NATIONAL HARBOR, MD. – Changes in the accounting for polypharmacy in the Centers for Medicare & Medicaid Services’ star rating system are on their way, and managed care organizations should start preparing now for the shift.

Panelists at an Oct. 30 session at the annual meeting of the Academy of Managed Care Pharmacy presented strategies for addressing the three areas of polypharmacy that will be tracked in the new rating system, which will replace the current high-risk medication measurement that is being retired this year.

Anticholinergic medications

The first area presented by the panelists was polypharmacy use of multiple anticholinergic medications in older adults (Poly-ACH). The new quality measure will examine the percentage of members aged 65 years or older who are using two or more anticholinergic medications concurrently.

“We know that anticholinergic burden increases the risk of cognitive decline in particular, but it’s also associated with a higher risk of falls, an increased number of hospitalizations, and [diminished] physical function,” said Marti Groeneweg, PharmD, supervisor of clinical pharmacy services at Kaiser Permanente.

Dr. Groeneweg noted that, in addition to using multiple drugs in this class, patients can also benefit from a decrease in the dosage of their drugs, so that should also be considered in managing the medication of beneficiaries.

She highlighted a program Kaiser Permanente started in the Northwest United States to reduce the concurrent use of these drugs. The program targeted tricyclic antidepressants – nortriptyline, in particular.

The company instituted a multipronged approach that included provider detailing of the risks of using multiple drugs and how they could taper schedules, as well as providing them with other supporting resources and a list of safer, alternative drugs. It also reached out to patients to educate them about the risks of their medications and why it was important for them to taper their medications. The third part of the approach was to use the EHR to provide doctors with the best-available information at the point of prescribing. And finally, there was a pharmacist review process put in place for more complex cases.

Dr. Groeneweg emphasized that this information was incorporated into existing programs.

The intervention, which is fairly new, has not been in place long enough to know exactly how well it is working, but early indicators suggest “we are on the right track,” she said, noting that to date there has been a decrease of 28% in the number of tricyclic antidepressant prescriptions per 1,000 Medicare members per month.
 

CNS medications

The second area the panelists addressed was the polypharmacy use of multiple CNS-active medications in older adults (Poly-CNS).

Rainelle Gaddy, PharmD, Rx clinical programs pharmacy lead at Humana Pharmacy Solutions, , noted that the clinical rationale for this measure was the “increased risk of falls and fractures when these medications are taken concurrently.”

She pointed out that taking one or more of the CNS medications can result in a 1.5-fold increase in the risk for falls, and that risk increases to 2.5-fold if two or more drugs are taken. In addition, a high-dose of these medications can lead to a threefold increase in risk of recurrent falls.

Dr. Gaddy highlighted a number of interventions that could be implemented when the managed care organization is not integrated in the way Kaiser Permanente is.

“Pharmacists can pay a pivotal role [in helping] patients who are receiving these Poly-CNS medications because they are able to interact and talk through the actual patient picture for all their medications ... because pharmacists have always been seen as being a trusted source,” she said.

Dr. Gaddy added that health plans can take a more direct role in reaching out to patients, for example, through telephone outreach, as well as direct mail, email, and newsletters.

“We want to make sure that members have as much information as possible,” she said.

She added that it is very important to include physicians and other prescribers in this process through faxes and information included in EHRs.


 

Opioids and benzodiazepines

The final measure highlighted during the session was the one measuring the concurrent use of opioids and benzodiazepines.

Dr. Gaddy noted that taking the two concurrently is associated with a fourfold increase in risk of opioid overdose and death, compared with opioid use without a benzodiazepine.

She noted that a black box warning on the risks of concurrent use was added to both opioids and benzodiazepines in August 2016 and that resulted in a 10% decrease in the concurrent use.

“This new measure is intended to ensure that the downward trend continues. CMS has indicated as such,” Dr. Gaddy said.

Most of the intervention strategies she highlighted were similar to those for the Poly-CNS category, including the use of medication therapy management programs and targeted interventions, telephone outreach to members, and provider detailing and outreach.

“Provider detailing is really key,” Dr. Gaddy said. “On any given day, it’s so easy for physicians to see 30 patients. The great thing about the provider detailing is that you are able to give the provider a ‘packet’ of their members, you can identify and/or aid in showing them the risk assessment associated with members taking these medications, and then equip them with pocket guides and [materials so they can] streamline the medications.”

[email protected]

NATIONAL HARBOR, MD. – Changes in the accounting for polypharmacy in the Centers for Medicare & Medicaid Services’ star rating system are on their way, and managed care organizations should start preparing now for the shift.

Panelists at an Oct. 30 session at the annual meeting of the Academy of Managed Care Pharmacy presented strategies for addressing the three areas of polypharmacy that will be tracked in the new rating system, which will replace the current high-risk medication measurement that is being retired this year.

Anticholinergic medications

The first area presented by the panelists was polypharmacy use of multiple anticholinergic medications in older adults (Poly-ACH). The new quality measure will examine the percentage of members aged 65 years or older who are using two or more anticholinergic medications concurrently.

“We know that anticholinergic burden increases the risk of cognitive decline in particular, but it’s also associated with a higher risk of falls, an increased number of hospitalizations, and [diminished] physical function,” said Marti Groeneweg, PharmD, supervisor of clinical pharmacy services at Kaiser Permanente.

Dr. Groeneweg noted that, in addition to using multiple drugs in this class, patients can also benefit from a decrease in the dosage of their drugs, so that should also be considered in managing the medication of beneficiaries.

She highlighted a program Kaiser Permanente started in the Northwest United States to reduce the concurrent use of these drugs. The program targeted tricyclic antidepressants – nortriptyline, in particular.

The company instituted a multipronged approach that included provider detailing of the risks of using multiple drugs and how they could taper schedules, as well as providing them with other supporting resources and a list of safer, alternative drugs. It also reached out to patients to educate them about the risks of their medications and why it was important for them to taper their medications. The third part of the approach was to use the EHR to provide doctors with the best-available information at the point of prescribing. And finally, there was a pharmacist review process put in place for more complex cases.

Dr. Groeneweg emphasized that this information was incorporated into existing programs.

The intervention, which is fairly new, has not been in place long enough to know exactly how well it is working, but early indicators suggest “we are on the right track,” she said, noting that to date there has been a decrease of 28% in the number of tricyclic antidepressant prescriptions per 1,000 Medicare members per month.
 

CNS medications

The second area the panelists addressed was the polypharmacy use of multiple CNS-active medications in older adults (Poly-CNS).

Rainelle Gaddy, PharmD, Rx clinical programs pharmacy lead at Humana Pharmacy Solutions, , noted that the clinical rationale for this measure was the “increased risk of falls and fractures when these medications are taken concurrently.”

She pointed out that taking one or more of the CNS medications can result in a 1.5-fold increase in the risk for falls, and that risk increases to 2.5-fold if two or more drugs are taken. In addition, a high-dose of these medications can lead to a threefold increase in risk of recurrent falls.

Dr. Gaddy highlighted a number of interventions that could be implemented when the managed care organization is not integrated in the way Kaiser Permanente is.

“Pharmacists can pay a pivotal role [in helping] patients who are receiving these Poly-CNS medications because they are able to interact and talk through the actual patient picture for all their medications ... because pharmacists have always been seen as being a trusted source,” she said.

Dr. Gaddy added that health plans can take a more direct role in reaching out to patients, for example, through telephone outreach, as well as direct mail, email, and newsletters.

“We want to make sure that members have as much information as possible,” she said.

She added that it is very important to include physicians and other prescribers in this process through faxes and information included in EHRs.


 

Opioids and benzodiazepines

The final measure highlighted during the session was the one measuring the concurrent use of opioids and benzodiazepines.

Dr. Gaddy noted that taking the two concurrently is associated with a fourfold increase in risk of opioid overdose and death, compared with opioid use without a benzodiazepine.

She noted that a black box warning on the risks of concurrent use was added to both opioids and benzodiazepines in August 2016 and that resulted in a 10% decrease in the concurrent use.

“This new measure is intended to ensure that the downward trend continues. CMS has indicated as such,” Dr. Gaddy said.

Most of the intervention strategies she highlighted were similar to those for the Poly-CNS category, including the use of medication therapy management programs and targeted interventions, telephone outreach to members, and provider detailing and outreach.

“Provider detailing is really key,” Dr. Gaddy said. “On any given day, it’s so easy for physicians to see 30 patients. The great thing about the provider detailing is that you are able to give the provider a ‘packet’ of their members, you can identify and/or aid in showing them the risk assessment associated with members taking these medications, and then equip them with pocket guides and [materials so they can] streamline the medications.”

[email protected]

NATIONAL HARBOR, MD. – Changes in the accounting for polypharmacy in the Centers for Medicare & Medicaid Services’ star rating system are on their way, and managed care organizations should start preparing now for the shift.

Panelists at an Oct. 30 session at the annual meeting of the Academy of Managed Care Pharmacy presented strategies for addressing the three areas of polypharmacy that will be tracked in the new rating system, which will replace the current high-risk medication measurement that is being retired this year.

Anticholinergic medications

The first area presented by the panelists was polypharmacy use of multiple anticholinergic medications in older adults (Poly-ACH). The new quality measure will examine the percentage of members aged 65 years or older who are using two or more anticholinergic medications concurrently.

“We know that anticholinergic burden increases the risk of cognitive decline in particular, but it’s also associated with a higher risk of falls, an increased number of hospitalizations, and [diminished] physical function,” said Marti Groeneweg, PharmD, supervisor of clinical pharmacy services at Kaiser Permanente.

Dr. Groeneweg noted that, in addition to using multiple drugs in this class, patients can also benefit from a decrease in the dosage of their drugs, so that should also be considered in managing the medication of beneficiaries.

She highlighted a program Kaiser Permanente started in the Northwest United States to reduce the concurrent use of these drugs. The program targeted tricyclic antidepressants – nortriptyline, in particular.

The company instituted a multipronged approach that included provider detailing of the risks of using multiple drugs and how they could taper schedules, as well as providing them with other supporting resources and a list of safer, alternative drugs. It also reached out to patients to educate them about the risks of their medications and why it was important for them to taper their medications. The third part of the approach was to use the EHR to provide doctors with the best-available information at the point of prescribing. And finally, there was a pharmacist review process put in place for more complex cases.

Dr. Groeneweg emphasized that this information was incorporated into existing programs.

The intervention, which is fairly new, has not been in place long enough to know exactly how well it is working, but early indicators suggest “we are on the right track,” she said, noting that to date there has been a decrease of 28% in the number of tricyclic antidepressant prescriptions per 1,000 Medicare members per month.
 

CNS medications

The second area the panelists addressed was the polypharmacy use of multiple CNS-active medications in older adults (Poly-CNS).

Rainelle Gaddy, PharmD, Rx clinical programs pharmacy lead at Humana Pharmacy Solutions, , noted that the clinical rationale for this measure was the “increased risk of falls and fractures when these medications are taken concurrently.”

She pointed out that taking one or more of the CNS medications can result in a 1.5-fold increase in the risk for falls, and that risk increases to 2.5-fold if two or more drugs are taken. In addition, a high-dose of these medications can lead to a threefold increase in risk of recurrent falls.

Dr. Gaddy highlighted a number of interventions that could be implemented when the managed care organization is not integrated in the way Kaiser Permanente is.

“Pharmacists can pay a pivotal role [in helping] patients who are receiving these Poly-CNS medications because they are able to interact and talk through the actual patient picture for all their medications ... because pharmacists have always been seen as being a trusted source,” she said.

Dr. Gaddy added that health plans can take a more direct role in reaching out to patients, for example, through telephone outreach, as well as direct mail, email, and newsletters.

“We want to make sure that members have as much information as possible,” she said.

She added that it is very important to include physicians and other prescribers in this process through faxes and information included in EHRs.


 

Opioids and benzodiazepines

The final measure highlighted during the session was the one measuring the concurrent use of opioids and benzodiazepines.

Dr. Gaddy noted that taking the two concurrently is associated with a fourfold increase in risk of opioid overdose and death, compared with opioid use without a benzodiazepine.

She noted that a black box warning on the risks of concurrent use was added to both opioids and benzodiazepines in August 2016 and that resulted in a 10% decrease in the concurrent use.

“This new measure is intended to ensure that the downward trend continues. CMS has indicated as such,” Dr. Gaddy said.

Most of the intervention strategies she highlighted were similar to those for the Poly-CNS category, including the use of medication therapy management programs and targeted interventions, telephone outreach to members, and provider detailing and outreach.

“Provider detailing is really key,” Dr. Gaddy said. “On any given day, it’s so easy for physicians to see 30 patients. The great thing about the provider detailing is that you are able to give the provider a ‘packet’ of their members, you can identify and/or aid in showing them the risk assessment associated with members taking these medications, and then equip them with pocket guides and [materials so they can] streamline the medications.”

[email protected]

Vaping-associated lung injury cases have now reached 1,888, according to the latest update provided by the Centers for Disease Control and Prevention. Thirty-seven deaths have been confirmed.

Deaths have occurred in 24 states and the District of Columbia: Alabama, California (3), Connecticut, Delaware, Florida, Georgia (3), Illinois (2), Indiana (3), Kansas (2), Massachusetts, Michigan, Minnesota (3), Mississippi, Missouri, Montana, Nebraska, New Jersey, New York, Oregon (2), Pennsylvania, Tennessee (2), Texas, Utah, and Virginia. As on Oct. 28, the median age of deceased patients was 49 years and ranged from 17 to 75 years.

The CDC is now doing additional testing on available samples for chemical in the bronchoalveolar lavage fluid, blood, or urine, as well as lung biopsy or autopsy specimens. It also is validating methods for aerosol emission testing of case-associated product samples from vaping products and e-liquids.

For more information and resources visit For the Public, For Healthcare Providers, and For State and Local Health Departments pages, as well as the CDC’s Publications and Resources page.

[email protected]

Vaping-associated lung injury cases have now reached 1,888, according to the latest update provided by the Centers for Disease Control and Prevention. Thirty-seven deaths have been confirmed.

Deaths have occurred in 24 states and the District of Columbia: Alabama, California (3), Connecticut, Delaware, Florida, Georgia (3), Illinois (2), Indiana (3), Kansas (2), Massachusetts, Michigan, Minnesota (3), Mississippi, Missouri, Montana, Nebraska, New Jersey, New York, Oregon (2), Pennsylvania, Tennessee (2), Texas, Utah, and Virginia. As on Oct. 28, the median age of deceased patients was 49 years and ranged from 17 to 75 years.

The CDC is now doing additional testing on available samples for chemical in the bronchoalveolar lavage fluid, blood, or urine, as well as lung biopsy or autopsy specimens. It also is validating methods for aerosol emission testing of case-associated product samples from vaping products and e-liquids.

For more information and resources visit For the Public, For Healthcare Providers, and For State and Local Health Departments pages, as well as the CDC’s Publications and Resources page.

[email protected]

Vaping-associated lung injury cases have now reached 1,888, according to the latest update provided by the Centers for Disease Control and Prevention. Thirty-seven deaths have been confirmed.

Deaths have occurred in 24 states and the District of Columbia: Alabama, California (3), Connecticut, Delaware, Florida, Georgia (3), Illinois (2), Indiana (3), Kansas (2), Massachusetts, Michigan, Minnesota (3), Mississippi, Missouri, Montana, Nebraska, New Jersey, New York, Oregon (2), Pennsylvania, Tennessee (2), Texas, Utah, and Virginia. As on Oct. 28, the median age of deceased patients was 49 years and ranged from 17 to 75 years.

The CDC is now doing additional testing on available samples for chemical in the bronchoalveolar lavage fluid, blood, or urine, as well as lung biopsy or autopsy specimens. It also is validating methods for aerosol emission testing of case-associated product samples from vaping products and e-liquids.

For more information and resources visit For the Public, For Healthcare Providers, and For State and Local Health Departments pages, as well as the CDC’s Publications and Resources page.

[email protected]

NATIONAL HARBOR, MD. – Synchronizing medication refills resulted in higher adherence, fewer hospitalizations, and lower health care costs in a cohort of patients with type 2 diabetes, according to research presented at the annual meeting of the Academy of Managed Care Pharmacy.

Denise Fulton/MDedge News

Investigators with Pharmacy Quality Alliance (PQA) used data from Truven MarketScan Research Databases to conduct a retrospective cohort study of more than 20,000 patients eligible for inclusion in PQA’s diabetes medication adherence measure. To be included, patients needed to have two or more prescriptions for diabetes medications (excluding insulin), statins, or renin-angiotensin system antagonists. About 80% of patients were commercially insured and 20% came from Medicare supplement insurance (Medigap) plans.

Commercially insured patients whose medication refills were synchronized had better medication adherence than did matched controls (67.7% vs. 57.4%) and lower median health care expenditures ($3,687 vs. $7,480).

The same was true for patients with Medicare supplemental insurance. Synchronized patients in this group also had better medication adherence than controls, at 86.5% vs. 70.4% and lower median health care expenditures ($7,353 vs. $10,592).

Based on their findings in diabetes patients, “I think we should synchronize refills,” Matthew K. Pickering, PharmD, senior director of research and quality strategies at PQA, said. “However, there are populations that were not represented in this, like COPD [chronic obstructive pulmonary disease]. That’s another high-comorbidity, high-cost population that should be studied.”

Session moderator Laura Happe, PharmD, editor in chief of the Journal of Managed Care and Specialty Pharmacy, questioned Dr. Pickering about the barriers to medication synchronization.

In previous research, “we discovered that some patients were resistant to synchronizing their medication refills because of the copays – having all of their copays at one time, rather than spreading them out over the month,” Dr. Happe said.

“Certainly, patients may not be able to afford all their copays at one time, so that can be a barrier,” Dr. Pickering said. “With medication synchronization programs, there’s a lot of variation across the board. Patients can choose which medication to synchronize in some programs. Others only synchronize the three-star medication, etc. But there are real barriers and they should be explored.”

Pharmacy Quality Alliance is a nonprofit public-private partnership that develops pharmacy quality measures in collaboration with the Centers for Medicare & Medicaid Services.

Dr. Pickering disclosed no relevant conflicts of interest.

[email protected]

NATIONAL HARBOR, MD. – Synchronizing medication refills resulted in higher adherence, fewer hospitalizations, and lower health care costs in a cohort of patients with type 2 diabetes, according to research presented at the annual meeting of the Academy of Managed Care Pharmacy.

Denise Fulton/MDedge News

Investigators with Pharmacy Quality Alliance (PQA) used data from Truven MarketScan Research Databases to conduct a retrospective cohort study of more than 20,000 patients eligible for inclusion in PQA’s diabetes medication adherence measure. To be included, patients needed to have two or more prescriptions for diabetes medications (excluding insulin), statins, or renin-angiotensin system antagonists. About 80% of patients were commercially insured and 20% came from Medicare supplement insurance (Medigap) plans.

Commercially insured patients whose medication refills were synchronized had better medication adherence than did matched controls (67.7% vs. 57.4%) and lower median health care expenditures ($3,687 vs. $7,480).

The same was true for patients with Medicare supplemental insurance. Synchronized patients in this group also had better medication adherence than controls, at 86.5% vs. 70.4% and lower median health care expenditures ($7,353 vs. $10,592).

Based on their findings in diabetes patients, “I think we should synchronize refills,” Matthew K. Pickering, PharmD, senior director of research and quality strategies at PQA, said. “However, there are populations that were not represented in this, like COPD [chronic obstructive pulmonary disease]. That’s another high-comorbidity, high-cost population that should be studied.”

Session moderator Laura Happe, PharmD, editor in chief of the Journal of Managed Care and Specialty Pharmacy, questioned Dr. Pickering about the barriers to medication synchronization.

In previous research, “we discovered that some patients were resistant to synchronizing their medication refills because of the copays – having all of their copays at one time, rather than spreading them out over the month,” Dr. Happe said.

“Certainly, patients may not be able to afford all their copays at one time, so that can be a barrier,” Dr. Pickering said. “With medication synchronization programs, there’s a lot of variation across the board. Patients can choose which medication to synchronize in some programs. Others only synchronize the three-star medication, etc. But there are real barriers and they should be explored.”

Pharmacy Quality Alliance is a nonprofit public-private partnership that develops pharmacy quality measures in collaboration with the Centers for Medicare & Medicaid Services.

Dr. Pickering disclosed no relevant conflicts of interest.

[email protected]

NATIONAL HARBOR, MD. – Synchronizing medication refills resulted in higher adherence, fewer hospitalizations, and lower health care costs in a cohort of patients with type 2 diabetes, according to research presented at the annual meeting of the Academy of Managed Care Pharmacy.

Denise Fulton/MDedge News

Investigators with Pharmacy Quality Alliance (PQA) used data from Truven MarketScan Research Databases to conduct a retrospective cohort study of more than 20,000 patients eligible for inclusion in PQA’s diabetes medication adherence measure. To be included, patients needed to have two or more prescriptions for diabetes medications (excluding insulin), statins, or renin-angiotensin system antagonists. About 80% of patients were commercially insured and 20% came from Medicare supplement insurance (Medigap) plans.

Commercially insured patients whose medication refills were synchronized had better medication adherence than did matched controls (67.7% vs. 57.4%) and lower median health care expenditures ($3,687 vs. $7,480).

The same was true for patients with Medicare supplemental insurance. Synchronized patients in this group also had better medication adherence than controls, at 86.5% vs. 70.4% and lower median health care expenditures ($7,353 vs. $10,592).

Based on their findings in diabetes patients, “I think we should synchronize refills,” Matthew K. Pickering, PharmD, senior director of research and quality strategies at PQA, said. “However, there are populations that were not represented in this, like COPD [chronic obstructive pulmonary disease]. That’s another high-comorbidity, high-cost population that should be studied.”

Session moderator Laura Happe, PharmD, editor in chief of the Journal of Managed Care and Specialty Pharmacy, questioned Dr. Pickering about the barriers to medication synchronization.

In previous research, “we discovered that some patients were resistant to synchronizing their medication refills because of the copays – having all of their copays at one time, rather than spreading them out over the month,” Dr. Happe said.

“Certainly, patients may not be able to afford all their copays at one time, so that can be a barrier,” Dr. Pickering said. “With medication synchronization programs, there’s a lot of variation across the board. Patients can choose which medication to synchronize in some programs. Others only synchronize the three-star medication, etc. But there are real barriers and they should be explored.”

Pharmacy Quality Alliance is a nonprofit public-private partnership that develops pharmacy quality measures in collaboration with the Centers for Medicare & Medicaid Services.

Dr. Pickering disclosed no relevant conflicts of interest.

[email protected]

Through the years, the surgical approach to hysterectomy has expanded from its early beginnings of being performed only through an abdominal or transvaginal route with traditional surgical clamps and suture. The late 1980s saw the advent of the laparoscopic-assisted vaginal hysterectomy (LAVH), and from that point forward several additional hysterectomy methods evolved, including today’s robotic approaches.

Although clinical evidence and societal endorsements support vaginal hysterectomy as a superior high-value modality, it remains one of the least performed among all available routes.^1-3 In an analysis of inpatient hysterectomies published by Wright and colleagues in 2013, 16.7% of hysterectomies were performed vaginally, a number that essentially has remained steady throughout the ensuing years.⁴

Attempts to improve the application of vaginal hysterectomy have been made.⁵ These include the development of various curriculum and simulation-based medical education programs on vaginal surgical skills training and acquisition in the hopes of improving utilization.⁶ An interesting recent development is the rethinking of vaginal hysterectomy by several surgeons globally who are applying facets of the various hysterectomy methods to a transvaginal approach known as vaginal natural orifice transluminal endoscopic surgery (vNOTES).^7,8 Unique to this thinking is the incorporation of conventional laparoscopic instrumentation.

Although I have not yet incorporated this approach in my surgical armamentarium at Columbia University Medical Center/New York–Presbyterian Hospital, I am intrigued by the possibility that this technique may serve as a rescue for vaginal hysterectomies that are at risk of conversion or of not being performed at all.⁹

At this time, vNOTES is not a standard of care and should be performed only by highly specialized surgeons. However, in the spirit of this Update on minimally invasive surgery and to keep our readers abreast of burgeoning techniques, I am delighted to bring you this overview by Dr. Xiaoming Guan, one of the pioneers of this surgical approach, and Dr. Tamisa Koythong and Dr. Juan Liu. I hope you find this recent development in hysterectomy of interest.

—Arnold P. Advincula, MD

Continue to: Development and evolution of NOTES...

Development and evolution of NOTES 

Over the past few decades, emphasis has shifted from laparotomy to minimally invasive surgery because of its proven significant advantages in patient care, such as improved cosmesis, shorter hospital stay, shorter postoperative recovery, and decreased postoperative pain and blood loss.¹⁰  Advances in laparoendoscopic surgery and instrumentation, including robot-assisted laparoscopy (RAL), single-incision laparoscopic surgery (SILS), and most recently natural orifice transluminal endoscopic surgery (NOTES), reflect ongoing innovative developments in the field of minimally invasive surgery. 

Here, we provide a brief literature review of the NOTES technique, focus on its application in gynecologic surgery, and describe how we perform NOTES at our institution. 

NOTES application in gynecology 

With NOTES, peritoneal access is gained through a natural orifice (such as the mouth, vagina, urethra, or anus) to perform endoscopic surgery, occasionally without requiring an abdominal incision. First described in 2004, transgastric peritoneoscopy was performed in a porcine model, and shortly thereafter the first transgastric appendectomy was performed in humans.^11,12 The technique has further been adopted in cholecystectomy, appendectomy, gastrectomy, and nephrectomy procedures.¹³ 

Given rapid interest in a possible paradigm shift in the field of minimally invasive surgery, the Natural Orifice Surgery Consortiumfor Assessment and Research (NOSCAR) was formed, and the group published an article on potential barriers to accepted practice and adoption of NOTES as a realistic alternative to traditional laparoscopic surgery.¹⁴ 

While transgastric and transanal access to the peritoneum were initially more popular, the risk of anastomotic leaks associated with incomplete closure and subsequent infection were thought to be prohibitively high.¹⁵ Transvaginal access was considered a safer and simpler alternative, allowing for complete closure without increased risk of infection, and this is now the route through which the majority of NOTES procedures are completed.^16,17 

The eventual application of NOTES in the field of gynecology seemed inevitable. The American College of Obstetricians and Gynecologists stated that transvaginal surgery is the most minimally invasive and preferred surgical route in the management of patients with benign gynecologic diseases.¹⁸ However, performing it can be challenging at times due to limited visualization and lack of the required skills for single-site surgery. NOTES allows a gynecologic surgeon to improve visualization through the use of laparoendoscopic instruments and to complete surgery through a transvaginal route. 

In 2012, Ahn and colleagues demonstrated the feasibility of the NOTES technique in gynecologic surgery after using it to successfully complete benign adnexal surgery in 10 patients.¹⁹ Vaginal NOTES (vNOTES) has since been further developed to include successful hysterectomy, myomectomy, sacrocolpopexy, tubal anastomosis, and even lymphadenectomy in the treatment of early- stage endometrial carcinoma.^20-26 vNOTES also can be considered a rescue approach for traditional vaginal hysterectomy in instances in which it is necessary to evaluate adnexal pathology.⁹ Most recently, vNOTES hysterectomy has been reported with da Vinci Si or Xi robotic platforms.^27,28 

Continue to: Operative time, post-op stay shorter in NAOC-treated patients...

Few studies have compared outcomes with vNOTES to those with traditional laparoscopy. In 2016, Wang and colleagues compared surgical outcomes between NOTES-assisted ovarian cystectomy (NAOC) and laparoscopic ovarian cystectomy (LOC) in a case-matched study that included 277 patients.²⁹ Although mean (SD) blood loss in patients who underwent LOC was significantly less compared with those who underwent NAOC (21.4 [14.7] mL vs 31.6 [24.1] mL; P = .028), absolute blood loss in both groups was deemed minimal. Additionally, mean (SD) operative time and postoperative stay were significantly less in patients undergoing NAOC compared with those having LOC (38.23 [10.19] minutes vs 53.82 [18.61] minutes; P≤.001; and 1.38 [0.55] days vs 1.82 [0.52] days; P≤.001; respectively).²⁹ 

How vNOTES hysterectomy stacked up against TLH 

In 2018, Baekelandt and colleagues compared outcomes between vNOTES hysterectomy and total laparoscopic hysterectomy (TLH) in a noninferiority single-blinded trial of 70 women.⁸ Compared with TLH, vNOTES hysterectomy was associated with shorter operative time (41 vs 75 minutes; P<.001), shorter hospital stay (0.8 vs 1.3 days; P = .004), and lower postoperative analgesic requirement (8 vs 14 U; P = .006). Additionally, there were no differences between the 2 groups in postoperative infection rate, intraoperative complications, or hospital readmissions within 6 weeks.⁸

Approach for performing vNOTES procedures 

At our institution, Baylor College of Medicine, the majority of gynecologic surgeries are performed via either transumbilical robot-assisted single-incision laparoscopy or vNOTES. Preoperative selection of appropriate candidates for vNOTES includes: 

• low suspicion for or prior diagnosis of endometriosis with obliteration of the posterior cul-de-sac 
• no surgical history suggestive of severe adhesive disease, and 
• adequate vaginal sidewall access and sufficient descent for instrumentation for entry into the peritoneal cavity. 

In general, a key concept in vNOTES is "vaginal pull, laparoscopic push," which means that the surgeon must pull the cervix while performing vaginal entry and then push the uterus back in the peritoneal cavity to increase surgical space during laparoscopic surgery. 

Continue to: Overview of vNOTES steps...

Below we break down a description of vNOTES in 6 sections. Our patients are always placed in dorsal lithotomy position with TrenGuard (D.A. Surgical) Trendelenburg restraint. We prep the abdomen in case we need to convert to transabdominal surgery via transumbilical single-incision laparoscopic surgery or traditional laparoscopic surgery. 

1. Vaginal entry 

Accessing the peritoneal cavity through the vagina initially proceeds like a vaginal hysterectomy. We inject dilute vasopressin (20 U in 20 mL of normal saline) circumferentially in the cervix (for hysterectomy) or in the posterior cervix in the cervicovaginal junction (for adnexal surgery without hysterectomy) for vasoconstriction and hydrodissection. 

We then incise the vaginal mucosa circumferentially with electrosurgical cautery and follow with posterior colpotomy. We find that reapproximating the posterior peritoneum to the posterior vagina with either figure-of-8 stitches or a running stitch of polyglactin 910 suture (2-0 Vicryl) assists in port placement, bleeding at the peritoneal edge, and closure of the cuff or colpotomy at the end of the case. We tag this suture with a curved hemostat. 

Depending on whether a hysterectomy is being performed, anterior colpotomy is made. Again, the anterior peritoneum is then tagged to the anterior vaginal cuff in similar fashion, and this suture is tagged with a different instrument; we typically use a straight hemostat or Sarot clamp (FIGURE 1). 

2. Traditional vaginal hysterectomy 

After colpotomy, we prefer to perform progressive clamping of the broad ligament from the uterosacral and cardinal ligaments to the level of uterine artery as in traditional vaginal hysterectomy, if feasible. 

3. Single-site port placement 

The assembled GelPOINT Mini advanced access platform (Applied Medical) (FIGURE 2) is introduced through the vagina after the Alexis wound protector (included with the kit) is first placed through the colpotomy with assistance of Babcock clamps (FIGURE 3). 

After ensuring that the green rigid ring of the Alexis wound protector is contained and completely expanded within the peritoneal cavity, we cross our previously tagged sutures as we find this helps with preventing the GelPOINT Mini access platform from inadvertently shifting out of the peritoneal cavity during surgery. The GelSeal cap is then secured and pneumoperitoneum is established (FIGURE 4). 

Continue to: 4. Laparoendoscopic surgery...

Instruments used in our surgeries include a 10-mm rigid 30° 43-cm working length laparoscope; a 44-cm LigaSure device (Medtronic); a 5-mm, 37-cm laparoscopic cobra grasping forceps and fenestrated grasper (Karl Storz); and a 5-mm, 45-cm laparoscopic suction with hydrodissection tip (Stryker) (FIGURE 5). 

vNOTES allows a gynecologic surgeon the unique ability to survey the upper abdomen. The remainder of the surgery proceeds using basic laparoscopic single-site skills. 

During vNOTES, as with all single-site surgical procedures, understanding the optimal placement of crossed instruments is important for successful completion. For example, when securing the right uterine artery, the surgeon needs to push the cervix toward the patient's left and slightly into the peritoneal cavity using a laparoscopic cobra grasper with his or her left hand while then securing the uterine pedicle using the LigaSure device with his or her right hand. This is then reversed when securing the left uterine artery, where the assistant surgeon pushes the cervix toward the patient's right while the surgeon secures the pedicle ("vaginal pull, laparoscopic push") (FIGURE 6). 

This again is reiterated in securing the ovarian pedicles, which are pushed into the peritoneal cavity while being secured with the LigaSure device. 

5. Specimen removal 

For large uteri or specimens that need morcellation, a 15-mm Endo Catch specimen retrieval bag (Medtronic) is introduced through the GelPOINT Mini system. The specimen is then placed in the bag and delivered to the vagina, where contained bag morcellation is performed in standard fashion (FIGURES 7 AND 8). We utilized the "big C" technique by first grasping the specimen with a penetrating clamp. The clamp is then held in our nondominant hand and a No. 10 blade scalpel is used to create a reverse c-incision, keeping one surface of the specimen intact. This is continued until the specimen can be completely delivered through the vagina. 

Specimens that do not require morcellation can be grasped laparoscopically, brought to the GelPOINT Mini port, which is quickly disassembled, and delivered. The GelSeal cap is then reassembled. 

6. Vaginal cuff closure 

The colpotomy or vaginal cuff is closed with barbed suture continuously, as in traditional vaginal hysterectomy cuff closure. Uterosacral ligament suspension should be performed for vaginal cuff support.  
 

Through the years, the surgical approach to hysterectomy has expanded from its early beginnings of being performed only through an abdominal or transvaginal route with traditional surgical clamps and suture. The late 1980s saw the advent of the laparoscopic-assisted vaginal hysterectomy (LAVH), and from that point forward several additional hysterectomy methods evolved, including today’s robotic approaches.

Although clinical evidence and societal endorsements support vaginal hysterectomy as a superior high-value modality, it remains one of the least performed among all available routes.^1-3 In an analysis of inpatient hysterectomies published by Wright and colleagues in 2013, 16.7% of hysterectomies were performed vaginally, a number that essentially has remained steady throughout the ensuing years.⁴

Attempts to improve the application of vaginal hysterectomy have been made.⁵ These include the development of various curriculum and simulation-based medical education programs on vaginal surgical skills training and acquisition in the hopes of improving utilization.⁶ An interesting recent development is the rethinking of vaginal hysterectomy by several surgeons globally who are applying facets of the various hysterectomy methods to a transvaginal approach known as vaginal natural orifice transluminal endoscopic surgery (vNOTES).^7,8 Unique to this thinking is the incorporation of conventional laparoscopic instrumentation.

Although I have not yet incorporated this approach in my surgical armamentarium at Columbia University Medical Center/New York–Presbyterian Hospital, I am intrigued by the possibility that this technique may serve as a rescue for vaginal hysterectomies that are at risk of conversion or of not being performed at all.⁹

At this time, vNOTES is not a standard of care and should be performed only by highly specialized surgeons. However, in the spirit of this Update on minimally invasive surgery and to keep our readers abreast of burgeoning techniques, I am delighted to bring you this overview by Dr. Xiaoming Guan, one of the pioneers of this surgical approach, and Dr. Tamisa Koythong and Dr. Juan Liu. I hope you find this recent development in hysterectomy of interest.

—Arnold P. Advincula, MD

Continue to: Development and evolution of NOTES...

Development and evolution of NOTES 

Over the past few decades, emphasis has shifted from laparotomy to minimally invasive surgery because of its proven significant advantages in patient care, such as improved cosmesis, shorter hospital stay, shorter postoperative recovery, and decreased postoperative pain and blood loss.¹⁰  Advances in laparoendoscopic surgery and instrumentation, including robot-assisted laparoscopy (RAL), single-incision laparoscopic surgery (SILS), and most recently natural orifice transluminal endoscopic surgery (NOTES), reflect ongoing innovative developments in the field of minimally invasive surgery. 

Here, we provide a brief literature review of the NOTES technique, focus on its application in gynecologic surgery, and describe how we perform NOTES at our institution. 

NOTES application in gynecology 

With NOTES, peritoneal access is gained through a natural orifice (such as the mouth, vagina, urethra, or anus) to perform endoscopic surgery, occasionally without requiring an abdominal incision. First described in 2004, transgastric peritoneoscopy was performed in a porcine model, and shortly thereafter the first transgastric appendectomy was performed in humans.^11,12 The technique has further been adopted in cholecystectomy, appendectomy, gastrectomy, and nephrectomy procedures.¹³ 

Given rapid interest in a possible paradigm shift in the field of minimally invasive surgery, the Natural Orifice Surgery Consortiumfor Assessment and Research (NOSCAR) was formed, and the group published an article on potential barriers to accepted practice and adoption of NOTES as a realistic alternative to traditional laparoscopic surgery.¹⁴ 

While transgastric and transanal access to the peritoneum were initially more popular, the risk of anastomotic leaks associated with incomplete closure and subsequent infection were thought to be prohibitively high.¹⁵ Transvaginal access was considered a safer and simpler alternative, allowing for complete closure without increased risk of infection, and this is now the route through which the majority of NOTES procedures are completed.^16,17 

The eventual application of NOTES in the field of gynecology seemed inevitable. The American College of Obstetricians and Gynecologists stated that transvaginal surgery is the most minimally invasive and preferred surgical route in the management of patients with benign gynecologic diseases.¹⁸ However, performing it can be challenging at times due to limited visualization and lack of the required skills for single-site surgery. NOTES allows a gynecologic surgeon to improve visualization through the use of laparoendoscopic instruments and to complete surgery through a transvaginal route. 

In 2012, Ahn and colleagues demonstrated the feasibility of the NOTES technique in gynecologic surgery after using it to successfully complete benign adnexal surgery in 10 patients.¹⁹ Vaginal NOTES (vNOTES) has since been further developed to include successful hysterectomy, myomectomy, sacrocolpopexy, tubal anastomosis, and even lymphadenectomy in the treatment of early- stage endometrial carcinoma.^20-26 vNOTES also can be considered a rescue approach for traditional vaginal hysterectomy in instances in which it is necessary to evaluate adnexal pathology.⁹ Most recently, vNOTES hysterectomy has been reported with da Vinci Si or Xi robotic platforms.^27,28 

Continue to: Operative time, post-op stay shorter in NAOC-treated patients...

Few studies have compared outcomes with vNOTES to those with traditional laparoscopy. In 2016, Wang and colleagues compared surgical outcomes between NOTES-assisted ovarian cystectomy (NAOC) and laparoscopic ovarian cystectomy (LOC) in a case-matched study that included 277 patients.²⁹ Although mean (SD) blood loss in patients who underwent LOC was significantly less compared with those who underwent NAOC (21.4 [14.7] mL vs 31.6 [24.1] mL; P = .028), absolute blood loss in both groups was deemed minimal. Additionally, mean (SD) operative time and postoperative stay were significantly less in patients undergoing NAOC compared with those having LOC (38.23 [10.19] minutes vs 53.82 [18.61] minutes; P≤.001; and 1.38 [0.55] days vs 1.82 [0.52] days; P≤.001; respectively).²⁹ 

How vNOTES hysterectomy stacked up against TLH 

In 2018, Baekelandt and colleagues compared outcomes between vNOTES hysterectomy and total laparoscopic hysterectomy (TLH) in a noninferiority single-blinded trial of 70 women.⁸ Compared with TLH, vNOTES hysterectomy was associated with shorter operative time (41 vs 75 minutes; P<.001), shorter hospital stay (0.8 vs 1.3 days; P = .004), and lower postoperative analgesic requirement (8 vs 14 U; P = .006). Additionally, there were no differences between the 2 groups in postoperative infection rate, intraoperative complications, or hospital readmissions within 6 weeks.⁸

Approach for performing vNOTES procedures 

At our institution, Baylor College of Medicine, the majority of gynecologic surgeries are performed via either transumbilical robot-assisted single-incision laparoscopy or vNOTES. Preoperative selection of appropriate candidates for vNOTES includes: 

• low suspicion for or prior diagnosis of endometriosis with obliteration of the posterior cul-de-sac 
• no surgical history suggestive of severe adhesive disease, and 
• adequate vaginal sidewall access and sufficient descent for instrumentation for entry into the peritoneal cavity. 

In general, a key concept in vNOTES is "vaginal pull, laparoscopic push," which means that the surgeon must pull the cervix while performing vaginal entry and then push the uterus back in the peritoneal cavity to increase surgical space during laparoscopic surgery. 

Continue to: Overview of vNOTES steps...

Below we break down a description of vNOTES in 6 sections. Our patients are always placed in dorsal lithotomy position with TrenGuard (D.A. Surgical) Trendelenburg restraint. We prep the abdomen in case we need to convert to transabdominal surgery via transumbilical single-incision laparoscopic surgery or traditional laparoscopic surgery. 

1. Vaginal entry 

Accessing the peritoneal cavity through the vagina initially proceeds like a vaginal hysterectomy. We inject dilute vasopressin (20 U in 20 mL of normal saline) circumferentially in the cervix (for hysterectomy) or in the posterior cervix in the cervicovaginal junction (for adnexal surgery without hysterectomy) for vasoconstriction and hydrodissection. 

We then incise the vaginal mucosa circumferentially with electrosurgical cautery and follow with posterior colpotomy. We find that reapproximating the posterior peritoneum to the posterior vagina with either figure-of-8 stitches or a running stitch of polyglactin 910 suture (2-0 Vicryl) assists in port placement, bleeding at the peritoneal edge, and closure of the cuff or colpotomy at the end of the case. We tag this suture with a curved hemostat. 

Depending on whether a hysterectomy is being performed, anterior colpotomy is made. Again, the anterior peritoneum is then tagged to the anterior vaginal cuff in similar fashion, and this suture is tagged with a different instrument; we typically use a straight hemostat or Sarot clamp (FIGURE 1). 

2. Traditional vaginal hysterectomy 

After colpotomy, we prefer to perform progressive clamping of the broad ligament from the uterosacral and cardinal ligaments to the level of uterine artery as in traditional vaginal hysterectomy, if feasible. 

3. Single-site port placement 

The assembled GelPOINT Mini advanced access platform (Applied Medical) (FIGURE 2) is introduced through the vagina after the Alexis wound protector (included with the kit) is first placed through the colpotomy with assistance of Babcock clamps (FIGURE 3). 

After ensuring that the green rigid ring of the Alexis wound protector is contained and completely expanded within the peritoneal cavity, we cross our previously tagged sutures as we find this helps with preventing the GelPOINT Mini access platform from inadvertently shifting out of the peritoneal cavity during surgery. The GelSeal cap is then secured and pneumoperitoneum is established (FIGURE 4). 

Continue to: 4. Laparoendoscopic surgery...

Instruments used in our surgeries include a 10-mm rigid 30° 43-cm working length laparoscope; a 44-cm LigaSure device (Medtronic); a 5-mm, 37-cm laparoscopic cobra grasping forceps and fenestrated grasper (Karl Storz); and a 5-mm, 45-cm laparoscopic suction with hydrodissection tip (Stryker) (FIGURE 5). 

vNOTES allows a gynecologic surgeon the unique ability to survey the upper abdomen. The remainder of the surgery proceeds using basic laparoscopic single-site skills. 

During vNOTES, as with all single-site surgical procedures, understanding the optimal placement of crossed instruments is important for successful completion. For example, when securing the right uterine artery, the surgeon needs to push the cervix toward the patient's left and slightly into the peritoneal cavity using a laparoscopic cobra grasper with his or her left hand while then securing the uterine pedicle using the LigaSure device with his or her right hand. This is then reversed when securing the left uterine artery, where the assistant surgeon pushes the cervix toward the patient's right while the surgeon secures the pedicle ("vaginal pull, laparoscopic push") (FIGURE 6). 

This again is reiterated in securing the ovarian pedicles, which are pushed into the peritoneal cavity while being secured with the LigaSure device. 

5. Specimen removal 

For large uteri or specimens that need morcellation, a 15-mm Endo Catch specimen retrieval bag (Medtronic) is introduced through the GelPOINT Mini system. The specimen is then placed in the bag and delivered to the vagina, where contained bag morcellation is performed in standard fashion (FIGURES 7 AND 8). We utilized the "big C" technique by first grasping the specimen with a penetrating clamp. The clamp is then held in our nondominant hand and a No. 10 blade scalpel is used to create a reverse c-incision, keeping one surface of the specimen intact. This is continued until the specimen can be completely delivered through the vagina. 

Specimens that do not require morcellation can be grasped laparoscopically, brought to the GelPOINT Mini port, which is quickly disassembled, and delivered. The GelSeal cap is then reassembled. 

6. Vaginal cuff closure 

The colpotomy or vaginal cuff is closed with barbed suture continuously, as in traditional vaginal hysterectomy cuff closure. Uterosacral ligament suspension should be performed for vaginal cuff support.  
 

Through the years, the surgical approach to hysterectomy has expanded from its early beginnings of being performed only through an abdominal or transvaginal route with traditional surgical clamps and suture. The late 1980s saw the advent of the laparoscopic-assisted vaginal hysterectomy (LAVH), and from that point forward several additional hysterectomy methods evolved, including today’s robotic approaches.

Although clinical evidence and societal endorsements support vaginal hysterectomy as a superior high-value modality, it remains one of the least performed among all available routes.^1-3 In an analysis of inpatient hysterectomies published by Wright and colleagues in 2013, 16.7% of hysterectomies were performed vaginally, a number that essentially has remained steady throughout the ensuing years.⁴

Attempts to improve the application of vaginal hysterectomy have been made.⁵ These include the development of various curriculum and simulation-based medical education programs on vaginal surgical skills training and acquisition in the hopes of improving utilization.⁶ An interesting recent development is the rethinking of vaginal hysterectomy by several surgeons globally who are applying facets of the various hysterectomy methods to a transvaginal approach known as vaginal natural orifice transluminal endoscopic surgery (vNOTES).^7,8 Unique to this thinking is the incorporation of conventional laparoscopic instrumentation.

Although I have not yet incorporated this approach in my surgical armamentarium at Columbia University Medical Center/New York–Presbyterian Hospital, I am intrigued by the possibility that this technique may serve as a rescue for vaginal hysterectomies that are at risk of conversion or of not being performed at all.⁹

At this time, vNOTES is not a standard of care and should be performed only by highly specialized surgeons. However, in the spirit of this Update on minimally invasive surgery and to keep our readers abreast of burgeoning techniques, I am delighted to bring you this overview by Dr. Xiaoming Guan, one of the pioneers of this surgical approach, and Dr. Tamisa Koythong and Dr. Juan Liu. I hope you find this recent development in hysterectomy of interest.

—Arnold P. Advincula, MD

Continue to: Development and evolution of NOTES...

Development and evolution of NOTES 

Over the past few decades, emphasis has shifted from laparotomy to minimally invasive surgery because of its proven significant advantages in patient care, such as improved cosmesis, shorter hospital stay, shorter postoperative recovery, and decreased postoperative pain and blood loss.¹⁰  Advances in laparoendoscopic surgery and instrumentation, including robot-assisted laparoscopy (RAL), single-incision laparoscopic surgery (SILS), and most recently natural orifice transluminal endoscopic surgery (NOTES), reflect ongoing innovative developments in the field of minimally invasive surgery. 

Here, we provide a brief literature review of the NOTES technique, focus on its application in gynecologic surgery, and describe how we perform NOTES at our institution. 

NOTES application in gynecology 

With NOTES, peritoneal access is gained through a natural orifice (such as the mouth, vagina, urethra, or anus) to perform endoscopic surgery, occasionally without requiring an abdominal incision. First described in 2004, transgastric peritoneoscopy was performed in a porcine model, and shortly thereafter the first transgastric appendectomy was performed in humans.^11,12 The technique has further been adopted in cholecystectomy, appendectomy, gastrectomy, and nephrectomy procedures.¹³ 

Given rapid interest in a possible paradigm shift in the field of minimally invasive surgery, the Natural Orifice Surgery Consortiumfor Assessment and Research (NOSCAR) was formed, and the group published an article on potential barriers to accepted practice and adoption of NOTES as a realistic alternative to traditional laparoscopic surgery.¹⁴ 

While transgastric and transanal access to the peritoneum were initially more popular, the risk of anastomotic leaks associated with incomplete closure and subsequent infection were thought to be prohibitively high.¹⁵ Transvaginal access was considered a safer and simpler alternative, allowing for complete closure without increased risk of infection, and this is now the route through which the majority of NOTES procedures are completed.^16,17 

The eventual application of NOTES in the field of gynecology seemed inevitable. The American College of Obstetricians and Gynecologists stated that transvaginal surgery is the most minimally invasive and preferred surgical route in the management of patients with benign gynecologic diseases.¹⁸ However, performing it can be challenging at times due to limited visualization and lack of the required skills for single-site surgery. NOTES allows a gynecologic surgeon to improve visualization through the use of laparoendoscopic instruments and to complete surgery through a transvaginal route. 

In 2012, Ahn and colleagues demonstrated the feasibility of the NOTES technique in gynecologic surgery after using it to successfully complete benign adnexal surgery in 10 patients.¹⁹ Vaginal NOTES (vNOTES) has since been further developed to include successful hysterectomy, myomectomy, sacrocolpopexy, tubal anastomosis, and even lymphadenectomy in the treatment of early- stage endometrial carcinoma.^20-26 vNOTES also can be considered a rescue approach for traditional vaginal hysterectomy in instances in which it is necessary to evaluate adnexal pathology.⁹ Most recently, vNOTES hysterectomy has been reported with da Vinci Si or Xi robotic platforms.^27,28 

Continue to: Operative time, post-op stay shorter in NAOC-treated patients...

Few studies have compared outcomes with vNOTES to those with traditional laparoscopy. In 2016, Wang and colleagues compared surgical outcomes between NOTES-assisted ovarian cystectomy (NAOC) and laparoscopic ovarian cystectomy (LOC) in a case-matched study that included 277 patients.²⁹ Although mean (SD) blood loss in patients who underwent LOC was significantly less compared with those who underwent NAOC (21.4 [14.7] mL vs 31.6 [24.1] mL; P = .028), absolute blood loss in both groups was deemed minimal. Additionally, mean (SD) operative time and postoperative stay were significantly less in patients undergoing NAOC compared with those having LOC (38.23 [10.19] minutes vs 53.82 [18.61] minutes; P≤.001; and 1.38 [0.55] days vs 1.82 [0.52] days; P≤.001; respectively).²⁹ 

How vNOTES hysterectomy stacked up against TLH 

In 2018, Baekelandt and colleagues compared outcomes between vNOTES hysterectomy and total laparoscopic hysterectomy (TLH) in a noninferiority single-blinded trial of 70 women.⁸ Compared with TLH, vNOTES hysterectomy was associated with shorter operative time (41 vs 75 minutes; P<.001), shorter hospital stay (0.8 vs 1.3 days; P = .004), and lower postoperative analgesic requirement (8 vs 14 U; P = .006). Additionally, there were no differences between the 2 groups in postoperative infection rate, intraoperative complications, or hospital readmissions within 6 weeks.⁸

Approach for performing vNOTES procedures 

At our institution, Baylor College of Medicine, the majority of gynecologic surgeries are performed via either transumbilical robot-assisted single-incision laparoscopy or vNOTES. Preoperative selection of appropriate candidates for vNOTES includes: 

• low suspicion for or prior diagnosis of endometriosis with obliteration of the posterior cul-de-sac 
• no surgical history suggestive of severe adhesive disease, and 
• adequate vaginal sidewall access and sufficient descent for instrumentation for entry into the peritoneal cavity. 

In general, a key concept in vNOTES is "vaginal pull, laparoscopic push," which means that the surgeon must pull the cervix while performing vaginal entry and then push the uterus back in the peritoneal cavity to increase surgical space during laparoscopic surgery. 

Continue to: Overview of vNOTES steps...

Below we break down a description of vNOTES in 6 sections. Our patients are always placed in dorsal lithotomy position with TrenGuard (D.A. Surgical) Trendelenburg restraint. We prep the abdomen in case we need to convert to transabdominal surgery via transumbilical single-incision laparoscopic surgery or traditional laparoscopic surgery. 

1. Vaginal entry 

Accessing the peritoneal cavity through the vagina initially proceeds like a vaginal hysterectomy. We inject dilute vasopressin (20 U in 20 mL of normal saline) circumferentially in the cervix (for hysterectomy) or in the posterior cervix in the cervicovaginal junction (for adnexal surgery without hysterectomy) for vasoconstriction and hydrodissection. 

We then incise the vaginal mucosa circumferentially with electrosurgical cautery and follow with posterior colpotomy. We find that reapproximating the posterior peritoneum to the posterior vagina with either figure-of-8 stitches or a running stitch of polyglactin 910 suture (2-0 Vicryl) assists in port placement, bleeding at the peritoneal edge, and closure of the cuff or colpotomy at the end of the case. We tag this suture with a curved hemostat. 

Depending on whether a hysterectomy is being performed, anterior colpotomy is made. Again, the anterior peritoneum is then tagged to the anterior vaginal cuff in similar fashion, and this suture is tagged with a different instrument; we typically use a straight hemostat or Sarot clamp (FIGURE 1). 

2. Traditional vaginal hysterectomy 

After colpotomy, we prefer to perform progressive clamping of the broad ligament from the uterosacral and cardinal ligaments to the level of uterine artery as in traditional vaginal hysterectomy, if feasible. 

3. Single-site port placement 

The assembled GelPOINT Mini advanced access platform (Applied Medical) (FIGURE 2) is introduced through the vagina after the Alexis wound protector (included with the kit) is first placed through the colpotomy with assistance of Babcock clamps (FIGURE 3). 

After ensuring that the green rigid ring of the Alexis wound protector is contained and completely expanded within the peritoneal cavity, we cross our previously tagged sutures as we find this helps with preventing the GelPOINT Mini access platform from inadvertently shifting out of the peritoneal cavity during surgery. The GelSeal cap is then secured and pneumoperitoneum is established (FIGURE 4). 

Continue to: 4. Laparoendoscopic surgery...

Instruments used in our surgeries include a 10-mm rigid 30° 43-cm working length laparoscope; a 44-cm LigaSure device (Medtronic); a 5-mm, 37-cm laparoscopic cobra grasping forceps and fenestrated grasper (Karl Storz); and a 5-mm, 45-cm laparoscopic suction with hydrodissection tip (Stryker) (FIGURE 5). 

vNOTES allows a gynecologic surgeon the unique ability to survey the upper abdomen. The remainder of the surgery proceeds using basic laparoscopic single-site skills. 

During vNOTES, as with all single-site surgical procedures, understanding the optimal placement of crossed instruments is important for successful completion. For example, when securing the right uterine artery, the surgeon needs to push the cervix toward the patient's left and slightly into the peritoneal cavity using a laparoscopic cobra grasper with his or her left hand while then securing the uterine pedicle using the LigaSure device with his or her right hand. This is then reversed when securing the left uterine artery, where the assistant surgeon pushes the cervix toward the patient's right while the surgeon secures the pedicle ("vaginal pull, laparoscopic push") (FIGURE 6). 

This again is reiterated in securing the ovarian pedicles, which are pushed into the peritoneal cavity while being secured with the LigaSure device. 

5. Specimen removal 

For large uteri or specimens that need morcellation, a 15-mm Endo Catch specimen retrieval bag (Medtronic) is introduced through the GelPOINT Mini system. The specimen is then placed in the bag and delivered to the vagina, where contained bag morcellation is performed in standard fashion (FIGURES 7 AND 8). We utilized the "big C" technique by first grasping the specimen with a penetrating clamp. The clamp is then held in our nondominant hand and a No. 10 blade scalpel is used to create a reverse c-incision, keeping one surface of the specimen intact. This is continued until the specimen can be completely delivered through the vagina. 

Specimens that do not require morcellation can be grasped laparoscopically, brought to the GelPOINT Mini port, which is quickly disassembled, and delivered. The GelSeal cap is then reassembled. 

6. Vaginal cuff closure 

The colpotomy or vaginal cuff is closed with barbed suture continuously, as in traditional vaginal hysterectomy cuff closure. Uterosacral ligament suspension should be performed for vaginal cuff support.  
 

The rapid development and identification of novel drugs has translated into innovative therapies in hematology and oncology. The aim of this piece is to present newly approved drugs and expanded indications to serve as a reference guide for practicing clinicians.

This article reviews therapies that were newly approved so far in 2019, as well as those previously approved whose indications were expanded this past year. The list highlights the most clinically important approvals, as well as adverse events that are unique or especially severe.
 

New approvals

Fedratinib (Inrebic)

Class: JAK2 and FLT3 selective kinase inhibitor.

Disease: Intermediate or high-risk primary or secondary (postpolycythemia vera or postessential thrombocythemia) myelofibrosis.

Dose: 400 mg orally once daily, with or without food.

Adverse events (AEs): Black box warning: Fatal encephalopathy, including Wernicke’s (thiamine level monitoring suggested).

Trials: In JAKARTA (NCT01437787), 37% of patients achieved a 35% or greater reduction in spleen volume and 40% received a 50% or greater reduction in myelofibrosis-related symptoms. In Jakarta-2, there was a 55% spleen response in patients resistant or intolerant to ruxolitinib.

Entrectinib (Rozlytrek)

Class: Tropomyosin receptor tyrosine kinase inhibitor.

Disease: Solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and for ROS-1 positive non–small cell lung cancer (NSCLC).

Dose: 600 mg orally once daily.

AEs: Heart failure, QT prolongation, skeletal fractures, hepatotoxicity, central nervous system effects, and hyperuricemia.

Trial: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267): Overall response rate of 57% for NTRK positive patients; response rate of 77% in ROS-1 positive NSCLC.

Pexidartinib (Turalio)

Class: Small molecule tyrosine kinase inhibitor targeting CSF1R.

Disease: Symptomatic tenosynovial giant cell tumor.

Dose: 400 mg orally twice daily without food.

AEs: Black box warning on hepatotoxicity.

Trial: ENLIVEN (NCT02371369): Overall response rate of 38% at 25 weeks, with a 15% complete response rate and a 23% partial response rate.

Darolutamide (Nubeqa)

Class: Androgen receptor inhibitor.

Disease: Nonmetastatic castration-resistant prostate cancer.

Dose: 600 mg orally twice daily with food with concomitant androgen deprivation therapy.

AEs: Fatigue, extremity pain, and rash.

Trial: ARAMIS (NCT02200614): Median metastasis free survival was 40.4 months for patients with darolutamide, compared with 18.4 months for controls.

Selinexor (Xpovio)

Class: Reversible inhibitor of nuclear export of tumor suppressor proteins, growth regulators, and mRNAs of oncogenic proteins.

Disease: Relapsed or refractory multiple myeloma. Indicated for patients who have received at least four prior therapies, including at least two immunomodulatory agents and an anti-CD38 monoclonal antibody.

Dose: 80 mg orally in combination with oral dexamethasone on days 1 and 3 of each week.

AEs: Thrombocytopenia, fatigue, pancytopenia, and hyponatremia.

Trial: STORM (NCT02336815): Overall response rate 25.3% with a median time to first response of 4 weeks and 3.8-month median duration of response.

Polatuzumab vedotin-piiq (Polivy)

Class: CD79b-directed antibody-drug conjugate.

Disease: Relapsed or refractory diffuse large B-cell lymphoma. Indicated for patients who have had at least two prior therapies.

Dose: 1.8 mg/kg intravenous infusion every 21 days for six cycles in combination with bendamustine and a rituximab product.

AEs: Pancytopenia, peripheral neuropathy.

Trial: GO29365 (NCT02257567): Complete response rate was 40% for polatuzumab vedotin-piiq plus bendamustine/rituximab, compared with 18% with bendamustine/rituximab alone.*

Caplacizumab-yhdp (Cablivi)

Class: Monoclonal antibody fragment directed against von Willebrand factor.

Disease: Thrombotic thrombocytopenic purpura.

Dose: 11 mg IV initially, then daily subcutaneously; in combination with plasma exchange and immunosuppressive therapy.

AEs: Epistaxis, headache, and gingival bleeding.

Trial: Hercules trial (NCT02553317): More rapid normalization of platelets, lower incidence of composite TTP-related death, and lower rate of recurrence when added to plasma exchange and steroids.
 

Alpelisib (Piqray)

Class: Phosphatidylinositol-3-kinase (PI3K) inhibitor.

Disease: Hormone receptor positive HER2-negative PIK3CA-mutated, advanced or metastatic breast cancer.

Dose: 300 mg orally once daily with food with concomitant fulvestrant.

AEs: Hyperglycemia, pancytopenia.

Trial: SOLAR-1 (NCT02437318): 11-month progression-free survival among patients treated with alpelisib and fulvestrant, compared with 5.7 months in fulvestrant alone control arm; overall response rate of 36% versus 16%, respectively.

Erdafitinib (Balversa)

Class: Fibroblast growth factor receptor kinase inhibitor.

Disease: Locally advanced or metastatic urothelial carcinoma with FGFR3 or FGFR2 mutations.

Dose: 8 mg orally once daily, with or without food.

AEs: Ocular disorders including retinopathy or retinal detachment.

Trial: BLC2001 (NCT02365597): Objective response rate of 32.2%, with a complete response in 2.3% of patients and partial response in 29.9% of patients.

Biosimilar approvals

Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta)

Biosimilar to: Trastuzumab.

Indication: HER2-overexpressing breast cancer.
 

Dr. Bryer is a resident in the department of internal medicine at the University of Pennsylvania, Philadelphia. Dr. Mintzer is chief of hematology-oncology at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania. Dr. Henry is a hematologist-oncologist at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania.

*Correction, 11/7/2019: An earlier version of this article misstated the drug combination in the GO29365 trial. 

The rapid development and identification of novel drugs has translated into innovative therapies in hematology and oncology. The aim of this piece is to present newly approved drugs and expanded indications to serve as a reference guide for practicing clinicians.

This article reviews therapies that were newly approved so far in 2019, as well as those previously approved whose indications were expanded this past year. The list highlights the most clinically important approvals, as well as adverse events that are unique or especially severe.
 

New approvals

Fedratinib (Inrebic)

Class: JAK2 and FLT3 selective kinase inhibitor.

Disease: Intermediate or high-risk primary or secondary (postpolycythemia vera or postessential thrombocythemia) myelofibrosis.

Dose: 400 mg orally once daily, with or without food.

Adverse events (AEs): Black box warning: Fatal encephalopathy, including Wernicke’s (thiamine level monitoring suggested).

Trials: In JAKARTA (NCT01437787), 37% of patients achieved a 35% or greater reduction in spleen volume and 40% received a 50% or greater reduction in myelofibrosis-related symptoms. In Jakarta-2, there was a 55% spleen response in patients resistant or intolerant to ruxolitinib.

Entrectinib (Rozlytrek)

Class: Tropomyosin receptor tyrosine kinase inhibitor.

Disease: Solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and for ROS-1 positive non–small cell lung cancer (NSCLC).

Dose: 600 mg orally once daily.

AEs: Heart failure, QT prolongation, skeletal fractures, hepatotoxicity, central nervous system effects, and hyperuricemia.

Trial: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267): Overall response rate of 57% for NTRK positive patients; response rate of 77% in ROS-1 positive NSCLC.

Pexidartinib (Turalio)

Class: Small molecule tyrosine kinase inhibitor targeting CSF1R.

Disease: Symptomatic tenosynovial giant cell tumor.

Dose: 400 mg orally twice daily without food.

AEs: Black box warning on hepatotoxicity.

Trial: ENLIVEN (NCT02371369): Overall response rate of 38% at 25 weeks, with a 15% complete response rate and a 23% partial response rate.

Darolutamide (Nubeqa)

Class: Androgen receptor inhibitor.

Disease: Nonmetastatic castration-resistant prostate cancer.

Dose: 600 mg orally twice daily with food with concomitant androgen deprivation therapy.

AEs: Fatigue, extremity pain, and rash.

Trial: ARAMIS (NCT02200614): Median metastasis free survival was 40.4 months for patients with darolutamide, compared with 18.4 months for controls.

Selinexor (Xpovio)

Class: Reversible inhibitor of nuclear export of tumor suppressor proteins, growth regulators, and mRNAs of oncogenic proteins.

Disease: Relapsed or refractory multiple myeloma. Indicated for patients who have received at least four prior therapies, including at least two immunomodulatory agents and an anti-CD38 monoclonal antibody.

Dose: 80 mg orally in combination with oral dexamethasone on days 1 and 3 of each week.

AEs: Thrombocytopenia, fatigue, pancytopenia, and hyponatremia.

Trial: STORM (NCT02336815): Overall response rate 25.3% with a median time to first response of 4 weeks and 3.8-month median duration of response.

Polatuzumab vedotin-piiq (Polivy)

Class: CD79b-directed antibody-drug conjugate.

Disease: Relapsed or refractory diffuse large B-cell lymphoma. Indicated for patients who have had at least two prior therapies.

Dose: 1.8 mg/kg intravenous infusion every 21 days for six cycles in combination with bendamustine and a rituximab product.

AEs: Pancytopenia, peripheral neuropathy.

Trial: GO29365 (NCT02257567): Complete response rate was 40% for polatuzumab vedotin-piiq plus bendamustine/rituximab, compared with 18% with bendamustine/rituximab alone.*

Caplacizumab-yhdp (Cablivi)

Class: Monoclonal antibody fragment directed against von Willebrand factor.

Disease: Thrombotic thrombocytopenic purpura.

Dose: 11 mg IV initially, then daily subcutaneously; in combination with plasma exchange and immunosuppressive therapy.

AEs: Epistaxis, headache, and gingival bleeding.

Trial: Hercules trial (NCT02553317): More rapid normalization of platelets, lower incidence of composite TTP-related death, and lower rate of recurrence when added to plasma exchange and steroids.
 

Alpelisib (Piqray)

Class: Phosphatidylinositol-3-kinase (PI3K) inhibitor.

Disease: Hormone receptor positive HER2-negative PIK3CA-mutated, advanced or metastatic breast cancer.

Dose: 300 mg orally once daily with food with concomitant fulvestrant.

AEs: Hyperglycemia, pancytopenia.

Trial: SOLAR-1 (NCT02437318): 11-month progression-free survival among patients treated with alpelisib and fulvestrant, compared with 5.7 months in fulvestrant alone control arm; overall response rate of 36% versus 16%, respectively.

Erdafitinib (Balversa)

Class: Fibroblast growth factor receptor kinase inhibitor.

Disease: Locally advanced or metastatic urothelial carcinoma with FGFR3 or FGFR2 mutations.

Dose: 8 mg orally once daily, with or without food.

AEs: Ocular disorders including retinopathy or retinal detachment.

Trial: BLC2001 (NCT02365597): Objective response rate of 32.2%, with a complete response in 2.3% of patients and partial response in 29.9% of patients.

Biosimilar approvals

Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta)

Biosimilar to: Trastuzumab.

Indication: HER2-overexpressing breast cancer.
 

Dr. Bryer is a resident in the department of internal medicine at the University of Pennsylvania, Philadelphia. Dr. Mintzer is chief of hematology-oncology at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania. Dr. Henry is a hematologist-oncologist at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania.

*Correction, 11/7/2019: An earlier version of this article misstated the drug combination in the GO29365 trial. 

The rapid development and identification of novel drugs has translated into innovative therapies in hematology and oncology. The aim of this piece is to present newly approved drugs and expanded indications to serve as a reference guide for practicing clinicians.

This article reviews therapies that were newly approved so far in 2019, as well as those previously approved whose indications were expanded this past year. The list highlights the most clinically important approvals, as well as adverse events that are unique or especially severe.
 

New approvals

Fedratinib (Inrebic)

Class: JAK2 and FLT3 selective kinase inhibitor.

Disease: Intermediate or high-risk primary or secondary (postpolycythemia vera or postessential thrombocythemia) myelofibrosis.

Dose: 400 mg orally once daily, with or without food.

Adverse events (AEs): Black box warning: Fatal encephalopathy, including Wernicke’s (thiamine level monitoring suggested).

Trials: In JAKARTA (NCT01437787), 37% of patients achieved a 35% or greater reduction in spleen volume and 40% received a 50% or greater reduction in myelofibrosis-related symptoms. In Jakarta-2, there was a 55% spleen response in patients resistant or intolerant to ruxolitinib.

Entrectinib (Rozlytrek)

Class: Tropomyosin receptor tyrosine kinase inhibitor.

Disease: Solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and for ROS-1 positive non–small cell lung cancer (NSCLC).

Dose: 600 mg orally once daily.

AEs: Heart failure, QT prolongation, skeletal fractures, hepatotoxicity, central nervous system effects, and hyperuricemia.

Trial: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267): Overall response rate of 57% for NTRK positive patients; response rate of 77% in ROS-1 positive NSCLC.

Pexidartinib (Turalio)

Class: Small molecule tyrosine kinase inhibitor targeting CSF1R.

Disease: Symptomatic tenosynovial giant cell tumor.

Dose: 400 mg orally twice daily without food.

AEs: Black box warning on hepatotoxicity.

Trial: ENLIVEN (NCT02371369): Overall response rate of 38% at 25 weeks, with a 15% complete response rate and a 23% partial response rate.

Darolutamide (Nubeqa)

Class: Androgen receptor inhibitor.

Disease: Nonmetastatic castration-resistant prostate cancer.

Dose: 600 mg orally twice daily with food with concomitant androgen deprivation therapy.

AEs: Fatigue, extremity pain, and rash.

Trial: ARAMIS (NCT02200614): Median metastasis free survival was 40.4 months for patients with darolutamide, compared with 18.4 months for controls.

Selinexor (Xpovio)

Class: Reversible inhibitor of nuclear export of tumor suppressor proteins, growth regulators, and mRNAs of oncogenic proteins.

Disease: Relapsed or refractory multiple myeloma. Indicated for patients who have received at least four prior therapies, including at least two immunomodulatory agents and an anti-CD38 monoclonal antibody.

Dose: 80 mg orally in combination with oral dexamethasone on days 1 and 3 of each week.

AEs: Thrombocytopenia, fatigue, pancytopenia, and hyponatremia.

Trial: STORM (NCT02336815): Overall response rate 25.3% with a median time to first response of 4 weeks and 3.8-month median duration of response.

Polatuzumab vedotin-piiq (Polivy)

Class: CD79b-directed antibody-drug conjugate.

Disease: Relapsed or refractory diffuse large B-cell lymphoma. Indicated for patients who have had at least two prior therapies.

Dose: 1.8 mg/kg intravenous infusion every 21 days for six cycles in combination with bendamustine and a rituximab product.

AEs: Pancytopenia, peripheral neuropathy.

Trial: GO29365 (NCT02257567): Complete response rate was 40% for polatuzumab vedotin-piiq plus bendamustine/rituximab, compared with 18% with bendamustine/rituximab alone.*

Caplacizumab-yhdp (Cablivi)

Class: Monoclonal antibody fragment directed against von Willebrand factor.

Disease: Thrombotic thrombocytopenic purpura.

Dose: 11 mg IV initially, then daily subcutaneously; in combination with plasma exchange and immunosuppressive therapy.

AEs: Epistaxis, headache, and gingival bleeding.

Trial: Hercules trial (NCT02553317): More rapid normalization of platelets, lower incidence of composite TTP-related death, and lower rate of recurrence when added to plasma exchange and steroids.
 

Alpelisib (Piqray)

Class: Phosphatidylinositol-3-kinase (PI3K) inhibitor.

Disease: Hormone receptor positive HER2-negative PIK3CA-mutated, advanced or metastatic breast cancer.

Dose: 300 mg orally once daily with food with concomitant fulvestrant.

AEs: Hyperglycemia, pancytopenia.

Trial: SOLAR-1 (NCT02437318): 11-month progression-free survival among patients treated with alpelisib and fulvestrant, compared with 5.7 months in fulvestrant alone control arm; overall response rate of 36% versus 16%, respectively.

Erdafitinib (Balversa)

Class: Fibroblast growth factor receptor kinase inhibitor.

Disease: Locally advanced or metastatic urothelial carcinoma with FGFR3 or FGFR2 mutations.

Dose: 8 mg orally once daily, with or without food.

AEs: Ocular disorders including retinopathy or retinal detachment.

Trial: BLC2001 (NCT02365597): Objective response rate of 32.2%, with a complete response in 2.3% of patients and partial response in 29.9% of patients.

Biosimilar approvals

Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta)

Biosimilar to: Trastuzumab.

Indication: HER2-overexpressing breast cancer.
 

Dr. Bryer is a resident in the department of internal medicine at the University of Pennsylvania, Philadelphia. Dr. Mintzer is chief of hematology-oncology at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania. Dr. Henry is a hematologist-oncologist at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania.

*Correction, 11/7/2019: An earlier version of this article misstated the drug combination in the GO29365 trial. 

Patients whose clear cell renal cell carcinoma (RCC) tumors lack the cytoskeleton linker protein ezrin have a poorer prognosis, finds a single-center retrospective cohort study.

The number of small renal masses discovered incidentally is rising, and some of these tumors can or must be treated less aggressively, according to lead investigator Marcos Vinicius O. Ferrari, MD, urology division, A.C. Camargo Cancer Center, São Paulo, and coinvestigators. “Thus, it is important to identify molecular markers that have prognostic value that can assist physicians in therapeutic strategies.”

The investigators studied 575 consecutive patients who underwent radical or partial nephrectomy for clear cell RCC during 1985-2016. A single pathologist reclassified all cases and determined the most representative tumor areas for tissue immunohistochemistry for ezrin and moesin, proteins that link the actin cytoskeleton to the cell membrane and that play roles in cell adhesion, migration, and growth.

Results reported in Urologic Oncology showed that 18.3% of tumors were negative for ezrin and 2.8% were negative for moesin.

Compared with counterparts who had ezrin-positive tumors, patients with ezrin-negative tumors had higher pathologic T stage (P less than .001); were less likely to have incidentally discovered tumors (P = .007); and were more likely to have clinical stage III or IV disease (P = .012), synchronous metastasis (P less than .001), and an International Society of Urological Pathology histologic grade of 3 or 4 (P = .025).

Similarly, compared with counterparts who had moesin-positive tumors, patients with moesin-negative tumors had higher pathologic T stage (P = .025) and pathologic N stage (P = .007), and were more likely to have clinical stage III or IV disease (P = .027).

The 10-year rate of disease-specific survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (70% vs. 88%; P less than .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 86%; P = .065). Similarly, the 10-year rate of overall survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (68% vs. 86%; P = .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 84%; P = .142).

In multivariate analyses, ezrin negativity was associated with a near doubling of the risk of disease-specific survival events (hazard ratio, 1.89; 95% confidence interval, 1.11-3.20) and with a trend toward poorer overall survival. Moesin negativity was not independently associated with either outcome.

“Negative expression of ezrin was associated with major prognostic factors in renal cancer and significantly influenced tumor-related death,” Dr. Ferrari and coinvestigators summarize, noting that this aligns with the pattern seen in bladder and ovarian cancers, but contrasts with the pattern seen in head and neck, colorectal, cervical, and breast cancers.

“The exact mechanism by which negative ezrin expression influences tumor progression and survival rates is unknown,” they conclude. “We encourage further prospective studies to analyze ezrin to determine its value in the prognosis of clear cell RCC.”

Dr. Ferrari disclosed that he had no relevant conflicts of interest. The study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

SOURCE: Ferrari MVO et al. Urol Oncol. 2019 Oct 22. doi: 10.1016/j.urolonc.2019.09.011.
 

Patients whose clear cell renal cell carcinoma (RCC) tumors lack the cytoskeleton linker protein ezrin have a poorer prognosis, finds a single-center retrospective cohort study.

The number of small renal masses discovered incidentally is rising, and some of these tumors can or must be treated less aggressively, according to lead investigator Marcos Vinicius O. Ferrari, MD, urology division, A.C. Camargo Cancer Center, São Paulo, and coinvestigators. “Thus, it is important to identify molecular markers that have prognostic value that can assist physicians in therapeutic strategies.”

The investigators studied 575 consecutive patients who underwent radical or partial nephrectomy for clear cell RCC during 1985-2016. A single pathologist reclassified all cases and determined the most representative tumor areas for tissue immunohistochemistry for ezrin and moesin, proteins that link the actin cytoskeleton to the cell membrane and that play roles in cell adhesion, migration, and growth.

Results reported in Urologic Oncology showed that 18.3% of tumors were negative for ezrin and 2.8% were negative for moesin.

Compared with counterparts who had ezrin-positive tumors, patients with ezrin-negative tumors had higher pathologic T stage (P less than .001); were less likely to have incidentally discovered tumors (P = .007); and were more likely to have clinical stage III or IV disease (P = .012), synchronous metastasis (P less than .001), and an International Society of Urological Pathology histologic grade of 3 or 4 (P = .025).

Similarly, compared with counterparts who had moesin-positive tumors, patients with moesin-negative tumors had higher pathologic T stage (P = .025) and pathologic N stage (P = .007), and were more likely to have clinical stage III or IV disease (P = .027).

The 10-year rate of disease-specific survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (70% vs. 88%; P less than .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 86%; P = .065). Similarly, the 10-year rate of overall survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (68% vs. 86%; P = .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 84%; P = .142).

In multivariate analyses, ezrin negativity was associated with a near doubling of the risk of disease-specific survival events (hazard ratio, 1.89; 95% confidence interval, 1.11-3.20) and with a trend toward poorer overall survival. Moesin negativity was not independently associated with either outcome.

“Negative expression of ezrin was associated with major prognostic factors in renal cancer and significantly influenced tumor-related death,” Dr. Ferrari and coinvestigators summarize, noting that this aligns with the pattern seen in bladder and ovarian cancers, but contrasts with the pattern seen in head and neck, colorectal, cervical, and breast cancers.

“The exact mechanism by which negative ezrin expression influences tumor progression and survival rates is unknown,” they conclude. “We encourage further prospective studies to analyze ezrin to determine its value in the prognosis of clear cell RCC.”

Dr. Ferrari disclosed that he had no relevant conflicts of interest. The study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

SOURCE: Ferrari MVO et al. Urol Oncol. 2019 Oct 22. doi: 10.1016/j.urolonc.2019.09.011.
 

Patients whose clear cell renal cell carcinoma (RCC) tumors lack the cytoskeleton linker protein ezrin have a poorer prognosis, finds a single-center retrospective cohort study.

The number of small renal masses discovered incidentally is rising, and some of these tumors can or must be treated less aggressively, according to lead investigator Marcos Vinicius O. Ferrari, MD, urology division, A.C. Camargo Cancer Center, São Paulo, and coinvestigators. “Thus, it is important to identify molecular markers that have prognostic value that can assist physicians in therapeutic strategies.”

The investigators studied 575 consecutive patients who underwent radical or partial nephrectomy for clear cell RCC during 1985-2016. A single pathologist reclassified all cases and determined the most representative tumor areas for tissue immunohistochemistry for ezrin and moesin, proteins that link the actin cytoskeleton to the cell membrane and that play roles in cell adhesion, migration, and growth.

Results reported in Urologic Oncology showed that 18.3% of tumors were negative for ezrin and 2.8% were negative for moesin.

Compared with counterparts who had ezrin-positive tumors, patients with ezrin-negative tumors had higher pathologic T stage (P less than .001); were less likely to have incidentally discovered tumors (P = .007); and were more likely to have clinical stage III or IV disease (P = .012), synchronous metastasis (P less than .001), and an International Society of Urological Pathology histologic grade of 3 or 4 (P = .025).

Similarly, compared with counterparts who had moesin-positive tumors, patients with moesin-negative tumors had higher pathologic T stage (P = .025) and pathologic N stage (P = .007), and were more likely to have clinical stage III or IV disease (P = .027).

The 10-year rate of disease-specific survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (70% vs. 88%; P less than .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 86%; P = .065). Similarly, the 10-year rate of overall survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (68% vs. 86%; P = .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 84%; P = .142).

In multivariate analyses, ezrin negativity was associated with a near doubling of the risk of disease-specific survival events (hazard ratio, 1.89; 95% confidence interval, 1.11-3.20) and with a trend toward poorer overall survival. Moesin negativity was not independently associated with either outcome.

“Negative expression of ezrin was associated with major prognostic factors in renal cancer and significantly influenced tumor-related death,” Dr. Ferrari and coinvestigators summarize, noting that this aligns with the pattern seen in bladder and ovarian cancers, but contrasts with the pattern seen in head and neck, colorectal, cervical, and breast cancers.

“The exact mechanism by which negative ezrin expression influences tumor progression and survival rates is unknown,” they conclude. “We encourage further prospective studies to analyze ezrin to determine its value in the prognosis of clear cell RCC.”

Dr. Ferrari disclosed that he had no relevant conflicts of interest. The study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

SOURCE: Ferrari MVO et al. Urol Oncol. 2019 Oct 22. doi: 10.1016/j.urolonc.2019.09.011.
 

Although most neonatal vascular lumps, bumps, and tumors are benign, proper diagnosis is important for prognosis and management. Therefore, knowledge of both common and rare conditions is important when evaluating a neonatal nodule. Differential diagnosis of neonatal vascular nodules must focus on important diagnostic clues that should prompt consideration and evaluation for less common and/or potentially threatening conditions. Infantile hemangioma (IH), congenital hemangioma (CH), venous malformation (VM), lymphatic malformation (LM), kaposiform hemangioendothelioma (KHE) and tufted angioma, and malignant tumors are reviewed here.

Infantile Hemangioma

Infantile hemangioma, a benign proliferation of capillaries, is the most common tumor of infancy with reported incidence of up to 5% in neonates.¹ As such, suspicion for less common lesions is often predicated on identifying features that would be atypical for an IH. A superficial IH presents as a bright red papule, nodule, or plaque, while a deep IH presents as a flesh-colored to bluish nodule. Mixed IHs combine features of both superficial and deep lesions. The distribution may be focal or segmental, with segmental lesions encompassing a larger territory–like distribution and frequently displaying a thin, coarsely telangiectatic appearance.

Knowledge of the natural history of IH generally is crucial in differentiating it from other neonatal lesions. Infantile hemangiomas display a natural history that is distinct and predictable. They typically manifest within the first few weeks of life, though up to 30% present at birth with a premonitory mark, which may be a light red, pink, bluish, or vasoconstricted patch. Thus, mere presence of a lesion at birth is not the feature that distinguishes other congenital lesions from an IH. After initial appearance, IHs undergo a period of proliferation that occurs over 4 to 6 months in most patients. In some cases, areas of proliferation may be subtle, but nonetheless the presence of some areas of increased redness and/or volumetric growth generally is required to firmly establish the diagnosis of IH. Thereafter, IH will involute, a process that begins before 1 year of age in most cases and continues over years. Although IHs undergo involution, complete clearance may not occur, as nearly 70% will leave permanent residua such as fibrofatty masses or anetodermic skin.² Nevertheless, the presence of a proliferative phase followed by a slower period of involution is a hallmark feature of the IH.

Biopsy and imaging rarely are required for establishing diagnosis of an IH. Histopathology showing a proliferation of capillaries with positive glucose transporter 1 (GLUT-1) staining is characteristic. Imaging with ultrasound reveals a fast-flow lesion. Apart from exceptionally rare cases, a cutaneous IH typically does not cross muscle fascia, and thus alternative diagnoses should be considered for a cutaneous lesion that demonstrates infiltration into nerve, bone, joint, or other deeper tissues. Most IHs do not require treatment; however, a small subset may be associated with complications and thus require intervention. Complications of IH may include impairment of function (eg, vision, feeding, respiratory), ulceration, and risk for permanent disfigurement. When treatment is indicated, the most commonly employed options during the proliferative phase are the topical beta-blocker timolol and the oral beta-blocker propranolol. In addition, certain IHs may be associated with either syndromic presentations and/or visceral involvement, thus requiring further workup (Table).

Congenital Hemangioma

A CH is an uncommon benign neonatal tumor that is distinct from an IH in behavior, biology, and treatment. Congenital hemangiomas may have a rapidly involuting course, referred to as RICH (rapidly involuting congenital hemangioma), or a noninvoluting course, referred to as NICH (noninvoluting congenital hemangioma). Partially involuting types also have been described.³ A RICH typically presents as a highly vascular, red-violaceous or bluish plaque, nodule, or large mass at birth. An NICH presents as a red-violaceous or bluish, coarsely telangiectatic patch, plaque, or nodule. A characteristic feature of the CH is the rim of vasoconstriction around the lesion, which is an important diagnostic clue (Figure 1). In contrast to IH, multifocal lesions are highly unlikely in CH, though it rarely has been reported.⁴

Regardless of subtype, CHs are fully developed at birth. Infantile hemangiomas, on the other hand, are either minimally present or not present at birth and thereafter proliferate. After birth, a RICH rapidly involutes over the first 9 to 12 months of life. This process generally is evident even in the first few weeks of life, which would not be expected of an IH and is therefore a major distinguishing factor. A NICH, on the other hand, is expected to be persistent, for the most part neither showing signs of proliferation nor involution.

Complications of CHs may include ulceration, functional impairment, or risk for permanent disfigurement depending on location. In addition, due to their fast-flow state and potential large size, some CHs may be complicated by high-output heart failure in the neonate. Distinguishing an IH from a CH is important not only for prognosis but also treatment. Beta-blocker therapy generally is not useful for CHs, and management usually is supportive in the neonatal period.

In the majority of cases, diagnosis can be achieved solely on clinical features. Biopsy with immunohistochemistry shows negative GLUT-1 staining, which will distinguish this lesion from an IH. At times, the highly vascular nature and/or striking size of a CH may lead some to consider the potential diagnosis of an arteriovenous malformation. However, soft-tissue arteriovenous malformations involving the skin are almost never fully developed in the neonatal period and generally take years to evolve from a quiescent state to a destructive lesion.

Venous Malformation

Venous malformations are congenital malformations of veins that may be apparent at birth or later. They appear as bluish to flesh-colored, compressible nodules or plaques. They tend to increase in size when the affected body part is in a dependent position, and this maneuver can be a helpful distinguishing clue. Although the majority of patients have a single lesion, multifocal involvement may occur uncommonly (Table). The diagnosis of VM usually is clinical, though at times, a VM may be difficult to distinguish from a purely deep IH. However, a VM will persist over time, growing in proportion to the patient. In addition, a VM displays low flow on ultrasound, a distinguishing feature from the fast-flow IH. Magnetic resonance imaging with and without contrast is the imaging study of choice. At times, cutaneous VMs will demonstrate infiltration into other tissue planes such as muscle and joint. Pain may occur secondary to thrombus formation within the malformation. In extensive lesions, intravascular coagulation may be notable, as reflected in elevated D-dimer and decreased fibrinogen levels. Treatment with sclerotherapy or surgery may be considered in select cases during infancy; however, in general, an asymptomatic VM may be observed early on in life.

Lymphatic Malformation

A lymphatic malformation (LM) is a congenital malformation of lymphatic vessels and may be further differentiated into microcystic, macrocystic, or mixed types depending on the size of the channels. An LM may present at birth or later and persists over time. Superficial microcystic LMs, synonymous with the term lymphangioma circumscriptum, characteristically appear as a group of clear and violaceous hemorrhagic vesicles on the skin. Deeper LMs appear as a tense or spongy, flesh-colored nodule or mass. Involvement of the head and neck is common. Complications frequently occur in LMs. Cutaneous LMs may ooze or bleed. Infection and hemorrhage into cysts may occur, which will cause acute pain, redness, swelling, and induration. Cervicofacial lesions may result in respiratory distress. Thus, the majority of LMs require treatment, though asymptomatic lesions may be observed in the neonate. An ultrasound will demonstrate a low-flow lesion, and magnetic resonance imaging is the diagnostic modality of choice for diagnosis and definition of extent.

KHE and Tufted Angioma

Kaposiform hemangioendothelioma is a rare, locally aggressive, vascular tumor that is frequently associated with a potentially life-threatening coagulopathy, Kasabach-Merritt phenomenon. Tufted angiomas are now understood to belong on a spectrum with KHEs, which usually present in the neonatal period or infancy as firm, red-violaceous plaques, nodules, or large tumors. Infiltration into nerve, muscle, and bone may occur. The firm/hard nature and deep violaceous appearance generally are initial clues that it is not an IH. Kasabach-Merritt phenomenon manifests as thrombocytopenia as well as low fibrinogen and elevated D-dimer levels. Thrombocytopenia is generally profound in Kasabach-Merritt phenomenon and results from platelet trapping within the vascular tumor. Given these potential complications, KHEs generally require immediate medical attention, and various treatment protocols including prednisone, vincristine, and sirolimus are utilized for complicated cases.⁵ The diagnosis may require biopsy to distinguish it from malignant tumors, particularly sarcomas.

Malignant Tumors

Various malignancies, including congenital leukemia, neuroblastoma, Langerhans cell histiocytosis, infantile fibrosarcoma, and rhabdomyosarcoma, rarely may present as cutaneous nodules or masses in a neonate mimicking hemangiomas or other vascular lesions (Figure 2). Neonates may present with multiple bluish papules and nodules resembling a blueberry muffin baby; multiple violaceous-red nodules; or a single red-violaceous, highly vascular–appearing mass mimicking hemangiomas. Malignant tumors may display vascularity on imaging, and thus the presence of vascular flow on ultrasound should not dissuade one from the possibility of a malignancy if other clinical features are atypical or unusual for a hemangioma. When a neonatal malignancy is suspected, a large punch biopsy or incisional biopsy is required for workup.

Final Thoughts

Although IHs are the most common vascular nodules in neonates and young infants, other conditions such as VMs, LMs, CHs, KHEs, and malignancy may occur less commonly. Identifying features that would be considered atypical for IH is crucial to recognize these less common possibilities.

Although most neonatal vascular lumps, bumps, and tumors are benign, proper diagnosis is important for prognosis and management. Therefore, knowledge of both common and rare conditions is important when evaluating a neonatal nodule. Differential diagnosis of neonatal vascular nodules must focus on important diagnostic clues that should prompt consideration and evaluation for less common and/or potentially threatening conditions. Infantile hemangioma (IH), congenital hemangioma (CH), venous malformation (VM), lymphatic malformation (LM), kaposiform hemangioendothelioma (KHE) and tufted angioma, and malignant tumors are reviewed here.

Infantile Hemangioma

Infantile hemangioma, a benign proliferation of capillaries, is the most common tumor of infancy with reported incidence of up to 5% in neonates.¹ As such, suspicion for less common lesions is often predicated on identifying features that would be atypical for an IH. A superficial IH presents as a bright red papule, nodule, or plaque, while a deep IH presents as a flesh-colored to bluish nodule. Mixed IHs combine features of both superficial and deep lesions. The distribution may be focal or segmental, with segmental lesions encompassing a larger territory–like distribution and frequently displaying a thin, coarsely telangiectatic appearance.

Knowledge of the natural history of IH generally is crucial in differentiating it from other neonatal lesions. Infantile hemangiomas display a natural history that is distinct and predictable. They typically manifest within the first few weeks of life, though up to 30% present at birth with a premonitory mark, which may be a light red, pink, bluish, or vasoconstricted patch. Thus, mere presence of a lesion at birth is not the feature that distinguishes other congenital lesions from an IH. After initial appearance, IHs undergo a period of proliferation that occurs over 4 to 6 months in most patients. In some cases, areas of proliferation may be subtle, but nonetheless the presence of some areas of increased redness and/or volumetric growth generally is required to firmly establish the diagnosis of IH. Thereafter, IH will involute, a process that begins before 1 year of age in most cases and continues over years. Although IHs undergo involution, complete clearance may not occur, as nearly 70% will leave permanent residua such as fibrofatty masses or anetodermic skin.² Nevertheless, the presence of a proliferative phase followed by a slower period of involution is a hallmark feature of the IH.

Biopsy and imaging rarely are required for establishing diagnosis of an IH. Histopathology showing a proliferation of capillaries with positive glucose transporter 1 (GLUT-1) staining is characteristic. Imaging with ultrasound reveals a fast-flow lesion. Apart from exceptionally rare cases, a cutaneous IH typically does not cross muscle fascia, and thus alternative diagnoses should be considered for a cutaneous lesion that demonstrates infiltration into nerve, bone, joint, or other deeper tissues. Most IHs do not require treatment; however, a small subset may be associated with complications and thus require intervention. Complications of IH may include impairment of function (eg, vision, feeding, respiratory), ulceration, and risk for permanent disfigurement. When treatment is indicated, the most commonly employed options during the proliferative phase are the topical beta-blocker timolol and the oral beta-blocker propranolol. In addition, certain IHs may be associated with either syndromic presentations and/or visceral involvement, thus requiring further workup (Table).

Congenital Hemangioma

A CH is an uncommon benign neonatal tumor that is distinct from an IH in behavior, biology, and treatment. Congenital hemangiomas may have a rapidly involuting course, referred to as RICH (rapidly involuting congenital hemangioma), or a noninvoluting course, referred to as NICH (noninvoluting congenital hemangioma). Partially involuting types also have been described.³ A RICH typically presents as a highly vascular, red-violaceous or bluish plaque, nodule, or large mass at birth. An NICH presents as a red-violaceous or bluish, coarsely telangiectatic patch, plaque, or nodule. A characteristic feature of the CH is the rim of vasoconstriction around the lesion, which is an important diagnostic clue (Figure 1). In contrast to IH, multifocal lesions are highly unlikely in CH, though it rarely has been reported.⁴

Regardless of subtype, CHs are fully developed at birth. Infantile hemangiomas, on the other hand, are either minimally present or not present at birth and thereafter proliferate. After birth, a RICH rapidly involutes over the first 9 to 12 months of life. This process generally is evident even in the first few weeks of life, which would not be expected of an IH and is therefore a major distinguishing factor. A NICH, on the other hand, is expected to be persistent, for the most part neither showing signs of proliferation nor involution.

Complications of CHs may include ulceration, functional impairment, or risk for permanent disfigurement depending on location. In addition, due to their fast-flow state and potential large size, some CHs may be complicated by high-output heart failure in the neonate. Distinguishing an IH from a CH is important not only for prognosis but also treatment. Beta-blocker therapy generally is not useful for CHs, and management usually is supportive in the neonatal period.

In the majority of cases, diagnosis can be achieved solely on clinical features. Biopsy with immunohistochemistry shows negative GLUT-1 staining, which will distinguish this lesion from an IH. At times, the highly vascular nature and/or striking size of a CH may lead some to consider the potential diagnosis of an arteriovenous malformation. However, soft-tissue arteriovenous malformations involving the skin are almost never fully developed in the neonatal period and generally take years to evolve from a quiescent state to a destructive lesion.

Venous Malformation

Venous malformations are congenital malformations of veins that may be apparent at birth or later. They appear as bluish to flesh-colored, compressible nodules or plaques. They tend to increase in size when the affected body part is in a dependent position, and this maneuver can be a helpful distinguishing clue. Although the majority of patients have a single lesion, multifocal involvement may occur uncommonly (Table). The diagnosis of VM usually is clinical, though at times, a VM may be difficult to distinguish from a purely deep IH. However, a VM will persist over time, growing in proportion to the patient. In addition, a VM displays low flow on ultrasound, a distinguishing feature from the fast-flow IH. Magnetic resonance imaging with and without contrast is the imaging study of choice. At times, cutaneous VMs will demonstrate infiltration into other tissue planes such as muscle and joint. Pain may occur secondary to thrombus formation within the malformation. In extensive lesions, intravascular coagulation may be notable, as reflected in elevated D-dimer and decreased fibrinogen levels. Treatment with sclerotherapy or surgery may be considered in select cases during infancy; however, in general, an asymptomatic VM may be observed early on in life.

Lymphatic Malformation

A lymphatic malformation (LM) is a congenital malformation of lymphatic vessels and may be further differentiated into microcystic, macrocystic, or mixed types depending on the size of the channels. An LM may present at birth or later and persists over time. Superficial microcystic LMs, synonymous with the term lymphangioma circumscriptum, characteristically appear as a group of clear and violaceous hemorrhagic vesicles on the skin. Deeper LMs appear as a tense or spongy, flesh-colored nodule or mass. Involvement of the head and neck is common. Complications frequently occur in LMs. Cutaneous LMs may ooze or bleed. Infection and hemorrhage into cysts may occur, which will cause acute pain, redness, swelling, and induration. Cervicofacial lesions may result in respiratory distress. Thus, the majority of LMs require treatment, though asymptomatic lesions may be observed in the neonate. An ultrasound will demonstrate a low-flow lesion, and magnetic resonance imaging is the diagnostic modality of choice for diagnosis and definition of extent.

KHE and Tufted Angioma

Kaposiform hemangioendothelioma is a rare, locally aggressive, vascular tumor that is frequently associated with a potentially life-threatening coagulopathy, Kasabach-Merritt phenomenon. Tufted angiomas are now understood to belong on a spectrum with KHEs, which usually present in the neonatal period or infancy as firm, red-violaceous plaques, nodules, or large tumors. Infiltration into nerve, muscle, and bone may occur. The firm/hard nature and deep violaceous appearance generally are initial clues that it is not an IH. Kasabach-Merritt phenomenon manifests as thrombocytopenia as well as low fibrinogen and elevated D-dimer levels. Thrombocytopenia is generally profound in Kasabach-Merritt phenomenon and results from platelet trapping within the vascular tumor. Given these potential complications, KHEs generally require immediate medical attention, and various treatment protocols including prednisone, vincristine, and sirolimus are utilized for complicated cases.⁵ The diagnosis may require biopsy to distinguish it from malignant tumors, particularly sarcomas.

Malignant Tumors

Various malignancies, including congenital leukemia, neuroblastoma, Langerhans cell histiocytosis, infantile fibrosarcoma, and rhabdomyosarcoma, rarely may present as cutaneous nodules or masses in a neonate mimicking hemangiomas or other vascular lesions (Figure 2). Neonates may present with multiple bluish papules and nodules resembling a blueberry muffin baby; multiple violaceous-red nodules; or a single red-violaceous, highly vascular–appearing mass mimicking hemangiomas. Malignant tumors may display vascularity on imaging, and thus the presence of vascular flow on ultrasound should not dissuade one from the possibility of a malignancy if other clinical features are atypical or unusual for a hemangioma. When a neonatal malignancy is suspected, a large punch biopsy or incisional biopsy is required for workup.

Final Thoughts

Although IHs are the most common vascular nodules in neonates and young infants, other conditions such as VMs, LMs, CHs, KHEs, and malignancy may occur less commonly. Identifying features that would be considered atypical for IH is crucial to recognize these less common possibilities.

Although most neonatal vascular lumps, bumps, and tumors are benign, proper diagnosis is important for prognosis and management. Therefore, knowledge of both common and rare conditions is important when evaluating a neonatal nodule. Differential diagnosis of neonatal vascular nodules must focus on important diagnostic clues that should prompt consideration and evaluation for less common and/or potentially threatening conditions. Infantile hemangioma (IH), congenital hemangioma (CH), venous malformation (VM), lymphatic malformation (LM), kaposiform hemangioendothelioma (KHE) and tufted angioma, and malignant tumors are reviewed here.

Infantile Hemangioma

Infantile hemangioma, a benign proliferation of capillaries, is the most common tumor of infancy with reported incidence of up to 5% in neonates.¹ As such, suspicion for less common lesions is often predicated on identifying features that would be atypical for an IH. A superficial IH presents as a bright red papule, nodule, or plaque, while a deep IH presents as a flesh-colored to bluish nodule. Mixed IHs combine features of both superficial and deep lesions. The distribution may be focal or segmental, with segmental lesions encompassing a larger territory–like distribution and frequently displaying a thin, coarsely telangiectatic appearance.

Knowledge of the natural history of IH generally is crucial in differentiating it from other neonatal lesions. Infantile hemangiomas display a natural history that is distinct and predictable. They typically manifest within the first few weeks of life, though up to 30% present at birth with a premonitory mark, which may be a light red, pink, bluish, or vasoconstricted patch. Thus, mere presence of a lesion at birth is not the feature that distinguishes other congenital lesions from an IH. After initial appearance, IHs undergo a period of proliferation that occurs over 4 to 6 months in most patients. In some cases, areas of proliferation may be subtle, but nonetheless the presence of some areas of increased redness and/or volumetric growth generally is required to firmly establish the diagnosis of IH. Thereafter, IH will involute, a process that begins before 1 year of age in most cases and continues over years. Although IHs undergo involution, complete clearance may not occur, as nearly 70% will leave permanent residua such as fibrofatty masses or anetodermic skin.² Nevertheless, the presence of a proliferative phase followed by a slower period of involution is a hallmark feature of the IH.

Biopsy and imaging rarely are required for establishing diagnosis of an IH. Histopathology showing a proliferation of capillaries with positive glucose transporter 1 (GLUT-1) staining is characteristic. Imaging with ultrasound reveals a fast-flow lesion. Apart from exceptionally rare cases, a cutaneous IH typically does not cross muscle fascia, and thus alternative diagnoses should be considered for a cutaneous lesion that demonstrates infiltration into nerve, bone, joint, or other deeper tissues. Most IHs do not require treatment; however, a small subset may be associated with complications and thus require intervention. Complications of IH may include impairment of function (eg, vision, feeding, respiratory), ulceration, and risk for permanent disfigurement. When treatment is indicated, the most commonly employed options during the proliferative phase are the topical beta-blocker timolol and the oral beta-blocker propranolol. In addition, certain IHs may be associated with either syndromic presentations and/or visceral involvement, thus requiring further workup (Table).

Congenital Hemangioma

A CH is an uncommon benign neonatal tumor that is distinct from an IH in behavior, biology, and treatment. Congenital hemangiomas may have a rapidly involuting course, referred to as RICH (rapidly involuting congenital hemangioma), or a noninvoluting course, referred to as NICH (noninvoluting congenital hemangioma). Partially involuting types also have been described.³ A RICH typically presents as a highly vascular, red-violaceous or bluish plaque, nodule, or large mass at birth. An NICH presents as a red-violaceous or bluish, coarsely telangiectatic patch, plaque, or nodule. A characteristic feature of the CH is the rim of vasoconstriction around the lesion, which is an important diagnostic clue (Figure 1). In contrast to IH, multifocal lesions are highly unlikely in CH, though it rarely has been reported.⁴

Regardless of subtype, CHs are fully developed at birth. Infantile hemangiomas, on the other hand, are either minimally present or not present at birth and thereafter proliferate. After birth, a RICH rapidly involutes over the first 9 to 12 months of life. This process generally is evident even in the first few weeks of life, which would not be expected of an IH and is therefore a major distinguishing factor. A NICH, on the other hand, is expected to be persistent, for the most part neither showing signs of proliferation nor involution.

Complications of CHs may include ulceration, functional impairment, or risk for permanent disfigurement depending on location. In addition, due to their fast-flow state and potential large size, some CHs may be complicated by high-output heart failure in the neonate. Distinguishing an IH from a CH is important not only for prognosis but also treatment. Beta-blocker therapy generally is not useful for CHs, and management usually is supportive in the neonatal period.

In the majority of cases, diagnosis can be achieved solely on clinical features. Biopsy with immunohistochemistry shows negative GLUT-1 staining, which will distinguish this lesion from an IH. At times, the highly vascular nature and/or striking size of a CH may lead some to consider the potential diagnosis of an arteriovenous malformation. However, soft-tissue arteriovenous malformations involving the skin are almost never fully developed in the neonatal period and generally take years to evolve from a quiescent state to a destructive lesion.

Venous Malformation

Venous malformations are congenital malformations of veins that may be apparent at birth or later. They appear as bluish to flesh-colored, compressible nodules or plaques. They tend to increase in size when the affected body part is in a dependent position, and this maneuver can be a helpful distinguishing clue. Although the majority of patients have a single lesion, multifocal involvement may occur uncommonly (Table). The diagnosis of VM usually is clinical, though at times, a VM may be difficult to distinguish from a purely deep IH. However, a VM will persist over time, growing in proportion to the patient. In addition, a VM displays low flow on ultrasound, a distinguishing feature from the fast-flow IH. Magnetic resonance imaging with and without contrast is the imaging study of choice. At times, cutaneous VMs will demonstrate infiltration into other tissue planes such as muscle and joint. Pain may occur secondary to thrombus formation within the malformation. In extensive lesions, intravascular coagulation may be notable, as reflected in elevated D-dimer and decreased fibrinogen levels. Treatment with sclerotherapy or surgery may be considered in select cases during infancy; however, in general, an asymptomatic VM may be observed early on in life.

Lymphatic Malformation

A lymphatic malformation (LM) is a congenital malformation of lymphatic vessels and may be further differentiated into microcystic, macrocystic, or mixed types depending on the size of the channels. An LM may present at birth or later and persists over time. Superficial microcystic LMs, synonymous with the term lymphangioma circumscriptum, characteristically appear as a group of clear and violaceous hemorrhagic vesicles on the skin. Deeper LMs appear as a tense or spongy, flesh-colored nodule or mass. Involvement of the head and neck is common. Complications frequently occur in LMs. Cutaneous LMs may ooze or bleed. Infection and hemorrhage into cysts may occur, which will cause acute pain, redness, swelling, and induration. Cervicofacial lesions may result in respiratory distress. Thus, the majority of LMs require treatment, though asymptomatic lesions may be observed in the neonate. An ultrasound will demonstrate a low-flow lesion, and magnetic resonance imaging is the diagnostic modality of choice for diagnosis and definition of extent.

KHE and Tufted Angioma

Kaposiform hemangioendothelioma is a rare, locally aggressive, vascular tumor that is frequently associated with a potentially life-threatening coagulopathy, Kasabach-Merritt phenomenon. Tufted angiomas are now understood to belong on a spectrum with KHEs, which usually present in the neonatal period or infancy as firm, red-violaceous plaques, nodules, or large tumors. Infiltration into nerve, muscle, and bone may occur. The firm/hard nature and deep violaceous appearance generally are initial clues that it is not an IH. Kasabach-Merritt phenomenon manifests as thrombocytopenia as well as low fibrinogen and elevated D-dimer levels. Thrombocytopenia is generally profound in Kasabach-Merritt phenomenon and results from platelet trapping within the vascular tumor. Given these potential complications, KHEs generally require immediate medical attention, and various treatment protocols including prednisone, vincristine, and sirolimus are utilized for complicated cases.⁵ The diagnosis may require biopsy to distinguish it from malignant tumors, particularly sarcomas.

Malignant Tumors

Various malignancies, including congenital leukemia, neuroblastoma, Langerhans cell histiocytosis, infantile fibrosarcoma, and rhabdomyosarcoma, rarely may present as cutaneous nodules or masses in a neonate mimicking hemangiomas or other vascular lesions (Figure 2). Neonates may present with multiple bluish papules and nodules resembling a blueberry muffin baby; multiple violaceous-red nodules; or a single red-violaceous, highly vascular–appearing mass mimicking hemangiomas. Malignant tumors may display vascularity on imaging, and thus the presence of vascular flow on ultrasound should not dissuade one from the possibility of a malignancy if other clinical features are atypical or unusual for a hemangioma. When a neonatal malignancy is suspected, a large punch biopsy or incisional biopsy is required for workup.

Final Thoughts

Although IHs are the most common vascular nodules in neonates and young infants, other conditions such as VMs, LMs, CHs, KHEs, and malignancy may occur less commonly. Identifying features that would be considered atypical for IH is crucial to recognize these less common possibilities.

While the symptoms of Takayasu’s and giant cell arteritis do not differ greatly, they are associated with different imaging findings of vascular inflammation and luminal damage, a retrospective cohort study has found.

“Clinical symptoms were not sensitive markers of underlying vascular pathology but were specific when present,” Despina Michailidou, MD, PhD, and colleagues wrote in Annals of the Rheumatic Diseases. “Vascular imaging should be considered in the management of these patients since reliance on the presence of clinical symptoms may not be sensitive to detect vascular pathology within an acceptable window to prevent or minimize damage.”

Dr. Michailidou and coauthors in the Systemic Autoimmunity Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) examined the relationships between clinical presentation and imaging findings in 110 patients involved in an ongoing observational cohort study at the National Institutes of Health, including 56 with Takayasu’s arteritis (TAK) and 54 with giant cell arteritis (GCA). The study included data from 270 visits. Dr. Michailidou conducted the study while she was a research fellow at NIAMS, and she is now a rheumatology fellow at the University of Washington, Seattle.

The team looked at 11 symptoms (lightheadedness, positional lightheadedness, carotidynia, arm claudication vertigo, frontotemporal and posterior headache, posterior neck pain, blurred vision, vision loss, and major CNS events, including stroke, transient ischemic attack, or syncope). These were related to findings on MR angiography (MRA) and 18F-fluorodeoxyglucose PET (FDG-PET).

There were no significant between-group differences in six of the symptoms. However, those with TAK had significantly higher rates of carotidynia (21% vs. 0%), lightheadedness (30% vs. 9%), positional lightheadedness (29% vs. 5%), major CNS events (25% vs. 9%), and arm claudication (52% vs. 28%). Arm claudication was the most common symptom in those with TAK (52%), and blurred vision the most common in patients with GCA (37%).

On the day of evaluation, 8% of patients with TAK reported carotidynia; none of the GCA patients reported this. On FDG-PET, carotidynia was more strongly associated with inflammation of the carotid artery than with damage of the carotid artery on MRA.

The sensitivity of this association was low, which indicates “that an absence of carotidynia could still be associated with imaging abnormalities in the carotid artery, particularly on MRA compared with FDG-PET,” the authors wrote. But specificity was high for both FDG-PET and MRA, suggesting that carotidynia was strongly associated with corresponding carotid artery abnormalities on both FDG-PET and MRA.

More of those with GCA than those with TAK reported posterior neck pain (18% vs. 7%). It was significantly associated with vertebral artery inflammation in those with GCA, but not in those with TAK. There was no significant association with vertebral artery damage in either group.

While sensitivity was low for posterior neck pain and imaging abnormalities, specificity was very high in both groups, which indicates “the presence of posterior neck pain was strongly associated with corresponding vertebral artery abnormalities on both FDG-PET and MRA.”

Posterior headache was present in 5% of GCA patients and was significantly associated with vertebral artery damage, but it was not associated with such damage in patients with TAK.

“While posterior headaches in the occipital region are uncommon in patients with GCA, this study emphasizes that presence of a posterior headache should alert the clinician to the likelihood of associated vascular inflammation and damage in the corresponding vertebral artery,” the researchers wrote.

About 6% of patients with TAK and 10% of those with GCA reported frontotemporal headache. The headache was not associated with carotid PET activity or damage in either group of patients.

“While frontotemporal headaches frequently occur in patients with TAK, and are a cardinal feature of GCA, headaches in this region may reflect inflammation in smaller branches of cranial arteries, rather than the corresponding larger arteries of the neck,” the investigators wrote.

Arm claudication was the most commonly reported symptom overall, present in 52% of those with TAK and 28% of those with GCA. It was more strongly associated with subclavian artery damage on MRA than with inflammation on FDG-PET.

The investigators also assessed the association between specific clinical symptoms and the number of affected neck arteries. Patients with large vessel vasculitis and an increased number of damaged neck arteries on MRA were significantly more likely to experience lightheadedness (odds ratio, 2.61), positional lightheadedness (OR, 3.51), or a major CNS event (OR, 3.23). But those with large vessel vasculitis and inflamed neck arteries on FDG-PET were more likely to experience posterior headache (OR, 2.84).

The study isn’t intended to dictate how MRA and FDG-PET should be employed with these patients, the authors noted.

“Rather, these findings may help clinicians predict imaging pathology in specific vascular territories based on patient-reported symptoms and may inform which type of imaging modality would be the most useful to obtain in certain clinical scenarios, recognizing that additional sequences to detect wall morphology may augment the ability of MR-based assessments to detect vascular inflammation in addition to luminal damage.”

The Division of Intramural Research at NIAMS funded the research. The authors had no financial disclosures.

[email protected]

SOURCE: Michailidou D et al. Ann Rheum Dis. 2019 Oct 24. doi: 10.1136/annrheumdis-2019-216145.

While the symptoms of Takayasu’s and giant cell arteritis do not differ greatly, they are associated with different imaging findings of vascular inflammation and luminal damage, a retrospective cohort study has found.

“Clinical symptoms were not sensitive markers of underlying vascular pathology but were specific when present,” Despina Michailidou, MD, PhD, and colleagues wrote in Annals of the Rheumatic Diseases. “Vascular imaging should be considered in the management of these patients since reliance on the presence of clinical symptoms may not be sensitive to detect vascular pathology within an acceptable window to prevent or minimize damage.”

Dr. Michailidou and coauthors in the Systemic Autoimmunity Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) examined the relationships between clinical presentation and imaging findings in 110 patients involved in an ongoing observational cohort study at the National Institutes of Health, including 56 with Takayasu’s arteritis (TAK) and 54 with giant cell arteritis (GCA). The study included data from 270 visits. Dr. Michailidou conducted the study while she was a research fellow at NIAMS, and she is now a rheumatology fellow at the University of Washington, Seattle.

The team looked at 11 symptoms (lightheadedness, positional lightheadedness, carotidynia, arm claudication vertigo, frontotemporal and posterior headache, posterior neck pain, blurred vision, vision loss, and major CNS events, including stroke, transient ischemic attack, or syncope). These were related to findings on MR angiography (MRA) and 18F-fluorodeoxyglucose PET (FDG-PET).

There were no significant between-group differences in six of the symptoms. However, those with TAK had significantly higher rates of carotidynia (21% vs. 0%), lightheadedness (30% vs. 9%), positional lightheadedness (29% vs. 5%), major CNS events (25% vs. 9%), and arm claudication (52% vs. 28%). Arm claudication was the most common symptom in those with TAK (52%), and blurred vision the most common in patients with GCA (37%).

On the day of evaluation, 8% of patients with TAK reported carotidynia; none of the GCA patients reported this. On FDG-PET, carotidynia was more strongly associated with inflammation of the carotid artery than with damage of the carotid artery on MRA.

The sensitivity of this association was low, which indicates “that an absence of carotidynia could still be associated with imaging abnormalities in the carotid artery, particularly on MRA compared with FDG-PET,” the authors wrote. But specificity was high for both FDG-PET and MRA, suggesting that carotidynia was strongly associated with corresponding carotid artery abnormalities on both FDG-PET and MRA.

More of those with GCA than those with TAK reported posterior neck pain (18% vs. 7%). It was significantly associated with vertebral artery inflammation in those with GCA, but not in those with TAK. There was no significant association with vertebral artery damage in either group.

While sensitivity was low for posterior neck pain and imaging abnormalities, specificity was very high in both groups, which indicates “the presence of posterior neck pain was strongly associated with corresponding vertebral artery abnormalities on both FDG-PET and MRA.”

Posterior headache was present in 5% of GCA patients and was significantly associated with vertebral artery damage, but it was not associated with such damage in patients with TAK.

“While posterior headaches in the occipital region are uncommon in patients with GCA, this study emphasizes that presence of a posterior headache should alert the clinician to the likelihood of associated vascular inflammation and damage in the corresponding vertebral artery,” the researchers wrote.

About 6% of patients with TAK and 10% of those with GCA reported frontotemporal headache. The headache was not associated with carotid PET activity or damage in either group of patients.

“While frontotemporal headaches frequently occur in patients with TAK, and are a cardinal feature of GCA, headaches in this region may reflect inflammation in smaller branches of cranial arteries, rather than the corresponding larger arteries of the neck,” the investigators wrote.

Arm claudication was the most commonly reported symptom overall, present in 52% of those with TAK and 28% of those with GCA. It was more strongly associated with subclavian artery damage on MRA than with inflammation on FDG-PET.

The investigators also assessed the association between specific clinical symptoms and the number of affected neck arteries. Patients with large vessel vasculitis and an increased number of damaged neck arteries on MRA were significantly more likely to experience lightheadedness (odds ratio, 2.61), positional lightheadedness (OR, 3.51), or a major CNS event (OR, 3.23). But those with large vessel vasculitis and inflamed neck arteries on FDG-PET were more likely to experience posterior headache (OR, 2.84).

The study isn’t intended to dictate how MRA and FDG-PET should be employed with these patients, the authors noted.

“Rather, these findings may help clinicians predict imaging pathology in specific vascular territories based on patient-reported symptoms and may inform which type of imaging modality would be the most useful to obtain in certain clinical scenarios, recognizing that additional sequences to detect wall morphology may augment the ability of MR-based assessments to detect vascular inflammation in addition to luminal damage.”

The Division of Intramural Research at NIAMS funded the research. The authors had no financial disclosures.

[email protected]

SOURCE: Michailidou D et al. Ann Rheum Dis. 2019 Oct 24. doi: 10.1136/annrheumdis-2019-216145.

While the symptoms of Takayasu’s and giant cell arteritis do not differ greatly, they are associated with different imaging findings of vascular inflammation and luminal damage, a retrospective cohort study has found.

“Clinical symptoms were not sensitive markers of underlying vascular pathology but were specific when present,” Despina Michailidou, MD, PhD, and colleagues wrote in Annals of the Rheumatic Diseases. “Vascular imaging should be considered in the management of these patients since reliance on the presence of clinical symptoms may not be sensitive to detect vascular pathology within an acceptable window to prevent or minimize damage.”

Dr. Michailidou and coauthors in the Systemic Autoimmunity Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) examined the relationships between clinical presentation and imaging findings in 110 patients involved in an ongoing observational cohort study at the National Institutes of Health, including 56 with Takayasu’s arteritis (TAK) and 54 with giant cell arteritis (GCA). The study included data from 270 visits. Dr. Michailidou conducted the study while she was a research fellow at NIAMS, and she is now a rheumatology fellow at the University of Washington, Seattle.

The team looked at 11 symptoms (lightheadedness, positional lightheadedness, carotidynia, arm claudication vertigo, frontotemporal and posterior headache, posterior neck pain, blurred vision, vision loss, and major CNS events, including stroke, transient ischemic attack, or syncope). These were related to findings on MR angiography (MRA) and 18F-fluorodeoxyglucose PET (FDG-PET).

There were no significant between-group differences in six of the symptoms. However, those with TAK had significantly higher rates of carotidynia (21% vs. 0%), lightheadedness (30% vs. 9%), positional lightheadedness (29% vs. 5%), major CNS events (25% vs. 9%), and arm claudication (52% vs. 28%). Arm claudication was the most common symptom in those with TAK (52%), and blurred vision the most common in patients with GCA (37%).

On the day of evaluation, 8% of patients with TAK reported carotidynia; none of the GCA patients reported this. On FDG-PET, carotidynia was more strongly associated with inflammation of the carotid artery than with damage of the carotid artery on MRA.

The sensitivity of this association was low, which indicates “that an absence of carotidynia could still be associated with imaging abnormalities in the carotid artery, particularly on MRA compared with FDG-PET,” the authors wrote. But specificity was high for both FDG-PET and MRA, suggesting that carotidynia was strongly associated with corresponding carotid artery abnormalities on both FDG-PET and MRA.

More of those with GCA than those with TAK reported posterior neck pain (18% vs. 7%). It was significantly associated with vertebral artery inflammation in those with GCA, but not in those with TAK. There was no significant association with vertebral artery damage in either group.

While sensitivity was low for posterior neck pain and imaging abnormalities, specificity was very high in both groups, which indicates “the presence of posterior neck pain was strongly associated with corresponding vertebral artery abnormalities on both FDG-PET and MRA.”

Posterior headache was present in 5% of GCA patients and was significantly associated with vertebral artery damage, but it was not associated with such damage in patients with TAK.

“While posterior headaches in the occipital region are uncommon in patients with GCA, this study emphasizes that presence of a posterior headache should alert the clinician to the likelihood of associated vascular inflammation and damage in the corresponding vertebral artery,” the researchers wrote.

About 6% of patients with TAK and 10% of those with GCA reported frontotemporal headache. The headache was not associated with carotid PET activity or damage in either group of patients.

“While frontotemporal headaches frequently occur in patients with TAK, and are a cardinal feature of GCA, headaches in this region may reflect inflammation in smaller branches of cranial arteries, rather than the corresponding larger arteries of the neck,” the investigators wrote.

Arm claudication was the most commonly reported symptom overall, present in 52% of those with TAK and 28% of those with GCA. It was more strongly associated with subclavian artery damage on MRA than with inflammation on FDG-PET.

The investigators also assessed the association between specific clinical symptoms and the number of affected neck arteries. Patients with large vessel vasculitis and an increased number of damaged neck arteries on MRA were significantly more likely to experience lightheadedness (odds ratio, 2.61), positional lightheadedness (OR, 3.51), or a major CNS event (OR, 3.23). But those with large vessel vasculitis and inflamed neck arteries on FDG-PET were more likely to experience posterior headache (OR, 2.84).

The study isn’t intended to dictate how MRA and FDG-PET should be employed with these patients, the authors noted.

“Rather, these findings may help clinicians predict imaging pathology in specific vascular territories based on patient-reported symptoms and may inform which type of imaging modality would be the most useful to obtain in certain clinical scenarios, recognizing that additional sequences to detect wall morphology may augment the ability of MR-based assessments to detect vascular inflammation in addition to luminal damage.”

The Division of Intramural Research at NIAMS funded the research. The authors had no financial disclosures.

[email protected]

SOURCE: Michailidou D et al. Ann Rheum Dis. 2019 Oct 24. doi: 10.1136/annrheumdis-2019-216145.

Background: Prior studies have suggested that NOACs have a favorable risk-benefit profile when compared with warfarin, but it is unclear if this advantage also is present for those high-risk patients for whom NOAC dose reduction is recommended.

Dr. Biddick is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine Harvard Medical School.

Background: Prior studies have suggested that NOACs have a favorable risk-benefit profile when compared with warfarin, but it is unclear if this advantage also is present for those high-risk patients for whom NOAC dose reduction is recommended.

Dr. Biddick is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine Harvard Medical School.

Background: Prior studies have suggested that NOACs have a favorable risk-benefit profile when compared with warfarin, but it is unclear if this advantage also is present for those high-risk patients for whom NOAC dose reduction is recommended.

Dr. Biddick is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine Harvard Medical School.

Combination pertuzumab, trastuzumab, and docetaxel provided better responses than did placebo, trastuzumab, and docetaxel in Asian patients with ERBB2-positive early or locally advanced breast cancer, according to a phase 3 trial.

The safety profile of the combination regimen was similar between the treatment arms and in accordance with that of pertuzumab alone, reported Zhimin Shao, MD, of Fudan (Shanghai) University Cancer Center, and colleagues. The study was published in JAMA Oncology.

The randomized, placebo-controlled, phase 3 PEONY study included 329 women with ERBB2-positive early or locally advanced disease. The effects of adding pertuzumab to trastuzumab and docetaxel was studied in 23 centers throughout Asia.

Prior to surgery, study subjects in the treatment arm received intravenous pertuzumab at a loading dose of 840 mg followed by 420 mg, trastuzumab at a loading dose of 8 mg/kg followed by 6 mg/kg, and 75 mg/m² of docetaxel, while patients in the placebo arm received placebo, trastuzumab, and docetaxel. Both regimens were administered every 3 weeks for a total of four cycles.

Post surgery, study patients received intravenous fluorouracil, cyclophosphamide, and epirubicin for a total of 3 cycles, followed by pertuzumab plus trastuzumab or placebo plus trastuzumab for a total of 13 cycles.

The primary outcome was the total pathologic complete response rate assessed at the completion of surgery.

After analysis, the researchers found that total pathologic complete response rates were significantly higher for patients in the pertuzumab arm (39.3%) compared with the placebo arm (21.8%) (difference, 17.5%; P = .001).

With respect to safety, the rates of common adverse events were similar between the groups, with the exception of diarrhea (38.5% in the pertuzumab arm vs. 16.4% in the placebo arm). The incidences of serious toxicities were slightly higher in the pertuzumab arm (10.1%) compared with the placebo arm (8.2%).

“Of the most common grade 3 or higher adverse events, there was a higher incidence of neutropenia in the pertuzumab group (38.1% vs. 32.7%),” they reported.

The researchers acknowledged a key limitation of the study was the short duration of follow-up. As a result, some secondary outcome data were immature at the time of the analysis.

“The PEONY trial adds to the totality of the data showing the benefit of pertuzumab and trastuzumab with chemotherapy in ERBB2-positive early breast cancer,” they concluded.

The authors reported financial affiliations with F. Hoffmann-La Roche Ltd., which funded the study, and Genentech.

SOURCE: Shao Z et al. JAMA Oncol. 2019 Oct 24. doi: 10.1001/jamaoncol.2019.3692.

Combination pertuzumab, trastuzumab, and docetaxel provided better responses than did placebo, trastuzumab, and docetaxel in Asian patients with ERBB2-positive early or locally advanced breast cancer, according to a phase 3 trial.

The safety profile of the combination regimen was similar between the treatment arms and in accordance with that of pertuzumab alone, reported Zhimin Shao, MD, of Fudan (Shanghai) University Cancer Center, and colleagues. The study was published in JAMA Oncology.

The randomized, placebo-controlled, phase 3 PEONY study included 329 women with ERBB2-positive early or locally advanced disease. The effects of adding pertuzumab to trastuzumab and docetaxel was studied in 23 centers throughout Asia.

Prior to surgery, study subjects in the treatment arm received intravenous pertuzumab at a loading dose of 840 mg followed by 420 mg, trastuzumab at a loading dose of 8 mg/kg followed by 6 mg/kg, and 75 mg/m² of docetaxel, while patients in the placebo arm received placebo, trastuzumab, and docetaxel. Both regimens were administered every 3 weeks for a total of four cycles.

Post surgery, study patients received intravenous fluorouracil, cyclophosphamide, and epirubicin for a total of 3 cycles, followed by pertuzumab plus trastuzumab or placebo plus trastuzumab for a total of 13 cycles.

The primary outcome was the total pathologic complete response rate assessed at the completion of surgery.

After analysis, the researchers found that total pathologic complete response rates were significantly higher for patients in the pertuzumab arm (39.3%) compared with the placebo arm (21.8%) (difference, 17.5%; P = .001).

With respect to safety, the rates of common adverse events were similar between the groups, with the exception of diarrhea (38.5% in the pertuzumab arm vs. 16.4% in the placebo arm). The incidences of serious toxicities were slightly higher in the pertuzumab arm (10.1%) compared with the placebo arm (8.2%).

“Of the most common grade 3 or higher adverse events, there was a higher incidence of neutropenia in the pertuzumab group (38.1% vs. 32.7%),” they reported.

The researchers acknowledged a key limitation of the study was the short duration of follow-up. As a result, some secondary outcome data were immature at the time of the analysis.

“The PEONY trial adds to the totality of the data showing the benefit of pertuzumab and trastuzumab with chemotherapy in ERBB2-positive early breast cancer,” they concluded.

The authors reported financial affiliations with F. Hoffmann-La Roche Ltd., which funded the study, and Genentech.

SOURCE: Shao Z et al. JAMA Oncol. 2019 Oct 24. doi: 10.1001/jamaoncol.2019.3692.

Combination pertuzumab, trastuzumab, and docetaxel provided better responses than did placebo, trastuzumab, and docetaxel in Asian patients with ERBB2-positive early or locally advanced breast cancer, according to a phase 3 trial.

The safety profile of the combination regimen was similar between the treatment arms and in accordance with that of pertuzumab alone, reported Zhimin Shao, MD, of Fudan (Shanghai) University Cancer Center, and colleagues. The study was published in JAMA Oncology.

The randomized, placebo-controlled, phase 3 PEONY study included 329 women with ERBB2-positive early or locally advanced disease. The effects of adding pertuzumab to trastuzumab and docetaxel was studied in 23 centers throughout Asia.

Prior to surgery, study subjects in the treatment arm received intravenous pertuzumab at a loading dose of 840 mg followed by 420 mg, trastuzumab at a loading dose of 8 mg/kg followed by 6 mg/kg, and 75 mg/m² of docetaxel, while patients in the placebo arm received placebo, trastuzumab, and docetaxel. Both regimens were administered every 3 weeks for a total of four cycles.

Post surgery, study patients received intravenous fluorouracil, cyclophosphamide, and epirubicin for a total of 3 cycles, followed by pertuzumab plus trastuzumab or placebo plus trastuzumab for a total of 13 cycles.

The primary outcome was the total pathologic complete response rate assessed at the completion of surgery.

After analysis, the researchers found that total pathologic complete response rates were significantly higher for patients in the pertuzumab arm (39.3%) compared with the placebo arm (21.8%) (difference, 17.5%; P = .001).

With respect to safety, the rates of common adverse events were similar between the groups, with the exception of diarrhea (38.5% in the pertuzumab arm vs. 16.4% in the placebo arm). The incidences of serious toxicities were slightly higher in the pertuzumab arm (10.1%) compared with the placebo arm (8.2%).

“Of the most common grade 3 or higher adverse events, there was a higher incidence of neutropenia in the pertuzumab group (38.1% vs. 32.7%),” they reported.

The researchers acknowledged a key limitation of the study was the short duration of follow-up. As a result, some secondary outcome data were immature at the time of the analysis.

“The PEONY trial adds to the totality of the data showing the benefit of pertuzumab and trastuzumab with chemotherapy in ERBB2-positive early breast cancer,” they concluded.

The authors reported financial affiliations with F. Hoffmann-La Roche Ltd., which funded the study, and Genentech.

SOURCE: Shao Z et al. JAMA Oncol. 2019 Oct 24. doi: 10.1001/jamaoncol.2019.3692.