According to the Centers for Disease Control and Preventions, in 2019 2.1% of all infants born in the United States were conceived by assisted reproductive technology (ART). Now 45 years old, ART, namely in vitro fertilization (IVF), is offered in nearly 500 clinics in the United States, contributing to over 300,000 treatment cycles per year.

A tubal factor is responsible for 30% of female infertility and may involve proximal and/or distal tubal occlusion, irrespective of pelvic adhesions.¹ Before the advent of IVF, the sole approach to the treatment of a tubal factor had been surgery. Given its success and minimal invasiveness, IVF is increasingly being offered to circumvent a tubal factor for infertility. This month we examine the utility of surgical treatment of tubal factor infertility. The options for fertility with a history of bilateral tubal ligation was covered in a prior Reproductive Rounds column.

Tubal disease and pelvic adhesions prevent the normal transport of the oocyte and sperm through the fallopian tube. The primary etiology of tubal factor infertility is pelvic inflammatory disease, mainly caused by chlamydia or gonorrhea. Other conditions that may interfere with tubal transport include severe endometriosis, adhesions from previous surgery, or nontubal infection (for example, appendicitis, inflammatory bowel disease), pelvic tuberculosis, and salpingitis isthmica nodosa (that is, diverticulosis of the fallopian tube).
 

Proximal tubal occlusion

During a hysterosalpingogram (HSG), transient uterine cornual spasm can result if a woman experiences significant uterine cramping, thereby resulting in a false-positive diagnosis of proximal tubal occlusion. When a repeat HSG is gently performed with slow instillation of contrast, uterine cramping is less likely, and the tubal patency rate is 60%. PTO may also result from plugs of mucus and amorphous debris, but this is not true occlusion.² In cases with unilateral PTO, controlled ovarian hyperstimulation with intrauterine insemination has resulted in pregnancy rates similar to those in patients with unexplained infertility.³

Reconstructive surgery for bilateral PTO has limited effectiveness and the risk of subsequent ectopic pregnancy is as high as 20%.⁴ A more successful option is fluoroscopic tubal catheterization (FTC), an outpatient procedure performed in a radiology or infertility center. FTC uses a coaxial catheter system where the outer catheter is guided through the tubal ostium and an inner catheter is atraumatically advanced to overcome the blockage. This procedure is 85% successful for tubal patency with 50% of patients conceiving in the first 12 months; one-third of time the tubes reocclude. After the reestablishment of patency with FTC, the chance of achieving a live birth is 22% and the risk of ectopic pregnancy is 4%.⁵

Treatment of distal tubal occlusion – the hydrosalpinx

Surgery for treating tubal factor infertility is most successful in women with distal tubal obstruction (DTO), often caused by a hydrosalpinx. Fimbrioplasty is the lysis of fimbrial adhesions or dilatation of fimbrial strictures; the tube is patent, but there are adhesive bands that surround the terminal end with preserved tubal rugae. Gentle introduction of an alligator laparoscopic forceps into the tubal ostium followed by opening and withdrawal of the forceps helps to stretch the tube and release minor degrees of fimbrial agglutination.⁶

A hydrosalpinx is diagnosed by DTO with dilation and intraluminal fluid accumulation along with the reduction/loss of endothelial cilia. Left untreated, a hydrosalpinx can lead to a 50% reduction in IVF pregnancy rates.⁷ Tube-sparing treatment involves neosalpingostomy to create a new tubal opening. A nonsurgical approach, ultrasound-guided aspiration of hydrosalpinges, has not been shown to significantly increase the rate of clinical pregnancy. Efficacy for improving fertility is generally poor, but depends upon tubal wall thickness, ampullary dilation, presence of mucosal folds, percentage of ciliated cells in the fimbrial end, and peritubal adhesions.⁸

Evidence supports that laparoscopic salpingectomy in women with hydrosalpinges improves the outcomes of IVF treatment, compared with no surgical intervention.⁹ The improvement in pregnancy and live birth rates likely stems from the elimination of the retrograde flow of embryotoxic fluid that disrupts implantation. Endometrial receptivity markers (endometrial cell adhesion molecules, integrins, and HOXA10) have been shown to be reduced in the presence of hydrosalpinx.¹⁰ A small, randomized trial demonstrated that bipolar diathermy prior to IVF improved pregnancy outcomes.¹¹ PTO was not more effective than salpingectomy. Conceptions, without IVF, have been reported following salpingectomy for unilateral hydrosalpinx.¹²

In a series including 434 patients with DTO who underwent laparoscopic fimbrioplasty (enlargement of the ostium) or neosalpingostomy (creation of a new ostium) by a single surgeon, 5-year actuarial delivery rates decreased as the severity of tubal occlusion increased; the ectopic rate was stable at approximately 15%.¹³ A prospective study reported that the relative increase in the pregnancy rate after salpingectomy was greatest in women with a large hydrosalpinx visible on ultrasound.¹⁴

Because of the possible risks of decreased ovarian reserve secondary to interruption of ovarian blood supply, salpingectomy should be done with minimal thermal injury and very close to the fallopian tube.

Summary

Surgery may be considered for young women with mild distal tubal disease as one surgical procedure can lead to several pregnancies whereas IVF must be performed each time pregnancy is desired. IVF is more likely than surgery to be successful in women with bilateral hydrosalpinx, in those with pelvic adhesions, in older reproductive aged women, and for both proximal and distal tubal occlusion.¹⁵ An online prediction calculator from the Society for Assisted Reproductive Technology (SART) can be helpful in counseling patients on personalized expectations for IVF pregnancy outcomes.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Ambildhuke K et al. Cureus. 2022;1:14(11):e30990.

2. Fatemeh Z et al. Br J Radiol. 2021 Jun 1;94(1122):20201386.

3. Farhi J et al. Fertil Steril. 2007 Aug;88(2):396.

4. Honoré GM et al. Fertil Steril. 1999;71(5):785.

5. De Silva PM et al. Hum Reprod. 2017;32(4):836.

6. Namnoum A and Murphy A. “Diagnostic and Operative Laparoscopy,” in Te Linde’s Operative Gynecology, 8th ed. Philadelphia: Lippincott-Raven, 1997, pp. 389.

7. Camus E et al.Hum Reprod. 1999;14(5):1243.

8. Marana R et al. Hum Reprod. 1999;14(12):2991-5.

9. Johnson N et al. Cochrane Database Syst Rev. 2010 Jan 20;2010(1):CD002125.

10. Savaris RF et al. Fertil Steril. 2006 Jan;85(1):188.

11. Kontoravdis A et al. Fertil Steril. 2006;86(6):1642.

12. Sagoskin AW et al. Hum Reprod. 2003;18(12):2634.

13. Audebert A et al. Fertil Steril. 2014;102(4):1203.

14. Bildirici I et al. Hum Reprod. 2001;16(11):2422.

15. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2012;97(3):539.

According to the Centers for Disease Control and Preventions, in 2019 2.1% of all infants born in the United States were conceived by assisted reproductive technology (ART). Now 45 years old, ART, namely in vitro fertilization (IVF), is offered in nearly 500 clinics in the United States, contributing to over 300,000 treatment cycles per year.

A tubal factor is responsible for 30% of female infertility and may involve proximal and/or distal tubal occlusion, irrespective of pelvic adhesions.¹ Before the advent of IVF, the sole approach to the treatment of a tubal factor had been surgery. Given its success and minimal invasiveness, IVF is increasingly being offered to circumvent a tubal factor for infertility. This month we examine the utility of surgical treatment of tubal factor infertility. The options for fertility with a history of bilateral tubal ligation was covered in a prior Reproductive Rounds column.

Tubal disease and pelvic adhesions prevent the normal transport of the oocyte and sperm through the fallopian tube. The primary etiology of tubal factor infertility is pelvic inflammatory disease, mainly caused by chlamydia or gonorrhea. Other conditions that may interfere with tubal transport include severe endometriosis, adhesions from previous surgery, or nontubal infection (for example, appendicitis, inflammatory bowel disease), pelvic tuberculosis, and salpingitis isthmica nodosa (that is, diverticulosis of the fallopian tube).
 

Proximal tubal occlusion

During a hysterosalpingogram (HSG), transient uterine cornual spasm can result if a woman experiences significant uterine cramping, thereby resulting in a false-positive diagnosis of proximal tubal occlusion. When a repeat HSG is gently performed with slow instillation of contrast, uterine cramping is less likely, and the tubal patency rate is 60%. PTO may also result from plugs of mucus and amorphous debris, but this is not true occlusion.² In cases with unilateral PTO, controlled ovarian hyperstimulation with intrauterine insemination has resulted in pregnancy rates similar to those in patients with unexplained infertility.³

Reconstructive surgery for bilateral PTO has limited effectiveness and the risk of subsequent ectopic pregnancy is as high as 20%.⁴ A more successful option is fluoroscopic tubal catheterization (FTC), an outpatient procedure performed in a radiology or infertility center. FTC uses a coaxial catheter system where the outer catheter is guided through the tubal ostium and an inner catheter is atraumatically advanced to overcome the blockage. This procedure is 85% successful for tubal patency with 50% of patients conceiving in the first 12 months; one-third of time the tubes reocclude. After the reestablishment of patency with FTC, the chance of achieving a live birth is 22% and the risk of ectopic pregnancy is 4%.⁵

Treatment of distal tubal occlusion – the hydrosalpinx

Surgery for treating tubal factor infertility is most successful in women with distal tubal obstruction (DTO), often caused by a hydrosalpinx. Fimbrioplasty is the lysis of fimbrial adhesions or dilatation of fimbrial strictures; the tube is patent, but there are adhesive bands that surround the terminal end with preserved tubal rugae. Gentle introduction of an alligator laparoscopic forceps into the tubal ostium followed by opening and withdrawal of the forceps helps to stretch the tube and release minor degrees of fimbrial agglutination.⁶

A hydrosalpinx is diagnosed by DTO with dilation and intraluminal fluid accumulation along with the reduction/loss of endothelial cilia. Left untreated, a hydrosalpinx can lead to a 50% reduction in IVF pregnancy rates.⁷ Tube-sparing treatment involves neosalpingostomy to create a new tubal opening. A nonsurgical approach, ultrasound-guided aspiration of hydrosalpinges, has not been shown to significantly increase the rate of clinical pregnancy. Efficacy for improving fertility is generally poor, but depends upon tubal wall thickness, ampullary dilation, presence of mucosal folds, percentage of ciliated cells in the fimbrial end, and peritubal adhesions.⁸

Evidence supports that laparoscopic salpingectomy in women with hydrosalpinges improves the outcomes of IVF treatment, compared with no surgical intervention.⁹ The improvement in pregnancy and live birth rates likely stems from the elimination of the retrograde flow of embryotoxic fluid that disrupts implantation. Endometrial receptivity markers (endometrial cell adhesion molecules, integrins, and HOXA10) have been shown to be reduced in the presence of hydrosalpinx.¹⁰ A small, randomized trial demonstrated that bipolar diathermy prior to IVF improved pregnancy outcomes.¹¹ PTO was not more effective than salpingectomy. Conceptions, without IVF, have been reported following salpingectomy for unilateral hydrosalpinx.¹²

In a series including 434 patients with DTO who underwent laparoscopic fimbrioplasty (enlargement of the ostium) or neosalpingostomy (creation of a new ostium) by a single surgeon, 5-year actuarial delivery rates decreased as the severity of tubal occlusion increased; the ectopic rate was stable at approximately 15%.¹³ A prospective study reported that the relative increase in the pregnancy rate after salpingectomy was greatest in women with a large hydrosalpinx visible on ultrasound.¹⁴

Because of the possible risks of decreased ovarian reserve secondary to interruption of ovarian blood supply, salpingectomy should be done with minimal thermal injury and very close to the fallopian tube.

Summary

Surgery may be considered for young women with mild distal tubal disease as one surgical procedure can lead to several pregnancies whereas IVF must be performed each time pregnancy is desired. IVF is more likely than surgery to be successful in women with bilateral hydrosalpinx, in those with pelvic adhesions, in older reproductive aged women, and for both proximal and distal tubal occlusion.¹⁵ An online prediction calculator from the Society for Assisted Reproductive Technology (SART) can be helpful in counseling patients on personalized expectations for IVF pregnancy outcomes.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Ambildhuke K et al. Cureus. 2022;1:14(11):e30990.

2. Fatemeh Z et al. Br J Radiol. 2021 Jun 1;94(1122):20201386.

3. Farhi J et al. Fertil Steril. 2007 Aug;88(2):396.

4. Honoré GM et al. Fertil Steril. 1999;71(5):785.

5. De Silva PM et al. Hum Reprod. 2017;32(4):836.

6. Namnoum A and Murphy A. “Diagnostic and Operative Laparoscopy,” in Te Linde’s Operative Gynecology, 8th ed. Philadelphia: Lippincott-Raven, 1997, pp. 389.

7. Camus E et al.Hum Reprod. 1999;14(5):1243.

8. Marana R et al. Hum Reprod. 1999;14(12):2991-5.

9. Johnson N et al. Cochrane Database Syst Rev. 2010 Jan 20;2010(1):CD002125.

10. Savaris RF et al. Fertil Steril. 2006 Jan;85(1):188.

11. Kontoravdis A et al. Fertil Steril. 2006;86(6):1642.

12. Sagoskin AW et al. Hum Reprod. 2003;18(12):2634.

13. Audebert A et al. Fertil Steril. 2014;102(4):1203.

14. Bildirici I et al. Hum Reprod. 2001;16(11):2422.

15. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2012;97(3):539.

According to the Centers for Disease Control and Preventions, in 2019 2.1% of all infants born in the United States were conceived by assisted reproductive technology (ART). Now 45 years old, ART, namely in vitro fertilization (IVF), is offered in nearly 500 clinics in the United States, contributing to over 300,000 treatment cycles per year.

A tubal factor is responsible for 30% of female infertility and may involve proximal and/or distal tubal occlusion, irrespective of pelvic adhesions.¹ Before the advent of IVF, the sole approach to the treatment of a tubal factor had been surgery. Given its success and minimal invasiveness, IVF is increasingly being offered to circumvent a tubal factor for infertility. This month we examine the utility of surgical treatment of tubal factor infertility. The options for fertility with a history of bilateral tubal ligation was covered in a prior Reproductive Rounds column.

Tubal disease and pelvic adhesions prevent the normal transport of the oocyte and sperm through the fallopian tube. The primary etiology of tubal factor infertility is pelvic inflammatory disease, mainly caused by chlamydia or gonorrhea. Other conditions that may interfere with tubal transport include severe endometriosis, adhesions from previous surgery, or nontubal infection (for example, appendicitis, inflammatory bowel disease), pelvic tuberculosis, and salpingitis isthmica nodosa (that is, diverticulosis of the fallopian tube).
 

Proximal tubal occlusion

During a hysterosalpingogram (HSG), transient uterine cornual spasm can result if a woman experiences significant uterine cramping, thereby resulting in a false-positive diagnosis of proximal tubal occlusion. When a repeat HSG is gently performed with slow instillation of contrast, uterine cramping is less likely, and the tubal patency rate is 60%. PTO may also result from plugs of mucus and amorphous debris, but this is not true occlusion.² In cases with unilateral PTO, controlled ovarian hyperstimulation with intrauterine insemination has resulted in pregnancy rates similar to those in patients with unexplained infertility.³

Reconstructive surgery for bilateral PTO has limited effectiveness and the risk of subsequent ectopic pregnancy is as high as 20%.⁴ A more successful option is fluoroscopic tubal catheterization (FTC), an outpatient procedure performed in a radiology or infertility center. FTC uses a coaxial catheter system where the outer catheter is guided through the tubal ostium and an inner catheter is atraumatically advanced to overcome the blockage. This procedure is 85% successful for tubal patency with 50% of patients conceiving in the first 12 months; one-third of time the tubes reocclude. After the reestablishment of patency with FTC, the chance of achieving a live birth is 22% and the risk of ectopic pregnancy is 4%.⁵

Treatment of distal tubal occlusion – the hydrosalpinx

Surgery for treating tubal factor infertility is most successful in women with distal tubal obstruction (DTO), often caused by a hydrosalpinx. Fimbrioplasty is the lysis of fimbrial adhesions or dilatation of fimbrial strictures; the tube is patent, but there are adhesive bands that surround the terminal end with preserved tubal rugae. Gentle introduction of an alligator laparoscopic forceps into the tubal ostium followed by opening and withdrawal of the forceps helps to stretch the tube and release minor degrees of fimbrial agglutination.⁶

A hydrosalpinx is diagnosed by DTO with dilation and intraluminal fluid accumulation along with the reduction/loss of endothelial cilia. Left untreated, a hydrosalpinx can lead to a 50% reduction in IVF pregnancy rates.⁷ Tube-sparing treatment involves neosalpingostomy to create a new tubal opening. A nonsurgical approach, ultrasound-guided aspiration of hydrosalpinges, has not been shown to significantly increase the rate of clinical pregnancy. Efficacy for improving fertility is generally poor, but depends upon tubal wall thickness, ampullary dilation, presence of mucosal folds, percentage of ciliated cells in the fimbrial end, and peritubal adhesions.⁸

Evidence supports that laparoscopic salpingectomy in women with hydrosalpinges improves the outcomes of IVF treatment, compared with no surgical intervention.⁹ The improvement in pregnancy and live birth rates likely stems from the elimination of the retrograde flow of embryotoxic fluid that disrupts implantation. Endometrial receptivity markers (endometrial cell adhesion molecules, integrins, and HOXA10) have been shown to be reduced in the presence of hydrosalpinx.¹⁰ A small, randomized trial demonstrated that bipolar diathermy prior to IVF improved pregnancy outcomes.¹¹ PTO was not more effective than salpingectomy. Conceptions, without IVF, have been reported following salpingectomy for unilateral hydrosalpinx.¹²

In a series including 434 patients with DTO who underwent laparoscopic fimbrioplasty (enlargement of the ostium) or neosalpingostomy (creation of a new ostium) by a single surgeon, 5-year actuarial delivery rates decreased as the severity of tubal occlusion increased; the ectopic rate was stable at approximately 15%.¹³ A prospective study reported that the relative increase in the pregnancy rate after salpingectomy was greatest in women with a large hydrosalpinx visible on ultrasound.¹⁴

Because of the possible risks of decreased ovarian reserve secondary to interruption of ovarian blood supply, salpingectomy should be done with minimal thermal injury and very close to the fallopian tube.

Summary

Surgery may be considered for young women with mild distal tubal disease as one surgical procedure can lead to several pregnancies whereas IVF must be performed each time pregnancy is desired. IVF is more likely than surgery to be successful in women with bilateral hydrosalpinx, in those with pelvic adhesions, in older reproductive aged women, and for both proximal and distal tubal occlusion.¹⁵ An online prediction calculator from the Society for Assisted Reproductive Technology (SART) can be helpful in counseling patients on personalized expectations for IVF pregnancy outcomes.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Ambildhuke K et al. Cureus. 2022;1:14(11):e30990.

2. Fatemeh Z et al. Br J Radiol. 2021 Jun 1;94(1122):20201386.

3. Farhi J et al. Fertil Steril. 2007 Aug;88(2):396.

4. Honoré GM et al. Fertil Steril. 1999;71(5):785.

5. De Silva PM et al. Hum Reprod. 2017;32(4):836.

6. Namnoum A and Murphy A. “Diagnostic and Operative Laparoscopy,” in Te Linde’s Operative Gynecology, 8th ed. Philadelphia: Lippincott-Raven, 1997, pp. 389.

7. Camus E et al.Hum Reprod. 1999;14(5):1243.

8. Marana R et al. Hum Reprod. 1999;14(12):2991-5.

9. Johnson N et al. Cochrane Database Syst Rev. 2010 Jan 20;2010(1):CD002125.

10. Savaris RF et al. Fertil Steril. 2006 Jan;85(1):188.

11. Kontoravdis A et al. Fertil Steril. 2006;86(6):1642.

12. Sagoskin AW et al. Hum Reprod. 2003;18(12):2634.

13. Audebert A et al. Fertil Steril. 2014;102(4):1203.

14. Bildirici I et al. Hum Reprod. 2001;16(11):2422.

15. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2012;97(3):539.

ORLANDO – From differentiating them from mimics to choosing the best treatment course, Molly Hinshaw, MD, reviewed some of the ins and outs of managing nail disorders at the ODAC Dermatology, Aesthetic, & Surgical Conference.

Dr. Hinshaw, professor of dermatology at the University of Wisconsin, Madison, reviewed several disorders and provided guidance on diagnosis, and achieving the best outcomes for patients.

Pyogenic granuloma (PG) in the nail: These are benign vascular tumors that can mimic more serious conditions, Dr. Hinshaw said. In adults, PG requires a histologic diagnosis, she said.

“So these all really should have a biopsy,” because of potential confusion with amelanotic melanoma or squamous cell carcinoma, she said, although in children, a biopsy is likely not necessary.

Treatment with topical beta-blockers can be effective for PG, she said, and avoids the scarring seen with surgical removal. “These are benign conditions – we want them to go away, but we want these patients to have a functional nail thereafter.”

Periungual or subungual warts: For these warts, which are alongside or under the nail, destructive approaches can cause scarring of the nail bed and are far from optimal, she said.

“We’d like to avoid that, of course.” Therefore, treatments such as lasers and liquid nitrogen “would be much further down, if at all, on my list,” she said.

Injections of the antiviral cidofovir, into the dermis right under the wart, can be highly effective, and one or two treatments is often enough, Dr. Hinshaw said. Sometimes, local anesthesia isn’t even needed for the injection, she said. “This is a wonderful option,” she added.

Dr. Hinshaw is co-owner and chief medical officer of Acure.

ORLANDO – From differentiating them from mimics to choosing the best treatment course, Molly Hinshaw, MD, reviewed some of the ins and outs of managing nail disorders at the ODAC Dermatology, Aesthetic, & Surgical Conference.

Dr. Hinshaw, professor of dermatology at the University of Wisconsin, Madison, reviewed several disorders and provided guidance on diagnosis, and achieving the best outcomes for patients.

Pyogenic granuloma (PG) in the nail: These are benign vascular tumors that can mimic more serious conditions, Dr. Hinshaw said. In adults, PG requires a histologic diagnosis, she said.

“So these all really should have a biopsy,” because of potential confusion with amelanotic melanoma or squamous cell carcinoma, she said, although in children, a biopsy is likely not necessary.

Treatment with topical beta-blockers can be effective for PG, she said, and avoids the scarring seen with surgical removal. “These are benign conditions – we want them to go away, but we want these patients to have a functional nail thereafter.”

Periungual or subungual warts: For these warts, which are alongside or under the nail, destructive approaches can cause scarring of the nail bed and are far from optimal, she said.

“We’d like to avoid that, of course.” Therefore, treatments such as lasers and liquid nitrogen “would be much further down, if at all, on my list,” she said.

Injections of the antiviral cidofovir, into the dermis right under the wart, can be highly effective, and one or two treatments is often enough, Dr. Hinshaw said. Sometimes, local anesthesia isn’t even needed for the injection, she said. “This is a wonderful option,” she added.

Dr. Hinshaw is co-owner and chief medical officer of Acure.

ORLANDO – From differentiating them from mimics to choosing the best treatment course, Molly Hinshaw, MD, reviewed some of the ins and outs of managing nail disorders at the ODAC Dermatology, Aesthetic, & Surgical Conference.

Dr. Hinshaw, professor of dermatology at the University of Wisconsin, Madison, reviewed several disorders and provided guidance on diagnosis, and achieving the best outcomes for patients.

Pyogenic granuloma (PG) in the nail: These are benign vascular tumors that can mimic more serious conditions, Dr. Hinshaw said. In adults, PG requires a histologic diagnosis, she said.

“So these all really should have a biopsy,” because of potential confusion with amelanotic melanoma or squamous cell carcinoma, she said, although in children, a biopsy is likely not necessary.

Treatment with topical beta-blockers can be effective for PG, she said, and avoids the scarring seen with surgical removal. “These are benign conditions – we want them to go away, but we want these patients to have a functional nail thereafter.”

Periungual or subungual warts: For these warts, which are alongside or under the nail, destructive approaches can cause scarring of the nail bed and are far from optimal, she said.

“We’d like to avoid that, of course.” Therefore, treatments such as lasers and liquid nitrogen “would be much further down, if at all, on my list,” she said.

Injections of the antiviral cidofovir, into the dermis right under the wart, can be highly effective, and one or two treatments is often enough, Dr. Hinshaw said. Sometimes, local anesthesia isn’t even needed for the injection, she said. “This is a wonderful option,” she added.

Dr. Hinshaw is co-owner and chief medical officer of Acure.

SAN DIEGO – When parents bring their children to Caroline Piggott, MD, to evaluate a suspicious mole on the scalp or other body location, the vast majority turn out to be benign, because the incidence of melanoma is rare, especially before puberty.

“Only 1%-2% of all melanomas in the world are in children, so most of my job is to provide reassurance,” Dr. Piggott, a pediatric dermatologist at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “Few pediatric studies exist. Why? Because children are excluded from most melanoma clinical trials. Our management is based mainly on adult National Comprehensive Cancer Network guidelines.”

Doug Brunk/MDedge News

To help parents identify melanoma, clinicians typically recommend the “ABCDE” rule, for Asymmetry, Border irregularity, Color variation (especially dark or multiple colors), Diameter greater than 6 mm, and Evolving (is it changing, bleeding or painful?).

While Dr. Piggott considers the standard ABCDE rules as important – especially in older children and teenagers – researchers led by Kelly M. Cordoro, MD, professor of dermatology at the University of California, San Francisco, proposed a modified ABCD criteria based on evaluating a cohort of 60 children who were diagnosed with melanoma and 10 who were diagnosed with ambiguous melanocytic tumors treated as melanoma before age 20 years at UCSF from 1984 to 2009.

The researchers divided patients into two groups: those aged 0-10 years (19; group A) and those aged 11-19 years (51; group B), and found that 60% of children in group A and 40% of those in group B did not present with conventional ABCDE criteria for children. Of the 60 melanoma patients, 10 died. Of these, 9 were older than age 10, and 70% had amelanotic lesions. Based on their analysis of clinical, histopathologic, and outcomes data, Dr. Cordoro and colleagues proposed additional ABCD criteria in which A stands for stands Amelanotic; B for Bleeding or Bump; C for Color uniformity, and D for De novo or any Diameter.

“This doesn’t mean you throw the old ABCDE criteria out the window,” Dr. Piggott said. “It means that you use this modified criteria in conjunction with the conventional ABCDE rules.”

Risk factors for melanoma in children are like those in adults, and include a family history of melanoma, large/giant congenital nevi, the presence of many atypical appearing nevi, having Fitzpatrick skin types I or II, a history of blistering sunburns, and the presence of genetic anomalies such as xeroderma pigmentosum.

According to an analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program, melanoma incidence increased in all individuals in the United States aged 0-19 years from 1973 to 2009. Key risk factors included White race, female sex, and living in a SEER registry categorized as low UVB exposure. Over the study period, boys experienced increased incidence rates of melanoma on the face and trunk, while girls experienced increased incidence rates of melanoma on the lower limbs and hip.

More recently, researchers extracted data from 988,103 cases of invasive melanoma in the 2001-2015 SEER database to determine the age-specific incidence of melanoma in the United States. In 2015, 83,362 cases of invasive melanoma were reported for all ages. Of these, only 67 cases were younger than age 10, while 251 were between the ages of 10 and 19 and 1,973 were young adults between the ages of 20 and 29.

In other findings, between 2006 and 2015, the overall incidence of invasive melanoma for all ages increased from 200 million to 229 cases per million person-years. “However, there were statistically significant decreases in melanoma incidence for individuals aged 10-19 years and for those aged 10-29 years,” said Dr. Piggott, who was not involved with the study. “The hypothesis is that public health efforts encouraging against sun exposure and tanning bed use may be influencing melanoma incidence in younger populations. What is interesting, though, is that young adult women have twice the melanoma risk as young adult men.”

In a separate study, researchers prospectively followed 60 melanoma-prone families for up to 40 years to evaluate the risk of pediatric melanoma in those with and without cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations. Regardless of their CDKN2A status, the percentage of pediatric melanoma cases was 6- to 28-fold higher among melanoma-prone families, compared with the general population. In addition, families who were CDKN2A positive had a significantly higher rate of pediatric melanoma cases compared with those who were CDKN2A negative (11.1% vs. 2.5%; P = .004).

As for treating pediatric melanoma, the standard of care is similar to that for adults: usually wide local surgical excision of the primary lesion, depending on depth. Clinicians typically follow adult parameters for sentinel lymph node biopsy, such as lesion depth and ulceration.

“We know that a positive sentinel node does have prognostic value, but there is great debate on whether to do a lymph node dissection if the sentinel lymph node is positive,” Dr. Piggott said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “This is determined on a case-by-case basis. We consider factors such as, are the nodes palpable? Is there evidence on ultrasound? But there are no formal guidelines.”

Limited studies of systemic therapy in children exist because this population is excluded from most melanoma clinical trials. “In the past, interferon was sometimes used,” she said. “But in recent years, as with adults, we have started to use targeted immunologic therapy. This is usually managed by a tertiary academic oncology center.”

The chance of surviving pediatric melanoma is good if caught early. As in adults, the stage correlates strongly with survival, and distant metastases carry a poor prognosis.

In 2020, researchers published a retrospective, multicenter review of 38 cases of fatal pediatric melanoma between 1994 and 2017. The analysis was limited to individuals 20 years of age and younger who were cared for at 12 academic medical centers. Of the 38 patients, 42% were male, 58% were female, and 57% were White. In addition, 19% were Hispanic, “which is a larger percentage than fatalities in adult [Hispanic] populations with melanoma,” said Dr. Piggott, who was not involved in the study.

The mean age at diagnosis was 12.7 years, the mean age at death was 15.6 , and the mean survival time after diagnosis was about 35 months. Of the 16 cases with known identifiable subtypes, 50% were nodular, 31% were superficial spreading, and 19% were spitzoid melanoma. In addition, one-quarter of melanomas arose in association with congenital melanocytic nevi.

“The good news is that there are only 38 total cases of fatal pediatric melanoma between 12 academic centers over a 23-year period,” Dr. Piggott said. “Thanks goodness the number is that low.”

Dr. Piggott reported having no relevant disclosures.

SAN DIEGO – When parents bring their children to Caroline Piggott, MD, to evaluate a suspicious mole on the scalp or other body location, the vast majority turn out to be benign, because the incidence of melanoma is rare, especially before puberty.

“Only 1%-2% of all melanomas in the world are in children, so most of my job is to provide reassurance,” Dr. Piggott, a pediatric dermatologist at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “Few pediatric studies exist. Why? Because children are excluded from most melanoma clinical trials. Our management is based mainly on adult National Comprehensive Cancer Network guidelines.”

Doug Brunk/MDedge News

To help parents identify melanoma, clinicians typically recommend the “ABCDE” rule, for Asymmetry, Border irregularity, Color variation (especially dark or multiple colors), Diameter greater than 6 mm, and Evolving (is it changing, bleeding or painful?).

While Dr. Piggott considers the standard ABCDE rules as important – especially in older children and teenagers – researchers led by Kelly M. Cordoro, MD, professor of dermatology at the University of California, San Francisco, proposed a modified ABCD criteria based on evaluating a cohort of 60 children who were diagnosed with melanoma and 10 who were diagnosed with ambiguous melanocytic tumors treated as melanoma before age 20 years at UCSF from 1984 to 2009.

The researchers divided patients into two groups: those aged 0-10 years (19; group A) and those aged 11-19 years (51; group B), and found that 60% of children in group A and 40% of those in group B did not present with conventional ABCDE criteria for children. Of the 60 melanoma patients, 10 died. Of these, 9 were older than age 10, and 70% had amelanotic lesions. Based on their analysis of clinical, histopathologic, and outcomes data, Dr. Cordoro and colleagues proposed additional ABCD criteria in which A stands for stands Amelanotic; B for Bleeding or Bump; C for Color uniformity, and D for De novo or any Diameter.

“This doesn’t mean you throw the old ABCDE criteria out the window,” Dr. Piggott said. “It means that you use this modified criteria in conjunction with the conventional ABCDE rules.”

Risk factors for melanoma in children are like those in adults, and include a family history of melanoma, large/giant congenital nevi, the presence of many atypical appearing nevi, having Fitzpatrick skin types I or II, a history of blistering sunburns, and the presence of genetic anomalies such as xeroderma pigmentosum.

According to an analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program, melanoma incidence increased in all individuals in the United States aged 0-19 years from 1973 to 2009. Key risk factors included White race, female sex, and living in a SEER registry categorized as low UVB exposure. Over the study period, boys experienced increased incidence rates of melanoma on the face and trunk, while girls experienced increased incidence rates of melanoma on the lower limbs and hip.

More recently, researchers extracted data from 988,103 cases of invasive melanoma in the 2001-2015 SEER database to determine the age-specific incidence of melanoma in the United States. In 2015, 83,362 cases of invasive melanoma were reported for all ages. Of these, only 67 cases were younger than age 10, while 251 were between the ages of 10 and 19 and 1,973 were young adults between the ages of 20 and 29.

In other findings, between 2006 and 2015, the overall incidence of invasive melanoma for all ages increased from 200 million to 229 cases per million person-years. “However, there were statistically significant decreases in melanoma incidence for individuals aged 10-19 years and for those aged 10-29 years,” said Dr. Piggott, who was not involved with the study. “The hypothesis is that public health efforts encouraging against sun exposure and tanning bed use may be influencing melanoma incidence in younger populations. What is interesting, though, is that young adult women have twice the melanoma risk as young adult men.”

In a separate study, researchers prospectively followed 60 melanoma-prone families for up to 40 years to evaluate the risk of pediatric melanoma in those with and without cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations. Regardless of their CDKN2A status, the percentage of pediatric melanoma cases was 6- to 28-fold higher among melanoma-prone families, compared with the general population. In addition, families who were CDKN2A positive had a significantly higher rate of pediatric melanoma cases compared with those who were CDKN2A negative (11.1% vs. 2.5%; P = .004).

As for treating pediatric melanoma, the standard of care is similar to that for adults: usually wide local surgical excision of the primary lesion, depending on depth. Clinicians typically follow adult parameters for sentinel lymph node biopsy, such as lesion depth and ulceration.

“We know that a positive sentinel node does have prognostic value, but there is great debate on whether to do a lymph node dissection if the sentinel lymph node is positive,” Dr. Piggott said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “This is determined on a case-by-case basis. We consider factors such as, are the nodes palpable? Is there evidence on ultrasound? But there are no formal guidelines.”

Limited studies of systemic therapy in children exist because this population is excluded from most melanoma clinical trials. “In the past, interferon was sometimes used,” she said. “But in recent years, as with adults, we have started to use targeted immunologic therapy. This is usually managed by a tertiary academic oncology center.”

The chance of surviving pediatric melanoma is good if caught early. As in adults, the stage correlates strongly with survival, and distant metastases carry a poor prognosis.

In 2020, researchers published a retrospective, multicenter review of 38 cases of fatal pediatric melanoma between 1994 and 2017. The analysis was limited to individuals 20 years of age and younger who were cared for at 12 academic medical centers. Of the 38 patients, 42% were male, 58% were female, and 57% were White. In addition, 19% were Hispanic, “which is a larger percentage than fatalities in adult [Hispanic] populations with melanoma,” said Dr. Piggott, who was not involved in the study.

The mean age at diagnosis was 12.7 years, the mean age at death was 15.6 , and the mean survival time after diagnosis was about 35 months. Of the 16 cases with known identifiable subtypes, 50% were nodular, 31% were superficial spreading, and 19% were spitzoid melanoma. In addition, one-quarter of melanomas arose in association with congenital melanocytic nevi.

“The good news is that there are only 38 total cases of fatal pediatric melanoma between 12 academic centers over a 23-year period,” Dr. Piggott said. “Thanks goodness the number is that low.”

Dr. Piggott reported having no relevant disclosures.

SAN DIEGO – When parents bring their children to Caroline Piggott, MD, to evaluate a suspicious mole on the scalp or other body location, the vast majority turn out to be benign, because the incidence of melanoma is rare, especially before puberty.

“Only 1%-2% of all melanomas in the world are in children, so most of my job is to provide reassurance,” Dr. Piggott, a pediatric dermatologist at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “Few pediatric studies exist. Why? Because children are excluded from most melanoma clinical trials. Our management is based mainly on adult National Comprehensive Cancer Network guidelines.”

Doug Brunk/MDedge News

To help parents identify melanoma, clinicians typically recommend the “ABCDE” rule, for Asymmetry, Border irregularity, Color variation (especially dark or multiple colors), Diameter greater than 6 mm, and Evolving (is it changing, bleeding or painful?).

While Dr. Piggott considers the standard ABCDE rules as important – especially in older children and teenagers – researchers led by Kelly M. Cordoro, MD, professor of dermatology at the University of California, San Francisco, proposed a modified ABCD criteria based on evaluating a cohort of 60 children who were diagnosed with melanoma and 10 who were diagnosed with ambiguous melanocytic tumors treated as melanoma before age 20 years at UCSF from 1984 to 2009.

The researchers divided patients into two groups: those aged 0-10 years (19; group A) and those aged 11-19 years (51; group B), and found that 60% of children in group A and 40% of those in group B did not present with conventional ABCDE criteria for children. Of the 60 melanoma patients, 10 died. Of these, 9 were older than age 10, and 70% had amelanotic lesions. Based on their analysis of clinical, histopathologic, and outcomes data, Dr. Cordoro and colleagues proposed additional ABCD criteria in which A stands for stands Amelanotic; B for Bleeding or Bump; C for Color uniformity, and D for De novo or any Diameter.

“This doesn’t mean you throw the old ABCDE criteria out the window,” Dr. Piggott said. “It means that you use this modified criteria in conjunction with the conventional ABCDE rules.”

Risk factors for melanoma in children are like those in adults, and include a family history of melanoma, large/giant congenital nevi, the presence of many atypical appearing nevi, having Fitzpatrick skin types I or II, a history of blistering sunburns, and the presence of genetic anomalies such as xeroderma pigmentosum.

According to an analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program, melanoma incidence increased in all individuals in the United States aged 0-19 years from 1973 to 2009. Key risk factors included White race, female sex, and living in a SEER registry categorized as low UVB exposure. Over the study period, boys experienced increased incidence rates of melanoma on the face and trunk, while girls experienced increased incidence rates of melanoma on the lower limbs and hip.

More recently, researchers extracted data from 988,103 cases of invasive melanoma in the 2001-2015 SEER database to determine the age-specific incidence of melanoma in the United States. In 2015, 83,362 cases of invasive melanoma were reported for all ages. Of these, only 67 cases were younger than age 10, while 251 were between the ages of 10 and 19 and 1,973 were young adults between the ages of 20 and 29.

In other findings, between 2006 and 2015, the overall incidence of invasive melanoma for all ages increased from 200 million to 229 cases per million person-years. “However, there were statistically significant decreases in melanoma incidence for individuals aged 10-19 years and for those aged 10-29 years,” said Dr. Piggott, who was not involved with the study. “The hypothesis is that public health efforts encouraging against sun exposure and tanning bed use may be influencing melanoma incidence in younger populations. What is interesting, though, is that young adult women have twice the melanoma risk as young adult men.”

In a separate study, researchers prospectively followed 60 melanoma-prone families for up to 40 years to evaluate the risk of pediatric melanoma in those with and without cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations. Regardless of their CDKN2A status, the percentage of pediatric melanoma cases was 6- to 28-fold higher among melanoma-prone families, compared with the general population. In addition, families who were CDKN2A positive had a significantly higher rate of pediatric melanoma cases compared with those who were CDKN2A negative (11.1% vs. 2.5%; P = .004).

As for treating pediatric melanoma, the standard of care is similar to that for adults: usually wide local surgical excision of the primary lesion, depending on depth. Clinicians typically follow adult parameters for sentinel lymph node biopsy, such as lesion depth and ulceration.

“We know that a positive sentinel node does have prognostic value, but there is great debate on whether to do a lymph node dissection if the sentinel lymph node is positive,” Dr. Piggott said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “This is determined on a case-by-case basis. We consider factors such as, are the nodes palpable? Is there evidence on ultrasound? But there are no formal guidelines.”

Limited studies of systemic therapy in children exist because this population is excluded from most melanoma clinical trials. “In the past, interferon was sometimes used,” she said. “But in recent years, as with adults, we have started to use targeted immunologic therapy. This is usually managed by a tertiary academic oncology center.”

The chance of surviving pediatric melanoma is good if caught early. As in adults, the stage correlates strongly with survival, and distant metastases carry a poor prognosis.

In 2020, researchers published a retrospective, multicenter review of 38 cases of fatal pediatric melanoma between 1994 and 2017. The analysis was limited to individuals 20 years of age and younger who were cared for at 12 academic medical centers. Of the 38 patients, 42% were male, 58% were female, and 57% were White. In addition, 19% were Hispanic, “which is a larger percentage than fatalities in adult [Hispanic] populations with melanoma,” said Dr. Piggott, who was not involved in the study.

The mean age at diagnosis was 12.7 years, the mean age at death was 15.6 , and the mean survival time after diagnosis was about 35 months. Of the 16 cases with known identifiable subtypes, 50% were nodular, 31% were superficial spreading, and 19% were spitzoid melanoma. In addition, one-quarter of melanomas arose in association with congenital melanocytic nevi.

“The good news is that there are only 38 total cases of fatal pediatric melanoma between 12 academic centers over a 23-year period,” Dr. Piggott said. “Thanks goodness the number is that low.”

Dr. Piggott reported having no relevant disclosures.

San Diego – The way Benjamin Kelley, MD, sees it, the term dysplastic nevi (DN) suffers from an identity crisis, with different clinicians using different terms to describe a subset of melanocytic nevi that are clinically atypical.

Doug Brunk/MDedge News

“There’s a confusion in the terminology, a term the late A. Bernard Ackerman, MD, called ‘patho-babel,’ ” Dr. Kelley, a Mohs micrographic surgeon and dermatopathologist in La Jolla, Calif., said at the annual Cutaneous Malignancy Update. “The idea of DN was originally used to describe a clinical melanoma syndrome. Now we use it for individual lesions, not just clinically but histologically. Some dermatologists refer to DN as ‘pre-melanoma,’ which is a negative framing,” he noted.

“We also refer to common nevi as ‘benign,’ which implies that DN are not benign,” he added. “The good news is that regardless of what they are called, the histologic criteria is generally agreed upon. The names can be used interchangeably.”

The bad news, he continued, is that there is less-than-perfect interobserver variability for grading DN lesions and significant variability in the treatment recommendations that pathologists give to clinicians. In one study, a group of pathology experts was asked to review 48 photomicrographs of melanocytic lesions and provide their diagnosis and treatment recommendations based on the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis scheme. For one, which showed a broad lesion with irregular epidermal thinning and thickening, the diagnoses ranged from solar lentigo to melanoma in situ. Treatment recommendations ranged from no treatment to re-excise with appropriate margins.

“This is an extreme example, but it shows you how difficult [establishing a diagnosis] can be,” Dr. Kelley said.

In a more recent study, researchers analyzed interobserver reproducibility in grading 179 DN cases among three observers who applied the 2018 World Health Organization grading criteria. The observers showed moderate to good agreement for most of the architectural features, except for criteria regarding focal continuous basal proliferation of melanocytes, density of non-nested junctional melanocytes, and presence of dyscohesive nests of intraepidermal melanocytes, whereas fair agreement was achieved for the cytological criteria. “So, it sounds to me like there was not a whole lot of agreement,” Dr. Kelley said.

An earlier single-center study titled “Clinicians Are From Mars and Pathologists Are From Venus” found that surgeons misunderstood the pathologist’s report 30% of the time.

In Dr. Kelly’s opinion, management of DNs will be successful if clinicians have a good working relationship with their dermatopathologists, if they biopsy to ensure an adequate, representative specimen, and if that they know what the terminology on the pathology report means and what actions to take. “The biopsy method matters,” he emphasized.

In a 14-year follow-up survey, investigators assessed DN management trends among 703 U.S. dermatologists. One key finding was that 69% of dermatologists in 2015 performed total removals when biopsying DN to achieve clear margins, compared with 86% in 2001.

A subsequent survey of 213 New England–based dermatologists found that the degree of clinical suspicion for melanoma was important in DN biopsy technique, with more respondents favoring shave biopsies for lesions with low suspicion and full-thickness biopsies for highly suspicious lesions.

“Misdiagnosis is more common for melanomas that have been assessed with punch and shave biopsies than with an excisional biopsy,” Dr. Kelley said. “I’m not too much of a stickler. I don’t require everyone to send me a giant excision, but I do want a representative sample.”

What about re-excision of DN considered to be mild or moderate? In 2015, members of the Pigmented Lesion Subcommittee of the Melanoma Prevention Working Group published a consensus statement on DN management recommendations for clinically atypical nevi/DN based on a review of published evidence. The subcommittee members concluded that mildly and moderately DN with clear margins do not need to be re-excised, and that mildly DN biopsied with positive histologic margins without clinical residual pigmentation may be safely observed rather than re-excised.

For moderately DN with positive histologic margins without clinically apparent residual pigmentation, the subcommittee members concluded that observation may be reasonable.

In his own informal analysis, Dr. Kelley compiled data from published studies he could find on DN management and divided them into two groups: the observation group, in which researchers from eight studies biopsied the DN lesion and watched the patients over time to see what happened, and the re-excision group, in which researchers from seven studies biopsied the DN lesion and subsequently re-excised it. There were about 1,500 patients in both groups. No deaths occurred in either group, he said, but 15 patients in the re-excision group developed a melanoma at the site of the original biopsy (1%), compared with 7 in the observation group (0.5%).

Six of seven melanomas in the observation group came from one article conducted at a VA clinic. In the study, 6 of 304 observed DN subsequently developed melanoma at the site of the lesion. “However, five of six that developed melanoma had an original biopsy that was a partial biopsy with grossly positive margins; I think that’s where the problem lies,” Dr. Kelley said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “All five grew lentigo maligna type melanoma, which we know can extend multiple millimeters beyond the clinically apparent lesion.”

The findings support mounting evidence that re-excising mild and moderate DN, regardless of border involvement, may not be necessary. “Currently, most clinicians still re-excise moderate and severe DN involving margins, especially if there is residual pigment,” Dr. Kelley said. “Most re-excise severe DN regardless of margin involvement, but beware if your biopsy was a partial sample of a larger lesion.”

He acknowledged limitations to pathologic studies of DN, including the potential for diagnostic uncertainty. “That doesn’t necessarily mean that the pathologist got the diagnosis wrong. It could be, what is the risk that the portion of tissue not visualized contains melanoma? If you give me a 5 mm sample of a DN, and I cut it into 4-micrometer sections, I’m only looking at less than 1% of the actual nevus. That’s compounded if the pathologist only receives a partial sample.”

Dr. Kelley reported having no relevant disclosures.

San Diego – The way Benjamin Kelley, MD, sees it, the term dysplastic nevi (DN) suffers from an identity crisis, with different clinicians using different terms to describe a subset of melanocytic nevi that are clinically atypical.

Doug Brunk/MDedge News

“There’s a confusion in the terminology, a term the late A. Bernard Ackerman, MD, called ‘patho-babel,’ ” Dr. Kelley, a Mohs micrographic surgeon and dermatopathologist in La Jolla, Calif., said at the annual Cutaneous Malignancy Update. “The idea of DN was originally used to describe a clinical melanoma syndrome. Now we use it for individual lesions, not just clinically but histologically. Some dermatologists refer to DN as ‘pre-melanoma,’ which is a negative framing,” he noted.

“We also refer to common nevi as ‘benign,’ which implies that DN are not benign,” he added. “The good news is that regardless of what they are called, the histologic criteria is generally agreed upon. The names can be used interchangeably.”

The bad news, he continued, is that there is less-than-perfect interobserver variability for grading DN lesions and significant variability in the treatment recommendations that pathologists give to clinicians. In one study, a group of pathology experts was asked to review 48 photomicrographs of melanocytic lesions and provide their diagnosis and treatment recommendations based on the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis scheme. For one, which showed a broad lesion with irregular epidermal thinning and thickening, the diagnoses ranged from solar lentigo to melanoma in situ. Treatment recommendations ranged from no treatment to re-excise with appropriate margins.

“This is an extreme example, but it shows you how difficult [establishing a diagnosis] can be,” Dr. Kelley said.

In a more recent study, researchers analyzed interobserver reproducibility in grading 179 DN cases among three observers who applied the 2018 World Health Organization grading criteria. The observers showed moderate to good agreement for most of the architectural features, except for criteria regarding focal continuous basal proliferation of melanocytes, density of non-nested junctional melanocytes, and presence of dyscohesive nests of intraepidermal melanocytes, whereas fair agreement was achieved for the cytological criteria. “So, it sounds to me like there was not a whole lot of agreement,” Dr. Kelley said.

An earlier single-center study titled “Clinicians Are From Mars and Pathologists Are From Venus” found that surgeons misunderstood the pathologist’s report 30% of the time.

In Dr. Kelly’s opinion, management of DNs will be successful if clinicians have a good working relationship with their dermatopathologists, if they biopsy to ensure an adequate, representative specimen, and if that they know what the terminology on the pathology report means and what actions to take. “The biopsy method matters,” he emphasized.

In a 14-year follow-up survey, investigators assessed DN management trends among 703 U.S. dermatologists. One key finding was that 69% of dermatologists in 2015 performed total removals when biopsying DN to achieve clear margins, compared with 86% in 2001.

A subsequent survey of 213 New England–based dermatologists found that the degree of clinical suspicion for melanoma was important in DN biopsy technique, with more respondents favoring shave biopsies for lesions with low suspicion and full-thickness biopsies for highly suspicious lesions.

“Misdiagnosis is more common for melanomas that have been assessed with punch and shave biopsies than with an excisional biopsy,” Dr. Kelley said. “I’m not too much of a stickler. I don’t require everyone to send me a giant excision, but I do want a representative sample.”

What about re-excision of DN considered to be mild or moderate? In 2015, members of the Pigmented Lesion Subcommittee of the Melanoma Prevention Working Group published a consensus statement on DN management recommendations for clinically atypical nevi/DN based on a review of published evidence. The subcommittee members concluded that mildly and moderately DN with clear margins do not need to be re-excised, and that mildly DN biopsied with positive histologic margins without clinical residual pigmentation may be safely observed rather than re-excised.

For moderately DN with positive histologic margins without clinically apparent residual pigmentation, the subcommittee members concluded that observation may be reasonable.

In his own informal analysis, Dr. Kelley compiled data from published studies he could find on DN management and divided them into two groups: the observation group, in which researchers from eight studies biopsied the DN lesion and watched the patients over time to see what happened, and the re-excision group, in which researchers from seven studies biopsied the DN lesion and subsequently re-excised it. There were about 1,500 patients in both groups. No deaths occurred in either group, he said, but 15 patients in the re-excision group developed a melanoma at the site of the original biopsy (1%), compared with 7 in the observation group (0.5%).

Six of seven melanomas in the observation group came from one article conducted at a VA clinic. In the study, 6 of 304 observed DN subsequently developed melanoma at the site of the lesion. “However, five of six that developed melanoma had an original biopsy that was a partial biopsy with grossly positive margins; I think that’s where the problem lies,” Dr. Kelley said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “All five grew lentigo maligna type melanoma, which we know can extend multiple millimeters beyond the clinically apparent lesion.”

The findings support mounting evidence that re-excising mild and moderate DN, regardless of border involvement, may not be necessary. “Currently, most clinicians still re-excise moderate and severe DN involving margins, especially if there is residual pigment,” Dr. Kelley said. “Most re-excise severe DN regardless of margin involvement, but beware if your biopsy was a partial sample of a larger lesion.”

He acknowledged limitations to pathologic studies of DN, including the potential for diagnostic uncertainty. “That doesn’t necessarily mean that the pathologist got the diagnosis wrong. It could be, what is the risk that the portion of tissue not visualized contains melanoma? If you give me a 5 mm sample of a DN, and I cut it into 4-micrometer sections, I’m only looking at less than 1% of the actual nevus. That’s compounded if the pathologist only receives a partial sample.”

Dr. Kelley reported having no relevant disclosures.

San Diego – The way Benjamin Kelley, MD, sees it, the term dysplastic nevi (DN) suffers from an identity crisis, with different clinicians using different terms to describe a subset of melanocytic nevi that are clinically atypical.

Doug Brunk/MDedge News

“There’s a confusion in the terminology, a term the late A. Bernard Ackerman, MD, called ‘patho-babel,’ ” Dr. Kelley, a Mohs micrographic surgeon and dermatopathologist in La Jolla, Calif., said at the annual Cutaneous Malignancy Update. “The idea of DN was originally used to describe a clinical melanoma syndrome. Now we use it for individual lesions, not just clinically but histologically. Some dermatologists refer to DN as ‘pre-melanoma,’ which is a negative framing,” he noted.

“We also refer to common nevi as ‘benign,’ which implies that DN are not benign,” he added. “The good news is that regardless of what they are called, the histologic criteria is generally agreed upon. The names can be used interchangeably.”

The bad news, he continued, is that there is less-than-perfect interobserver variability for grading DN lesions and significant variability in the treatment recommendations that pathologists give to clinicians. In one study, a group of pathology experts was asked to review 48 photomicrographs of melanocytic lesions and provide their diagnosis and treatment recommendations based on the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis scheme. For one, which showed a broad lesion with irregular epidermal thinning and thickening, the diagnoses ranged from solar lentigo to melanoma in situ. Treatment recommendations ranged from no treatment to re-excise with appropriate margins.

“This is an extreme example, but it shows you how difficult [establishing a diagnosis] can be,” Dr. Kelley said.

In a more recent study, researchers analyzed interobserver reproducibility in grading 179 DN cases among three observers who applied the 2018 World Health Organization grading criteria. The observers showed moderate to good agreement for most of the architectural features, except for criteria regarding focal continuous basal proliferation of melanocytes, density of non-nested junctional melanocytes, and presence of dyscohesive nests of intraepidermal melanocytes, whereas fair agreement was achieved for the cytological criteria. “So, it sounds to me like there was not a whole lot of agreement,” Dr. Kelley said.

An earlier single-center study titled “Clinicians Are From Mars and Pathologists Are From Venus” found that surgeons misunderstood the pathologist’s report 30% of the time.

In Dr. Kelly’s opinion, management of DNs will be successful if clinicians have a good working relationship with their dermatopathologists, if they biopsy to ensure an adequate, representative specimen, and if that they know what the terminology on the pathology report means and what actions to take. “The biopsy method matters,” he emphasized.

In a 14-year follow-up survey, investigators assessed DN management trends among 703 U.S. dermatologists. One key finding was that 69% of dermatologists in 2015 performed total removals when biopsying DN to achieve clear margins, compared with 86% in 2001.

A subsequent survey of 213 New England–based dermatologists found that the degree of clinical suspicion for melanoma was important in DN biopsy technique, with more respondents favoring shave biopsies for lesions with low suspicion and full-thickness biopsies for highly suspicious lesions.

“Misdiagnosis is more common for melanomas that have been assessed with punch and shave biopsies than with an excisional biopsy,” Dr. Kelley said. “I’m not too much of a stickler. I don’t require everyone to send me a giant excision, but I do want a representative sample.”

What about re-excision of DN considered to be mild or moderate? In 2015, members of the Pigmented Lesion Subcommittee of the Melanoma Prevention Working Group published a consensus statement on DN management recommendations for clinically atypical nevi/DN based on a review of published evidence. The subcommittee members concluded that mildly and moderately DN with clear margins do not need to be re-excised, and that mildly DN biopsied with positive histologic margins without clinical residual pigmentation may be safely observed rather than re-excised.

For moderately DN with positive histologic margins without clinically apparent residual pigmentation, the subcommittee members concluded that observation may be reasonable.

In his own informal analysis, Dr. Kelley compiled data from published studies he could find on DN management and divided them into two groups: the observation group, in which researchers from eight studies biopsied the DN lesion and watched the patients over time to see what happened, and the re-excision group, in which researchers from seven studies biopsied the DN lesion and subsequently re-excised it. There were about 1,500 patients in both groups. No deaths occurred in either group, he said, but 15 patients in the re-excision group developed a melanoma at the site of the original biopsy (1%), compared with 7 in the observation group (0.5%).

Six of seven melanomas in the observation group came from one article conducted at a VA clinic. In the study, 6 of 304 observed DN subsequently developed melanoma at the site of the lesion. “However, five of six that developed melanoma had an original biopsy that was a partial biopsy with grossly positive margins; I think that’s where the problem lies,” Dr. Kelley said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “All five grew lentigo maligna type melanoma, which we know can extend multiple millimeters beyond the clinically apparent lesion.”

The findings support mounting evidence that re-excising mild and moderate DN, regardless of border involvement, may not be necessary. “Currently, most clinicians still re-excise moderate and severe DN involving margins, especially if there is residual pigment,” Dr. Kelley said. “Most re-excise severe DN regardless of margin involvement, but beware if your biopsy was a partial sample of a larger lesion.”

He acknowledged limitations to pathologic studies of DN, including the potential for diagnostic uncertainty. “That doesn’t necessarily mean that the pathologist got the diagnosis wrong. It could be, what is the risk that the portion of tissue not visualized contains melanoma? If you give me a 5 mm sample of a DN, and I cut it into 4-micrometer sections, I’m only looking at less than 1% of the actual nevus. That’s compounded if the pathologist only receives a partial sample.”

Dr. Kelley reported having no relevant disclosures.

Follow-up radiographs after an initial baseline reading in patients with rheumatoid arthritis or psoriatic arthritis may still show radiographic progression despite treatment with current therapies, but it’s unclear if they will affect treatment decisions between patients and doctors that may take place regardless of the radiographic information, according to arguments made for and against their usefulness in a point-counterpoint session at the 2023 Rheumatology Winter Clinical Symposium.

Alvin Wells, MD, PhD, director of the department of rheumatology at Advocate Aurora Health in Franklin, Wisc., said that x-rays “reflect the history of joint pathology” and can get worse over time, correlating with disease activity and severity.

BSIP/UIG/GettyImages

While RA does not yet have the “holy grail” of complete or true remission, Dr. Wells argued, the combination of clinical remission, laboratory remission, and imaging remission gets patients with RA close to the ideal when measured over time. “You need to continue to monitor these patients as you follow them along,” he said.

The BARFOT study, which evaluated 1,938 patients with early RA in two cohorts during 1992-1999 and again between 2000 and 2006, showed that more active treatments in the 2000s did not result in improvements in Health Assessment Questionnaire (HAQ) and pain scores, compared with patients treated in the 1990s. “You can see in some of those patients those scores do increase, and that even despite aggressive therapies that we had in 2006, you can still see some of those patients still have progression of the disease,” Dr. Wells explained. “How did they know? Because they looked.”

He also cited a study from researchers at the Mayo Clinic who examined 586 patients with RA that showed a higher prevalence of functional disability in patients with RA who also had radiographic changes, compared with patients without RA. “Radiographic changes correlate with disease severity and functional disability as well,” Dr. Wells said.

Just as prostate-specific antigen levels are used in prostate cancer screening and hemoglobin A1c is measured in diabetes management, radiographs should be used to track progression of disease in RA and PsA, Dr. Wells argued. “[I]f you don’t know, you can’t treat,” he said.

Some patients near remission may have radiographic progression even though disease activity measurements such as C-reactive protein (CRP) values do not show presence of active disease. In a study analyzing 1,184 patients with RA in the ASPIRE, ERA, Leflunomide, PREMIER and TEMPO trials, swollen joint count (SJC) was a better predictor of radiographic progression than CRP in patients near remission.

“[E]ven where you don’t see smoke, there still could be fire,” Dr. Wells said. “Some of these patients still progress and these are outliers, and the way they saw that [was] because they followed those patients along. If you don’t look, you don’t know.”

Radiographic progression can also be seen among nonswollen joints in patients with RA and PsA. In a study of 1,207 joints in 55 patients with RA and 352 joints in 18 patients with PsA, researchers in Austria found tenderness in nonswollen joints was associated with radiographic progression.

Despite having effective treatments in RA and PsA, “none of our therapies show that they’re able to prevent progression,” Dr. Wells said.

When it comes to hitting the treatment target in RA, some rheumatologists may think they can accomplish it without use of repeated radiographs. “I have a different perspective on that – that you really do indeed need to do the x-rays today and follow those x-rays along, especially if it’s going to change your treatment paradigm and what your treatment decision would be for the patient,” he said.
 

Counterpoint: Repeat radiographs aren’t helpful

Almost all rheumatologists would likely order an initial radiograph for their patients with RA or PsA, Roy M. Fleischmann, MD, clinical professor of medicine at the University of Texas and codirector of the Metroplex Clinical Research Center, both in Dallas, said in his presentation.

“If you see erosions when you start, chances are you’re going to be much more aggressive,” Dr. Fleischmann said. “So it is justification for early, more aggressive treatment of disease.”

In recent decades, radiographic progression in RA has decreased as more effective antirheumatic treatments have come into use, Dr. Fleischmann argued.

“We had x-ray progression in virtually everybody, and it was consistent no matter what we treated with, which was gold or penicillamine or any of the NSAIDs or sulfasalazine,” he said. “With methotrexate ... about 60% of patients actually have no x-ray progression, and that was a major change, and that’s one of the reasons why methotrexate has become the keystone of therapy. But even with methotrexate, [we] still had many patients who progressed.”

After the introduction of tumor necrosis factor inhibitors and other mechanisms in the late 1990s, “all of a sudden, you don’t see x-ray progression – mean x-ray progression – in a group of patients,” he noted.

Many rheumatologists now use a treat-to-target strategy, and if the patient achieves true clinical remission or sustained very low disease activity as measured by Boolean remission, Simple Disease Activity Index, or Clinical Disease Activity Index, they have “very little chance of radiographic progression and functional decline,” he said.

“If a patient doesn’t achieve remission or very low disease activity, obtaining a radiograph doesn’t change what you do because the patient’s not where they want to be, where you want them to be; you’re going to make a change anyway,” Dr. Fleischmann explained. “The radiograph isn’t going to help you do that.”

If a patient is in sustained remission but a radiograph is ordered and shows disease progression, he questioned what the rheumatologist would do in that situation.

“Now the patient’s in, let’s say, a Boolean remission. They have no tender joints. They have no swollen joints ... their pain assessment is zero, their CRP is zero, and they do have some x-ray progression. Where are you going to change?” Dr. Fleischmann asked. “There’s no data that anything else would work. I don’t know what you would do. So, in conclusion, I would say you really don’t need to repeat an x-ray.”
 

AI reading x-rays?

Commenting on the point-counterpoint session, Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego, and director of RWCS, asked Dr. Fleischmann and Dr. Wells how they address the issue of how many radiologists seem to be unfamiliar with reading hand radiographs and RA progression.

Dr. Fleischmann said he was trained in how to read hand radiographs in medical school, but that training no longer appears to be occurring. “If you have a good bone radiologist, of which there are not a lot, you’re great. But if you don’t have a really good bone radiologist, it’s difficult,” he said.

Dr. Kavanaugh alluded to the advancement of artificial intelligence (AI) in radiology and posed the question of how both rheumatologists felt about AI reading and interpreting their radiographs. “If you could reliably submit x-rays and they would say what the Sharp score was and where the differences were, would that change anything?” he asked.

“I think having artificial intelligence read the x-ray or an MRI is really, really good. It’ll be better than the radiologists,” Dr. Fleischmann responded. “But I don’t think that you really need to repeat the x-ray. I mean, I really don’t think you need to repeat it. You need to treat the patient.”

Dr. Wells reported having financial relationships with numerous pharmaceutical companies. Dr. Fleischmann reported no relevant financial relationships.

Follow-up radiographs after an initial baseline reading in patients with rheumatoid arthritis or psoriatic arthritis may still show radiographic progression despite treatment with current therapies, but it’s unclear if they will affect treatment decisions between patients and doctors that may take place regardless of the radiographic information, according to arguments made for and against their usefulness in a point-counterpoint session at the 2023 Rheumatology Winter Clinical Symposium.

Alvin Wells, MD, PhD, director of the department of rheumatology at Advocate Aurora Health in Franklin, Wisc., said that x-rays “reflect the history of joint pathology” and can get worse over time, correlating with disease activity and severity.

BSIP/UIG/GettyImages

While RA does not yet have the “holy grail” of complete or true remission, Dr. Wells argued, the combination of clinical remission, laboratory remission, and imaging remission gets patients with RA close to the ideal when measured over time. “You need to continue to monitor these patients as you follow them along,” he said.

The BARFOT study, which evaluated 1,938 patients with early RA in two cohorts during 1992-1999 and again between 2000 and 2006, showed that more active treatments in the 2000s did not result in improvements in Health Assessment Questionnaire (HAQ) and pain scores, compared with patients treated in the 1990s. “You can see in some of those patients those scores do increase, and that even despite aggressive therapies that we had in 2006, you can still see some of those patients still have progression of the disease,” Dr. Wells explained. “How did they know? Because they looked.”

He also cited a study from researchers at the Mayo Clinic who examined 586 patients with RA that showed a higher prevalence of functional disability in patients with RA who also had radiographic changes, compared with patients without RA. “Radiographic changes correlate with disease severity and functional disability as well,” Dr. Wells said.

Just as prostate-specific antigen levels are used in prostate cancer screening and hemoglobin A1c is measured in diabetes management, radiographs should be used to track progression of disease in RA and PsA, Dr. Wells argued. “[I]f you don’t know, you can’t treat,” he said.

Some patients near remission may have radiographic progression even though disease activity measurements such as C-reactive protein (CRP) values do not show presence of active disease. In a study analyzing 1,184 patients with RA in the ASPIRE, ERA, Leflunomide, PREMIER and TEMPO trials, swollen joint count (SJC) was a better predictor of radiographic progression than CRP in patients near remission.

“[E]ven where you don’t see smoke, there still could be fire,” Dr. Wells said. “Some of these patients still progress and these are outliers, and the way they saw that [was] because they followed those patients along. If you don’t look, you don’t know.”

Radiographic progression can also be seen among nonswollen joints in patients with RA and PsA. In a study of 1,207 joints in 55 patients with RA and 352 joints in 18 patients with PsA, researchers in Austria found tenderness in nonswollen joints was associated with radiographic progression.

Despite having effective treatments in RA and PsA, “none of our therapies show that they’re able to prevent progression,” Dr. Wells said.

When it comes to hitting the treatment target in RA, some rheumatologists may think they can accomplish it without use of repeated radiographs. “I have a different perspective on that – that you really do indeed need to do the x-rays today and follow those x-rays along, especially if it’s going to change your treatment paradigm and what your treatment decision would be for the patient,” he said.
 

Counterpoint: Repeat radiographs aren’t helpful

Almost all rheumatologists would likely order an initial radiograph for their patients with RA or PsA, Roy M. Fleischmann, MD, clinical professor of medicine at the University of Texas and codirector of the Metroplex Clinical Research Center, both in Dallas, said in his presentation.

“If you see erosions when you start, chances are you’re going to be much more aggressive,” Dr. Fleischmann said. “So it is justification for early, more aggressive treatment of disease.”

In recent decades, radiographic progression in RA has decreased as more effective antirheumatic treatments have come into use, Dr. Fleischmann argued.

“We had x-ray progression in virtually everybody, and it was consistent no matter what we treated with, which was gold or penicillamine or any of the NSAIDs or sulfasalazine,” he said. “With methotrexate ... about 60% of patients actually have no x-ray progression, and that was a major change, and that’s one of the reasons why methotrexate has become the keystone of therapy. But even with methotrexate, [we] still had many patients who progressed.”

After the introduction of tumor necrosis factor inhibitors and other mechanisms in the late 1990s, “all of a sudden, you don’t see x-ray progression – mean x-ray progression – in a group of patients,” he noted.

Many rheumatologists now use a treat-to-target strategy, and if the patient achieves true clinical remission or sustained very low disease activity as measured by Boolean remission, Simple Disease Activity Index, or Clinical Disease Activity Index, they have “very little chance of radiographic progression and functional decline,” he said.

“If a patient doesn’t achieve remission or very low disease activity, obtaining a radiograph doesn’t change what you do because the patient’s not where they want to be, where you want them to be; you’re going to make a change anyway,” Dr. Fleischmann explained. “The radiograph isn’t going to help you do that.”

If a patient is in sustained remission but a radiograph is ordered and shows disease progression, he questioned what the rheumatologist would do in that situation.

“Now the patient’s in, let’s say, a Boolean remission. They have no tender joints. They have no swollen joints ... their pain assessment is zero, their CRP is zero, and they do have some x-ray progression. Where are you going to change?” Dr. Fleischmann asked. “There’s no data that anything else would work. I don’t know what you would do. So, in conclusion, I would say you really don’t need to repeat an x-ray.”
 

AI reading x-rays?

Commenting on the point-counterpoint session, Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego, and director of RWCS, asked Dr. Fleischmann and Dr. Wells how they address the issue of how many radiologists seem to be unfamiliar with reading hand radiographs and RA progression.

Dr. Fleischmann said he was trained in how to read hand radiographs in medical school, but that training no longer appears to be occurring. “If you have a good bone radiologist, of which there are not a lot, you’re great. But if you don’t have a really good bone radiologist, it’s difficult,” he said.

Dr. Kavanaugh alluded to the advancement of artificial intelligence (AI) in radiology and posed the question of how both rheumatologists felt about AI reading and interpreting their radiographs. “If you could reliably submit x-rays and they would say what the Sharp score was and where the differences were, would that change anything?” he asked.

“I think having artificial intelligence read the x-ray or an MRI is really, really good. It’ll be better than the radiologists,” Dr. Fleischmann responded. “But I don’t think that you really need to repeat the x-ray. I mean, I really don’t think you need to repeat it. You need to treat the patient.”

Dr. Wells reported having financial relationships with numerous pharmaceutical companies. Dr. Fleischmann reported no relevant financial relationships.

Follow-up radiographs after an initial baseline reading in patients with rheumatoid arthritis or psoriatic arthritis may still show radiographic progression despite treatment with current therapies, but it’s unclear if they will affect treatment decisions between patients and doctors that may take place regardless of the radiographic information, according to arguments made for and against their usefulness in a point-counterpoint session at the 2023 Rheumatology Winter Clinical Symposium.

Alvin Wells, MD, PhD, director of the department of rheumatology at Advocate Aurora Health in Franklin, Wisc., said that x-rays “reflect the history of joint pathology” and can get worse over time, correlating with disease activity and severity.

BSIP/UIG/GettyImages

While RA does not yet have the “holy grail” of complete or true remission, Dr. Wells argued, the combination of clinical remission, laboratory remission, and imaging remission gets patients with RA close to the ideal when measured over time. “You need to continue to monitor these patients as you follow them along,” he said.

The BARFOT study, which evaluated 1,938 patients with early RA in two cohorts during 1992-1999 and again between 2000 and 2006, showed that more active treatments in the 2000s did not result in improvements in Health Assessment Questionnaire (HAQ) and pain scores, compared with patients treated in the 1990s. “You can see in some of those patients those scores do increase, and that even despite aggressive therapies that we had in 2006, you can still see some of those patients still have progression of the disease,” Dr. Wells explained. “How did they know? Because they looked.”

He also cited a study from researchers at the Mayo Clinic who examined 586 patients with RA that showed a higher prevalence of functional disability in patients with RA who also had radiographic changes, compared with patients without RA. “Radiographic changes correlate with disease severity and functional disability as well,” Dr. Wells said.

Just as prostate-specific antigen levels are used in prostate cancer screening and hemoglobin A1c is measured in diabetes management, radiographs should be used to track progression of disease in RA and PsA, Dr. Wells argued. “[I]f you don’t know, you can’t treat,” he said.

Some patients near remission may have radiographic progression even though disease activity measurements such as C-reactive protein (CRP) values do not show presence of active disease. In a study analyzing 1,184 patients with RA in the ASPIRE, ERA, Leflunomide, PREMIER and TEMPO trials, swollen joint count (SJC) was a better predictor of radiographic progression than CRP in patients near remission.

“[E]ven where you don’t see smoke, there still could be fire,” Dr. Wells said. “Some of these patients still progress and these are outliers, and the way they saw that [was] because they followed those patients along. If you don’t look, you don’t know.”

Radiographic progression can also be seen among nonswollen joints in patients with RA and PsA. In a study of 1,207 joints in 55 patients with RA and 352 joints in 18 patients with PsA, researchers in Austria found tenderness in nonswollen joints was associated with radiographic progression.

Despite having effective treatments in RA and PsA, “none of our therapies show that they’re able to prevent progression,” Dr. Wells said.

When it comes to hitting the treatment target in RA, some rheumatologists may think they can accomplish it without use of repeated radiographs. “I have a different perspective on that – that you really do indeed need to do the x-rays today and follow those x-rays along, especially if it’s going to change your treatment paradigm and what your treatment decision would be for the patient,” he said.
 

Counterpoint: Repeat radiographs aren’t helpful

Almost all rheumatologists would likely order an initial radiograph for their patients with RA or PsA, Roy M. Fleischmann, MD, clinical professor of medicine at the University of Texas and codirector of the Metroplex Clinical Research Center, both in Dallas, said in his presentation.

“If you see erosions when you start, chances are you’re going to be much more aggressive,” Dr. Fleischmann said. “So it is justification for early, more aggressive treatment of disease.”

In recent decades, radiographic progression in RA has decreased as more effective antirheumatic treatments have come into use, Dr. Fleischmann argued.

“We had x-ray progression in virtually everybody, and it was consistent no matter what we treated with, which was gold or penicillamine or any of the NSAIDs or sulfasalazine,” he said. “With methotrexate ... about 60% of patients actually have no x-ray progression, and that was a major change, and that’s one of the reasons why methotrexate has become the keystone of therapy. But even with methotrexate, [we] still had many patients who progressed.”

After the introduction of tumor necrosis factor inhibitors and other mechanisms in the late 1990s, “all of a sudden, you don’t see x-ray progression – mean x-ray progression – in a group of patients,” he noted.

Many rheumatologists now use a treat-to-target strategy, and if the patient achieves true clinical remission or sustained very low disease activity as measured by Boolean remission, Simple Disease Activity Index, or Clinical Disease Activity Index, they have “very little chance of radiographic progression and functional decline,” he said.

“If a patient doesn’t achieve remission or very low disease activity, obtaining a radiograph doesn’t change what you do because the patient’s not where they want to be, where you want them to be; you’re going to make a change anyway,” Dr. Fleischmann explained. “The radiograph isn’t going to help you do that.”

If a patient is in sustained remission but a radiograph is ordered and shows disease progression, he questioned what the rheumatologist would do in that situation.

“Now the patient’s in, let’s say, a Boolean remission. They have no tender joints. They have no swollen joints ... their pain assessment is zero, their CRP is zero, and they do have some x-ray progression. Where are you going to change?” Dr. Fleischmann asked. “There’s no data that anything else would work. I don’t know what you would do. So, in conclusion, I would say you really don’t need to repeat an x-ray.”
 

AI reading x-rays?

Commenting on the point-counterpoint session, Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego, and director of RWCS, asked Dr. Fleischmann and Dr. Wells how they address the issue of how many radiologists seem to be unfamiliar with reading hand radiographs and RA progression.

Dr. Fleischmann said he was trained in how to read hand radiographs in medical school, but that training no longer appears to be occurring. “If you have a good bone radiologist, of which there are not a lot, you’re great. But if you don’t have a really good bone radiologist, it’s difficult,” he said.

Dr. Kavanaugh alluded to the advancement of artificial intelligence (AI) in radiology and posed the question of how both rheumatologists felt about AI reading and interpreting their radiographs. “If you could reliably submit x-rays and they would say what the Sharp score was and where the differences were, would that change anything?” he asked.

“I think having artificial intelligence read the x-ray or an MRI is really, really good. It’ll be better than the radiologists,” Dr. Fleischmann responded. “But I don’t think that you really need to repeat the x-ray. I mean, I really don’t think you need to repeat it. You need to treat the patient.”

Dr. Wells reported having financial relationships with numerous pharmaceutical companies. Dr. Fleischmann reported no relevant financial relationships.

Maternal primary antibody immunodeficiencies (PIDs) are tied to increased risk for psychiatric disorders and suicidality in offspring, new research suggests.

Results from a cohort study of more than 4.2 million individuals showed that offspring of mothers with PIDs had a 17% increased risk for a psychiatric disorder and a 20% increased risk for suicidal behavior, compared with their peers with mothers who did not have PIDs.

The risk was more pronounced in offspring of mothers with both PIDs and autoimmune diseases. These risks remained after strictly controlling for different covariates, such as the parents’ psychiatric history, offspring PIDs, and offspring autoimmune diseases.

The investigators, led by Josef Isung, MD, PhD, Centre for Psychiatry Research, department of clinical neuroscience, Karolinska Institutet, Stockholm, noted that they could not “pinpoint a precise causal mechanism” underlying these findings.

Still, “the results add to the existing literature suggesting that the intrauterine immune environment may have implications for fetal neurodevelopment and that a compromised maternal immune system during pregnancy may be a risk factor for psychiatric disorders and suicidal behavior in their offspring in the long term,” they wrote.

The findings were published online in JAMA Psychiatry.
 

‘Natural experiment’

Maternal immune activation (MIA) is “an overarching term for aberrant and disrupted immune activity in the mother during gestation [and] has long been of interest in relation to adverse health outcomes in the offspring,” Dr. Isung noted.

“In relation to negative psychiatric outcomes, there is an abundance of preclinical evidence that has shown a negative impact on offspring secondary to MIA. And in humans, there are several observational studies supporting this link,” he said in an interview.

Dr. Isung added that PIDs are “rare conditions” known to be associated with repeated infections and high rates of autoimmune diseases, causing substantial disability.

“PIDs represent an interesting ‘natural experiment’ for researchers to understand more about the association between immune system dysfunctions and mental health,” he said.

Dr. Isung’s group previously showed that individuals with PIDs have increased odds of psychiatric disorders and suicidal behavior. The link was more pronounced in women with PIDs – and was even more pronounced in those with both PIDs and autoimmune diseases.

In the current study, “we wanted to see whether offspring of individuals were differentially at risk of psychiatric disorders and suicidal behavior, depending on being offspring of mothers or fathers with PIDs,” Dr. Isung said.

“Our hypothesis was that mothers with PIDs would have an increased risk of having offspring with neuropsychiatric outcomes, and that this risk could be due to MIA,” he added.

The researchers turned to Swedish nationwide health and administrative registers. They analyzed data on all individuals with diagnoses of PIDs identified between 1973 and 2013. Offspring born prior to 2003 were included, and parent-offspring pairs in which both parents had a history of PIDs were excluded.

The final study sample consisted of 4,294,169 offspring (51.4% boys). Of these participants, 7,270 (0.17%) had a parent with PIDs.

The researchers identified lifetime records of 10 psychiatric disorders: obsessive-compulsive disorder, ADHD, autism spectrum disorders, schizophrenia and other psychotic disorders, bipolar disorders, major depressive disorder and other mood disorders, anxiety and stress-related disorders, eating disorders, substance use disorders, and Tourette syndrome and chronic tic disorders.

The investigators included parental birth year, psychopathology, suicide attempts, suicide deaths, and autoimmune diseases as covariates, as well as offsprings’ birth year and gender.
 

Elucidation needed

Results showed that, of the 4,676 offspring of mothers with PID, 17.1% had a psychiatric disorder versus 12.7% of offspring of mothers without PIDs. This translated “into a 17% increased risk for offspring of mothers with PIDs in the fully adjusted model,” the investigators reported.

The risk was even higher for offspring of mothers who had not only PIDs but also one of six of the individual psychiatric disorders, with incident rate ratios ranging from 1.15 to 1.71.

Important piece of the puzzle?

In a comment, Michael Eriksen Benros, MD, PhD, professor of immunopsychiatry, department of immunology and microbiology, health, and medical sciences, University of Copenhagen, said this was a “high-quality study” that used a “rich data source.”

Dr. Benros, who is also head of research (biological and precision psychiatry) at the Copenhagen Research Centre for Mental Health, Copenhagen University Hospital, was not involved with the current study.

He noted that prior studies, including some conducted by his own group, have shown that maternal infections overall did not seem to be “specifically linked to mental disorders in the offspring.”

However, “specific maternal infections or specific brain-reactive antibodies during the pregnancy period have been shown to be associated with neurodevelopmental outcomes among the children,” such as intellectual disability, he said.

Regarding direct clinical implications of the study, “it is important to note that the increased risk of psychiatric disorders and suicidality in the offspring of mothers with PID were small,” Dr. Benros said.

“However, it adds an important part to the scientific puzzle regarding the role of maternal immune activation during pregnancy and the risk of mental disorders,” he added.

The study was funded by the Söderström König Foundation and the Fredrik and Ingrid Thuring Foundation. Neither Dr. Isung nor Dr. Benros reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Maternal primary antibody immunodeficiencies (PIDs) are tied to increased risk for psychiatric disorders and suicidality in offspring, new research suggests.

Results from a cohort study of more than 4.2 million individuals showed that offspring of mothers with PIDs had a 17% increased risk for a psychiatric disorder and a 20% increased risk for suicidal behavior, compared with their peers with mothers who did not have PIDs.

The risk was more pronounced in offspring of mothers with both PIDs and autoimmune diseases. These risks remained after strictly controlling for different covariates, such as the parents’ psychiatric history, offspring PIDs, and offspring autoimmune diseases.

The investigators, led by Josef Isung, MD, PhD, Centre for Psychiatry Research, department of clinical neuroscience, Karolinska Institutet, Stockholm, noted that they could not “pinpoint a precise causal mechanism” underlying these findings.

Still, “the results add to the existing literature suggesting that the intrauterine immune environment may have implications for fetal neurodevelopment and that a compromised maternal immune system during pregnancy may be a risk factor for psychiatric disorders and suicidal behavior in their offspring in the long term,” they wrote.

The findings were published online in JAMA Psychiatry.
 

‘Natural experiment’

Maternal immune activation (MIA) is “an overarching term for aberrant and disrupted immune activity in the mother during gestation [and] has long been of interest in relation to adverse health outcomes in the offspring,” Dr. Isung noted.

“In relation to negative psychiatric outcomes, there is an abundance of preclinical evidence that has shown a negative impact on offspring secondary to MIA. And in humans, there are several observational studies supporting this link,” he said in an interview.

Dr. Isung added that PIDs are “rare conditions” known to be associated with repeated infections and high rates of autoimmune diseases, causing substantial disability.

“PIDs represent an interesting ‘natural experiment’ for researchers to understand more about the association between immune system dysfunctions and mental health,” he said.

Dr. Isung’s group previously showed that individuals with PIDs have increased odds of psychiatric disorders and suicidal behavior. The link was more pronounced in women with PIDs – and was even more pronounced in those with both PIDs and autoimmune diseases.

In the current study, “we wanted to see whether offspring of individuals were differentially at risk of psychiatric disorders and suicidal behavior, depending on being offspring of mothers or fathers with PIDs,” Dr. Isung said.

“Our hypothesis was that mothers with PIDs would have an increased risk of having offspring with neuropsychiatric outcomes, and that this risk could be due to MIA,” he added.

The researchers turned to Swedish nationwide health and administrative registers. They analyzed data on all individuals with diagnoses of PIDs identified between 1973 and 2013. Offspring born prior to 2003 were included, and parent-offspring pairs in which both parents had a history of PIDs were excluded.

The final study sample consisted of 4,294,169 offspring (51.4% boys). Of these participants, 7,270 (0.17%) had a parent with PIDs.

The researchers identified lifetime records of 10 psychiatric disorders: obsessive-compulsive disorder, ADHD, autism spectrum disorders, schizophrenia and other psychotic disorders, bipolar disorders, major depressive disorder and other mood disorders, anxiety and stress-related disorders, eating disorders, substance use disorders, and Tourette syndrome and chronic tic disorders.

The investigators included parental birth year, psychopathology, suicide attempts, suicide deaths, and autoimmune diseases as covariates, as well as offsprings’ birth year and gender.
 

Elucidation needed

Results showed that, of the 4,676 offspring of mothers with PID, 17.1% had a psychiatric disorder versus 12.7% of offspring of mothers without PIDs. This translated “into a 17% increased risk for offspring of mothers with PIDs in the fully adjusted model,” the investigators reported.

The risk was even higher for offspring of mothers who had not only PIDs but also one of six of the individual psychiatric disorders, with incident rate ratios ranging from 1.15 to 1.71.

Important piece of the puzzle?

In a comment, Michael Eriksen Benros, MD, PhD, professor of immunopsychiatry, department of immunology and microbiology, health, and medical sciences, University of Copenhagen, said this was a “high-quality study” that used a “rich data source.”

Dr. Benros, who is also head of research (biological and precision psychiatry) at the Copenhagen Research Centre for Mental Health, Copenhagen University Hospital, was not involved with the current study.

He noted that prior studies, including some conducted by his own group, have shown that maternal infections overall did not seem to be “specifically linked to mental disorders in the offspring.”

However, “specific maternal infections or specific brain-reactive antibodies during the pregnancy period have been shown to be associated with neurodevelopmental outcomes among the children,” such as intellectual disability, he said.

Regarding direct clinical implications of the study, “it is important to note that the increased risk of psychiatric disorders and suicidality in the offspring of mothers with PID were small,” Dr. Benros said.

“However, it adds an important part to the scientific puzzle regarding the role of maternal immune activation during pregnancy and the risk of mental disorders,” he added.

The study was funded by the Söderström König Foundation and the Fredrik and Ingrid Thuring Foundation. Neither Dr. Isung nor Dr. Benros reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Maternal primary antibody immunodeficiencies (PIDs) are tied to increased risk for psychiatric disorders and suicidality in offspring, new research suggests.

Results from a cohort study of more than 4.2 million individuals showed that offspring of mothers with PIDs had a 17% increased risk for a psychiatric disorder and a 20% increased risk for suicidal behavior, compared with their peers with mothers who did not have PIDs.

The risk was more pronounced in offspring of mothers with both PIDs and autoimmune diseases. These risks remained after strictly controlling for different covariates, such as the parents’ psychiatric history, offspring PIDs, and offspring autoimmune diseases.

The investigators, led by Josef Isung, MD, PhD, Centre for Psychiatry Research, department of clinical neuroscience, Karolinska Institutet, Stockholm, noted that they could not “pinpoint a precise causal mechanism” underlying these findings.

Still, “the results add to the existing literature suggesting that the intrauterine immune environment may have implications for fetal neurodevelopment and that a compromised maternal immune system during pregnancy may be a risk factor for psychiatric disorders and suicidal behavior in their offspring in the long term,” they wrote.

The findings were published online in JAMA Psychiatry.
 

‘Natural experiment’

Maternal immune activation (MIA) is “an overarching term for aberrant and disrupted immune activity in the mother during gestation [and] has long been of interest in relation to adverse health outcomes in the offspring,” Dr. Isung noted.

“In relation to negative psychiatric outcomes, there is an abundance of preclinical evidence that has shown a negative impact on offspring secondary to MIA. And in humans, there are several observational studies supporting this link,” he said in an interview.

Dr. Isung added that PIDs are “rare conditions” known to be associated with repeated infections and high rates of autoimmune diseases, causing substantial disability.

“PIDs represent an interesting ‘natural experiment’ for researchers to understand more about the association between immune system dysfunctions and mental health,” he said.

Dr. Isung’s group previously showed that individuals with PIDs have increased odds of psychiatric disorders and suicidal behavior. The link was more pronounced in women with PIDs – and was even more pronounced in those with both PIDs and autoimmune diseases.

In the current study, “we wanted to see whether offspring of individuals were differentially at risk of psychiatric disorders and suicidal behavior, depending on being offspring of mothers or fathers with PIDs,” Dr. Isung said.

“Our hypothesis was that mothers with PIDs would have an increased risk of having offspring with neuropsychiatric outcomes, and that this risk could be due to MIA,” he added.

The researchers turned to Swedish nationwide health and administrative registers. They analyzed data on all individuals with diagnoses of PIDs identified between 1973 and 2013. Offspring born prior to 2003 were included, and parent-offspring pairs in which both parents had a history of PIDs were excluded.

The final study sample consisted of 4,294,169 offspring (51.4% boys). Of these participants, 7,270 (0.17%) had a parent with PIDs.

The researchers identified lifetime records of 10 psychiatric disorders: obsessive-compulsive disorder, ADHD, autism spectrum disorders, schizophrenia and other psychotic disorders, bipolar disorders, major depressive disorder and other mood disorders, anxiety and stress-related disorders, eating disorders, substance use disorders, and Tourette syndrome and chronic tic disorders.

The investigators included parental birth year, psychopathology, suicide attempts, suicide deaths, and autoimmune diseases as covariates, as well as offsprings’ birth year and gender.
 

Elucidation needed

Results showed that, of the 4,676 offspring of mothers with PID, 17.1% had a psychiatric disorder versus 12.7% of offspring of mothers without PIDs. This translated “into a 17% increased risk for offspring of mothers with PIDs in the fully adjusted model,” the investigators reported.

The risk was even higher for offspring of mothers who had not only PIDs but also one of six of the individual psychiatric disorders, with incident rate ratios ranging from 1.15 to 1.71.

Important piece of the puzzle?

In a comment, Michael Eriksen Benros, MD, PhD, professor of immunopsychiatry, department of immunology and microbiology, health, and medical sciences, University of Copenhagen, said this was a “high-quality study” that used a “rich data source.”

Dr. Benros, who is also head of research (biological and precision psychiatry) at the Copenhagen Research Centre for Mental Health, Copenhagen University Hospital, was not involved with the current study.

He noted that prior studies, including some conducted by his own group, have shown that maternal infections overall did not seem to be “specifically linked to mental disorders in the offspring.”

However, “specific maternal infections or specific brain-reactive antibodies during the pregnancy period have been shown to be associated with neurodevelopmental outcomes among the children,” such as intellectual disability, he said.

Regarding direct clinical implications of the study, “it is important to note that the increased risk of psychiatric disorders and suicidality in the offspring of mothers with PID were small,” Dr. Benros said.

“However, it adds an important part to the scientific puzzle regarding the role of maternal immune activation during pregnancy and the risk of mental disorders,” he added.

The study was funded by the Söderström König Foundation and the Fredrik and Ingrid Thuring Foundation. Neither Dr. Isung nor Dr. Benros reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Physicians routinely monitor cholesterol, blood pressure, and glucose levels to get a clearer picture of their patients’ overall health. But a group of experts argues that having an accurate read of a person’s ability to absorb oxygen during peak exertion – VO₂ max – is just as important.

Once the focus of cyclists and other elite athletes, VO₂ max has in recent years caught the attention of geriatricians, who have linked the measure to maximum functional capacity – an umbrella term for the body’s ability to perform aerobic exercise.

“Function is prognostic of mortality,” said Daniel E. Forman, MD, FAHA, FACC, professor of medicine and chair of the section of geriatric cardiology at the University of Pittsburgh Medical Center. “If you aren’t looking at that, you’re missing the boat.”

Although cardiopulmonary exercise testing (CPET) remains the gold standard for assessing VO₂ max, Dr. Forman said clinicians often overlook CPET because it is old.
 

Getting precise

As a person ages, the amount of physical activity needed to stay fit varies, depending on genes, health, and fitness history. Measuring VO₂ max can help doctors better prescribe physical activity, both with regard to specific exercises and for how long, Claudio Gil Araújo, MD, PhD, dean of research and education at the Exercise Medicine Clinic at CLINIMEX in Rio de Janeiro, Brazil, told this news organization. The test can also measure progress.

“Guidelines talk about how much exercise you should do every week, but it’s somewhat misleading because the health outcomes are much more linked to physical fitness than the amount of exercise you do,” Dr. Araújo said. Treating a patient with hypertension requires an individualized approach. “The same thing is true with exercise,” he said.

A person with high aerobic fitness, either because of favorable genetics or because he or she has maintained good fitness by exercising, may need less activity, but 200 minutes per week may not be enough for someone else.

In his own lab, Dr. Araújo is following “dozens” of men and women who have been able to increase their ability to exercise – especially high-intensity activity – over time. And their VO₂ max readings have risen, he said.

Getting patients moving and collecting data on VO₂ max is the most precise way to measure aerobic fitness. But the test is far from a staple in primary care.

Dr. Araújo said a growing body of research has long shown VO₂ max to be a significant determinant of health and one that physicians should be paying closer attention to, especially for aging patients.

“If someone has a low VO₂ max, the treatment to correct this unfavorable health profile is to increase exercise levels,” Dr. Araújo said. “This is a very relevant public health message.”

Investigators have found that inactivity increases a person’s risk of dying from an atherosclerotic cardiovascular disease event by about the same amount as smoking, and that a sedentary lifestyle increases with age . A patient’s fitness is crucial to his or her overall health, and VO₂ max can play a key role. Poor performance on CPET could be a warning regarding a number of conditions, particularly cardiovascular and lung disease, Dr. Araújo said.

Indeed, acing the CPET is not easy.

“Your joints have to be normal, you can’t have low potassium, low sodium, or high blood sugar, your heart has to pump well, your blood vessels have to be healthy,” said Thomas Allison, PhD, MPH, director of the Integrated Stress Testing Center and the Sports Cardiology Clinic at Mayo Clinic, in Rochester, Minn. “All of those things can show up on the treadmill in terms of your VO₂ max.”

Low VO₂ max can be a physician’s first indication to investigate further. A review published in November 2022 in the International Journal of Cardiology Cardiovascular Risk and Prevention outlined what cross-sectional and longitudinal studies have documented regarding how VO₂ max changes as people age. From ages 18 to 35, VO₂ max remains fairly consistent. Between 35 and 55, it drops slightly but inexorably before falling sharply, if inconsistently. This inconsistency is where the important data lie.

“That lower level of physical activity may just be a behavioral change that needs to be reversed, or it could be a change that has been forced by underlying occult disease,” Dr. Allison said. That older people can’t run as fast as young people or are more likely to die in a given period than young people is not surprising. “The question is, at any given age, does your fitness level predict good health outcomes?” he said. “And the answer is yes.”

Fitness should be treated as any other data point, he added.

“If I want to know your blood pressure, I’m going to check your blood pressure; I’m not going to just ask you what it is,” Dr. Allison said. “If I ask if you have any limitations or symptoms with exercise or how physically active you are, if possible, I want to check that.”
 

Culture shift

Dr. Forman acknowledged that VO₂ max tests can be difficult and expensive to administer in offices that aren’t already equipped with CPET machines. He said conducting other assessments, such as observing the patient performing a short walk, won’t provide as accurate data but is better than not assessing function at all.

“Specialists all have different things they measure, but function is the common denominator. For an aging population, it is the number one thing we should be looking at,” Dr. Forman said. “It’s a skill set, it’s an investment, it’s a change in culture at a time when cardiologists are obsessed with getting the latest imaging machines.”

Dr. Allison said all cardiologists should assess their patients’ VO₂ max and that family medicine doctors should use the test for certain patients, such as those who have gained an unusual amount of weight or report being out of breath more than usual.

“We have all sorts of things that can go wrong with us as we get older, but if we’re sitting in a doctor’s office, it may not be apparent what they are,” Dr. Allison said. “We have to get patients up and moving.”

The authors have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Physicians routinely monitor cholesterol, blood pressure, and glucose levels to get a clearer picture of their patients’ overall health. But a group of experts argues that having an accurate read of a person’s ability to absorb oxygen during peak exertion – VO₂ max – is just as important.

Once the focus of cyclists and other elite athletes, VO₂ max has in recent years caught the attention of geriatricians, who have linked the measure to maximum functional capacity – an umbrella term for the body’s ability to perform aerobic exercise.

“Function is prognostic of mortality,” said Daniel E. Forman, MD, FAHA, FACC, professor of medicine and chair of the section of geriatric cardiology at the University of Pittsburgh Medical Center. “If you aren’t looking at that, you’re missing the boat.”

Although cardiopulmonary exercise testing (CPET) remains the gold standard for assessing VO₂ max, Dr. Forman said clinicians often overlook CPET because it is old.
 

Getting precise

As a person ages, the amount of physical activity needed to stay fit varies, depending on genes, health, and fitness history. Measuring VO₂ max can help doctors better prescribe physical activity, both with regard to specific exercises and for how long, Claudio Gil Araújo, MD, PhD, dean of research and education at the Exercise Medicine Clinic at CLINIMEX in Rio de Janeiro, Brazil, told this news organization. The test can also measure progress.

“Guidelines talk about how much exercise you should do every week, but it’s somewhat misleading because the health outcomes are much more linked to physical fitness than the amount of exercise you do,” Dr. Araújo said. Treating a patient with hypertension requires an individualized approach. “The same thing is true with exercise,” he said.

A person with high aerobic fitness, either because of favorable genetics or because he or she has maintained good fitness by exercising, may need less activity, but 200 minutes per week may not be enough for someone else.

In his own lab, Dr. Araújo is following “dozens” of men and women who have been able to increase their ability to exercise – especially high-intensity activity – over time. And their VO₂ max readings have risen, he said.

Getting patients moving and collecting data on VO₂ max is the most precise way to measure aerobic fitness. But the test is far from a staple in primary care.

Dr. Araújo said a growing body of research has long shown VO₂ max to be a significant determinant of health and one that physicians should be paying closer attention to, especially for aging patients.

“If someone has a low VO₂ max, the treatment to correct this unfavorable health profile is to increase exercise levels,” Dr. Araújo said. “This is a very relevant public health message.”

Investigators have found that inactivity increases a person’s risk of dying from an atherosclerotic cardiovascular disease event by about the same amount as smoking, and that a sedentary lifestyle increases with age . A patient’s fitness is crucial to his or her overall health, and VO₂ max can play a key role. Poor performance on CPET could be a warning regarding a number of conditions, particularly cardiovascular and lung disease, Dr. Araújo said.

Indeed, acing the CPET is not easy.

“Your joints have to be normal, you can’t have low potassium, low sodium, or high blood sugar, your heart has to pump well, your blood vessels have to be healthy,” said Thomas Allison, PhD, MPH, director of the Integrated Stress Testing Center and the Sports Cardiology Clinic at Mayo Clinic, in Rochester, Minn. “All of those things can show up on the treadmill in terms of your VO₂ max.”

Low VO₂ max can be a physician’s first indication to investigate further. A review published in November 2022 in the International Journal of Cardiology Cardiovascular Risk and Prevention outlined what cross-sectional and longitudinal studies have documented regarding how VO₂ max changes as people age. From ages 18 to 35, VO₂ max remains fairly consistent. Between 35 and 55, it drops slightly but inexorably before falling sharply, if inconsistently. This inconsistency is where the important data lie.

“That lower level of physical activity may just be a behavioral change that needs to be reversed, or it could be a change that has been forced by underlying occult disease,” Dr. Allison said. That older people can’t run as fast as young people or are more likely to die in a given period than young people is not surprising. “The question is, at any given age, does your fitness level predict good health outcomes?” he said. “And the answer is yes.”

Fitness should be treated as any other data point, he added.

“If I want to know your blood pressure, I’m going to check your blood pressure; I’m not going to just ask you what it is,” Dr. Allison said. “If I ask if you have any limitations or symptoms with exercise or how physically active you are, if possible, I want to check that.”
 

Culture shift

Dr. Forman acknowledged that VO₂ max tests can be difficult and expensive to administer in offices that aren’t already equipped with CPET machines. He said conducting other assessments, such as observing the patient performing a short walk, won’t provide as accurate data but is better than not assessing function at all.

“Specialists all have different things they measure, but function is the common denominator. For an aging population, it is the number one thing we should be looking at,” Dr. Forman said. “It’s a skill set, it’s an investment, it’s a change in culture at a time when cardiologists are obsessed with getting the latest imaging machines.”

Dr. Allison said all cardiologists should assess their patients’ VO₂ max and that family medicine doctors should use the test for certain patients, such as those who have gained an unusual amount of weight or report being out of breath more than usual.

“We have all sorts of things that can go wrong with us as we get older, but if we’re sitting in a doctor’s office, it may not be apparent what they are,” Dr. Allison said. “We have to get patients up and moving.”

The authors have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Physicians routinely monitor cholesterol, blood pressure, and glucose levels to get a clearer picture of their patients’ overall health. But a group of experts argues that having an accurate read of a person’s ability to absorb oxygen during peak exertion – VO₂ max – is just as important.

Once the focus of cyclists and other elite athletes, VO₂ max has in recent years caught the attention of geriatricians, who have linked the measure to maximum functional capacity – an umbrella term for the body’s ability to perform aerobic exercise.

“Function is prognostic of mortality,” said Daniel E. Forman, MD, FAHA, FACC, professor of medicine and chair of the section of geriatric cardiology at the University of Pittsburgh Medical Center. “If you aren’t looking at that, you’re missing the boat.”

Although cardiopulmonary exercise testing (CPET) remains the gold standard for assessing VO₂ max, Dr. Forman said clinicians often overlook CPET because it is old.
 

Getting precise

As a person ages, the amount of physical activity needed to stay fit varies, depending on genes, health, and fitness history. Measuring VO₂ max can help doctors better prescribe physical activity, both with regard to specific exercises and for how long, Claudio Gil Araújo, MD, PhD, dean of research and education at the Exercise Medicine Clinic at CLINIMEX in Rio de Janeiro, Brazil, told this news organization. The test can also measure progress.

“Guidelines talk about how much exercise you should do every week, but it’s somewhat misleading because the health outcomes are much more linked to physical fitness than the amount of exercise you do,” Dr. Araújo said. Treating a patient with hypertension requires an individualized approach. “The same thing is true with exercise,” he said.

A person with high aerobic fitness, either because of favorable genetics or because he or she has maintained good fitness by exercising, may need less activity, but 200 minutes per week may not be enough for someone else.

In his own lab, Dr. Araújo is following “dozens” of men and women who have been able to increase their ability to exercise – especially high-intensity activity – over time. And their VO₂ max readings have risen, he said.

Getting patients moving and collecting data on VO₂ max is the most precise way to measure aerobic fitness. But the test is far from a staple in primary care.

Dr. Araújo said a growing body of research has long shown VO₂ max to be a significant determinant of health and one that physicians should be paying closer attention to, especially for aging patients.

“If someone has a low VO₂ max, the treatment to correct this unfavorable health profile is to increase exercise levels,” Dr. Araújo said. “This is a very relevant public health message.”

Investigators have found that inactivity increases a person’s risk of dying from an atherosclerotic cardiovascular disease event by about the same amount as smoking, and that a sedentary lifestyle increases with age . A patient’s fitness is crucial to his or her overall health, and VO₂ max can play a key role. Poor performance on CPET could be a warning regarding a number of conditions, particularly cardiovascular and lung disease, Dr. Araújo said.

Indeed, acing the CPET is not easy.

“Your joints have to be normal, you can’t have low potassium, low sodium, or high blood sugar, your heart has to pump well, your blood vessels have to be healthy,” said Thomas Allison, PhD, MPH, director of the Integrated Stress Testing Center and the Sports Cardiology Clinic at Mayo Clinic, in Rochester, Minn. “All of those things can show up on the treadmill in terms of your VO₂ max.”

Low VO₂ max can be a physician’s first indication to investigate further. A review published in November 2022 in the International Journal of Cardiology Cardiovascular Risk and Prevention outlined what cross-sectional and longitudinal studies have documented regarding how VO₂ max changes as people age. From ages 18 to 35, VO₂ max remains fairly consistent. Between 35 and 55, it drops slightly but inexorably before falling sharply, if inconsistently. This inconsistency is where the important data lie.

“That lower level of physical activity may just be a behavioral change that needs to be reversed, or it could be a change that has been forced by underlying occult disease,” Dr. Allison said. That older people can’t run as fast as young people or are more likely to die in a given period than young people is not surprising. “The question is, at any given age, does your fitness level predict good health outcomes?” he said. “And the answer is yes.”

Fitness should be treated as any other data point, he added.

“If I want to know your blood pressure, I’m going to check your blood pressure; I’m not going to just ask you what it is,” Dr. Allison said. “If I ask if you have any limitations or symptoms with exercise or how physically active you are, if possible, I want to check that.”
 

Culture shift

Dr. Forman acknowledged that VO₂ max tests can be difficult and expensive to administer in offices that aren’t already equipped with CPET machines. He said conducting other assessments, such as observing the patient performing a short walk, won’t provide as accurate data but is better than not assessing function at all.

“Specialists all have different things they measure, but function is the common denominator. For an aging population, it is the number one thing we should be looking at,” Dr. Forman said. “It’s a skill set, it’s an investment, it’s a change in culture at a time when cardiologists are obsessed with getting the latest imaging machines.”

Dr. Allison said all cardiologists should assess their patients’ VO₂ max and that family medicine doctors should use the test for certain patients, such as those who have gained an unusual amount of weight or report being out of breath more than usual.

“We have all sorts of things that can go wrong with us as we get older, but if we’re sitting in a doctor’s office, it may not be apparent what they are,” Dr. Allison said. “We have to get patients up and moving.”

The authors have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Treatment for breast cancer exacts a high financial toll on patients, not just in the United States and other high-income countries but in low- and middle-income countries as well, a meta-analysis found.

Although the rate of financial toxicity was much higher in low- and middle-income countries – affecting 79% of patients – more than 35% of patients in high-income countries also incurred financial hardship, the study team found.

The findings highlight the need for policies to offset the burden of direct and indirect costs for breast cancer care and improve the financial health of vulnerable patients, said the study authors, led by Kavitha Ranganathan, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston.

The study was published online in JAMA Network Open.

 

The most expensive malignancy?

Patients with breast cancer may be particularly burdened by costs of care, with one study showing substantially higher out-of-pocket costs for patients with breast cancer than colorectal, lung, and prostate cancer combined.

A Lancet Oncology Commission report revealed that breast cancer was the most expensive cancer in the United States in 2010, accounting for $16.5 billion, or 13% of all cancer-related spending. A separate analysis found that individual direct medical costs of breast cancer care can reach $100,000.

In high-income countries, the financial burden of breast cancer care may be the result of novel and costly cancer therapeutics and interventions, overuse of services, increased willingness to pay, and varying insurance coverage. In low- and middle-income countries, women may experience delayed diagnosis because of limited access to screening and high-quality diagnostic services, leading to more later-stage diagnoses requiring more extensive treatments. Lower baseline income, limited insurance coverage, and greater distance to treatment centers may also be factors.

“Establishing the global extent of financial toxicity and comparing the economic burden of disease in different populations is imperative to help policy makers prioritize funding of breast cancer care infrastructure,” Dr. Ranganathan and colleagues write.

In their meta-analysis of 18 studies – 14 from high-income countries and 4 from low – published from 2008 to 2021, the authors found that the definition of financial toxicity varied widely across studies.

For example, some used specific numerical criteria for defining financial toxicity, such as medical cost exceeding 40% of household capacity to pay or potential income or out-of-pocket costs exceeding 30% of annual household income.

Others used patient-reported outcome measures instruments evaluating subjective statements of financial difficulty, such as an affirmative answer to having financial difficulty or trouble paying medical bills, or paying more for medical care than is affordable.

In other studies, financial toxicity was defined according to a patient’s report of specific, objective financial consequences of care, including losing income or a job; having to borrow money or go into debt; having trouble paying for food, rent, or transportation; or having to forgo any type of medical care because of cost.

In their analysis, the pooled rate of financial toxicity among patients with breast cancer was 35.3% in high-income countries and 78.8% in low/middle-income countries, both demonstrating high heterogeneity or variability (P for heterogeneity < .001). In contrast, typical financial toxicity rates across all health conditions in low-income countries ranged from 6% to 12%, the investigators noted.

One study assessing quality of life measures in Egypt found that 47.5% of patients were food insecure, 66% needed financial assistance, 34% used savings to pay for treatment, and 41.2% lacked savings altogether.
 

Burden reduction

Given the high rates of financial toxicity associated with breast cancer, what strategies might reduce this cost burden?

When exploring potential factors associated with financial toxicity, the researchers found no clear association between financial toxicity and race, employment status, and age, and could draw no firm conclusions about the impact of comorbidities and urban vs. rural place of residence. In addition, cancer stage and treatments were “extremely” heterogeneous across studies and the authors found no clear association between either factor and financial toxicity.

But the authors noted that the highest-priority patients are typically those who have low education, have low socioeconomic status, lack health insurance, and live in low-resource areas.

To reduce financial toxicity and improve outcomes among patients with breast cancer, the study team recommended four potential strategies:

• Use targeted educational campaigns to raise awareness about the signs and symptoms of breast cancer and the importance of early diagnosis and treatment.
• Expand health care coverage to minimize direct medical out-of-pocket costs.
• Develop programs to assist with direct nonmedical and indirect costs, such as transportation to and lodging near treatment centers and childcare.
• Improve screening, referral, and treatment infrastructure for breast cancer care.

The researchers also noted that their data highlight the value of universal health care coverage as a policy strategy, with evidence of lower financial toxicity rates in countries with universal health coverage.

Support for the study was provided in part by the National Cancer Institute, United Nations Institute for Training and Research and the Global Surgery Foundation, Harvard Global Health Institute, Connors Center for Women’s Health and Gender Biology, the Center for Surgery and Public Health, and the National Endowment for Plastic Surgery. Dr. Ranganathan reports no relevant financial relationships. Several coauthors have disclosures; the full list can be found with the original article.

A version of this article originally appeared on Medscape.com.

Treatment for breast cancer exacts a high financial toll on patients, not just in the United States and other high-income countries but in low- and middle-income countries as well, a meta-analysis found.

Although the rate of financial toxicity was much higher in low- and middle-income countries – affecting 79% of patients – more than 35% of patients in high-income countries also incurred financial hardship, the study team found.

The findings highlight the need for policies to offset the burden of direct and indirect costs for breast cancer care and improve the financial health of vulnerable patients, said the study authors, led by Kavitha Ranganathan, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston.

The study was published online in JAMA Network Open.

 

The most expensive malignancy?

Patients with breast cancer may be particularly burdened by costs of care, with one study showing substantially higher out-of-pocket costs for patients with breast cancer than colorectal, lung, and prostate cancer combined.

A Lancet Oncology Commission report revealed that breast cancer was the most expensive cancer in the United States in 2010, accounting for $16.5 billion, or 13% of all cancer-related spending. A separate analysis found that individual direct medical costs of breast cancer care can reach $100,000.

In high-income countries, the financial burden of breast cancer care may be the result of novel and costly cancer therapeutics and interventions, overuse of services, increased willingness to pay, and varying insurance coverage. In low- and middle-income countries, women may experience delayed diagnosis because of limited access to screening and high-quality diagnostic services, leading to more later-stage diagnoses requiring more extensive treatments. Lower baseline income, limited insurance coverage, and greater distance to treatment centers may also be factors.

“Establishing the global extent of financial toxicity and comparing the economic burden of disease in different populations is imperative to help policy makers prioritize funding of breast cancer care infrastructure,” Dr. Ranganathan and colleagues write.

In their meta-analysis of 18 studies – 14 from high-income countries and 4 from low – published from 2008 to 2021, the authors found that the definition of financial toxicity varied widely across studies.

For example, some used specific numerical criteria for defining financial toxicity, such as medical cost exceeding 40% of household capacity to pay or potential income or out-of-pocket costs exceeding 30% of annual household income.

Others used patient-reported outcome measures instruments evaluating subjective statements of financial difficulty, such as an affirmative answer to having financial difficulty or trouble paying medical bills, or paying more for medical care than is affordable.

In other studies, financial toxicity was defined according to a patient’s report of specific, objective financial consequences of care, including losing income or a job; having to borrow money or go into debt; having trouble paying for food, rent, or transportation; or having to forgo any type of medical care because of cost.

In their analysis, the pooled rate of financial toxicity among patients with breast cancer was 35.3% in high-income countries and 78.8% in low/middle-income countries, both demonstrating high heterogeneity or variability (P for heterogeneity < .001). In contrast, typical financial toxicity rates across all health conditions in low-income countries ranged from 6% to 12%, the investigators noted.

One study assessing quality of life measures in Egypt found that 47.5% of patients were food insecure, 66% needed financial assistance, 34% used savings to pay for treatment, and 41.2% lacked savings altogether.
 

Burden reduction

Given the high rates of financial toxicity associated with breast cancer, what strategies might reduce this cost burden?

When exploring potential factors associated with financial toxicity, the researchers found no clear association between financial toxicity and race, employment status, and age, and could draw no firm conclusions about the impact of comorbidities and urban vs. rural place of residence. In addition, cancer stage and treatments were “extremely” heterogeneous across studies and the authors found no clear association between either factor and financial toxicity.

But the authors noted that the highest-priority patients are typically those who have low education, have low socioeconomic status, lack health insurance, and live in low-resource areas.

To reduce financial toxicity and improve outcomes among patients with breast cancer, the study team recommended four potential strategies:

• Use targeted educational campaigns to raise awareness about the signs and symptoms of breast cancer and the importance of early diagnosis and treatment.
• Expand health care coverage to minimize direct medical out-of-pocket costs.
• Develop programs to assist with direct nonmedical and indirect costs, such as transportation to and lodging near treatment centers and childcare.
• Improve screening, referral, and treatment infrastructure for breast cancer care.

The researchers also noted that their data highlight the value of universal health care coverage as a policy strategy, with evidence of lower financial toxicity rates in countries with universal health coverage.

Support for the study was provided in part by the National Cancer Institute, United Nations Institute for Training and Research and the Global Surgery Foundation, Harvard Global Health Institute, Connors Center for Women’s Health and Gender Biology, the Center for Surgery and Public Health, and the National Endowment for Plastic Surgery. Dr. Ranganathan reports no relevant financial relationships. Several coauthors have disclosures; the full list can be found with the original article.

A version of this article originally appeared on Medscape.com.

Treatment for breast cancer exacts a high financial toll on patients, not just in the United States and other high-income countries but in low- and middle-income countries as well, a meta-analysis found.

Although the rate of financial toxicity was much higher in low- and middle-income countries – affecting 79% of patients – more than 35% of patients in high-income countries also incurred financial hardship, the study team found.

The findings highlight the need for policies to offset the burden of direct and indirect costs for breast cancer care and improve the financial health of vulnerable patients, said the study authors, led by Kavitha Ranganathan, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston.

The study was published online in JAMA Network Open.

 

The most expensive malignancy?

Patients with breast cancer may be particularly burdened by costs of care, with one study showing substantially higher out-of-pocket costs for patients with breast cancer than colorectal, lung, and prostate cancer combined.

A Lancet Oncology Commission report revealed that breast cancer was the most expensive cancer in the United States in 2010, accounting for $16.5 billion, or 13% of all cancer-related spending. A separate analysis found that individual direct medical costs of breast cancer care can reach $100,000.

In high-income countries, the financial burden of breast cancer care may be the result of novel and costly cancer therapeutics and interventions, overuse of services, increased willingness to pay, and varying insurance coverage. In low- and middle-income countries, women may experience delayed diagnosis because of limited access to screening and high-quality diagnostic services, leading to more later-stage diagnoses requiring more extensive treatments. Lower baseline income, limited insurance coverage, and greater distance to treatment centers may also be factors.

“Establishing the global extent of financial toxicity and comparing the economic burden of disease in different populations is imperative to help policy makers prioritize funding of breast cancer care infrastructure,” Dr. Ranganathan and colleagues write.

In their meta-analysis of 18 studies – 14 from high-income countries and 4 from low – published from 2008 to 2021, the authors found that the definition of financial toxicity varied widely across studies.

For example, some used specific numerical criteria for defining financial toxicity, such as medical cost exceeding 40% of household capacity to pay or potential income or out-of-pocket costs exceeding 30% of annual household income.

Others used patient-reported outcome measures instruments evaluating subjective statements of financial difficulty, such as an affirmative answer to having financial difficulty or trouble paying medical bills, or paying more for medical care than is affordable.

In other studies, financial toxicity was defined according to a patient’s report of specific, objective financial consequences of care, including losing income or a job; having to borrow money or go into debt; having trouble paying for food, rent, or transportation; or having to forgo any type of medical care because of cost.

In their analysis, the pooled rate of financial toxicity among patients with breast cancer was 35.3% in high-income countries and 78.8% in low/middle-income countries, both demonstrating high heterogeneity or variability (P for heterogeneity < .001). In contrast, typical financial toxicity rates across all health conditions in low-income countries ranged from 6% to 12%, the investigators noted.

One study assessing quality of life measures in Egypt found that 47.5% of patients were food insecure, 66% needed financial assistance, 34% used savings to pay for treatment, and 41.2% lacked savings altogether.
 

Burden reduction

Given the high rates of financial toxicity associated with breast cancer, what strategies might reduce this cost burden?

When exploring potential factors associated with financial toxicity, the researchers found no clear association between financial toxicity and race, employment status, and age, and could draw no firm conclusions about the impact of comorbidities and urban vs. rural place of residence. In addition, cancer stage and treatments were “extremely” heterogeneous across studies and the authors found no clear association between either factor and financial toxicity.

But the authors noted that the highest-priority patients are typically those who have low education, have low socioeconomic status, lack health insurance, and live in low-resource areas.

To reduce financial toxicity and improve outcomes among patients with breast cancer, the study team recommended four potential strategies:

• Use targeted educational campaigns to raise awareness about the signs and symptoms of breast cancer and the importance of early diagnosis and treatment.
• Expand health care coverage to minimize direct medical out-of-pocket costs.
• Develop programs to assist with direct nonmedical and indirect costs, such as transportation to and lodging near treatment centers and childcare.
• Improve screening, referral, and treatment infrastructure for breast cancer care.

The researchers also noted that their data highlight the value of universal health care coverage as a policy strategy, with evidence of lower financial toxicity rates in countries with universal health coverage.

Support for the study was provided in part by the National Cancer Institute, United Nations Institute for Training and Research and the Global Surgery Foundation, Harvard Global Health Institute, Connors Center for Women’s Health and Gender Biology, the Center for Surgery and Public Health, and the National Endowment for Plastic Surgery. Dr. Ranganathan reports no relevant financial relationships. Several coauthors have disclosures; the full list can be found with the original article.

A version of this article originally appeared on Medscape.com.

Slowing progression of, rather than stopping, Alzheimer’s disease (AD) has measurable benefits for patients and families and may be a more realistic goal for clinical AD drug trials, a new report suggests.

The report is a yearlong undertaking by an expert work group convened by the Alzheimer’s Association and was prompted, in part, by the fallout from the U.S. Food and Drug Administration’s controversial decision to grant aducanumab (Aduhelm) accelerated approval, which came over the objection of an advisory panel that found the drug was ineffective.

The report’s authors call for a “reframing” of how researchers define “clinically meaningful” in randomized controlled trials (RCTs), noting that it’s time to adjust expectations of outcomes from relatively short clinical trials.

“Without lowering the bar, are we expecting too much from a clinical trial by expecting that unless the disease is halted in its tracks and there’s no progression, we failed at treatment?” the report’s lead author and group leader Ronald C. Petersen, MD, PhD, lead author, chair of the work group, and professor of neurology at the Mayo Clinic, Rochester, Minn., told this news organization.

Interpretations of clinical meaningfulness are used in the drug approval process and in decisions about whether an insurer will cover the cost of treatment, the authors note.

While the report doesn’t provide a consensus definition of clinically meaningful benefit, it does offer a starting point for a conversation about how the phrase should be defined in the context of RCTs for disease-modifying therapies (DMTs) in AD, Dr. Petersen said.

“What we tried to do was to put it into some kind of perspective and at least have people reflect on this: If you’re going to design the perfect drug trial in Alzheimer’s disease, what would it be? We wanted to get people to think about it without digging in their heels for or against,” he added.

The report was published online  in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.
 

A proactive measure

The expert group began its work in January 2022, less than a year after the FDA approved aducanumab. Since the panel began its work, the FDA has approved a second AD drug, lecanemab (Leqembi), and denied accelerated approval of a third medication, donanemab.

“At the time we started this group, we had one approved treatment, and we just knew that there were others on the way, and we needed to be prepared to have this conversation and be more proactive than reactive,” Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association and co-author of the report, said in an interview.

The work group suggests that simply slowing disease progression might be a desired goal for drug trials, especially early on, before cognition and memory are affected.

They also note that a benefit identified during an 18-month clinical trial may ultimately lead to even more meaningful changes over coming years, well beyond the trial’s end.

In addition, the report authors call for the development of better research tools to more accurately assess meaningful change. The Clinical Dementia Rating (CDR) scale is currently the key instrument used as a primary outcome measure in RCTs. However, the report’s authors note that it may not be adequate to measure meaningful change in early-stage disease.

“Developing better tools certainly should be on the radar screen for all of us, because I think we can do better,” Dr. Petersen said. “The CDR, as good as it is and as long as it’s been used in the field, is a pretty blunt instrument, and it’s the result of subjective ratings.”
 

‘Quality of mind’

Jason Karlawish, MD, professor of medicine, medical ethics, health policy, and neurology at the University of Pennsylvania, Philadelphia, said measuring the actual impact of a drug on a patient’s disease and quality of life has been a hot topic in the AD field for some time, but settling on a definition of “clinically meaningful” that everyone agrees upon will be a challenge.

“I think the idea of ‘clinically meaningful’ is truly a socially constructed idea,” said Dr. Karlawish, co-director of Penn’s Memory Center, who did not work on the report.

“You can come up with objective measures of cognition, but a measure to call something ‘clinically meaningful’ ultimately requires some sort of negotiated social order among clinicians and patients and others who have immediate interest in the health and well-being of the patient.”

Dr. Karlawish added that he’s interested in the conversations the report might prompt and the challenges it could highlight, especially when it comes to how meaningful clinical benefit can be measured, regardless of how it’s defined.

“Hidden in this conversation about clinically meaningful treatments in Alzheimer’s disease is, frankly, not quality of life, but quality of mind,” said Dr. Karlawish. “No measure captures acceptably the very thing that everyone actually cares a lot about and why we view this disease as so dreadful, which is damage to our mind.”
 

More evidence needed

The development of such tools will take time. What does that mean for drugs already in the pipeline? Members of the work group argue that those trials must move forward at the same time new tools are being created.

“We need to continue to refine, develop better instruments, [and] develop tools that are going to assess the disease in its more subtle features early on, even in the so-called ‘pre-symptomatic’ stage of the disease,” said lead author Dr. Petersen. “We shouldn’t wait for the development of that before intervening if we have a drug that seems to work.”

However, not everyone who agrees with the premise of the report agrees with this position, including Joel S. Perlmutter, MD, professor of neurology, Washington University School of Medicine, St. Louis, who also commented on the report.

As reported by this news organization, Dr. Perlmutter was one of three physicians who resigned from the FDA advisory panel that voted against approving aducanumab after the agency moved forward anyway.

“We have to be careful not to recommend DMTs that we hope will help without strong evidence, especially when potential side effects are not trivial,” Dr. Perlmutter said. “We have to have evidence before making these recommendations so we don’t end up harming people more than helping them.”

The report received no specific funding. Dr. Petersen received consulting fees from Roche, Nestle, Merck, Biogen, Eisai, and Genentech. Full disclosures are included in the original article. Dr. Perlmutter and Dr. Karlawish report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Slowing progression of, rather than stopping, Alzheimer’s disease (AD) has measurable benefits for patients and families and may be a more realistic goal for clinical AD drug trials, a new report suggests.

The report is a yearlong undertaking by an expert work group convened by the Alzheimer’s Association and was prompted, in part, by the fallout from the U.S. Food and Drug Administration’s controversial decision to grant aducanumab (Aduhelm) accelerated approval, which came over the objection of an advisory panel that found the drug was ineffective.

The report’s authors call for a “reframing” of how researchers define “clinically meaningful” in randomized controlled trials (RCTs), noting that it’s time to adjust expectations of outcomes from relatively short clinical trials.

“Without lowering the bar, are we expecting too much from a clinical trial by expecting that unless the disease is halted in its tracks and there’s no progression, we failed at treatment?” the report’s lead author and group leader Ronald C. Petersen, MD, PhD, lead author, chair of the work group, and professor of neurology at the Mayo Clinic, Rochester, Minn., told this news organization.

Interpretations of clinical meaningfulness are used in the drug approval process and in decisions about whether an insurer will cover the cost of treatment, the authors note.

While the report doesn’t provide a consensus definition of clinically meaningful benefit, it does offer a starting point for a conversation about how the phrase should be defined in the context of RCTs for disease-modifying therapies (DMTs) in AD, Dr. Petersen said.

“What we tried to do was to put it into some kind of perspective and at least have people reflect on this: If you’re going to design the perfect drug trial in Alzheimer’s disease, what would it be? We wanted to get people to think about it without digging in their heels for or against,” he added.

The report was published online  in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.
 

A proactive measure

The expert group began its work in January 2022, less than a year after the FDA approved aducanumab. Since the panel began its work, the FDA has approved a second AD drug, lecanemab (Leqembi), and denied accelerated approval of a third medication, donanemab.

“At the time we started this group, we had one approved treatment, and we just knew that there were others on the way, and we needed to be prepared to have this conversation and be more proactive than reactive,” Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association and co-author of the report, said in an interview.

The work group suggests that simply slowing disease progression might be a desired goal for drug trials, especially early on, before cognition and memory are affected.

They also note that a benefit identified during an 18-month clinical trial may ultimately lead to even more meaningful changes over coming years, well beyond the trial’s end.

In addition, the report authors call for the development of better research tools to more accurately assess meaningful change. The Clinical Dementia Rating (CDR) scale is currently the key instrument used as a primary outcome measure in RCTs. However, the report’s authors note that it may not be adequate to measure meaningful change in early-stage disease.

“Developing better tools certainly should be on the radar screen for all of us, because I think we can do better,” Dr. Petersen said. “The CDR, as good as it is and as long as it’s been used in the field, is a pretty blunt instrument, and it’s the result of subjective ratings.”
 

‘Quality of mind’

Jason Karlawish, MD, professor of medicine, medical ethics, health policy, and neurology at the University of Pennsylvania, Philadelphia, said measuring the actual impact of a drug on a patient’s disease and quality of life has been a hot topic in the AD field for some time, but settling on a definition of “clinically meaningful” that everyone agrees upon will be a challenge.

“I think the idea of ‘clinically meaningful’ is truly a socially constructed idea,” said Dr. Karlawish, co-director of Penn’s Memory Center, who did not work on the report.

“You can come up with objective measures of cognition, but a measure to call something ‘clinically meaningful’ ultimately requires some sort of negotiated social order among clinicians and patients and others who have immediate interest in the health and well-being of the patient.”

Dr. Karlawish added that he’s interested in the conversations the report might prompt and the challenges it could highlight, especially when it comes to how meaningful clinical benefit can be measured, regardless of how it’s defined.

“Hidden in this conversation about clinically meaningful treatments in Alzheimer’s disease is, frankly, not quality of life, but quality of mind,” said Dr. Karlawish. “No measure captures acceptably the very thing that everyone actually cares a lot about and why we view this disease as so dreadful, which is damage to our mind.”
 

More evidence needed

The development of such tools will take time. What does that mean for drugs already in the pipeline? Members of the work group argue that those trials must move forward at the same time new tools are being created.

“We need to continue to refine, develop better instruments, [and] develop tools that are going to assess the disease in its more subtle features early on, even in the so-called ‘pre-symptomatic’ stage of the disease,” said lead author Dr. Petersen. “We shouldn’t wait for the development of that before intervening if we have a drug that seems to work.”

However, not everyone who agrees with the premise of the report agrees with this position, including Joel S. Perlmutter, MD, professor of neurology, Washington University School of Medicine, St. Louis, who also commented on the report.

As reported by this news organization, Dr. Perlmutter was one of three physicians who resigned from the FDA advisory panel that voted against approving aducanumab after the agency moved forward anyway.

“We have to be careful not to recommend DMTs that we hope will help without strong evidence, especially when potential side effects are not trivial,” Dr. Perlmutter said. “We have to have evidence before making these recommendations so we don’t end up harming people more than helping them.”

The report received no specific funding. Dr. Petersen received consulting fees from Roche, Nestle, Merck, Biogen, Eisai, and Genentech. Full disclosures are included in the original article. Dr. Perlmutter and Dr. Karlawish report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Slowing progression of, rather than stopping, Alzheimer’s disease (AD) has measurable benefits for patients and families and may be a more realistic goal for clinical AD drug trials, a new report suggests.

The report is a yearlong undertaking by an expert work group convened by the Alzheimer’s Association and was prompted, in part, by the fallout from the U.S. Food and Drug Administration’s controversial decision to grant aducanumab (Aduhelm) accelerated approval, which came over the objection of an advisory panel that found the drug was ineffective.

The report’s authors call for a “reframing” of how researchers define “clinically meaningful” in randomized controlled trials (RCTs), noting that it’s time to adjust expectations of outcomes from relatively short clinical trials.

“Without lowering the bar, are we expecting too much from a clinical trial by expecting that unless the disease is halted in its tracks and there’s no progression, we failed at treatment?” the report’s lead author and group leader Ronald C. Petersen, MD, PhD, lead author, chair of the work group, and professor of neurology at the Mayo Clinic, Rochester, Minn., told this news organization.

Interpretations of clinical meaningfulness are used in the drug approval process and in decisions about whether an insurer will cover the cost of treatment, the authors note.

While the report doesn’t provide a consensus definition of clinically meaningful benefit, it does offer a starting point for a conversation about how the phrase should be defined in the context of RCTs for disease-modifying therapies (DMTs) in AD, Dr. Petersen said.

“What we tried to do was to put it into some kind of perspective and at least have people reflect on this: If you’re going to design the perfect drug trial in Alzheimer’s disease, what would it be? We wanted to get people to think about it without digging in their heels for or against,” he added.

The report was published online  in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.
 

A proactive measure

The expert group began its work in January 2022, less than a year after the FDA approved aducanumab. Since the panel began its work, the FDA has approved a second AD drug, lecanemab (Leqembi), and denied accelerated approval of a third medication, donanemab.

“At the time we started this group, we had one approved treatment, and we just knew that there were others on the way, and we needed to be prepared to have this conversation and be more proactive than reactive,” Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association and co-author of the report, said in an interview.

The work group suggests that simply slowing disease progression might be a desired goal for drug trials, especially early on, before cognition and memory are affected.

They also note that a benefit identified during an 18-month clinical trial may ultimately lead to even more meaningful changes over coming years, well beyond the trial’s end.

In addition, the report authors call for the development of better research tools to more accurately assess meaningful change. The Clinical Dementia Rating (CDR) scale is currently the key instrument used as a primary outcome measure in RCTs. However, the report’s authors note that it may not be adequate to measure meaningful change in early-stage disease.

“Developing better tools certainly should be on the radar screen for all of us, because I think we can do better,” Dr. Petersen said. “The CDR, as good as it is and as long as it’s been used in the field, is a pretty blunt instrument, and it’s the result of subjective ratings.”
 

‘Quality of mind’

Jason Karlawish, MD, professor of medicine, medical ethics, health policy, and neurology at the University of Pennsylvania, Philadelphia, said measuring the actual impact of a drug on a patient’s disease and quality of life has been a hot topic in the AD field for some time, but settling on a definition of “clinically meaningful” that everyone agrees upon will be a challenge.

“I think the idea of ‘clinically meaningful’ is truly a socially constructed idea,” said Dr. Karlawish, co-director of Penn’s Memory Center, who did not work on the report.

“You can come up with objective measures of cognition, but a measure to call something ‘clinically meaningful’ ultimately requires some sort of negotiated social order among clinicians and patients and others who have immediate interest in the health and well-being of the patient.”

Dr. Karlawish added that he’s interested in the conversations the report might prompt and the challenges it could highlight, especially when it comes to how meaningful clinical benefit can be measured, regardless of how it’s defined.

“Hidden in this conversation about clinically meaningful treatments in Alzheimer’s disease is, frankly, not quality of life, but quality of mind,” said Dr. Karlawish. “No measure captures acceptably the very thing that everyone actually cares a lot about and why we view this disease as so dreadful, which is damage to our mind.”
 

More evidence needed

The development of such tools will take time. What does that mean for drugs already in the pipeline? Members of the work group argue that those trials must move forward at the same time new tools are being created.

“We need to continue to refine, develop better instruments, [and] develop tools that are going to assess the disease in its more subtle features early on, even in the so-called ‘pre-symptomatic’ stage of the disease,” said lead author Dr. Petersen. “We shouldn’t wait for the development of that before intervening if we have a drug that seems to work.”

However, not everyone who agrees with the premise of the report agrees with this position, including Joel S. Perlmutter, MD, professor of neurology, Washington University School of Medicine, St. Louis, who also commented on the report.

As reported by this news organization, Dr. Perlmutter was one of three physicians who resigned from the FDA advisory panel that voted against approving aducanumab after the agency moved forward anyway.

“We have to be careful not to recommend DMTs that we hope will help without strong evidence, especially when potential side effects are not trivial,” Dr. Perlmutter said. “We have to have evidence before making these recommendations so we don’t end up harming people more than helping them.”

The report received no specific funding. Dr. Petersen received consulting fees from Roche, Nestle, Merck, Biogen, Eisai, and Genentech. Full disclosures are included in the original article. Dr. Perlmutter and Dr. Karlawish report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Butylphthalide, a medication derived from celery seed, may improve outcomes after an acute ischemic stroke when given in addition to thrombolysis or endovascular treatment, a new report suggests.

Patients treated with butylphthalide had fewer severe neurologic symptoms and better function 90 days after the stroke, compared with those receiving placebo.

Butylphthalide is approved and available for use in China, where the study was conducted. However, the medication hasn’t been approved for use by the U.S. Food and Drug Administration.

“Patients who received butylphthalide had less severe neurological symptoms and a better living status at 90 days post stroke, compared to those who received the placebo,” said coauthor Baixue Jia, MD, an attending physician in interventional neuroradiology at the Beijing Tiantan Hospital of Capital Medical University and a faculty member at the China National Clinical Research Center for Neurological Diseases in Beijing. “If the results are confirmed in other trials, this may lead to more options to treat strokes caused by clots.”

The study was presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
 

Studying stroke outcomes

The researchers described butylphthalide as a cerebroprotective drug that was originally extracted from seeds of Apium graveolens. In China, previous studies have shown that the drug has cerebroprotective effects in animal models of ischemia-reperfusion, they noted.

In this randomized, double-blind, placebo-controlled trial, Dr. Jia and colleagues evaluated whether treatment with butylphthalide could improve 90-day outcomes for adults with acute ischemic stroke who received intravenous recombinant tissue plasminogen activator (tPA), endovascular treatment, or both.

The participants were treated at one of 59 medical centers in China between July 2018 and February 2022. Those who had minimal stroke symptoms on their initial exam, defined as a score of 0-3 on the National Institutes of Health Stroke Scale, or had severe stroke symptoms, defined as having a score of 26 or higher on the NIHSS, were excluded from the study.

Along with an initial revascularization intervention chosen by their physician, participants were randomly selected to receive either butylphthalide or a placebo daily for 90 days. The drug was administered through daily intravenous injections for the first 14 days, after which patients received oral capsules for 76 days.

The research team defined the outcomes as “favorable” if a patient fell into one of the following categories 90 days after the stroke: an initially mild to moderate stroke (NIHSS, 4-7) and no symptoms after treatment, defined as a score of 0 on the Modified Rankin Scale (mRS), which measures disability and dependence; an initially moderate to serious stroke (NIHSS, 8-14) and no residual symptoms or mild symptoms that don’t impair the ability to perform routine activities of daily living without assistance (mRS, 0-1); or an initially serious to severe stroke (NIHSS, 15-25) and no remaining symptoms or a slight disability that impairs some activities but allows one to conduct daily living without assistance (mRS, 0-2).

Secondary outcomes included symptomatic intracranial hemorrhage, recurrent stroke, and mortality.

Among the 1,216 participants, 607 were assigned to the treatment group, and 609 were assigned to the placebo group. The average age was 66 years, and 68% were men.

Overall, participants in the butylphthalide group were 70% more likely to have a favorable 90-day outcome, compared with the placebo group. Favorable outcomes occurred in 344 patients (56.7%) in the butylphthalide group, compared with 268 patients (44%) in the placebo group (odds ratio, 1.70; 95% confidence interval, 1.35-2.14; P < .001).

In addition, butylphthalide improved function equally well for the patients who initially received tPA, those who received endovascular treatment, and those who received both tPA and endovascular treatment.

Secondary events, such as recurrent stroke and intracranial hemorrhage, weren’t significantly different between the butylphthalide and placebo groups.
 

Ongoing questions

Dr. Jia and colleagues noted the need to understand how butylphthalide works in the brain. Animal studies have suggested several possible mechanisms, but it remains unclear.

“The next step should be investigating the exact mechanisms of butylphthalide in humans,” Dr. Jia said.

Additional research should assess the medication in other populations, the authors noted, particularly because the study involved participants who received initial treatment with tPA, endovascular treatment, or both. The results may not be generalizable to stroke patients who receive other treatments or to populations outside of China.

“While these are interesting results, this is only one relatively small study on a fairly select population in China. Butylphthalide, a medication initially compounded from celery seed, is not ready for use in standard stroke treatment,” said Daniel Lackland, DrPH, professor of neurology and director of the division of translational neurosciences and population studies at the Medical University of South Carolina, Charleston.

Dr. Lackland, who wasn’t involved with the study, is a member of the American Stroke Association’s Stroke Council. Although butylphthalide was originally extracted from seeds, he noted, it’s not what patients would find commercially available.

“The medication used in this study is not the same as celery seed or celery seed extract supplements,” he said. “Stroke survivors should always consult with their neurologist or healthcare professional regarding diet after a stroke.”

The study was funded by the National Key Technology Research and Development Program of the Ministry of Science and Technology of the People’s Republic of China and Shijiazhuang Pharmaceutical Group dl-3-butylphthalide Pharmaceutical. Several authors are employed with Beijing Tiantan Hospital and the Beijing Institute of Brain Disorders. Dr. Lackland reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Butylphthalide, a medication derived from celery seed, may improve outcomes after an acute ischemic stroke when given in addition to thrombolysis or endovascular treatment, a new report suggests.

Patients treated with butylphthalide had fewer severe neurologic symptoms and better function 90 days after the stroke, compared with those receiving placebo.

Butylphthalide is approved and available for use in China, where the study was conducted. However, the medication hasn’t been approved for use by the U.S. Food and Drug Administration.

“Patients who received butylphthalide had less severe neurological symptoms and a better living status at 90 days post stroke, compared to those who received the placebo,” said coauthor Baixue Jia, MD, an attending physician in interventional neuroradiology at the Beijing Tiantan Hospital of Capital Medical University and a faculty member at the China National Clinical Research Center for Neurological Diseases in Beijing. “If the results are confirmed in other trials, this may lead to more options to treat strokes caused by clots.”

The study was presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
 

Studying stroke outcomes

The researchers described butylphthalide as a cerebroprotective drug that was originally extracted from seeds of Apium graveolens. In China, previous studies have shown that the drug has cerebroprotective effects in animal models of ischemia-reperfusion, they noted.

In this randomized, double-blind, placebo-controlled trial, Dr. Jia and colleagues evaluated whether treatment with butylphthalide could improve 90-day outcomes for adults with acute ischemic stroke who received intravenous recombinant tissue plasminogen activator (tPA), endovascular treatment, or both.

The participants were treated at one of 59 medical centers in China between July 2018 and February 2022. Those who had minimal stroke symptoms on their initial exam, defined as a score of 0-3 on the National Institutes of Health Stroke Scale, or had severe stroke symptoms, defined as having a score of 26 or higher on the NIHSS, were excluded from the study.

Along with an initial revascularization intervention chosen by their physician, participants were randomly selected to receive either butylphthalide or a placebo daily for 90 days. The drug was administered through daily intravenous injections for the first 14 days, after which patients received oral capsules for 76 days.

The research team defined the outcomes as “favorable” if a patient fell into one of the following categories 90 days after the stroke: an initially mild to moderate stroke (NIHSS, 4-7) and no symptoms after treatment, defined as a score of 0 on the Modified Rankin Scale (mRS), which measures disability and dependence; an initially moderate to serious stroke (NIHSS, 8-14) and no residual symptoms or mild symptoms that don’t impair the ability to perform routine activities of daily living without assistance (mRS, 0-1); or an initially serious to severe stroke (NIHSS, 15-25) and no remaining symptoms or a slight disability that impairs some activities but allows one to conduct daily living without assistance (mRS, 0-2).

Secondary outcomes included symptomatic intracranial hemorrhage, recurrent stroke, and mortality.

Among the 1,216 participants, 607 were assigned to the treatment group, and 609 were assigned to the placebo group. The average age was 66 years, and 68% were men.

Overall, participants in the butylphthalide group were 70% more likely to have a favorable 90-day outcome, compared with the placebo group. Favorable outcomes occurred in 344 patients (56.7%) in the butylphthalide group, compared with 268 patients (44%) in the placebo group (odds ratio, 1.70; 95% confidence interval, 1.35-2.14; P < .001).

In addition, butylphthalide improved function equally well for the patients who initially received tPA, those who received endovascular treatment, and those who received both tPA and endovascular treatment.

Secondary events, such as recurrent stroke and intracranial hemorrhage, weren’t significantly different between the butylphthalide and placebo groups.
 

Ongoing questions

Dr. Jia and colleagues noted the need to understand how butylphthalide works in the brain. Animal studies have suggested several possible mechanisms, but it remains unclear.

“The next step should be investigating the exact mechanisms of butylphthalide in humans,” Dr. Jia said.

Additional research should assess the medication in other populations, the authors noted, particularly because the study involved participants who received initial treatment with tPA, endovascular treatment, or both. The results may not be generalizable to stroke patients who receive other treatments or to populations outside of China.

“While these are interesting results, this is only one relatively small study on a fairly select population in China. Butylphthalide, a medication initially compounded from celery seed, is not ready for use in standard stroke treatment,” said Daniel Lackland, DrPH, professor of neurology and director of the division of translational neurosciences and population studies at the Medical University of South Carolina, Charleston.

Dr. Lackland, who wasn’t involved with the study, is a member of the American Stroke Association’s Stroke Council. Although butylphthalide was originally extracted from seeds, he noted, it’s not what patients would find commercially available.

“The medication used in this study is not the same as celery seed or celery seed extract supplements,” he said. “Stroke survivors should always consult with their neurologist or healthcare professional regarding diet after a stroke.”

The study was funded by the National Key Technology Research and Development Program of the Ministry of Science and Technology of the People’s Republic of China and Shijiazhuang Pharmaceutical Group dl-3-butylphthalide Pharmaceutical. Several authors are employed with Beijing Tiantan Hospital and the Beijing Institute of Brain Disorders. Dr. Lackland reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Butylphthalide, a medication derived from celery seed, may improve outcomes after an acute ischemic stroke when given in addition to thrombolysis or endovascular treatment, a new report suggests.

Patients treated with butylphthalide had fewer severe neurologic symptoms and better function 90 days after the stroke, compared with those receiving placebo.

Butylphthalide is approved and available for use in China, where the study was conducted. However, the medication hasn’t been approved for use by the U.S. Food and Drug Administration.

“Patients who received butylphthalide had less severe neurological symptoms and a better living status at 90 days post stroke, compared to those who received the placebo,” said coauthor Baixue Jia, MD, an attending physician in interventional neuroradiology at the Beijing Tiantan Hospital of Capital Medical University and a faculty member at the China National Clinical Research Center for Neurological Diseases in Beijing. “If the results are confirmed in other trials, this may lead to more options to treat strokes caused by clots.”

The study was presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
 

Studying stroke outcomes

The researchers described butylphthalide as a cerebroprotective drug that was originally extracted from seeds of Apium graveolens. In China, previous studies have shown that the drug has cerebroprotective effects in animal models of ischemia-reperfusion, they noted.

In this randomized, double-blind, placebo-controlled trial, Dr. Jia and colleagues evaluated whether treatment with butylphthalide could improve 90-day outcomes for adults with acute ischemic stroke who received intravenous recombinant tissue plasminogen activator (tPA), endovascular treatment, or both.

The participants were treated at one of 59 medical centers in China between July 2018 and February 2022. Those who had minimal stroke symptoms on their initial exam, defined as a score of 0-3 on the National Institutes of Health Stroke Scale, or had severe stroke symptoms, defined as having a score of 26 or higher on the NIHSS, were excluded from the study.

Along with an initial revascularization intervention chosen by their physician, participants were randomly selected to receive either butylphthalide or a placebo daily for 90 days. The drug was administered through daily intravenous injections for the first 14 days, after which patients received oral capsules for 76 days.

The research team defined the outcomes as “favorable” if a patient fell into one of the following categories 90 days after the stroke: an initially mild to moderate stroke (NIHSS, 4-7) and no symptoms after treatment, defined as a score of 0 on the Modified Rankin Scale (mRS), which measures disability and dependence; an initially moderate to serious stroke (NIHSS, 8-14) and no residual symptoms or mild symptoms that don’t impair the ability to perform routine activities of daily living without assistance (mRS, 0-1); or an initially serious to severe stroke (NIHSS, 15-25) and no remaining symptoms or a slight disability that impairs some activities but allows one to conduct daily living without assistance (mRS, 0-2).

Secondary outcomes included symptomatic intracranial hemorrhage, recurrent stroke, and mortality.

Among the 1,216 participants, 607 were assigned to the treatment group, and 609 were assigned to the placebo group. The average age was 66 years, and 68% were men.

Overall, participants in the butylphthalide group were 70% more likely to have a favorable 90-day outcome, compared with the placebo group. Favorable outcomes occurred in 344 patients (56.7%) in the butylphthalide group, compared with 268 patients (44%) in the placebo group (odds ratio, 1.70; 95% confidence interval, 1.35-2.14; P < .001).

In addition, butylphthalide improved function equally well for the patients who initially received tPA, those who received endovascular treatment, and those who received both tPA and endovascular treatment.

Secondary events, such as recurrent stroke and intracranial hemorrhage, weren’t significantly different between the butylphthalide and placebo groups.
 

Ongoing questions

Dr. Jia and colleagues noted the need to understand how butylphthalide works in the brain. Animal studies have suggested several possible mechanisms, but it remains unclear.

“The next step should be investigating the exact mechanisms of butylphthalide in humans,” Dr. Jia said.

Additional research should assess the medication in other populations, the authors noted, particularly because the study involved participants who received initial treatment with tPA, endovascular treatment, or both. The results may not be generalizable to stroke patients who receive other treatments or to populations outside of China.

“While these are interesting results, this is only one relatively small study on a fairly select population in China. Butylphthalide, a medication initially compounded from celery seed, is not ready for use in standard stroke treatment,” said Daniel Lackland, DrPH, professor of neurology and director of the division of translational neurosciences and population studies at the Medical University of South Carolina, Charleston.

Dr. Lackland, who wasn’t involved with the study, is a member of the American Stroke Association’s Stroke Council. Although butylphthalide was originally extracted from seeds, he noted, it’s not what patients would find commercially available.

“The medication used in this study is not the same as celery seed or celery seed extract supplements,” he said. “Stroke survivors should always consult with their neurologist or healthcare professional regarding diet after a stroke.”

The study was funded by the National Key Technology Research and Development Program of the Ministry of Science and Technology of the People’s Republic of China and Shijiazhuang Pharmaceutical Group dl-3-butylphthalide Pharmaceutical. Several authors are employed with Beijing Tiantan Hospital and the Beijing Institute of Brain Disorders. Dr. Lackland reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.