Maria Marples | University of Leeds (original) (raw)
Papers by Maria Marples
European Journal of Cancer
Journal of the Endocrine Society
Introduction Immune checkpoint inhibitors (ICIs) are immunomodulatory molecules that downregulate... more Introduction Immune checkpoint inhibitors (ICIs) are immunomodulatory molecules that downregulate T-cell inhibiting-receptors or ligands to promote an enhanced anti-tumour response. Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) that has been shown to significantly improve survival in patients with metastatic melanoma. Immune-related adverse events (irAEs) occur in some patients with increased T-cell activation, of which ipilimumab-related hypophysitis (IH) is an important endocrine complication. The aim of this study is to determine the incidence of IH and characterise clinical presentation and outcomes in these patients. Patients and Methods We retrospectively evaluated consecutive adult patients with melanoma treated between December 2010 and August 2019 at a tertiary cancer centre. All patients received ipilimumab (3mg/kg) monotherapy or in combination with PD-1 (programmed cell death protein 1) inhibitors (nivolumab or pembr...
Journal of Clinical Oncology
LBA9000 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (... more LBA9000 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June, 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Journal of Clinical Oncology
8523 Background: The median overall survival (OS) for metastatic uveal melanoma is less than 6 mo... more 8523 Background: The median overall survival (OS) for metastatic uveal melanoma is less than 6 months with a median progression free survival(PFS) of 3 months. No systemic or regional therapy has shown a survival advantage over best supportive care. Despite pre-clinical evidence suggesting anti-tumour activity for the KIT tyrosine kinase inhibitor imatinib, there are several negative phase II trials in unselected patients. Our primary aim was to test the efficacy of imatinib in patients with prospectively-tested c-kit immunopositive metastatic uveal melanoma. Secondary aims included assessment of toxicity and patient recruitment. Methods: A phase II UK multicentre single-arm, two-stage Gehan design recruited 25 evaluable patients receiving imatinib 400mg OD until progression/unacceptable toxicity. Primary efficacy outcome was PFS at 3 months. Secondary outcomes were OS, overall PFS, disease response (RECIST) and toxicity. Prospective sample collection for putative biomarkers was inc...
Journal of Clinical Oncology
9501 Background: Bevacizumab (Bev) is a recombinant humanised monoclonal antibody to vascular end... more 9501 Background: Bevacizumab (Bev) is a recombinant humanised monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumours. As VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in melanoma patients at high risk of recurrence. Methods: AVAST-M (ISRCTN81261306) is a randomised phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy after resection of AJCC stage IIB, IIC and III cutaneous melanoma compared to standard observation (Obs). 1320 patients were needed to detect 8% differences in 5 year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint was OS; secondary endpoints included disease free interval (DFI), distant-metastasis free interval (DMFI). BRAF and NRASmutation status were obtained in 682 patients in a translational sub-study. Results: From July 2007 to March 2012, 1343 patients were recruited (671 to B...
Journal of Clinical Oncology
Annals of oncology : official journal of the European Society for Medical Oncology, 2018
Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor ... more Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevac...
Annals of surgical oncology, Jan 31, 2018
In the peripheral blood, the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR... more In the peripheral blood, the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) change in response to malignancy. These biomarkers are associated with adverse outcomes in numerous cancers, but the evidence is limited in relation to melanoma. This study sought to investigate the association between these biomarkers and survival in Stages I-III cutaneous melanoma. This multicenter cohort study investigated a consecutive series of patients who underwent wide excision of biopsy-proven cutaneous melanoma and sentinel lymph node biopsy during a 10-year period. The baseline NLR and PLR were calculated immediately before sentinel lymph node biopsy. Adjusted hazard ratios (HRs) for overall and melanoma-specific survival were generated. Overall, 1351 patients were included in the study. During surveillance, 184 of these patients died (14%), with 141 of the deaths (77%) attributable to melanoma. Worse overall survival was associated with a baseline NLR lower than 2.5 [HR 2.2...
Global Dermatology
Two months later, she was admitted with a five day history of worsening breathlessness, that was ... more Two months later, she was admitted with a five day history of worsening breathlessness, that was initially on exertion but then at rest. There was an associated dry cough and low grade fever. She was still taking prednisolone 25 mg/day and one 500mg calcium/400 international units colecalciferol tablet per day but no other regular medications. Clinical assessment revealed normal air entry on the left side of the chest with signs of a right pneumonectomy. She was tachycardic at 101 beats per minute, respiratory rate was raised at 24 per minute, oxygen saturation was reduced at 96% on 2 L/minute of oxygen. Chest radiograph demonstrated the left lung to be clear. Blood tests showed a white cell count of 14 x 10 9 /L (normal range 4-11 x 10 9 /L) with a neutrophilia and C reactive protein of 22 mg/L (normal range <10 mg/L). Computed tomography pulmonary angiography excluded pulmonary embolus but did show new left sided patchy and widespread ground glass changes with mediastinal lymphadenopathy (Figure 1). Treatment for community acquired pneumonia with intravenous piperacillin/tazobactam and clarithromycin was given but she failed to improve. Screens for atypical bacterial, viral and fungal pneumonia screens were negative for legionella, mycoplasma, psittacosis, Q fever,
Journal of Bone Oncology
Introduction: Metastatic bone disease (MBD) carries significant morbidity for patients with cance... more Introduction: Metastatic bone disease (MBD) carries significant morbidity for patients with cancer. MBD from malignant melanoma (MM) is understudied. We examined the characteristics, morbidity, management and outcome of MBD in patients with MM. Methods: Patients with metastatic MM managed at two referral cancer centres in England were identified. Those with bone metastases (BMs) were selected. Patient and disease characteristics including skeletal related events (SREs) were extracted from medical records. The Kaplan Meier method was used to calculate median survival. Results: Five hundred and eighteen patients with metastatic MM were managed between years 2000 and 2008. Eighty nine (17.2%) patients had BMs and are the subject of this study. Median age at diagnosis was 53 years and 55% were males. BMs were identified at the time of diagnosis of metastatic disease in 68.5% patients. Sixty-six (74.2%) had multiple bone lesions and 80.9% had axial skeleton involvement. One hundred and twenty nine skeletal related events occurred in 59 (66.3%) patients (50 radiotherapy, 28 hypercalcaemia, 20 bone fractures, 18 spinal cord compression and 13 orthopaedic surgery). The annual skeletal morbidity rate was 2.5. Median survival from diagnosis of BMs was 17.3 weeks and was 5.6 weeks from the first episode of hypercalcaemia. Conclusion: MBD affects a clinically important proportion (17.2%) of patients with metastatic MM. It carries a substantial morbidity and mortality exceeding that caused by BMs from breast and prostate cancer. These patients should receive the currently licensed bone modifying agents and should be included in clinical trials addressing MBD.
The Lancet Oncology
Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated adva... more Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. The Lancet Oncology, 18 (10). pp. 1397-1410.
Journal of Clinical Oncology
119 Background: Treatment with palliative imatinib has improved outcomes in advanced GISTs, with ... more 119 Background: Treatment with palliative imatinib has improved outcomes in advanced GISTs, with a reported 2 year PFS of 50%. Guidelines suggest monitoring during imatinib by CT scan at 12 week intervals. There are no validated biomarkers to assist in disease evaluation. High d-dimer levels are associated with poor prognosis in several cancers and are predictive of disease progression during chemotherapy. In the diagnosis of venous thromboembolism, low D-dimer levels have a high negative predictive value (npv) for thrombosis. We investigated whether low d-dimers have a clinically useful npv for GIST progression. Methods: We retrospectively identified all patients treated with palliative Imatinib for GIST in a single tertiary referral centre using a systematic search of an electronic clinical database. Every 12 weeks during treatment patients were assessed by clinical evaluation, CT and a d-dimer measurement (HemosIL HS assay). The prognostic value of d-dimers was assessed by Cox re...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 20, 2013
LBA9000 Background: Bevacizumab (Bev) is a recombinant humanized monoclonal antibody to vascular ... more LBA9000 Background: Bevacizumab (Bev) is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumors. Multiple adjuvant trials are underway, but trials that have reported in colon and triple-negative breast cancer did not meet their primary end points. Since VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in patients (pts) with resected melanoma at high risk of recurrence. AVAST-M is a randomized phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy following resection of AJCC stage IIB, IIC, and III cutaneous melanoma compared to standard observation (Obs). 1,320 pts were required to detect 8% differences in 5-year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint is OS; secondary endpoints are disease free interval (DFI), distant-metastasis free interval (DMFI), safety, and quality...
Scientific reports, Dec 7, 2016
We examined the predictive value of neutrophil-lymphocyte ratio (NLR) by examining their associat... more We examined the predictive value of neutrophil-lymphocyte ratio (NLR) by examining their association with the baseline presence and subsequent development of brain metastases in patients with stage IV non-small cell lung cancer (NSCLC). We examined the predictive value of NLR for brain metastasis in 260 stage IV NSCLC. Logistic regression models and competing risk analysis were used to determine the association of NLR with baseline and subsequent presence of brain metastases. Multivariate analysis reveals that patients with high NLR (≥4.95) had significantly more brain metastases at diagnosis than those with low NLR (Odds Ratio = 2.59, P = 0.01). In patients who had no baseline brain metastasis, competing risks analysis revealed that patients with high NLR showed higher cumulative incidence of subsequent brain metastases, compared to those with low NLR (P = 0.017). A high NLR was associated with the baseline presence or the subsequent development of brain metastases, particularly in...
European Journal of Cancer
Journal of the Endocrine Society
Introduction Immune checkpoint inhibitors (ICIs) are immunomodulatory molecules that downregulate... more Introduction Immune checkpoint inhibitors (ICIs) are immunomodulatory molecules that downregulate T-cell inhibiting-receptors or ligands to promote an enhanced anti-tumour response. Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) that has been shown to significantly improve survival in patients with metastatic melanoma. Immune-related adverse events (irAEs) occur in some patients with increased T-cell activation, of which ipilimumab-related hypophysitis (IH) is an important endocrine complication. The aim of this study is to determine the incidence of IH and characterise clinical presentation and outcomes in these patients. Patients and Methods We retrospectively evaluated consecutive adult patients with melanoma treated between December 2010 and August 2019 at a tertiary cancer centre. All patients received ipilimumab (3mg/kg) monotherapy or in combination with PD-1 (programmed cell death protein 1) inhibitors (nivolumab or pembr...
Journal of Clinical Oncology
LBA9000 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (... more LBA9000 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June, 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Journal of Clinical Oncology
8523 Background: The median overall survival (OS) for metastatic uveal melanoma is less than 6 mo... more 8523 Background: The median overall survival (OS) for metastatic uveal melanoma is less than 6 months with a median progression free survival(PFS) of 3 months. No systemic or regional therapy has shown a survival advantage over best supportive care. Despite pre-clinical evidence suggesting anti-tumour activity for the KIT tyrosine kinase inhibitor imatinib, there are several negative phase II trials in unselected patients. Our primary aim was to test the efficacy of imatinib in patients with prospectively-tested c-kit immunopositive metastatic uveal melanoma. Secondary aims included assessment of toxicity and patient recruitment. Methods: A phase II UK multicentre single-arm, two-stage Gehan design recruited 25 evaluable patients receiving imatinib 400mg OD until progression/unacceptable toxicity. Primary efficacy outcome was PFS at 3 months. Secondary outcomes were OS, overall PFS, disease response (RECIST) and toxicity. Prospective sample collection for putative biomarkers was inc...
Journal of Clinical Oncology
9501 Background: Bevacizumab (Bev) is a recombinant humanised monoclonal antibody to vascular end... more 9501 Background: Bevacizumab (Bev) is a recombinant humanised monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumours. As VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in melanoma patients at high risk of recurrence. Methods: AVAST-M (ISRCTN81261306) is a randomised phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy after resection of AJCC stage IIB, IIC and III cutaneous melanoma compared to standard observation (Obs). 1320 patients were needed to detect 8% differences in 5 year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint was OS; secondary endpoints included disease free interval (DFI), distant-metastasis free interval (DMFI). BRAF and NRASmutation status were obtained in 682 patients in a translational sub-study. Results: From July 2007 to March 2012, 1343 patients were recruited (671 to B...
Journal of Clinical Oncology
Annals of oncology : official journal of the European Society for Medical Oncology, 2018
Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor ... more Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevac...
Annals of surgical oncology, Jan 31, 2018
In the peripheral blood, the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR... more In the peripheral blood, the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) change in response to malignancy. These biomarkers are associated with adverse outcomes in numerous cancers, but the evidence is limited in relation to melanoma. This study sought to investigate the association between these biomarkers and survival in Stages I-III cutaneous melanoma. This multicenter cohort study investigated a consecutive series of patients who underwent wide excision of biopsy-proven cutaneous melanoma and sentinel lymph node biopsy during a 10-year period. The baseline NLR and PLR were calculated immediately before sentinel lymph node biopsy. Adjusted hazard ratios (HRs) for overall and melanoma-specific survival were generated. Overall, 1351 patients were included in the study. During surveillance, 184 of these patients died (14%), with 141 of the deaths (77%) attributable to melanoma. Worse overall survival was associated with a baseline NLR lower than 2.5 [HR 2.2...
Global Dermatology
Two months later, she was admitted with a five day history of worsening breathlessness, that was ... more Two months later, she was admitted with a five day history of worsening breathlessness, that was initially on exertion but then at rest. There was an associated dry cough and low grade fever. She was still taking prednisolone 25 mg/day and one 500mg calcium/400 international units colecalciferol tablet per day but no other regular medications. Clinical assessment revealed normal air entry on the left side of the chest with signs of a right pneumonectomy. She was tachycardic at 101 beats per minute, respiratory rate was raised at 24 per minute, oxygen saturation was reduced at 96% on 2 L/minute of oxygen. Chest radiograph demonstrated the left lung to be clear. Blood tests showed a white cell count of 14 x 10 9 /L (normal range 4-11 x 10 9 /L) with a neutrophilia and C reactive protein of 22 mg/L (normal range <10 mg/L). Computed tomography pulmonary angiography excluded pulmonary embolus but did show new left sided patchy and widespread ground glass changes with mediastinal lymphadenopathy (Figure 1). Treatment for community acquired pneumonia with intravenous piperacillin/tazobactam and clarithromycin was given but she failed to improve. Screens for atypical bacterial, viral and fungal pneumonia screens were negative for legionella, mycoplasma, psittacosis, Q fever,
Journal of Bone Oncology
Introduction: Metastatic bone disease (MBD) carries significant morbidity for patients with cance... more Introduction: Metastatic bone disease (MBD) carries significant morbidity for patients with cancer. MBD from malignant melanoma (MM) is understudied. We examined the characteristics, morbidity, management and outcome of MBD in patients with MM. Methods: Patients with metastatic MM managed at two referral cancer centres in England were identified. Those with bone metastases (BMs) were selected. Patient and disease characteristics including skeletal related events (SREs) were extracted from medical records. The Kaplan Meier method was used to calculate median survival. Results: Five hundred and eighteen patients with metastatic MM were managed between years 2000 and 2008. Eighty nine (17.2%) patients had BMs and are the subject of this study. Median age at diagnosis was 53 years and 55% were males. BMs were identified at the time of diagnosis of metastatic disease in 68.5% patients. Sixty-six (74.2%) had multiple bone lesions and 80.9% had axial skeleton involvement. One hundred and twenty nine skeletal related events occurred in 59 (66.3%) patients (50 radiotherapy, 28 hypercalcaemia, 20 bone fractures, 18 spinal cord compression and 13 orthopaedic surgery). The annual skeletal morbidity rate was 2.5. Median survival from diagnosis of BMs was 17.3 weeks and was 5.6 weeks from the first episode of hypercalcaemia. Conclusion: MBD affects a clinically important proportion (17.2%) of patients with metastatic MM. It carries a substantial morbidity and mortality exceeding that caused by BMs from breast and prostate cancer. These patients should receive the currently licensed bone modifying agents and should be included in clinical trials addressing MBD.
The Lancet Oncology
Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated adva... more Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. The Lancet Oncology, 18 (10). pp. 1397-1410.
Journal of Clinical Oncology
119 Background: Treatment with palliative imatinib has improved outcomes in advanced GISTs, with ... more 119 Background: Treatment with palliative imatinib has improved outcomes in advanced GISTs, with a reported 2 year PFS of 50%. Guidelines suggest monitoring during imatinib by CT scan at 12 week intervals. There are no validated biomarkers to assist in disease evaluation. High d-dimer levels are associated with poor prognosis in several cancers and are predictive of disease progression during chemotherapy. In the diagnosis of venous thromboembolism, low D-dimer levels have a high negative predictive value (npv) for thrombosis. We investigated whether low d-dimers have a clinically useful npv for GIST progression. Methods: We retrospectively identified all patients treated with palliative Imatinib for GIST in a single tertiary referral centre using a systematic search of an electronic clinical database. Every 12 weeks during treatment patients were assessed by clinical evaluation, CT and a d-dimer measurement (HemosIL HS assay). The prognostic value of d-dimers was assessed by Cox re...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 20, 2013
LBA9000 Background: Bevacizumab (Bev) is a recombinant humanized monoclonal antibody to vascular ... more LBA9000 Background: Bevacizumab (Bev) is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumors. Multiple adjuvant trials are underway, but trials that have reported in colon and triple-negative breast cancer did not meet their primary end points. Since VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in patients (pts) with resected melanoma at high risk of recurrence. AVAST-M is a randomized phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy following resection of AJCC stage IIB, IIC, and III cutaneous melanoma compared to standard observation (Obs). 1,320 pts were required to detect 8% differences in 5-year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint is OS; secondary endpoints are disease free interval (DFI), distant-metastasis free interval (DMFI), safety, and quality...
Scientific reports, Dec 7, 2016
We examined the predictive value of neutrophil-lymphocyte ratio (NLR) by examining their associat... more We examined the predictive value of neutrophil-lymphocyte ratio (NLR) by examining their association with the baseline presence and subsequent development of brain metastases in patients with stage IV non-small cell lung cancer (NSCLC). We examined the predictive value of NLR for brain metastasis in 260 stage IV NSCLC. Logistic regression models and competing risk analysis were used to determine the association of NLR with baseline and subsequent presence of brain metastases. Multivariate analysis reveals that patients with high NLR (≥4.95) had significantly more brain metastases at diagnosis than those with low NLR (Odds Ratio = 2.59, P = 0.01). In patients who had no baseline brain metastasis, competing risks analysis revealed that patients with high NLR showed higher cumulative incidence of subsequent brain metastases, compared to those with low NLR (P = 0.017). A high NLR was associated with the baseline presence or the subsequent development of brain metastases, particularly in...