon MS, Tiu RV, and Hong DS
- Subjects
- Adult, Aged, Aged, 80 and over, Cell Line, Tumor, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Phenylurea Compounds pharmacology, Pyrimidines pharmacology, Young Adult, Neoplasms drug therapy, Phenylurea Compounds therapeutic use, Pyrimidines therapeutic use
- Abstract
Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS - and BRAF -mutated cell lines including BRAF -mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively ( N = 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue ( n = 15), nausea ( n = 12), dermatitis acneiform ( n = 10), decreased appetite ( n = 7), and maculopapular rash ( n = 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed., (©2019 American Association for Cancer Research.)
- Published
- 2020
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25. Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of N -Methylation for PI3Kδ Activity.
- Author
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Barnes L, Blaber H, Brooks DTK, Byers L, Buckley D, Byron ZC, Chilvers RG, Cochrane L, Cooney E, Damian HA, Francis L, Fu He D, Grace JMJ, Green HJ, Hogarth EJP, Jusu L, Killalea CE, King O, Lambert J, Lee ZJ, Lima NS, Long CL, Mackinnon ML, Mahdy S, Matthews-Wright J, Millward MJ, Meehan MF, Merrett C, Morrison L, Parke HRI, Payne C, Payne L, Pike C, Seal A, Senior AJ, Smith KM, Stanelyte K, Stillibrand J, Szpara R, Taday FFH, Threadgould AM, Trainor RJ, Waters J, Williams O, Wong CKW, Wood K, Barton N, Gruszka A, Henley Z, Rowedder JE, Cookson R, Jones KL, Nadin A, Smith IE, Macdonald SJF, and Nortcliffe A
- Subjects
- Amines chemistry, Humans, Isoenzymes chemistry, Isoenzymes metabolism, Methylation, Nitrogen chemistry, Phosphatidylinositol 3-Kinases chemistry, Phosphoinositide-3 Kinase Inhibitors chemical synthesis, Pyrimidines chemistry, Serum Albumin, Human metabolism, Phosphatidylinositol 3-Kinases metabolism, Phosphoinositide-3 Kinase Inhibitors chemistry, Phosphoinositide-3 Kinase Inhibitors pharmacology, Structure-Activity Relationship
- Abstract
Phosphoinositide-3-kinase δ (PI3Kδ) is a critical regulator of cell growth and transformation and has been explored as a therapeutic target for a range of diseases. Through the exploration of the thienopyrimidine scaffold, we have identified a ligand-efficient methylation that leads to remarkable selectivity for PI3Kδ over the closely related isoforms. Interrogation through the Free-Wilson analysis highlights the innate selectivity the thienopyrimidine scaffold has for PI3Kδ and provides a predictive model for the activity against the PI3K isoforms.
- Published
- 2019
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26. Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment.
- Author
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Zemek RM, De Jong E, Chin WL, Schuster IS, Fear VS, Casey TH, Forbes C, Dart SJ, Leslie C, Zaitouny A, Small M, Boon L, Forrest ARR, Muiri DO, Degli-Esposti MA, Millward MJ, Nowak AK, Lassmann T, Bosco A, Lake RA, and Lesterhuis WJ
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation, Clone Cells, Combined Modality Therapy, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Humans, Inflammation pathology, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms genetics, Neoplasms immunology, Neoplasms pathology, Phenotype, Immunotherapy, Killer Cells, Natural immunology, STAT1 Transcription Factor metabolism, Signal Transduction, Tumor Microenvironment immunology
- Abstract
Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combination treatments. We set out to define the pretreatment microenvironment associated with an effective outcome by using the fact that inbred mouse strains bearing monoclonal cancer cell line-derived tumors respond in a dichotomous manner to immune checkpoint blockade (ICB). We compared the cellular composition and gene expression profiles of responsive and nonresponsive tumors from mice before ICB and validated the findings in cohorts of patients with cancer treated with ICB antibodies. We found that responsive tumors were characterized by an inflammatory gene expression signature consistent with up-regulation of signal transducer and activator of transcription 1 (STAT1) and Toll-like receptor 3 (TLR3) signaling and down-regulation of interleukin-10 (IL-10) signaling. In addition, responsive tumors had more infiltrating-activated natural killer (NK) cells, which were necessary for response. Pretreatment of mice with large established tumors using the STAT1-activating cytokine interferon-γ (IFNγ), the TLR3 ligand poly(I:C), and an anti-IL-10 antibody sensitized tumors to ICB by attracting IFNγ-producing NK cells into the tumor, resulting in increased cure rates. Our results identify a pretreatment tumor microenvironment that predicts response to ICB, which can be therapeutically attained. These data suggest a biomarker-driven approach to patient management to establish whether a patient would benefit from treatment with sensitizing therapeutics before ICB., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2019
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27. Phase IB Trial of the Anti-Cancer Stem Cell DLL4-Binding Agent Demcizumab with Pemetrexed and Carboplatin as First-Line Treatment of Metastatic Non-Squamous NSCLC.
- Author
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McKeage MJ, Kotasek D, Markman B, Hidalgo M, Millward MJ, Jameson MB, Harris DL, Stagg RJ, Kapoun AM, Xu L, and Hughes BGM
- Subjects
- Adult, Aged, Antibodies, Monoclonal, Humanized pharmacology, Carboplatin pharmacology, Carcinoma, Non-Small-Cell Lung pathology, Female, Humans, Lung Neoplasms pathology, Male, Middle Aged, Pemetrexed pharmacology, Antibodies, Monoclonal, Humanized therapeutic use, Carboplatin therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Pemetrexed therapeutic use
- Abstract
Background: Delta-like ligand 4-Notch (DLL4-Notch) signaling contributes to the maintenance of chemotherapy-resistant cancer stem cells and tumor vasculature., Objective: This phase IB trial of demcizumab, an IgG2 humanized monoclonal antibody directed against DLL4, was undertaken to determine its maximum tolerated dose, safety, immunogenicity, preliminary efficacy, pharmacokinetics, and pharmacodynamics, combined with standard chemotherapy., Patients and Methods: Forty-six treatment-naive patients with metastatic non-squamous non-small cell lung cancer (NSCLC) were enrolled in this open-label, dose-escalation study using a standard 6 + 6 design. Demcizumab (2.5, 5.0, and 7.5 mg/kg) was given once every 3 weeks with standard doses of pemetrexed and carboplatin using a continuous (six cycles followed by demcizumab maintenance) or a truncated demcizumab regimen (four cycles followed by pemetrexed maintenance)., Results: Initially, continuous demcizumab was given until progression but two patients developed grade 3 pulmonary hypertension and congestive heart failure after eight or more infusions. Thereafter, 23 patients were treated with a truncated regimen of demcizumab, which was not associated with any grade 3 or greater cardiopulmonary toxicity. Common adverse events were hypertension, raised brain natriuretic peptide, and those expected from carboplatin and pemetrexed alone. Twenty of 40 evaluable patients (50%) had objective tumor responses. In peripheral blood, demcizumab treatment modulated the expression of genes regulating Notch signaling and angiogenesis, and achieved concentrations exceeding those saturating DLL4 binding., Conclusions: This study has identified a truncated dosing regimen and recommended phase II dose of demcizumab (5 mg/kg q3-weekly ×4) for subsequent clinical evaluation in combination with standard carboplatin and pemetrexed chemotherapy. NCT01189968.
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- 2018
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28. Dynamic versus static biomarkers in cancer immune checkpoint blockade: unravelling complexity.
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Lesterhuis WJ, Bosco A, Millward MJ, Small M, Nowak AK, and Lake RA
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- Animals, Humans, Nonlinear Dynamics, Biomarkers, Tumor, Immune System drug effects, Molecular Targeted Therapy methods, Neoplasms drug therapy, Neoplasms immunology
- Abstract
Recently, there has been a coordinated effort from academic institutions and the pharmaceutical industry to identify biomarkers that can predict responses to immune checkpoint blockade in cancer. Several biomarkers have been identified; however, none has reliably predicted response in a sufficiently rigorous manner for routine use. Here, we argue that the therapeutic response to immune checkpoint blockade is a critical state transition of a complex system. Such systems are highly sensitive to initial conditions, and critical transitions are notoriously difficult to predict far in advance. Nevertheless, warning signals can be detected closer to the tipping point. Advances in mathematics and network biology are starting to make it possible to identify such warning signals. We propose that these dynamic biomarkers could prove to be useful in distinguishing responding from non-responding patients, as well as facilitate the identification of new therapeutic targets for combination therapy.
- Published
- 2017
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29. Phase I Clinical Trial of Marizomib (NPI-0052) in Patients with Advanced Malignancies Including Multiple Myeloma: Study NPI-0052-102 Final Results.
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Harrison SJ, Mainwaring P, Price T, Millward MJ, Padrik P, Underhill CR, Cannell PK, Reich SD, Trikha M, and Spencer A
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Drug Administration Schedule, Female, Humans, Lactones administration & dosage, Lactones adverse effects, Lactones pharmacokinetics, Male, Middle Aged, Neoplasm Staging, Proteasome Inhibitors administration & dosage, Proteasome Inhibitors adverse effects, Proteasome Inhibitors pharmacokinetics, Pyrroles administration & dosage, Pyrroles adverse effects, Pyrroles pharmacokinetics, Recurrence, Retreatment, Treatment Outcome, Young Adult, Antineoplastic Agents therapeutic use, Lactones therapeutic use, Multiple Myeloma drug therapy, Multiple Myeloma pathology, Neoplasms drug therapy, Neoplasms pathology, Proteasome Inhibitors therapeutic use, Pyrroles therapeutic use
- Abstract
Purpose: Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors., Experimental Design: Phase I study (NPI-0052-102) evaluated the MTD, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules., Results: Forty-two patients with advanced malignancies received Schedule A (0.1-0.9 mg/m(2) over 1-10 minutes on days 1, 8, 15 in 4-week cycles); 44 patients with relapsed and/or refractory multiple myeloma (RRMM) and other hematologic malignancies received Schedule B (0.075-0.6 mg/m(2) over 1 minute to 2 hours on days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended phase II dose was 0.7 mg/m(2) over 10 minutes; Schedule B was 0.5 mg/m(2) over 2 hours. The most common (>25% of patients) related adverse events were fatigue, nausea, diarrhea, and infusion site pain (Schedule A); and fatigue (Schedule B). Overall response rate of 11% was seen in 27 efficacy-evaluable RRMM Schedule B patients (1 very good partial response, 3 partial responses, 4 minimal responses, and 12 stable disease). One Schedule A patient with transformed marginal zone lymphoma had complete response. Marizomib has a short half-life (<30 minutes), with high volume of distribution (∼15-416 L) and clearance (∼0.9-22 L/minutes)., Conclusions: Marizomib does not exhibit the severe peripheral neuropathy or hematologic toxicity observed with other proteasome inhibitors. Marizomib was generally well tolerated with low-dose dexamethasone, demonstrated activity in heavily pretreated RRMM patients, and warrants further evaluation. Clin Cancer Res; 22(18); 4559-66. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
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30. PD-L1 on peripheral blood T lymphocytes is prognostic in patients with non-small cell lung cancer (NSCLC) treated with EGFR inhibitors.
- Author
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Meniawy TM, Lake RA, McDonnell AM, Millward MJ, and Nowak AK
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Biomarkers, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung drug therapy, Case-Control Studies, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Female, Humans, Immunophenotyping, Kaplan-Meier Estimate, Lung Neoplasms diagnosis, Lung Neoplasms drug therapy, Male, Middle Aged, Mutation, Prognosis, Proportional Hazards Models, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Retreatment, T-Lymphocytes immunology, Treatment Outcome, B7-H1 Antigen metabolism, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung mortality, Lung Neoplasms metabolism, Lung Neoplasms mortality, T-Lymphocytes metabolism
- Abstract
Objectives: The immune effects of EGFR tyrosine kinase inhibitors (EGFR-TKIs) are poorly understood. Identifying immune biomarkers could guide patient selection and optimisation of EGFR-TKI-immunotherapy combinations., Materials and Methods: 33 patients with NSCLC treated with an EGFR-TKI were prospectively enrolled. Peripheral blood mononuclear cells were collected pre-treatment, and after 1, 3 and 8 weeks. Flow cytometry was used to identify immune cell subsets, including PD-1 and PD-L1 expressing T cells. Immune parameters were correlated with clinical outcomes., Results: Compared to healthy donors (n=10), patients had higher pre-treatment proportions of proliferating and PD-L1(+)CD3(+) T cells (p<0.001). Compared to patients with an EGFR mutation (n=12), patients without a known mutation (n=21) had higher proportions of proliferating CD4(+) and PD-L1(+)CD3(+) T cells (p=0.03). There was a significant increase in PD-L1(+) T cells after 1 week of EGFR-TKI in patients whose disease progressed compared to non-progressors. Patients with higher PD-L1(+)CD3(+) T cells at 1-week were more likely to progress (OR 30.3, p<0.01) and had shorter PFS (1.6 vs. 8.8m; p<0.01) and OS (3.8 vs 23.2m; p<0.001) than those with fewer PD-L1(+)CD3(+) T cells. On multivariate analysis, high PD-L1(+)CD3(+) T cells was the only independent predictor for PFS (HR 3.7, p=0.01), while for OS independent predictors were high PD-L1(+)CD3(+) T cells (HR 6.5, p<0.01) and EGFR-negative status (HR 3.3, p=0.04)., Conclusions: There was a significant correlation between PD-L1 expression on peripheral T cells and clinical outcomes in EGFR-TKI-treated NSCLC. This warrants further validation as a blood-based biomarker that may identify candidates for PD-1 inhibitors or immunotherapy-EGFR-TKI combinations., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2016
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31. A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma.
- Author
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Nowak AK, Cook AM, McDonnell AM, Millward MJ, Creaney J, Francis RJ, Hasani A, Segal A, Musk AW, Turlach BA, McCoy MJ, Robinson BW, and Lake RA
- Subjects
- Adult, Aged, Antibodies, Monoclonal, Humanized, CD40 Antigens agonists, Cohort Studies, Female, Follow-Up Studies, Humans, Lung Neoplasms diagnosis, Lung Neoplasms metabolism, Male, Mesothelioma diagnosis, Mesothelioma metabolism, Mesothelioma, Malignant, Middle Aged, Pleural Neoplasms diagnosis, Pleural Neoplasms metabolism, Prospective Studies, Antibodies, Monoclonal administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, CD40 Antigens metabolism, Cisplatin administration & dosage, Lung Neoplasms drug therapy, Mesothelioma drug therapy, Pemetrexed administration & dosage, Pleural Neoplasms drug therapy
- Abstract
Background: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM)., Patients and Methods: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry., Results: Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P < 0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P < 0.001) and activated CD86+CD27+ memory B cells (P < 0.001), as an immunopharmacodynamic marker of CD40 activation., Conclusions: CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival., Australia New Zealand Clinical Trials Registry Number: ACTRN12609000294257., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
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32. Characterization of hypoxia in malignant pleural mesothelioma with FMISO PET-CT.
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Francis RJ, Segard T, Morandeau L, Lee YC, Millward MJ, Segal A, and Nowak AK
- Subjects
- Aged, Aged, 80 and over, Cell Hypoxia physiology, Female, Humans, Lung Neoplasms pathology, Male, Mesothelioma pathology, Mesothelioma, Malignant, Middle Aged, Misonidazole analysis, Pilot Projects, Pleural Neoplasms pathology, Positron-Emission Tomography methods, Prognosis, Prospective Studies, Tomography, X-Ray Computed methods, Fluorodeoxyglucose F18 analysis, Lung Neoplasms diagnostic imaging, Lung Neoplasms metabolism, Mesothelioma diagnostic imaging, Mesothelioma metabolism, Misonidazole analogs & derivatives, Pleural Neoplasms diagnostic imaging, Pleural Neoplasms metabolism, Radiopharmaceuticals analysis
- Abstract
Objectives: Malignant pleural mesothelioma (MPM) is a chemotherapy resistant tumor with a poor prognosis. Hypoxia is increasingly recognized as an important factor in tumor aggressiveness and cellular resistance to chemotherapy and radiation treatment. This prospective pilot study was performed with [F-18] fluoromisonidazole (FMISO) PET-CT to characterize hypoxia in patients with MPM., Materials and Methods: Twenty prospectively recruited patients with histologically or cytologically confirmed MPM not currently receiving systemic or local treatment underwent both FMISO and fluorodeoxyglucose (FDG) PET-CT scans within 2 weeks. FMISO and FDG PET-CT scans were independently analyzed visually and semi-quantitatively using SUVmax and tumor to background ratio (TBR) in order to assess tumor hypoxia and metabolic activity. Lesion by lesion analysis was performed in sites of measurable pleural masses., Results: Visual analysis demonstrated tumor FMISO activity in 17 of 20 patients, and tumor FDG activity in 19 of 20 patients. Focal areas of bulky tumor were most likely to demonstrate hypoxia. In 19 patients suitable for semi-quantitative analysis the median FDG SUVmax was 6.4 (range 1.9-19.1), median FMISO SUVmax was 2.5 (range 1.4-3.7) and median FMISO TBR was 1.8 (1.1-2.5). There was a positive correlation between intensity of metabolic activity and hypoxia (r=0.72, p=0.001). Lesion by lesion analysis demonstrated a positive correlation between tumor thickness and FMISO activity (r=0.77, p<0.001)., Conclusion: This pilot study confirms that MPM is a tumor with significant areas of hypoxia, particularly in dominant tumor masses. The relationship of tumor hypoxia to effectiveness of chemotherapy and/or radiation therapy warrants prospective assessment., (Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2015
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33. The aggregation of early-onset melanoma in young Western Australian families.
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Ward SV, Dowty JG, Webster RJ, Cadby G, Glasson EJ, Heyworth JS, Emery J, Cole JM, Millward MJ, Wood FM, and Palmer LJ
- Subjects
- Adult, Age of Onset, Australia epidemiology, Female, Humans, Incidence, Male, Middle Aged, Proportional Hazards Models, Risk, Western Australia epidemiology, Genetic Predisposition to Disease, Melanoma epidemiology, Melanoma genetics
- Abstract
Background: Few studies have examined the familial aggregation of melanoma or its co-aggregation with other cancers using whole-population based designs. This study aimed to investigate aggregation patterns in young Western Australian families, using population-based linked health data to identify individuals born in Western Australia between 1974 and 2007, their known relatives, and all incident cancer diagnoses within the resulting 1,506,961 individuals., Methods: Cox proportional hazards regression models were used to compare the risk of melanoma for first-degree relatives of melanoma cases to that for first-degree relatives of controls, with bootstrapping used to account for correlations within families. The risk of (i) developing melanoma based on the number of first-degree relatives with other cancers, and (ii) developing non-melanoma cancers based on the number of first-degree relatives diagnosed with melanoma was also investigated., Results: First-degree relatives of melanoma cases had a significantly greater incidence of melanoma than first-degree relatives of individuals not affected with melanoma (Hazard Ratio (HR)=3.58, 95% bootstrap confidence interval (CI): 2.43-5.43). Sensitivity analyses produced a higher hazard ratio estimate when restricted to melanoma cases diagnosed before 40 years of age (HR=3.77, bootstrap 95% CI: 2.49-6.39) and a lower estimate when only later-onset cases (>40 years) were considered (HR=2.45, bootstrap 95% CI: 1.23-4.82). No significant evidence was found for co-aggregation between melanoma and any other cancers., Conclusions: Results indicated a strong familial basis of melanoma, with the higher than expected hazard ratio observed likely to reflect early-age at onset cases in this young cohort, supported by the results of the sensitivity analyses. Exploratory analyses suggested that the determinants of melanoma causing the observed aggregation within families may be independent of other malignancies, although these analyses were limited by the young age of the sample. Determining familial aggregation patterns will provide valuable knowledge regarding improved clinical risk prediction and the underlying biological mechanisms of melanoma and other cancers., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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34. Mycobacterium mimicking metastatic melanoma.
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Teh RW, Feeney K, Francis RJ, Phillips M, and Millward MJ
- Subjects
- Adult, Aged, 80 and over, Bacterial Infections complications, Bacterial Infections diagnosis, Bacterial Infections therapy, Diagnosis, Differential, Female, Humans, Lung Neoplasms diagnosis, Lung Neoplasms microbiology, Male, Melanoma microbiology, Middle Aged, Mycobacterium pathogenicity, Pneumonia, Bacterial complications, Pneumonia, Bacterial therapy, Skin Neoplasms complications, Skin Neoplasms microbiology, Lung Neoplasms secondary, Melanoma diagnosis, Melanoma secondary, Mycobacterium isolation & purification, Pneumonia, Bacterial diagnosis, Skin Neoplasms diagnosis
- Abstract
We present three patients with lung nodules with an antecedent history of primary cutaneous melanoma or metastasis of melanoma to extrathoracic lymph nodes. Based on radiological findings, it was suspected that these patients had metastatic disease. Subsequent investigations confirmed the cause of the nodules was non-tuberculous mycobacterial infection. We discuss the similarities in symptoms and radiological features between atypical mycobacterial infections and metastatic disease and why a biopsy is important prior to planning a patient's treatment., (© 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.)
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- 2013
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35. A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma.
- Author
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Nowak AK, Brown C, Millward MJ, Creaney J, Byrne MJ, Hughes B, Kremmidiotis G, Bibby DC, Leske AF, Mitchell PLR, Pavlakis N, Boyer M, and Stockler MR
- Subjects
- Adult, Aged, Aged, 80 and over, Benzofurans administration & dosage, Benzofurans adverse effects, Biomarkers blood, Biomarkers metabolism, Female, GPI-Linked Proteins blood, GPI-Linked Proteins metabolism, Humans, Lung Neoplasms diagnostic imaging, Lung Neoplasms mortality, Male, Mesothelin, Mesothelioma diagnostic imaging, Mesothelioma mortality, Mesothelioma, Malignant, Middle Aged, Neoplasm Staging, Organophosphates administration & dosage, Organophosphates adverse effects, Pleural Neoplasms diagnostic imaging, Pleural Neoplasms mortality, Radiography, Treatment Outcome, Tubulin Modulators administration & dosage, Tubulin Modulators adverse effects, Tumor Burden, Antineoplastic Agents therapeutic use, Benzofurans therapeutic use, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Mesothelioma drug therapy, Mesothelioma pathology, Organophosphates therapeutic use, Pleural Neoplasms drug therapy, Pleural Neoplasms pathology, Tubulin Modulators therapeutic use
- Abstract
BNC105P is a tubulin polymerisation inhibitor that selectively disrupts tumour vasculature and suppresses cancer cell proliferation. This agent has exhibited preclinical and phase I activity in Malignant Pleural Mesothelioma (MPM). This phase II, single arm trial investigated the efficacy and safety of BNC105P as second line therapy in MPM. Participants had progressive MPM after first line pemetrexed/platinum chemotherapy, ECOG PS 0-1, adequate organ function, and measurable disease. BNC105P 16 mg/m(2) was administered intravenously on day 1 and 8 every 21 days until progression or undue toxicity. The primary endpoint was centrally reviewed objective response rate (RR). Tumour response was assessed every two cycles using modified RECIST. 30 patients were enrolled in 10 months, predominantly male (90%), ECOG PS 1 (77%), epithelioid histology (67%), and non-metastatic disease (67%). All patients received at least one dose of study drug, with a median of 2 cycles. No significant haematologic, biochemical, or cardiac adverse events (AEs) were observed. Grade 3 or 4 AEs occurred in 10 patients (33%). There were 2 deaths on study: 1 cardiorespiratory, the other to pneumonia. We observed 1 partial response (3%); 13 patients had stable disease (43%). Median progression free survival was 1.5 months (95% CI 1.4-2.4); median overall survival was 8.2 months (95% CI 3.8-11.9). BNC105P was safe and tolerable. The sole response was insufficient to warrant further research as a single agent., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2013
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36. Using expert panels to determine the level of cancer knowledge required of junior doctors in australia. Part 2: sources of variability.
- Author
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Starmer DL, Chapman E, and Millward MJ
- Subjects
- Australia, Humans, Clinical Competence standards, Expert Testimony methods, Health Knowledge, Attitudes, Practice, Medical Staff, Hospital education, Medicine standards, Neoplasms prevention & control
- Abstract
This paper describes the sources of variability encountered in the use of an expert panel to review cancer-related knowledge items, necessary for medical students. Variability was observed in the interpretation of written material relating to the definition and rationale for the task to be completed by individual panel members, including the definition of a junior doctor, and levels of understanding and specificity. Panel sessions undertaken in phase II provided facilitated discussion and the ability to clearly define the aims and tasks required of participants, resulting in data of a higher quality. Consensus was achieved in a single session that would have likely taken several iterations of individual data collection to achieve. Eliminating phase I has the potential to remove the majority of variability encountered in this study. Subsequently, the resultant decrease in time demanded of participants would likely result in higher recruitment and participation rates.
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- 2013
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37. Using expert panels to determine the level of cancer knowledge required of junior doctors in Australia. Part 1: methodology and results.
- Author
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Starmer DL, Chapman E, and Millward MJ
- Subjects
- Australia, Communication, Female, Humans, Male, Clinical Competence standards, Expert Testimony methods, Health Knowledge, Attitudes, Practice, Medical Staff, Hospital education, Neoplasms prevention & control
- Abstract
A number of curricula have been developed to address shortfalls in cancer education. However, no standardised means of assessing medical graduates against such curricula currently exist. This paper describes the use of expert panels to determine the level of cancer-related knowledge required by junior doctors. Participants individually reviewed knowledge items from the Ideal Oncology Curriculum for Medical Students and rated the level of understanding and specificity of each. On completion, panel sessions were convened to reach consensus. Fifty-two (17 %) items were considered irrelevant for junior doctors, whilst 164 items (54 %) and 85 items (28 %) were deemed appropriate at a moderate and high level of understanding, respectively. As a result, 249 (83 %) of the 301 items were deemed appropriate for junior doctors. Expert panels provide an important insight into the requirements of junior doctors, reduce ambiguity and facilitate discussion, resulting in higher quality data than that produced solely through individual reviews.
- Published
- 2013
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38. Role of endobronchial ultrasound in diagnosis and molecular assessment of metastatic melanoma.
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Jennings BR, Millward MJ, Amanuel B, Mulrennan S, Joosten SA, and Phillips MJ
- Subjects
- Humans, Lymphatic Metastasis, Mediastinal Neoplasms genetics, Melanoma genetics, Mutation, Proto-Oncogene Proteins B-raf genetics, Retrospective Studies, Endoscopic Ultrasound-Guided Fine Needle Aspiration methods, Mediastinal Neoplasms diagnostic imaging, Mediastinal Neoplasms pathology, Melanoma diagnostic imaging, Melanoma secondary
- Abstract
Background and Objective: Vemurafenib is a new inhibitor of the mutated BRAF oncogene. In the presence of mutated BRAF in metastatic melanoma, treatment with vemurafenib leads to a reduction in mortality and in tumour progression when compared with chemotherapy. This study describes nine cases in which endobronchial ultrasound (EBUS) guided transbronchial needle aspiration (TBNA) was used to assess mediastinal and hilar lymph nodes for the presence of metastatic melanoma and demonstrates the ability to detect mutations in BRAF on the tissue obtained., Methods: A retrospective review was performed of all patients who had a history of melanoma and underwent EBUS TBNA to investigate hilar or mediastinal lymphadenopathy for the presence of metastatic melanoma., Results: In seven of the nine cases, metastatic melanoma was confirmed on cytology. The two negative cases were proven to be true negatives by follow up or by demonstrating an alternate diagnosis. In five cases, analysis for BRAF mutation was performed. Four cases were positive for mutation and one demonstrated wild-type BRAF., Conclusions: Tissue samples obtained from EBUS TBNA are adequate to diagnose metastatic melanoma in hilar and mediastinal lymph nodes and to detect the presence or absence of mutations in the BRAF gene. Our findings suggest that close collaboration between bronchoscopists and pathologists will be needed to implement BRAF testing in routine practice in the era of targeted therapy., (© 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.)
- Published
- 2012
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39. A phase 2 study of tasisulam sodium (LY573636 sodium) as second-line treatment for patients with unresectable or metastatic melanoma.
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Kirkwood JM, Gonzalez R, Reintgen D, Clingan PR, McWilliams RR, de Alwis DP, Zimmermann A, Brown MP, Ilaria RL Jr, and Millward MJ
- Subjects
- Adult, Aged, Aged, 80 and over, Algorithms, Angiogenesis Inhibitors administration & dosage, Angiogenesis Inhibitors adverse effects, Angiogenesis Inhibitors pharmacokinetics, Benzamides administration & dosage, Benzamides adverse effects, Benzamides pharmacokinetics, Body Weight, Disease-Free Survival, Drug Administration Schedule, Fatigue chemically induced, Female, Humans, Kaplan-Meier Estimate, Male, Melanoma mortality, Middle Aged, Skin Neoplasms mortality, Sulfonamides administration & dosage, Sulfonamides adverse effects, Sulfonamides pharmacokinetics, Thrombocytopenia chemically induced, Treatment Outcome, Angiogenesis Inhibitors therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Apoptosis drug effects, Benzamides therapeutic use, Melanoma drug therapy, Skin Neoplasms drug therapy, Sulfonamides therapeutic use
- Abstract
Background: Tasisulam sodium (hereafter, tasisulam) is a novel anticancer agent that induces apoptosis through the intrinsic pathway and has antiangiogenic activity in preclinical models. Tasisulam demonstrated activity across a broad range of tumors, including melanoma. The primary objective of this phase 2 study was to determine the objective response rate (ORR) in patients who had received 1 previous systemic chemotherapy for unresectable/metastatic melanoma; secondary objectives were to evaluate the clinical response rate (CRR), progression-free survival (PFS), overall survival (OS), duration of response, safety, and pharmacokinetics., Methods: Tasisulam was administered intravenously on Day 1 of 21-day cycles according to a lean body weight-based dosing algorithm targeting a peak plasma concentration (C(max)) of 420 μg/mL., Results: In 68 enrolled patients, the median age was 59 years (range, 26-83 years). No patients had a complete response (CR), 8 patients had a partial response (PR), and 24 patients had stable disease (SD); the ORR (CR + PR) was 11.8%, and the CRR (CR + PR + SD) was 47.1%. The median PFS was 2.6 months, and the median OS was 9.6 months. The predominant treatment-related grade 3/4 toxicity was thrombocytopenia (20.6% of patients). Tasisulam exhibited a biexponential disposition with a predicted distribution half-life of 0.3 hours to 2.8 hours and a median terminal elimination half-life of 10 days (consistent with the turnover of albumin), suggesting that tasisulam is very tightly bound to albumin., Conclusions: Tasisulam administered at a targeted C(max) of 420 μg/mL on Day 1 of 21-day cycles demonstrated activity and tolerable toxicity as second-line treatment in malignant melanoma. These results led to a registration trial in metastatic melanoma., (Copyright © 2011 American Cancer Society.)
- Published
- 2011
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40. The Western Australian Melanoma Health Study: study design and participant characteristics.
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Ward SV, Cadby G, Lee A, Cole JM, Heyworth JS, Millward MJ, Wood FM, and Palmer LJ
- Subjects
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Female, Humans, Male, Melanoma mortality, Middle Aged, Neoplasm Staging, Pilot Projects, Prognosis, Public Health, Risk Factors, Skin Neoplasms mortality, Surveys and Questionnaires, Survival Rate, Western Australia epidemiology, Young Adult, Melanoma epidemiology, Melanoma genetics, Research Design, Skin Neoplasms epidemiology, Skin Neoplasms genetics
- Abstract
Background: Cutaneous malignant melanoma is a major public health issue in Australia and other nations. A greater understanding of the genetic determinants and their interactions with environmental factors may lead to better interventions and control of the disease. The Western Australian Melanoma Health Study (WAMHS) is a population-based case-collection and biospecimen resource established to investigate the genetic epidemiology of melanoma. This manuscript discusses the design of the WAMHS and the characteristics of the participants., Methods: Participants were recruited through the Western Australian Cancer Registry, which is notified of all incident cancers in the state of Western Australia by law. Once the diagnosing doctor's consent was obtained, all eligible, resident Western Australian, adult cases of melanoma diagnosed between January 2006 and September 2009, were contacted by mail and invited to participate. Clinical, questionnaire-based phenotypic and blood samples for extraction of DNA, RNA and serum were collected from consenting cases. Clinical data consisted of all pathological data recorded by the cancer registry and the questionnaire, administered by telephone interview, covered major risk factors for melanoma, such as sun exposure history and skin type., Results: The final sample consisted of 1643 consenting cases out of 3420 cancer notifications (48.04%), of which 1455 cases completed one or more components of the study and 1157 completed all components. The WAMHS sample differed to all melanoma notifications only in age, with a bias towards older individuals (P<0.0001). No significant differences were observed in sex, melanoma site, Breslow thickness or Clark's level., Conclusions: The WAMHS study is novel in its non-family based approach and focus on common (low penetrance) genetic determinants. This comprehensive resource will enable further steps to be taken towards understanding the complex pathways involved in melanoma., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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41. Applying global frameworks to assessment in medical education: an example of a nationally produced curriculum for cancer education.
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Starmer DL, Chapman E, and Millward MJ
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- Education, Medical organization & administration, Humans, Learning, Problem-Based Learning, Curriculum standards, Education, Medical standards, Health Knowledge, Attitudes, Practice, Medical Oncology education, Neoplasms prevention & control, Schools, Medical standards
- Abstract
The past decade has seen an increased effort to standardized medical curricula internationally. Despite these efforts, a lack of standardization remains evident, most likely owing to the lack of specificity with which such frameworks are often (out of necessity) constructed. As such, inconsistencies may arise owing to differences in adopted definitions and approaches to assessment. The authors highlight six key points to aid the individual educator in translating overarching frameworks into specific learning objectives that are measurable, written at a level of generality, complexity and difficulty that is clear, appropriate and explicit in what is required of the student.
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- 2010
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42. A novel prognostic model for malignant mesothelioma incorporating quantitative FDG-PET imaging with clinical parameters.
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Nowak AK, Francis RJ, Phillips MJ, Millward MJ, van der Schaaf AA, Boucek J, Musk AW, McCoy MJ, Segal A, Robins P, and Byrne MJ
- Subjects
- Female, Humans, Male, Mesothelioma pathology, Pleural Neoplasms pathology, Prognosis, Survival Rate, Tomography, X-Ray Computed, Fluorodeoxyglucose F18, Mesothelioma diagnostic imaging, Pleural Neoplasms diagnostic imaging, Positron-Emission Tomography, Radiopharmaceuticals
- Abstract
Purpose: Existing prognostic systems for malignant pleural mesothelioma do not incorporate imaging information. We aimed to identify the contribution of quantitative fluorodeoxyglucose positron emission tomography (FDG-PET) analysis to other prognostic variables in this disease., Experimental Design: Patients with malignant pleural mesothelioma underwent helical thoracoabdominal computed tomography and FDG-PET scans at baseline. Patients were treated as clinically indicated and followed for survival. FDG-PET variables derived included total glycolytic volume, a composite of tumor volume and glycolytic activity., Results: Ninety-three patients were accrued from 2003 to 2006. Of 89 eligible assessable patients, 28 had undergone pleurodesis before enrolment. Seventeen patients remained alive at analysis; median survival is 15.4 months. On univariate analysis, significant prognostic factors were: total glycolytic volume on FDG-PET (P = 0.003), sarcomatoid histology (P < 0.0005), weight loss (P = 0.031), computed tomography stage (P = 0.015), and European Organization for Research and Treatment of Cancer good prognostic score (P = 0.049). In patients with epithelioid or biphasic histology, baseline total glycolytic volume remained predictive of survival in patients with (P = 0.01) or without (P = 0.018) previous pleurodesis. In multivariate analysis, no variable other than histology contributed to the model in patients with sarcomatoid histology; total glycolytic volume and weight loss contributed to the models in patients with nonsarcomatoid histology. computed tomography-assessed tumor-node-metastasis stage did not contribute to the model. A nomogram, which incorporates quantitative PET parameters and pleurodesis into prognostic information, is presented., Conclusions: Sarcomatoid histology remains the strongest prognostic factor. In patients with non sarcomatoid disease, volumetric FDG-PET parameters are more predictive of survival than tumor-node-metastasis staging, suggesting that tumor volume and glycolytic activity may be more important determinants of prognosis in malignant pleural mesothelioma than anatomic extent of disease.
- Published
- 2010
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43. Long-term survival following chemoradiation for inoperable non-small cell lung cancer.
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Plumridge NM, Millward MJ, Rischin D, Macmanus MP, Wirth A, Michael M, Yuen K, and Ball DL
- Subjects
- Adult, Aged, Antineoplastic Agents therapeutic use, Carboplatin therapeutic use, Carcinoma, Non-Small-Cell Lung pathology, Cisplatin therapeutic use, Etoposide therapeutic use, Female, Fluorouracil therapeutic use, Follow-Up Studies, Humans, Lung Neoplasms pathology, Male, Middle Aged, Radiotherapy, Adjuvant, Survival Rate, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung therapy, Lung Neoplasms mortality, Lung Neoplasms therapy
- Abstract
Objective: To measure long-term survival following combined chemotherapy and radiotherapy for inoperable non-small cell lung cancer., Design and Setting: Two prospective Phase I/II studies in the multidisciplinary Lung Service of a dedicated cancer hospital in Victoria, commencing in 1996 and 1997-1998., Patients: 33 patients referred for treatment of histologically or cytologically proven inoperable non-small cell lung cancer, who had no evidence of distant metastases, Karnofsky performance status > 70%, weight loss < 10%, and no prior treatment for lung cancer. Patients were followed until death or for a minimum of 9 years., Interventions: Patients in both studies were treated concomitantly with chemotherapy and radiotherapy 60 Gy in 30 fractions over 6 weeks. Chemotherapy in the first study (LURTCE) consisted of cisplatin and etoposide; in the second study (LURTCF), chemotherapy consisted of escalating doses of carboplatin and fluorouracil., Main Outcome Measure: Overall survival., Results: Six of 33 patients were still alive 9 years after commencement of treatment. Median survival for the whole group was 2.1 years (95% CI, 1.3-3.1 years), with 18% (95% CI, 8%-35%) of patients still alive at 5 years (plateau)., Conclusion: Long-term survival can be achieved in some patients with inoperable non-small cell lung cancer treated by radical chemoradiation alone, suggesting the possibility of cure.
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- 2008
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44. Overexpression and altered glycosylation of MUC1 in malignant mesothelioma.
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Creaney J, Segal A, Sterrett G, Platten MA, Baker E, Murch AR, Nowak AK, Robinson BW, and Millward MJ
- Subjects
- Aged, Aged, 80 and over, Alternative Splicing, Biomarkers, Tumor analysis, Biomarkers, Tumor blood, Female, Gene Expression Regulation, Neoplastic, Glycosylation, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Male, Mesothelioma blood, Mesothelioma chemistry, Middle Aged, Mucin-1 analysis, Mucin-1 blood, Mucin-1 genetics, Pleural Effusion, Malignant blood, Pleural Effusion, Malignant chemistry, Polymerase Chain Reaction, RNA, Messenger metabolism, Sensitivity and Specificity, Up-Regulation, Biomarkers, Tumor metabolism, Mesothelioma diagnosis, Mesothelioma metabolism, Mucin-1 metabolism, Pleural Effusion, Malignant diagnosis, Pleural Effusion, Malignant metabolism
- Abstract
Current interest in the MUC1/EMA mucin relates to its role in malignancy, and its potential as a therapeutic target. MUC1/EMA expression has been observed in the majority of epithelioid mesotheliomas. However, little is known of the characteristics of MUC1/EMA in mesothelioma. Herein, we studied the cell surface and soluble expression of the MUC1/EMA glycoprotein, and determined the mRNA and genomic expression profiles in mesothelioma. We found that the anti-MUC1 antibody, E29, was the most diagnostically useful of seven antibody clones examined with a sensitivity of 84% (16 out of 19 cases) and no false positive results. MUC1 mRNA expression was significantly higher in mesothelioma samples than in benign mesothelial cells. No amplification of the MUC1 gene was observed by FISH. Seven of 9 mesothelioma samples expressed MUC1-secreted mRNA isoform in addition to the archetypal MUC1/transmembrane form. CA15.3 (soluble MUC1) levels were significantly higher in the serum of mesothelioma patients than in healthy controls but were not significantly different to levels in patients with benign asbestos-related disease. CA15-3 in effusions could differentiate malignant from benign effusions but were not specific for mesothelioma. Thus, as in other cancers, alterations in MUC1 biology occur in mesothelioma and these results suggest that specific MUC1 characteristics may be useful for mesothelioma diagnosis and should also be investigated as a potential therapeutic target.
- Published
- 2008
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45. A phase II study of the heparanase inhibitor PI-88 in patients with advanced melanoma.
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Lewis KD, Robinson WA, Millward MJ, Powell A, Price TJ, Thomson DB, Walpole ET, Haydon AM, Creese BR, Roberts KL, Zalcberg JR, and Gonzalez R
- Subjects
- Adult, Aged, Alanine Transaminase blood, Contusions etiology, Drug Administration Schedule, Fatigue chemically induced, Female, Humans, Injections, Subcutaneous adverse effects, Kaplan-Meier Estimate, Male, Melanoma pathology, Middle Aged, Nausea chemically induced, Neoplasm Metastasis, Oligosaccharides administration & dosage, Oligosaccharides adverse effects, Pain etiology, Severity of Illness Index, Thrombocytopenia chemically induced, Treatment Outcome, Glucuronidase antagonists & inhibitors, Melanoma drug therapy, Oligosaccharides therapeutic use
- Abstract
Treatment options for advanced melanoma are limited. PI-88, a potent inhibitor of heparanase, demonstrates anitangiogenic properties and has shown activity against melanoma in phase I studies. This was an open-label, multicenter, phase II study of PI-88 in patients with advanced melanoma. Patients received a fixed-dose of 250 mg/day given subcutaneously for four consecutive days followed by three drug-free days per week in a 28-day cycle. A total of 44 patients were enrolled in the intent to treat population, with 59.1% having received previous therapy. The median time to progression and overall survival was 1.7 months and 9 months, respectively. Forty-one patients are included in the efficacy analysis. One (2.4%) patient achieved a partial response, six (14.6%) patients had stable disease as best response, and 30 (73.2%) had progressive disease. At the end of six cycles of treatment, three of the 41 evaluable patients had non-progressive disease. Treatment was generally well tolerated. Injection site bruising occurred in 45% of patients. Serious bleeding did occur in two patients and three patients developed a positive anti-platelet antibody test during the study. One of these four patients experienced an associated thrombosis. In patients with advanced melanoma, PI-88 demonstrates an overall survival and time to progression similar to standard chemotherapy. Although the current study did not meet the primary end-point of progression free survival of >or=20%, there is some evidence of activity and further investigation is warranted.
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- 2008
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46. Early prediction of response to chemotherapy and survival in malignant pleural mesothelioma using a novel semiautomated 3-dimensional volume-based analysis of serial 18F-FDG PET scans.
- Author
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Francis RJ, Byrne MJ, van der Schaaf AA, Boucek JA, Nowak AK, Phillips M, Price R, Patrikeos AP, Musk AW, and Millward MJ
- Subjects
- Aged, Female, Humans, Male, Mesothelioma drug therapy, Mesothelioma mortality, Middle Aged, Pleural Neoplasms drug therapy, Pleural Neoplasms mortality, Positron-Emission Tomography methods, Prognosis, Survival Rate, Fluorodeoxyglucose F18, Mesothelioma diagnostic imaging, Pleural Neoplasms diagnostic imaging, Radiopharmaceuticals
- Abstract
Unlabelled: The aim of chemotherapy for mesothelioma is to palliate symptoms and improve survival. Measuring response using CT is challenging because of the circumferential tumor growth pattern. This study aims to evaluate the role of serial (18)F-FDG PET in the assessment of response to chemotherapy in patients with mesothelioma., Methods: Patients were prospectively recruited and underwent both (18)F-FDG PET and conventional radiological response assessment before and after 1 cycle of chemotherapy. Quantitative volume-based (18)F-FDG PET analysis was performed to obtain the total glycolytic volume (TGV) of the tumor. Survival outcomes were measured., Results: Twenty-three patients were suitable for both radiological and (18)F-FDG PET analysis, of whom 20 had CT measurable disease. After 1 cycle of chemotherapy, 7 patients attained a partial response and 13 had stable disease on CT assessment by modified RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In the 7 patients with radiological partial response, the median TGV on quantitative PET analysis fell to 30% of baseline (range, 11%-71%). After 1 cycle of chemotherapy, Cox regression analysis demonstrated a statistically significant relationship between a fall in TGV and improved patient survival (P = 0.015). Neither a reduction in the maximum standardized uptake value (P = 0.097) nor CT (P = 0.131) demonstrated a statistically significant association with patient survival., Conclusion: Semiquantitative (18)F-FDG PET using the volume-based parameter of TGV is feasible in mesothelioma and may predict response to chemotherapy and patient survival after 1 cycle of treatment. Therefore, metabolic imaging has the potential to improve the care of patients receiving chemotherapy for mesothelioma by the early identification of responding patients. This technology may also be useful in the assessment of new systemic treatments for mesothelioma.
- Published
- 2007
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47. Cost effectiveness of trastuzumab in the adjuvant treatment of early breast cancer: a lifetime model.
- Author
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Millar JA and Millward MJ
- Subjects
- Antibodies, Monoclonal, Humanized, Australia, Breast Neoplasms genetics, Chemotherapy, Adjuvant, Cost-Benefit Analysis, Female, Genes, erbB-2 genetics, Humans, Markov Chains, Middle Aged, Models, Economic, Neoplasm Recurrence, Local economics, Neoplasm Recurrence, Local prevention & control, Trastuzumab, Antibodies, Monoclonal economics, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents economics, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms economics
- Abstract
Background: Recent randomised trials have demonstrated a statistically significant effect of trastuzumab on disease-free survival when used as adjuvant therapy for human epidermal growth factor receptor 2 protein (HER2)-positive resectable early stage breast cancer, with a treatment course lasting either 9 or 52 weeks. However, the cost effectiveness of adjuvant trastuzumab with respect to mortality remains uncertain, especially in an Australian setting., Objective: To estimate the cost effectiveness of trastuzumab in Australia, in a cohort of 50-year-old patients with HER2-positive breast cancer over a lifetime, using (i) disease-free survival and cardiotoxicity data from recent randomised trials; (ii) information on long-term survival of patients with treated primary breast cancer; and (iii) costs of treating local and distant relapses and disease from causes other than breast cancer., Methods: A Markov model consisting of four health states (remission, loco-regional recurrence, metastatic disease and death) was developed. Transition probabilities corresponded to patterns of relapse and metastases seen in recent trials. The model was run until age 100 years to allow calculation of average survival. Outcome measures were life-years and QALYs (calculated using utility weights reported in the literature). The model was calibrated to reflect literature evidence that the risk of breast cancer recurrence following primary treatment diminishes progressively to zero after about 20 years. It was assumed that the morbidity benefit of trastuzumab observed in trials would be present for 5 years but would then diminish progressively to zero after 8 years. Costs (year 2005 values) and benefits were discounted at 3% per annum., Results: For every 1000 patients treated with a 52-week course of trastuzumab, there were 136 fewer breast cancer deaths (relative risk reduction 28%). The incremental cost-effectiveness ratios (ICERs) were Australian dollars ($ A)13 730 per year of life saved (YOLS) and $ A22 793 per QALY. The net incremental cost was $ A56.3 million ($ A414 012/cancer death avoided). Cost effectiveness declined (ICER = $ A27 734/QALY) in older patients (age 65 years at treatment initiation). The ICER was driven mainly by the drug acquisition costs, the assumption of the duration of benefit and the discount rate. Cost offsets from reduced costs of treating recurrent or metastatic breast cancer during follow-up were present but these factors were of less importance according to sensitivity analyses. The 9-week treatment schedule approached economic dominance (ICER = $ A1700/QALY) because of decreased costs, improved relative risk for prevention of metastases and more cancer deaths avoided (196)., Conclusion: The results suggest that trastuzumab as adjuvant therapy for early breast cancer may be cost effective when given over either 52 or 9 weeks at current acquisition costs in Australia. However, the overall budget impact of the 52-week course is significant, and the 9-week course appears economically attractive.
- Published
- 2007
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48. The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study.
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Millward MJ, House C, Bowtell D, Webster L, Olver IN, Gore M, Copeman M, Lynch K, Yap A, Wang Y, Cohen PS, and Zalcberg J
- Subjects
- Adult, Aged, Blotting, Western, Chromatography, High Pressure Liquid, Female, Humans, Isoenzymes drug effects, Isoenzymes metabolism, Male, Melanoma mortality, Middle Aged, Protein Kinase C drug effects, Protein Kinase C metabolism, Staurosporine adverse effects, Staurosporine analysis, Staurosporine metabolism, Survival Analysis, Treatment Outcome, Antineoplastic Agents adverse effects, Melanoma drug therapy, Staurosporine analogs & derivatives
- Abstract
Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had >50% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies.
- Published
- 2006
- Full Text
- View/download PDF
49. Detection of metastatic disease in patients with uveal melanoma using positron emission tomography.
- Author
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Francken AB, Fulham MJ, Millward MJ, and Thompson JF
- Subjects
- Adult, Aged, Female, Fluorodeoxyglucose F18, Humans, Liver Neoplasms diagnostic imaging, Liver Neoplasms secondary, Male, Middle Aged, Neoplasm Metastasis, Predictive Value of Tests, Radiopharmaceuticals, Sensitivity and Specificity, Melanoma diagnostic imaging, Melanoma secondary, Positron-Emission Tomography, Uveal Neoplasms pathology
- Abstract
Objective: Positron emission tomography with [(18)F]fluorodeoxyglucose (FDG-PET) is of proven value in the detection of metastases in patients with cutaneous melanoma. However, little is known about its value in uveal melanoma (UM). In this study the results of FDG-PET in patients with UM were evaluated., Methods: Patients with UM recorded in the Sydney Melanoma Unit database who had been assessed with FDG-PET were selected. Comparative data (imaging or histopathology) providing information about metastatic disease were obtained within 14 weeks of the FDG-PET study and compared with the FDG-PET result. Sensitivity, specificity, accuracy, and positive and negative predictive values for the detection of liver metastases (LMs) by FDG-PET were calculated., Results: FDG-PET was performed in 22 patients with UM between April 1993 and March 2003. The presence of at least one focus of metastatic melanoma was confirmed in 14 of 18 patients with positive FDG-PET, and three of four negative FDG-PET studies were confirmed. LMs were demonstrated by FDG-PET in 17 patients. In 15 of these patients this finding was confirmed with anatomical imaging. In two patients LMs indicated by FDG-PET initially appeared to be false positive, but in one of them the diagnosis was confirmed after longer follow-up. Seven of the confirmed lesions were isolated LMs. For LMs FDG-PET showed sensitivity, specificity and accuracy of 100%, 67% and 90% respectively, a positive predictive value of 88% and a negative predictive value of 100%., Conclusion: FDG-PET is a valuable investigation for the detection of LMs in UM patients. It appears to be particularly useful in the detection of isolated LMs that are potentially resectable.
- Published
- 2006
- Full Text
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50. Promoter hypermethylation of the O(6)-methylguanine DNA methyltransferase gene and microsatellite instability in metastatic melanoma.
- Author
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Kohonen-Corish MR, Cooper WA, Saab J, Thompson JF, Trent RJ, and Millward MJ
- Subjects
- Drug Resistance, Neoplasm genetics, Humans, Melanoma secondary, Prognosis, Promoter Regions, Genetic genetics, Skin Neoplasms pathology, DNA Methylation, Genomic Instability, Melanoma genetics, Microsatellite Repeats genetics, O(6)-Methylguanine-DNA Methyltransferase genetics, Skin Neoplasms genetics
- Abstract
Tumor spread to distant organs is the most serious consequence of melanoma, as only 10-20% of stage IV patients respond to current chemotherapies. Tumor sensitivity to alkylating agents is affected by the activity of cellular DNA repair proteins, such as O(6)-methylguanine DNA methyltransferase (MGMT) and the DNA mismatch repair proteins. Chemosensitivity may be enhanced by reduced MGMT activity, but the frequency of MGMT promoter silencing through hypermethylation is unknown in distant melanoma metastases. The frequency and significance of microsatellite instability (MSI) in metastatic melanoma is also unclear, and it has been suggested that MSI frequency increases during the metastatic process. We undertook an analysis of 84 melanoma metastases from 47 patients. MGMT methylation was detected using methylation-specific PCR in 26 of the 84 metastases (31%), but there was discordance between individual metastases from the same patient. Therefore, as a result of this variation, MGMT methylation may have only limited value as a predictor of chemosensitivity. High MSI involving mononucleotide repeat markers was not found. Low MSI was detected in five of 50 metastases (10%) and only one of the five metastases also had MGMT methylation. These results demonstrate that in contrast to some previous reports, these tumors have a low frequency of MSI.
- Published
- 2006
- Full Text
- View/download PDF
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