LAS VEGAS – A more-specific nomenclature of depression would help in the prescribing of better treatments or might prevent it altogether, according to Dr. Vladimir Maletic, a psychiatrist who spoke at this year’s Nevada Psychiatric Association’s annual Psychopharmacology update meeting.

But to do so requires psychiatry to find its own Darwinian moment, where the etiology of depression is made clear. In the conversation with Dr. Maletic, recorded at the meeting, hear his thoughts on the differences between existential and biological depression, how allowing patients to choose their treatment can double their response rate, and the lasting, negative effects on cognition post depression.

[email protected]

On Twitter @whitneymcknight

LAS VEGAS – A more-specific nomenclature of depression would help in the prescribing of better treatments or might prevent it altogether, according to Dr. Vladimir Maletic, a psychiatrist who spoke at this year’s Nevada Psychiatric Association’s annual Psychopharmacology update meeting.

But to do so requires psychiatry to find its own Darwinian moment, where the etiology of depression is made clear. In the conversation with Dr. Maletic, recorded at the meeting, hear his thoughts on the differences between existential and biological depression, how allowing patients to choose their treatment can double their response rate, and the lasting, negative effects on cognition post depression.

[email protected]

On Twitter @whitneymcknight

LAS VEGAS – A more-specific nomenclature of depression would help in the prescribing of better treatments or might prevent it altogether, according to Dr. Vladimir Maletic, a psychiatrist who spoke at this year’s Nevada Psychiatric Association’s annual Psychopharmacology update meeting.

But to do so requires psychiatry to find its own Darwinian moment, where the etiology of depression is made clear. In the conversation with Dr. Maletic, recorded at the meeting, hear his thoughts on the differences between existential and biological depression, how allowing patients to choose their treatment can double their response rate, and the lasting, negative effects on cognition post depression.

[email protected]

On Twitter @whitneymcknight

To the Editor: I read with avid interest the IM Board Review by Pagán et al on a man with pheochromocytoma.¹ The article stated that the classic triad is headache, hypertension, and hyperglycemia. I found this to be incorrect. And Harrison’s Principles of Internal Medicine² states that the classic triad is palpitations, headaches, and profuse sweating. I hope you will clarify this in the interest of the readers as it is a board review article.

To the Editor: I read with avid interest the IM Board Review by Pagán et al on a man with pheochromocytoma.¹ The article stated that the classic triad is headache, hypertension, and hyperglycemia. I found this to be incorrect. And Harrison’s Principles of Internal Medicine² states that the classic triad is palpitations, headaches, and profuse sweating. I hope you will clarify this in the interest of the readers as it is a board review article.

To the Editor: I read with avid interest the IM Board Review by Pagán et al on a man with pheochromocytoma.¹ The article stated that the classic triad is headache, hypertension, and hyperglycemia. I found this to be incorrect. And Harrison’s Principles of Internal Medicine² states that the classic triad is palpitations, headaches, and profuse sweating. I hope you will clarify this in the interest of the readers as it is a board review article.

EVIDENCE SUMMARY

Women with PCOS who are not seeking pregnancy commonly have symptoms such as excessive weight, hirsutism, and menstrual irregularities. This review focuses on interventions to manage those symptoms. The TABLE summarizes the results of the interventions.

Lifestyle modification improves symptoms; no benefit to adding metformin

A Cochrane meta-analysis of 6 RCTs with 164 patients compared LSM (with diet and exercise) and no or minimal intervention. LSM reduced weight more than minimal intervention (mean difference [MD]=-3.5 kg; 95% confidence interval [CI], -4.5 to -2.0).¹ It also improved hirsutism, assessed with the 36-point FG score, where a lower score corresponds to less hirsutism (MD=-1.2 points, 95% CI, -2.4 to -0.1). No data were available on menstrual regularity.

A double-blind RCT comparing LSM alone with LSM plus metformin in 114 patients with PCOS found no difference in mean weight reduction (-2- to -3 kg, data from graph), ovulation rate, or androgen levels at 6 months.² Six patients dropped out of the LSM-with-metformin group, whereas no patients dropped out of the LSM-alone group.

Metformin decreases BMI more than thiazolidinediones

In a meta-analysis of 10 RCTs (459 patients) comparing the effects of metformin and thiazolidinediones (TZDs), metformin reduced body mass index (BMI) more than TZDs at 3 months (weighted mean difference [WMD]=-2.5 kg/m²; 95% CI, -3.3 to -.6) and 6 months (WMD=-0.70 kg/m²; 95% CI, -0.76 to -0.65).³

In a prospective cohort dose-comparison study, 201 women with PCOS received either metformin 1000 mg or 1500 to 1700 mg daily for 6 months. Patients were asked not to modify their diet or exercise routines. In both dosage groups, patients lost weight from baseline (-3 kg; P<.01), and the number of menstrual cycles increased (0.7 per 6 months; P<.001).⁴ No clear dose-response relationship was observed.

Spironolactone can significantly reduce hirsutism

A systematic review identified 4 studies (132 patients) of antiandrogen therapy for hirsutism in PCOS. The 3 studies that used the FG score as an outcome all showed significant reductions in hirsutism after 6 to 12 months of treatment with spironolactone.⁵

Lifestyle modification and metformin both reduce body weight, but lifestyle modification may be better tolerated.

A 6-month RCT of 198 patients with PCOS compared outcomes for spironolactone (50 mg/d), metformin (1000 mg/d), or both. Combined therapy was marginally better than either agent alone for reducing the FG score (end score for combined therapy 9.1 vs 9.6 for spironolactone and 9.7 for metformin, an absolute difference for combined therapy vs spironolactone of -0.5 FG points or -1.4%; P<.05).⁶

OCPs normalize menstrual cycles and reduce hirsutism

A Cochrane review evaluating the effects of OCPs on patients with PCOS included 4 RCTs (104 patients) that compared OCPs with metformin (1500-2000 mg/d) and 2 RCTs (70 patients) that compared the combination of an OCP and metformin with the OCP alone. Use of an OCP was much more likely to normalize menstrual cycling than metformin alone (2 trials, N=35; odds ratio [OR]=12; 95% CI, 2.2-100). Combining an OCP with metformin resulted in slightly better FG scores than an OCP alone (1 trial, N=40; WMD=-2.8 points; 95% CI, -5.4 to -0.17).⁷ There was no difference in the final BMI between patients taking an OCP alone, metformin alone, or both.

An RCT of 35 patients compared the effect on insulin levels of an OCP with rosiglitazone 4 mg/d and also looked at menstrual cycling as a secondary outcome. The study found no difference in effect on insulin levels in the 2 groups. All patients taking the OCP reported regular menstrual cycles at the end of the study compared with 75% of the patients taking rosiglitazone (P=.7).⁸ The study was underpowered to find a difference, however.

Statins alone don’t affect hirsutism, menstruation, or BMI

A Cochrane review identified 4 RCTs (244 women, ages 18-39 years) that compared a statin alone with placebo, another agent, or another agent plus a statin.⁹ One RCT of 48 patients found that a statin combined with an OCP improved hirsutism compared with a statin alone. Two RCTs (85 patients) found that statins didn’t lead to resumption of regular menstrual cycles. Statins also didn’t alter BMI in 3 studies of 105 patients.

Trials report no adverse effects, but VTE may be a concern with OCPs

A meta-analysis evaluated the safety of metformin, OCPs, and antiandrogens in 22 clinical trials with 1335 patients, primarily PCOS patients. The trials reported no cases of lactic acidosis with metformin, no drug-induced liver injury with antiandrogens, and no venous thromboembolism (VTE) with OCPs. The meta-analysis authors noted, however, that in a cohort trial of 1.6 million Danish women followed for 15 years, OCPs were associated with a 2- to 3-fold increase in risk of VTE, with higher risks linked to higher ethinyl estradiol content.¹⁰

RECOMMENDATIONS

A 2009 practice bulletin from The American College of Obestetrics and Gynecology (ACOG) recommends OCPs, progestin, metformin, and TZDs for anovulation and amenorrhea in patients with PCOS. OCPs, antiandrogens, metformin, eflornithine, and mechanical hair removal are recommended for hirsutism. ACOG advocates LSM, insulin-sensitizing agents (such as metformin), and statins to prevent cardiovascular disease and diabetes.¹¹

EVIDENCE SUMMARY

Women with PCOS who are not seeking pregnancy commonly have symptoms such as excessive weight, hirsutism, and menstrual irregularities. This review focuses on interventions to manage those symptoms. The TABLE summarizes the results of the interventions.

Lifestyle modification improves symptoms; no benefit to adding metformin

A Cochrane meta-analysis of 6 RCTs with 164 patients compared LSM (with diet and exercise) and no or minimal intervention. LSM reduced weight more than minimal intervention (mean difference [MD]=-3.5 kg; 95% confidence interval [CI], -4.5 to -2.0).¹ It also improved hirsutism, assessed with the 36-point FG score, where a lower score corresponds to less hirsutism (MD=-1.2 points, 95% CI, -2.4 to -0.1). No data were available on menstrual regularity.

A double-blind RCT comparing LSM alone with LSM plus metformin in 114 patients with PCOS found no difference in mean weight reduction (-2- to -3 kg, data from graph), ovulation rate, or androgen levels at 6 months.² Six patients dropped out of the LSM-with-metformin group, whereas no patients dropped out of the LSM-alone group.

Metformin decreases BMI more than thiazolidinediones

In a meta-analysis of 10 RCTs (459 patients) comparing the effects of metformin and thiazolidinediones (TZDs), metformin reduced body mass index (BMI) more than TZDs at 3 months (weighted mean difference [WMD]=-2.5 kg/m²; 95% CI, -3.3 to -.6) and 6 months (WMD=-0.70 kg/m²; 95% CI, -0.76 to -0.65).³

In a prospective cohort dose-comparison study, 201 women with PCOS received either metformin 1000 mg or 1500 to 1700 mg daily for 6 months. Patients were asked not to modify their diet or exercise routines. In both dosage groups, patients lost weight from baseline (-3 kg; P<.01), and the number of menstrual cycles increased (0.7 per 6 months; P<.001).⁴ No clear dose-response relationship was observed.

Spironolactone can significantly reduce hirsutism

A systematic review identified 4 studies (132 patients) of antiandrogen therapy for hirsutism in PCOS. The 3 studies that used the FG score as an outcome all showed significant reductions in hirsutism after 6 to 12 months of treatment with spironolactone.⁵

Lifestyle modification and metformin both reduce body weight, but lifestyle modification may be better tolerated.

A 6-month RCT of 198 patients with PCOS compared outcomes for spironolactone (50 mg/d), metformin (1000 mg/d), or both. Combined therapy was marginally better than either agent alone for reducing the FG score (end score for combined therapy 9.1 vs 9.6 for spironolactone and 9.7 for metformin, an absolute difference for combined therapy vs spironolactone of -0.5 FG points or -1.4%; P<.05).⁶

OCPs normalize menstrual cycles and reduce hirsutism

A Cochrane review evaluating the effects of OCPs on patients with PCOS included 4 RCTs (104 patients) that compared OCPs with metformin (1500-2000 mg/d) and 2 RCTs (70 patients) that compared the combination of an OCP and metformin with the OCP alone. Use of an OCP was much more likely to normalize menstrual cycling than metformin alone (2 trials, N=35; odds ratio [OR]=12; 95% CI, 2.2-100). Combining an OCP with metformin resulted in slightly better FG scores than an OCP alone (1 trial, N=40; WMD=-2.8 points; 95% CI, -5.4 to -0.17).⁷ There was no difference in the final BMI between patients taking an OCP alone, metformin alone, or both.

An RCT of 35 patients compared the effect on insulin levels of an OCP with rosiglitazone 4 mg/d and also looked at menstrual cycling as a secondary outcome. The study found no difference in effect on insulin levels in the 2 groups. All patients taking the OCP reported regular menstrual cycles at the end of the study compared with 75% of the patients taking rosiglitazone (P=.7).⁸ The study was underpowered to find a difference, however.

Statins alone don’t affect hirsutism, menstruation, or BMI

A Cochrane review identified 4 RCTs (244 women, ages 18-39 years) that compared a statin alone with placebo, another agent, or another agent plus a statin.⁹ One RCT of 48 patients found that a statin combined with an OCP improved hirsutism compared with a statin alone. Two RCTs (85 patients) found that statins didn’t lead to resumption of regular menstrual cycles. Statins also didn’t alter BMI in 3 studies of 105 patients.

Trials report no adverse effects, but VTE may be a concern with OCPs

A meta-analysis evaluated the safety of metformin, OCPs, and antiandrogens in 22 clinical trials with 1335 patients, primarily PCOS patients. The trials reported no cases of lactic acidosis with metformin, no drug-induced liver injury with antiandrogens, and no venous thromboembolism (VTE) with OCPs. The meta-analysis authors noted, however, that in a cohort trial of 1.6 million Danish women followed for 15 years, OCPs were associated with a 2- to 3-fold increase in risk of VTE, with higher risks linked to higher ethinyl estradiol content.¹⁰

RECOMMENDATIONS

A 2009 practice bulletin from The American College of Obestetrics and Gynecology (ACOG) recommends OCPs, progestin, metformin, and TZDs for anovulation and amenorrhea in patients with PCOS. OCPs, antiandrogens, metformin, eflornithine, and mechanical hair removal are recommended for hirsutism. ACOG advocates LSM, insulin-sensitizing agents (such as metformin), and statins to prevent cardiovascular disease and diabetes.¹¹

EVIDENCE SUMMARY

Women with PCOS who are not seeking pregnancy commonly have symptoms such as excessive weight, hirsutism, and menstrual irregularities. This review focuses on interventions to manage those symptoms. The TABLE summarizes the results of the interventions.

Lifestyle modification improves symptoms; no benefit to adding metformin

A Cochrane meta-analysis of 6 RCTs with 164 patients compared LSM (with diet and exercise) and no or minimal intervention. LSM reduced weight more than minimal intervention (mean difference [MD]=-3.5 kg; 95% confidence interval [CI], -4.5 to -2.0).¹ It also improved hirsutism, assessed with the 36-point FG score, where a lower score corresponds to less hirsutism (MD=-1.2 points, 95% CI, -2.4 to -0.1). No data were available on menstrual regularity.

A double-blind RCT comparing LSM alone with LSM plus metformin in 114 patients with PCOS found no difference in mean weight reduction (-2- to -3 kg, data from graph), ovulation rate, or androgen levels at 6 months.² Six patients dropped out of the LSM-with-metformin group, whereas no patients dropped out of the LSM-alone group.

Metformin decreases BMI more than thiazolidinediones

In a meta-analysis of 10 RCTs (459 patients) comparing the effects of metformin and thiazolidinediones (TZDs), metformin reduced body mass index (BMI) more than TZDs at 3 months (weighted mean difference [WMD]=-2.5 kg/m²; 95% CI, -3.3 to -.6) and 6 months (WMD=-0.70 kg/m²; 95% CI, -0.76 to -0.65).³

In a prospective cohort dose-comparison study, 201 women with PCOS received either metformin 1000 mg or 1500 to 1700 mg daily for 6 months. Patients were asked not to modify their diet or exercise routines. In both dosage groups, patients lost weight from baseline (-3 kg; P<.01), and the number of menstrual cycles increased (0.7 per 6 months; P<.001).⁴ No clear dose-response relationship was observed.

Spironolactone can significantly reduce hirsutism

A systematic review identified 4 studies (132 patients) of antiandrogen therapy for hirsutism in PCOS. The 3 studies that used the FG score as an outcome all showed significant reductions in hirsutism after 6 to 12 months of treatment with spironolactone.⁵

Lifestyle modification and metformin both reduce body weight, but lifestyle modification may be better tolerated.

A 6-month RCT of 198 patients with PCOS compared outcomes for spironolactone (50 mg/d), metformin (1000 mg/d), or both. Combined therapy was marginally better than either agent alone for reducing the FG score (end score for combined therapy 9.1 vs 9.6 for spironolactone and 9.7 for metformin, an absolute difference for combined therapy vs spironolactone of -0.5 FG points or -1.4%; P<.05).⁶

OCPs normalize menstrual cycles and reduce hirsutism

A Cochrane review evaluating the effects of OCPs on patients with PCOS included 4 RCTs (104 patients) that compared OCPs with metformin (1500-2000 mg/d) and 2 RCTs (70 patients) that compared the combination of an OCP and metformin with the OCP alone. Use of an OCP was much more likely to normalize menstrual cycling than metformin alone (2 trials, N=35; odds ratio [OR]=12; 95% CI, 2.2-100). Combining an OCP with metformin resulted in slightly better FG scores than an OCP alone (1 trial, N=40; WMD=-2.8 points; 95% CI, -5.4 to -0.17).⁷ There was no difference in the final BMI between patients taking an OCP alone, metformin alone, or both.

An RCT of 35 patients compared the effect on insulin levels of an OCP with rosiglitazone 4 mg/d and also looked at menstrual cycling as a secondary outcome. The study found no difference in effect on insulin levels in the 2 groups. All patients taking the OCP reported regular menstrual cycles at the end of the study compared with 75% of the patients taking rosiglitazone (P=.7).⁸ The study was underpowered to find a difference, however.

Statins alone don’t affect hirsutism, menstruation, or BMI

A Cochrane review identified 4 RCTs (244 women, ages 18-39 years) that compared a statin alone with placebo, another agent, or another agent plus a statin.⁹ One RCT of 48 patients found that a statin combined with an OCP improved hirsutism compared with a statin alone. Two RCTs (85 patients) found that statins didn’t lead to resumption of regular menstrual cycles. Statins also didn’t alter BMI in 3 studies of 105 patients.

Trials report no adverse effects, but VTE may be a concern with OCPs

A meta-analysis evaluated the safety of metformin, OCPs, and antiandrogens in 22 clinical trials with 1335 patients, primarily PCOS patients. The trials reported no cases of lactic acidosis with metformin, no drug-induced liver injury with antiandrogens, and no venous thromboembolism (VTE) with OCPs. The meta-analysis authors noted, however, that in a cohort trial of 1.6 million Danish women followed for 15 years, OCPs were associated with a 2- to 3-fold increase in risk of VTE, with higher risks linked to higher ethinyl estradiol content.¹⁰

RECOMMENDATIONS

A 2009 practice bulletin from The American College of Obestetrics and Gynecology (ACOG) recommends OCPs, progestin, metformin, and TZDs for anovulation and amenorrhea in patients with PCOS. OCPs, antiandrogens, metformin, eflornithine, and mechanical hair removal are recommended for hirsutism. ACOG advocates LSM, insulin-sensitizing agents (such as metformin), and statins to prevent cardiovascular disease and diabetes.¹¹

In Reply: Thanks to Dr. Belur for his observation. He is correct in that the classic triad includes headaches, palpitations, and diaphoresis, although hypertension and hyperglycemia have been described in the literature as frequently occurring, and the clinical presentation can be extremely variable.

In Reply: Thanks to Dr. Belur for his observation. He is correct in that the classic triad includes headaches, palpitations, and diaphoresis, although hypertension and hyperglycemia have been described in the literature as frequently occurring, and the clinical presentation can be extremely variable.

In Reply: Thanks to Dr. Belur for his observation. He is correct in that the classic triad includes headaches, palpitations, and diaphoresis, although hypertension and hyperglycemia have been described in the literature as frequently occurring, and the clinical presentation can be extremely variable.

To the Editor: The article by Dr. Catherine Curley,¹ “Rule out pulmonary tuberculosis: clinical and radiographic clues for the internist,” was very well written, but we would like to point out two facts regarding the diagnosis of pulmonary tuberculosis, especially in high-prevalence countries like India, that might make the article more informative.

First, it has been shown conclusively that good-quality microscopy of two consecutive sputum specimens identifies the majority (95%–98%) of smear-positive tuberculosis patients. The World Health Organization (WHO) therefore revised its policy on case detection by microscopy² in 2007 to recommend a reduction in the number of specimens examined, from three to two in settings with appropriate external quality assurance and documented good-quality microscopy. This approach greatly reduces the workload of laboratories, a considerable advantage in countries with a high proportion of smear-negative tuberculosis patients because of human immunodeficiency virus (HIV), extrapulmonary disease, or both.

Moreover, in 2011, the WHO recommended in a policy statement that countries that have implemented the current WHO policy for two-specimen case-finding consider switching to same-day diagnosis, especially in settings where patients are likely to default from the diagnostic pathway.³

Second, regarding the interferon-gamma-release assay, the 2011 WHO policy stated that there are not only insufficient data and low-quality evidence on the performance of this assay in low- and middle-income countries, typically those with a high tuberculosis and HIV burden, but also that the interferon-gamma-release assay and the tuberculin skin test cannot accurately predict the risk of infected individuals developing active tuberculosis. Moreover, neither the assay nor the skin test should be used for the diagnosis of active tuberculosis disease. The interferon-gamma-release assay is more costly and technically complex than the skin test. Given comparable performance but the increased cost, replacing the skin test with the interferon-gamma-release assay is not recommended as a public health intervention in resource-constrained settings.⁴ The majority of tuberculosis cases (on average 85.8%) were detected with the first sputum specimen. With the second sputum specimen, the average incremental yield was 11.9%, while the incremental yield of the third specimen, when the first two specimens were negative, was 3.1%.⁵

To the Editor: The article by Dr. Catherine Curley,¹ “Rule out pulmonary tuberculosis: clinical and radiographic clues for the internist,” was very well written, but we would like to point out two facts regarding the diagnosis of pulmonary tuberculosis, especially in high-prevalence countries like India, that might make the article more informative.

First, it has been shown conclusively that good-quality microscopy of two consecutive sputum specimens identifies the majority (95%–98%) of smear-positive tuberculosis patients. The World Health Organization (WHO) therefore revised its policy on case detection by microscopy² in 2007 to recommend a reduction in the number of specimens examined, from three to two in settings with appropriate external quality assurance and documented good-quality microscopy. This approach greatly reduces the workload of laboratories, a considerable advantage in countries with a high proportion of smear-negative tuberculosis patients because of human immunodeficiency virus (HIV), extrapulmonary disease, or both.

Moreover, in 2011, the WHO recommended in a policy statement that countries that have implemented the current WHO policy for two-specimen case-finding consider switching to same-day diagnosis, especially in settings where patients are likely to default from the diagnostic pathway.³

Second, regarding the interferon-gamma-release assay, the 2011 WHO policy stated that there are not only insufficient data and low-quality evidence on the performance of this assay in low- and middle-income countries, typically those with a high tuberculosis and HIV burden, but also that the interferon-gamma-release assay and the tuberculin skin test cannot accurately predict the risk of infected individuals developing active tuberculosis. Moreover, neither the assay nor the skin test should be used for the diagnosis of active tuberculosis disease. The interferon-gamma-release assay is more costly and technically complex than the skin test. Given comparable performance but the increased cost, replacing the skin test with the interferon-gamma-release assay is not recommended as a public health intervention in resource-constrained settings.⁴ The majority of tuberculosis cases (on average 85.8%) were detected with the first sputum specimen. With the second sputum specimen, the average incremental yield was 11.9%, while the incremental yield of the third specimen, when the first two specimens were negative, was 3.1%.⁵

To the Editor: The article by Dr. Catherine Curley,¹ “Rule out pulmonary tuberculosis: clinical and radiographic clues for the internist,” was very well written, but we would like to point out two facts regarding the diagnosis of pulmonary tuberculosis, especially in high-prevalence countries like India, that might make the article more informative.

First, it has been shown conclusively that good-quality microscopy of two consecutive sputum specimens identifies the majority (95%–98%) of smear-positive tuberculosis patients. The World Health Organization (WHO) therefore revised its policy on case detection by microscopy² in 2007 to recommend a reduction in the number of specimens examined, from three to two in settings with appropriate external quality assurance and documented good-quality microscopy. This approach greatly reduces the workload of laboratories, a considerable advantage in countries with a high proportion of smear-negative tuberculosis patients because of human immunodeficiency virus (HIV), extrapulmonary disease, or both.

Moreover, in 2011, the WHO recommended in a policy statement that countries that have implemented the current WHO policy for two-specimen case-finding consider switching to same-day diagnosis, especially in settings where patients are likely to default from the diagnostic pathway.³

Second, regarding the interferon-gamma-release assay, the 2011 WHO policy stated that there are not only insufficient data and low-quality evidence on the performance of this assay in low- and middle-income countries, typically those with a high tuberculosis and HIV burden, but also that the interferon-gamma-release assay and the tuberculin skin test cannot accurately predict the risk of infected individuals developing active tuberculosis. Moreover, neither the assay nor the skin test should be used for the diagnosis of active tuberculosis disease. The interferon-gamma-release assay is more costly and technically complex than the skin test. Given comparable performance but the increased cost, replacing the skin test with the interferon-gamma-release assay is not recommended as a public health intervention in resource-constrained settings.⁴ The majority of tuberculosis cases (on average 85.8%) were detected with the first sputum specimen. With the second sputum specimen, the average incremental yield was 11.9%, while the incremental yield of the third specimen, when the first two specimens were negative, was 3.1%.⁵

In Reply: Thank you for your interesting and appropriate comments. The workup and testing of patients with suspected tuberculosis is clearly different in countries with a higher prevalence of tuberculosis than in countries with a lower prevalence. I appreciate that both the purified protein derivative and the interferon-gamma-release assay have very limited utility in the evaluation for active tuberculosis when there is a very high background prevalence of latent tuberculosis infection. In low-prevalence countries like the United States, tuberculosis is often considered in the differential diagnosis even when other infections or lung cancer is more likely. The tests for latent tuberculosis are considered quite important in the workup of active tuberculosis in this setting.

In Reply: Thank you for your interesting and appropriate comments. The workup and testing of patients with suspected tuberculosis is clearly different in countries with a higher prevalence of tuberculosis than in countries with a lower prevalence. I appreciate that both the purified protein derivative and the interferon-gamma-release assay have very limited utility in the evaluation for active tuberculosis when there is a very high background prevalence of latent tuberculosis infection. In low-prevalence countries like the United States, tuberculosis is often considered in the differential diagnosis even when other infections or lung cancer is more likely. The tests for latent tuberculosis are considered quite important in the workup of active tuberculosis in this setting.

In Reply: Thank you for your interesting and appropriate comments. The workup and testing of patients with suspected tuberculosis is clearly different in countries with a higher prevalence of tuberculosis than in countries with a lower prevalence. I appreciate that both the purified protein derivative and the interferon-gamma-release assay have very limited utility in the evaluation for active tuberculosis when there is a very high background prevalence of latent tuberculosis infection. In low-prevalence countries like the United States, tuberculosis is often considered in the differential diagnosis even when other infections or lung cancer is more likely. The tests for latent tuberculosis are considered quite important in the workup of active tuberculosis in this setting.

EVIDENCE SUMMARY

A systematic review including 4 case-control and 3 cohort studies of the impact of nocturnal enuresis on children and young people found that bedwetting was often, but not always, associated with lower self-esteem scores (or scores for symptoms similar to lower self-esteem) on standardized questionnaires.¹ The studies defined self-esteem in various ways and used a variety of questionnaires to measure it, so direct comparisons weren’t possible.

The first case-control study in the review found that enuretic older children (10-12 years) and girls had lower self-esteem scores than younger children (8-9 years) and boys. The second case-control study reported lower self-esteem scores on only 1 of 3 assessment instruments.

The third case-control study, which compared self-esteem scores in enuretic children with scores for children who had asthma and heart disease, found that enuresis was associated with the lowest self-esteem. The final case-control study reported that young adolescents with enuresis were more likely to suffer “angry distress.”

The first cohort study in the systematic review found a significantly higher incidence of sadness, anxiety, and social fears in children with enuresis than in children without and reported that 65% were “not happy” about having enuresis.

In the second cohort study, children with more severe enuresis, and girls, had significantly worse self-esteem scores than children with mild enuresis or boys (actual scores and some statistics not supplied), although these findings weren’t replicated on the second standardized scale that the investigators used.

The third cohort study reported that 37% of approximately 800 children with enuresis rated it “really difficult,” on a 4-point Likert scale.

How enuresis treatment affects self-esteem

The same systematic review, plus 2 additional studies, demonstrated that successful treatment of enuresis improves self-esteem scores, likely to normal.^1-3 A randomized controlled trial found that treatment improved self-esteem scores by about 5%; children with the greatest treatment success showed the largest improvement (no statistics supplied).²

In a prospective cohort study, treated children demonstrated about a 30% improvement in scores measuring anxiety, depression, and internal distress.³ A case-control study in the systematic review also found about a 30% improvement in self-esteem scores among successfully treated children (both boys and girls) and a return to nonenuretic norms.¹ Scores for unsuccessfully treated children didn’t improve.

RECOMMENDATIONS

A guideline on the management of bedwetting from the National Institute for Health and Clinical Excellence (now called the National Institute for Health and Care Excellence) says that enuresis can have a deep impact on a child’s behavior and emotional well-being and that treatment has a positive effect on self-esteem.⁴

The Evidence-Based Medicine guidelines for enuresis in a child⁵ say that enuresis as such does not indicate a psychological disturbance and that psychotherapy may be useful when enuresis is associated with significant problems of self-esteem or behavior.

The American Academy of Child and Adolescent Psychiatry practice parameter for children with enuresis states that the psychological consequences of enuresis must be recognized and addressed with sensitivity during evaluation and management.⁶

EVIDENCE SUMMARY

A systematic review including 4 case-control and 3 cohort studies of the impact of nocturnal enuresis on children and young people found that bedwetting was often, but not always, associated with lower self-esteem scores (or scores for symptoms similar to lower self-esteem) on standardized questionnaires.¹ The studies defined self-esteem in various ways and used a variety of questionnaires to measure it, so direct comparisons weren’t possible.

The first case-control study in the review found that enuretic older children (10-12 years) and girls had lower self-esteem scores than younger children (8-9 years) and boys. The second case-control study reported lower self-esteem scores on only 1 of 3 assessment instruments.

The third case-control study, which compared self-esteem scores in enuretic children with scores for children who had asthma and heart disease, found that enuresis was associated with the lowest self-esteem. The final case-control study reported that young adolescents with enuresis were more likely to suffer “angry distress.”

The first cohort study in the systematic review found a significantly higher incidence of sadness, anxiety, and social fears in children with enuresis than in children without and reported that 65% were “not happy” about having enuresis.

In the second cohort study, children with more severe enuresis, and girls, had significantly worse self-esteem scores than children with mild enuresis or boys (actual scores and some statistics not supplied), although these findings weren’t replicated on the second standardized scale that the investigators used.

The third cohort study reported that 37% of approximately 800 children with enuresis rated it “really difficult,” on a 4-point Likert scale.

How enuresis treatment affects self-esteem

The same systematic review, plus 2 additional studies, demonstrated that successful treatment of enuresis improves self-esteem scores, likely to normal.^1-3 A randomized controlled trial found that treatment improved self-esteem scores by about 5%; children with the greatest treatment success showed the largest improvement (no statistics supplied).²

In a prospective cohort study, treated children demonstrated about a 30% improvement in scores measuring anxiety, depression, and internal distress.³ A case-control study in the systematic review also found about a 30% improvement in self-esteem scores among successfully treated children (both boys and girls) and a return to nonenuretic norms.¹ Scores for unsuccessfully treated children didn’t improve.

RECOMMENDATIONS

A guideline on the management of bedwetting from the National Institute for Health and Clinical Excellence (now called the National Institute for Health and Care Excellence) says that enuresis can have a deep impact on a child’s behavior and emotional well-being and that treatment has a positive effect on self-esteem.⁴

The Evidence-Based Medicine guidelines for enuresis in a child⁵ say that enuresis as such does not indicate a psychological disturbance and that psychotherapy may be useful when enuresis is associated with significant problems of self-esteem or behavior.

The American Academy of Child and Adolescent Psychiatry practice parameter for children with enuresis states that the psychological consequences of enuresis must be recognized and addressed with sensitivity during evaluation and management.⁶

EVIDENCE SUMMARY

A systematic review including 4 case-control and 3 cohort studies of the impact of nocturnal enuresis on children and young people found that bedwetting was often, but not always, associated with lower self-esteem scores (or scores for symptoms similar to lower self-esteem) on standardized questionnaires.¹ The studies defined self-esteem in various ways and used a variety of questionnaires to measure it, so direct comparisons weren’t possible.

The first case-control study in the review found that enuretic older children (10-12 years) and girls had lower self-esteem scores than younger children (8-9 years) and boys. The second case-control study reported lower self-esteem scores on only 1 of 3 assessment instruments.

The third case-control study, which compared self-esteem scores in enuretic children with scores for children who had asthma and heart disease, found that enuresis was associated with the lowest self-esteem. The final case-control study reported that young adolescents with enuresis were more likely to suffer “angry distress.”

The first cohort study in the systematic review found a significantly higher incidence of sadness, anxiety, and social fears in children with enuresis than in children without and reported that 65% were “not happy” about having enuresis.

In the second cohort study, children with more severe enuresis, and girls, had significantly worse self-esteem scores than children with mild enuresis or boys (actual scores and some statistics not supplied), although these findings weren’t replicated on the second standardized scale that the investigators used.

The third cohort study reported that 37% of approximately 800 children with enuresis rated it “really difficult,” on a 4-point Likert scale.

How enuresis treatment affects self-esteem

The same systematic review, plus 2 additional studies, demonstrated that successful treatment of enuresis improves self-esteem scores, likely to normal.^1-3 A randomized controlled trial found that treatment improved self-esteem scores by about 5%; children with the greatest treatment success showed the largest improvement (no statistics supplied).²

In a prospective cohort study, treated children demonstrated about a 30% improvement in scores measuring anxiety, depression, and internal distress.³ A case-control study in the systematic review also found about a 30% improvement in self-esteem scores among successfully treated children (both boys and girls) and a return to nonenuretic norms.¹ Scores for unsuccessfully treated children didn’t improve.

RECOMMENDATIONS

A guideline on the management of bedwetting from the National Institute for Health and Clinical Excellence (now called the National Institute for Health and Care Excellence) says that enuresis can have a deep impact on a child’s behavior and emotional well-being and that treatment has a positive effect on self-esteem.⁴

The Evidence-Based Medicine guidelines for enuresis in a child⁵ say that enuresis as such does not indicate a psychological disturbance and that psychotherapy may be useful when enuresis is associated with significant problems of self-esteem or behavior.

The American Academy of Child and Adolescent Psychiatry practice parameter for children with enuresis states that the psychological consequences of enuresis must be recognized and addressed with sensitivity during evaluation and management.⁶

 

 

Woman sunbathing

 

Vitamin D deficiency may negatively impact outcomes in patients with follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.

The study showed that FL patients with vitamin D deficiency had inferior progression-free survival (PFS) and overall survival (OS) compared to patients with higher vitamin D levels.

According to researchers, this suggests serum vitamin D might be the first potentially modifiable factor to be associated with survival in FL.

However, additional research is needed to determine the effects of vitamin D supplementation in these patients.

Jonathan W. Friedberg, MD, of the Wilmot Cancer Institute at the University of Rochester in New York, and his colleagues conducted this research, analyzing data from 2 cohorts of FL patients.

One cohort consisted of patients derived from 3 SWOG trials (S9800, S9911, and S0016), and the other consisted of patients from a Lymphoma Study Association (LYSA) trial known as PRIMA.

SWOG patients had received CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab), and LYSA patients had received rituximab plus chemotherapy (and were randomized to rituximab maintenance or observation).

SWOG cohort

After a median follow-up of 5.4 years, patients with vitamin D deficiency (defined as <20 ng/mL) had significantly inferior PFS (hazard ratio [HR]=2.00; P=0.011) and OS (HR=3.57; P=0.003) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (IPI), body mass index, and latitude (≥ vs <35°N). For PFS, the adjusted HR was 1.97 (P=0.023). And for OS, the adjusted HR was 4.16 (P=0.002).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but neither result was significant.

LYSA cohort

After a median follow-up of 6.6 years, patients with vitamin D deficiency (defined as <10 ng/mL) had significantly inferior PFS (HR=1.66; P=0.013) but not OS (HR=1.84; P=0.14) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (FLIPI), body mass index, latitude (Europe vs Australia), and hemoglobin. For PFS, the adjusted HR was 1.50 (P=0.095). For OS, the adjusted HR was 1.92 (P=0.192).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but only the association with OS reached statistical significance (HR=5.32; P=0.037).

Dr Friedberg said that, taken together, these results suggest vitamin D levels may be a modifiable factor associated with prognosis in patients with FL.

“Our data, replicated internationally, supports other published observations linking vitamin D deficiency with inferior cancer outcomes,” he said. “However, the mechanisms of this link are likely complex and require further study.”

 

 

Woman sunbathing

 

Vitamin D deficiency may negatively impact outcomes in patients with follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.

The study showed that FL patients with vitamin D deficiency had inferior progression-free survival (PFS) and overall survival (OS) compared to patients with higher vitamin D levels.

According to researchers, this suggests serum vitamin D might be the first potentially modifiable factor to be associated with survival in FL.

However, additional research is needed to determine the effects of vitamin D supplementation in these patients.

Jonathan W. Friedberg, MD, of the Wilmot Cancer Institute at the University of Rochester in New York, and his colleagues conducted this research, analyzing data from 2 cohorts of FL patients.

One cohort consisted of patients derived from 3 SWOG trials (S9800, S9911, and S0016), and the other consisted of patients from a Lymphoma Study Association (LYSA) trial known as PRIMA.

SWOG patients had received CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab), and LYSA patients had received rituximab plus chemotherapy (and were randomized to rituximab maintenance or observation).

SWOG cohort

After a median follow-up of 5.4 years, patients with vitamin D deficiency (defined as <20 ng/mL) had significantly inferior PFS (hazard ratio [HR]=2.00; P=0.011) and OS (HR=3.57; P=0.003) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (IPI), body mass index, and latitude (≥ vs <35°N). For PFS, the adjusted HR was 1.97 (P=0.023). And for OS, the adjusted HR was 4.16 (P=0.002).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but neither result was significant.

LYSA cohort

After a median follow-up of 6.6 years, patients with vitamin D deficiency (defined as <10 ng/mL) had significantly inferior PFS (HR=1.66; P=0.013) but not OS (HR=1.84; P=0.14) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (FLIPI), body mass index, latitude (Europe vs Australia), and hemoglobin. For PFS, the adjusted HR was 1.50 (P=0.095). For OS, the adjusted HR was 1.92 (P=0.192).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but only the association with OS reached statistical significance (HR=5.32; P=0.037).

Dr Friedberg said that, taken together, these results suggest vitamin D levels may be a modifiable factor associated with prognosis in patients with FL.

“Our data, replicated internationally, supports other published observations linking vitamin D deficiency with inferior cancer outcomes,” he said. “However, the mechanisms of this link are likely complex and require further study.”

 

 

Woman sunbathing

 

Vitamin D deficiency may negatively impact outcomes in patients with follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.

The study showed that FL patients with vitamin D deficiency had inferior progression-free survival (PFS) and overall survival (OS) compared to patients with higher vitamin D levels.

According to researchers, this suggests serum vitamin D might be the first potentially modifiable factor to be associated with survival in FL.

However, additional research is needed to determine the effects of vitamin D supplementation in these patients.

Jonathan W. Friedberg, MD, of the Wilmot Cancer Institute at the University of Rochester in New York, and his colleagues conducted this research, analyzing data from 2 cohorts of FL patients.

One cohort consisted of patients derived from 3 SWOG trials (S9800, S9911, and S0016), and the other consisted of patients from a Lymphoma Study Association (LYSA) trial known as PRIMA.

SWOG patients had received CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab), and LYSA patients had received rituximab plus chemotherapy (and were randomized to rituximab maintenance or observation).

SWOG cohort

After a median follow-up of 5.4 years, patients with vitamin D deficiency (defined as <20 ng/mL) had significantly inferior PFS (hazard ratio [HR]=2.00; P=0.011) and OS (HR=3.57; P=0.003) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (IPI), body mass index, and latitude (≥ vs <35°N). For PFS, the adjusted HR was 1.97 (P=0.023). And for OS, the adjusted HR was 4.16 (P=0.002).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but neither result was significant.

LYSA cohort

After a median follow-up of 6.6 years, patients with vitamin D deficiency (defined as <10 ng/mL) had significantly inferior PFS (HR=1.66; P=0.013) but not OS (HR=1.84; P=0.14) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (FLIPI), body mass index, latitude (Europe vs Australia), and hemoglobin. For PFS, the adjusted HR was 1.50 (P=0.095). For OS, the adjusted HR was 1.92 (P=0.192).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but only the association with OS reached statistical significance (HR=5.32; P=0.037).

Dr Friedberg said that, taken together, these results suggest vitamin D levels may be a modifiable factor associated with prognosis in patients with FL.

“Our data, replicated internationally, supports other published observations linking vitamin D deficiency with inferior cancer outcomes,” he said. “However, the mechanisms of this link are likely complex and require further study.”

The US Food and Drug Administration (FDA) has granted accelerated approval for Jadenu, a new oral formulation of Exjade (deferasirox).

Jadenu is now approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions. The drug is also approved to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.

Jadenu can be swallowed whole and taken with or without a light meal. Exjade is a dispersible tablet that must be mixed in liquid and taken on an empty stomach.

Jadenu has been approved with a boxed warning, which states that the drug may cause serious and fatal renal toxicity (including failure), hepatic toxicity (including failure), and gastrointestinal hemorrhage. Therefore, treatment with Jadenu requires close patient monitoring, including laboratory tests of renal and hepatic function.

The FDA has granted Jadenu accelerated approval based on the drug showing a reduction of liver iron concentrations and serum ferritin levels. Continued FDA approval for Jadenu may be contingent upon verification and description of clinical benefit in confirmatory trials.

Jadenu has been evaluated in trials of healthy volunteers, but there are no clinical data showing the effects of Jadenu in patients with chronic iron overload.

Exjade, on the other hand, has been evaluated in several trials of patients with chronic iron overload resulting from transfusions and patients with non-transfusion-dependent thalassemia who have chronic iron overload.

Data from these trials can be found in the prescribing information for Jadenu, available at www.jadenu.com.

The US Food and Drug Administration (FDA) has granted accelerated approval for Jadenu, a new oral formulation of Exjade (deferasirox).

Jadenu is now approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions. The drug is also approved to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.

Jadenu can be swallowed whole and taken with or without a light meal. Exjade is a dispersible tablet that must be mixed in liquid and taken on an empty stomach.

Jadenu has been approved with a boxed warning, which states that the drug may cause serious and fatal renal toxicity (including failure), hepatic toxicity (including failure), and gastrointestinal hemorrhage. Therefore, treatment with Jadenu requires close patient monitoring, including laboratory tests of renal and hepatic function.

The FDA has granted Jadenu accelerated approval based on the drug showing a reduction of liver iron concentrations and serum ferritin levels. Continued FDA approval for Jadenu may be contingent upon verification and description of clinical benefit in confirmatory trials.

Jadenu has been evaluated in trials of healthy volunteers, but there are no clinical data showing the effects of Jadenu in patients with chronic iron overload.

Exjade, on the other hand, has been evaluated in several trials of patients with chronic iron overload resulting from transfusions and patients with non-transfusion-dependent thalassemia who have chronic iron overload.

Data from these trials can be found in the prescribing information for Jadenu, available at www.jadenu.com.

The US Food and Drug Administration (FDA) has granted accelerated approval for Jadenu, a new oral formulation of Exjade (deferasirox).

Jadenu is now approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions. The drug is also approved to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.

Jadenu can be swallowed whole and taken with or without a light meal. Exjade is a dispersible tablet that must be mixed in liquid and taken on an empty stomach.

Jadenu has been approved with a boxed warning, which states that the drug may cause serious and fatal renal toxicity (including failure), hepatic toxicity (including failure), and gastrointestinal hemorrhage. Therefore, treatment with Jadenu requires close patient monitoring, including laboratory tests of renal and hepatic function.

The FDA has granted Jadenu accelerated approval based on the drug showing a reduction of liver iron concentrations and serum ferritin levels. Continued FDA approval for Jadenu may be contingent upon verification and description of clinical benefit in confirmatory trials.

Jadenu has been evaluated in trials of healthy volunteers, but there are no clinical data showing the effects of Jadenu in patients with chronic iron overload.

Exjade, on the other hand, has been evaluated in several trials of patients with chronic iron overload resulting from transfusions and patients with non-transfusion-dependent thalassemia who have chronic iron overload.

Data from these trials can be found in the prescribing information for Jadenu, available at www.jadenu.com.

Maria E. Figueroa, MD

Photo courtesy of

University of Michigan

Newly identified molecular signatures may allow us to predict which patients with chronic myelomonocytic leukemia (CMML) will respond to treatment, according to a study published in The Journal of Clinical Investigation.

Finding effective biomarkers is particularly crucial for CMML, the investigators said, because current treatment is slow-acting. Patients must often undergo as much as 6 months of treatment before there are signs of response.

“The slow kinetics is what gets us,” said study author Maria E. Figueroa, MD, of the University of Michigan Medical School in Ann Arbor.

“It’s not just one week or one dose to see signs of response. A good biomarker test could potentially prevent patients who are unlikely to respond from receiving prolonged, unwarranted treatments.”

With this in mind, Dr Figueroa and her colleagues used next-generation sequencing techniques to analyze 40 CMML samples from patients treated with the DNA methyltransferase inhibitor decitabine.

The researchers found 167 differentially methylated regions of DNA at baseline that distinguished patients who responded to decitabine from those who did not. There was a methylation difference of 25% or more between responders and nonresponders.

The investigators speculated that the baseline differences in DNA methylation could be used to predict treatment response at diagnosis.

So they used the percentage of cytosine methylation at each genomic location among the 40 patients as potential predictors and applied a machine-learning approach to build an epigenetic classifier.

The investigators tested the classifier in 28 additional CMML samples and found it was 87% accurate in predicting a patient’s response to decitabine.

The researchers also investigated why nonresponders were resistant to decitabine and found that 2 proteins, CXCL4 and CXCL7, were overexpressed in nonresponders. In cells exposed to high levels of these chemokines, the effects of decitabine were blocked.

“We are pursuing this to understand why these proteins block the effect of the drug and whether we can develop a new compound that could be used along with decitabine to turn nonresponders into responders,” Dr Figueroa said.

The researchers are also working to refine and translate their findings into a viable biomarker test that could be used in the clinic.

Maria E. Figueroa, MD

Photo courtesy of

University of Michigan

Newly identified molecular signatures may allow us to predict which patients with chronic myelomonocytic leukemia (CMML) will respond to treatment, according to a study published in The Journal of Clinical Investigation.

Finding effective biomarkers is particularly crucial for CMML, the investigators said, because current treatment is slow-acting. Patients must often undergo as much as 6 months of treatment before there are signs of response.

“The slow kinetics is what gets us,” said study author Maria E. Figueroa, MD, of the University of Michigan Medical School in Ann Arbor.

“It’s not just one week or one dose to see signs of response. A good biomarker test could potentially prevent patients who are unlikely to respond from receiving prolonged, unwarranted treatments.”

With this in mind, Dr Figueroa and her colleagues used next-generation sequencing techniques to analyze 40 CMML samples from patients treated with the DNA methyltransferase inhibitor decitabine.

The researchers found 167 differentially methylated regions of DNA at baseline that distinguished patients who responded to decitabine from those who did not. There was a methylation difference of 25% or more between responders and nonresponders.

The investigators speculated that the baseline differences in DNA methylation could be used to predict treatment response at diagnosis.

So they used the percentage of cytosine methylation at each genomic location among the 40 patients as potential predictors and applied a machine-learning approach to build an epigenetic classifier.

The investigators tested the classifier in 28 additional CMML samples and found it was 87% accurate in predicting a patient’s response to decitabine.

The researchers also investigated why nonresponders were resistant to decitabine and found that 2 proteins, CXCL4 and CXCL7, were overexpressed in nonresponders. In cells exposed to high levels of these chemokines, the effects of decitabine were blocked.

“We are pursuing this to understand why these proteins block the effect of the drug and whether we can develop a new compound that could be used along with decitabine to turn nonresponders into responders,” Dr Figueroa said.

The researchers are also working to refine and translate their findings into a viable biomarker test that could be used in the clinic.

Maria E. Figueroa, MD

Photo courtesy of

University of Michigan

Newly identified molecular signatures may allow us to predict which patients with chronic myelomonocytic leukemia (CMML) will respond to treatment, according to a study published in The Journal of Clinical Investigation.

Finding effective biomarkers is particularly crucial for CMML, the investigators said, because current treatment is slow-acting. Patients must often undergo as much as 6 months of treatment before there are signs of response.

“The slow kinetics is what gets us,” said study author Maria E. Figueroa, MD, of the University of Michigan Medical School in Ann Arbor.

“It’s not just one week or one dose to see signs of response. A good biomarker test could potentially prevent patients who are unlikely to respond from receiving prolonged, unwarranted treatments.”

With this in mind, Dr Figueroa and her colleagues used next-generation sequencing techniques to analyze 40 CMML samples from patients treated with the DNA methyltransferase inhibitor decitabine.

The researchers found 167 differentially methylated regions of DNA at baseline that distinguished patients who responded to decitabine from those who did not. There was a methylation difference of 25% or more between responders and nonresponders.

The investigators speculated that the baseline differences in DNA methylation could be used to predict treatment response at diagnosis.

So they used the percentage of cytosine methylation at each genomic location among the 40 patients as potential predictors and applied a machine-learning approach to build an epigenetic classifier.

The investigators tested the classifier in 28 additional CMML samples and found it was 87% accurate in predicting a patient’s response to decitabine.

The researchers also investigated why nonresponders were resistant to decitabine and found that 2 proteins, CXCL4 and CXCL7, were overexpressed in nonresponders. In cells exposed to high levels of these chemokines, the effects of decitabine were blocked.

“We are pursuing this to understand why these proteins block the effect of the drug and whether we can develop a new compound that could be used along with decitabine to turn nonresponders into responders,” Dr Figueroa said.

The researchers are also working to refine and translate their findings into a viable biomarker test that could be used in the clinic.