Gout’s association with a host of vascular events was confirmed in a new study that explored the links between the inflammatory condition and coronary artery disease, peripheral vascular disease, and cerebrovascular events.

Though both men and women with gout were at increased risk for vascular events overall, the association appeared strongest for women. Dr. Lorna Clarson of Keele (England) University and her associates drew these conclusions from a retrospective cohort study of men and women with an incident diagnosis of gout (Ann. Rheum. Dis. 2015;74:642-7).

Gout, caused by the deposition of uric acid crystals in joints, is characterized by acute flares of intensely painful and inflamed joints. However, the state of hyperuricemia that predisposes patients to acute attacks of gout may precede the first attack by years, and may persist between flares. The proinflammatory course of the natural history of gout has increasingly been recognized as a potential contributor to vascular disease.

The precise mechanism by which gout may increase vascular risk has not been identified. Dr. Clarson and associates noted that in addition to the acute and chronic inflammation associated with gout and hyperuricemia, serum uric acid may have a more direct effect on vascular health, as urate crystal deposition on vessel walls may promote vascular damage.

To clarify gout’s impact on vascular risk, Dr. Clarson and her associates used the Clinical Practice Datalink, a large United Kingdom health database, to compare 8,366 patients with gout to 39,766 age- and sex-matched controls. None of those studied had a baseline history of vascular disease, and all were aged 50 or older.

Careful accounting for covariates was accomplished by multivariate analysis that took into account sex, age, body mass index, tobacco and alcohol consumption, statin or aspirin use, and any history of hypertension, dyslipidemia, or chronic kidney disease. In addition, the study employed the composite Charlson Comorbidity Index, which weights 19 comorbid conditions – including diabetes – to arrive at a single score that captures many risk factors. Patients in the cohort were tracked until their first vascular event, or until death or loss to follow-up. Patient data collection was censored at 10 years from baseline or at the end of study data collection, whichever came first.

To assess the incidence of vascular events, the study noted the first recording in the medical record of any events signaling vascular disease. These included angina or myocardial infarction, transient ischemic attack and stroke, and a range of diagnoses associated with peripheral vascular disease.

Final analysis after accounting for the many covariates tracked in the study showed increased risk for vascular events for those with gout, with a definite difference between the sexes. For men, gout predicted an increased risk of any vascular event (hazard ratio, 1.06; 95% confidence interval, 1.01–1.12) and of coronary heart disease and peripheral vascular disease. For women, gout predicted an increased risk of all vascular events (HR, 1.25; 95% CI, 1.15-1.35) except myocardial infarction and cerebrovascular disease overall. Further, the degree of increased risk of vascular events was greater for women than for men with gout (P< .001 for intersex difference).

Dr. Clarson and her associates proposed that the higher risk for vascular events among women with gout may arise from the longer exposure to elevated serum uric acid, since women have a longer prodrome before first gout attack, though they recommend further study to elucidate the mechanism.

Noting that “clinical management of gout in primary care is suboptimal,” Dr. Clarson and her colleagues urged greater attention to screening for vascular risk in those diagnosed with gout; these individuals comprise a significant population of over 8 million people in the United States. International guidelines recommend screening for cardiovascular risk when gout is diagnosed, but only one in four gout patients are so evaluated.

Regarding the sex differences unearthed in their study, Dr. Clarson and her associates observed that “both gout and vascular disease have historically been considered diseases of men ... [M]ore attention should be paid to prompt and reliable diagnosis of gout, followed by optimal management in female patients, including serious consideration of vascular risk reduction.”

The United Kingdom’s National School for Primary Research funded the study. The authors reported no relevant disclosures.

Gout’s association with a host of vascular events was confirmed in a new study that explored the links between the inflammatory condition and coronary artery disease, peripheral vascular disease, and cerebrovascular events.

Though both men and women with gout were at increased risk for vascular events overall, the association appeared strongest for women. Dr. Lorna Clarson of Keele (England) University and her associates drew these conclusions from a retrospective cohort study of men and women with an incident diagnosis of gout (Ann. Rheum. Dis. 2015;74:642-7).

Gout, caused by the deposition of uric acid crystals in joints, is characterized by acute flares of intensely painful and inflamed joints. However, the state of hyperuricemia that predisposes patients to acute attacks of gout may precede the first attack by years, and may persist between flares. The proinflammatory course of the natural history of gout has increasingly been recognized as a potential contributor to vascular disease.

The precise mechanism by which gout may increase vascular risk has not been identified. Dr. Clarson and associates noted that in addition to the acute and chronic inflammation associated with gout and hyperuricemia, serum uric acid may have a more direct effect on vascular health, as urate crystal deposition on vessel walls may promote vascular damage.

To clarify gout’s impact on vascular risk, Dr. Clarson and her associates used the Clinical Practice Datalink, a large United Kingdom health database, to compare 8,366 patients with gout to 39,766 age- and sex-matched controls. None of those studied had a baseline history of vascular disease, and all were aged 50 or older.

Careful accounting for covariates was accomplished by multivariate analysis that took into account sex, age, body mass index, tobacco and alcohol consumption, statin or aspirin use, and any history of hypertension, dyslipidemia, or chronic kidney disease. In addition, the study employed the composite Charlson Comorbidity Index, which weights 19 comorbid conditions – including diabetes – to arrive at a single score that captures many risk factors. Patients in the cohort were tracked until their first vascular event, or until death or loss to follow-up. Patient data collection was censored at 10 years from baseline or at the end of study data collection, whichever came first.

To assess the incidence of vascular events, the study noted the first recording in the medical record of any events signaling vascular disease. These included angina or myocardial infarction, transient ischemic attack and stroke, and a range of diagnoses associated with peripheral vascular disease.

Final analysis after accounting for the many covariates tracked in the study showed increased risk for vascular events for those with gout, with a definite difference between the sexes. For men, gout predicted an increased risk of any vascular event (hazard ratio, 1.06; 95% confidence interval, 1.01–1.12) and of coronary heart disease and peripheral vascular disease. For women, gout predicted an increased risk of all vascular events (HR, 1.25; 95% CI, 1.15-1.35) except myocardial infarction and cerebrovascular disease overall. Further, the degree of increased risk of vascular events was greater for women than for men with gout (P< .001 for intersex difference).

Dr. Clarson and her associates proposed that the higher risk for vascular events among women with gout may arise from the longer exposure to elevated serum uric acid, since women have a longer prodrome before first gout attack, though they recommend further study to elucidate the mechanism.

Noting that “clinical management of gout in primary care is suboptimal,” Dr. Clarson and her colleagues urged greater attention to screening for vascular risk in those diagnosed with gout; these individuals comprise a significant population of over 8 million people in the United States. International guidelines recommend screening for cardiovascular risk when gout is diagnosed, but only one in four gout patients are so evaluated.

Regarding the sex differences unearthed in their study, Dr. Clarson and her associates observed that “both gout and vascular disease have historically been considered diseases of men ... [M]ore attention should be paid to prompt and reliable diagnosis of gout, followed by optimal management in female patients, including serious consideration of vascular risk reduction.”

The United Kingdom’s National School for Primary Research funded the study. The authors reported no relevant disclosures.

Gout’s association with a host of vascular events was confirmed in a new study that explored the links between the inflammatory condition and coronary artery disease, peripheral vascular disease, and cerebrovascular events.

Though both men and women with gout were at increased risk for vascular events overall, the association appeared strongest for women. Dr. Lorna Clarson of Keele (England) University and her associates drew these conclusions from a retrospective cohort study of men and women with an incident diagnosis of gout (Ann. Rheum. Dis. 2015;74:642-7).

Gout, caused by the deposition of uric acid crystals in joints, is characterized by acute flares of intensely painful and inflamed joints. However, the state of hyperuricemia that predisposes patients to acute attacks of gout may precede the first attack by years, and may persist between flares. The proinflammatory course of the natural history of gout has increasingly been recognized as a potential contributor to vascular disease.

The precise mechanism by which gout may increase vascular risk has not been identified. Dr. Clarson and associates noted that in addition to the acute and chronic inflammation associated with gout and hyperuricemia, serum uric acid may have a more direct effect on vascular health, as urate crystal deposition on vessel walls may promote vascular damage.

To clarify gout’s impact on vascular risk, Dr. Clarson and her associates used the Clinical Practice Datalink, a large United Kingdom health database, to compare 8,366 patients with gout to 39,766 age- and sex-matched controls. None of those studied had a baseline history of vascular disease, and all were aged 50 or older.

Careful accounting for covariates was accomplished by multivariate analysis that took into account sex, age, body mass index, tobacco and alcohol consumption, statin or aspirin use, and any history of hypertension, dyslipidemia, or chronic kidney disease. In addition, the study employed the composite Charlson Comorbidity Index, which weights 19 comorbid conditions – including diabetes – to arrive at a single score that captures many risk factors. Patients in the cohort were tracked until their first vascular event, or until death or loss to follow-up. Patient data collection was censored at 10 years from baseline or at the end of study data collection, whichever came first.

To assess the incidence of vascular events, the study noted the first recording in the medical record of any events signaling vascular disease. These included angina or myocardial infarction, transient ischemic attack and stroke, and a range of diagnoses associated with peripheral vascular disease.

Final analysis after accounting for the many covariates tracked in the study showed increased risk for vascular events for those with gout, with a definite difference between the sexes. For men, gout predicted an increased risk of any vascular event (hazard ratio, 1.06; 95% confidence interval, 1.01–1.12) and of coronary heart disease and peripheral vascular disease. For women, gout predicted an increased risk of all vascular events (HR, 1.25; 95% CI, 1.15-1.35) except myocardial infarction and cerebrovascular disease overall. Further, the degree of increased risk of vascular events was greater for women than for men with gout (P< .001 for intersex difference).

Dr. Clarson and her associates proposed that the higher risk for vascular events among women with gout may arise from the longer exposure to elevated serum uric acid, since women have a longer prodrome before first gout attack, though they recommend further study to elucidate the mechanism.

Noting that “clinical management of gout in primary care is suboptimal,” Dr. Clarson and her colleagues urged greater attention to screening for vascular risk in those diagnosed with gout; these individuals comprise a significant population of over 8 million people in the United States. International guidelines recommend screening for cardiovascular risk when gout is diagnosed, but only one in four gout patients are so evaluated.

Regarding the sex differences unearthed in their study, Dr. Clarson and her associates observed that “both gout and vascular disease have historically been considered diseases of men ... [M]ore attention should be paid to prompt and reliable diagnosis of gout, followed by optimal management in female patients, including serious consideration of vascular risk reduction.”

The United Kingdom’s National School for Primary Research funded the study. The authors reported no relevant disclosures.

HM15 presenters: Joshua D. Lenchus, DO, FACP, SFHM, and Nilam Soni, MD, FHM

Summary: Drs. Lenchus and Soni focused on the forces that are driving the value and success of established procedure teams in hospital medicine groups (HMGs). These stem from a need to rapidly address the growing shortage of skilled internists who can perform diagnostic and therapeutic procedures, thus leading to a subset of hospitalists who are willing to provide these services, particularly with the assistance of bedside ultrasonography.

They stressed the importance of providing a platform that is preemptive, proprietary, and scalable. With a defined set of value-creating metrics such as faster turn-around times, a reduction in complication rates, and ultimately a reduction in cost, LOS, and utilization, data must be collected to adequately measure the impact of these services on the institution.

They also discussed the key components necessary to create a procedure service, starting with the logistics of adequate training and demonstration of competence, proper staffing, supplies and equipment, ultrasound image archiving, and the use of documentation templates. The process is followed by the development of pre-procedure and post-procedure guidelines, as well as standardized procedural techniques.

The session also reviewed billing practices and professional fees. An analysis was made comparing Medicare reimbursement and work RVUs for each procedure service with and without a full procedure consultation. A complete consultation significantly increases the allowable fee and associated wRVU. The caveat is that billing for consults is limited to services rendered for patients that are not cared for by the same hospitalist group.

Furthermore, sub-specialists historically perform these procedures. The argument can be made that hospitalists will reduce an unnecessary burden on interventional radiologists, thereby enabling them to focus on more acomplex invasive and highly technical procedures.

The key to success is the ability to find a strategic partner in the C-suite who will directly or indirectly provide the financial and political support. Other sources of funding include private foundations, medical schools, the Department of Veteran Affairs, and such patient safety organizations as AHRQ, IOM, and IHI. HMG leaders also should consider scalability across other hospitalist groups.

“If you build it, they will come."

HM takeaways

• Create a business plan;
• Find institutional financial and political support;
• Start small and selective;
• Plan for standardization and training of colleagues;
• Create a credentialing/privileging process;
• Bill for services and consider billing for full consults; and
• Gather baseline and follow-up data.

HM15 presenters: Joshua D. Lenchus, DO, FACP, SFHM, and Nilam Soni, MD, FHM

Summary: Drs. Lenchus and Soni focused on the forces that are driving the value and success of established procedure teams in hospital medicine groups (HMGs). These stem from a need to rapidly address the growing shortage of skilled internists who can perform diagnostic and therapeutic procedures, thus leading to a subset of hospitalists who are willing to provide these services, particularly with the assistance of bedside ultrasonography.

They stressed the importance of providing a platform that is preemptive, proprietary, and scalable. With a defined set of value-creating metrics such as faster turn-around times, a reduction in complication rates, and ultimately a reduction in cost, LOS, and utilization, data must be collected to adequately measure the impact of these services on the institution.

They also discussed the key components necessary to create a procedure service, starting with the logistics of adequate training and demonstration of competence, proper staffing, supplies and equipment, ultrasound image archiving, and the use of documentation templates. The process is followed by the development of pre-procedure and post-procedure guidelines, as well as standardized procedural techniques.

The session also reviewed billing practices and professional fees. An analysis was made comparing Medicare reimbursement and work RVUs for each procedure service with and without a full procedure consultation. A complete consultation significantly increases the allowable fee and associated wRVU. The caveat is that billing for consults is limited to services rendered for patients that are not cared for by the same hospitalist group.

Furthermore, sub-specialists historically perform these procedures. The argument can be made that hospitalists will reduce an unnecessary burden on interventional radiologists, thereby enabling them to focus on more acomplex invasive and highly technical procedures.

The key to success is the ability to find a strategic partner in the C-suite who will directly or indirectly provide the financial and political support. Other sources of funding include private foundations, medical schools, the Department of Veteran Affairs, and such patient safety organizations as AHRQ, IOM, and IHI. HMG leaders also should consider scalability across other hospitalist groups.

“If you build it, they will come."

HM takeaways

• Create a business plan;
• Find institutional financial and political support;
• Start small and selective;
• Plan for standardization and training of colleagues;
• Create a credentialing/privileging process;
• Bill for services and consider billing for full consults; and
• Gather baseline and follow-up data.

HM15 presenters: Joshua D. Lenchus, DO, FACP, SFHM, and Nilam Soni, MD, FHM

Summary: Drs. Lenchus and Soni focused on the forces that are driving the value and success of established procedure teams in hospital medicine groups (HMGs). These stem from a need to rapidly address the growing shortage of skilled internists who can perform diagnostic and therapeutic procedures, thus leading to a subset of hospitalists who are willing to provide these services, particularly with the assistance of bedside ultrasonography.

They stressed the importance of providing a platform that is preemptive, proprietary, and scalable. With a defined set of value-creating metrics such as faster turn-around times, a reduction in complication rates, and ultimately a reduction in cost, LOS, and utilization, data must be collected to adequately measure the impact of these services on the institution.

They also discussed the key components necessary to create a procedure service, starting with the logistics of adequate training and demonstration of competence, proper staffing, supplies and equipment, ultrasound image archiving, and the use of documentation templates. The process is followed by the development of pre-procedure and post-procedure guidelines, as well as standardized procedural techniques.

The session also reviewed billing practices and professional fees. An analysis was made comparing Medicare reimbursement and work RVUs for each procedure service with and without a full procedure consultation. A complete consultation significantly increases the allowable fee and associated wRVU. The caveat is that billing for consults is limited to services rendered for patients that are not cared for by the same hospitalist group.

Furthermore, sub-specialists historically perform these procedures. The argument can be made that hospitalists will reduce an unnecessary burden on interventional radiologists, thereby enabling them to focus on more acomplex invasive and highly technical procedures.

The key to success is the ability to find a strategic partner in the C-suite who will directly or indirectly provide the financial and political support. Other sources of funding include private foundations, medical schools, the Department of Veteran Affairs, and such patient safety organizations as AHRQ, IOM, and IHI. HMG leaders also should consider scalability across other hospitalist groups.

“If you build it, they will come."

HM takeaways

• Create a business plan;
• Find institutional financial and political support;
• Start small and selective;
• Plan for standardization and training of colleagues;
• Create a credentialing/privileging process;
• Bill for services and consider billing for full consults; and
• Gather baseline and follow-up data.

Wyndham Wilson, MD, PhD

Photo by Larry Young

Surveillance of circulating tumor DNA (ctDNA) can help predict relapse in most patients with diffuse large B-cell lymphoma before there is clinical evidence of the disease, according to a study published in The Lancet Oncology.

Investigators analyzed ctDNA using the clonoSEQ minimal residual disease (MRD) test and found they could predict relapse with a positive predictive value (PPV) of 88% and a negative predictive value (NPV) of 98%.

The test detected relapse a median of 3.5 months quicker than computed tomography (CT) scans.

“Patients with DLBCL with low amounts of disease at relapse have better survival than those with more disease, which is the rationale for surveillance CT scans,” said study author Wyndham Wilson, MD, PhD, of the National Cancer Institute in Bethesda, Maryland.

“Because the ctDNA test detects disease at a molecular level, it detects microscopic disease, which cannot be detected by CT scans, and may improve patient survival. Furthermore, ctDNA is non-invasive and can be employed as frequently needed, unlike surveillance CT scans, which expose patients to radiation and intravenous contrast.”

For this study, Dr Wilson and his colleagues evaluated 126 DLBCL patients who had participated in clinical trials from May 1993 to June 2013 and were followed for a median of 11 years post-treatment.

Surveillance monitoring

To investigate whether ctDNA monitoring could overcome the limitations of standard imaging techniques, the researchers compared serial ctDNA samples to CT scans taken at the same time post-treatment in patients who had achieved complete remission. This was known as “surveillance monitoring.”

The investigators performed surveillance monitoring of ctDNA in 107 patients who achieved complete remission.

The hazard ratio for clinical disease progression was 228 for patients who had detectable ctDNA during surveillance, when compared to patients with undetectable ctDNA (P<0.0001).

Surveillance ctDNA had a PPV of 88.2% and an NPV of 97.8%. And it revealed the risk of recurrence at a median of 3.5 months (range, 0-200 months) before there was evidence of clinical disease.

Interim monitoring

The researchers also analyzed whether the presence of ctDNA at the beginning of the third cycle of treatment predicted relapse, regardless of whether patients achieved complete remission by the end of treatment. This was known as “interim monitoring.”

Of the 108 patients included in the interim monitoring analysis, ctDNA was detected in 24 patients, 15 of whom eventually relapsed. Only 17 of the 84 patients with undetectable interim ctDNA relapsed.

Five years after the interim serum samples were taken, 80.2% of the patients who were negative for ctDNA were relapse-free, as were 41.7% of patients who were positive for ctDNA (P<0.0001).

Detectable interim ctDNA had a PPV of 62.5% and an NPV of 79.8%.

Fourteen of the 15 patients with detectable ctDNA who relapsed did so within 6 months of the end of treatment, as did 7 of the 17 patients without interim ctDNA.

Based on these results, the investigators concluded that surveillance monitoring of ctDNA identifies DLBCL patients at risk of disease recurrence before clinical evidence of disease in most patients, and interim monitoring of ctDNA is a promising biomarker to identify patients at high risk of treatment failure.

This research was funded by Adaptive Biotechnologies, the company developing the clonoSEQ MRD test, as well as the National Cancer Institute.

Wyndham Wilson, MD, PhD

Photo by Larry Young

Surveillance of circulating tumor DNA (ctDNA) can help predict relapse in most patients with diffuse large B-cell lymphoma before there is clinical evidence of the disease, according to a study published in The Lancet Oncology.

Investigators analyzed ctDNA using the clonoSEQ minimal residual disease (MRD) test and found they could predict relapse with a positive predictive value (PPV) of 88% and a negative predictive value (NPV) of 98%.

The test detected relapse a median of 3.5 months quicker than computed tomography (CT) scans.

“Patients with DLBCL with low amounts of disease at relapse have better survival than those with more disease, which is the rationale for surveillance CT scans,” said study author Wyndham Wilson, MD, PhD, of the National Cancer Institute in Bethesda, Maryland.

“Because the ctDNA test detects disease at a molecular level, it detects microscopic disease, which cannot be detected by CT scans, and may improve patient survival. Furthermore, ctDNA is non-invasive and can be employed as frequently needed, unlike surveillance CT scans, which expose patients to radiation and intravenous contrast.”

For this study, Dr Wilson and his colleagues evaluated 126 DLBCL patients who had participated in clinical trials from May 1993 to June 2013 and were followed for a median of 11 years post-treatment.

Surveillance monitoring

To investigate whether ctDNA monitoring could overcome the limitations of standard imaging techniques, the researchers compared serial ctDNA samples to CT scans taken at the same time post-treatment in patients who had achieved complete remission. This was known as “surveillance monitoring.”

The investigators performed surveillance monitoring of ctDNA in 107 patients who achieved complete remission.

The hazard ratio for clinical disease progression was 228 for patients who had detectable ctDNA during surveillance, when compared to patients with undetectable ctDNA (P<0.0001).

Surveillance ctDNA had a PPV of 88.2% and an NPV of 97.8%. And it revealed the risk of recurrence at a median of 3.5 months (range, 0-200 months) before there was evidence of clinical disease.

Interim monitoring

The researchers also analyzed whether the presence of ctDNA at the beginning of the third cycle of treatment predicted relapse, regardless of whether patients achieved complete remission by the end of treatment. This was known as “interim monitoring.”

Of the 108 patients included in the interim monitoring analysis, ctDNA was detected in 24 patients, 15 of whom eventually relapsed. Only 17 of the 84 patients with undetectable interim ctDNA relapsed.

Five years after the interim serum samples were taken, 80.2% of the patients who were negative for ctDNA were relapse-free, as were 41.7% of patients who were positive for ctDNA (P<0.0001).

Detectable interim ctDNA had a PPV of 62.5% and an NPV of 79.8%.

Fourteen of the 15 patients with detectable ctDNA who relapsed did so within 6 months of the end of treatment, as did 7 of the 17 patients without interim ctDNA.

Based on these results, the investigators concluded that surveillance monitoring of ctDNA identifies DLBCL patients at risk of disease recurrence before clinical evidence of disease in most patients, and interim monitoring of ctDNA is a promising biomarker to identify patients at high risk of treatment failure.

This research was funded by Adaptive Biotechnologies, the company developing the clonoSEQ MRD test, as well as the National Cancer Institute.

Wyndham Wilson, MD, PhD

Photo by Larry Young

Surveillance of circulating tumor DNA (ctDNA) can help predict relapse in most patients with diffuse large B-cell lymphoma before there is clinical evidence of the disease, according to a study published in The Lancet Oncology.

Investigators analyzed ctDNA using the clonoSEQ minimal residual disease (MRD) test and found they could predict relapse with a positive predictive value (PPV) of 88% and a negative predictive value (NPV) of 98%.

The test detected relapse a median of 3.5 months quicker than computed tomography (CT) scans.

“Patients with DLBCL with low amounts of disease at relapse have better survival than those with more disease, which is the rationale for surveillance CT scans,” said study author Wyndham Wilson, MD, PhD, of the National Cancer Institute in Bethesda, Maryland.

“Because the ctDNA test detects disease at a molecular level, it detects microscopic disease, which cannot be detected by CT scans, and may improve patient survival. Furthermore, ctDNA is non-invasive and can be employed as frequently needed, unlike surveillance CT scans, which expose patients to radiation and intravenous contrast.”

For this study, Dr Wilson and his colleagues evaluated 126 DLBCL patients who had participated in clinical trials from May 1993 to June 2013 and were followed for a median of 11 years post-treatment.

Surveillance monitoring

To investigate whether ctDNA monitoring could overcome the limitations of standard imaging techniques, the researchers compared serial ctDNA samples to CT scans taken at the same time post-treatment in patients who had achieved complete remission. This was known as “surveillance monitoring.”

The investigators performed surveillance monitoring of ctDNA in 107 patients who achieved complete remission.

The hazard ratio for clinical disease progression was 228 for patients who had detectable ctDNA during surveillance, when compared to patients with undetectable ctDNA (P<0.0001).

Surveillance ctDNA had a PPV of 88.2% and an NPV of 97.8%. And it revealed the risk of recurrence at a median of 3.5 months (range, 0-200 months) before there was evidence of clinical disease.

Interim monitoring

The researchers also analyzed whether the presence of ctDNA at the beginning of the third cycle of treatment predicted relapse, regardless of whether patients achieved complete remission by the end of treatment. This was known as “interim monitoring.”

Of the 108 patients included in the interim monitoring analysis, ctDNA was detected in 24 patients, 15 of whom eventually relapsed. Only 17 of the 84 patients with undetectable interim ctDNA relapsed.

Five years after the interim serum samples were taken, 80.2% of the patients who were negative for ctDNA were relapse-free, as were 41.7% of patients who were positive for ctDNA (P<0.0001).

Detectable interim ctDNA had a PPV of 62.5% and an NPV of 79.8%.

Fourteen of the 15 patients with detectable ctDNA who relapsed did so within 6 months of the end of treatment, as did 7 of the 17 patients without interim ctDNA.

Based on these results, the investigators concluded that surveillance monitoring of ctDNA identifies DLBCL patients at risk of disease recurrence before clinical evidence of disease in most patients, and interim monitoring of ctDNA is a promising biomarker to identify patients at high risk of treatment failure.

This research was funded by Adaptive Biotechnologies, the company developing the clonoSEQ MRD test, as well as the National Cancer Institute.

Micrograph showing CML

Image courtesy of UCSD

New discoveries concerning a well-known tumor suppressor protein could help advance the diagnosis and treatment of chronic myeloid leukemia (CML), according to researchers.

They found that levels of the protein, BRCA1, are significantly decreased in advanced phases of CML, the expression of BCR-ABL1 correlates with decreased levels of BRCA1, and this downregulation of BRCA1 is caused by the inhibition of BRCA1 messenger RNA (mRNA) translation.

These discoveries explain the mechanism that supports CML development and uncover its weakness, the investigators said. They reported their findings in Cell Cycle.

“Our data demonstrated that BRCA1 synthesis is diminished in [the] advanced stage[s] of CML,” said study author Paulina Podszywałow-Bartnicka, PhD, of the Nencki Institute in Warsaw, Poland.

“The gene coding for BRCA1 protein is not mutated. However, BRCA1 mRNA, which is necessary for the protein production, is aggregated and stored in protein complexes [and], thus, not available for the protein synthesis.”

To gain more insight into this phenomenon, the investigators looked at 2 mRNA-binding proteins, HuR and TIAR. They found that BCR-ABL1 promoted cytosolic localization of TIAR and HuR, the proteins’ binding to BRCA1 mRNA, and formation of the TIAR-HuR complex.

The researchers also found that HuR positively regulated BRCA1 mRNA stability and translation, while TIAR negatively regulated BRCA1 translation.

TIAR-dependent downregulation of BRCA1 was a result of endoplasmic reticulum stress, which is activated in BCR-ABL1 expressing cells. And experiments showed that silencing TIAR in CML cells elevated BRCA1 levels.

This suggests that TIAR-mediated repression of BRCA1 mRNA translation is responsible for the downregulation of BRCA1 observed in BCR-ABL1-positive leukemia cells.

The investigators said this research indicates that BRCA1 deficiency, which supports CML, can be also used as a weapon against the disease.

“When a cell has damaged one signaling pathway or one gene, it may function properly due to alternative pathways . . . ,” explained study author Tomasz Skorski, MD, PhD, of Temple University School of Medicine in Philadelphia, Pennsylvania.

“Only when this alternative pathway is inhibited [do cells] lose the ability to survive. As we know that one of the [DNA double-strand break] repair pathways which depend on BRCA1 is blocked in leukemia cells, we can try to find the alternative, parallel pathway and inhibit it as well.”

This will induce apoptosis via synthetic lethality, but only in leukemia cells, because healthy cells still have functional BRCA1-dependent signaling. Dr Skorski noted that therapies based on BRCA1 deficiency are currently under investigation in clinical trials.

Micrograph showing CML

Image courtesy of UCSD

New discoveries concerning a well-known tumor suppressor protein could help advance the diagnosis and treatment of chronic myeloid leukemia (CML), according to researchers.

They found that levels of the protein, BRCA1, are significantly decreased in advanced phases of CML, the expression of BCR-ABL1 correlates with decreased levels of BRCA1, and this downregulation of BRCA1 is caused by the inhibition of BRCA1 messenger RNA (mRNA) translation.

These discoveries explain the mechanism that supports CML development and uncover its weakness, the investigators said. They reported their findings in Cell Cycle.

“Our data demonstrated that BRCA1 synthesis is diminished in [the] advanced stage[s] of CML,” said study author Paulina Podszywałow-Bartnicka, PhD, of the Nencki Institute in Warsaw, Poland.

“The gene coding for BRCA1 protein is not mutated. However, BRCA1 mRNA, which is necessary for the protein production, is aggregated and stored in protein complexes [and], thus, not available for the protein synthesis.”

To gain more insight into this phenomenon, the investigators looked at 2 mRNA-binding proteins, HuR and TIAR. They found that BCR-ABL1 promoted cytosolic localization of TIAR and HuR, the proteins’ binding to BRCA1 mRNA, and formation of the TIAR-HuR complex.

The researchers also found that HuR positively regulated BRCA1 mRNA stability and translation, while TIAR negatively regulated BRCA1 translation.

TIAR-dependent downregulation of BRCA1 was a result of endoplasmic reticulum stress, which is activated in BCR-ABL1 expressing cells. And experiments showed that silencing TIAR in CML cells elevated BRCA1 levels.

This suggests that TIAR-mediated repression of BRCA1 mRNA translation is responsible for the downregulation of BRCA1 observed in BCR-ABL1-positive leukemia cells.

The investigators said this research indicates that BRCA1 deficiency, which supports CML, can be also used as a weapon against the disease.

“When a cell has damaged one signaling pathway or one gene, it may function properly due to alternative pathways . . . ,” explained study author Tomasz Skorski, MD, PhD, of Temple University School of Medicine in Philadelphia, Pennsylvania.

“Only when this alternative pathway is inhibited [do cells] lose the ability to survive. As we know that one of the [DNA double-strand break] repair pathways which depend on BRCA1 is blocked in leukemia cells, we can try to find the alternative, parallel pathway and inhibit it as well.”

This will induce apoptosis via synthetic lethality, but only in leukemia cells, because healthy cells still have functional BRCA1-dependent signaling. Dr Skorski noted that therapies based on BRCA1 deficiency are currently under investigation in clinical trials.

Micrograph showing CML

Image courtesy of UCSD

New discoveries concerning a well-known tumor suppressor protein could help advance the diagnosis and treatment of chronic myeloid leukemia (CML), according to researchers.

They found that levels of the protein, BRCA1, are significantly decreased in advanced phases of CML, the expression of BCR-ABL1 correlates with decreased levels of BRCA1, and this downregulation of BRCA1 is caused by the inhibition of BRCA1 messenger RNA (mRNA) translation.

These discoveries explain the mechanism that supports CML development and uncover its weakness, the investigators said. They reported their findings in Cell Cycle.

“Our data demonstrated that BRCA1 synthesis is diminished in [the] advanced stage[s] of CML,” said study author Paulina Podszywałow-Bartnicka, PhD, of the Nencki Institute in Warsaw, Poland.

“The gene coding for BRCA1 protein is not mutated. However, BRCA1 mRNA, which is necessary for the protein production, is aggregated and stored in protein complexes [and], thus, not available for the protein synthesis.”

To gain more insight into this phenomenon, the investigators looked at 2 mRNA-binding proteins, HuR and TIAR. They found that BCR-ABL1 promoted cytosolic localization of TIAR and HuR, the proteins’ binding to BRCA1 mRNA, and formation of the TIAR-HuR complex.

The researchers also found that HuR positively regulated BRCA1 mRNA stability and translation, while TIAR negatively regulated BRCA1 translation.

TIAR-dependent downregulation of BRCA1 was a result of endoplasmic reticulum stress, which is activated in BCR-ABL1 expressing cells. And experiments showed that silencing TIAR in CML cells elevated BRCA1 levels.

This suggests that TIAR-mediated repression of BRCA1 mRNA translation is responsible for the downregulation of BRCA1 observed in BCR-ABL1-positive leukemia cells.

The investigators said this research indicates that BRCA1 deficiency, which supports CML, can be also used as a weapon against the disease.

“When a cell has damaged one signaling pathway or one gene, it may function properly due to alternative pathways . . . ,” explained study author Tomasz Skorski, MD, PhD, of Temple University School of Medicine in Philadelphia, Pennsylvania.

“Only when this alternative pathway is inhibited [do cells] lose the ability to survive. As we know that one of the [DNA double-strand break] repair pathways which depend on BRCA1 is blocked in leukemia cells, we can try to find the alternative, parallel pathway and inhibit it as well.”

This will induce apoptosis via synthetic lethality, but only in leukemia cells, because healthy cells still have functional BRCA1-dependent signaling. Dr Skorski noted that therapies based on BRCA1 deficiency are currently under investigation in clinical trials.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan drug designation for IMO-8400, an antagonist of the endosomal toll-like receptors (TLRs) 7, 8, and 9, for the treatment of diffuse large B-cell lymphoma (DLBCL).

The FDA grants orphan designation to drugs intended to treat conditions that affect fewer than 200,000 people in the US.

The designation will provide Idera Pharmaceuticals, the company developing IMO-8400, with certain incentives. These include eligibility for federal grants, research and development tax credits, and a 7-year period of marketing exclusivity if the product is approved.

Relevant research

Preclinical research published in Leukemia showed that the MYD88 L265P oncogenic mutation is an independent prognostic factor in DLBCL. In DLBCL patients with this mutation, TLR signaling is over-activated, which enables tumor cell survival and proliferation.

Data presented at the 2014 AACR Annual Meeting showed that IMO-8400 inhibited the survival and proliferation of DLBCL cells and Waldenstrom’s macroglobulinemia (WM) cells harboring the MYD88 L265P mutation.

A phase 1 trial of IMO-8400 presented at the 2013 FOCIS Annual Meeting showed the drug was active and well-tolerated in 42 healthy subjects. IMO-8400 was given at single and multiple escalating doses up to 0.6 mg/kg for 4 weeks. The drug inhibited immune responses mediated by TLRs 7, 8, and 9.

Idera Pharmaceuticals is currently conducting a phase 1/2 trial of IMO-8400 in patients with relapsed or refractory DLBCL who harbor the MYD88 L265P mutation. The protocol includes 3 dose-escalation cohorts in which IMO-8400 is administered subcutaneously.

Idera is also pursuing clinical development of IMO-8400 in WM. The FDA recently granted the drug orphan designation to treat WM.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan drug designation for IMO-8400, an antagonist of the endosomal toll-like receptors (TLRs) 7, 8, and 9, for the treatment of diffuse large B-cell lymphoma (DLBCL).

The FDA grants orphan designation to drugs intended to treat conditions that affect fewer than 200,000 people in the US.

The designation will provide Idera Pharmaceuticals, the company developing IMO-8400, with certain incentives. These include eligibility for federal grants, research and development tax credits, and a 7-year period of marketing exclusivity if the product is approved.

Relevant research

Preclinical research published in Leukemia showed that the MYD88 L265P oncogenic mutation is an independent prognostic factor in DLBCL. In DLBCL patients with this mutation, TLR signaling is over-activated, which enables tumor cell survival and proliferation.

Data presented at the 2014 AACR Annual Meeting showed that IMO-8400 inhibited the survival and proliferation of DLBCL cells and Waldenstrom’s macroglobulinemia (WM) cells harboring the MYD88 L265P mutation.

A phase 1 trial of IMO-8400 presented at the 2013 FOCIS Annual Meeting showed the drug was active and well-tolerated in 42 healthy subjects. IMO-8400 was given at single and multiple escalating doses up to 0.6 mg/kg for 4 weeks. The drug inhibited immune responses mediated by TLRs 7, 8, and 9.

Idera Pharmaceuticals is currently conducting a phase 1/2 trial of IMO-8400 in patients with relapsed or refractory DLBCL who harbor the MYD88 L265P mutation. The protocol includes 3 dose-escalation cohorts in which IMO-8400 is administered subcutaneously.

Idera is also pursuing clinical development of IMO-8400 in WM. The FDA recently granted the drug orphan designation to treat WM.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan drug designation for IMO-8400, an antagonist of the endosomal toll-like receptors (TLRs) 7, 8, and 9, for the treatment of diffuse large B-cell lymphoma (DLBCL).

The FDA grants orphan designation to drugs intended to treat conditions that affect fewer than 200,000 people in the US.

The designation will provide Idera Pharmaceuticals, the company developing IMO-8400, with certain incentives. These include eligibility for federal grants, research and development tax credits, and a 7-year period of marketing exclusivity if the product is approved.

Relevant research

Preclinical research published in Leukemia showed that the MYD88 L265P oncogenic mutation is an independent prognostic factor in DLBCL. In DLBCL patients with this mutation, TLR signaling is over-activated, which enables tumor cell survival and proliferation.

Data presented at the 2014 AACR Annual Meeting showed that IMO-8400 inhibited the survival and proliferation of DLBCL cells and Waldenstrom’s macroglobulinemia (WM) cells harboring the MYD88 L265P mutation.

A phase 1 trial of IMO-8400 presented at the 2013 FOCIS Annual Meeting showed the drug was active and well-tolerated in 42 healthy subjects. IMO-8400 was given at single and multiple escalating doses up to 0.6 mg/kg for 4 weeks. The drug inhibited immune responses mediated by TLRs 7, 8, and 9.

Idera Pharmaceuticals is currently conducting a phase 1/2 trial of IMO-8400 in patients with relapsed or refractory DLBCL who harbor the MYD88 L265P mutation. The protocol includes 3 dose-escalation cohorts in which IMO-8400 is administered subcutaneously.

Idera is also pursuing clinical development of IMO-8400 in WM. The FDA recently granted the drug orphan designation to treat WM.

Doctor examining a child

Photo by Logan Tuttle

New research suggests the prevalence of childhood cancer survivors in the US has increased, and the majority of pediatric patients who have survived 5

or more years beyond cancer diagnosis may have at least one chronic health condition.

About 70% of the childhood cancer survivors studied were estimated to have a mild or moderate chronic condition, and nearly a third were estimated to have a severe, disabling, or life-threatening chronic condition.

“Our study findings highlight that a singular focus on curing cancer yields an incomplete picture of childhood cancer survivorship,” said study author Siobhan M. Phillips, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“The burden of chronic conditions in this population is profound, both in occurrence and severity. Efforts to understand how to effectively decrease morbidity burden and incorporate effective care coordination and rehabilitation models to optimize longevity and well-being in this population should be a priority.”

Dr Phillips and her colleagues reported their findings in Cancer Epidemiology, Biomarkers & Prevention.

The researchers analyzed data on cancer incidence and survival for children who were diagnosed with cancer between 0 and 19 years of age. The data had been recorded between 1975 and 2011 in 9 different US Surveillance, Epidemiology, and End Results (SEER) registries.

The team also used data from the Childhood Cancer Survivor Study (CCSS) cohort, which had information on a range of potential adverse and late effects of cancer treatment from more than 14,000 long-term survivors of childhood cancers who were treated at 26 cancer centers across the US and Canada.

The investigators first obtained estimates of the probability of each measure of morbidity from CCSS and then multiplied these estimates by the relevant number of survivors in the US estimated from the SEER data.

The researchers estimated the number of childhood cancer survivors in the US to be 388,501, which is an increase of 59,849 from the previous estimate made in 2005 by a team from the National Cancer Institute.

Of these patients, about 84% had survived 5 or more years post-diagnosis, and about 45% had survived for 20 years or more.

About 70% of the survivors were estimated to have a mild or moderate chronic condition (grade 1-2), and about 32% were estimated to have a severe, disabling, or life-threatening chronic condition (grade 3-4).

An estimated 35% of the survivors, ages 20 to 49, had neurocognitive dysfunction. About 13% to 17% of survivors in this age group had self-reported functional impairment, activity limitations, impaired mental health, pain, or anxiety/fear.

“We know that many of these morbidities are at least somewhat modifiable in the general population,” Dr Phillips noted. “However, we don’t know if typical population guidelines for preventive behaviors apply to [childhood cancer survivors].”

“We need to develop a better understanding of the multilevel factors—including, but not limited to, physical activity, diet, and treatment characteristics—which influence childhood cancer survivors’ susceptibility to these morbidities in order to effectively prevent and delay their onset.”

Doctor examining a child

Photo by Logan Tuttle

New research suggests the prevalence of childhood cancer survivors in the US has increased, and the majority of pediatric patients who have survived 5

or more years beyond cancer diagnosis may have at least one chronic health condition.

About 70% of the childhood cancer survivors studied were estimated to have a mild or moderate chronic condition, and nearly a third were estimated to have a severe, disabling, or life-threatening chronic condition.

“Our study findings highlight that a singular focus on curing cancer yields an incomplete picture of childhood cancer survivorship,” said study author Siobhan M. Phillips, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“The burden of chronic conditions in this population is profound, both in occurrence and severity. Efforts to understand how to effectively decrease morbidity burden and incorporate effective care coordination and rehabilitation models to optimize longevity and well-being in this population should be a priority.”

Dr Phillips and her colleagues reported their findings in Cancer Epidemiology, Biomarkers & Prevention.

The researchers analyzed data on cancer incidence and survival for children who were diagnosed with cancer between 0 and 19 years of age. The data had been recorded between 1975 and 2011 in 9 different US Surveillance, Epidemiology, and End Results (SEER) registries.

The team also used data from the Childhood Cancer Survivor Study (CCSS) cohort, which had information on a range of potential adverse and late effects of cancer treatment from more than 14,000 long-term survivors of childhood cancers who were treated at 26 cancer centers across the US and Canada.

The investigators first obtained estimates of the probability of each measure of morbidity from CCSS and then multiplied these estimates by the relevant number of survivors in the US estimated from the SEER data.

The researchers estimated the number of childhood cancer survivors in the US to be 388,501, which is an increase of 59,849 from the previous estimate made in 2005 by a team from the National Cancer Institute.

Of these patients, about 84% had survived 5 or more years post-diagnosis, and about 45% had survived for 20 years or more.

About 70% of the survivors were estimated to have a mild or moderate chronic condition (grade 1-2), and about 32% were estimated to have a severe, disabling, or life-threatening chronic condition (grade 3-4).

An estimated 35% of the survivors, ages 20 to 49, had neurocognitive dysfunction. About 13% to 17% of survivors in this age group had self-reported functional impairment, activity limitations, impaired mental health, pain, or anxiety/fear.

“We know that many of these morbidities are at least somewhat modifiable in the general population,” Dr Phillips noted. “However, we don’t know if typical population guidelines for preventive behaviors apply to [childhood cancer survivors].”

“We need to develop a better understanding of the multilevel factors—including, but not limited to, physical activity, diet, and treatment characteristics—which influence childhood cancer survivors’ susceptibility to these morbidities in order to effectively prevent and delay their onset.”

Doctor examining a child

Photo by Logan Tuttle

New research suggests the prevalence of childhood cancer survivors in the US has increased, and the majority of pediatric patients who have survived 5

or more years beyond cancer diagnosis may have at least one chronic health condition.

About 70% of the childhood cancer survivors studied were estimated to have a mild or moderate chronic condition, and nearly a third were estimated to have a severe, disabling, or life-threatening chronic condition.

“Our study findings highlight that a singular focus on curing cancer yields an incomplete picture of childhood cancer survivorship,” said study author Siobhan M. Phillips, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“The burden of chronic conditions in this population is profound, both in occurrence and severity. Efforts to understand how to effectively decrease morbidity burden and incorporate effective care coordination and rehabilitation models to optimize longevity and well-being in this population should be a priority.”

Dr Phillips and her colleagues reported their findings in Cancer Epidemiology, Biomarkers & Prevention.

The researchers analyzed data on cancer incidence and survival for children who were diagnosed with cancer between 0 and 19 years of age. The data had been recorded between 1975 and 2011 in 9 different US Surveillance, Epidemiology, and End Results (SEER) registries.

The team also used data from the Childhood Cancer Survivor Study (CCSS) cohort, which had information on a range of potential adverse and late effects of cancer treatment from more than 14,000 long-term survivors of childhood cancers who were treated at 26 cancer centers across the US and Canada.

The investigators first obtained estimates of the probability of each measure of morbidity from CCSS and then multiplied these estimates by the relevant number of survivors in the US estimated from the SEER data.

The researchers estimated the number of childhood cancer survivors in the US to be 388,501, which is an increase of 59,849 from the previous estimate made in 2005 by a team from the National Cancer Institute.

Of these patients, about 84% had survived 5 or more years post-diagnosis, and about 45% had survived for 20 years or more.

About 70% of the survivors were estimated to have a mild or moderate chronic condition (grade 1-2), and about 32% were estimated to have a severe, disabling, or life-threatening chronic condition (grade 3-4).

An estimated 35% of the survivors, ages 20 to 49, had neurocognitive dysfunction. About 13% to 17% of survivors in this age group had self-reported functional impairment, activity limitations, impaired mental health, pain, or anxiety/fear.

“We know that many of these morbidities are at least somewhat modifiable in the general population,” Dr Phillips noted. “However, we don’t know if typical population guidelines for preventive behaviors apply to [childhood cancer survivors].”

“We need to develop a better understanding of the multilevel factors—including, but not limited to, physical activity, diet, and treatment characteristics—which influence childhood cancer survivors’ susceptibility to these morbidities in order to effectively prevent and delay their onset.”

Day Four highlights from HM15, the Society of Hospital Medicine’s (SHM) annual meeting in National Harbor, Md., just outside Washington, D.C.

Day Four highlights from HM15, the Society of Hospital Medicine’s (SHM) annual meeting in National Harbor, Md., just outside Washington, D.C.

Day Four highlights from HM15, the Society of Hospital Medicine’s (SHM) annual meeting in National Harbor, Md., just outside Washington, D.C.

HM15 presenters: Verity Schaye, Michael Janjigian, Frank Volpicelli, Susan Hunt.

Performing a physical exam is the standard of care for evaluating patients. It has been shown to have higher diagnostic utility than many technology based tests. The physical exam is the Gold Standard for dermatological and mental status assessment for which technological tests are not readily available. The tradition “laying on of hands” has important benefits for the physician patient relationship.

The teaching of physical exam skills is increasingly problematic. Barriers include attending time, comfort and skill level as well as challenges of patient comfort and potential isolation issues.

The Peyton Model provides a better means of teaching physical exam skills than the traditional “See one, do one, teach one” model. The Peyton Model has four steps:

1. Demonstration. The teacher performs the exam at normal speed without commentary.
2. Deconstruction. The teacher performs the exam while describing the steps.
3. Comprehension. The teacher performs the exam while the learner describes the steps.
4. Performance. The learner performs the exam while also describing the steps.

This approach can be abbreviated for more advanced learners with the middle two steps being combined to a discussion between the teacher and learner to highlight any differences or changes in technique. TH

HM15 presenters: Verity Schaye, Michael Janjigian, Frank Volpicelli, Susan Hunt.

Performing a physical exam is the standard of care for evaluating patients. It has been shown to have higher diagnostic utility than many technology based tests. The physical exam is the Gold Standard for dermatological and mental status assessment for which technological tests are not readily available. The tradition “laying on of hands” has important benefits for the physician patient relationship.

The teaching of physical exam skills is increasingly problematic. Barriers include attending time, comfort and skill level as well as challenges of patient comfort and potential isolation issues.

The Peyton Model provides a better means of teaching physical exam skills than the traditional “See one, do one, teach one” model. The Peyton Model has four steps:

1. Demonstration. The teacher performs the exam at normal speed without commentary.
2. Deconstruction. The teacher performs the exam while describing the steps.
3. Comprehension. The teacher performs the exam while the learner describes the steps.
4. Performance. The learner performs the exam while also describing the steps.

This approach can be abbreviated for more advanced learners with the middle two steps being combined to a discussion between the teacher and learner to highlight any differences or changes in technique. TH

HM15 presenters: Verity Schaye, Michael Janjigian, Frank Volpicelli, Susan Hunt.

Performing a physical exam is the standard of care for evaluating patients. It has been shown to have higher diagnostic utility than many technology based tests. The physical exam is the Gold Standard for dermatological and mental status assessment for which technological tests are not readily available. The tradition “laying on of hands” has important benefits for the physician patient relationship.

The teaching of physical exam skills is increasingly problematic. Barriers include attending time, comfort and skill level as well as challenges of patient comfort and potential isolation issues.

The Peyton Model provides a better means of teaching physical exam skills than the traditional “See one, do one, teach one” model. The Peyton Model has four steps:

1. Demonstration. The teacher performs the exam at normal speed without commentary.
2. Deconstruction. The teacher performs the exam while describing the steps.
3. Comprehension. The teacher performs the exam while the learner describes the steps.
4. Performance. The learner performs the exam while also describing the steps.

This approach can be abbreviated for more advanced learners with the middle two steps being combined to a discussion between the teacher and learner to highlight any differences or changes in technique. TH