Critical Reviews in Oncology Hematology, Mar 1, 2005
This review examines the current evidence for the use of temozolomide in the treatment of solid t... more This review examines the current evidence for the use of temozolomide in the treatment of solid tumours. The possible molecular and clinical advantages of temozolomide are identified and the molecular mechanism of temozolomide resistance is explored. Attempts to maximise efficacy have led to manipulation of both dosage and drug scheduling and the evidence for the various strategies is reviewed. Finally, the potential role of combination therapy is considered.
Background Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFβ and VEGF... more Background Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFβ and VEGF receptors that is licensed for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Current evidence-based post-nephrectomy management of individuals with localized RCC consists of surveillance-based follow up. The SORCE trial is designed to investigate whether treatment with adjuvant sorafenib can reduce recurrence rates in this cohort. Case presentation Here we report an idiosyncratic reaction to sorafenib resulting in fatal hepatotoxicity and associated renal failure in a 62 year-old man treated with sorafenib within the SORCE trial. Conclusion This is the first reported case of sorafenib exposure associated fatal toxicity in the adjuvant setting and highlights the unpredictable adverse effects of novel adjuvant therapies.
Background: Uterine sarcomas are a group of rare tumors that include different subtypes. Patients... more Background: Uterine sarcomas are a group of rare tumors that include different subtypes. Patients with histopathological high-grade diseases are at high-risk of recurrence or progression, and have a poor prognosis. We aim to explore the most appropriate management in patients with uterine high-grade sarcomas. Primary objective: To assess the efficacy of maintenance treatment with cabozantinib in patients with high-grade uterine sarcomas who achieved clinical benefit after standard chemotherapy. Study hypothesis: Maintenance treatment with cabozantinib after standard chemotherapy given as an adjuvant treatment after curative surgery, or in locally advanced or metastatic disease, increases progression-free survival compared with placebo Trial design: This is a randomized double blinded phase II trial. Major inclusion/exclusion criteria: The study is enrolling adult patients with high-grade undifferentiated uterine sarcomas, high-grade endometrial stromal sarcomas, high-grade leiomyosa...
Aims Tenosynovial giant cell tumour (TGCT) is one of the most common soft-tissue tumours of the f... more Aims Tenosynovial giant cell tumour (TGCT) is one of the most common soft-tissue tumours of the foot and ankle and can behave in a locally aggressive manner. Tumour control can be difficult, despite the various methods of treatment available. Since treatment guidelines are lacking, the aim of this study was to review the multidisciplinary management by presenting the largest series of TGCT of the foot and ankle to date from two specialized sarcoma centres. Methods The Oxford Tumour Registry and the Leiden University Medical Centre Sarcoma Registry were retrospectively reviewed for patients with histologically proven foot and ankle TGCT diagnosed between January 2002 and August 2019. Results A total of 84 patients were included. There were 39 men and 45 women with a mean age at primary treatment of 38.3 years (9 to 72). The median follow-up was 46.5 months (interquartile range (IQR) 21.3 to 82.3). Localized-type TGCT (n = 15) predominantly affected forefoot, whereas diffuse-type TGCT...
BackgroundUterine sarcomas are a group of rare tumors that include different subtypes. Patients w... more BackgroundUterine sarcomas are a group of rare tumors that include different subtypes. Patients with histopathological high-grade diseases are at high-risk of recurrence or progression, and have a poor prognosis. We aim to explore the most appropriate management in patients with uterine high-grade sarcomas.Primary objectiveTo assess the efficacy of maintenance treatment with cabozantinib in patients with high-grade uterine sarcomas who achieved clinical benefit after standard chemotherapy.Study hypothesisMaintenance treatment with cabozantinib after standard chemotherapy given as an adjuvant treatment after curative surgery, or in locally advanced or metastatic disease, increases progression-free survival compared with placeboTrial designThis is a randomized double blinded phase II trial.Major inclusion/exclusion criteriaThe study is enrolling adult patients with high-grade undifferentiated uterine sarcomas, high-grade endometrial stromal sarcomas, high-grade leiomyosarcoma, and hig...
The use of F-FDG PET-CT (PET-CT) is widespread in many cancer types compared to sarcoma. We repor... more The use of F-FDG PET-CT (PET-CT) is widespread in many cancer types compared to sarcoma. We report a large retrospective audit of PET-CT in bone and soft tissue sarcoma with varied grade in a single multi-disciplinary centre. We also sought to answer three questions. Firstly, the correlation between sarcoma sub-type and grade with FDG SUVmax, secondly, the practical uses of PET-CT in the clinical setting of staging (during initial diagnosis), restaging (new baseline prior to definitive intervention) and treatment response. Finally, we also attempted to evaluate the potential additional benefit of PET-CT over concurrent conventional CT and MRI. A total of 957 consecutive PET-CT scans were performed in a single supra-regional centre in 493 sarcoma patients (excluding GIST) between 2007 and 2014. We compared, PET-CT SUVmax values in relation to histology and FNCCC grading. We compared PET-CT findings relative to concurrent conventional imaging (MRI and CT) in staging, restaging and tre...
The transcription factor FOXP3 plays a key role in CD4(+)CD25(+) regulatory T cell function and r... more The transcription factor FOXP3 plays a key role in CD4(+)CD25(+) regulatory T cell function and represents a specific marker for these cells. Despite its strong association with regulatory T cell function, in humans little is known about the frequency of CD4(+)CD25(+) cells that express FOXP3 protein nor the distribution of these cells in vivo. Here we report the characterization of seven anti-FOXP3 monoclonal antibodies enabling the detection of endogenous human FOXP3 protein by flow cytometry and immunohistochemistry. Flow-cytometric analysis showed that FOXP3 was expressed by the majority of CD4(+)CD25(high) T cells in peripheral blood. By contrast, less than half of the CD4(+)CD25(int) population were FOXP3(+), providing an explanation for observations in human T cells that regulatory activity is enriched within the CD4(+)CD25(high) pool. Although FOXP3 expression was primarily restricted to CD4(+)CD25(+) cells, it was induced following activation of both CD4(+) and CD8(+) T cell clones. These findings indicate that the frequency of FOXP3(+) cells correlates with the level of expression of CD25 in naturally arising regulatory T cells and that FOXP3 protein is expressed by some activated CD4(+) and CD8(+) T cell clones. These reagents represent valuable research tools to further investigate FOXP3 function and are applicable for routine clinical use.
INTRODUCTION There is recent evidence advocating the use of post-chemotherapy MRI for safe resect... more INTRODUCTION There is recent evidence advocating the use of post-chemotherapy MRI for safe resection of primary bone sarcoma in providing a clear margin of disease. This paper challenges this view by providing evidence obtained from comparing surgical resection margin measurements calculated off the pre- and post-chemotherapy MRIs to the post-operative histological analysis. METHOD A retrospective patho-radiological analysis of 10 patients treated for long bone Ewing's sarcoma. The pre- and post-chemotherapy MRI radiological measurements were correlated with the post-operative gross and microscopic histological specimens with the principle aim of determining which represented the accurate histological extent of disease and therefore which image set should be used in determining the surgical resection margins. RESULTS In the 10 cases there was a discrepancy in the extent of pathological disease on comparative histological and radiological assessment. The mean age at presentation was 19.5years [4-45 years], with a female bias (n = 7/10). The lower limbs were more commonly involved than the upper limb (femur n = 2/10, tibia n = 3/10, fibula n = 2/10, humerus n = 2/10, ulna n = 1/10). There was no correlation between the percentage reduction in measured volume/length of pathological bone on sequential MRI and the percentage necrosis on histology. The average discrepancy between the length of pathological bone on histology and on MRI was 2.7 cm. Using the baseline pre-chemotherapy MRI to plan the surgical resection margins, 7/10 patients had their surgical resection margins through radiologically clear but pathologically abnormal bone (without histological evidence of residual tumour). Had the post-chemotherapy MRI been used a further 3 patients would have had their tumour resected through pathologically abnormal bone. No patients had or would have had tumour resected through residual tumour. CONCLUSIONS The use of the post-chemotherapy MRI for planning surgical resection margins increases the risk of resecting through histologically abnormal bone that may have been previously contaminated by tumour, without significant benefit of preserving sufficient bone to facilitate joint or physeal sparing surgery. The evidence from this study supports current guidelines recommending the use of pre-chemotherapy MRI to plan safe surgical resection margins in Ewing's sarcoma.
International journal of cancer. Journal international du cancer, Jan 15, 2015
Vaccination strategies based on repeated injections of NY-ESO-1 protein formulated in ISCOMATRIX ... more Vaccination strategies based on repeated injections of NY-ESO-1 protein formulated in ISCOMATRIX particles (NY-ESO-1 ISCOMATRIX) have shown to elicit combined NY-ESO-1 specific antibody and T cell responses. However, it remains unclear whether heterologous prime-boost strategies based on the combination with NY-ESO-1 ISCOMATRIX with different NY-ESO-1 boosting reagents could be used to increase NY-ESO-1 CD8(+) or CD4(+) T cell responses. To address this question, we carried out a randomized clinical trial in 39 high-risk, resected melanoma patients vaccinated with NY-ESO-1 ISCOMATRIX, and then boosted with repeated injections of either recombinant fowlpox virus encoding full length NY-ESO-1 (rF-NY-ESO-1) (Arm A) or NY-ESO-1 ISCOMATRIX alone (Arm B). We have comprehensively analyzed NY-ESO-1 specific T cells and B cells response in all patients before and after vaccination for a total of seven time points per patient. NY-ESO-1 ISCOMATRIX alone elicited a strong NY-ESO-1 specific CD4(...
Critical Reviews in Oncology Hematology, Mar 1, 2005
This review examines the current evidence for the use of temozolomide in the treatment of solid t... more This review examines the current evidence for the use of temozolomide in the treatment of solid tumours. The possible molecular and clinical advantages of temozolomide are identified and the molecular mechanism of temozolomide resistance is explored. Attempts to maximise efficacy have led to manipulation of both dosage and drug scheduling and the evidence for the various strategies is reviewed. Finally, the potential role of combination therapy is considered.
Background Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFβ and VEGF... more Background Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFβ and VEGF receptors that is licensed for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Current evidence-based post-nephrectomy management of individuals with localized RCC consists of surveillance-based follow up. The SORCE trial is designed to investigate whether treatment with adjuvant sorafenib can reduce recurrence rates in this cohort. Case presentation Here we report an idiosyncratic reaction to sorafenib resulting in fatal hepatotoxicity and associated renal failure in a 62 year-old man treated with sorafenib within the SORCE trial. Conclusion This is the first reported case of sorafenib exposure associated fatal toxicity in the adjuvant setting and highlights the unpredictable adverse effects of novel adjuvant therapies.
Background: Uterine sarcomas are a group of rare tumors that include different subtypes. Patients... more Background: Uterine sarcomas are a group of rare tumors that include different subtypes. Patients with histopathological high-grade diseases are at high-risk of recurrence or progression, and have a poor prognosis. We aim to explore the most appropriate management in patients with uterine high-grade sarcomas. Primary objective: To assess the efficacy of maintenance treatment with cabozantinib in patients with high-grade uterine sarcomas who achieved clinical benefit after standard chemotherapy. Study hypothesis: Maintenance treatment with cabozantinib after standard chemotherapy given as an adjuvant treatment after curative surgery, or in locally advanced or metastatic disease, increases progression-free survival compared with placebo Trial design: This is a randomized double blinded phase II trial. Major inclusion/exclusion criteria: The study is enrolling adult patients with high-grade undifferentiated uterine sarcomas, high-grade endometrial stromal sarcomas, high-grade leiomyosa...
Aims Tenosynovial giant cell tumour (TGCT) is one of the most common soft-tissue tumours of the f... more Aims Tenosynovial giant cell tumour (TGCT) is one of the most common soft-tissue tumours of the foot and ankle and can behave in a locally aggressive manner. Tumour control can be difficult, despite the various methods of treatment available. Since treatment guidelines are lacking, the aim of this study was to review the multidisciplinary management by presenting the largest series of TGCT of the foot and ankle to date from two specialized sarcoma centres. Methods The Oxford Tumour Registry and the Leiden University Medical Centre Sarcoma Registry were retrospectively reviewed for patients with histologically proven foot and ankle TGCT diagnosed between January 2002 and August 2019. Results A total of 84 patients were included. There were 39 men and 45 women with a mean age at primary treatment of 38.3 years (9 to 72). The median follow-up was 46.5 months (interquartile range (IQR) 21.3 to 82.3). Localized-type TGCT (n = 15) predominantly affected forefoot, whereas diffuse-type TGCT...
BackgroundUterine sarcomas are a group of rare tumors that include different subtypes. Patients w... more BackgroundUterine sarcomas are a group of rare tumors that include different subtypes. Patients with histopathological high-grade diseases are at high-risk of recurrence or progression, and have a poor prognosis. We aim to explore the most appropriate management in patients with uterine high-grade sarcomas.Primary objectiveTo assess the efficacy of maintenance treatment with cabozantinib in patients with high-grade uterine sarcomas who achieved clinical benefit after standard chemotherapy.Study hypothesisMaintenance treatment with cabozantinib after standard chemotherapy given as an adjuvant treatment after curative surgery, or in locally advanced or metastatic disease, increases progression-free survival compared with placeboTrial designThis is a randomized double blinded phase II trial.Major inclusion/exclusion criteriaThe study is enrolling adult patients with high-grade undifferentiated uterine sarcomas, high-grade endometrial stromal sarcomas, high-grade leiomyosarcoma, and hig...
The use of F-FDG PET-CT (PET-CT) is widespread in many cancer types compared to sarcoma. We repor... more The use of F-FDG PET-CT (PET-CT) is widespread in many cancer types compared to sarcoma. We report a large retrospective audit of PET-CT in bone and soft tissue sarcoma with varied grade in a single multi-disciplinary centre. We also sought to answer three questions. Firstly, the correlation between sarcoma sub-type and grade with FDG SUVmax, secondly, the practical uses of PET-CT in the clinical setting of staging (during initial diagnosis), restaging (new baseline prior to definitive intervention) and treatment response. Finally, we also attempted to evaluate the potential additional benefit of PET-CT over concurrent conventional CT and MRI. A total of 957 consecutive PET-CT scans were performed in a single supra-regional centre in 493 sarcoma patients (excluding GIST) between 2007 and 2014. We compared, PET-CT SUVmax values in relation to histology and FNCCC grading. We compared PET-CT findings relative to concurrent conventional imaging (MRI and CT) in staging, restaging and tre...
The transcription factor FOXP3 plays a key role in CD4(+)CD25(+) regulatory T cell function and r... more The transcription factor FOXP3 plays a key role in CD4(+)CD25(+) regulatory T cell function and represents a specific marker for these cells. Despite its strong association with regulatory T cell function, in humans little is known about the frequency of CD4(+)CD25(+) cells that express FOXP3 protein nor the distribution of these cells in vivo. Here we report the characterization of seven anti-FOXP3 monoclonal antibodies enabling the detection of endogenous human FOXP3 protein by flow cytometry and immunohistochemistry. Flow-cytometric analysis showed that FOXP3 was expressed by the majority of CD4(+)CD25(high) T cells in peripheral blood. By contrast, less than half of the CD4(+)CD25(int) population were FOXP3(+), providing an explanation for observations in human T cells that regulatory activity is enriched within the CD4(+)CD25(high) pool. Although FOXP3 expression was primarily restricted to CD4(+)CD25(+) cells, it was induced following activation of both CD4(+) and CD8(+) T cell clones. These findings indicate that the frequency of FOXP3(+) cells correlates with the level of expression of CD25 in naturally arising regulatory T cells and that FOXP3 protein is expressed by some activated CD4(+) and CD8(+) T cell clones. These reagents represent valuable research tools to further investigate FOXP3 function and are applicable for routine clinical use.
INTRODUCTION There is recent evidence advocating the use of post-chemotherapy MRI for safe resect... more INTRODUCTION There is recent evidence advocating the use of post-chemotherapy MRI for safe resection of primary bone sarcoma in providing a clear margin of disease. This paper challenges this view by providing evidence obtained from comparing surgical resection margin measurements calculated off the pre- and post-chemotherapy MRIs to the post-operative histological analysis. METHOD A retrospective patho-radiological analysis of 10 patients treated for long bone Ewing's sarcoma. The pre- and post-chemotherapy MRI radiological measurements were correlated with the post-operative gross and microscopic histological specimens with the principle aim of determining which represented the accurate histological extent of disease and therefore which image set should be used in determining the surgical resection margins. RESULTS In the 10 cases there was a discrepancy in the extent of pathological disease on comparative histological and radiological assessment. The mean age at presentation was 19.5years [4-45 years], with a female bias (n = 7/10). The lower limbs were more commonly involved than the upper limb (femur n = 2/10, tibia n = 3/10, fibula n = 2/10, humerus n = 2/10, ulna n = 1/10). There was no correlation between the percentage reduction in measured volume/length of pathological bone on sequential MRI and the percentage necrosis on histology. The average discrepancy between the length of pathological bone on histology and on MRI was 2.7 cm. Using the baseline pre-chemotherapy MRI to plan the surgical resection margins, 7/10 patients had their surgical resection margins through radiologically clear but pathologically abnormal bone (without histological evidence of residual tumour). Had the post-chemotherapy MRI been used a further 3 patients would have had their tumour resected through pathologically abnormal bone. No patients had or would have had tumour resected through residual tumour. CONCLUSIONS The use of the post-chemotherapy MRI for planning surgical resection margins increases the risk of resecting through histologically abnormal bone that may have been previously contaminated by tumour, without significant benefit of preserving sufficient bone to facilitate joint or physeal sparing surgery. The evidence from this study supports current guidelines recommending the use of pre-chemotherapy MRI to plan safe surgical resection margins in Ewing's sarcoma.
International journal of cancer. Journal international du cancer, Jan 15, 2015
Vaccination strategies based on repeated injections of NY-ESO-1 protein formulated in ISCOMATRIX ... more Vaccination strategies based on repeated injections of NY-ESO-1 protein formulated in ISCOMATRIX particles (NY-ESO-1 ISCOMATRIX) have shown to elicit combined NY-ESO-1 specific antibody and T cell responses. However, it remains unclear whether heterologous prime-boost strategies based on the combination with NY-ESO-1 ISCOMATRIX with different NY-ESO-1 boosting reagents could be used to increase NY-ESO-1 CD8(+) or CD4(+) T cell responses. To address this question, we carried out a randomized clinical trial in 39 high-risk, resected melanoma patients vaccinated with NY-ESO-1 ISCOMATRIX, and then boosted with repeated injections of either recombinant fowlpox virus encoding full length NY-ESO-1 (rF-NY-ESO-1) (Arm A) or NY-ESO-1 ISCOMATRIX alone (Arm B). We have comprehensively analyzed NY-ESO-1 specific T cells and B cells response in all patients before and after vaccination for a total of seven time points per patient. NY-ESO-1 ISCOMATRIX alone elicited a strong NY-ESO-1 specific CD4(...
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Papers by Sarah Pratap