ABSTRACT In this study, we report a differential response of mitogen-activated protein kinase–kin... more ABSTRACT In this study, we report a differential response of mitogen-activated protein kinase–kinase (MEK) inhibitor trametinib in 20 head and neck squamous cell carcinoma (HNSCC) patients’ tumor-derived cell cultures. Relatively sensitive and resistant cases to trametinib were identified using high throughput metabolic assays and validated in extended dose response studies in vitro. High throughput metabolic assays exploring combination therapies with trametinib were subjected to synergy models and maximal synergistic dose analyses. These yielded several candidates, including axtinib, GDC-0032, GSK-690693, and SGX-523. The combination regimen of trametinib and AXL/MET/VEGFR inhibitor glesatinib showed initial efficacy both in vitro and in vivo (92% reduction in tumor volume). Sensitivity was validated in vivo in a patient-derived xenograft (PDX) model in which trametinib as a single agent effected reduction in tumor volume up to 72%. Reverse Phase Protein Arrays (RPPA) demonstrated differentially expressed proteins and phosphoproteins upon trametinib treatment. Furthermore, resistant cell lines showed a compensatory mechanism via increases in MAPK and non-MAPK pathway proteins that may represent targets for future combination regimens. Intrinsic-targeted options have potential to address paucity of medical treatment options for HNSCC cancer patients, enhance response to extrinsic targeted agents, and/or reduce morbidity as neoadjuvant to surgical treatments.
International Journal of Technology Assessment in Health Care, 2022
Objectives While ethics has been identified as a core component of health technology assessment (... more Objectives While ethics has been identified as a core component of health technology assessment (HTA), there are few examples of practical, systematic inclusion of ethics analysis in HTA. Some attribute the scarcity of ethics analysis in HTA to debates about appropriate methodology and the need for ethics frameworks that are relevant to local social values. The “South African Values and Ethics for Universal Health Coverage” (SAVE-UHC) project models an approach that countries can use to develop HTA ethics frameworks that are specific to their national contexts. Methods The SAVE-UHC approach consisted of two phases. In Phase I, the research team convened and facilitated a national multistakeholder working group to develop a provisional ethics framework through a collaborative, engagement-driven process. In Phase II, the research team refined the model framework by piloting it through three simulated HTA appraisal committee meetings. Each simulated committee reviewed two case studies ...
Whilst much research has been undertaken on establishing what factors influence improved decision... more Whilst much research has been undertaken on establishing what factors influence improved decision-making including good governance structures, expertise, political and institutional factors, resources and participation, how such influences on decision-making interact with local context and health systems, leading to impact on health outcomes, is less understood. The focus of our research is on the impact of Health Technology Assessment (HTA) as a tool for priority-setting with its explicit consideration of costs and benefits. Where evaluations have been undertaken, they mainly focus on processes or outcomes at the decision-making level, with impact on health outcomes rarely measured. Even in countries where HTA programmes are well established, evidence which identifies their outcomes and impact in terms of health gains is limited. For countries with greater capacity constraints, how decision-making interacts with ‘context’ leading to health outcomes is even less explored and arguabl...
Kelly Boothby, Colin Enderud, Trevor Lanting, Reza Molavi, Nicholas Tsai, Mark H. Volkmann, Fabio... more Kelly Boothby, Colin Enderud, Trevor Lanting, Reza Molavi, Nicholas Tsai, Mark H. Volkmann, Fabio Altomare, Mohammad H. Amin, Michael Babcock, Andrew J. Berkley, Catia Baron Aznar, Martin Boschnak, Holly Christiani, Sara Ejtemaee, Bram Evert, Matthew Gullen, Markus Hager, Richard Harris, Emile Hoskinson, Jeremy P. Hilton, Kais Jooya, Ann Huang, Mark W. Johnson, Andrew D. King, Eric Ladizinsky, Ryan Li, Allison MacDonald, Teresa Medina Fernandez, Richard Neufeld, Mana Norouzpour, Travis Oh, Isil Ozfidan, Paul Paddon, Ilya Perminov, Gabriel Poulin-Lamarre, Thomas Prescott, Jack Raymond, Mauricio Reis, Chris Rich, Aidan Roy, Hossein Sadeghi Esfahani, Yuki Sato, Ben Sheldan, Anatoly Smirnov, Loren J. Swenson, Jed Whittaker, Jason Yao, Alexander Yarovoy, and Paul I. Bunyk
This paper identifies key insights from the international Decision Support Initiative (iDSI) work... more This paper identifies key insights from the international Decision Support Initiative (iDSI) workshop on Supporting Evidence-Informed Policymaking, held in Seattle (October 2015), drawn from the full report of the workshop (Lavis, 2016), with additional reflections on how iDSI aims to implement these best practices. The five key areas for iDSI to address are: knowing the policy context, enhancing knowledge brokers, enhancing evidence producers, better communication, and aligning theories of change. iDSI is already conducting a number of activities in these areas and will continue to do so throughout 2016-2018, to support evidence-informed priority-setting in low and middleincome countries, and to strengthen institutional capacities for sustainable knowledge transfer and exchange.
In this work, we leverage a deep learning pipeline for training a network to improve the resoluti... more In this work, we leverage a deep learning pipeline for training a network to improve the resolution of MRI images, leading to shorter image acquisition times. Using a Generative Adversarial Network, we extend previous approaches and focus specifically on super-resolution of the MRIs of pediatric patients, which tend to have more artifacts. While our results show promise, further research into solving vanishing gradients and decreasing pixelation is needed.
The promise of quantum computing lies in harnessing programmable quantum devices for practical ap... more The promise of quantum computing lies in harnessing programmable quantum devices for practical applications such as efficient simulation of quantum materials and condensed matter systems. One important task is the simulation of geometrically frustrated magnets in which topological phenomena can emerge from competition between quantum and thermal fluctuations. Here we report on experimental observations of equilibration in such simulations, measured on up to 1440 qubits with microsecond resolution. By initializing the system in a state with topological obstruction, we observe quantum annealing (QA) equilibration timescales in excess of one microsecond. Measurements indicate a dynamical advantage in the quantum simulation compared with spatially local update dynamics of path-integral Monte Carlo (PIMC). The advantage increases with both system size and inverse temperature, exceeding a million-fold speedup over an efficient CPU implementation. PIMC is a leading classical method for suc...
Importance The negative association of low lean muscle mass (sarcopenia) with survival outcomes i... more Importance The negative association of low lean muscle mass (sarcopenia) with survival outcomes in head and neck cancers, including oropharyngeal carcinoma, is established. However, it is not known whether the choice of primary treatment modality (surgery or radiotherapy) is associated with oncologic outcomes of patients with sarcopenia and oropharyngeal squamous cell carcinoma (OPSCC). Objective To examine whether primary surgical resection or definitive radiotherapy is associated with improved survival for patients with sarcopenia and localized OPSCC. Design, Setting, and Participants A cohort study was conducted of patients with clinically staged T1 to T2, N0 to N2 OPSCC with cross-sectional abdominal imaging within 60 days prior to treatment and treated between January 1, 2005, and December 31, 2017. Skeletal muscle mass was measured at the third lumbar vertebra using previously defined techniques and sarcopenia was defined as less than 52.4 cm2/m2 of muscle for men and less than 38.5 cm2/m2 for women. In addition, associated patient demographic characteristics, cancer data, treatment information, and survival outcomes were assessed. Statistical analysis was performed from December 3, 2018, to August 28, 2019. Main Outcomes and Measures Primary outcomes were overall survival and disease-specific survival. Results Among the 245 patients who met study inclusion criteria, 209 were men (85.3%) and the mean (SD) age was 62.3 (7.8) years. Sarcopenia was detected in 135 patients (55.1%), while normal skeletal muscle mass was detected in 110 patients (44.9%). For the 110 patients without sarcopenia, primary treatment modality was not associated with improved survival. For patients with sarcopenia at diagnosis, primary surgical resection was associated with improved overall survival (hazard ratio [HR], 0.37; 95% CI, 0.17-0.82) and disease-specific survival (HR, 0.22; 95% CI, 0.07-0.68). This association persisted after propensity score matching, as up-front surgery was associated with improved overall survival (HR, 0.33; 95% CI, 0.12-0.91) and disease-specific survival (HR, 0.17; 95% CI, 0.04-0.75) survival. Conclusions and Relevance This study suggests that sarcopenia has a negative association with survival for patients with OPSCC. Primary surgery and radiotherapy confer similar survival associations for patients with normal skeletal muscle mass and localized OPSCC. However, up-front surgical resection may be associated with improved survival outcomes for patients with sarcopenia.
Hepatocellular carcinoma (HCC) continues to pose a worldwide burden on health resources with an o... more Hepatocellular carcinoma (HCC) continues to pose a worldwide burden on health resources with an occurrence of 1.4 million cases annually. It represents the fifth most common cancer in men and eighth most common in women worldwide. Eighty per cent of patients have a background cirrhotic liver, most commonly in the United States, resulting from chronic hepatitis C infection, whereas alcoholism also commonly contributes to the development of cirrhosis. Fifty per cent of patients diagnosed with HCC present with metastatic disease. Sites of metastasis commonly include the lungs, vertebral bones, and abdominal lymph nodes. Metastasis to the oral region is very rare. We report a 55-year-old man with metastatic HCC to the mandible. The patient was previously diagnosed with unresectable HCC and had undergone six cycles of chemoembolization therapy. Although the lesion remained stable in size, he did not qualify for liver transplantation because of active alcohol use. He presented to the emer...
OBJECTIVE Interposition vein grafting in free flap reconstruction is often viewed as a risky proc... more OBJECTIVE Interposition vein grafting in free flap reconstruction is often viewed as a risky procedure, but is necessary in cases of inadequate pedicle length. MATERIALS AND METHODS Two tertiary care centers retrospectively.reviewed 3008 head and neck free flap reconstructions from 2008 to 2017 91 patients were identified requiring interposition vein grafting during reconstruction. Pre and perioperative characteristics were recorded Univariate and multivariate analyses were conducted with a p value <0.05 indicating statistical significance. RESULTS Of the 91 patients 75% had undergone reconstruction for cancer, 66% of these cases were in the setting of recurrence or complication, 33% had a previous free flap, and 52% had prior radiation therapy. Surgical site was primarily craniofacial (36%) or oral cavity (26%). The majority of vein grafts were saphenous (64%), average graft length 18 cm (SD 11 cm). Half were used for both artery and vein anastomosis. Flap survival was 85% overall and only prior free flap was predictive of failure on multivariate analysis. No other peri-operative or graft variable assessed in this study were predictive of flap failure. CONCLUSION In a multi-institutional study of head and neck free flap reconstructions using interposition vein grafts, we identified an overall 85% success rate with no significant difference between soft tissue and osteocutaneous flaps despite the complicated nature of these cases.
ABSTRACT In this study, we report a differential response of mitogen-activated protein kinase–kin... more ABSTRACT In this study, we report a differential response of mitogen-activated protein kinase–kinase (MEK) inhibitor trametinib in 20 head and neck squamous cell carcinoma (HNSCC) patients’ tumor-derived cell cultures. Relatively sensitive and resistant cases to trametinib were identified using high throughput metabolic assays and validated in extended dose response studies in vitro. High throughput metabolic assays exploring combination therapies with trametinib were subjected to synergy models and maximal synergistic dose analyses. These yielded several candidates, including axtinib, GDC-0032, GSK-690693, and SGX-523. The combination regimen of trametinib and AXL/MET/VEGFR inhibitor glesatinib showed initial efficacy both in vitro and in vivo (92% reduction in tumor volume). Sensitivity was validated in vivo in a patient-derived xenograft (PDX) model in which trametinib as a single agent effected reduction in tumor volume up to 72%. Reverse Phase Protein Arrays (RPPA) demonstrated differentially expressed proteins and phosphoproteins upon trametinib treatment. Furthermore, resistant cell lines showed a compensatory mechanism via increases in MAPK and non-MAPK pathway proteins that may represent targets for future combination regimens. Intrinsic-targeted options have potential to address paucity of medical treatment options for HNSCC cancer patients, enhance response to extrinsic targeted agents, and/or reduce morbidity as neoadjuvant to surgical treatments.
International Journal of Technology Assessment in Health Care, 2022
Objectives While ethics has been identified as a core component of health technology assessment (... more Objectives While ethics has been identified as a core component of health technology assessment (HTA), there are few examples of practical, systematic inclusion of ethics analysis in HTA. Some attribute the scarcity of ethics analysis in HTA to debates about appropriate methodology and the need for ethics frameworks that are relevant to local social values. The “South African Values and Ethics for Universal Health Coverage” (SAVE-UHC) project models an approach that countries can use to develop HTA ethics frameworks that are specific to their national contexts. Methods The SAVE-UHC approach consisted of two phases. In Phase I, the research team convened and facilitated a national multistakeholder working group to develop a provisional ethics framework through a collaborative, engagement-driven process. In Phase II, the research team refined the model framework by piloting it through three simulated HTA appraisal committee meetings. Each simulated committee reviewed two case studies ...
Whilst much research has been undertaken on establishing what factors influence improved decision... more Whilst much research has been undertaken on establishing what factors influence improved decision-making including good governance structures, expertise, political and institutional factors, resources and participation, how such influences on decision-making interact with local context and health systems, leading to impact on health outcomes, is less understood. The focus of our research is on the impact of Health Technology Assessment (HTA) as a tool for priority-setting with its explicit consideration of costs and benefits. Where evaluations have been undertaken, they mainly focus on processes or outcomes at the decision-making level, with impact on health outcomes rarely measured. Even in countries where HTA programmes are well established, evidence which identifies their outcomes and impact in terms of health gains is limited. For countries with greater capacity constraints, how decision-making interacts with ‘context’ leading to health outcomes is even less explored and arguabl...
Kelly Boothby, Colin Enderud, Trevor Lanting, Reza Molavi, Nicholas Tsai, Mark H. Volkmann, Fabio... more Kelly Boothby, Colin Enderud, Trevor Lanting, Reza Molavi, Nicholas Tsai, Mark H. Volkmann, Fabio Altomare, Mohammad H. Amin, Michael Babcock, Andrew J. Berkley, Catia Baron Aznar, Martin Boschnak, Holly Christiani, Sara Ejtemaee, Bram Evert, Matthew Gullen, Markus Hager, Richard Harris, Emile Hoskinson, Jeremy P. Hilton, Kais Jooya, Ann Huang, Mark W. Johnson, Andrew D. King, Eric Ladizinsky, Ryan Li, Allison MacDonald, Teresa Medina Fernandez, Richard Neufeld, Mana Norouzpour, Travis Oh, Isil Ozfidan, Paul Paddon, Ilya Perminov, Gabriel Poulin-Lamarre, Thomas Prescott, Jack Raymond, Mauricio Reis, Chris Rich, Aidan Roy, Hossein Sadeghi Esfahani, Yuki Sato, Ben Sheldan, Anatoly Smirnov, Loren J. Swenson, Jed Whittaker, Jason Yao, Alexander Yarovoy, and Paul I. Bunyk
This paper identifies key insights from the international Decision Support Initiative (iDSI) work... more This paper identifies key insights from the international Decision Support Initiative (iDSI) workshop on Supporting Evidence-Informed Policymaking, held in Seattle (October 2015), drawn from the full report of the workshop (Lavis, 2016), with additional reflections on how iDSI aims to implement these best practices. The five key areas for iDSI to address are: knowing the policy context, enhancing knowledge brokers, enhancing evidence producers, better communication, and aligning theories of change. iDSI is already conducting a number of activities in these areas and will continue to do so throughout 2016-2018, to support evidence-informed priority-setting in low and middleincome countries, and to strengthen institutional capacities for sustainable knowledge transfer and exchange.
In this work, we leverage a deep learning pipeline for training a network to improve the resoluti... more In this work, we leverage a deep learning pipeline for training a network to improve the resolution of MRI images, leading to shorter image acquisition times. Using a Generative Adversarial Network, we extend previous approaches and focus specifically on super-resolution of the MRIs of pediatric patients, which tend to have more artifacts. While our results show promise, further research into solving vanishing gradients and decreasing pixelation is needed.
The promise of quantum computing lies in harnessing programmable quantum devices for practical ap... more The promise of quantum computing lies in harnessing programmable quantum devices for practical applications such as efficient simulation of quantum materials and condensed matter systems. One important task is the simulation of geometrically frustrated magnets in which topological phenomena can emerge from competition between quantum and thermal fluctuations. Here we report on experimental observations of equilibration in such simulations, measured on up to 1440 qubits with microsecond resolution. By initializing the system in a state with topological obstruction, we observe quantum annealing (QA) equilibration timescales in excess of one microsecond. Measurements indicate a dynamical advantage in the quantum simulation compared with spatially local update dynamics of path-integral Monte Carlo (PIMC). The advantage increases with both system size and inverse temperature, exceeding a million-fold speedup over an efficient CPU implementation. PIMC is a leading classical method for suc...
Importance The negative association of low lean muscle mass (sarcopenia) with survival outcomes i... more Importance The negative association of low lean muscle mass (sarcopenia) with survival outcomes in head and neck cancers, including oropharyngeal carcinoma, is established. However, it is not known whether the choice of primary treatment modality (surgery or radiotherapy) is associated with oncologic outcomes of patients with sarcopenia and oropharyngeal squamous cell carcinoma (OPSCC). Objective To examine whether primary surgical resection or definitive radiotherapy is associated with improved survival for patients with sarcopenia and localized OPSCC. Design, Setting, and Participants A cohort study was conducted of patients with clinically staged T1 to T2, N0 to N2 OPSCC with cross-sectional abdominal imaging within 60 days prior to treatment and treated between January 1, 2005, and December 31, 2017. Skeletal muscle mass was measured at the third lumbar vertebra using previously defined techniques and sarcopenia was defined as less than 52.4 cm2/m2 of muscle for men and less than 38.5 cm2/m2 for women. In addition, associated patient demographic characteristics, cancer data, treatment information, and survival outcomes were assessed. Statistical analysis was performed from December 3, 2018, to August 28, 2019. Main Outcomes and Measures Primary outcomes were overall survival and disease-specific survival. Results Among the 245 patients who met study inclusion criteria, 209 were men (85.3%) and the mean (SD) age was 62.3 (7.8) years. Sarcopenia was detected in 135 patients (55.1%), while normal skeletal muscle mass was detected in 110 patients (44.9%). For the 110 patients without sarcopenia, primary treatment modality was not associated with improved survival. For patients with sarcopenia at diagnosis, primary surgical resection was associated with improved overall survival (hazard ratio [HR], 0.37; 95% CI, 0.17-0.82) and disease-specific survival (HR, 0.22; 95% CI, 0.07-0.68). This association persisted after propensity score matching, as up-front surgery was associated with improved overall survival (HR, 0.33; 95% CI, 0.12-0.91) and disease-specific survival (HR, 0.17; 95% CI, 0.04-0.75) survival. Conclusions and Relevance This study suggests that sarcopenia has a negative association with survival for patients with OPSCC. Primary surgery and radiotherapy confer similar survival associations for patients with normal skeletal muscle mass and localized OPSCC. However, up-front surgical resection may be associated with improved survival outcomes for patients with sarcopenia.
Hepatocellular carcinoma (HCC) continues to pose a worldwide burden on health resources with an o... more Hepatocellular carcinoma (HCC) continues to pose a worldwide burden on health resources with an occurrence of 1.4 million cases annually. It represents the fifth most common cancer in men and eighth most common in women worldwide. Eighty per cent of patients have a background cirrhotic liver, most commonly in the United States, resulting from chronic hepatitis C infection, whereas alcoholism also commonly contributes to the development of cirrhosis. Fifty per cent of patients diagnosed with HCC present with metastatic disease. Sites of metastasis commonly include the lungs, vertebral bones, and abdominal lymph nodes. Metastasis to the oral region is very rare. We report a 55-year-old man with metastatic HCC to the mandible. The patient was previously diagnosed with unresectable HCC and had undergone six cycles of chemoembolization therapy. Although the lesion remained stable in size, he did not qualify for liver transplantation because of active alcohol use. He presented to the emer...
OBJECTIVE Interposition vein grafting in free flap reconstruction is often viewed as a risky proc... more OBJECTIVE Interposition vein grafting in free flap reconstruction is often viewed as a risky procedure, but is necessary in cases of inadequate pedicle length. MATERIALS AND METHODS Two tertiary care centers retrospectively.reviewed 3008 head and neck free flap reconstructions from 2008 to 2017 91 patients were identified requiring interposition vein grafting during reconstruction. Pre and perioperative characteristics were recorded Univariate and multivariate analyses were conducted with a p value <0.05 indicating statistical significance. RESULTS Of the 91 patients 75% had undergone reconstruction for cancer, 66% of these cases were in the setting of recurrence or complication, 33% had a previous free flap, and 52% had prior radiation therapy. Surgical site was primarily craniofacial (36%) or oral cavity (26%). The majority of vein grafts were saphenous (64%), average graft length 18 cm (SD 11 cm). Half were used for both artery and vein anastomosis. Flap survival was 85% overall and only prior free flap was predictive of failure on multivariate analysis. No other peri-operative or graft variable assessed in this study were predictive of flap failure. CONCLUSION In a multi-institutional study of head and neck free flap reconstructions using interposition vein grafts, we identified an overall 85% success rate with no significant difference between soft tissue and osteocutaneous flaps despite the complicated nature of these cases.
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