Citation: Health Technology Assessment. 2020, 24(2), 1-180
Author: Nigel Fleeman, Rachel Houten, Adrian Bagust, Marty Richardson, Sophie Beale, Angela Boland, Yenal Dundar, Janette Greenhalgh, Juliet Hounsome, Rui Duarte, Aditya Shenoy
Abstract: Background: Thyroid cancer is a rare cancer, accounting for only 1% of all malignancies in England and Wales. Differentiated thyroid cancer (DTC) accounts for ≈94% of all thyroid cancers. Patients with DTC often require treatment with radioactive iodine. Treatment for DTC that is refractory to radioactive iodine [radioactive iodine-refractory DTC (RR-DTC)] is often limited to best supportive care (BSC).
Objectives: We aimed to assess the clinical effectiveness and cost-effectiveness of lenvatinib (Lenvima®; Eisai Ltd, Hertfordshire, UK) and sorafenib (Nexar®; Bayer HealthCare, Leverkusen, Germany) for the treatment of patients with RR-DTC.
Data sources: EMBASE, MEDLINE, PubMed, The Cochrane Library and EconLit were searched (date range 1999 to 10 January 2017; searched on 10 January 2017). The bibliographies of retrieved citations were also examined.
Review methods: We searched for randomised controlled trials (RCTs), systematic reviews, prospective observational studies and economic evaluations of lenvatinib or sorafenib. In the absence of relevant economic evaluations, we constructed a de novo economic model to compare the cost-effectiveness of lenvatinib and sorafenib with that of BSC.
Results: Two RCTs were identified: SELECT (Study of [E7080] LEnvatinib in 131I-refractory differentiated Cancer of the Thyroid) and DECISION (StuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine-refractory thyrOid caNcer). Lenvatinib and sorafenib were both reported to improve median progression-free survival (PFS) compared with placebo: 18.3 months (lenvatinib) vs. 3.6 months (placebo) and 10.8 months (sorafenib) vs. 5.8 months (placebo). Patient crossover was high (≥ 75%) in both trials, confounding estimates of overall survival (OS). Using OS data adjusted for crossover, trial authors reported a statistically significant improvement in OS for patients treated with lenvatinib compared with those given placebo (SELECT) but not for patients treated with sorafenib compared with those given placebo (DECISION). Both lenvatinib and sorafenib increased the incidence of adverse events (AEs), and dose reductions were required (for > 60% of patients). The results from nine prospective observational studies and 13 systematic reviews of lenvatinib or sorafenib were broadly comparable to those from the RCTs. Health-related quality-of-life (HRQoL) data were collected only in DECISION. We considered the feasibility of comparing lenvatinib with sorafenib via an indirect comparison but concluded that this would not be appropriate because of differences in trial and participant characteristics, risk profiles of the participants in the placebo arms and because the proportional hazard assumption was violated for five of the six survival outcomes available from the trials. In the base-case economic analysis, using list prices only, the cost-effectiveness comparison of lenvatinib versus BSC yields an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £65,872, and the comparison of sorafenib versus BSC yields an ICER of £85,644 per QALY gained. The deterministic sensitivity analyses show that none of the variations lowered the base-case ICERs to < £50,000 per QALY gained.
Limitations: We consider that it is not possible to compare the clinical effectiveness or cost-effectiveness of lenvatinib and sorafenib.
Conclusions: Compared with placebo/BSC, treatment with lenvatinib or sorafenib results in an improvement in PFS, objective tumour response rate and possibly OS, but dose modifications were required to treat AEs. Both treatments exhibit estimated ICERs of > £50,000 per QALY gained. Further research should include examination of the effects of lenvatinib, sorafenib and BSC (including HRQoL) for both symptomatic and asymptomatic patients, and the positioning of treatments in the treatment pathway.
Study registration: This study is registered as PROSPERO CRD42017055516.
Funding: The National Institute for Health Research Health Technology Assessment programme.
Keywords: IODINE RADIOISOTOPES; LENVATINIB; MODELS, ECONOMIC; SORAFENIB; SYSTEMATIC REVIEW; THERAPEUTIC USE; THYROID NEOPLASMS.
Link to PubMed record
Wednesday, 29 January 2020
CCC publication: The Role of Multidisciplinary Decision Making in Oropharyngeal Cancer: Do We Follow Guidelines and Are Treatment Decisions Being Implemented?
Citation: European archives of Otorhinolaryngology. 2020, 277(3), 947-952
Author: Randa Ghazal Asswad, Sirhan Alvi, Katharine Davies, Terry M Jones, David W Hamilton, Caroline Brammer, Jeffrey Lancaster, Christopher Loh, Sankalap Tandon, Nick Roland
Abstract: Purpose: A multidisciplinary team (MDT) approach to cancer management is gold-standard. With an increasing disease incidence and growing research into human papillomavirus (HPV)-related oropharyngeal cancer (OPC), updated UK management guidelines were recently published. This study aimed to evaluate the MDT decision-making process among OPC patients at a tertiary centre.
Methods: MDT meetings over a 12-month period were analysed retrospectively. MDT decisions were compared with guidelines and patient records examined to identify decision implementation. Reasons behind any discordant decisions were explored.
Results: This study included 140 OPC patients. Thirty-three (23.6%) were not tested for HPV. Patients over 70 years with a smoking history treated palliatively were less likely to be tested (P = 0.017). Eighty-five percent of MDT decisions followed guidelines with the majority not complying (76.2%) related to patient comorbidity. Ten decisions (7.1%) were not implemented. Reasons included: Seven due to patient choice, of which four patients (57.1%) were only seen following the MDT meeting, and three due to clinician decisions as new clinical information emerged.
Conclusion: The majority of MDT decisions followed guidelines and any discordant decisions were justifiable. Discussing management options with patients beforehand facilitates decision implementation as decisions can potentially change after seeing the patient. Progress is still needed with regards to HPV testing. Reasons for not testing could include subliminal decision-making among clinicians, and patients falling between centres. Crucially, the role of the MDT in head and neck cancer should be to ratify decisions rather than making them, hence the need to see patients prior to MDT discussion.
Keywords: Decision implementation; Decision making; Human papillomavirus; Multi-disciplinary team; Oropharyngeal neoplasms; Patient preference.
Link to PubMed record
Author: Randa Ghazal Asswad, Sirhan Alvi, Katharine Davies, Terry M Jones, David W Hamilton, Caroline Brammer, Jeffrey Lancaster, Christopher Loh, Sankalap Tandon, Nick Roland
Abstract: Purpose: A multidisciplinary team (MDT) approach to cancer management is gold-standard. With an increasing disease incidence and growing research into human papillomavirus (HPV)-related oropharyngeal cancer (OPC), updated UK management guidelines were recently published. This study aimed to evaluate the MDT decision-making process among OPC patients at a tertiary centre.
Methods: MDT meetings over a 12-month period were analysed retrospectively. MDT decisions were compared with guidelines and patient records examined to identify decision implementation. Reasons behind any discordant decisions were explored.
Results: This study included 140 OPC patients. Thirty-three (23.6%) were not tested for HPV. Patients over 70 years with a smoking history treated palliatively were less likely to be tested (P = 0.017). Eighty-five percent of MDT decisions followed guidelines with the majority not complying (76.2%) related to patient comorbidity. Ten decisions (7.1%) were not implemented. Reasons included: Seven due to patient choice, of which four patients (57.1%) were only seen following the MDT meeting, and three due to clinician decisions as new clinical information emerged.
Conclusion: The majority of MDT decisions followed guidelines and any discordant decisions were justifiable. Discussing management options with patients beforehand facilitates decision implementation as decisions can potentially change after seeing the patient. Progress is still needed with regards to HPV testing. Reasons for not testing could include subliminal decision-making among clinicians, and patients falling between centres. Crucially, the role of the MDT in head and neck cancer should be to ratify decisions rather than making them, hence the need to see patients prior to MDT discussion.
Keywords: Decision implementation; Decision making; Human papillomavirus; Multi-disciplinary team; Oropharyngeal neoplasms; Patient preference.
Link to PubMed record
CCC publication: CD40L Membrane Retention Enhances the Immunostimulatory Effects of CD40 Ligation
Citation: Scientific Reports. 2020, 10(1), 342
Author: Taha Elmetwali, Asmaa Salman, Wenbin Wei, Syed A Hussain, Lawrence S Young, Daniel H Palmer
Abstract: In carcinomas, the nature of CD40 ligand shapes the outcome of CD40 ligation. To date, the consequences of membrane-bound CD40L (mCD40L) on its immune-stimulatory function are unknown. Here, we examined the impact of mCD40L versus soluble CD40L (sCD40L) on T24 bladder carcinoma gene expression profiling. Of 410 differentially expressed genes, 286 were upregulated and 124 downregulated by mCD40L versus sCD40L. Gene ontology enrichment analysis revealed immune-stimulatory function as the most significant enriched biological process affected by upregulated transcripts, while those downregulated were critical for cell growth and division. Furthermore, immature dendritic cells (iDC) responded to mCD40L with enhanced maturation and activation over sCD40L evidenced by higher expression levels of CD83, CD86, HLA-DR and CD54, increased secretion of IL12 and IL10 and higher tumour-antigen (TA) uptake capacity. Furthermore, autologus CD3+ T cells responded to TA-loaded mCD40L-activated DC with increased proliferation and cytotoxic response (CD107a and IFN-γ-producing CD3+ CD8+ T cells) to the tumour-loaded autologous PBMCs compared to sCD40L. Thus, these data indicate that mCD40L enhances the immunostimulatory capacity over sCD40L. Furthermore, the ability of mCD40L to also directly induce cell death in CD40-expressing carcinomas, subsequently releasing tumour-specific antigens into the tumour microenvironment highlights the potential for mCD40L as a multi-faceted anti-cancer immunotherapeutic.
Link to PubMed record
Author: Taha Elmetwali, Asmaa Salman, Wenbin Wei, Syed A Hussain, Lawrence S Young, Daniel H Palmer
Abstract: In carcinomas, the nature of CD40 ligand shapes the outcome of CD40 ligation. To date, the consequences of membrane-bound CD40L (mCD40L) on its immune-stimulatory function are unknown. Here, we examined the impact of mCD40L versus soluble CD40L (sCD40L) on T24 bladder carcinoma gene expression profiling. Of 410 differentially expressed genes, 286 were upregulated and 124 downregulated by mCD40L versus sCD40L. Gene ontology enrichment analysis revealed immune-stimulatory function as the most significant enriched biological process affected by upregulated transcripts, while those downregulated were critical for cell growth and division. Furthermore, immature dendritic cells (iDC) responded to mCD40L with enhanced maturation and activation over sCD40L evidenced by higher expression levels of CD83, CD86, HLA-DR and CD54, increased secretion of IL12 and IL10 and higher tumour-antigen (TA) uptake capacity. Furthermore, autologus CD3+ T cells responded to TA-loaded mCD40L-activated DC with increased proliferation and cytotoxic response (CD107a and IFN-γ-producing CD3+ CD8+ T cells) to the tumour-loaded autologous PBMCs compared to sCD40L. Thus, these data indicate that mCD40L enhances the immunostimulatory capacity over sCD40L. Furthermore, the ability of mCD40L to also directly induce cell death in CD40-expressing carcinomas, subsequently releasing tumour-specific antigens into the tumour microenvironment highlights the potential for mCD40L as a multi-faceted anti-cancer immunotherapeutic.
Link to PubMed record
CCC publication: Molecular MRD status and outcome after transplantation in NPM1 mutated AML: results from the UK NCRI AML17 study
Citation: Blood. 2020 Jan 13[Online ahead of print]
Author: Richard Dillon, Robert K Hills, Sylvie D Freeman, Nicola Potter, Jelena Jovanovic, Adam Ivey, Anju Shankar Kanda, Manohursingh Runglall, Nicola Foot, Mikel Valganon, Asim Khwaja, Jamie Cavenagh, Matthew L Smith, Hans Beier Ommen, Ulrik Overgaard, Mike Dennis, Steven Knapper, Harpreet Kaur, David C Taussig, Priyanka Mehta, Kavita Raj, Igor Novitzky-Basso, Emmanouil Nikolousis, Robert D Danby, Pramila Krishnamurthy, Kate Hill, Damian Finnegan, Samah Alimam, Erin Hurst, Peter Johnson, Anjum Bashir Khan, Rahuman Salim, Charles F Craddock, Ruth Lilian Spearing, Amanda Frances Gilkes, Rosemary E Gale, Alan Kenneth Burnett, Nigel H Russell, David Grimwade
Abstract: Relapse remains the most common cause of treatment failure for patients with acute myeloid leukaemia (AML) who undergo allogeneic stem cell transplantation (alloSCT) and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry (FCM) prior to alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays which have far greater sensitivity. We analysed pre-transplant blood and bone marrow samples by reverse-transcription polymerase chain reaction (RT-qPCR) in 107 patients with NPM1 mutant AML enrolled in the UK National Cancer Research Institute (NCRI) AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies / 105 ABL in the PB and <1000 copies in the BM) and high levels of MRD had an estimated 2y overall survival (OS) of 83%, 63% and 13% respectively (p<0.0001). Focussing on patients with low level MRD prior to alloSCT, those with FLT3 ITD had significantly poorer outcome (hazard ratio, HR, 6.14, p=0.01). Combining these variables was highly prognostic, dividing patients into two groups with 2y OS of 17% and 82% (HR 13.2, p<0.0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y OS 56% vs 96%, HR 3.24, p=0.0005) and in MRD positive patients (2y OS 34% vs 100%, HR 3.78, p=0.003) but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).
Link to PubMed record
Author: Richard Dillon, Robert K Hills, Sylvie D Freeman, Nicola Potter, Jelena Jovanovic, Adam Ivey, Anju Shankar Kanda, Manohursingh Runglall, Nicola Foot, Mikel Valganon, Asim Khwaja, Jamie Cavenagh, Matthew L Smith, Hans Beier Ommen, Ulrik Overgaard, Mike Dennis, Steven Knapper, Harpreet Kaur, David C Taussig, Priyanka Mehta, Kavita Raj, Igor Novitzky-Basso, Emmanouil Nikolousis, Robert D Danby, Pramila Krishnamurthy, Kate Hill, Damian Finnegan, Samah Alimam, Erin Hurst, Peter Johnson, Anjum Bashir Khan, Rahuman Salim, Charles F Craddock, Ruth Lilian Spearing, Amanda Frances Gilkes, Rosemary E Gale, Alan Kenneth Burnett, Nigel H Russell, David Grimwade
Abstract: Relapse remains the most common cause of treatment failure for patients with acute myeloid leukaemia (AML) who undergo allogeneic stem cell transplantation (alloSCT) and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry (FCM) prior to alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays which have far greater sensitivity. We analysed pre-transplant blood and bone marrow samples by reverse-transcription polymerase chain reaction (RT-qPCR) in 107 patients with NPM1 mutant AML enrolled in the UK National Cancer Research Institute (NCRI) AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies / 105 ABL in the PB and <1000 copies in the BM) and high levels of MRD had an estimated 2y overall survival (OS) of 83%, 63% and 13% respectively (p<0.0001). Focussing on patients with low level MRD prior to alloSCT, those with FLT3 ITD had significantly poorer outcome (hazard ratio, HR, 6.14, p=0.01). Combining these variables was highly prognostic, dividing patients into two groups with 2y OS of 17% and 82% (HR 13.2, p<0.0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y OS 56% vs 96%, HR 3.24, p=0.0005) and in MRD positive patients (2y OS 34% vs 100%, HR 3.78, p=0.003) but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).
Link to PubMed record
CCC publication: Digitising a consultant radiographer led palliative radiotherapy service,
Citation: Radiography. 2020, 26(Sup1), S22
Author: Conor Fitzpatrick,
Author: Conor Fitzpatrick,
CCC publication: Improving patient pathways in head and neck cancer at a UK Cancer Centre. Results of a dietetic pre-treatment project (DPP)
Citation: Clinical Nutrition ESPEN. 2020, 35, 250
Author: Parr K.; Johnson F.; Langley N.; Richardson P.
Author: Parr K.; Johnson F.; Langley N.; Richardson P.
CCC publication: Evaluation of erectile potency and radiation dose to the penile bulb using image guided radiotherapy in the CHHiP trial,
Citation: Clinical and Translational Radiation Oncology. 2019 Dec 31, 21, 77-84. eCollection Mar 2020
Author: J. Murray, S. Gulliford, C. Griffin, A. Wilkins, I. Syndikus, J. Staffurth, M. Panades, C. Scrase, C. Parker, V. Khoo, J. Dean, H. Mayles, P. Mayles, S. Thomas, O. Naismith, H. Mossop, C. Cruickshank, E. Hall, D. Dearnaley
Abstract: Background and purpose: The penile bulb (PB) dose may be critical in development of post prostate radiotherapy erectile dysfunction (ED). This study aimed to generate PB dose constraints based on dose-volume histograms (DVHs) in patients treated with prostate radiotherapy, and to identify clinical and dosimetric parameters that predict the risk of ED post prostate radiotherapy.
Materials and methods: Penile bulb DVHs were generated for 276 patients treated within the randomised IGRT substudy of the multicentre randomised trial, CHHiP. Incidence of ED in relation to dose and randomised IGRT groups were evaluated using Wilcoxon rank sum, Chi-squared test and atlases of complication incidence. Youden index was used to find dose-volume constraints that discriminated for ED. Multivariate analysis (MVA) of effect of dosimetry, clinical and patient-related variables was performed.
Results: Reduced treatment margins using IGRT (IGRT-R) produced significantly reduced mean PB dose compared with standard margins (IGRT-S) (median: 25 Gy (IGRT-S) versus 11 Gy (IGRT-R); p < 0.0001). Significant difference in both mean (median: 23 Gy (ED) vs. 18 Gy (no ED); p = 0.011) and maximum (median: 59 Gy (ED) vs. 52 Gy (no ED); p = 0.018) PB doses between those with and without clinician reported ED were identified. Mean PB dose cut-point for ED was derived at around 20 Gy. On MVA, PB mean dose and age predicted for impotence.
Conclusion: PB dose appears predictive of post-radiotherapy ED with calculated threshold mean dose of around 20 Gy, substantially lower than published recommendations. IGRT-R enables favourable PB dosimetry and can be recommended provided prostate coverage is not compromised.
Keywords: Erectile dysfunction; Image-guided radiotherapy; Penile bulb; Prostate.
Link to PubMed record
Author: J. Murray, S. Gulliford, C. Griffin, A. Wilkins, I. Syndikus, J. Staffurth, M. Panades, C. Scrase, C. Parker, V. Khoo, J. Dean, H. Mayles, P. Mayles, S. Thomas, O. Naismith, H. Mossop, C. Cruickshank, E. Hall, D. Dearnaley
Abstract: Background and purpose: The penile bulb (PB) dose may be critical in development of post prostate radiotherapy erectile dysfunction (ED). This study aimed to generate PB dose constraints based on dose-volume histograms (DVHs) in patients treated with prostate radiotherapy, and to identify clinical and dosimetric parameters that predict the risk of ED post prostate radiotherapy.
Materials and methods: Penile bulb DVHs were generated for 276 patients treated within the randomised IGRT substudy of the multicentre randomised trial, CHHiP. Incidence of ED in relation to dose and randomised IGRT groups were evaluated using Wilcoxon rank sum, Chi-squared test and atlases of complication incidence. Youden index was used to find dose-volume constraints that discriminated for ED. Multivariate analysis (MVA) of effect of dosimetry, clinical and patient-related variables was performed.
Results: Reduced treatment margins using IGRT (IGRT-R) produced significantly reduced mean PB dose compared with standard margins (IGRT-S) (median: 25 Gy (IGRT-S) versus 11 Gy (IGRT-R); p < 0.0001). Significant difference in both mean (median: 23 Gy (ED) vs. 18 Gy (no ED); p = 0.011) and maximum (median: 59 Gy (ED) vs. 52 Gy (no ED); p = 0.018) PB doses between those with and without clinician reported ED were identified. Mean PB dose cut-point for ED was derived at around 20 Gy. On MVA, PB mean dose and age predicted for impotence.
Conclusion: PB dose appears predictive of post-radiotherapy ED with calculated threshold mean dose of around 20 Gy, substantially lower than published recommendations. IGRT-R enables favourable PB dosimetry and can be recommended provided prostate coverage is not compromised.
Keywords: Erectile dysfunction; Image-guided radiotherapy; Penile bulb; Prostate.
Link to PubMed record
CCC publication: CApecitabine plus Radium-223 (Xofigo™) in breast cancer patients with BONe metastases (CARBON): study protocol for a phase IB/IIA randomised controlled trial.
Citation: Trials. 2020, 21(1), 89
Author: Rob Coleman, Janet Brown, Emma Rathbone, Louise Flanagan, Amber Reid, Jessica Kendall, Sacha Howell, Chris Twelves, Carlo Palmieri, Anjana Anand, Iain MacPherson, Sarah Brown
Abstract: Background: A substantial proportion of breast cancer patients develop metastatic disease, with over 450,000 deaths globally per year. Bone is the most common first site of metastatic disease accounting for 40% of all first recurrence and 70% of patients with advanced disease develop skeletal involvement. Treatment of bone metastases currently focusses on symptom relief and prevention and treatment of skeletal complications. However, there remains a need for further treatment options for patients with bone metastases. Combining systemic therapy with a bone-targeted agent, such as radium-223, may provide an effective treatment with minimal additional side effects.
Methods/design: CARBON is a UK-based, open-label, multi-centre study which comprises an initial safety phase to establish the feasibility and safety of combining radium-223 given on a 6-weekly schedule in combination with orally administered capecitabine followed by a randomised extension phase to further characterise the safety profile and provide preliminary estimation of efficacy.
Discussion: The CARBON study is important as the results will be the first to assess radium-223 with chemotherapy in advanced breast cancer. If the results find acceptable rates of toxicity with a decrease in bone turnover markers, further work will be necessary in a phase II/III setting to assess the efficacy and clinical benefit.
Trial registration: ISRCTN, ISRCTN92755158, Registered on 17 February 2016.
Keywords: Bone metastases; Bone turnover markers; Breast cancer; Capecitabine; Radium-223
Link to PubMed record
Author: Rob Coleman, Janet Brown, Emma Rathbone, Louise Flanagan, Amber Reid, Jessica Kendall, Sacha Howell, Chris Twelves, Carlo Palmieri, Anjana Anand, Iain MacPherson, Sarah Brown
Abstract: Background: A substantial proportion of breast cancer patients develop metastatic disease, with over 450,000 deaths globally per year. Bone is the most common first site of metastatic disease accounting for 40% of all first recurrence and 70% of patients with advanced disease develop skeletal involvement. Treatment of bone metastases currently focusses on symptom relief and prevention and treatment of skeletal complications. However, there remains a need for further treatment options for patients with bone metastases. Combining systemic therapy with a bone-targeted agent, such as radium-223, may provide an effective treatment with minimal additional side effects.
Methods/design: CARBON is a UK-based, open-label, multi-centre study which comprises an initial safety phase to establish the feasibility and safety of combining radium-223 given on a 6-weekly schedule in combination with orally administered capecitabine followed by a randomised extension phase to further characterise the safety profile and provide preliminary estimation of efficacy.
Discussion: The CARBON study is important as the results will be the first to assess radium-223 with chemotherapy in advanced breast cancer. If the results find acceptable rates of toxicity with a decrease in bone turnover markers, further work will be necessary in a phase II/III setting to assess the efficacy and clinical benefit.
Trial registration: ISRCTN, ISRCTN92755158, Registered on 17 February 2016.
Keywords: Bone metastases; Bone turnover markers; Breast cancer; Capecitabine; Radium-223
Link to PubMed record
CCC publication: Development of an orthotopic syngeneic murine model of colorectal cancer for use in translational research
Citation: Laboratory Animals. 2019, 53(6), 598-609
Author: Evans J.P. (jpevans@liverpool.ac.uk); Sutton P.A.; Palmer D.H.; Winiarski B.K.; Goldring C.E.; Kitteringham N.R.; Ressel L.; Duckworth C.A.; Pritchard D.M.
Abstract: Improving outcomes in colorectal cancer requires more accurate in vivo modelling of the disease in humans, allowing more reliable pre-clinical assessment of potential therapies. Novel imaging techniques are necessary to improve the longitudinal assessment of disease burden in these models, reducing the number of animals required for translational studies. This report describes the development of an immune-competent syngeneic orthotopic murine model of colorectal cancer, utilising caecal implantation of CT26 cells stably transfected with the luciferase gene into immune-competent BALB/c mice, allowing serial bioluminescent imaging of cancer progression. Luminescence in the stably transfected CT26 cell line, after pre-conditioning in the flank of a BALB/c mouse, accurately reflected cell viability and resulted in primary caecal tumours in five of eight (63%) mice in the initial pilot study following caecal injection. Luminescent signal continued to increase throughout the study period with one mouse (20%) developing a liver metastasis. Histopathological assessment confirmed tumours to be consistent with a poorly differentiated adenocarcinoma. We have now performed this technique in 68 immune-competent BALB/c mice. There have been no complications from the procedure or peri-operative deaths, with primary tumours developing in 44 (65%) mice and liver metastases in nine (20%) of these. This technique provides an accurate model of colorectal cancer with tumours developing in the correct microenvironment and metastasising to the liver with a similar frequency to that seen in patients presenting with colorectal cancer, with serial bioluminescent reducing the murine numbers required in studies by removing the need for cull for assessment of disease burden.
KEYWORDS: Colorectal cancer; bioluminescent imaging; orthotopic syngeneic model
Link to PubMed record
Author: Evans J.P. (jpevans@liverpool.ac.uk); Sutton P.A.; Palmer D.H.; Winiarski B.K.; Goldring C.E.; Kitteringham N.R.; Ressel L.; Duckworth C.A.; Pritchard D.M.
Abstract: Improving outcomes in colorectal cancer requires more accurate in vivo modelling of the disease in humans, allowing more reliable pre-clinical assessment of potential therapies. Novel imaging techniques are necessary to improve the longitudinal assessment of disease burden in these models, reducing the number of animals required for translational studies. This report describes the development of an immune-competent syngeneic orthotopic murine model of colorectal cancer, utilising caecal implantation of CT26 cells stably transfected with the luciferase gene into immune-competent BALB/c mice, allowing serial bioluminescent imaging of cancer progression. Luminescence in the stably transfected CT26 cell line, after pre-conditioning in the flank of a BALB/c mouse, accurately reflected cell viability and resulted in primary caecal tumours in five of eight (63%) mice in the initial pilot study following caecal injection. Luminescent signal continued to increase throughout the study period with one mouse (20%) developing a liver metastasis. Histopathological assessment confirmed tumours to be consistent with a poorly differentiated adenocarcinoma. We have now performed this technique in 68 immune-competent BALB/c mice. There have been no complications from the procedure or peri-operative deaths, with primary tumours developing in 44 (65%) mice and liver metastases in nine (20%) of these. This technique provides an accurate model of colorectal cancer with tumours developing in the correct microenvironment and metastasising to the liver with a similar frequency to that seen in patients presenting with colorectal cancer, with serial bioluminescent reducing the murine numbers required in studies by removing the need for cull for assessment of disease burden.
KEYWORDS: Colorectal cancer; bioluminescent imaging; orthotopic syngeneic model
Link to PubMed record
Friday, 24 January 2020
WUTH publication: 'Tax-otsubo': stress cardiomyopathy following an encounter with the Inland Revenue
Citation: BMJ Case Reports. 2020, 13(1), e232225
Author: Roach MW, Currie P
Abstract: An 89-year-old man developed chest pain and palpitations shortly after finishing a stressful 40 min phone call to HM Revenue and Customs. After admission to the emergency department, he had a cardiovascular collapse followed soon after by a cardiac arrest due to ventricular fibrillation (VF). The troponin T was elevated and his ECG showed extensive deep T wave inversion with prolongation of the QT interval. A portable hand-held ultrasound device (VScan; GE Healthcare) was used to demonstrate classical apical ballooning of the left ventricular apex indicating a diagnosis of takotsubo stress cardiomyopathy. Shortly following admission to the cardiac care unit, he had a further episode of VF, which was successfully defibrillated. A coronary angiogram was performed, which was normal. He was treated with a short course of benzodiazepines. He was discharged after 8 days without any neurological deficit. His echocardiogram subsequently showed complete resolution of the abnormalities of the left ventricular function.
© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
KEYWORDS: arrhythmias; clinical diagnostic tests; heart failure
Link to PubMed record
Author: Roach MW, Currie P
Abstract: An 89-year-old man developed chest pain and palpitations shortly after finishing a stressful 40 min phone call to HM Revenue and Customs. After admission to the emergency department, he had a cardiovascular collapse followed soon after by a cardiac arrest due to ventricular fibrillation (VF). The troponin T was elevated and his ECG showed extensive deep T wave inversion with prolongation of the QT interval. A portable hand-held ultrasound device (VScan; GE Healthcare) was used to demonstrate classical apical ballooning of the left ventricular apex indicating a diagnosis of takotsubo stress cardiomyopathy. Shortly following admission to the cardiac care unit, he had a further episode of VF, which was successfully defibrillated. A coronary angiogram was performed, which was normal. He was treated with a short course of benzodiazepines. He was discharged after 8 days without any neurological deficit. His echocardiogram subsequently showed complete resolution of the abnormalities of the left ventricular function.
© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
KEYWORDS: arrhythmias; clinical diagnostic tests; heart failure
Link to PubMed record
Subscribe to:
Posts (Atom)